Cellular Dynamics

Cellular Dynamics International (CDI), a FUJIFILM company, is a leading developer and manufacturer of human cells used in drug discovery, toxicity testing, stem cell banking, and cell therapy development. The Company partners with innovators from around the world to combine biologically relevant human cells with the newest technologies to drive advancements in medicine and healthier living. CDIs technology offers the potential to create induced pluripotent stem cells (iPSCs) from anyone, starting with a standard blood draw, and followed by the powerful capability to develop into virtually any cell type in the human body. Our proprietary manufacturing system produces billions of cells daily, resulting in inventoried iCell products and donor-specific MyCell Products in the quantity, quality, purity, and reproducibility required for drug and cell therapy development. Founded in 2004 by Dr. James Thomson, a pioneer in human pluripotent stem cell research, Cellular Dynamics is based in Madison, Wisconsin, with a second facility in Novato, California. For more information, please visit http://www.cellulardynamics.com, and follow us on Twitter @CellDynamics. FUJIFILM Holdings Corporation, Tokyo, Japan brings continuous innovation and leading-edge products to a broad spectrum of industries, including: healthcare, with medical systems, pharmaceuticals and cosmetics; graphic systems; highly functional materials, such as flat panel display materials; optical devices, such as broadcast and cinema lenses; digital imaging; and document products. These are based on a vast portfolio of chemical, mechanical, optical, electronic, software and production technologies. In the year ended March 31, 2015, the company had global revenues of $20.8 billion, at an exchange rate of 120 yen to the dollar. Fujifilm is committed to environmental stewardship and good corporate citizenship. For more information, please visit: http://www.fujifilmholdings.com.

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Introduction

[Note: Many of the medical and scientific terms used in this summary are found in the NCI Dictionary of Genetics Terms. When a linked term is clicked, the definition will appear in a separate window.]

[Note: A concerted effort is being made within the genetics community to shift terminology used to describe genetic variation. The shift is to use the term variant rather than the term mutation to describe a difference that exists between the person or group being studied and the reference sequence. Variants can then be further classified as benign (harmless), likely benign, of uncertain significance, likely pathogenic, or pathogenic (disease causing). Throughout this summary, we will use the term pathogenic variant to describe a disease-causing mutation. Refer to the Cancer Genetics Overview summary for more information about variant classification.]

This summary describes current approaches to assessing and counseling people about their chance of having an inherited susceptibility to cancer. Genetic counseling is defined by the National Society of Genetic Counselors as the process of helping people understand and adapt to the medical, psychological, and familial implications of genetic contributions to disease. Several reviews present overviews of the cancer risk assessment, counseling, and genetic testing process.[1,2]

Individuals are considered to be candidates for cancer risk assessment if they have a personal and/or family history (maternal or paternal lineage) with features suggestive of hereditary cancer.[1] These features vary by type of cancer and specific hereditary syndrome. Criteria have been published to help identify individuals who may benefit from genetic counseling.[1,3] The PDQ cancer genetics information summaries on breast, ovarian, endometrial, colorectal, prostate, kidney, and skin cancers and endocrine and neuroendocrine neoplasias describe the clinical features of hereditary syndromes associated with these conditions.

The following are features that suggest hereditary cancer:

As part of the process of genetic education and counseling, genetic testing may be considered when the following factors are present:

It is important that individuals who are candidates for genetic testing undergo genetic education and counseling before testing to facilitate informed decision making and adaptation to the risk or condition.[1] Genetic education and counseling allows individuals to consider the various medical uncertainties, diagnosis, or medical management based on varied test results, and the risks, benefits, and limitations of genetic testing.

Comprehensive cancer risk assessment is a consultative service that includes clinical assessment, genetic testing when appropriate, and risk management recommendations delivered in the context of one or more genetic counseling sessions. Pretest genetic counseling is an important part of the risk assessment process and helps patients understand their genetic testing options and potential outcomes. Posttest genetic counseling helps patients understand their test results, including the medical implications for themselves and their relatives.

Several professional organizations emphasize the importance of genetic counseling in the cancer risk assessment and genetic testing process. Examples of these organizations include the following:

A list of organizations that have published clinical practices guidelines related to genetic counseling, risk assessment, genetic testing, and/or management for hereditary breast and ovarian cancers is available in the PDQ summary on Genetics of Breast and Gynecologic Cancers.

Genetic counseling informs the consultand about potential cancer risks and the benefits and limitations of genetic testing and offers an opportunity to consider the potential medical, psychological, familial, and social implications of genetic information.[8,15] Descriptions of genetic counseling and the specialized practice of cancer risk assessment counseling are detailed below.

Genetic counseling has been defined by the American Society of Human Genetics as a communication process that deals with the human problems associated with the occurrence, or risk of occurrence, of a genetic disorder in a family." The process involves an attempt by one or more appropriately trained persons to help the individual or family do the following:

In 2006, the National Society of Genetic Counselors further refined the definition of genetic counseling to include the process of helping people understand and adapt to the medical, psychological, and familial implications of genetic contributions to disease, including integration of the following:

Central to the philosophy and practice of genetic counseling are the principles of voluntary utilization of services, informed decision making, attention to psychosocial and affective dimensions of coping with genetic risk, and protection of patient confidentiality and privacy. This is facilitated through a combination of rapport building and information gathering; establishing or verifying diagnoses; risk assessment and calculation of quantitative occurrence/recurrence risks; education and informed consent processes; psychosocial assessment, support, and counseling appropriate to a familys culture and ethnicity; and other relevant background characteristics.[17,18] The psychosocial assessment is especially important in the genetic counseling process because individuals most vulnerable to adverse effects of genetic information may include those who have had difficulty dealing with stressful life events in the past.[19] Variables that may influence psychosocial adjustment to genetic information include individual and familial factors; cultural factors; and health system factors such as the type of test, disease status, and risk information.[19] Findings from a psychosocial assessment can be used to help guide the direction of the counseling session.[9] An important objective of genetic counseling is to provide an opportunity for shared decision making when the medical benefits of one course of action are not demonstrated to be superior to another. The relationship between the availability of effective medical treatment for carriers of pathogenic variants and the clinical validity of a given test affects the degree to which personal choice or physician recommendation is supported in counseling at-risk individuals.[20] Uptake of genetic counseling services among those referred varies based on the cancer syndrome and the clinical setting. Efforts to decrease barriers to service utilization are ongoing (e.g., a patient navigator telephone call may increase utilization of these services).[21] Readers interested in the nature and history of genetic counseling are referred to a number of comprehensive reviews.[22-27]

Cancer risk assessment counseling has emerged as a specialized practice that requires knowledge of genetics, oncology, and individual and family counseling skills that may be provided by health care providers with this interdisciplinary training.[28] Some centers providing cancer risk assessment services involve a multidisciplinary team, which may include a genetic counselor; a genetics advanced practice nurse; a medical geneticist or a physician, such as an oncologist, surgeon, or internist; and a mental health professional. The Cancer Genetics Services Directory provides a partial list of individuals involved in cancer risk assessment, genetic counseling, testing, and other related services and is available on the National Cancer Institute's website.

The need for advanced professional training in cancer genetics for genetics counselors, physicians, nurses, laboratory technicians, and others has been widely reported.[29-32] Despite these identified needs, the evidence indicates that competency in genetics and genomics remains limited across all health care disciplines, with the exception of genetic specialists.[33] Deficits in the following have been identified: (1) knowledge about hereditary cancer syndromes [34] and risk-appropriate management strategies;[35] (2) provision of genetic counseling services;[35] (3) documentation and use of personal and family cancer history to identify and refer patients at increased risk of hereditary cancer syndromes;[36-39] and (4) knowledge about genetic nondiscrimination laws.[36,40] (Refer to the table on Health Professional Practice and Genetic Education Information in the PDQ Cancer Genetics Overview summary for more information.)

The National Coalition for Health Professional Education in Genetics (whose work was transitioned to The Jackson Laboratory in 2013) has published core competencies for all health professionals. Building on this work, individual health professions, such as physicians,[32] nurses,[41,42] physician assistants,[43] pharmacists,[44] and genetic counselors,[45] have developed and published core competencies specific to their profession. A number of other organizations have also published professional guidelines, scopes, and standards of practice.

Traditionally, genetic counseling services have been delivered using individualized in-person appointments. However, other methodologies are being explored, including group sessions, telephone counseling, and telemedicine by videoconferencing.[46-53] Additionally, computer programs and websites designed to provide genetics education can be successful adjuncts to personal genetic counseling services in a computer-literate population.[54-58]

Some studies of patient satisfaction with cancer genetic counseling services have been published. For example, one survey of individuals who participated in a cancer genetics program in its inaugural year reported that the clinical services met the needs and expectations of most people.[59] Patients reported that the best parts of the experience were simply having a chance to talk to someone about cancer concerns, having personalized summary letters and family pedigrees, learning that cancer risk was lower than expected, or realizing that one had been justified in suspecting the inheritance of cancer in ones family.

Several studies have since shown that the majority of individuals are satisfied with their genetic counseling experience.[60-63] However, one study of 61 women participating in a BRCA1/2 genetic testing program found that satisfaction with genetic counseling was influenced by psychological variables including optimism, family functioning, and general and cancer-specific distress.[64]

A meta-analysis of several controlled studies showed that outcomes of genetic counseling included improvement in cancer genetic knowledge (pooled short-term difference, 0.70 U; 95% confidence interval, 0.151.26 U). Overall, no long-term increases in general anxiety, cancer-specific worry, distress, or depression were detected as a consequence of genetic counseling. However, the impact of genetic counseling on risk perception is less clear, with some studies reporting no change in risk perception while others report significant differences before and after counseling.[65]

This section provides an overview of critical elements in the cancer risk assessment process.

A number of professional guidelines on the elements of cancer genetics risk assessment and counseling are available.[1-4] Except where noted, the discussion below is based on these guidelines.

The cancer risk assessment and counseling process, which may vary among providers, requires one or more consultative sessions and generally includes the following:

At the outset of the initial counseling session, eliciting and addressing the consultand's perceptions and concerns about cancer and his or her expectations of the risk assessment process helps to engage the consultand in the session. This also helps inform the provider about practical or psychosocial issues and guides the focus of counseling and strategies for risk assessment.

The counseling process that takes place as part of a cancer risk assessment can identify factors that contribute to the consultand's perception of cancer risk and motivations to seek cancer risk assessment and genetic testing. It can also identify potential psychological issues that may need to be addressed during or beyond the session. Information collected before and/or during the session may include the following:

Either alone or in consultation with a mental health provider, health care providers offering cancer risk counseling attempt to assess whether the individual's expectations of counseling are realistic and whether there are factors suggesting risk of adverse psychological outcomes after disclosure of risk and/or genetic status. In some cases, referral for psychotherapeutic treatment may be recommended prior to, or in lieu of, testing.[5]

Concepts of personal cancer risk, genetics, and the relationship between the two can be complex and can be difficult for patients to understand. A number of factors influence a persons concept of his or her risk, which may not be congruent with evidence-based quantitative calculations. These factors include:

A thorough understanding of these issues can greatly inform genetic education and counseling. These factors influence the processing of risk information and subsequent health behaviors.[9]

The communication of risk involves the delivery of quantitative information regarding what the data indicate about the likelihood of developing illness given various preventive actions. More broadly, however, risk communication is an interactive process regarding the individuals knowledge, beliefs, emotions, and behaviors associated with risk and the risk message conveyed. Accordingly, the goal of risk communication may be to impact the individuals knowledge of risk factors, risk likelihoods, potential consequences of risk, and the benefits and drawbacks of preventive actions.

Even before the provision of risk information, the provider may anticipate that the individual already has some sense of his or her own risk of cancer. The individual may have derived this information from multiple sources, including physicians, family members, and the media.[10] This information may be more salient or emotional if a family member has recently died from cancer or if there is a new family diagnosis.[11,12] Additionally, individuals may have beliefs about how genetic susceptibility works in their family.[13,14] For example, in a family where only females have been affected with an autosomal dominant cancer susceptibility syndrome thus far, it may be difficult to convince the consultand that her sons have a 50% risk of inheriting the disease-related pathogenic variant. The social-ecological context through which risk beliefs develop and are maintained are important as potential moderators of individuals receptivity to the cancer risk communication process and also represent the context in which individuals will return to continue ongoing decision making about how to manage their risk.[15,16] As such, individuals beliefs, and the social context of risk, are important to discuss in education and genetic risk counseling.

Perceived risk can play an important role in an individuals decision to participate in counseling,[17] despite the fact that perceived risk often varies substantially from statistical risk estimates.[18-20]

Consideration of the consultand's personal health history is essential in cancer risk assessment, regardless of whether the individual has a personal history of cancer. Important information to obtain about the consultand's health history includes the following:

For consultands with a history of cancer, additional information collected includes the following:

In some cases, a physical exam is conducted by a qualified medical professional to determine whether the individual has physical findings suggestive of a hereditary cancer predisposition syndrome or to rule out evidence of an existing malignancy. For example, a medical professional may look for the sebaceous adenomas seen in Muir-Torre syndrome, measure the head circumference or perform a skin exam to rule out benign cutaneous features associated with Cowden syndrome, or perform a clinical breast and axillary lymph node exam on a woman undergoing a breast cancer risk assessment.

The family history is an essential tool for cancer risk assessment. The family history can be obtained via interview or written self-report; both were found to result in equivalent information in a study that utilized a sample (N = 104) that varied widely in educational attainment.[22] A nine-question family history screening tool has been shown to identify individuals at increased risk of common health conditions, including cancer, who warrant a more detailed family history (receiver operating characteristic, 84.6% [range, 81.2%88.1%]; sensitivity, 95% [range, 92%98%]; specificity, 54% [range, 48%60%]).[23] Studies suggest that paper-based family history questionnaires completed before the appointment provide accurate family history information [24] and that the use of these questionnaires is an acceptable and understandable family history collection method.[25] However, questionnaire-based assessments may lead to some underreporting of family history; therefore, a follow-up interview to confirm the reported information and to capture all relevant family history information may be required.[26] Routine chart reviews (e.g., via electronic medical records) may be worthwhile to maximize the identification of appropriate candidates for genetic counseling referral. In a single nonacademic institution, systematic chart review by a genetic counselor increased the number of referrals for genetics consultation.[27] The most significant improvement was in ovarian cancer referrals. In conjunction with other efforts to collect and review family history, the performance of routine chart reviews may help identify gaps in existing referral patterns. Additionally, collecting family history from multiple relatives in a single family has been shown to increase the number of reported family members with cancer, compared with family history information provided by a single family member.[28]

Details of the family health history are best summarized in the form of a family tree, or pedigree. The pedigree, a standardized graphic representation of family relationships, facilitates identification of patterns of disease transmission, recognition of the clinical characteristics associated with specific hereditary cancer syndromes, and determination of the best strategies and tools for risk assessment.[29,30] Factors suggesting inherited cancer risk in a family are described below.

Both multimedia-based (e.g., Internet) and print-based (e.g., family history questionnaires) tools are currently available to gather information about family history. In the United States, many are written at reading grade levels above 8th grade, which may reduce their effectiveness in gathering accurate family history information. On average, print-based tools have been found to be written at lower reading grade levels than multimedia-based tools.[31]

Standards of pedigree nomenclature have been established.[29,30] Refer to Figure 1 for common pedigree symbols.

Figure 1. Standard pedigree nomenclature. Common symbols are used to draw a pedigree (family tree). A pedigree shows relationships between family members and patterns of inheritance for certain traits and diseases.

Documentation of a family cancer history typically includes the following:

A three-generation family history includes the following:

For any relative with cancer, collect the following information:[33]

For relatives not affected with cancer, collect the following information:

The accuracy of the family history has a direct bearing on determining the differential diagnoses, selecting appropriate testing, interpreting results of the genetic tests, refining individual cancer risk estimates, and outlining screening and risk reduction recommendations. In a telephone survey of 1,019 individuals, only 6% did not know whether a first-degree relative had cancer; this increased to 8.5% for second-degree relatives.[34] However, people often have incomplete or inaccurate information about the cancer history in their family.[30,33,35-41] Patient education has been shown to improve the completeness of family history collection and may lead to more-accurate risk stratification, referrals for genetic counseling, and changes to management recommendations.[42] Confirming the primary site of cancers in the family that will affect the calculation of hereditary predisposition probabilities and/or estimation of empiric cancer risks may be important, especially if decisions about treatments such as risk-reducing surgery will be based on this family history.[37,43]

A population-based survey of 2,605 first- and second-degree relatives confirmed proband reports of cancer diagnoses and found that the accuracy of reported cancer diagnoses in relatives was low to moderate, while reports of no history of cancer were accurate.[39] Accuracy varies by cancer site and degree of relatedness.[39,44,45] Reporting of cancer family histories may be most accurate for breast cancer [39,45] and less accurate for gynecologic malignancies [39,45] and colon cancer.[39] Self-reported family histories may contain errors and, in rare instances, could be fictitious.[37,43,45] The most reliable documentation of cancer histology is the pathology report. Verification of cancers can also be made through other medical records, tumor registries, or death certificates. A U.K. study illustrates the importance of verification of the cancer family history in individuals with a family history of breast cancer (n = 2,278) and colon cancer (n = 1,184).[41] Changes in genetic risk assignment (reassignment) from baseline to final time points (e.g., low risk to high risk) warranting management changes were reported in nearly 30% of families with colorectal cancer and 20% of families with breast cancer. Verification of reported cancer diagnoses in this cohort revealed a lower overall degree of consistency between reported and confirmed diagnoses than in other studies.[37,46]

It is also important to consider limited, missing, or questionable information when reviewing a pedigree for cancer risk assessment. It is more difficult to identify features of hereditary disease in families with a truncated family structure due to loss of contact with relatives, small family size, or deaths at an early age from unrelated conditions. When there are few family members of the at-risk gender when considering a particular syndrome with primarily male or female specific disease manifestations, the family history may be difficult to assess (e.g., few female members in a family at risk of hereditary breast and ovarian cancer syndrome). In addition, information collected on risk-reducing surgical procedures, such as oophorectomy, could significantly change prior probability estimation and the constellation of cancers observed in a family.[47] Other factors to clarify and document whenever possible are adoptions, use of donor egg or sperm, consanguinity, and uncertain paternity.

Additionally, family histories are dynamic. The occurrence of additional cancers may alter the likelihood of a hereditary predisposition to cancer, and consideration of differential diagnoses or empiric cancer risk estimates may change if additional cancers arise in the family. Furthermore, changes in the cancer family history over time may alter recommendations for earlier or more intense cancer screening. A descriptive study that examined baseline and follow-up family history data from a U.S. population-based cancer registry reported that family history of breast cancer or colorectal cancer becomes increasingly relevant in early adulthood and changes significantly from age 30 years to age 50 years.[48] Therefore, it is important to advise the consultand to take note of, confirm, and report cancer diagnoses or other pertinent family health history that occurs after completion of the initial risk assessment process. This is especially important if genetic testing was not performed or was uninformative.

Finally, the process of taking the family history has a psychosocial dimension. Discussing and documenting discrete aspects of family relationships and health brings the family into the session symbolically, even when a single person is being counseled. Problems that may be encountered in eliciting a family history and constructing a pedigree include difficulty contacting relatives with whom one has little or no relationship, differing views between family members about the value of genetic information, resistance to discussion of cancer and cancer-related illness, unanticipated discovery of previously unknown medical or family information, and coercion of one relative by another regarding testing decisions. In addition, unexpected emotional distress may be experienced by the consultand in the process of gathering family history information.

After an individuals personal and family cancer histories have been collected, several factors could warrant referral to a genetics professional for evaluation of hereditary cancer susceptibility syndromes. The American College of Medical Genetics and Genomics and the National Society of Genetic Counselors have published a comprehensive set of personal and family history criteria to guide the identification of at-risk individuals and appropriate referral for cancer genetic risk consultation.[49] These practice guidelines take into account tumor types or other features and related criteria that would indicate a need for a genetics referral. The authors state that the guidelines are intended to maximize appropriate referral of at-risk individuals for cancer genetic consultation but are not meant to provide genetic testing or treatment recommendations.

Because a family history of cancer is one of the important predictors of cancer risk, analysis of the pedigree constitutes an important aspect of risk assessment. This analysis might be thought of as a series of the following questions:

The following sections relate to the way that each of these questions might be addressed:

The clues to a hereditary syndrome are based on pedigree analysis and physical findings. The index of suspicion is raised by the following:

Clinical characteristics associated with distinctive risk ranges for different cancer genetic syndromes are summarized in the second edition of the Concise Handbook of Familial Cancer Susceptibility Syndromes.[50]

Hundreds of inherited conditions are associated with an increased risk of cancer. These have been summarized in texts [51-53] and a concise review.[50] Diagnostic criteria for different hereditary syndromes incorporate different features from the list above, depending on the original purpose of defining the syndrome (e.g., for gene mapping, genotype -phenotype studies, epidemiological investigations, population screening, or clinical service). Thus, a syndrome such as Lynch syndrome (also called hereditary nonpolyposis colorectal cancer [HNPCC]) can be defined for research purposes by the Amsterdam criteria as having three related individuals with colorectal cancer, with one person being a first-degree relative of the other two; spanning two generations; and including one person who was younger than age 50 years at cancer diagnosis, better known as the 3-2-1 rule. These criteria have limitations in the clinical setting, however, in that they ignore endometrial and other extracolonic tumors known to be important features of Lynch syndrome. Revised published criteria that consider extracolonic cancers of Lynch syndrome have been subsequently developed and include the Amsterdam criteria II and the revised Bethesda guidelines.

Other factors may complicate recognition of basic inheritance patterns or represent different types of disease etiology. These factors include the following:

The mode of inheritance refers to the way that genetic traits are transmitted in the family. Mendels laws of inheritance posit that genetic factors are transmitted from parents to offspring as discrete units known as genes that are inherited independently from each other and are passed on from an older generation to the following generation. The most common forms of Mendelian inheritance are autosomal dominant, autosomal recessive, and X-linked. Non-Mendelian forms of inheritance include chromosomal, complex, and mitochondrial. Researchers have learned from cancer and other inherited diseases that even Mendelian inheritance is modified by environmental and other genetic factors and that there are variations in the ways that the laws of inheritance work.[54-56]

Most commonly, Mendelian inheritance is established by a combination of clinical diagnosis with a compatible, but not in itself conclusive, pedigree pattern.[57] Below is a list of inheritance patterns with clues to their recognition in the pedigree, followed by a list of situations that may complicate pedigree interpretation.

Autosomal dominant

Autosomal recessive

X-linked

Chromosomal

Complex

Susceptibility or resistance shows a more or less normal distribution in the population. Most people have an intermediate susceptibility, with those at the tails of the distribution curve having unusually low or unusually high susceptibility. Affected individuals are presumably those who are past a point of threshold for being affected due to their particular combination of risk factors. Outside of the few known Mendelian syndromes that predispose to a high incidence of specific cancer, most cancers are complex in etiology.

Clustering of cancer among relatives is common, but teasing out the underlying causes when there is no clear pattern is more difficult. With many common malignancies, such as lung cancer, an excess of cancers in relatives can be seen. These familial aggregations are seen as being due to combinations of exposures to known carcinogens, such as tobacco smoke, and to pathogenic variants in high penetrance genes or alterations in genes with low penetrance that affect the metabolism of the carcinogens in question.[58]

The general practitioner is likely to encounter some families with a strong genetic predisposition to cancer and the recognition of cancer susceptibility may have dramatic consequences for a given individual's health and management. Although pathogenic variants in major cancer susceptibility genes lead to recognizable Mendelian inheritance patterns, they are uncommon. Nonetheless, cancer susceptibility genes are estimated to contribute to the occurrence of organ-specific cancers from less than 1% to up to 15%.[59] Pathogenic variants in these genes confer high relative risk and high absolute risk. The attributable risk is low, however, because they are so rare.

In contrast, scientists now know of polymorphisms or alterations in deoxyribonucleic acid that are very common in the general population. Each polymorphism may confer low relative and absolute risks, but collectively they may account for high attributable risk because they are so common. Development of clinically significant disease in the presence of certain genetic polymorphisms may be highly dependent on environmental exposure to a potent carcinogen. People carrying polymorphisms associated with weak disease susceptibility may constitute a target group for whom avoidance of carcinogen exposure may be highly useful in preventing full-blown disease from occurring.

For more information about specific low-penetrance genes, please refer to the summaries on genetics of specific types of cancer.

Complex inheritance might be considered in a pedigree showing the following:

These probabilities vary by syndrome, family, gene, and pathogenic variant, with different variants in the same gene sometimes conferring different cancer risks, or the same variant being associated with different clinical manifestations in different families. These phenomena relate to issues such as penetrance and expressivity discussed elsewhere.

A positive family history may sometimes provide risk information in the absence of a specific genetically determined cancer syndrome. For example, the risk associated with having a single affected relative with breast or colorectal cancer can be estimated from data derived from epidemiologic and family studies. Examples of empiric risk estimates of this kind are provided in the PDQ summaries on Genetics of Breast and Gynecologic Cancers and Genetics of Colorectal Cancer.

The overarching goal of cancer risk assessment is to individualize cancer risk management recommendations based on personalized risk. Methods to calculate risk utilize health history information and risk factor and family history data often in combination with emerging biologic and genetic/genomic evidence to establish predictions.[60] Multiple methodologies are used to calculate risk, including statistical models, prevalence data from specific populations, penetrance data when a documented pathogenic variant has been identified in a family, Mendelian inheritance, and Bayesian analysis. All models have distinct capabilities, weaknesses, and limitations based on the methodology, sample size, and/or population used to create the model. Methods to individually quantify risk encompass two primary areas: the probability of harboring a pathogenic variant in a cancer susceptibility gene and the risk of developing a specific form of cancer.[60]

The decision to offer genetic testing for cancer susceptibility is complex and can be aided in part by objectively assessing an individual's and/or family's probability of harboring a pathogenic variant.[61] Predicting the probability of harboring a pathogenic variant in a cancer susceptibility gene can be done using several strategies, including empiric data, statistical models, population prevalence data, Mendels laws, Bayesian analysis, and specific health information, such as tumor-specific features.[61,62] All of these methods are gene specific or cancer-syndrome specific and are employed only after a thorough assessment has been completed and genetic differential diagnoses have been established.

If a gene or hereditary cancer syndrome is suspected, models specific to that disorder can be used to determine whether genetic testing may be informative. (Refer to the PDQ summaries on the Genetics of Breast and Gynecologic Cancers; Genetics of Colorectal Cancer; or the Genetics of Skin Cancer for more information about cancer syndrome-specific probability models.) The key to using specific models or prevalence data is to apply the model or statistics only in the population best suited for its use. For instance, a model or prevalence data derived from a population study of individuals older than 35 years may not accurately be applied in a population aged 35 years and younger. Care must be taken when interpreting the data obtained from various risk models because they differ with regard to what is actually being estimated. Some models estimate the risk of a pathogenic variant being present in the family; others estimate the risk of a pathogenic variant being present in the individual being counseled. Some models estimate the risk of specific cancers developing in an individual, while others estimate more than one of the data above. (Refer to NCI's Risk Prediction Models website or the disease-specific PDQ cancer genetics summaries for more information about specific cancer risk prediction and pathogenic variant probability models.) Other important considerations include critical family constructs, which can significantly impact model reliability, such as small family size or male-dominated families when the cancer risks are predominately female in origin, adoption, and early deaths from other causes.[62,63] In addition, most models provide gene and/or syndrome-specific probabilities but do not account for the possibility that the personal and/or family history of cancer may be conferred by an as-yet-unidentified cancer susceptibility gene.[64] In the absence of a documented pathogenic variant in the family, critical assessment of the personal and family history is essential in determining the usefulness and limitations of probability estimates used to aid in the decisions regarding indications for genetic testing.[61,62,64]

When a pathogenic variant has been identified in a family and a test report documents that finding, prior probabilities can be ascertained with a greater degree of reliability. In this setting, probabilities can be calculated based on the pattern of inheritance associated with the gene in which the pathogenic variant has been identified. In addition, critical to the application of Mendelian inheritance is the consideration of integrating Bayes Theorem, which incorporates other variables, such as current age, into the calculation for a more accurate posterior probability.[1,65] This is especially useful in individuals who have lived to be older than the age at which cancer is likely to develop based on the pathogenic variant identified in their family and therefore have a lower likelihood of harboring the family pathogenic variant when compared with the probability based on their relationship to the carrier in the family.

Even in the case of a documented pathogenic variant on one side of the family, careful assessment and evaluation of the individuals personal and family history of cancer is essential to rule out cancer risk or suspicion of a cancer susceptibility gene pathogenic variant on the other side of the family (maternal or paternal, as applicable).[66] Segregation of more than one pathogenic variant in a family is possible (e.g., in circumstances in which a cancer syndrome has founder pathogenic variants associated with families of particular ancestral origin).

Unlike pathogenic variant probability models that predict the likelihood that a given personal and/or family history of cancer could be associated with a pathogenic variant in a specific gene(s), other methods and models can be used to estimate the risk of developing cancer over time. Similar to pathogenic variant probability assessments, cancer risk calculations are also complex and necessitate a detailed health history and family history. In the presence of a documented pathogenic variant, cancer risk estimates can be derived from peer-reviewed penetrance data.[1] Penetrance data are constantly being refined and many genetic variants have variable penetrance because other variables may impact the absolute risk of cancer in any given patient. Modifiers of cancer risk in carriers of pathogenic variants include the variant's effect on the function of the gene/protein (e.g., variant type and position), the contributions of modifier genes, and personal and environmental factors (e.g., the impact of bilateral salpingo-oophorectomy performed for other indications in a woman who harbors a BRCA pathogenic variant).[67] When there is evidence of an inherited susceptibility to cancer but genetic testing has not been performed, analysis of the pedigree can be used to estimate cancer risk. This type of calculation uses the probability the individual harbors a genetic variant and variant-specific penetrance data to calculate cancer risk.[1]

In the absence of evidence of a hereditary cancer syndrome, several methods can be utilized to estimate cancer risk. Relative risk data from studies of specific risk factors provide ratios of observed versus expected cancers associated with a given risk factor. However, utilizing relative risk data for individualized risk assessment can have significant limitations: relative risk calculations will differ based on the type of control group and other study-associated biases, and comparability across studies can vary widely.[65] In addition, relative risks are lifetime ratios and do not provide age-specific calculations, nor can the relative risk be multiplied by population risk to provide an individual's risk estimate.[65,68]

In spite of these limitations, disease-specific cumulative risk estimates are most often employed in clinical settings. These estimates usually provide risk for a given time interval and can be anchored to cumulative risks of other health conditions in a given population (e.g., the 5-year risk by the Gail model).[65,68] Cumulative risk models have limitations that may underestimate or overestimate risk. For example, the Gail model excludes paternal family histories of breast cancer.[62] Furthermore, many of these models were constructed from data derived from predominately Caucasian populations and may have limited validity when used to estimate risk in other ethnicities.[69]

Cumulative risk estimates are best used when evidence of other underlying significant risk factors have been ruled out. Careful evaluation of an individual's personal health and family history can identify other confounding risk factors that may outweigh a risk estimate derived from a cumulative risk model. For example, a woman with a prior biopsy showing lobular carcinoma in situ (LCIS) whose mother was diagnosed with breast cancer at age 65 years has a greater lifetime risk from her history of LCIS than her cumulative lifetime risk of breast cancer based on one first-degree relative.[70,71] In this circumstance, recommendations for cancer risk management would be based on the risk associated with her LCIS. Unfortunately, there is no reliable method for combining all of an individual's relevant risk factors for an accurate absolute cancer risk estimate, nor are individual risk factors additive.

In summary, careful ascertainment and review of personal health and cancer family history are essential adjuncts to the use of prior probability models and cancer risk assessment models to assure that critical elements influencing risk calculations are considered.[61] Influencing factors include the following:

A number of investigators are developing health care provider decision support tools such as the Genetic Risk Assessment on the Internet with Decision Support (GRAIDS),[72] but at this time, clinical judgment remains a key component of any prior probability or absolute cancer risk estimation.[61]

Specific clinical programs for risk management may be offered to persons with an increased genetic risk of cancer. These programs may differ from those offered to persons of average risk in several ways: screening may be initiated at an earlier age or involve shorter screening intervals; screening strategies not in routine use, such as screening for ovarian cancer, may be offered; and interventions to reduce cancer risk, such as risk-reducing surgery, may be offered. Current recommendations are summarized in the PDQ summaries addressing the genetics of specific cancers.

The goal of genetic education and counseling is to help individuals understand their personal risk status, their options for cancer risk management, and to explore feelings regarding their personal risk status. Counseling focuses on obtaining and giving information, promoting autonomous decision making, and facilitating informed consent if genetic testing is pursued.

Optimally, education and counseling about cancer risk includes providing the following information:

When a clinically valid genetic test is available, education and counseling for genetic testing typically includes the following:

If a second session is held to disclose and interpret genetic test results, education and counseling focuses on the following:

The process of counseling may require more than one visit to address medical, genetic testing, and psychosocial support issues. Additional case-related preparation time is spent before and after the consultation sessions to obtain and review medical records, complete case documentation, seek information about differential diagnoses, identify appropriate laboratories for genetic tests, find patient support groups, research resources, and communicate with or refer to other specialists.[1]

Information about inherited risk of cancer is growing rapidly. Many of the issues discussed in a counseling session may need to be revisited as new information emerges. At the end of the counseling process, individuals are typically reminded of the possibility that future research may provide new options and/or new information on risk. Individuals may be advised to check in with the health care provider periodically to determine whether new information is sufficient to merit an additional counseling session. The obligation of health care providers to recontact individuals when new genetic testing or treatment options are available is controversial, and standards have not been established.

The usage of numerical probabilities to communicate risk may overestimate the level of risk certainty, especially when wide confidence intervals exist to the estimates or when the individual may differ in important ways from the sample on which the risk estimate was derived. Also, numbers are often inadequate for expressing gut-level or emotional aspects of risk. Finally, there are wide variations in individuals level of understanding of mathematical concepts (i.e., numeracy). For all the above reasons, conveying risk in multiple ways, both numerically and verbally, with discussion of important caveats, may be a useful strategy to increase risk comprehension. The numerical format that facilitates the best understanding is natural frequencies because frequencies include information concerning the denominator, the reference group to which the individual may refer. In general, logarithmic scales are to be avoided.[2] Additionally, important contextual risks may be included with the frequency in order to increase risk comprehension; these may include how the persons risk compares with those who do not have the risk factor in question and the risks associated with common hazards, such as being in a car accident. Additional suggestions include being consistent in risk formats (do not mix odds and percentages), using the same denominator across risk estimates, avoiding decimal points, including base rate information, and providing more explanation if the risk is less than 1%.

The communication of risk may be numerical, verbal, or visual. Use of multiple strategies may increase comprehension and retention of cancer genetic risk information.[2] Recently, use of visual risk communication strategies has increased (e.g., histograms, pie charts, and Venn diagrams). Visual depictions of risk may be very useful in avoiding problems with comprehension of numbers, but research that confirms this is lacking.[3,4] A study published in 2008 examined the use of two different visual aids to communicate breast cancer risk. Women at an increased risk of breast cancer were randomized to receive feedback via a bar graph alone or a bar graph plus a frequency diagram (i.e., highlighted human figures). Results indicate that overall, there were no differences in improved accuracy of risk perception between the two groups, but among those women who inaccurately perceived very high risk at baseline, the group receiving both visual aids showed greater improvement in accuracy.[5]

The purpose of risk counseling is to provide individuals with accurate information about their risk, help them understand and interpret their risk, assist them as they use this information to make important health care decisions, and help them make the best possible adjustment to their situation. A systematic review of 28 studies that evaluated communication interventions showed that risk communication benefits users cognitively by increasing their knowledge and understanding of risk perception and does not negatively influence affect (anxiety, cancer-related worry, and depression). Risk communication does not appear to result in a change in use of screening practices and tests. Users received the most benefit from an approach utilizing risk communication along with genetic counseling.[6,7] Perceptions of risk are affected by the manner in which risk information is presented, difficulty understanding probability and heredity,[8,9] and other psychological processes on the part of individuals and providers.[10] Risk may be communicated in many ways (e.g., with numbers, words, or graphics; alone or in relation to other risks; as the probability of having an adverse event; in relative or absolute terms; and through combinations of these methods). The way in which risk information is communicated may affect the individuals perception of the magnitude of that risk. In general, relative risk estimates (e.g., "You have a threefold increased risk of colorectal cancer") are perceived as less informative than absolute risk (e.g., "You have a 25% risk of colorectal cancer") [11] or risk information presented as a ratio (e.g., 1 in 4).[9] A strong preference for having BRCA1/2 pathogenic variant risk estimates expressed numerically is reported by women considering testing.[12] Individuals associate widely differing quantitative risks with qualitative descriptors of risk such as rare or common.[13] More research is needed on the best methods of communicating risk in order to help individuals develop an accurate understanding of their cancer risks.

Recent descriptive examination of the process of cancer genetic counseling has found that counseling sessions are predominantly focused on the biomedical teaching required to inform clients of their choices and to put genetic findings in perspective but that attention to psychosocial issues does not detract from teaching goals and may enhance satisfaction in clients undergoing counseling. For instance, one study of communication patterns in 167 pretest counseling sessions for BRCA1 found the sessions to have a predominantly biomedical and educational focus;[14] however, this approach was client focused, with the counselor and client contributing equally to the dialogue. These authors note that there was a marked diversity in counselor styles, both between counselors and within different sessions, for each counselor. The finding of a didactic style was corroborated by other researchers who examined observer-rated content checklists and videotape of 51 counseling sessions for breast cancer susceptibility.[15] Of note, genetic counselors seemed to rely on demographic information and breast cancer history to tailor genetic counseling sessions rather than clients self-reported expectations or psychosocial factors.[16] Concurrent provision of psychosocial and scientific information may be important in reducing worry in the context of counseling about cancer genetics topics.[17] An increasing appreciation of language choices may contribute to enhanced understanding and reduced anxiety levels in the session; for example, it was noted that patients may appreciate synonymic choices for the word mutation, such as altered gene.[18] Some authors have published recommendations for cultural tailoring of educational materials for the African-American population, such as a large flip chart, including the use of simple language and pictures, culturally identifiable images (e.g., spiritual symbols and tribal patterns), bright colors, and humor.[19]

Studies have examined novel channels to communicate genetic cancer risk information, deliver psychosocial support, and standardize the genetic counseling process for individuals at increased risk of cancer.[20-27] Much of this literature has attempted to make the genetic counseling session more efficient or to limit the need for the counselor to address basic genetic principles in the session to free up time for the clients personal and emotional concerns about his or her risk. For example, the receipt of genetic feedback for BRCA1/2 and mismatch repair gene testing by letter, rather than a face-to-face genetic counseling feedback session, has been investigated.[28] Other modalities include the development of patient assessments or checklists, CD-ROM programs, and interactive computer programs.

Patient assessments or checklists have been developed to facilitate coverage of important areas in the counseling session. One study assessed patients psychosocial needs before a hereditary cancer counseling session to determine the assessments effect on the session.[29] A total of 246 participants from two familial cancer clinics were randomly assigned to either an intervention arm in which the counselor received assessment results or a usual care control arm. Study results demonstrated that psychosocial concerns were discussed more frequently among intervention participants than among controls, without affecting session length. Moreover, cancer worry and psychological distress were significantly lower for intervention versus control participants 4 weeks after the counseling session.

A second study compared a feedback checklist completed by 197 women attending a high-risk breast clinic prior to the counseling session to convey prior genetic knowledge and misconceptions to aid the counselor in tailoring the session for that client.[22] The use of the feedback checklist led to gains in knowledge from the counseling session but did not reduce genetic counseling time, perhaps because the genetic counselor chose to spend time discussing topics such as psychosocial issues. Use of the checklist did decrease the time spent with the medical oncologist, however. The feedback checklist was compared to a CD-ROM that outlined basic genetic concepts and the benefits and limitations of testing and found that those viewing the CD-ROM spent less time with counselors and were less likely to choose to undergo genetic testing. The CD-ROM did not lead to increased knowledge of genetic concepts, as did use of the checklist.

A prospective study evaluated the effects of a CD-ROM decisional support aid for microsatellite instability (MSI) tumor testing in 239 colorectal cancer patients who met the revised Bethesda criteria but who did not meet the Amsterdam criteria.[30] The study also tested a theoretical model of factors influencing decisional conflict surrounding decisions to pursue MSI tumor testing. Within the study, half of the sample was randomly assigned to receive a brief description of MSI testing within the clinical encounter, and the other half was provided the CD-ROM decisional support aid in addition to the brief description. The CD-ROM and brief description intervention increased knowledge about MSI testing more than the brief description alone did. As a result, decisional conflict decreased because participants felt more prepared to make a decision about the test and had increased perceived benefits of MSI testing.

Other innovative strategies include educational materials and interactive computer technology. In one study, a 13-page color communication aid using a diverse format for conveying risk, including graphic representations and verbal descriptions, was developed.[23] The authors evaluated the influence of the communication aid in 27 women at high risk of a BRCA1/2 pathogenic variant and compared those who had read the aid to a comparison sample of 107 women who received standard genetic counseling. Improvements in genetic knowledge and accuracy of risk perception were documented in those who had read the aid, with no differences in anxiety or depression between groups. Personalized, interactive electronic materials have also been developed to aid in genetic education and counseling.[24,25] In one study, an interactive computer education program available prior to the genetic counseling session was compared with genetic counseling alone in women undergoing counseling for BRCA1/2 testing.[25] Use of the computer program prior to genetic counseling reduced face-time with the genetic counselor, particularly for those at lower risk of a BRCA1/2 pathogenic variant. Many of the counselors reported that their clients use of the computer program allowed them to be more efficient and to reallocate time spent in the sessions to clients unique concerns.

Videoconferencing is an innovative strategy to facilitate genetic counseling sessions with clients who cannot travel to specialized clinic settings. In 37 individuals in the United Kingdom, real-time video conferencing was compared with face-to-face counseling sessions; both methods were found to improve knowledge and reduce anxiety levels.[26] Similarly, teleconferencing sessions, in which the client and genetic specialists were able to talk with each other in real time, were used in rural Maine communities [27] in the pediatric context to convey genetic information and findings for developmental delays and were found to be comparable to in-person consultations in terms of decision-making confidence and satisfaction with the consultations. An Australian study compared the experiences of 106 women who received hereditary breast and ovarian cancer genetic counseling via videoconferencing with the experiences of 89 women who received counseling face to face. Pre- and 1-month postcounseling assessments revealed no significant differences in knowledge gains, satisfaction, cancer-specific anxiety, generalized anxiety, depression, and perceived empathy of the genetic counselor.[31]

More:
Cancer Genetics Risk Assessment and Counseling (PDQ ...

Recommendation and review posted by sam

After a massive mess up with the NHS recently (a long story) I finally managed to get my AMH (Anti-Mullerian hormones) tested last week at a private clinic.

Facts and Figures

Im sure lots of you are already too familiar with the meaning of AMH, but just incase you are unfamiliar here is a bit more information from Lane Fertility Magazine:

Anti Mullerian Hormones (AMH)

Many physicians and researchers believe that the best blood test to assess the supply of follicles in a womans ovaries is Anti-Mullerian Hormone (AMH), also known as Mullerian Inhibiting Substance (MIS). In females, this hormone is secreted by a particular group of cells in the follicles called granulosa cells. Thus, the more follicles there are in the ovaries, the greater the amount of AMH in the blood. Conversely, the fewer follicles there are in the ovaries, the lower the amount of AMH in the blood. Therefore, AMH is a reflection of the number of follicles in both ovaries. With time, as women become older, the level of AMH will naturally decrease.

This graph was interesting about how AMH levels decline with age, read more about it atFertility Associates.

The ranges used in the U.K. and U.S. should be as follows:

U.K.

U.S.

AMH Blood Level

Interpretation

AMH Blood Level

Interpretation

>68pmol/L

High

Over 3.0 ng/ml

High (often PCOS)

22 40pmol/L

Satisfactory

Over 1.0 ng/ml

Normal

3.1 22pmol/L

Low

0.7 0.9 ng/ml

Low Normal Range

0 3.1pmol/L

Very Low

0.3 0.6 ng/ml

Low

Note:Reference range formerly in g/L(conversion g/L pmol/L = 7.14)

Less than 0.3 ng/ml

Very Low

I also found a great conversion chart, which was very useful as different information/labs seems to use different units of measurement.

Confusion

Once again there is quite a lot of differing opinions about AMH. On my mission to source information I have found out that:

Can you imagine my surprise when I discovered that (once again) there are differing opinions and inconsistencies in the facts? Detect a hint of sarcasm? Sorry, I just couldnt resist! Once again my search for clear cut facts was in vain another grey area in this mixed up IF world.

My Results

My result came back as 8 pmol/L, in the low fertility bracket. My first reaction was to be upset (of course), but the nurse kindly explained that it isnt too bad; it is age related and lots can be done with an AMH of that level especially if I have been pregnant before. Also that it is more about quality, not quantity.

I also had a go at converting my result into ng/ml (as per the U.S. figures). I know, I know, before you say it, this is probably the wrong thing to do. They probably use different methods of testing, blah blah blah. But I couldnt resist, I was grasping at straws. And the result? 1.12 ng/ml which puts me in the normal range. Do I believe this? Im not sure, but I do like the sound of normal much more than low fertility.

So, yet again an emotional roller-coaster (albeit a small one this time) began:

What can I do about it? Nothing! Absolutely nothing! It frustrates me that time is my enemy and Im feeling the sense of urgency more than ever. But its not like Hubby and I havent been trying for the last two years what more can we do?

Your AMH Levels

Id love to hear what your AMH levels were and what you have been told about it. And Im sure there are plenty of others out there who are just as confused as I am about all this. Please comment, and lets get to the bottom of this!

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Originally posted here:
Worrying about Anti Mullerian Hormones? | Baby Hopeful

Recommendation and review posted by Bethany Smith

Venus de Milo at the Louvre has been described as a "classical vision of beauty".[1][2][3] However, one expert claimed her "almost matronly representation" was meant to convey an "impressive appearance" rather than "ideal female beauty".[4]

Physical attractiveness is the degree to which a person's physical features are considered aesthetically pleasing or beautiful. The term often implies sexual attractiveness or desirability, but can also be distinct from either. There are many factors which influence one person's attraction to another, with physical aspects being one of them. Physical attraction itself includes universal perceptions common to all human cultures, as well as aspects that are culturally and socially dependent, along with individual subjective preferences.

In many cases, humans subconsciously attribute positive characteristics, such as intelligence and honesty, to physically attractive people.[9] From research done in the United States and United Kingdom, it was found that the association between intelligence and physical attractiveness is stronger among men than among women.[10]Evolutionary psychologists have tried to answer why individuals who are more physically attractive should also, on average, be more intelligent, and have put forward the notion that both general intelligence and physical attractiveness may be indicators of underlying genetic fitness.[11] A person's physical characteristics can signal cues to fertility and health. Attending to these factors increases reproductive success, furthering the representation of one's genes in the population.[12]

Men, on average, tend to be attracted to women who are shorter than they are, have a youthful appearance, and exhibit features such as a symmetrical face,[13] full breasts, full lips, and a low waist-hip ratio.[14] Women, on average, tend to be attracted to men who are taller than they are, display a high degree of facial symmetry, masculine facial dimorphism, and who have broad shoulders, a relatively narrow waist, and a V-shaped torso.[15][16]

Generally, physical attractiveness can be viewed from a number of perspectives; with universal perceptions being common to all human cultures, cultural and social aspects, and individual subjective preferences. The perception of attractiveness can have a significant effect on how people are judged in terms of employment or social opportunities, friendship, sexual behavior, and marriage.[17]

Some physical features are attractive in both men and women, particularly bodily[18] and facial symmetry,[19][20][21][22] although one contrary report suggests that "absolute flawlessness" with perfect symmetry can be "disturbing".[23] Symmetry may be evolutionarily beneficial as a sign of health because asymmetry "signals past illness or injury".[24] One study suggested people were able to "gauge beauty at a subliminal level" by seeing only a glimpse of a picture for one-hundredth of a second.[24] Other important factors include youthfulness, skin clarity and smoothness of skin; and "vivid color" in the eyes and hair.[19] However, there are numerous differences based on gender.

A 1921 study, of the reports of college students regarding those traits in individuals which make for attractiveness and repulsiveness argued that static traits, such as beauty or ugliness of features, hold a position subordinate to groups of physical elements like expressive behavior, affectionate disposition, grace of manner, aristocratic bearing, social accomplishments, and personal habits.[25]

Grammer and colleagues have identified eight "pillars" of beauty: youthfulness, symmetry, averageness, sex-hormone markers, body odor, motion, skin complexion and hair texture.[26]

Most studies of the brain activations associated with the perception of attractiveness show photographs of faces to their participants and let them or a comparable group of people rate the attractiveness of these faces. Such studies consistently find that activity in certain parts of the orbitofrontal cortex increases with increasing attractiveness of faces.[27][28][29][30][31] This neural response has been interpreted as a reaction on the rewarding nature of attractiveness, as similar increases in activation in the medial orbitofrontal cortex can be seen in response to smiling faces[32] and to statements of morally good actions.[29][31] While most of these studies have not assessed participants of both genders or homosexual individuals, evidence from one study including male and female hetero- and homosexual individuals indicate that some of the aforementioned increases in brain activity are restricted to images of faces of the gender participants feel sexually attracted to.[33]

With regard to brain activation related to the perception of attractive bodies, one study with heterosexual participants suggests that activity in the nucleus accumbens and the anterior cingulate cortex increases with increasing attractiveness. The same study finds that for faces and bodies alike, the medial part of the orbitofrontal cortex responds with greater activity to both very attractive and very unattractive pictures.[34]

Women, on average, tend to be more attracted to men who have a relatively narrow waist, a V-shaped torso, and broad shoulders. Women also tend to be more attracted to men who are taller than they are, and display a high degree of facial symmetry, as well as relatively masculine facial dimorphism.[15][16] With regard to male-male-attractiveness, one source reports that the most important factor that attracts gay men to other males is the man's physical attractiveness.[35]

Studies have shown that ovulating heterosexual women prefer faces with masculine traits associated with increased exposure to testosterone during key developmental stages, such as a broad forehead, relatively longer lower face, prominent chin and brow, chiseled jaw and defined cheekbones.[36] The degree of differences between male and female anatomical traits is called sexual dimorphism. Female respondents in the follicular phase of their menstrual cycle were significantly more likely to choose a masculine face than those in menses and luteal phases,[37] (or in those taking hormonal contraception).[15][16][38][39] This distinction supports the sexy son hypothesis, which posits that it is evolutionarily advantageous for women to select potential fathers who are more genetically attractive,[40] rather than the best caregivers.[41] However, women's likeliness to exert effort to view male faces does not seem to depend on their masculinity, but to a general increase with women's testosterone levels.[42]

It is suggested that the masculinity of facial features is a reliable indication of good health, or, alternatively, that masculine-looking males are more likely to achieve high status.[43] However, the correlation between attractive facial features and health has been questioned.[44] Sociocultural factors, such as self-perceived attractiveness, status in a relationship and degree of gender-conformity, have been reported to play a role in female preferences for male faces.[45] Studies have found that women who perceive themselves as physically attractive are more likely to choose men with masculine facial dimorphism, than are women who perceive themselves as physically unattractive.[46] In men, facial masculinity significantly correlates with facial symmetryit has been suggested that both are signals of developmental stability and genetic health.[47] One study called into question the importance of facial masculinity in physical attractiveness in men arguing that when perceived health, which is factored into facial masculinity, is discounted it makes little difference in physical attractiveness.[48] In a cross-country study involving 4,794 women in their early twenties, a difference was found in women's average "masculinity preference" between countries.[49]

A study found that the same genetic factors cause facial masculinity in both males and females such that a male with a more masculine face would likely have a sister with a more masculine face due to the siblings having shared genes. The study also found that, although female faces that were more feminine were judged to be more attractive, there was no association between male facial masculinity and male facial attractiveness for female judges. With these findings, the study reasoned that if a woman were to reproduce with a man with a more masculine face, then her daughters would also inherit a more masculine face, making the daughters less attractive. The study concluded that there must be other factors that advantage the genetics for masculine male faces to offset their reproductive disadvantage in terms of "health", "fertility" and "facial attractiveness" when the same genetics are present in females. The study reasoned that the "selective advantage" for masculine male faces must "have (or had)" been due to some factor that is not directly tied to female perceptions of male facial attractiveness.[50]

In a study of 447 gay men in China, researchers said that tops preferred feminized male faces, bottoms preferred masculinized male faces and versatiles had no preference for either feminized or masculinized male faces.[51]

In pre-modern Chinese literature, the ideal man in caizi jiaren romances was said to have "rosy lips, sparkling white teeth" and a "jasper-like face" (Chinese: ).[52][53]

In Middle English literature, a beautiful man should have a long, broad and strong face.[54]

A study that used Chinese, Malay and Indian judges said that Chinese men with orthognathism where the mouth is flat and in-line with the rest of the face were judged to be the most attractive and Chinese men with a protruding mandible where the jaw projects outward were judged to be the least attractive.[55]

Symmetrical faces and bodies may be signs of good inheritance to women of child-bearing age seeking to create healthy offspring. Studies suggest women are less attracted to men with asymmetrical faces,[56] and symmetrical faces correlate with long term mental performance[57] and are an indication that a man has experienced "fewer genetic and environmental disturbances such as diseases, toxins, malnutrition or genetic mutations" while growing.[57] Since achieving symmetry is a difficult task during human growth, requiring billions of cell reproductions while maintaining a parallel structure, achieving symmetry is a visible signal of genetic health.

Studies have also suggested that women at peak fertility were more likely to fantasize about men with greater facial symmetry,[58] and other studies have found that male symmetry was the only factor that could significantly predict the likelihood of a woman experiencing orgasm during sex. Women with partners possessing greater symmetry reported significantly more copulatory female orgasms than were reported by women with partners possessing low symmetry, even with many potential confounding variables controlled.[59] This finding has been found to hold across different cultures. It has been argued that masculine facial dimorphism (in men) and symmetry in faces are signals advertising genetic quality in potential mates.[60] Low facial and body fluctuating asymmetry may indicate good health and intelligence, which are desirable features.[61] Studies have found that women who perceive themselves as being more physically attractive are more likely to favor men with a higher degree of facial symmetry, than are women who perceive themselves as being less physically attractive.[46] It has been found that symmetrical men (and women) have a tendency to begin to have sexual intercourse at an earlier age, to have more sexual partners, and to have more one-night stands. They are also more likely to be prone to infidelity.[62] A study of quarterbacks in the American National Football League found a positive correlation between facial symmetry and salaries.[20]

Double-blind studies found that women prefer the scent of men who are rated as facially attractive.[63] For example, both males and females were more attracted to the natural scent of individuals who had been rated by consensus as facially attractive.[64] Additionally, it has also been shown that women have a preference for the scent of men with more symmetrical faces, and that women's preference for the scent of more symmetrical men is strongest during the most fertile period of their menstrual cycle.[65] Within the set of normally cycling women, individual women's preference for the scent of men with high facial symmetry correlated with their probability of conception.[65]

Studies have explored the genetic basis behind such issues as facial symmetry and body scent and how they influence physical attraction. In one study in which women wore men's T-shirts, researchers found that women were more attracted to the bodily scents in shirts of men who had a different type of gene section within the DNA called Major histocompatibility complex (MHC).[66] MHC is a large gene area within the DNA of vertebrates which encodes proteins dealing with the immune system[67] and which influences individual bodily odors.[68] One hypothesis is that humans are naturally attracted by the sense of smell and taste to others with dissimilar MHC sections, perhaps to avoid subsequent inbreeding while increasing the genetic diversity of offspring.[67] Further, there are studies showing that women's natural attraction for men with dissimilar immune profiles can be distorted with use of birth control pills.[68] Other research findings involving the genetic foundations of attraction suggest that MHC heterozygosity positively correlates with male facial attractiveness. Women judge the faces of men who are heterozygous at all three MHC loci to be more attractive than the faces of men who are homozygous at one or more of these loci. Additionally, a second experiment with genotyped women raters, found these preferences were independent of the degree of MHC similarity between the men and the female rater. With MHC heterozygosity independently seen as a genetic advantage, the results suggest that facial attractiveness in men may be a measure of genetic quality.[69][70]

A 2010 OkCupid study on 200,000 of its male and female dating site users found that women are, except those during their early to mid-twenties, open to relationships with both somewhat older and somewhat younger men; they have a larger potential dating pool than men until age 26. At age 20, women, in a "dramatic change", begin sending private messages to significantly older men. At age 29 they become "even more open to older men". Male desirability to women peaks in the late 20s and does not fall below the average for all men until 36.[71] Other research indicates that women, irrespective of their own age, are attracted to men who are the same age or older.[72]

For the Romans especially, "beardlessness" and "smooth young bodies" were considered beautiful to both men and women.[73] For Greek and Roman men, the most desirable traits of boys were their "youth" and "hairlessness". Pubescent boys were considered a socially appropriate object of male desire, while post-pubescent boys were considered to be "" or "past the prime".[73] This was largely in the context of pederasty (adult male interest in adolescent boys). Today, men and women's attitudes towards male beauty has changed. For example, body hair on men may even be preferred (see below).

A 1984 study said that gay men tend to prefer gay men of the same age as ideal partners, but there was a statistically significant effect (p < 0.05) of masculinity-femininity. The study said that more feminine men tended to prefer relatively older men than themselves and more masculine men tended to prefer relatively younger men than themselves.[74]

The physique of a slim waist, broad shoulders and muscular chest are often found to be attractive to females.[75] Further research has shown that, when choosing a mate, the traits females look for indicate higher social status, such as dominance, resources, and protection.[76] An indicator of health in males (a contributing factor to physical attractiveness) is the android fat distribution pattern which is categorized as more fat distributed on the upper body and abdomen, commonly referred to as the "V shape."[76] When asked to rate other men, both heterosexual and homosexual men found low waist-to-chest ratios (WCR) to be more attractive on other men, with the gay men showing a preference for lower WCR (more V-shaped) than the straight men.[77]

Other researchers found waist-to-chest ratio the largest determinant of male attractiveness, with body mass index and waist-to-hip ratio not as significant.[78]

Women focus primarily on the ratio waist to chest or more specifically waist to shoulder. This is analogous to the waist to hip ratio (WHR) that men prefer. Key body image for a man in the eyes of a woman would include big shoulders, chest, and upper back, and a slim waist area.[79] Research has additionally shown that college males had a better satisfaction with their body than college females. The research also found that when a college female's waist to hip ratio went up, their body image satisfaction decreased.[80] The results indicate that males had significantly greater body image satisfaction than did females.

Some research has shown that body weight may have a stronger effect than WHR when it comes to perceiving attractiveness of the opposite sex. It was found that waist to hip ratio played a smaller role in body preference than body weight in regards to both sexes.[81]

Psychologists Viren Swami and Martin J. Tovee compared female preference for male attractiveness cross culturally, between Britain and Malaysia. They found that females placed more importance on WCR (and therefore body shape) in urban areas of Britain and Malaysia, while females in rural areas placed more importance on BMI (therefore weight and body size). Both WCR and BMI are indicative of male status and ability to provide for offspring, as noted by evolutionary theory.[82]

Females have been found to desire males that are normal weight and have the average WHR for a male. Females view these males as attractive and healthy. Males who had the average WHR but were overweight or underweight are not perceived as attractive to females. This suggests that WHR is not a major factor in male attractiveness, but a combination of body weight and a typical male WHR seem to be the most attractive. Research has shown that men who have a higher waist to hip ratio and a higher salary are perceived as more attractive to women.[83]

A 1982 study, found that an abdomen that protrudes was the "least attractive" trait for men.[84]

In Middle English literature, a beautiful man should have a flat abdomen.[54]

Men's bodies portrayed in magazines marketed to men are more muscular than the men's bodies portrayed in magazines marketed to women. From this, some have concluded that men perceive a more muscular male body to be ideal, as distinct from a woman's ideal male, which is less muscular than what men perceive to be ideal.[85] This is due to the within-gender prestige granted by increased muscularity and within-gender competition for increased muscularity.[85] Men perceive the attractiveness of their own musculature by how closely their bodies resemble the "muscle man."[86] This "muscle man" ideal is characterized by large muscular arms, especially biceps, a large muscular chest that tapers to their waist and broad shoulders.[86]

In a study of stated profile preferences on Match.com, a greater percentage of gay men than lesbians selected their ideal partner's body type as "Athletic and Toned" as opposed to the other two options of "Average" or "Overweight".[87]

In pre-modern Chinese literature, such as in The Story of the Western Wing, a type of masculinity called "scholar masculinity" is depicted wherein the "ideal male lover" is "weak, vulnerable, feminine, and pedantic".[52]

In Middle English literature, a beautiful man should have thick, broad shoulders, a square and muscular chest, a muscular back, strong sides that taper to a small waist, large hands and arms and legs with huge muscles.[54]

A 2006 study, of 25,594 heterosexual men found that men who perceived themselves as having a large penis were more satisfied with their own appearance.[88]

A 2014 study, criticized previous studies based on the fact that they relied on images and used terms such as "small", "medium", and "large" when asking for female preference. The new study used 3D models of penises from sizes of 4 inches (10cm) long and 2.5 inches (6.4cm) in circumference to 8.5 inches (22cm) long and 7 inches (18cm) in circumference and let the women "view and handle" them. It was found that women overestimated the actual size of the penises they have experimented with when asked in a follow-up survey. The study concluded that women on average preferred the 6.5-inch (17cm) penis in length both for long-term and for one-time partners. Penises with larger girth were preferred for one-time partners.[89]

Females' sexual attraction towards males may be determined by the height of the man.[91] Height in men is associated with status or wealth in many cultures (in particular those where malnutrition is common),[92] which is beneficial to women romantically involved with them. One study conducted of women's personal ads support the existence of this preference; the study found that in ads requesting height in a mate, 80% requested a height of 6 feet (1.83m) or taller.[92] The online dating Website eHarmony only matches women with taller men because of complaints from women matched with shorter men.[93]

Other studies have shown that heterosexual women often prefer men taller than they are rather than a man with above average height. While women usually desire men to be at least the same height as themselves or taller, several other factors also determine male attractiveness, and the male-taller norm is not universal.[94] For example, taller women are more likely to relax the "taller male" norm than shorter women.[95] Furthermore, professor Adam Eyre-Walker, from the University of Sussex, has stated that there is, as of yet, no evidence that these preferences are evolutionary preferences, as opposed to merely cultural preferences.[96] In a double-blind study by Graziano et al., it was found that, in person, using a sample of women of normal size, they were on average most attracted to men who were of medium height (5'9" 5'11", 1.75m 1.80m) and less attracted to both men of shorter height (5'5" 5'7", 1.65m 1.70m) and men of tallest height (6'2" 6'4", 1.88m 1.93m).[97]

Additionally, women seem more receptive to an erect posture than men, though both prefer it as an element within beauty.[92] According to one study (Yee N., 2002), gay men who identify as "only tops" tend to prefer shorter men, while gay men who identify as "only bottoms" tend to prefer taller men.[98]

In romances in Middle English literature, all of the "ideal" male heroes are tall, and the vast majority of the "valiant" male heroes are tall too.[54]

Studies based in the United States, New Zealand, and China have shown that women rate men with no trunk (chest and abdominal) hair as most attractive, and that attractiveness ratings decline as hairiness increases.[99][100] Another study, however, found that moderate amounts of trunk hair on men was most attractive, to the sample of British and Sri Lankan women.[101] Further, a degree of hirsuteness (hairiness) and a waist-to-shoulder ratio of 0.6 is often preferred when combined with a muscular physique.[101]

In a study using Finnish women, women with hairy fathers were more likely to prefer hairy men, suggesting that preference for hairy men is the result of either genetics or imprinting.[102] Among gay men, another study (Yee N., 2002) reported gay males who identify as "only tops" prefer less hairy men, while gay males who identify as "only bottoms" prefer hairier men.[98]

Testosterone has been shown to darken skin color in laboratory experiments.[103] In his foreword to Peter Frost's 2005 Fair Women, Dark Men, University of Washington sociologist Pierre L. van den Berghe writes: "Although virtually all cultures express a marked preference for fair female skin, even those with little or no exposure to European imperialism, and even those whose members are heavily pigmented, many are indifferent to male pigmentation or even prefer men to be darker."[104] Despite this, the aesthetics of skin tone varies from culture to culture. Manual laborers who spent extended periods of time outside developed a darker skin tone due to exposure to the sun. As a consequence, an association between dark skin and the lower classes developed. Light skin became an aesthetic ideal because it symbolized wealth. "Over time society attached various meanings to these colored differences. Including assumptions about a person's race, socioeconomic class, intelligence, and physical attractiveness."[105]

A scientific review published in 2011, identified from a vast body of empirical research that skin colour as well as skin tone tend to be preferred as they act as indicators of good health. More specifically, these indicators are thought to suggest to potential mates that the beholder has strong or good genes capable of fighting off disease.[106]

According to one study (Yee N., 2002), gay men who identify as "only tops" tend to prefer lighter-skinned men while gay men who identify as "only bottoms" tend to prefer darker-skinned men.[98]

More recent research has suggested that redder and yellower skin tones,[107] reflecting higher levels of oxygenated blood,[108] carotenoid and to a lesser extent melanin pigment, and net dietary intakes of fruit and vegetables,[109] appears healthier, and therefore more attractive.[110]

Research indicates that heterosexual men tend to be attracted to young[111] and beautiful women[112] with bodily symmetry.[113] Rather than decreasing it, modernity has only increased the emphasis men place on women's looks.[114]Evolutionary psychologists attribute such attraction to an evaluation of the fertility potential in a prospective mate.[111]

Research has attempted to determine which facial features communicate attractiveness. Facial symmetry has been shown to be considered attractive in women,[117][118] and men have been found to prefer full lips,[119] high forehead, broad face, small chin, small nose, short and narrow jaw, high cheekbones,[56][120] clear and smooth skin, and wide-set eyes.[111] The shape of the face in terms of "how everything hangs together" is an important determinant of beauty.[121] A University of Toronto study found correlations between facial measurements and attractiveness; researchers varied the distance between eyes, and between eyes and mouth, in different drawings of the same female face, and had the drawings evaluated; they found there were ideal proportions perceived as attractive (see photo).[115] These proportions (46% and 36%) were close to the average of all female profiles.[115] Women with thick, dark limbal rings in their eyes have also been found to be more attractive. The explanation given is that because the ring tends to fade with age and medical problems, a prominent limbal ring gives an honest indicator of youth.[122]

In a cross-cultural study, more neotenized (i.e., youthful looking) female faces were found to be most attractive to men while less neotenized female faces were found to be less attractive to men, regardless of the females' actual age.[123] One of these desired traits was a small jaw.[124] In a study of Italian women who have won beauty competitions, it was found that their faces had more "babyish" (pedomorphic) traits than those of the "normal" women used as a reference.[125]

In a cross-cultural study, Marcinkowska et al. said that 18- to 45-year-old heterosexual men in all 28 countries surveyed preferred photographs of 18- to 24-year-old Caucasian women whose faces were feminized using Psychomorph software over faces of 18- to 24-year-old Caucasian women that were masculinized using that software, but there were differences in preferences for femininity across countries. The higher the National Health Index of a country, the more were the feminized faces preferred over the masculinized faces. Among the countries surveyed, Japan had the highest femininity preference and Nepal had the lowest femininity preference.[128]

Michael R. Cunningham of the Department of Psychology at the University of Louisville found, using a panel of East Asian, Hispanic and White judges, that the Asian, Hispanic and White female faces found most attractive were those that had "neonate large eyes, greater distance between eyes, and small noses"[129] and his study led him to conclude that "large eyes" were the most "effective" of the "neonate cues".[129] Cunningham also said that "shiny" hair may be indicative of "neonate vitality".[129] Using a panel of blacks and whites as judges, Cunningham found more neotenous faces were perceived as having both higher "femininity" and "sociability".[129] In contrast, Cunningham found that faces that were "low in neoteny" were judged as "intimidating".[129] Cunningham noted a "difference" in the preferences of Asian and white judges with Asian judges preferring women with "less mature faces" and smaller mouths than the White judges.[129] Cunningham hypothesized that this difference in preference may stem from "ethnocentrism" since "Asian faces possess those qualities", so Cunningham re-analyzed the data with "11 Asian targets excluded" and concluded that "ethnocentrism was not a primary determinant of Asian preferences."[129] Rather than finding evidence for purely "neonate" faces being most appealing, Cunningham found faces with "sexually-mature" features at the "periphery" of the face combined with "neonate" features in the "center of the face" most appealing in men and women.[129] Upon analyzing the results of his study, Cunningham concluded that preference for "neonate features may display the least cross-cultural variability" in terms of "attractiveness ratings"[129] and, in another study, Cunningham concluded that there exists a large agreement on the characteristics of an attractive face.[130][131]

In computer face averaging tests, women with averaged faces have been shown to be considered more attractive.[22][132] This is possibly due to average features being more familiar and, therefore, more comfortable.[117]

Commenting on the prevalence of whiteness in supposed beauty ideals in his book White Lies: Race and the Myth of Whiteness, Maurice Berger states that the schematic rendering in the idealized face of a study conducted with American subjects had "straight hair," "light skin," "almond-shaped eyes," "thin, arched eyebrows," "a long, thin nose, closely set and tiny nostrils" and "a large mouth and thin lips",[133] though the author of the study stated that there was consistency between his results and those conducted on other races. Scholar Liu Jieyu says in the article White Collar Beauties, "The criterion of beauty is both arbitrary and gendered. The implicit consensus is that women who have fair skin and a slim figure with symmetrical facial features are pretty." He says that all of these requirements are socially constructed and force people to change themselves to fit these criteria.[134]

One psychologist speculated there were two opposing principles of female beauty: prettiness and rarity. So on average, symmetrical features are one ideal, while unusual, stand-out features are another.[135] A study performed by the University of Toronto found that the most attractive facial dimensions were those found in the average female face. However, that particular University of Toronto study looked only at white women.[136]

A study that used Chinese, Malay and Indian judges said that Chinese women with orthognathism where the mouth is flat and in-line with the rest of the face were judged to be the most attractive and Chinese women with a protruding mandible where the jaw projects outward were judged to be the least attractive.[55]

A 2011 study, by Wilkins, Chan and Kaiser found correlations between perceived femininity and attractiveness, that is, women's faces which were seen as more feminine were judged by both men and women to be more attractive.[137]

A component of the female beauty ideal in Persian literature is for women to have faces like a full moon.[138][139][140]

In Arabian society in the Middle Ages, a component of the female beauty ideal was for women to have round faces which were like a "full moon".[141]

In Japan, during the Edo period, a component of the female beauty ideal was for women to have long and narrow faces which were shaped like ovals.[142]

In Jewish Rabbinic literature, the Rabbis considered full lips to be the ideal type of lips for women.[143]

Historically, in Chinese and Japanese literature, the feminine ideal was said to include small lips.[144] Women would paint their lips thinner and narrower to align with this ideal.[145][146]

Classical Persian literature, paintings, and miniatures portrayed traits such as long black curly hair, a small mouth, long arched eyebrows, large almond shaped eyes, a small nose, and beauty spots as being beautiful for women.[147]

Evidence from various cultures suggests that heterosexual men tend to find the sight of women's genitalia to be sexually arousing.[148]

Cross-cultural data shows that the reproductive success of women is tied to their youth and physical attractiveness[149] such as the pre-industrial Sami where the most reproductively successful women were 15 years younger than their man.[150] One study covering 37 cultures showed that, on average, a woman was 2.5 years younger than her male partner, with the age difference in Nigeria and Zambia being at the far extreme of 6.5 to 7.5 years. As men age, they tend to seek a mate who is ever younger.[111]

25% of eHarmony's male customers over the age of 50 request to only be matched with women younger than 40.[93] A 2010 OkCupid study, of 200,000 users found that female desirability to its male users peaks at age 21, and falls below the average for all women at 31. After age 26, men have a larger potential dating pool than women on the site; and by age 48, their pool is almost twice as large. The median 31-year-old male user searches for women aged 22 to 35, while the median 42-year-old male searches for women 27 to 45. The age skew is even greater with messages to other users; the median 30-year-old male messages teenage girls as often as women his own age, while mostly ignoring women a few years older than him. Excluding the 10% most and 10% least beautiful of women, however, women's attractiveness does not change between 18 and 40, but if extremes are not excluded "There's no doubt that younger [women] are more physically attractiveindeed in many ways beauty and youth are inextricable. That's why most of the models you see in magazines are teenagers".[71]

Pheromones (detected by female hormone markers) reflects female fertility and the reproductive value mean.[151] As females age, the estrogen-to-androgen production ratio changes and results in female faces to appear more and more masculine (thus appearing less "attractive").[151] In a small (n=148) study performed in the United States, using male college students at one university, the mean age expressed as ideal for a wife was found to be 16.87 years old, while 17.76 was the mean ideal age for a brief sexual encounter. However, the study sets up a framework where "taboos against sex with young girls" are purposely diminished, and biased their sample by removing any participant over the age of 30, with a mean participant age of 19.83.[152] In a study of penile tumescence, men were found most aroused by pictures of young adult females.[153]

Signals of fertility in women are often also seen as signals of youth. The evolutionary perspective proposes the idea that when it comes to sexual reproduction, the minimal parental investment required by men gives them the ability and want to simply reproduce 'as much as possible.'[154] It therefore makes sense that men are attracted to the features in women which signal youthfulness, and thus fertility.[154] Their chances of reproductive success are much higher than they would be should they pick someone olderand therefore less fertile.

This may explain why combating age declines in attractiveness occurs from a younger age in women than in men. For example, the removal of one's body hair is considered a very feminine thing to do.[155] This can be explained by the fact that aging results in raised levels of testosterone and thus, body hair growth. Shaving reverts one's appearance to a more youthful stage[155] and although this may not be an honest signal, men will interpret this as a reflection of increased fertile value. Research supports this, showing hairlessness to considered sexually attractive by men.[156]

Research has shown that most heterosexual men enjoy the sight of female breasts,[157] with a preference for large, firm breasts.[158] However, a contradictory study of British undergraduates found younger men preferred small breasts on women.[159] Smaller breasts were widely associated with youthfulness.[160] Cross-culturally, another study found "high variability" regarding the ideal breast size.[159] Some researchers in the United Kingdom have speculated that a preference for larger breasts may have developed in Western societies because women with larger breasts tend to have higher levels of the hormones estradiol and progesterone, which both promote fertility.[161]

A study showed that men prefer symmetrical breasts.[113][162] Breast symmetry may be particularly sensitive to developmental disturbances and the symmetry differences for breasts are large compared to other body parts. Women who have more symmetrical breasts tend to have more children.[163]

Historical literature often includes specific features of individuals or a gender that are considered desirable. These have often become a matter of convention, and should be interpreted with caution. In Arabian society in the Middle Ages, a component of the female beauty ideal was for women to have small breasts.[141] In Persian literature, beautiful women are said to have breasts like pomegranates or lemons.[138] In the Chinese text "Jeweled Chamber Secrets" (Chinese: ) from the Six Dynasties period, the ideal woman was described as having firm breasts.[142] In Sanskrit literature, beautiful women are often said to have breasts so large that they cause the women to bend a little bit from their weight.[164] In Middle English literature, beautiful women should have small breasts that are round like an apple or a pear.[54]

Biological anthropologist Helen E. Fisher of the Center for Human Evolution Studies in the Department of Anthropology of Rutgers University said that, "perhaps, the fleshy, rounded buttocks... attracted males during rear-entry intercourse."[166] Bobbi S. Low et al. of the School of Natural Resources and Environment at the University of Michigan, said the female "buttocks evolved in the context of females competing for the attention and parental commitment of powerful resource-controlling males" as an "honest display of fat reserves" that could not be confused with another type of tissue,[167] although T. M. Caro, professor in the Center for Population Biology and the Department of Wildlife, Fish, and Conservation Biology, at University of California, Davis, rejected that as being a necessary conclusion, stating that female fatty deposits on the hips improve "individual fitness of the female", regardless of sexual selection.[167]

In a 1995 study, black men were more likely than white men to use the words "big" or "large" to describe their conception of an attractive woman's posterior.[168]

Body Mass Index (BMI) is an important determinant to the perception of beauty.[169] Even though the Western ideal is for a thin woman, some cultures prefer plumper women,[129][170] which has been argued to support that attraction for a particular BMI merely is a cultural artifact.[170] The attraction for a proportionate body also influences an appeal for erect posture.[171] One cross-cultural survey comparing body-mass preferences among 300 of the most thoroughly studied cultures in the world showed that 81% of cultures preferred a female body size that in English would be described as "plump".[172]

Availability of food influences which female body size is attractive which may have evolutionary reasons. Societies with food scarcities prefer larger female body size than societies that have plenty of food. In Western society males who are hungry prefer a larger female body size than they do when not hungry.[173]

In the United States, women overestimate men's preferences for thinness in a mate. In one study, American women were asked to choose what their ideal build was and what they thought the build most attractive to men was. Women chose slimmer than average figures for both choices. When American men were independently asked to choose the female build most attractive to them, the men chose figures of average build. This indicates that women may be misled as to how thin men prefer women to be.[170] Some speculate that thinness as a beauty standard is one way in which women judge each other[135] and that thinness is viewed as prestigious for within-gender evaluations of other women.[citation needed] A reporter surmised that thinness is prized among women as a "sign of independence, strength and achievement."[135] Some implicated the fashion industry for the promulgation of the notion of thinness as attractive.[174]

East Asians have historically preferred women whose bodies had small features. For example, during the Spring and Autumn period of Chinese history, women in Chinese harems wanted to have a thin body in order to be attractive for the Chinese emperor. Later, during the Tang Dynasty, a less thin body type was seen as most attractive for Chinese women.[175] In Arabian society in the Middle Ages, a component of the female beauty ideal was for women to be slender like a "cane" or a "twig".[141] In the Chinese text "Jeweled Chamber Secrets" (Chinese: ) from the Six Dynasties period, the ideal woman was described as not being "large-boned".[142]

In the Victorian era, women who adhered to Victorian ideals were expected to limit their food consumption to attain the ideal slim figure.[176] In Middle English literature, "slender" women are considered beautiful.[54]

A WHR of 0.7 for women has been shown to correlate strongly with general health and fertility. Women within the 0.7 range have optimal levels of estrogen and are less susceptible to major diseases such as diabetes, heart disease, and ovarian cancers.[178] Women with high WHR (0.80 or higher) have significantly lower pregnancy rates than women with lower WHRs (0.700.79), independent of their BMIs.[179][180] Female waist-to-hip ratio (WHR) has been proposed by evolutionary psychologists to be an important component of human male mate choice, because this trait is thought to provide a reliable cue to a woman's reproductive value.[181]

Both men and women judge women with smaller waist-to-hip ratios more attractive.[182] Ethnic groups vary with regard to their ideal waist-to-hip ratio for women,[183] ranging from 0.6 in China,[184] to 0.8 or 0.9 in parts of South America and Africa,[185][186][187] and divergent preferences based on ethnicity, rather than nationality, have also been noted.[188][189] A study found the Machiguenga people, an isolated indigenous South American ethnic group, prefer women with high WHR (0.9).[190] The preference for heavier women, has been interpreted to belong to societies where there is no risk of obesity.[191]

In Chinese, the phrase "willow waist" (Chinese: ) is used to denote a beautiful woman by describing her waist as being slender like a willow branch.[142]

In the Victorian era, a small waist was considered the main trait of a beautiful woman.[176]

Most men tend to be taller than their female partner.[192] It has been found that, in Western societies, most men prefer shorter women. Having said this, height is a more important factor for a woman when choosing a man than it is for a man choosing a woman.[193] Men tend to view taller women as less attractive,[194] and people view heterosexual couples where the woman is taller to be less ideal.[194] Women who are 0.7 to 1.7 standard deviations below the mean female height have been reported to be the most reproductively successful,[195] since fewer tall women get married compared to shorter women.[194] However, in other ethnic groups, such as the Hadza, study has found that height is irrelevant in choosing a mate.[94]

In Middle English literature, 'tallness' is a characteristic of ideally beautiful women.[54]

A study using Polish participants by Sorokowski found 5% longer legs than average person leg to body ratio for both on man and woman was considered most attractive.[196] The study concluded this preference might stem from the influence of leggy runway models.[197] Another study using British and American participants, found "mid-ranging" leg-to-body ratios to be most ideal.[198]

A study by Swami et al. of British male and female undergraduates showed a preference for men with legs as long as the rest of their body and women with 40% longer legs than the rest of their body.[90] The researcher concluded that this preference might be influenced by American culture where long legged women are portrayed as more attractive.[90]

Marco Bertamini criticized the Swami et al. study for using a picture of the same person with digitally altered leg lengths which he felt would make the modified image appear unrealistic.[199] Bertamini also criticized the Swami study for only changing the leg length while keeping the arm length constant.[199] After accounting for these concerns in his own study, Bertamini's study which used stick figures also found a preference for women with proportionately longer legs than men.[199] When Bertamini investigated the issue of possible sexual dimorphism of leg length, he found two sources that indicated that men usually have slightly proportionately longer legs than women or that differences in leg length proportion may not exist between men and women.[199] Following this review of existing literature on the subject, he conducted his own calculations using data from 1774 men and 2208 women. Using this data, he similarly found that men usually have slightly proportionately longer legs than women or that differences in leg length proportion may not exist between men and women. These findings made him rule out the possibility that a preference for women with proportionately longer legs than men is due proportionately longer legs being a secondary sex characteristic of women.[199]

According to some studies, most men prefer women with small feet,[200][201] such as in ancient China where foot binding was practiced.[202]

In Jewish Rabbinic literature, the Rabbis considered small feet to be the ideal type of feet for women.[143]

Men have been found to prefer long-haired women.[111][203][204] An evolutionary psychology explanation for this is that malnutrition and deficiencies in minerals and vitamins causes loss of hair or hair changes. Hair therefore indicates health and nutrition during the last 23 years. Lustrous hair is also often a cross-cultural preference.[205] One study reported non-Asian men to prefer blondes and Asian men to prefer black-haired women.[204]

A component of the female beauty ideal in Persian literature is for women to have black hair,[138] which was also preferred in Arabian society in the Middle Ages.[141] In Middle English literature, curly hair is a necessary component of a beautiful woman.[54]

The way an individual moves can indicate health and even age and influence attractiveness.[205] A study reflecting the views of 700 individuals and that involved animated representations of people walking, found that the physical attractiveness of women increased by about 50 percent when they walked with a hip sway. Similarly, the perceived attractiveness of males doubled when they moved with a swagger in their shoulders.[206]

A preference for lighter-skinned women has remained prevalent over time, even in cultures without European contact, though exceptions have been found.[208] Anthropologist Peter Frost stated that since higher-ranking men were allowed to marry the perceived more attractive women, who tended to have fair skin, the upper classes of a society generally tended to develop a lighter complexion than the lower classes by sexual selection (see also Fisherian runaway).[104][208][209] In contrast, one study on men of the Bikosso tribe in Cameroon found no preference for attractiveness of females based on lighter skin color, bringing into question the universality of earlier studies that had exclusively focused on skin color preferences among non-African populations.[209]

Today, skin bleaching is not uncommon in parts of the world such as Africa,[210] and a preference for lighter-skinned women generally holds true for African Americans,[211] Latin Americans,[212] and Asians.[213] One exception to this has been in contemporary Western culture, where tanned skin used to be associated with the sun-exposed manual labor of the lower-class, but has generally been considered more attractive and healthier since the mid-20th century.[214][215][216][217][218]

More recent work has extended skin color research beyond preferences for lightness, arguing that redder (higher a* in the CIELab colour space) and yellower (higher b*) skin has healthier appearance.[107] These preferences have been attributed to higher levels of red oxygenated blood in the skin, which is associated with aerobic fitness and lack of cardiac and respiratory illnesses,[108] and to higher levels of yellow-red antioxidant carotenoids in the skin, indicative of more fruit and vegetables in the diet and, possibly more efficient immune and reproductive systems.[109]

Research has additionally shown that skin radiance or glowing skin indicates health, thus skin radiance influences perception of beauty and physical attractiveness.[219][220]

In Persian literature, beautiful women are said to have noses like hazelnuts.[138]

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Physical attractiveness - Wikipedia

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PRL Available structures PDB Ortholog search: PDBe RCSB List of PDB id codes

1RW5, 2Q98, 3D48, 3EW3, 3MZG, 3N06, 3N0P, 3NCB, 3NCC, 3NCE, 3NCF, 3NPZ

Prolactin (PRL), also known as luteotropic hormone or luteotropin, is a protein that in humans is best known for its role in enabling mammals, usually females, to produce milk. It is influential in over 300 separate processes in various vertebrates.[4] Prolactin is secreted from the pituitary gland in response to eating, mating, estrogen treatment, ovulation and nursing. Prolactin is secreted in pulses in between these events. Prolactin plays an essential role in metabolism, regulation of the immune system and pancreatic development.

Discovered in non-human animals around 1930 by Oscar Riddle[5] and confirmed in humans in 1970 by Henry Friesen[6] prolactin is a peptide hormone, encoded by the PRL gene.[7]

It is associated with human milk production. In fish it is thought to be related to control of water and salt balance. Prolactin also acts in a cytokine-like manner and as an important regulator of the immune system. It has important cell cycle-related functions as a growth-, differentiating- and anti-apoptotic factor. As a growth factor, binding to cytokine-like receptors, it influences hematopoiesis, angiogenesis and is involved in the regulation of blood clotting through several pathways. The hormone acts in endocrine, autocrine and paracrine manner through the prolactin receptor and a large number of cytokine receptors.[4]

Pituitary prolactin secretion is regulated by endocrine neurons in the hypothalamus. The most important ones are the neurosecretory tuberoinfundibulum (TIDA) neurons of the arcuate nucleus that secrete dopamine (aka Prolactin Inhibitory Hormone) to act on the D2 receptors of lactotrophs, causing inhibition of prolactin secretion. Thyrotropin-releasing factor (thyrotropin-releasing hormone) has a stimulatory effect on prolactin release, however prolactin is the only adenohypophyseal hormone whose principal control is inhibitory.

Several variants and forms are known per species. Many fish have variants prolactin A and prolactin B. Most vertebrates including humans also have the closely related somatolactin. In humans, three smaller (4, 16 and 22kDa) and several larger (so called big and big-big) variants exist.[not verified in body]

Prolactin has a wide variety of effects. It stimulates the mammary glands to produce milk (lactation): increased serum concentrations of prolactin during pregnancy cause enlargement of the mammary glands and prepare for milk production, which normally starts when the levels of progesterone fall by the end of pregnancy and a suckling stimulus is present. Sometimes, newborns (males as well as females) secrete a milky substance from their nipples known as witch's milk. This is in part caused by maternal prolactin and other hormones. Prolactin plays an important role in maternal behavior.[8]

Prolactin provides the body with sexual gratification after sexual acts: The hormone counteracts the effect of dopamine, which is linked to sexual arousal. This is thought to cause the sexual refractory period. The amount of prolactin can be an indicator for the amount of sexual satisfaction and relaxation. Unusually high amounts are suspected to be responsible for impotence and loss of libido (see hyperprolactinemia symptoms).

Elevated levels of prolactin decrease the levels of sex hormones estrogen in women and testosterone in men.[9] The effects of mildly elevated levels of prolactin are much more variable, in women, substantially increasing or decreasing estrogen levels.

Prolactin is sometimes classified as a gonadotropin[10] although in humans it has only a weak luteotropic effect while the effect of suppressing classical gonadotropic hormones is more important.[11] Prolactin within the normal reference ranges can act as a weak gonadotropin, but at the same time suppresses GnRH secretion. The exact mechanism by which it inhibits GnRH is poorly understood. Although expression of prolactin receptors (PRL-R) have been demonstrated in rat hypothalamus, the same has not been observed in GnRH neurons.[12] Physiologic levels of prolactin in males enhance luteinizing hormone-receptors in Leydig cells, resulting in testosterone secretion, which leads to spermatogenesis.[13]

Prolactin also stimulates proliferation of oligodendrocyte precursor cells. These cells differentiate into oligodendrocytes, the cells responsible for the formation of myelin coatings on axons in the central nervous system.[14]

Other actions include contributing to pulmonary surfactant synthesis of the fetal lungs at the end of the pregnancy and immune tolerance of the fetus by the maternal organism during pregnancy. Prolactin delays hair regrowth in mice.[15] Prolactin promotes neurogenesis in maternal and fetal brains.[16][17]

In humans, prolactin is produced at least in the anterior pituitary, decidua, myometrium, breast, lymphocytes, leukocytes and prostate.[18][19]

Pituitary PRL is controlled by the Pit-1 transcription factor that binds to the prolactin gene at several sites. Ultimately dopamine, extrapituitary PRL is controlled by a superdistal promoter and apparently unaffected by dopamine.[19] The thyrotropin-releasing hormone and the vasoactive intestinal peptide stimulate the secretion of prolactin in experimental settings, however their physiological influence is unclear. The main stimulus for prolactin secretion is suckling, the effect of which is neuronally mediated.[20] A key regulator of prolactin production is estrogens that enhance growth of prolactin-producing cells and stimulate prolactin production directly, as well as suppressing dopamine.

In decidual cells and in lymphocytes the distal promoter and thus prolactin expression is stimulated by cAMP. Responsivness to cAMP is mediated by an imperfect cAMPresponsive element and two CAAT/enhancer binding proteins (C/EBP).[19]Progesterone upregulates prolactin synthesis in the endometrium and decreases it in myometrium and breast glandular tissue.[21] Breast and other tissues may express the Pit-1 promoter in addition to the distal promoter.

Extrapituitary production of prolactin is thought to be special to humans and primates and may serve mostly tissue specific paracrine and autocrine purposes. It has been hypothesized that in vertebrates such as mice a similar tissue specific effect is achieved by a large family of prolactin-like proteins controlled by at least 26 paralogous PRL genes not present in primates.[19]

Vasoactive intestinal peptide and peptide histidine isoleucine help to regulate prolactin secretion in humans, but the functions of these hormones in birds can be quite different.[22]

Prolactin follows diurnal and ovulatory cycles. Prolactin levels peak during REM sleep and in the early morning. Many mammals experience a seasonal cycle.

During pregnancy, high circulating concentrations of estrogen and progesterone increase prolactin levels by 10- to 20-fold. Estrogen and progesterone inhibit the stimulatory effects of prolactin on milk production. The abrupt drop of estrogen and progesterone levels following delivery allow prolactinwhich temporarily remains highto induce lactation.[verification needed]

Sucking on the nipple offsets the fall in prolactin as the internal stimulus for them is removed. The sucking activates mechanoreceptors in and around the nipple. These signals are carried by nerve fibers through the spinal cord to the hypothalamus, where changes in the electrical activity of neurons that regulate the pituitary gland increase prolactin secretion. The suckling stimulus also triggers the release of oxytocin from the posterior pituitary gland, which triggers milk let-down: Prolactin controls milk production (lactogenesis) but not the milk-ejection reflex; the rise in prolactin fills the breast with milk in preparation for the next feed.

In usual circumstances, in the absence of galactorrhea, lactation ceases within one or two weeks following the end of breastfeeding.

Compared to un-mated males, fathers and expectant fathers have increased prolactin concentrations.[23]

Levels can rise after exercise, high-protein meals,[24]sexual intercourse, breast examination,[24] minor surgical procedures,[25] following epileptic seizures[26] or due to physical or emotional stress.[24][27] In a study on female volunteers under hypnosis, prolactin surges resulted from the evocation, with rage, of humiliating experiences, but not from the fantasy of nursing.[27]

Prolactin levels have also been found to rise with use of the drug MDMA (Ecstasy), leading to speculation that prolactin may have a role in the post-orgasmic state as well as decreased sexual desire.[28]

Hypersecretion is more common than hyposecretion. Hyperprolactinemia is the most frequent abnormality of the anterior pituitary tumors, termed prolactinomas. Prolactinomas may disrupt the hypothalamic-pituitary-gonadal axis as prolactin tends to suppress the secretion of GnRH from the hypothalamus and in turn decreases the secretion of follicle-stimulating hormone (FSH) and luteinizing hormone (LH) from the anterior pituitary, therefore disrupting the ovulatory cycle.[29] Such hormonal changes may manifest as amenorrhea and infertility in females as well as impotence in males. Inappropriate lactation (galactorrhoea) is another important clinical sign of prolactinomas.

The structure of prolactin is similar to that of growth hormone and placental lactogen. The molecule is folded due to the activity of three disulfide bonds. Significant heterogeneity of the molecule has been described, thus bioassays and immunoassays can give different results due to differing glycosylation, phosphorylationsandulfation, as well as degradation. The non-glycosylated form of prolactin is the dominant form at is secreted by the pituitary gland.

The three different sizes of prolactin are:

The levels of larger ones are somewhat higher during the early postpartum period.[33]

Prolactin receptors are present in the mammillary glands, ovaries, pituitary glands, heart, lung, thymus, spleen, liver, pancreas, kidney, adrenal gland, uterus, skeletal muscle, skin and areas of the central nervous system.[34] When prolactin binds to the receptor, it causes it to dimerize with another prolactin receptor. This results in the activation of Janus kinase 2, a tyrosine kinase that initiates the JAK-STAT pathway. Activation also results in the activation of mitogen-activated protein kinases and Src kinase.[34]

Human prolactin receptors are insensitive to mouse prolactin.[35]

Prolactin levels may be checked as part of a sex hormone workup, as elevated prolactin secretion can suppress the secretion of FSH and GnRH, leading to hypogonadism and sometimes causing erectile dysfunction.

Prolactin levels may be of some use in distinguishing epileptic seizures from psychogenic non-epileptic seizures. The serum prolactin level usually rises following an epileptic seizure.[36]

The serum concentration of prolactin can be given in mass concentration (g/L or ng/mL), molar concentration (nmol/L or pmol/L) or in international units (typically mIU/L). The current IU is calibrated against the third International Standard for Prolactin, IS 84/500.[37][38] Reference ampoules of IS 84/500 contain 2.5g of lyophilized human prolactin[39] and have been assigned an activity of .053 International Units.[37][38] Measurements that are calibrated against the current international standard can be converted into mass units using this ratio of grams to IUs;[40] prolactin concentrations expressed in mIU/L can be converted to g/L by dividing by 21.2. Previous standards use other ratios.[41][42][43][44]

The first International Reference Preparation (or IRP) of human Prolactin for Immunoassay was established in 1978 (75/504 1st IRP for human Prolactin) at a time when purified human prolactin was in short supply.[40][41] Previous standards relied on prolactin from animal sources.[44] Purified human prolactin was scarce, heterogeneous, unstable and difficult to characterize. A preparation labelled 81/541 was distributed by the WHO Expert Committee on Biological Standardization without official status and given the assigned value of 50 mIU/ampoule based on an earlier collaborative study.[40][42] It was determined that this preparation behaved anomalously in certain immunoassays and was not suitable as an IS.[40]

Three different human pituitary extracts containing prolactin were subsequently obtained as candidates for an IS. These were distributed into ampoules coded 83/562, 83/573 and 84/500.[37][38][40][43] Collaborative studies involving 20 different laboratories found little difference between these three preparations. 83/562 appeared to be the most stable. This preparation was largely free of dimers and polymers of prolactin. On the basis of these investigations 83/562 was established as the Second IS for human Prolactin.[43] Once stocks of these ampoules were depleted, 84/500 was established as the Third IS for human Prolactin.[37][40]

General guidelines for diagnosing prolactin excess (hyperprolactinemia) define the upper threshold of normal prolactin at 25g/L for women and 20g/L for men.[34] Similarly, guidelines for diagnosing prolactin deficiency (hypoprolactinemia) are defined as prolactin levels below 3g/L in women[45][46] and 5g/L in men.[47][48][49] However, different assays and methods for measuring prolactin are employed by different laboratories and as such the serum reference range for prolactin is often determined by the laboratory performing the measurement.[34][50] Furthermore, prolactin levels also vary factors including age,[51] sex,[51]menstrual cycle stage[51] and pregnancy.[51] The circumstances surrounding a given prolactin measurement (assay, patient condition, etc.) must therefore be considered before the measurement can be accurately interpreted.[34]

The following chart illustrates the variations seen in normal prolactin measurements across different populations. Prolactin values were obtained from specific control groups of varying sizes using the IMMULITE assay.[51]

The following table illustrates variability in reference ranges of serum prolactin between some commonly used assay methods (as of 2008), using a control group of healthy health care professionals (53 males, age 2064 years, median 28 years; 97 females, age 1959 years, median 29 years) in Essex, England:[50]

An example usage of table above is, if using the Centaur assay to estimate prolactin values in g/L for females, the mean is 7.92g/L and the reference range is 3.3516.4g/L.

Hyperprolactinaemia, or excess serum prolactin, is associated with hypoestrogenism, anovulatory infertility, oligomenorrhoea, amenorrhoea, unexpected lactation and loss of libido in women and erectile dysfunction and loss of libido in men.[53]

Hypoprolactinemia, or serum prolactin deficiency, is associated with ovarian dysfunction in women,[45][46] and arteriogenic erectile dysfunction, premature ejaculation,[47]oligozoospermia, asthenospermia, hypofunction of seminal vesicles and hypoandrogenism[48] in men. In one study, normal sperm characteristics were restored when prolactin levels were raised to normal values in hypoprolactinemic men.[49]

Hypoprolactinemia can result from hypopituitarism, excessive dopaminergic action in the tuberoinfundibular pathway and ingestion of D2 receptor agonists such as bromocriptine.

While there is evidence that women who smoke tend to breast feed for shorter periods, there is a wide variation of breast-feeding rates in women who do smoke. This suggest that psychosocial factors rather than physiological mechanisms (e.g., nicotine suppressing prolactin levels) are responsible for the lower rates of breast feeding in women who do smoke.[54][55]

Prolactin is available commercially for use in animals, but not in humans.[56] It is used to stimulate lactation in animals.[56] The biological half-life of prolactin in humans is around 1520 minutes.[57] The D2 receptor is involved in the regulation of prolactin secretion, and agonists of the receptor such as bromocriptine and cabergoline decrease prolactin levels while antagonists of the receptor such as domperidone, metoclopramide, haloperidol, risperidone, and sulpiride increase prolactin levels.[58] D2 receptor antagonists like domperidone, metoclopramide, and sulpiride are used as galactogogues to increase prolatin secretion and induce lactation in humans.[59]

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A bone is a rigid organ that constitutes part of the vertebral skeleton. Bones support and protect the various organs of the body, produce red and white blood cells, store minerals and also enable mobility as well as support for the body. Bone tissue is a type of dense connective tissue. Bones come in a variety of shapes and sizes and have a complex internal and external structure. They are lightweight yet strong and hard, and serve multiple functions. Mineralized osseous tissue, or bone tissue, is of two types, cortical and cancellous, and gives a bone rigidity and a coral-like three-dimensional internal structure. Other types of tissue found in bones include marrow, endosteum, periosteum, nerves, blood vessels and cartilage.

Bone is an active tissue composed of different types of bone cells. Osteoblasts and osteocytes are involved in the creation and mineralisation of bone; osteoclasts are involved in the reabsorption of bone tissue. The mineralised matrix of bone tissue has an organic component of mainly collagen called ossein and an inorganic component of bone mineral made up of various salts.

In the human body at birth, there are over 270 bones,[1] but many of these fuse together during development, leaving a total of 206 separate bones in the adult,[2] not counting numerous small sesamoid bones. The largest bone in the body is the thigh-bone (femur) and the smallest is the stapes in the middle ear.

Bone is not a uniformly solid material, but is mostly a matrix. The primary tissue of bone, bone tissue (osseous tissue), is relatively hard and lightweight. Its matrix is mostly made up of a composite material incorporating the inorganic mineral calcium phosphate in the chemical arrangement termed calcium hydroxylapatite (this is the bone mineral that gives bones their rigidity) and collagen, an elastic protein which improves fracture resistance.[3] Bone is formed by the hardening of this matrix around entrapped cells. When these cells become entrapped from osteoblasts they become osteocytes.[citation needed]

The hard outer layer of bones is composed of cortical bone also called compact bone. Cortical referring to the outer (cortex) layer. The hard outer layer gives bone its smooth, white, and solid appearance, and accounts for 80% of the total bone mass of an adult human skeleton.[citation needed] However, that proportion may be much lower, especially in marine mammals and marine turtles, or in various Mesozoic marine reptiles, such as ichthyosaurs,[4] among others.[5]

Cortical bone consists of multiple microscopic columns, each called an osteon. Each column is multiple layers of osteoblasts and osteocytes around a central canal called the Haversian canal. Volkmann's canals at right angles connect the osteons together. The columns are metabolically active, and as bone is reabsorbed and created the nature and location of the cells within the osteon will change. Cortical bone is covered by a periosteum on its outer surface, and an endosteum on its inner surface. The endosteum is the boundary between the cortical bone and the cancellous bone.

Filling the interior of the bone is the cancellous bone also known as trabecular or spongy bone tissue. It is an open cell porous network. Thin formations of osteoblasts covered in endosteum create an irregular network of spaces. Within these spaces are bone marrow and hematopoietic stem cells that give rise to platelets, red blood cells and white blood cells. Trabecular marrow is composed of a network of rod- and plate-like elements that make the overall organ lighter and allow room for blood vessels and marrow. Trabecular bone accounts for the remaining 20% of total bone mass but has nearly ten times the surface area of compact bone.[8]

Bone marrow, also known as myeloid tissue, can be found in almost any bone that holds cancellous tissue. In newborns, all such bones are filled exclusively with red marrow, but as the child ages it is mostly replaced by yellow, or fatty marrow. In adults, red marrow is mostly found in the bone marrow of the femur, the ribs, the vertebrae and pelvic bones.[citation needed]

Bone is a metabolically active tissue composed of several types of cells. These cells include osteoblasts, which are involved in the creation and mineralization of bone tissue, osteocytes, and osteoclasts, which are involved in the reabsorption of bone tissue. Osteoblasts and osteocytes are derived from osteoprogenitor cells, but osteoclasts are derived from the same cells that differentiate to form macrophages and monocytes. Within the marrow of the bone there are also hematopoietic stem cells. These cells give rise to other cells, including white blood cells, red blood cells, and platelets.

Bones consist of living cells embedded in a mineralized organic matrix. This matrix consists of organic components, mainly collagen "organic" referring to materials produced as a result of the human body and inorganic components, primarily hydroxyapatite and other salts of calcium and phosphate. Above 30% of the acellular part of bone consists of the organic components, and 70% of salts. The strands of collagen give bone its tensile strength, and the interspersed crystals of hydroxyapatite give bone its compressional strength. These effects are synergistic.

The inorganic composition of bone (bone mineral) is primarily formed from salts of calcium and phosphate, the major salt being hydroxyapatite (Ca10(PO4)6(OH)2). The exact composition of the matrix may change over time and with nutrition, with the ratio of calcium to phosphate varying between 1.3 and 2.0 (per weight), and trace minerals such as magnesium, sodium, potassium and carbonate also being found.

The organic part of matrix is mainly composed of Type I collagen. Collagen composes 9095% of the organic matrix, with remainder of the matrix being a homogenous liquid called ground substance consisting of proteoglycans such as hyaluronic acid and chondroitin sulfate. Collagen consists of strands of repeating units, which give bone tensile strength, and are arranged in an overlapping fashion that prevents shear stress. The function of ground substance is not fully known. Two types of bone can be identified microscopically according to the arrangement of collagen:

Woven bone is produced when osteoblasts produce osteoid rapidly, which occurs initially in all fetal bones, but is later replaced by more resilient lamellar bone. In adults woven bone is created after fractures or in Paget's disease. Woven bone is weaker, with a smaller number of randomly oriented collagen fibers, but forms quickly; it is for this appearance of the fibrous matrix that the bone is termed woven. It is soon replaced by lamellar bone, which is highly organized in concentric sheets with a much lower proportion of osteocytes to surrounding tissue. Lamellar bone, which makes its first appearance in humans in the fetus during the third trimester,[16] is stronger and filled with many collagen fibers parallel to other fibers in the same layer (these parallel columns are called osteons). In cross-section, the fibers run in opposite directions in alternating layers, much like in plywood, assisting in the bone's ability to resist torsion forces. After a fracture, woven bone forms initially and is gradually replaced by lamellar bone during a process known as "bony substitution." Compared to woven bone, lamellar bone formation takes place more slowly. The orderly deposition of collagen fibers restricts the formation of osteoid to about 1 to 2m per day. Lamellar bone also requires a relatively flat surface to lay the collagen fibers in parallel or concentric layers.[citation needed]

The extracellular matrix of bone is laid down by osteoblasts, which secrete both collagen and ground substance. These synthesise collagen within the cell, and then secrete collagen fibrils. The collagen fibres rapidly polymerise to form collagen strands. At this stage they are not yet mineralised, and are called "osteoid". Around the strands calcium and phosphate precipitate on the surface of these strands, within a days to weeks becoming crystals of hydroxyapatite.

In order to mineralise the bone, the osteoblasts secrete vesicles containing alkaline phosphatase. This cleaves the phosphate groups and acts as the foci for calcium and phosphate deposition. The vesicles then rupture and act as a centre for crystals to grow on. More particularly, bone mineral is formed from globular and plate structures.[17][18]

There are five types of bones in the human body: long, short, flat, irregular, and sesamoid.[19]

In the study of anatomy, anatomists use a number of anatomical terms to describe the appearance, shape and function of bones. Other anatomical terms are also used to describe the location of bones. Like other anatomical terms, many of these derive from Latin and Greek. Some anatomists still use Latin to refer to bones. The term "osseous", and the prefix "osteo-", referring to things related to bone, are still used commonly today.

Some examples of terms used to describe bones include the term "foramen" to describe a hole through which something passes, and a "canal" or "meatus" to describe a tunnel-like structure. A protrusion from a bone can be called a number of terms, including a "condyle", "crest", "spine", "eminence", "tubercle" or "tuberosity", depending on the protrusion's shape and location. In general, long bones are said to have a "head", "neck", and "body".

When two bones join together, they are said to "articulate". If the two bones have a fibrous connection and are relatively immobile, then the joint is called a "suture".

The formation of bone is called ossification. During the fetal stage of development this occurs by two processes, Intramembranous ossification and endochondral ossification.[citation needed] Intramembranous ossification involves the creation of bone from connective tissue, whereas in the process of endochondral ossification bone is created from cartilage.

Intramembranous ossification mainly occurs during formation of the flat bones of the skull but also the mandible, maxilla, and clavicles; the bone is formed from connective tissue such as mesenchyme tissue rather than from cartilage. The steps in intramembranous ossification are:[citation needed]

Endochondral ossification, on the other hand, occurs in long bones and most of the rest of the bones in the body; it involves an initial hyaline cartilage that continues to grow. The steps in endochondral ossification are:[citation needed]

Endochondral ossification begins with points in the cartilage called "primary ossification centers." They mostly appear during fetal development, though a few short bones begin their primary ossification after birth. They are responsible for the formation of the diaphyses of long bones, short bones and certain parts of irregular bones. Secondary ossification occurs after birth, and forms the epiphyses of long bones and the extremities of irregular and flat bones. The diaphysis and both epiphyses of a long bone are separated by a growing zone of cartilage (the epiphyseal plate). When the child reaches skeletal maturity (18 to 25 years of age), all of the cartilage is replaced by bone, fusing the diaphysis and both epiphyses together (epiphyseal closure).[citation needed] In the upper limbs, only the diaphyses of the long bones and scapula are ossified. The epiphyses, carpal bones, coracoid process, medial border of the scapula, and acromion are still cartilaginous.[21]

The following steps are followed in the conversion of cartilage to bone:

Bones have a variety of functions:

Bones serve a variety of mechanical functions. Together the bones in the body form the skeleton. They provide a frame to keep the body supported, and an attachment point for skeletal muscles, tendons, ligaments and joints, which function together to generate and transfer forces so that individual body parts or the whole body can be manipulated in three-dimensional space (the interaction between bone and muscle is studied in biomechanics).

Bones protect internal organs, such as the skull protecting the brain or the ribs protecting the heart and lungs. Because of the way that bone is formed, bone has a high compressive strength of about 170 MPa (1800 kgf/cm),[3] poor tensile strength of 104121 MPa, and a very low shear stress strength (51.6 MPa).[23][24] This means that bone resists pushing(compressional) stress well, resist pulling(tensional) stress less well, but only poorly resists shear stress (such as due to torsional loads). While bone is essentially brittle, bone does have a significant degree of elasticity, contributed chiefly by collagen. The macroscopic yield strength of cancellous bone has been investigated using high resolution computer models.[25]

Mechanically, bones also have a special role in hearing. The ossicles are three small bones in the middle ear which are involved in sound transduction.

Cancellous bones contain bone marrow. Bone marrow produces blood cells in a process called hematopoiesis.[26] Blood cells that are created in bone marrow include red blood cells, platelets and white blood cells. Progenitor cells such as the hematopoietic stem cell divide in a process called mitosis to produce precursor cells. These include precursors which eventually give rise to white blood cells, and erythroblasts which give rise to red blood cells. Unlike red and white blood cells, created by mitosis, platelets are shed from very large cells called megakaryocytes. This process of progressive differentiation occurs within the bone marrow. After the cells are matured, they enter the circulation. Every day, over 2.5 billion red blood cells and platelets, and 50100 billion granulocytes are produced in this way.

As well as creating cells, bone marrow is also one of the major sites where defective or aged red blood cells are destroyed.

Bone is constantly being created and replaced in a process known as remodeling. This ongoing turnover of bone is a process of resorption followed by replacement of bone with little change in shape. This is accomplished through osteoblasts and osteoclasts. Cells are stimulated by a variety of signals, and together referred to as a remodeling unit. Approximately 10% of the skeletal mass of an adult is remodelled each year.[32] The purpose of remodeling is to regulate calcium homeostasis, repair microdamaged bones from everyday stress, and also to shape and sculpt the skeleton during growth.[citation needed]. Repeated stress, such as weight-bearing exercise or bone healing, results in the bone thickening at the points of maximum stress (Wolff's law). It has been hypothesized that this is a result of bone's piezoelectric properties, which cause bone to generate small electrical potentials under stress.[33]

The action of osteoblasts and osteoclasts are controlled by a number of chemical enzymes that either promote or inhibit the activity of the bone remodeling cells, controlling the rate at which bone is made, destroyed, or changed in shape. The cells also use paracrine signalling to control the activity of each other.[citation needed] For example, the rate at which osteoclasts resorb bone is inhibited by calcitonin and osteoprotegerin. Calcitonin is produced by parafollicular cells in the thyroid gland, and can bind to receptors on osteoclasts to directly inhibit osteoclast activity. Osteoprotegerin is secreted by osteoblasts and is able to bind RANK-L, inhibiting osteoclast stimulation.[34]

Osteoblasts can also be stimulated to increase bone mass through increased secretion of osteoid and by inhibiting the ability of osteoclasts to break down osseous tissue.[citation needed] Increased secretion of osteoid is stimulated by the secretion of growth hormone by the pituitary, thyroid hormone and the sex hormones (estrogens and androgens). These hormones also promote increased secretion of osteoprotegerin.[34] Osteoblasts can also be induced to secrete a number of cytokines that promote reabsorbtion of bone by stimulating osteoclast activity and differentiation from progenitor cells. Vitamin D, parathyroid hormone and stimulation from osteocytes induce osteoblasts to increase secretion of RANK-ligand and interleukin 6, which cytokines then stimulate increased reabsorption of bone by osteoclasts. These same compounds also increase secretion of macrophage colony-stimulating factor by osteoblasts, which promotes the differentiation of progenitor cells into osteoclasts, and decrease secretion of osteoprotegerin.[citation needed]

Bone volume is determined by the rates of bone formation and bone resorption. Recent research has suggested that certain growth factors may work to locally alter bone formation by increasing osteoblast activity. Numerous bone-derived growth factors have been isolated and classified via bone cultures. These factors include insulin-like growth factors I and II, transforming growth factor-beta, fibroblast growth factor, platelet-derived growth factor, and bone morphogenetic proteins.[35] Evidence suggests that bone cells produce growth factors for extracellular storage in the bone matrix. The release of these growth factors from the bone matrix could cause the proliferation of osteoblast precursors. Essentially, bone growth factors may act as potential determinants of local bone formation.[35] Research has suggested that trabecular bone volume in postemenopausal osteoporosis may be determined by the relationship between the total bone forming surface and the percent of surface resorption.[36]

A number of diseases can affect bone, including arthritis, fractures, infections, osteoporosis and tumours. Conditions relating to bone can be managed by a variety of doctors, including rheumatologists for joints, and orthopedic surgeons, who may conduct surgery to fix broken bones. Other doctors, such as rehabilitation specialists may be involved in recovery, radiologists in interpreting the findings on imaging, and pathologists in investigating the cause of the disease, and family doctors may play a role in preventing complications of bone disease such as osteoporosis.

When a doctor sees a patient, a history and exam will be taken. Bones are then often imaged, called radiography. This might include ultrasound X-ray, CT scan, MRI scan and other imaging such as a Bone scan, which may be used to investigate cancer. Other tests such as a blood test for autoimmune markers may be taken, or a synovial fluid aspirate may be taken.

In normal bone, fractures occur when there is significant force applied, or repetitive trauma over a long time. Fractures can also occur when a bone is weakened, such as with osteoporosis, or when there is a structural problem, such as when the bone remodels excessively (such as Paget's disease) or is the site of the growth of cancer. Common fractures include wrist fractures and hip fractures, associated with osteoporosis, vertebral fractures associated with high-energy trauma and cancer, and fractures of long-bones. Not all fractures are painful. When serious, depending on the fractures type and location, complications may include flail chest, compartment syndromes or fat embolism. Compound fractures involve the bone's penetration through the skin.

Fractures and their underlying causes can be investigated by X-rays, CT scans and MRIs. Fractures are described by their location and shape, and several classification systems exist, depending on the location of the fracture. A common long bone fracture in children is a SalterHarris fracture.[39] When fractures are managed, pain relief is often given, and the fractured area is often immobilised. This is to promote bone healing. In addition, surgical measures such as internal fixation may be used. Because of the immobilisation, people with fractures are often advised to undergo rehabilitation.

There are several types of tumour that can affect bone; examples of benign bone tumours include osteoma, osteoid osteoma, osteochondroma, osteoblastoma, enchondroma, giant cell tumor of bone, aneurysmal bone cyst, and fibrous dysplasia of bone.

Cancer can arise in bone tissue, and bones are also a common site for other cancers to spread (metastasise) to. Cancers that arise in bone are called "primary" cancers, although such cancers are rare. Metastases within bone are "secondary" cancers, with the most common being breast cancer, lung cancer, prostate cancer, thyroid cancer, and kidney cancer. Secondary cancers that affect bone can either destroy bone (called a "lytic" cancer) or create bone (a "sclerotic" cancer). Cancers of the bone marrow inside the bone can also affect bone tissue, examples including leukemia and multiple myeloma. Bone may also be affected by cancers in other parts of the body. Cancers in other parts of the body may release parathyroid hormone or parathyroid hormone-related peptide. This increases bone reabsorption, and can lead to bone fractures.

Bone tissue that is destroyed or altered as a result of cancers is distorted, weakened, and more prone to fracture. This may lead to compression of the spinal cord, destruction of the marrow resulting in bruising, bleeding and immunosuppression, and is one cause of bone pain. If the cancer is metastatic, then there might be other symptoms depending on the site of the original cancer. Some bone cancers can also be felt.

Cancers of the bone are managed according to their type, their stage, prognosis, and what symptoms they cause. Many primary cancers of bone are treated with radiotherapy. Cancers of bone marrow may be treated with chemotherapy, and other forms of targeted therapy such as immunotherapy may be used.Palliative care, which focuses on maximising a person's quality of life, may play a role in management, particularly if the likelihood of survival within five years is poor.

Osteoporosis is a disease of bone where there is reduced bone mineral density, increasing the likelihood of fractures. Osteoporosis is defined by the World Health Organization in women as a bone mineral density 2.5 standard deviations below peak bone mass, relative to the age and sex-matched average, as measured by Dual energy X-ray absorptiometry, with the term "established osteoporosis" including the presence of a fragility fracture.[43] Osteoporosis is most common in women after menopause, when it is called "postmenopausal osteoporosis", but may develop in men and premenopausal women in the presence of particular hormonal disorders and other chronic diseases or as a result of smoking and medications, specifically glucocorticoids. Osteoporosis usually has no symptoms until a fracture occurs. For this reason, DEXA scans are often done in people with one or more risk factors, who have developed osteoporosis and be at risk of fracture.

Osteoporosis treatment includes advice to stop smoking, decrease alcohol consumption, exercise regularly, and have a healthy diet. Calcium supplements may also be advised, as may Vitamin D. When medication is used, it may include bisphosphonates, Strontium ranelate, and osteoporosis may be one factor considered when commencing Hormone replacement therapy.[44]

The study of bones and teeth is referred to as osteology. It is frequently used in anthropology, archeology and forensic science for a variety of tasks. This can include determining the nutritional, health, age or injury status of the individual the bones were taken from. Preparing fleshed bones for these types of studies can involve the process of maceration.

Typically anthropologists and archeologists study bone tools made by Homo sapiens and Homo neanderthalensis. Bones can serve a number of uses such as projectile points or artistic pigments, and can also be made from external bones such as antlers.

Bird skeletons are very lightweight. Their bones are smaller and thinner, to aid flight. Among mammals, bats come closest to birds in terms of bone density, suggesting that small dense bones are a flight adaptation. Many bird bones have little marrow due to their being hollow.[45]

A bird's beak is primarily made of bone as projections of the mandibles which are covered in keratin.

A deer's antlers are composed of bone which is an unusual example of bone being outside the skin of the animal once the velvet is shed.[46]

The extinct predatory fish Dunkleosteus had sharp edges of hard exposed bone along its jaws.[citation needed]

Many animals possess an exoskeleton that is not made of bone, These include insects and crustaceans.

Bones from slaughtered animals have a number of uses. In prehistoric times, they have been used for making bone tools. They have further been used in bone carving, already important in prehistoric art, and also in modern time as crafting materials for buttons, beads, handles, bobbins, calculation aids, head nuts, dice, poker chips, pick-up sticks, ornaments, etc. A special genre is scrimshaw.

Bone glue can be made by prolonged boiling of ground or cracked bones, followed by filtering and evaporation to thicken the resulting fluid. Historically once important, bone glue and other animal glues today have only a few specialized uses, such as in antiques restoration. Essentially the same process, with further refinement, thickening and drying, is used to make gelatin.

Broth is made by simmering several ingredients for a long time, traditionally including bones.

Ground bones are used as an organic phosphorus-nitrogen fertilizer and as additive in animal feed. Bones, in particular after calcination to bone ash, are used as source of calcium phosphate for the production of bone china and previously also phosphorus chemicals.[citation needed]

Bone char, a porous, black, granular material primarily used for filtration and also as a black pigment, is produced by charring mammal bones.

Oracle bone script was a writing system used in Ancient china based on inscriptions in bones.

To point the bone at someone is considered bad luck in some cultures, such as Australian aborigines, such as by the Kurdaitcha.

Osteopathic medicine is a school of medical thought originally developed based on the idea of the link between the musculoskeletal system and overall health, but now very similar to mainstream medicine. As of 2012[update], over 77,000 physicians in the United States are trained in Osteopathic medicine colleges.[47]

The wishbones of fowl have been used for divination, and are still customarily used in a tradition to determine which one of two people pulling on either prong of the bone may make a wish.

Various cultures throughout history have adopted the custom of shaping an infant's head by the practice of artificial cranial deformation. A widely practised custom in China was that of foot binding to limit the normal growth of the foot.

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This article is about the heritable unit for transmission of biological traits. For other uses, see Gene (disambiguation).

A gene is a locus (or region) of DNA which is made up of nucleotides and is the molecular unit of heredity.[1][2]:Glossary The transmission of genes to an organism's offspring is the basis of the inheritance of phenotypic traits. Most biological traits are under the influence of polygenes (many different genes) as well as geneenvironment interactions. Some genetic traits are instantly visible, such as eye colour or number of limbs, and some are not, such as blood type, risk for specific diseases, or the thousands of basic biochemical processes that comprise life.

Genes can acquire mutations in their sequence, leading to different variants, known as alleles, in the population. These alleles encode slightly different versions of a protein, which cause different phenotype traits. Colloquial usage of the term "having a gene" (e.g., "good genes," "hair colour gene") typically refers to having a different allele of the gene. Genes evolve due to natural selection or survival of the fittest of the alleles.

The concept of a gene continues to be refined as new phenomena are discovered.[3] For example, regulatory regions of a gene can be far removed from its coding regions, and coding regions can be split into several exons. Some viruses store their genome in RNA instead of DNA and some gene products are functional non-coding RNAs. Therefore, a broad, modern working definition of a gene is any discrete locus of heritable, genomic sequence which affect an organism's traits by being expressed as a functional product or by regulation of gene expression.[4][5]

The existence of discrete inheritable units was first suggested by Gregor Mendel (18221884).[6] From 1857 to 1864, he studied inheritance patterns in 8000 common edible pea plants, tracking distinct traits from parent to offspring. He described these mathematically as 2ncombinations where n is the number of differing characteristics in the original peas. Although he did not use the term gene, he explained his results in terms of discrete inherited units that give rise to observable physical characteristics. This description prefigured the distinction between genotype (the genetic material of an organism) and phenotype (the visible traits of that organism). Mendel was also the first to demonstrate independent assortment, the distinction between dominant and recessive traits, the distinction between a heterozygote and homozygote, and the phenomenon of discontinuous inheritance.

Prior to Mendel's work, the dominant theory of heredity was one of blending inheritance, which suggested that each parent contributed fluids to the fertilisation process and that the traits of the parents blended and mixed to produce the offspring. Charles Darwin developed a theory of inheritance he termed pangenesis, from Greek pan ("all, whole") and genesis ("birth") / genos ("origin").[7][8] Darwin used the term gemmule to describe hypothetical particles that would mix during reproduction.

Mendel's work went largely unnoticed after its first publication in 1866, but was rediscovered in the late 19th century by Hugo de Vries, Carl Correns, and Erich von Tschermak, who (claimed to have) reached similar conclusions in their own research.[9] Specifically, in 1889, Hugo de Vries published his book Intracellular Pangenesis,[10] in which he postulated that different characters have individual hereditary carriers and that inheritance of specific traits in organisms comes in particles. De Vries called these units "pangenes" (Pangens in German), after Darwin's 1868 pangenesis theory.

Sixteen years later, in 1905, the word genetics was first used by William Bateson,[11] while Eduard Strasburger, amongst others, still used the term pangene for the fundamental physical and functional unit of heredity.[12] In 1909 the Danish botanist Wilhelm Johannsen shortened the name to "gene". [13]

Advances in understanding genes and inheritance continued throughout the 20th century. Deoxyribonucleic acid (DNA) was shown to be the molecular repository of genetic information by experiments in the 1940s to 1950s.[14][15] The structure of DNA was studied by Rosalind Franklin and Maurice Wilkins using X-ray crystallography, which led James D. Watson and Francis Crick to publish a model of the double-stranded DNA molecule whose paired nucleotide bases indicated a compelling hypothesis for the mechanism of genetic replication.[16][17]

In the early 1950s the prevailing view was that the genes in a chromosome acted like discrete entities, indivisible by recombination and arranged like beads on a string. The experiments of Benzer using mutants defective in the rII region of bacteriophage T4 (1955-1959) showed that individual genes have a simple linear structure and are likely to be equivalent to a linear section of DNA.[18][19]

Collectively, this body of research established the central dogma of molecular biology, which states that proteins are translated from RNA, which is transcribed from DNA. This dogma has since been shown to have exceptions, such as reverse transcription in retroviruses. The modern study of genetics at the level of DNA is known as molecular genetics.

In 1972, Walter Fiers and his team at the University of Ghent were the first to determine the sequence of a gene: the gene for Bacteriophage MS2 coat protein.[20] The subsequent development of chain-termination DNA sequencing in 1977 by Frederick Sanger improved the efficiency of sequencing and turned it into a routine laboratory tool.[21] An automated version of the Sanger method was used in early phases of the Human Genome Project.[22]

The theories developed in the 1930s and 1940s to integrate molecular genetics with Darwinian evolution are called the modern evolutionary synthesis, a term introduced by Julian Huxley.[23] Evolutionary biologists subsequently refined this concept, such as George C. Williams' gene-centric view of evolution. He proposed an evolutionary concept of the gene as a unit of natural selection with the definition: "that which segregates and recombines with appreciable frequency."[24]:24 In this view, the molecular gene transcribes as a unit, and the evolutionary gene inherits as a unit. Related ideas emphasizing the centrality of genes in evolution were popularized by Richard Dawkins.[25][26]

The vast majority of living organisms encode their genes in long strands of DNA (deoxyribonucleic acid). DNA consists of a chain made from four types of nucleotide subunits, each composed of: a five-carbon sugar (2'-deoxyribose), a phosphate group, and one of the four bases adenine, cytosine, guanine, and thymine.[2]:2.1

Two chains of DNA twist around each other to form a DNA double helix with the phosphate-sugar backbone spiralling around the outside, and the bases pointing inwards with adenine base pairing to thymine and guanine to cytosine. The specificity of base pairing occurs because adenine and thymine align to form two hydrogen bonds, whereas cytosine and guanine form three hydrogen bonds. The two strands in a double helix must therefore be complementary, with their sequence of bases matching such that the adenines of one strand are paired with the thymines of the other strand, and so on.[2]:4.1

Due to the chemical composition of the pentose residues of the bases, DNA strands have directionality. One end of a DNA polymer contains an exposed hydroxyl group on the deoxyribose; this is known as the 3'end of the molecule. The other end contains an exposed phosphate group; this is the 5'end. The two strands of a double-helix run in opposite directions. Nucleic acid synthesis, including DNA replication and transcription occurs in the 5'3'direction, because new nucleotides are added via a dehydration reaction that uses the exposed 3'hydroxyl as a nucleophile.[27]:27.2

The expression of genes encoded in DNA begins by transcribing the gene into RNA, a second type of nucleic acid that is very similar to DNA, but whose monomers contain the sugar ribose rather than deoxyribose. RNA also contains the base uracil in place of thymine. RNA molecules are less stable than DNA and are typically single-stranded. Genes that encode proteins are composed of a series of three-nucleotide sequences called codons, which serve as the "words" in the genetic "language". The genetic code specifies the correspondence during protein translation between codons and amino acids. The genetic code is nearly the same for all known organisms.[2]:4.1

The total complement of genes in an organism or cell is known as its genome, which may be stored on one or more chromosomes. A chromosome consists of a single, very long DNA helix on which thousands of genes are encoded.[2]:4.2 The region of the chromosome at which a particular gene is located is called its locus. Each locus contains one allele of a gene; however, members of a population may have different alleles at the locus, each with a slightly different gene sequence.

The majority of eukaryotic genes are stored on a set of large, linear chromosomes. The chromosomes are packed within the nucleus in complex with storage proteins called histones to form a unit called a nucleosome. DNA packaged and condensed in this way is called chromatin.[2]:4.2 The manner in which DNA is stored on the histones, as well as chemical modifications of the histone itself, regulate whether a particular region of DNA is accessible for gene expression. In addition to genes, eukaryotic chromosomes contain sequences involved in ensuring that the DNA is copied without degradation of end regions and sorted into daughter cells during cell division: replication origins, telomeres and the centromere.[2]:4.2 Replication origins are the sequence regions where DNA replication is initiated to make two copies of the chromosome. Telomeres are long stretches of repetitive sequence that cap the ends of the linear chromosomes and prevent degradation of coding and regulatory regions during DNA replication. The length of the telomeres decreases each time the genome is replicated and has been implicated in the aging process.[29] The centromere is required for binding spindle fibres to separate sister chromatids into daughter cells during cell division.[2]:18.2

Prokaryotes (bacteria and archaea) typically store their genomes on a single large, circular chromosome. Similarly, some eukaryotic organelles contain a remnant circular chromosome with a small number of genes.[2]:14.4 Prokaryotes sometimes supplement their chromosome with additional small circles of DNA called plasmids, which usually encode only a few genes and are transferable between individuals. For example, the genes for antibiotic resistance are usually encoded on bacterial plasmids and can be passed between individual cells, even those of different species, via horizontal gene transfer.[30]

Whereas the chromosomes of prokaryotes are relatively gene-dense, those of eukaryotes often contain regions of DNA that serve no obvious function. Simple single-celled eukaryotes have relatively small amounts of such DNA, whereas the genomes of complex multicellular organisms, including humans, contain an absolute majority of DNA without an identified function.[31] This DNA has often been referred to as "junk DNA". However, more recent analyses suggest that, although protein-coding DNA makes up barely 2% of the human genome, about 80% of the bases in the genome may be expressed, so the term "junk DNA" may be a misnomer.[5]

The structure of a gene consists of many elements of which the actual protein coding sequence is often only a small part. These include DNA regions that are not transcribed as well as untranslated regions of the RNA.

Firstly, flanking the open reading frame, all genes contain a regulatory sequence that is required for their expression. In order to be expressed, genes require a promoter sequence. The promoter is recognized and bound by transcription factors and RNA polymerase to initiate transcription.[2]:7.1 A gene can have more than one promoter, resulting in messenger RNAs (mRNA) that differ in how far they extend in the 5'end.[32] Promoter regions have a consensus sequence, however highly transcribed genes have "strong" promoter sequences that bind the transcription machinery well, whereas others have "weak" promoters that bind poorly and initiate transcription less frequently.[2]:7.2Eukaryotic promoter regions are much more complex and difficult to identify than prokaryotic promoters.[2]:7.3

Additionally, genes can have regulatory regions many kilobases upstream or downstream of the open reading frame. These act by binding to transcription factors which then cause the DNA to loop so that the regulatory sequence (and bound transcription factor) become close to the RNA polymerase binding site.[33] For example, enhancers increase transcription by binding an activator protein which then helps to recruit the RNA polymerase to the promoter; conversely silencers bind repressor proteins and make the DNA less available for RNA polymerase.[34]

The transcribed pre-mRNA contains untranslated regions at both ends which contain a ribosome binding site, terminator and start and stop codons.[35] In addition, most eukaryotic open reading frames contain untranslated introns which are removed before the exons are translated. The sequences at the ends of the introns, dictate the splice sites to generate the final mature mRNA which encodes the protein or RNA product.[36]

Many prokaryotic genes are organized into operons, with multiple protein-coding sequences that are transcribed as a unit.[37][38] The genes in an operon are transcribed as a continuous messenger RNA, referred to as a polycistronic mRNA. The term cistron in this context is equivalent to gene. The transcription of an operons mRNA is often controlled by a repressor that can occur in an active or inactive state depending on the presence of certain specific metabolites.[39] When active, the repressor binds to a DNA sequence at the beginning of the operon, called the operator region, and represses transcription of the operon; when the repressor is inactive transcription of the operon can occur (see e.g. Lac operon). The products of operon genes typically have related functions and are involved in the same regulatory network.[2]:7.3

Defining exactly what section of a DNA sequence comprises a gene is difficult.[3]Regulatory regions of a gene such as enhancers do not necessarily have to be close to the coding sequence on the linear molecule because the intervening DNA can be looped out to bring the gene and its regulatory region into proximity. Similarly, a gene's introns can be much larger than its exons. Regulatory regions can even be on entirely different chromosomes and operate in trans to allow regulatory regions on one chromosome to come in contact with target genes on another chromosome.[40][41]

Early work in molecular genetics suggested the concept that one gene makes one protein. This concept (originally called the one gene-one enzyme hypothesis) emerged from an influential 1941 paper by George Beadle and Edward Tatum on experiments with mutants of the fungus Neurospora crassa.[42]Norman Horowitz, an early colleague on the Neurospora research, reminisced in 2004 that these experiments founded the science of what Beadle and Tatum called biochemical genetics. In actuality they proved to be the opening gun in what became molecular genetics and all the developments that have followed from that.[43] The one gene-one protein concept has been refined since the discovery of genes that can encode multiple proteins by alternative splicing and coding sequences split in short section across the genome whose mRNAs are concatenated by trans-splicing.[5][44][45]

A broad operational definition is sometimes used to encompass the complexity of these diverse phenomena, where a gene is defined as a union of genomic sequences encoding a coherent set of potentially overlapping functional products.[11] This definition categorizes genes by their functional products (proteins or RNA) rather than their specific DNA loci, with regulatory elements classified as gene-associated regions.[11]

In all organisms, two steps are required to read the information encoded in a gene's DNA and produce the protein it specifies. First, the gene's DNA is transcribed to messenger RNA (mRNA).[2]:6.1 Second, that mRNA is translated to protein.[2]:6.2 RNA-coding genes must still go through the first step, but are not translated into protein.[46] The process of producing a biologically functional molecule of either RNA or protein is called gene expression, and the resulting molecule is called a gene product.

The nucleotide sequence of a gene's DNA specifies the amino acid sequence of a protein through the genetic code. Sets of three nucleotides, known as codons, each correspond to a specific amino acid.[2]:6 The principle that three sequential bases of DNA code for each amino acid was demonstrated in 1961 using frameshift mutations in the rIIB gene of bacteriophage T4[47] (see Crick, Brenner et al. experiment).

Additionally, a "start codon", and three "stop codons" indicate the beginning and end of the protein coding region. There are 64possible codons (four possible nucleotides at each of three positions, hence 43possible codons) and only 20standard amino acids; hence the code is redundant and multiple codons can specify the same amino acid. The correspondence between codons and amino acids is nearly universal among all known living organisms.[48]

Transcription produces a single-stranded RNA molecule known as messenger RNA, whose nucleotide sequence is complementary to the DNA from which it was transcribed.[2]:6.1 The mRNA acts as an intermediate between the DNA gene and its final protein product. The gene's DNA is used as a template to generate a complementary mRNA. The mRNA matches the sequence of the gene's DNA coding strand because it is synthesised as the complement of the template strand. Transcription is performed by an enzyme called an RNA polymerase, which reads the template strand in the 3' to 5'direction and synthesizes the RNA from 5' to 3'. To initiate transcription, the polymerase first recognizes and binds a promoter region of the gene. Thus, a major mechanism of gene regulation is the blocking or sequestering the promoter region, either by tight binding by repressor molecules that physically block the polymerase, or by organizing the DNA so that the promoter region is not accessible.[2]:7

In prokaryotes, transcription occurs in the cytoplasm; for very long transcripts, translation may begin at the 5'end of the RNA while the 3'end is still being transcribed. In eukaryotes, transcription occurs in the nucleus, where the cell's DNA is stored. The RNA molecule produced by the polymerase is known as the primary transcript and undergoes post-transcriptional modifications before being exported to the cytoplasm for translation. One of the modifications performed is the splicing of introns which are sequences in the transcribed region that do not encode protein. Alternative splicing mechanisms can result in mature transcripts from the same gene having different sequences and thus coding for different proteins. This is a major form of regulation in eukaryotic cells and also occurs in some prokaryotes.[2]:7.5[49]

Translation is the process by which a mature mRNA molecule is used as a template for synthesizing a new protein.[2]:6.2 Translation is carried out by ribosomes, large complexes of RNA and protein responsible for carrying out the chemical reactions to add new amino acids to a growing polypeptide chain by the formation of peptide bonds. The genetic code is read three nucleotides at a time, in units called codons, via interactions with specialized RNA molecules called transfer RNA (tRNA). Each tRNA has three unpaired bases known as the anticodon that are complementary to the codon it reads on the mRNA. The tRNA is also covalently attached to the amino acid specified by the complementary codon. When the tRNA binds to its complementary codon in an mRNA strand, the ribosome attaches its amino acid cargo to the new polypeptide chain, which is synthesized from amino terminus to carboxyl terminus. During and after synthesis, most new proteins must fold to their active three-dimensional structure before they can carry out their cellular functions.[2]:3

Genes are regulated so that they are expressed only when the product is needed, since expression draws on limited resources.[2]:7 A cell regulates its gene expression depending on its external environment (e.g. available nutrients, temperature and other stresses), its internal environment (e.g. cell division cycle, metabolism, infection status), and its specific role if in a multicellular organism. Gene expression can be regulated at any step: from transcriptional initiation, to RNA processing, to post-translational modification of the protein. The regulation of lactose metabolism genes in E. coli (lac operon) was the first such mechanism to be described in 1961.[50]

A typical protein-coding gene is first copied into RNA as an intermediate in the manufacture of the final protein product.[2]:6.1 In other cases, the RNA molecules are the actual functional products, as in the synthesis of ribosomal RNA and transfer RNA. Some RNAs known as ribozymes are capable of enzymatic function, and microRNA has a regulatory role. The DNA sequences from which such RNAs are transcribed are known as non-coding RNA genes.[46]

Some viruses store their entire genomes in the form of RNA, and contain no DNA at all.[51][52] Because they use RNA to store genes, their cellular hosts may synthesize their proteins as soon as they are infected and without the delay in waiting for transcription.[53] On the other hand, RNA retroviruses, such as HIV, require the reverse transcription of their genome from RNA into DNA before their proteins can be synthesized. RNA-mediated epigenetic inheritance has also been observed in plants and very rarely in animals.[54]

Organisms inherit their genes from their parents. Asexual organisms simply inherit a complete copy of their parent's genome. Sexual organisms have two copies of each chromosome because they inherit one complete set from each parent.[2]:1

According to Mendelian inheritance, variations in an organism's phenotype (observable physical and behavioral characteristics) are due in part to variations in its genotype (particular set of genes). Each gene specifies a particular trait with different sequence of a gene (alleles) giving rise to different phenotypes. Most eukaryotic organisms (such as the pea plants Mendel worked on) have two alleles for each trait, one inherited from each parent.[2]:20

Alleles at a locus may be dominant or recessive; dominant alleles give rise to their corresponding phenotypes when paired with any other allele for the same trait, whereas recessive alleles give rise to their corresponding phenotype only when paired with another copy of the same allele. For example, if the allele specifying tall stems in pea plants is dominant over the allele specifying short stems, then pea plants that inherit one tall allele from one parent and one short allele from the other parent will also have tall stems. Mendel's work demonstrated that alleles assort independently in the production of gametes, or germ cells, ensuring variation in the next generation. Although Mendelian inheritance remains a good model for many traits determined by single genes (including a number of well-known genetic disorders) it does not include the physical processes of DNA replication and cell division.[55][56]

The growth, development, and reproduction of organisms relies on cell division, or the process by which a single cell divides into two usually identical daughter cells. This requires first making a duplicate copy of every gene in the genome in a process called DNA replication.[2]:5.2 The copies are made by specialized enzymes known as DNA polymerases, which "read" one strand of the double-helical DNA, known as the template strand, and synthesize a new complementary strand. Because the DNA double helix is held together by base pairing, the sequence of one strand completely specifies the sequence of its complement; hence only one strand needs to be read by the enzyme to produce a faithful copy. The process of DNA replication is semiconservative; that is, the copy of the genome inherited by each daughter cell contains one original and one newly synthesized strand of DNA.[2]:5.2

The rate of DNA replication in living cells was first measured as the rate of phage T4 DNA elongation in phage-infected E. coli and found to be impressively rapid.[57] During the period of exponential DNA increase at 37 C, the rate of elongation was 749 nucleotides per second.

After DNA replication is complete, the cell must physically separate the two copies of the genome and divide into two distinct membrane-bound cells.[2]:18.2 In prokaryotes(bacteria and archaea) this usually occurs via a relatively simple process called binary fission, in which each circular genome attaches to the cell membrane and is separated into the daughter cells as the membrane invaginates to split the cytoplasm into two membrane-bound portions. Binary fission is extremely fast compared to the rates of cell division in eukaryotes. Eukaryotic cell division is a more complex process known as the cell cycle; DNA replication occurs during a phase of this cycle known as S phase, whereas the process of segregating chromosomes and splitting the cytoplasm occurs during M phase.[2]:18.1

The duplication and transmission of genetic material from one generation of cells to the next is the basis for molecular inheritance, and the link between the classical and molecular pictures of genes. Organisms inherit the characteristics of their parents because the cells of the offspring contain copies of the genes in their parents' cells. In asexually reproducing organisms, the offspring will be a genetic copy or clone of the parent organism. In sexually reproducing organisms, a specialized form of cell division called meiosis produces cells called gametes or germ cells that are haploid, or contain only one copy of each gene.[2]:20.2 The gametes produced by females are called eggs or ova, and those produced by males are called sperm. Two gametes fuse to form a diploid fertilized egg, a single cell that has two sets of genes, with one copy of each gene from the mother and one from the father.[2]:20

During the process of meiotic cell division, an event called genetic recombination or crossing-over can sometimes occur, in which a length of DNA on one chromatid is swapped with a length of DNA on the corresponding homologous non-sister chromatid. This can result in reassortment of otherwise linked alleles.[2]:5.5 The Mendelian principle of independent assortment asserts that each of a parent's two genes for each trait will sort independently into gametes; which allele an organism inherits for one trait is unrelated to which allele it inherits for another trait. This is in fact only true for genes that do not reside on the same chromosome, or are located very far from one another on the same chromosome. The closer two genes lie on the same chromosome, the more closely they will be associated in gametes and the more often they will appear together; genes that are very close are essentially never separated because it is extremely unlikely that a crossover point will occur between them. This is known as genetic linkage.[58]

DNA replication is for the most part extremely accurate, however errors (mutations) do occur.[2]:7.6 The error rate in eukaryotic cells can be as low as 108 per nucleotide per replication,[59][60] whereas for some RNA viruses it can be as high as 103.[61] This means that each generation, each human genome accumulates 12 new mutations.[61] Small mutations can be caused by DNA replication and the aftermath of DNA damage and include point mutations in which a single base is altered and frameshift mutations in which a single base is inserted or deleted. Either of these mutations can change the gene by missense (change a codon to encode a different amino acid) or nonsense (a premature stop codon).[62] Larger mutations can be caused by errors in recombination to cause chromosomal abnormalities including the duplication, deletion, rearrangement or inversion of large sections of a chromosome. Additionally, DNA repair mechanisms can introduce mutational errors when repairing physical damage to the molecule. The repair, even with mutation, is more important to survival than restoring an exact copy, for example when repairing double-strand breaks.[2]:5.4

When multiple different alleles for a gene are present in a species's population it is called polymorphic. Most different alleles are functionally equivalent, however some alleles can give rise to different phenotypic traits. A gene's most common allele is called the wild type, and rare alleles are called mutants. The genetic variation in relative frequencies of different alleles in a population is due to both natural selection and genetic drift.[63] The wild-type allele is not necessarily the ancestor of less common alleles, nor is it necessarily fitter.

Most mutations within genes are neutral, having no effect on the organism's phenotype (silent mutations). Some mutations do not change the amino acid sequence because multiple codons encode the same amino acid (synonymous mutations). Other mutations can be neutral if they lead to amino acid sequence changes, but the protein still functions similarly with the new amino acid (e.g. conservative mutations). Many mutations, however, are deleterious or even lethal, and are removed from populations by natural selection. Genetic disorders are the result of deleterious mutations and can be due to spontaneous mutation in the affected individual, or can be inherited. Finally, a small fraction of mutations are beneficial, improving the organism's fitness and are extremely important for evolution, since their directional selection leads to adaptive evolution.[2]:7.6

Genes with a most recent common ancestor, and thus a shared evolutionary ancestry, are known as homologs.[64] These genes appear either from gene duplication within an organism's genome, where they are known as paralogous genes, or are the result of divergence of the genes after a speciation event, where they are known as orthologous genes,[2]:7.6 and often perform the same or similar functions in related organisms. It is often assumed that the functions of orthologous genes are more similar than those of paralogous genes, although the difference is minimal.[65][66]

The relationship between genes can be measured by comparing the sequence alignment of their DNA.[2]:7.6 The degree of sequence similarity between homologous genes is called conserved sequence. Most changes to a gene's sequence do not affect its function and so genes accumulate mutations over time by neutral molecular evolution. Additionally, any selection on a gene will cause its sequence to diverge at a different rate. Genes under stabilizing selection are constrained and so change more slowly whereas genes under directional selection change sequence more rapidly.[67] The sequence differences between genes can be used for phylogenetic analyses to study how those genes have evolved and how the organisms they come from are related.[68][69]

The most common source of new genes in eukaryotic lineages is gene duplication, which creates copy number variation of an existing gene in the genome.[70][71] The resulting genes (paralogs) may then diverge in sequence and in function. Sets of genes formed in this way comprise a gene family. Gene duplications and losses within a family are common and represent a major source of evolutionary biodiversity.[72] Sometimes, gene duplication may result in a nonfunctional copy of a gene, or a functional copy may be subject to mutations that result in loss of function; such nonfunctional genes are called pseudogenes.[2]:7.6

"Orphan" genes, whose sequence shows no similarity to existing genes, are less common than gene duplicates. Estimates of the number of genes with no homologs outside humans range from 18[73] to 60.[74] Two primary sources of orphan protein-coding genes are gene duplication followed by extremely rapid sequence change, such that the original relationship is undetectable by sequence comparisons, and de novo conversion of a previously non-coding sequence into a protein-coding gene.[75] De novo genes are typically shorter and simpler in structure than most eukaryotic genes, with few if any introns.[70] Over long evolutionary time periods, de novo gene birth may be responsible for a significant fraction of taxonomically-restricted gene families.[76]

Horizontal gene transfer refers to the transfer of genetic material through a mechanism other than reproduction. This mechanism is a common source of new genes in prokaryotes, sometimes thought to contribute more to genetic variation than gene duplication.[77] It is a common means of spreading antibiotic resistance, virulence, and adaptive metabolic functions.[30][78] Although horizontal gene transfer is rare in eukaryotes, likely examples have been identified of protist and alga genomes containing genes of bacterial origin.[79][80]

The genome is the total genetic material of an organism and includes both the genes and non-coding sequences.[81]

The genome size, and the number of genes it encodes varies widely between organisms. The smallest genomes occur in viruses (which can have as few as 2 protein-coding genes),[90] and viroids (which act as a single non-coding RNA gene).[91] Conversely, plants can have extremely large genomes,[92] with rice containing >46,000 protein-coding genes.[93] The total number of protein-coding genes (the Earth's proteome) is estimated to be 5million sequences.[94]

Although the number of base-pairs of DNA in the human genome has been known since the 1960s, the estimated number of genes has changed over time as definitions of genes, and methods of detecting them have been refined. Initial theoretical predictions of the number of human genes were as high as 2,000,000.[95] Early experimental measures indicated there to be 50,000100,000 transcribed genes (expressed sequence tags).[96] Subsequently, the sequencing in the Human Genome Project indicated that many of these transcripts were alternative variants of the same genes, and the total number of protein-coding genes was revised down to ~20,000[89] with 13 genes encoded on the mitochondrial genome.[87] Of the human genome, only 12% consists of protein-coding genes,[97] with the remainder being 'noncoding' DNA such as introns, retrotransposons, and noncoding RNAs.[97][98] Every multicellular organism has all its genes in each cell of its body but not every gene functions in every cell .

Essential genes are the set of genes thought to be critical for an organism's survival.[100] This definition assumes the abundant availability of all relevant nutrients and the absence of environmental stress. Only a small portion of an organism's genes are essential. In bacteria, an estimated 250400 genes are essential for Escherichia coli and Bacillus subtilis, which is less than 10% of their genes.[101][102][103] Half of these genes are orthologs in both organisms and are largely involved in protein synthesis.[103] In the budding yeast Saccharomyces cerevisiae the number of essential genes is slightly higher, at 1000 genes (~20% of their genes).[104] Although the number is more difficult to measure in higher eukaryotes, mice and humans are estimated to have around 2000 essential genes (~10% of their genes).[105] The synthetic organism, Syn 3, has a minimal genome of 473 essential genes and quasi-essential genes (necessary for fast growth), although 149 have unknown function.[99]

Essential genes include Housekeeping genes (critical for basic cell functions)[106] as well as genes that are expressed at different times in the organisms development or life cycle.[107] Housekeeping genes are used as experimental controls when analysing gene expression, since they are constitutively expressed at a relatively constant level.

Gene nomenclature has been established by the HUGO Gene Nomenclature Committee (HGNC) for each known human gene in the form of an approved gene name and symbol (short-form abbreviation), which can be accessed through a database maintained by HGNC. Symbols are chosen to be unique, and each gene has only one symbol (although approved symbols sometimes change). Symbols are preferably kept consistent with other members of a gene family and with homologs in other species, particularly the mouse due to its role as a common model organism.[108]

Genetic engineering is the modification of an organism's genome through biotechnology. Since the 1970s, a variety of techniques have been developed to specifically add, remove and edit genes in an organism.[109] Recently developed genome engineering techniques use engineered nuclease enzymes to create targeted DNA repair in a chromosome to either disrupt or edit a gene when the break is repaired.[110][111][112][113] The related term synthetic biology is sometimes used to refer to extensive genetic engineering of an organism.[114]

Genetic engineering is now a routine research tool with model organisms. For example, genes are easily added to bacteria[115] and lineages of knockout mice with a specific gene's function disrupted are used to investigate that gene's function.[116][117] Many organisms have been genetically modified for applications in agriculture, industrial biotechnology, and medicine.

For multicellular organisms, typically the embryo is engineered which grows into the adult genetically modified organism.[118] However, the genomes of cells in an adult organism can be edited using gene therapy techniques to treat genetic diseases.

Alberts B, Johnson A, Lewis J, Raff M, Roberts K, Walter P (2002). Molecular Biology of the Cell (Fourth ed.). New York: Garland Science. ISBN978-0-8153-3218-3. A molecular biology textbook available free online through NCBI Bookshelf.

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Recommendation and review posted by Bethany Smith

Despite bouncing off a 2-year low, biotech is still an unpopular sector and investors are rightfully concerned about its near-term prospects. Recent drug failures, growing pricing pressure and the potential impact of biosimilars all contribute to the negative sentiment, but the main problem is the lack of growth drivers for the remainder of 2016 (and potentially 2017).

The biotech industry relies on innovation cycles to create new revenue sources. This was the case in the 2013-2014 biotech bull market, which was driven by a wave of medical breakthroughs (PD-1, HCV, CAR/TCR, oral MS drugs, CF etc.). These waves typically involve new therapeutic approaches coupled with disruptive technologies as their enablers.

In oncology, for example, the understanding that cancer is driven by aberrant signaling coupled with advances in medicinal chemistry and antibody engineering led to the development of kinase inhibitors and monoclonal antibodies as blockers of signaling. A decade later, insights around cancer immunology gave rise to the immuno-oncology field and PD-1 inhibitors in particular, which are expected to become the biggest oncology franchise ever.

Gene therapy ticks all the boxes

While there are several hot areas in biotech such as gene editing and microbiome, most are still early and their applicability is unclear. Gene therapy, on the other hand, is more mature and de-risked with tens of clinical studies and the potential to treat (and perhaps cure) a wide range of diseases where treatment is inadequate or non-existent. The commercial upside from these programs is huge and should expand as additional indications are pursued.

As I previously discussed, the past two years saw a surge in the number of clinical-stage gene therapies, some of which already generated impressive efficacy across multiple indications. This makes gene therapy the only truly disruptive field which is mature enough not only from a technology but also from a clinical standpoint. Importantly, most studies are conducted by companies according to industry and regulatory standards, in contrast to historical gene therapy studies that were run by academic groups.

To me, the striking thing about the results is the breadth of technologies, indications and modes of administrations evaluated to date. This versatility is very important for the future of gene therapy as it reduces overall development risk and increases likelihood of success by allowing companies to tailor the right product for each indication. Parameters include mode of administration (local vs. systemic vs. ex vivo), tropism for the target tissue (eye, bone marrow, liver etc.), immunogenicity and onset of activity.

Building a diversified gene therapy basket

Given the early development stage and large number of technologies, I prefer to own a basket of gene therapy stocks with a focus on the more clinically validated ones: Spark (ONCE), Bluebird (BLUE) and Avexis (AVXS).

Bluebird and Spark are the most further along (and also the largest based on market cap) gene therapy companies and should be the basis for any gene therapy portfolio. With two completely different technologies, the two companies have strong clinical proof-of-concept for their respective lead programs.

Avexis is less advanced without a clinically validated product, but recent data for its lead program are too promising to ignore.

Spark Clinical validation for retinal and liver indications

Sparks lead programs (SPK-RPE65) will probably become the first gene therapy to get FDA approval. In October, the company reported strong P3 data in rare genetic retinal conditions caused by RPE65 mutations, the first randomized and statistically significant data for a gene therapy. The company is expected to complete its BLA submission later in 2016 which should lead to FDA approval in 2017. Sparks second ophthalmology program for choroideremia is in P1 with efficacy data expected later in 2016.

Earlier this month, Spark released an encouraging update for its Hemophilia B program, SPK-9001 (partnered with Pfizer [PFE]). A single administration of SPK-9001 led to a sustained and clinically meaningful production of Factor IX, a clotting factor which is dysfunctional in Hemophilia B patients. All four treated patients experienced a clinically significant increase in Factor IX activity from <2% to 26%-41% (12% is predicted to be sufficient for minimizing incidence bleeding events). Due to the limited follow up (under 6 months), durability is still an open question.

Spark intends to advance its wholly-owned Hemophilia A program (SPK-8011) to the clinic later in 2016 with initial data expected in H1:2017. Results in the Hemophilia B should be viewed as a positive read-through but Hemophilia A still presents certain technical challenges (e.g. missing protein is several fold larger) which required Spark to use a different vector. Hemophilia A represents a $5B opportunity compared to $1B for Hemophilia B.

Bluebird

Despite being one of the worst biotech performers, Bluebird remains the largest and most visible gene therapy company. In contrast to most gene therapy companies, Bluebird treats patients cells ex-vivo (outside of the body) in a process that resembles stem cell transplant or adoptive cell transfer (CAR, TCR). Progenitor cells are collected from the patient, a genetic modification is integrated into the genome followed by infusion of the cells that repopulate the bone marrow. This enables Bluebird to go after hematologic diseases like beta thalassemia and Sickle-cell disease (SCD) where target cells are constantly dividing.

Sentiment around Bluebirds lead program, Lenti-globin , plummeted last year after a series of disappointing results in a subset of beta-thal patients and preliminary data in SCD, which represents the more important commercial opportunity. Particularly in SCD patients, post-treatment hemoglobin levels were relatively low and although some increase has been noted with time, it is still unclear what the maximal effect would be. Market reaction was brutal, sending shares down 75% in just over a year.

Next update for Lenti-globin is expected at ASH in December. Despite the disappointing efficacy observed in SCD and beta-thal, I am cautiously optimistic about Bluebirds efforts to optimize treatment protocols and regimens. These include specific conditioning regimens and ex-vivo treatment of cells that may improve transduction rate and hemoglobin production in patients. Some of these modifications are already being implemented in newly recruited patients and hopefully longer follow up will lead to higher hemoglobin levels in already-reported patients.

The only clinical update so far in 2016 was for Lenti-D in C-ALD, a rare neurological disease that affects infants in their first years. Results demonstrated that of 17 patients treated to date (median follow-up of 16 months), all remain alive and free of major functional deterioration (defined as major functional disabilities, MFD). The primary endpoint, defined as no MFD at 2 years, was reached for 3/3 patients with sufficient follow-up and assuming the trend continues Bluebird may be in a position to file for approval in H2:2017.

Lenti-Ds commercial opportunity is limited (200 patients diagnosed each year in developed countries) so investors understandably focus on Lenti-globin, which is being developed for beta thal (~20k patients in developed countries) and SCD (~160k patients).

Bluebird is expected to end 2016 with ~$650M in cash. Current market cap is $1.7B.

Avexis

Avexis is developing AVXS-101 for Spinal muscular atrophy Type 1 (SMA1), a rapidly deteriorating and fatal neuro-muscular disease. SMA1 is characterized by rapid deterioration in motor and neuronal functions with 50% of patients experiencing death or permanent ventilation by their first anniversary. Most patients die from respiratory failure by the age of two. SMA Type 2 and Type 3 are also caused by SMN1 mutations and are characterized by a later onset and milder disease burden (but unmet need is still significant in these indications). The US prevalence of SMA is 10,000, 600 of which are SMA1.

In contrast to Bluebird and Spark, Avexis does not have conclusive proof it can lead to expression of the missing protein (SMN1) in the target tissue nor does it have randomized clinical data but the results generated to date are simply too provocative to ignore.

At the most recent update, Avexis presented data for 15 patients who received AVXS-101 in their first months of life. 3 patients were treated with a low dose and 12 were treated with a high dose. Strikingly, none of the children experienced an event (defined as ventilation or death), including patients who reached 2 years of age. All 9 patients with sufficient follow up, reached the age of 13.6 months without an event in contrast to historical data that show an event-free survival of 25%. AVXS-101 also led to a dose dependent increase in motor function which had a quick onset especially at the higher dose.

As with any results from an open label study without a control arm, these data should be analyzed with caution, as they need to be corroborated by large controlled studies (expected to start next year). Still, the data point to an overwhelming benefit in a very aggressive disease. One of the most exciting aspects of this program is the fact that it is given systemically via IV administration, which implies the treatment reaches the neurons in the CNS. Avexis plans to start a trial in SMA2 in H2:16 using intrathecal delivery (directly to the spinal canal). This decision is surprising given the results with IV administration in SMA1 and the fact that the BBB immaturity hypothesis in babies is not considered relevant anymore. (See this review)

AVXS-101s main competitor is Biogens (BIIB) and Ionis (IONS) nusinersen, an antisense molecule that needs to be intrathecally injected 3-4 times a year. As both drugs generated encouraging clinical data in small non-randomized studies, it is hard to compare them, however, AVXS-101 has an obvious advantage of being a potentially one time IV injection. Nusinersen is in P3 with topline data expected in mid-2017.

AVXS-101 is based on an AAV9 vector developed by REGENXBIO (RGNX), which licensed the technology to Avexis. Beyond the 5%-10% in royalties REGENXBIO is eligible to receive, data for AVXS-101 bode well for the companys proprietary programs in MPS-I and MPS-II, two other rare diseases with neurological involvement where BBB penetration is crucial. These programs are also based on REGENXBIOs AAV9.

Beyond AVXS-101, REGENXBIO has an impressive partnered pipeline which includes collaborations with Voyager (VYGR), Dimension (DMTX) , Baxalta and Lysogene.

Portfolio updates Immunogen, Marinus, Esperion

June was a rough month for three of my holdings. Immunogen (IMGN) had a disappointing data set at ASCO, Marinus (MRNS) reported a P3 failure in epilepsy and most recently, Esperion was dealt a regulatory blow from the FDA that may push development timelines by several years. I am selling Immunogen and Marinus due to the lack of near-term catalysts although long-term their respective drugs could still be valuable. I decided to keep Esperion as I still find ETC-1002 very attractive and hope that PCSK9s CVOT data will soften FDAs concerns about LDL-C reduction as an approvable endpoint.

Three additional companies with important binary readouts in the coming months are Array Biopharma (ARRY), SAGE (SAGE) and Aurinia (AUPH). Array will have P3 data for selumetinib (partnered with AstraZeneca) in KRAS+ NSCLC. SAGE will report data from a randomized P2 in PPD following a promising single-arm data set. Aurinia will report results from the AURA study in lupus nephritis patients, where there is a strong rationale for using the companys drug (voclosporin) but limited direct clinical validation.

Portfolio holdings July 4, 2016

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Could gene therapy become biotechs growth driver in 2017 ...

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DIM (diindolylmethane), is a food-based compound found in cruciferous vegetables like broccoli, cabbage, cauliflower and Brussels sprouts.Studies have shown that it has the ability to reduce the risk of certain cancers, especiallythose influenced by excessive estrogen levels, such as breast, uterine and prostate. DIM can also stimulatefat breakdown and encourage an increase in muscle mass. I can attest, through my own personal experience supplementing with DIM as well as that of quite a few clients (both male and female), that DIM effectively modulates estrogen metabolism helping to do away with uncomfortable symptoms of PMS, perimenopause and prostate issues.

The following excerpt comes from Dr. Scott Rollins, MD, founder and Medical Director at the Integrative Medicine Center of Western Colorado (http://imcwc.com/news/index.php?id=3271124400587032289). Thisis a very well-written and comprehensive account of the effects of DIM and how to best use this supplement to make the most out of its incredible benefits:

Lower your risk of cancer, help lose weight and build muscle all remarkable benefits of a simple food supplement called DIM. For men or women, DIM is something to consider as part of an overall supplement program.

DIM, or diindolylmethane, is a plant based compound found in cruciferous vegetables, such as brussel sprouts,cabbage, broccoli and cauliflower. DIM has been shown in studies to reduce the risk of certain cancers, especiallythose driven by abnormally high estrogen levels, such as breast, uterus and prostate cancer. DIM can also stimulate the breakdown of fat while encouraging muscle development.

Estrogen hormones are naturally found in men and women and have many benefits such as preserving artery healthand brain function while fighting oxidative free radical damage. Higher estrogen levels found in women cause thefemale body shape with breast and hip development. Many women are estrogen dominant however, meaning theyhave too much estrogen accumulating in the body for the complementary progesterone to balance.

Natural estrogen dominance occurs as women near menopause, starting even ten years prior to menopause, where theyoften dont make as much progesterone to balance their estrogen. Symptoms such breast pain, water retention, heavypainful menstrual cycles, or irritable anxious moods are typical bothersome symptoms. Estrogens over-stimulation ofbreasts and uterus tissue can lead to breast cysts or adenomas and uterine growths both unpleasant and potentiallydangerous physical outcomes are too often accompanied by worrisome mammograms and hysterectomies.

Some women have estrogen dominance throughout their life for various reasons, such as low thyroid, high cortisol,exposure to environmental estrogen-like chemicals, or impaired detoxification pathways for estrogen.

Men often suffer from estrogen overload as well. With normal aging our testosterone levels drop as the conversion toestrogen increases, leading to a falling ratio of testosterone to estrogen. Higher estrogen levels in men lead to weightgain, loss of muscle mass, feminization of the body, further decreases in already falling testosterone levels, andincrease the risk of diseases such as heart disease and prostate cancer. The enzyme that normally converts testosteroneto estrogen is most abundant in fat, so as men put on weight the cycle of falling testosterone and rising estrogen simply picks up steam!

There are two main pathways in the liver for our estrogen to be normally metabolized and excreted. One pathwayleads to very good metabolites called 2-hydroxy estrogens. The other pathway leads to bad metabolites called 4 or 16-hydroxy estrogens. DIM stimulates the favorable 2-hydroxy pathway for estrogen metabolism and this is how DIMworks to improve our health.DIM is not a hormone, nor is it a hormone replacement. It is a plant compound that will improve our hormonebalance. By improving the metabolism of our natural estrogens DIM will help lower high levels of estrogen in thebody. This alone can help remedy estrogen dominant conditions and restore a healthy estrogen/testosterone ratio inmen and women.The favorable 2-hydroxy metabolites promoted by DIM are potent anti-oxidants and help prevent muscle breakdownafter exercise, as evidenced by female athletes having less muscle tissue breakdown after intense exercise than men.By reducing the estrogen dominance and also reducing the accumulation of cancer-promoting 4/16-hydroxymetabolites DIM can help lower the risk of cancer.The 2-hydroxy metabolites help increase the active testosterone levels in men and women by displacing inactiveprotein-bound testosterone to its active free portion. This leads to significant improvements in the ability to buildmuscle and enjoy the benefits of testosterone including better mood, increased stamina, endurance, sex drive anderectile function.The accumulation of fat around the belly, hips and buttocks is partly due to excess estrogen levels combined withfalling testosterone levels. DIM will help lower excess estrogen and promote the fat-burning 2-hydroxy metabolites.This can help you achieve a leaner body with less body fat.

More here:
DIM for Hormone Balance - blog.healthybynaturehwc.com

Recommendation and review posted by Bethany Smith

Leslie Carol Botha: I originally posted this article in 2009. Thought it was well-written then and still think so. However, in the past two weeks readers of my blog have dug back into the HHH archives and have commented on their own hormonal anxiety so I decided to repost it in June 2012. Now 288 posts later it appears that hormone imbalance has become a silent epidemic affecting women of all ages.

Hormone imbalance -in the form of estrogen dominance which can cause hormone-related anxiety, insomnia, weight gain, emotional rage, phobias, and diabetes is due to the plastics in our environment. throw out all of your plastic water bottles they contain high amounts of estrogen mimickers, AND DO NOT MICROWAVE IN PLASTIC. Estrogen mimickers are found in food, household chemicals and our water supply from the high amounts of synthetic estrogen being excreted into the water streams from synthetic birth control and HRT. I kid you not. There have been plenty of articles about fishing changing their sex because of excreted hormones.

Lastly we are now 3 to 4 generations into synthetic hormone suppression, i.e., birth control (pills, IUDs implants, injections, rings, and patches). All of the estrogen is being built up in the body and passed in-utero to the fetus. So you will note many young women who have posted comments about hormone imbalance too. This is sad. We are upsetting the hormone chemical balance in the body. Women are suffering. And if we do not correct the imbalance it will only get worse. Such is the nature of not taking care of our health.

I believe that most women experience hormonal anxiety in one form or another. Unfortunately, the medical and psychiatric professions are quick to diagnosis and label with syndromes and then proceed to treat with drugs.

Now we know that source of this misdiagnosis is, in most cases hormone imbalance it can be corrected through nutritional supplementation, and hormone balancing. Most women are estrogen dependent. I have been recommending Progessence Plus that contains a wild yam extract infused with essential oils that repair the DNA and clear off the receptor sites on our cells so that the natural progesterone can be absorbed into the cell and not remain in fatty tissue of the body.

ehow.com By Shelly Mcrae, eHow Editor

2009

Everyone experiences anxiety at one point or another, such as before an important test in school, an important presentation at work, during the holidays or when experiencing a crisis of any kind. Anxiety in these instances help you stay alert, focus on tasks at hand or make quick decisions.

But when anxiety turns into an ongoing sense of apprehension, or begins to manifest as debilitating fear, it may be due to personality disorder or a hormonal imbalance. Its important to determine the cause of your anxiety and determine how to treat it.

When these fears and paranoid thoughts manifest themselves and then fade within 30 minutes or so, it is referred to as a panic attack. You may be so overwhelmed by the mental and physical symptoms that you feel unable to go on and instead try to escape, literally going home or someplace you feel safe. In such cases, you may have a personality disorder.

In cases in which hormonal imbalances are the root cause, as opposed to a personality disorder, the anxiety may not be so severe as to be labeled a panic attack. Rather, it more closely resembles mood swings or depression. But rather than feeling sad or irritable, you feel apprehension and uneasiness.

Anxiety induced by hormonal imbalances, such as estrogen dominance in which the level of the hormone progesterone is very low, differs from those panic attacks associated with personality disorders such as bipolar or obsessive-compulsive disorders. But there are also similarities. Determining the root cause of the anxiety can determine which treatment is appropriate.

The inability to control the onslaught of negative thoughts is symptomatic in both panic attacks and anxiety. Anxiety, though, may be more consistent and you may display fewer physical symptoms. You may feel that it is all in your head.

The sense of anxiety may not be as exaggerated as for those suffering from personality disorders. Instead, you may feel uneasy in social situations, be reluctant to make decisions or continually worry over problems that are relatively minor.

But your anxiety may not be limited to the more subtle form. In cases of severe hormonal imbalance, you may suffer full-blown panic attacks in which fear, though irrational, overwhelms your reasoning. You may be unable to explain why you are reacting to a simple incident as if it were a life crisis.

One of the characteristics of both panic attack and anxiety due to hormonal imbalances is the levels of cortisol in the system. Cortisol is the chemical released by the adrenals that activates the fight or flight response.The hypothalamic-pituitary-adrenal (HPA) axis is the hormonal system that controls your mood. If you suffer from a hormonal imbalance, this system may go into overdrive. The result is that your body and mind will believe a threatening situation exists, which in turn results in feelings of apprehension, fear and dread.

Treatments for hormonal imbalance range from basic lifestyle changes to replacement hormone therapy. Bioidentical hormones, which are naturally occurring hormones found in plants and synthesized for human consumption, are a common treatment when anxiety is one of the symptoms of hormonal imbalance.

In the case of severe panic attacks, such medications as benzodiazepines and antidepressants may be necessary to control the attacks. These are common treatments for personality disorders. (I DO NOT AGREE WITH THIS STATEMENT. LB.)

Left untreated, mild anxiety can worsen, resulting in debilitating behavior patterns due to unwarranted fear. Whether the underlying cause is personality disorder or hormonal imbalance, effective treatment is available.

Read More

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Hormonal Imbalance Anxiety a Precursor to Other Health ...

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What Is Hypopituitarism?

The pituitary gland is one of the smallest parts of the endocrine system, yet it is also one of the most important. Without this tiny gland functioning as it should, your body is not going to function well either. Hypopituitarism, also known as pituitary insufficiency, is one condition that affects this important gland and can impact the health and well-being of your entire body.

The pituitary gland is a small gland that sits at the base of the brain, right behind the nose and between the ears. This gland may be small, but its powerful hormones affect almost every area of the body. In fact, the gland is so important to the overall function of the body that it is sometimes called the "master gland." The pituitary gland signals other glands in the body to produce their own hormones, and as such has a role to play in almost every bodily function. A deficiency in these hormones can affect many different functions, including reproduction, sexual health, growth and blood pressure.

Hypopituitarism is a condition that occurs when the pituitary gland does not produce enough of its important hormones. Because the hormones are lacking, the condition is sometimes called pituitary insufficiency. It can occur for a variety of reasons and cause a wide range of symptoms because of the far-reaching effects of the pituitary gland.

Hypopituitarism has a wide range of causes. Sometimes, tumors, also known as adenomas, in the pituitary gland can interfere with the production of pituitary hormones. While these tumors are rarely cancerous, they can have far-reaching effects.

Some patients who have undergone radiation treatment to remove pituitary gland tumors may notice a poor function of the gland. This occurs because the pituitary gland tissue is destroyed during the radiation treatment. Similarly, chemotherapy can destroy the tissue and leave the pituitary gland without proper function.

Patients who have had brain surgery or a traumatic brain injury may have a pituitary insufficiency. Severe bleeding on the brain or loss of blood, especially if it occurs during childbirth, can also have this impact. Patients who have had meningitis or tuberculosis may have damaged pituitary glands. In a small portion of patients, the cause is never found.

Pituitary insufficiency is a rare condition, but for those who have it, this disease can be life changing. While it can be controlled with medication, it must be dealt with consistently to ensure that the patient suffers no ill effects from the hormonal insufficiencies.

Visit link:
What is Hypopituitarism, Pituitary Insufficiency | Hormone.org

Recommendation and review posted by simmons

Hypopituitarism in Children (cont.) Hypopituitarism Treatment

Treatment primarily involves hormone replacement therapy.

Drugs used to treat hypopituitarism replace the deficient hormone.

Surgery may be performed if a tumor is present within or near the pituitary gland, depending on the type and location of the tumor, and depending on the symptoms being experienced.

The doctor or health care practitioner may schedule routine checkups every three months to monitor growth and development.

Frequent checkups for children on growth hormone replacement therapy may be scheduled to monitor progress and side effects.

A doctor who specializes in studying hormones (a pediatric endocrinologist) should supervise the treatment of children with hypopituitarism.

With appropriate treatment, the prognosis is very good.

The Magic Foundation

The Hormone Foundation

John A. Seibel, MD; Board Certified Internal Medicine with a subspecialty in Endocrinology & Metabolism

REFERENCE:

"Causes and clinical manifestations of central adrenal insufficiency in children" UpToDate.com

Medically Reviewed by a Doctor on 12/24/2015

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Hypopituitarism in Children Causes, Symptoms, Treatment ...

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Solutions for less moustache and Beard growth

I am 21, but I dont have enough moustache and beard d in my face, how to grow it up, is there any medicines for it? My friends tease me.

I scared of getting married since my moustache and beard not developed. Would it affect my personal life?

Normally boys show their growth between the ages of 13 to 16 years. The secondary sexual characters like hair growth, starts from above the upper lip, chin and body. Only the sexual hormones bring these changes. Serum Testosterone is the authority for Masculine features. How Moustache and Beard develope?

Normally when the boy attains puberty, possible between ages of 13 to 16 years, the hair growth starts from above the upper lip, chin and body. This happens when the male sex hormone Testosterone is secreted from the testes. When a boy attains puberty, a centre in the brain called Hypothalamus, stimulates the Pituitary gland, which secretes two important hormones. The FSH ( Follicular stimulating hormone) stimulate the special cells in the Testes to produce sperms and the another hormone LH ( Luetinizing Hormone) stimulates the special cells to secretes the testosterone hormone. Testosterone is responsible for sudden growth in males with good musculature and bone density . The changes would lead to deepening in voice and enlargement of penis

Hair grows from hair follicles within the skin. There are about 50 million hair follicles covering the body of which one fifth is located in the scalp. Only the soles and palms are free of hair follicles. As long as follicles are not destroyed, hair continues to grow even if it is plucked, depilated or removed in any other fashion.

Various hormones control hair growth. Thyroid hormone and growth hormone affects hair growth. The most important hormone controlling growth are "androgens" commonly known as male hormones. Except in the scalp, androgens cause hair to change from "vellus" to "terminal". All women have terminal hair in some parts of the body, specifically the scalp, pubic and axillary area. A few hairs around the nipple or over the thighs may be normal. Hirsutism or excess body hair in women is the presence of thick, dark hair over the face, chest, abdomen, upper thighs or upper arms. It occurs when the androgenic hormone rises in some conditions.

The most important is Testosterone, one of a group of hormones called Androgens, which are responsible for "male" characteristics such as hair patterns and deeper voices. Hirsutism occurs when hair follicles become unusually sensitive to normal androgen levels in the blood, or when Androgen levels rise.

Every boy has same number of soft light colored hair on face in beard moustache area and other part of body. These are called vellus hair they are soft and light in colour , so that they are less easily visible. At the time of puberty and. beginning of genital development male hormone testosterone act on the various sensors in the hair roots of face and other parts of body. The blood supply in the hair root increases and hair grow from each follicle resulting in faster, darker and stronger hair. Thus in normal boys in two to three years full beard and moustache develops. When serum testosterone falls down the hair follicle fails or shows less growth

The vellus hair becomes dark terminal hair like our scalp hair and also appearance of hairs in pubis and armpits.

Testosterone is absolutely essential to maintain typical male features such as growth of beard and moustache, maintenance of bone and muscle strength, energy, and positive effect on mood, sperm production and sexual drive. Serum Testosterone is the authority for Masculine features.

Symptoms of Male Hypogonadism

Besides the retarded growth, there are many different symptoms of male hypogonadism. Coexists depend on the stage of life at which they occur. Symptoms during fetal development will differ from symptoms during puberty and adulthood

When the secretion falls down the youngsters may from

When the secretion falls downan adult may from

Retarded moustache , beard

Gynaecomastia

What Causes Male Hypogonadism?

Male Hypogonadism is caused by either an abnormality of the testicles or a defect in the pituitary gland. Hypothalamic dysfunction also encountered in many cases. Youngsters Testes fail to secrete Testosterone, when it has some congenital defects, following an infection such as mumps, other endocrine dysfunctions and tumours. Normally an adult, at the age of forty years may have reduced secretion. Sometimes smoking, alcoholism drugs and general diseases may enhance it. Even emotions may predispose.

There are few case in which the f hair roots resistant to normal level of testeosterone and its allied hormones. In this condition the hair roots do not grow because in hair root there is less male hormone receptor so that male hormone is unable to work and hair do not grow well.

How to rectify?

Homoeopathy finds solution to the problem successfully in many cases. The imaging study for Testes and brain will rule out the Endocrine pathology. A blood study on hormone will locate the problem. Unlike other systems of medicine Homoeopathy wont replace the hormones by a medicine; indeed it is applied naturally in dynamic doses to stimulate the blockage at the cellular level.

It is possible to maintains the axis equally between the Hypothalamus, pituitary and testicular functions to regenerate the testosterone level. The hair apparatus sensitivity could be enhanced by the dynamic application of the Homoeopathic remedies top respond The clinical studies had shown excellent results in the growth of Moustache, Beard, Erectile dysfunction and Infertility, due to low production of sperms Many cases had been demonstrated with blood study also scientifically.

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Hypogonadism No Moustache! No Beard

Recommendation and review posted by Bethany Smith

Actin is a family of globular multi-functional proteins that form microfilaments. It is found in essentially all eukaryotic cells (the only known exception being nematode sperm), where it may be present at a concentration of over 100 M. An actin protein's mass is roughly 42-kDa, with a diameter of 4 to 7nm, and it is the monomeric subunit of two types of filaments in cells: microfilaments, one of the three major components of the cytoskeleton, and thin filaments, part of the contractile apparatus in muscle cells. It can be present as either a free monomer called G-actin (globular) or as part of a linear polymer microfilament called F-actin (filamentous), both of which are essential for such important cellular functions as the mobility and contraction of cells during cell division.

Actin participates in many important cellular processes, including muscle contraction, cell motility, cell division and cytokinesis, vesicle and organelle movement, cell signaling, and the establishment and maintenance of cell junctions and cell shape. Many of these processes are mediated by extensive and intimate interactions of actin with cellular membranes.[2] In vertebrates, three main groups of actin isoforms, alpha, beta, and gamma have been identified. The alpha actins, found in muscle tissues, are a major constituent of the contractile apparatus. The beta and gamma actins coexist in most cell types as components of the cytoskeleton, and as mediators of internal cell motility. It is believed that the diverse range of structures formed by actin enabling it to fulfill such a large range of functions is regulated through the binding of tropomyosin along the filaments.[3]

A cells ability to dynamically form microfilaments provides the scaffolding that allows it to rapidly remodel itself in response to its environment or to the organisms internal signals, for example, to increase cell membrane absorption or increase cell adhesion in order to form cell tissue. Other enzymes or organelles such as cilia can be anchored to this scaffolding in order to control the deformation of the external cell membrane, which allows endocytosis and cytokinesis. It can also produce movement either by itself or with the help of molecular motors. Actin therefore contributes to processes such as the intracellular transport of vesicles and organelles as well as muscular contraction and cellular migration. It therefore plays an important role in embryogenesis, the healing of wounds and the invasivity of cancer cells. The evolutionary origin of actin can be traced to prokaryotic cells, which have equivalent proteins.[4] Actin homologs from prokaryotes and archaea polymerize into different helical or linear filaments consisting of one or multiple strands. However the in-strand contacts and nucleotide binding sites are preserved in prokaryotes and in archaea.[5] Lastly, actin plays an important role in the control of gene expression.

A large number of illnesses and diseases are caused by mutations in alleles of the genes that regulate the production of actin or of its associated proteins. The production of actin is also key to the process of infection by some pathogenic microorganisms. Mutations in the different genes that regulate actin production in humans can cause muscular diseases, variations in the size and function of the heart as well as deafness. The make-up of the cytoskeleton is also related to the pathogenicity of intracellular bacteria and viruses, particularly in the processes related to evading the actions of the immune system.[6]

Actin was first observed experimentally in 1887 by W.D. Halliburton, who extracted a protein from muscle that 'coagulated' preparations of myosin that he called "myosin-ferment".[7] However, Halliburton was unable to further refine his findings, and the discovery of actin is credited instead to Brun Ferenc Straub, a young biochemist working in Albert Szent-Gyrgyi's laboratory at the Institute of Medical Chemistry at the University of Szeged, Hungary.

In 1942, Straub developed a novel technique for extracting muscle protein that allowed him to isolate substantial amounts of relatively pure actin. Straub's method is essentially the same as that used in laboratories today. Szent-Gyorgyi had previously described the more viscous form of myosin produced by slow muscle extractions as 'activated' myosin, and, since Straub's protein produced the activating effect, it was dubbed actin. Adding ATP to a mixture of both proteins (called actomyosin) causes a decrease in viscosity. The hostilities of World War II meant Szent-Gyorgyi and Straub were unable to publish the work in Western scientific journals. Actin therefore only became well known in the West in 1945, when their paper was published as a supplement to the Acta Physiologica Scandinavica.[8] Straub continued to work on actin, and in 1950 reported that actin contains bound ATP[9] and that, during polymerization of the protein into microfilaments, the nucleotide is hydrolyzed to ADP and inorganic phosphate (which remain bound to the microfilament). Straub suggested that the transformation of ATP-bound actin to ADP-bound actin played a role in muscular contraction. In fact, this is true only in smooth muscle, and was not supported through experimentation until 2001.[9][10]

The amino acid sequencing of actin was completed by M. Elzinga and co-workers in 1973.[11] The crystal structure of G-actin was solved in 1990 by Kabsch and colleagues.[12] In the same year, a model for F-actin was proposed by Holmes and colleagues following experiments using co-crystallization with different proteins.[13] The procedure of co-crystallization with different proteins was used repeatedly during the following years, until in 2001 the isolated protein was crystallized along with ADP. However, there is still no high-resolution X-ray structure of F-actin. The crystallization of F-actin was possible due to the use of a rhodamine conjugate that impedes polymerization by blocking the amino acid cys-374.[1] Christine Oriol-Audit died in the same year that actin was first crystallized but she was the researcher that in 1977 first crystallized actin in the absence of Actin Binding Proteins (ABPs). However, the resulting crystals were too small for the available technology of the time.[14]

Although no high-resolution model of actins filamentous form currently exists, in 2008 Sawayas team were able to produce a more exact model of its structure based on multiple crystals of actin dimers that bind in different places.[15] This model has subsequently been further refined by Sawaya and Lorenz. Other approaches such as the use of cryo-electron microscopy and synchrotron radiation have recently allowed increasing resolution and better understanding of the nature of the interactions and conformational changes implicated in the formation of actin filaments.[16][17][18]

Its amino acid sequence is also one of the most highly conserved of the proteins as it has changed little over the course of evolution, differing by no more than 20% in species as diverse as algae and humans. It is therefore considered to have an optimised structure.[4] It has two distinguishing features: it is an enzyme that slowly hydrolizes ATP, the "universal energy currency" of biological processes. However, the ATP is required in order to maintain its structural integrity. Its efficient structure is formed by an almost unique folding process. In addition, it is able to carry out more interactions than any other protein, which allows it to perform a wider variety of functions than other proteins at almost every level of cellular life.[4]Myosin is an example of a protein that bonds with actin. Another example is villin, which can weave actin into bundles or cut the filaments depending on the concentration of calcium cations in the surrounding medium.[19]

Actin is one of the most abundant proteins in eukaryotes, where it is found throughout the cytoplasm.[19] In fact, in muscle fibres it comprises 20% of total cellular protein by weight and between 1% and 5% in other cells. However, there is not only one type of actin, the genes that code for actin are defined as a gene family (a family that in plants contains more than 60 elements, including genes and pseudogenes and in humans more than 30 elements).[4][20] This means that the genetic information of each individual contains instructions that generate actin variants (called isoforms) that possess slightly different functions. This, in turn, means that eukaryotic organisms express different genes that give rise to: -actin, which is found in contractile structures; -actin, found at the expanding edge of cells that use the projection of their cellular structures as their means of mobility; and -actin, which is found in the filaments of stress fibres.[21] In addition to the similarities that exist between an organisms isoforms there is also an evolutionary conservation in the structure and function even between organisms contained in different eukaryotic domains: in bacteria the actin homologue MreB has been identified, which is a protein that is capable of polymerizing into microfilaments;[4][17] and in archaea the homologue Ta0583 is even more similar to the eukaryotic actins.[22]

Cellular actin has two forms: monomeric globules called G-actin and polymeric filaments called F-actin (that is, as filaments made up of many G-actin monomers). F-actin can also be described as a microfilament. Two parallel F-actin strands must rotate 166 degrees to lie correctly on top of each other. This creates the double helix structure of the microfilaments found in the cytoskeleton. Microfilaments measure approximately 7 nm in diameter with the helix repeating every 37nm. Each molecule of actin is bound to a molecule of adenosine triphosphate (ATP) or adenosine diphosphate (ADP) that is associated with a Mg2+ cation. The most commonly found forms of actin, compared to all the possible combinations, are ATP-G-Actin and ADP-F-actin.[23][24]

Scanning electron microscope images indicate that G-actin has a globular structure; however, X-ray crystallography shows that each of these globules consists of two lobes separated by a cleft. This structure represents the ATPase fold, which is a centre of enzymatic catalysis that binds ATP and Mg2+ and hydrolyzes the former to ADP plus phosphate. This fold is a conserved structural motif that is also found in other proteins that interact with triphosphate nucleotides such as hexokinase (an enzyme used in energy metabolism) or in Hsp70 proteins (a protein family that play an important part in protein folding).[25] G-actin is only functional when it contains either ADP or ATP in its cleft but the form that is bound to ATP predominates in cells when actin is present in its free state.[23]

The X-ray crystallography model of actin that was produced by Kabsch from the striated muscle tissue of rabbits is the most commonly used in structural studies as it was the first to be purified. The G-actin crystallized by Kabsch is approximately 67 x 40 x 37 in size, has a molecular mass of 41,785 Da and an estimated isoelectric point of 4.8. Its net charge at pH = 7 is -7.[11][26]

Elzinga and co-workers first determined the complete peptide sequence for this type of actin in 1973, with later work by the same author adding further detail to the model. It contains 374 amino acid residues. Its N-terminus is highly acidic and starts with an acetyled aspartate in its amino group. While its C-terminus is alkaline and is formed by a phenylalanine preceded by a cysteine, which has a degree of functional importance. Both extremes are in close proximity within the I-subdomain. An anomalous N-methylhistidine is located at position 73.[26]

The tertiary structure is formed by two domains known as the large and the small, which are separated by a cleft centred around the location of the bond with ATP-ADP+Pi. Below this there is a deeper notch called a groove. In the native state, despite their names, both have a comparable depth.[11]

The normal convention in topological studies means that a protein is shown with the biggest domain on the left-hand side and the smallest domain on the right-hand side. In this position the smaller domain is in turn divided into two: subdomain I (lower position, residues 1-32, 70-144 and 338-374) and subdomain II (upper position, residues 33-69). The larger domain is also divided in two: subdomain III (lower, residues 145-180 and 270-337) and subdomain IV (higher, residues 181-269). The exposed areas of subdomains I and III are referred to as the barbed ends, while the exposed areas of domains II and IV are termed the pointed" ends. This nomenclature refers to the fact that, due to the small mass of subdomain II actin is polar; the importance of this will be discussed below in the discussion on assembly dynamics. Some authors call the subdomains Ia, Ib, IIa and IIb, respectively.[27]

The most notable supersecondary structure is a five chain beta sheet that is composed of a -meander and a -- clockwise unit. It is present in both domains suggesting that the protein arose from gene duplication.[12]

The classical description of F-actin states that it has a filamentous structure that can be considered to be a single stranded levorotatory helix with a rotation of 166 around the helical axis and an axial translation of 27.5 , or a single stranded dextrorotatory helix with a cross over spacing of 350-380 , with each actin surrounded by four more.[29] The symmetry of the actin polymer at 2.17 subunits per turn of a helix is incompatible with the formation of crystals, which is only possible with a symmetry of exactly 2, 3, 4 or 6 subunits per turn. Therefore, models have to be constructed that explain these anomalies using data from electron microscopy, cryo-electron microscopy, crystallization of dimers in different positions and diffraction of X-rays.[17][18] It should be pointed out that it is not correct to talk of a structure for a molecule as dynamic as the actin filament. In reality we talk of distinct structural states, in these the measurement of axial translation remains constant at 27.5 while the subunit rotation data shows considerable variability, with displacements of up to 10% from its optimum position commonly seen. Some proteins, such as cofilin appear to increase the angle of turn, but again this could be interpreted as the establishment of different "structural states". These could be important in the polymerization process.[30]

There is less agreement regarding measurements of the turn radius and filament thickness: while the first models assigned a longitude of 25 , current X-ray diffraction data, backed up by cryo-electron microscopy suggests a longitude of 23.7 . These studies have shown the precise contact points between monomers. Some are formed with units of the same chain, between the "barbed" end on one monomer and the "pointed" end of the next one. While the monomers in adjacent chains make lateral contact through projections from subdomain IV, with the most important projections being those formed by the C-terminus and the hydrophobic link formed by three bodies involving residues 39-42, 201-203 and 286. This model suggests that a filament is formed by monomers in a "sheet" formation, in which the subdomains turn about themselves, this form is also found in the bacterial actin homologue MreB.[17]

The F-actin polymer is considered to have structural polarity due to the fact that all the microfilaments subunits point towards the same end. This gives rise to a naming convention: the end that possesses an actin subunit that has its ATP binding site exposed is called the "(-) end", while the opposite end where the cleft is directed at a different adjacent monomer is called the "(+) end".[21] The terms "pointed" and "barbed" referring to the two ends of the microfilaments derive from their appearance under transmission electron microscopy when samples are examined following a preparation technique called "decoration". This method consists of the addition of myosin S1 fragments to tissue that has been fixed with tannic acid. This myosin forms polar bonds with actin monomers, giving rise to a configuration that looks like arrows with feather fletchings along its shaft, where the shaft is the actin and the fletchings are the myosin. Following this logic, the end of the microfilament that does not have any protruding myosin is called the point of the arrow (- end) and the other end is called the barbed end (+ end).[31] A S1 fragment is composed of the head and neck domains of myosin II. Under physiological conditions, G-actin (the monomer form) is transformed to F-actin (the polymer form) by ATP, where the role of ATP is essential.[32]

The helical F-actin filament found in muscles also contains a tropomyosin molecule, which is a 40 nanometre long protein that is wrapped around the F-actin helix.[18] During the resting phase the tropomyosin covers the actins active sites so that the actin-myosin interaction cannot take place and produce muscular contraction. There are other protein molecules bound to the tropomyosin thread, these are the troponins that have three polymers: troponin I, troponin T and troponin C.[33]

Actin can spontaneously acquire a large part of its tertiary structure.[35] However, the way it acquires its fully functional form from its newly synthesized native form is special and almost unique in protein chemistry. The reason for this special route could be the need to avoid the presence of incorrectly folded actin monomers, which could be toxic as they can act as inefficient polymerization terminators. Nevertheless, it is key to establishing the stability of the cytoskeleton, and additionally, it is an essential process for coordinating the cell cycle.[36][37]

CCT is required in order to ensure that folding takes place correctly. CCT is a group II cytosolic molecular chaperone (or chaperonin, a protein that assists in the folding of other macromolecular structures). CCT is formed of a double ring of eight different subunits (hetero-octameric) and it differs from other molecular chaperones, particularly from its homologue GroEL which is found in the Archaea, as it does not require a co-chaperone to act as a lid over the central catalytic cavity. Substrates bind to CCT through specific domains. It was initially thought that it only bound with actin and tubulin, although recent immunoprecipitation studies have shown that it interacts with a large number of polypeptides, which possibly function as substrates. It acts through ATP-dependent conformational changes that on occasion require several rounds of liberation and catalysis in order to complete a reaction.[38]

In order to successfully complete their folding, both actin and tubulin need to interact with another protein called prefoldin, which is a heterohexameric complex (formed by six distinct subunits), in an interaction that is so specific that the molecules have coevolved[citation needed]. Actin complexes with prefoldin while it is still being formed, when it is approximately 145 amino acids long, specifically those at the N-terminal.[39]

Different recognition sub-units are used for actin or tubulin although there is some overlap. In actin the subunits that bind with prefoldin are probably PFD3 and PFD4, which bind in two places one between residues 60-79 and the other between residues 170-198. The actin is recognized, loaded and delivered to the cytosolic chaperonin (CCT) in an open conformation by the inner end of prefoldins "tentacles (see the image and note).[35] The contact when actin is delivered is so brief that a tertiary complex is not formed, immediately freeing the prefoldin.[34]

The CCT then causes actin's sequential folding by forming bonds with its subunits rather than simply enclosing it in its cavity.[40] This is why it possesses specific recognition areas in its apical -domain. The first stage in the folding consists of the recognition of residues 245-249. Next, other determinants establish contact.[41] Both actin and tubulin bind to CCT in open conformations in the absence of ATP. In actins case, two subunits are bound during each conformational change, whereas for tubulin binding takes place with four subunits. Actin has specific binding sequences, which interact with the and -CCT subunits or with -CCT and -CCT. After AMP-PNP is bound to CCT the substrates move within the chaperonins cavity. It also seems that in the case of actin, the CAP protein is required as a possible cofactor in actin's final folding states.[37]

The exact manner by which this process is regulated is still not fully understood, but it is known that the protein PhLP3 (a protein similar to phosducin) inhibits its activity through the formation of a tertiary complex.[38]

Actin is an ATPase, which means that it is an enzyme that hydrolyzes ATP. This group of enzymes is characterised by their slow reaction rates. It is known that this ATPase is active, that is, its speed increases by some 40,000 times when the actin forms part of a filament.[30] A reference value for this rate of hydrolysis under ideal conditions is around 0.3 s1. Then, the Pi remains bound to the actin next to the ADP for a long time, until it is liberated next to the end of the filament.[42]

The exact molecular details of the catalytic mechanism are still not fully understood. Although there is much debate on this issue, it seems certain that a "closed" conformation is required for the hydrolysis of ATP, and it is thought that the residues that are involved in the process move to the appropriate distance.[30] The glutamic acid Glu137 is one of the key residues, which is located in subdomain 1. Its function is to bind the water molecule that produces a nucleophilic attack on the ATPs -phosphate bond, while the nucleotide is strongly bound to subdomains 3 and 4. The slowness of the catalytic process is due to the large distance and skewed position of the water molecule in relation to the reactant. It is highly likely that the conformational change produced by the rotation of the domains between actins G and F forms moves the Glu137 closer allowing its hydrolysis. This model suggests that the polymerization and ATPases function would be decoupled straight away.[17][18]

Principal interactions of structural proteins are at cadherin-based adherens junction. Actin filaments are linked to -actinin and to the membrane through vinculin. The head domain of vinculin associates to E-cadherin via -catenin, -catenin, and -catenin. The tail domain of vinculin binds to membrane lipids and to actin filaments.

Actin has been one of the most highly conserved proteins throughout evolution because it interacts with a large number of other proteins. It has 80.2% sequence conservation at the gene level between Homo sapiens and Saccharomyces cerevisiae (a species of yeast), and 95% conservation of the primary structure of the protein product.[4]

Although most yeasts have only a single actin gene, higher eukaryotes, in general, express several isoforms of actin encoded by a family of related genes. Mammals have at least six actin isoforms coded by separate genes,[43] which are divided into three classes (alpha, beta and gamma) according to their isoelectric points. In general, alpha actins are found in muscle (-skeletal, -aortic smooth, -cardiac, and 2-enteric smooth), whereas beta and gamma isoforms are prominent in non-muscle cells (- and 1-cytoplasmic). Although the amino acid sequences and in vitro properties of the isoforms are highly similar, these isoforms cannot completely substitute for one another in vivo.[44]

The typical actin gene has an approximately 100-nucleotide 5' UTR, a 1200-nucleotide translated region, and a 200-nucleotide 3' UTR. The majority of actin genes are interrupted by introns, with up to six introns in any of 19 well-characterised locations. The high conservation of the family makes actin the favoured model for studies comparing the introns-early and introns-late models of intron evolution.

All non-spherical prokaryotes appear to possess genes such as MreB, which encode homologues of actin; these genes are required for the cell's shape to be maintained. The plasmid-derived gene ParM encodes an actin-like protein whose polymerized form is dynamically unstable, and appears to partition the plasmid DNA into its daughter cells during cell division by a mechanism analogous to that employed by microtubules in eukaryotic mitosis.[45] Actin is found in both smooth and rough endoplasmic reticulums.

Actin polymerization and depolymerization is necessary in chemotaxis and cytokinesis. Nucleating factors are necessary to stimulate actin polymerization. One such nucleating factor is the Arp2/3 complex, which mimics a G-actin dimer in order to stimulate the nucleation (or formation of the first trimer) of monomeric G-actin. The Arp2/3 complex binds to actin filaments at 70 degrees to form new actin branches off existing actin filaments. Also, actin filaments themselves bind ATP, and hydrolysis of this ATP stimulates destabilization of the polymer.

The growth of actin filaments can be regulated by thymosin and profilin. Thymosin binds to G-actin to buffer the polymerizing process, while profilin binds to G-actin to exchange ADP for ATP, promoting the monomeric addition to the barbed, plus end of F-actin filaments.

F-actin is both strong and dynamic. Unlike other polymers, such as DNA, whose constituent elements are bound together with covalent bonds, the monomers of actin filaments are assembled by weaker bonds. The lateral bonds with neighbouring monomers resolve this anomaly, which in theory should weaken the structure as they can be broken by thermal agitation. In addition, the weak bonds give the advantage that the filament ends can easily release or incorporate monomers. This means that the filaments can be rapidly remodelled and can change cellular structure in response to an environmental stimulus. Which, along with the biochemical mechanism by which it is brought about is known as the "assembly dynamic".[6]

Studies focusing on the accumulation and loss of subunits by microfilaments are carried out in vitro (that is, in the laboratory and not on cellular systems) as the polymerization of the resulting actin gives rise to the same F-actin as produced in vivo. The in vivo process is controlled by a multitude of proteins in order to make it responsive to cellular demands, this makes it difficult to observe its basic conditions.[46]

In vitro production takes place in a sequential manner: first, there is the "activation phase", when the bonding and exchange of divalent cations occurs in specific places on the G-actin, which is bound to ATP. This produces a conformational change, sometimes called G*-actin or F-actin monomer as it is very similar to the units that are located on the filament.[27] This prepares it for the "nucleation phase", in which the G-actin gives rise to small unstable fragments of F-actin that are able to polymerize. Unstable dimers and trimers are initially formed. The "elongation phase" begins when there are a sufficiently large number of these short polymers. In this phase the filament forms and rapidly grows through the reversible addition of new monomers at both extremes.[47] Finally, a "stationary equilibrium" is achieved where the G-actin monomers are exchanged at both ends of the microfilament without any change to its total length.[19] In this last phase the "critical concentration Cc" is defined as the ratio between the assembly constant and the dissociation constant for G-actin, where the dynamic for the addition and elimination of dimers and trimers does not produce a change in the microfilament's length. Under normal in vitro conditions Cc is 0.1 M,[48] which means that at higher values polymerization occurs and at lower values depolymerization occurs.[49]

As indicated above, although actin hydrolyzes ATP, everything points to the fact that ATP is not required for actin to be assembled, given that, on one hand, the hydrolysis mainly takes place inside the filament, and on the other hand the ADP could also instigate polymerization. This poses the question of understanding which thermodynamically unfavourable process requires such a prodigious expenditure of energy. The so-called actin cycle, which couples ATP hydrolysis to actin polymerization, consists of the preferential addition of G-actin-ATP monomers to a filaments barbed end, and the simultaneous disassembly of F-actin-ADP monomers at the pointed end where the ADP is subsequently changed into ATP, thereby closing the cycle, this aspect of actin filament formation is known as treadmilling.

ATP is hydrolysed relatively rapidly just after the addition of a G-actin monomer to the filament. There are two hypotheses regarding how this occurs; the stochastic, which suggests that hydrolysis randomly occurs in a manner that is in some way influenced by the neighbouring molecules; and the vectoral, which suggests that hydrolysis only occurs adjacent to other molecules whose ATP has already been hydrolysed. In either case, the resulting Pi is not released, it remains for some time noncovalently bound to actins ADP, in this way there are three species of actin in a filament: ATP-Actin, ADP+Pi-Actin and ADP-Actin.[42][50] The amount of each one of these species present in a filament depends on its length and state: as elongation commences the filament has an approximately equal amount of actin monomers bound with ATP and ADP+Pi and a small amount of ADP-Actin at the (-) end. As the stationary state is reached the situation reverses, with ADP present along the majority of the filament and only the area nearest the (+) end containing ADP+Pi and with ATP only present at the tip.[51]

If we compare the filaments that only contain ADP-Actin with those that include ATP, in the former the critical constants are similar at both ends, while Cc for the other two nucleotides is different: At the (+) end Cc+=0.1 M, while at the (-) end Cc=0.8 M, which gives rise to the following situations:[21]

It is therefore possible to deduce that the energy produced by hydrolysis is used to create a true stationary state, that is a flux, instead of a simple equilibrium, one that is dynamic, polar and attached to the filament. This justifies the expenditure of energy as it promotes essential biological functions.[42] In addition, the configuration of the different monomer types is detected by actin binding proteins, which also control this dynamism, as will be described in the following section.

Microfilament formation by treadmilling has been found to be atypical in stereocilia. In this case the control of the structure's size is totally apical and it is controlled in some way by gene expression, that is, by the total quantity of protein monomer synthesized in any given moment.[52]

The actin cytoskeleton in vivo is not exclusively composed of actin, other proteins are required for its formation, continuance and function. These proteins are called actin-binding proteins (ABP) and they are involved in actins polymerization, depolymerization, stability, organisation in bundles or networks, fragmentation and destruction.[19] The diversity of these proteins is such that actin is thought to be the protein that takes part in the greatest number of protein-protein interactions.[54] For example, G-actin sequestering elements exist that impede its incorporation into microfilaments. There are also proteins that stimulate its polymerization or that give complexity to the synthesizing networks.[21]

Other proteins that bind to actin regulate the length of the microfilaments by cutting them, which gives rise to new active ends for polymerization. For example, if a microfilament with two ends is cut twice, there will be three new microfilaments with six ends. This new situation favors the dynamics of assembly and disassembly. The most notable of these proteins are gelsolin and cofilin. These proteins first achieve a cut by binding to an actin monomer located in the polymer they then change the actin monomers conformation while remaining bound to the newly generated (+) end. This has the effect of impeding the addition or exchange of new G-actin subunits. Depolymerization is encouraged as the (-) ends are not linked to any other molecule.[60]

Other proteins that bind with actin cover the ends of F-actin in order to stabilize them, but they are unable to break them. Examples of this type of protein are CapZ (that binds the (+) ends depending on a cells levels of Ca2+/calmodulin. These levels depend on the cells internal and external signals and are involved in the regulation of its biological functions).[61] Another example is tropomodulin (that binds to the (-) end). Tropomodulin basically acts to stabilize the F-actin present in the myofibrils present in muscle sarcomeres, which are structures characterized by their great stability.[62]

The Arp2/3 complex is widely found in all eukaryotic organisms.[64] It is composed of seven subunits, some of which possess a topology that is clearly related to their biological function: two of the subunits, "ARP2 and "ARP3, have a structure similar to that of actin monomers. This homology allows both units to act as nucleation agents in the polymerization of G-actin and F-actin. This complex is also required in more complicated processes such as in establishing dendritic structures and also in anastomosis (the reconnection of two branching structures that had previously been joined, such as in blood vessels).[65]

There are a number of toxins that interfere with actins dynamics, either by preventing it from polymerizing (latrunculin and cytochalasin D) or by stabilizing it (phalloidin):

Actin forms filaments ('F-actin' or microfilaments) that are essential elements of the eukaryotic cytoskeleton, able to undergo very fast polymerization and depolymerization dynamics. In most cells actin filaments form larger-scale networks which are essential for many key functions in cells:[69]

The actin protein is found in both the cytoplasm and the cell nucleus.[70] Its location is regulated by cell membrane signal transduction pathways that integrate the stimuli that a cell receives stimulating the restructuring of the actin networks in response. In Dictyostelium, phospholipase D has been found to intervene in inositol phosphate pathways.[71] Actin filaments are particularly stable and abundant in muscle fibres. Within the sarcomere (the basic morphological and physiological unit of muscle fibres) actin is present in both the I and A bands; myosin is also present in the latter.[72]

Microfilaments are involved in the movement of all mobile cells, including non-muscular types, and drugs that disrupt F-actin organization (such as the cytochalasins) affect the activity of these cells. Actin comprises 2% of the total amount of proteins in hepatocytes, 10% in fibroblasts, 15% in amoebas and up to 50-80% in activated platelets.[73] There are a number of different types of actin with slightly different structures and functions. This means that -actin is found exclusively in muscle fibres, while types and are found in other cells. In addition, as the latter types have a high turnover rate the majority of them are found outside permanent structures. This means that the microfilaments found in cells other than muscle cells are present in two forms:[74]

Actins cytoskeleton is key to the processes of endocytosis, cytokinesis, determination of cell polarity and morphogenesis in yeasts. In addition to relying on actin these processes involve 20 or 30 associated proteins, which all have a high degree of evolutionary conservation, along with many signalling molecules. Together these elements allow a spatially and temporally modulated assembly that defines a cells response to both internal and external stimuli.[76]

Yeasts contain three main elements that are associated with actin: patches, cables and rings that, despite being present for long, are subject to a dynamic equilibrium due to continual polymerization and depolymerization. They possess a number of accessory proteins including ADF/cofilin, which has a molecular weight of 16kDa and is coded for by a single gene, called COF1; Aip1, a cofilin cofactor that promotes the disassembly of microfilaments; Srv2/CAP, a process regulator related to adenylate cyclase proteins; a profilin with a molecular weight of approximately 14 kDa that is associated with actin monomers; and twinfilin, a 40 kDa protein involved in the organization of patches.[76]

Plant genome studies have revealed the existence of protein isovariants within the actin family of genes. Within Arabidopsis thaliana, a dicotyledon used as a model organism, there are ten types of actin, nine types of -tubulins, six -tubulins, six profilins and dozens of myosins. This diversity is explained by the evolutionary necessity of possessing variants that slightly differ in their temporal and spatial expression.[4] The majority of these proteins were jointly expressed in the tissue analysed. Actin networks are distributed throughout the cytoplasm of cells that have been cultivated in vitro. There is a concentration of the network around the nucleus that is connected via spokes to the cellular cortex, this network is highly dynamic, with a continuous polymerization and depolymerization.[77]

Even though the majority of plant cells have a cell wall that defines their morphology and impedes their movement, their microfilaments can generate sufficient force to achieve a number of cellular activities, such as, the cytoplasmic currents generated by the microfilaments and myosin. Actin is also involved in the movement of organelles and in cellular morphogenesis, which involve cell division as well as the elongation and differentiation of the cell.[79]

The most notable proteins associated with the actin cytoskeleton in plants include:[79]villin, which belongs to the same family as gelsolin/severin and is able to cut microfilaments and bind actin monomers in the presence of calcium cations; fimbrin, which is able to recognize and unite actin monomers and which is involved in the formation of networks (by a different regulation process from that of animals and yeasts);[80]formins, which are able to act as an F-actin polymerization nucleating agent; myosin, a typical molecular motor that is specific to eukaryotes and which in Arabidopsis thaliana is coded for by 17 genes in two distinct classes; CHUP1, which can bind actin and is implicated in the spatial distribution of chloroplasts in the cell; KAM1/MUR3 that define the morphology of the Golgi apparatus as well as the composition of xyloglucans in the cell wall; NtWLIM1, which facilitates the emergence of actin cell structures; and ERD10, which is involved in the association of organelles within membranes and microfilaments and which seems to play a role that is involved in an organisms reaction to stress.

Nuclear actin was first noticed and described in 1977 by Clark and Merriam.[81] Authors describe a protein present in the nuclear fraction, obtained from Xenopus laevis oocytes, which shows the same features such skeletal muscle actin. Since that time there have been many scientific reports about the structure and functions of actin in the nucleus (for review see: Hofmann 2009.[82]) The controlled level of actin in the nucleus, its interaction with actin-binding proteins (ABP) and the presence of different isoforms allows actin to play an important role in many important nuclear processes.

The actin sequence does not contain a nuclear localization signal. The small size of actin (about 43 kDa) allows it to enter the nucleus by passive diffusion.[83] Actin however shuttles between cytoplasm and nucleus quite quickly, which indicates the existence of active transport. The import of actin into the nucleus (probably in a complex with cofilin) is facilitated by the import protein importin 9.[84]

Low level of actin in the nucleus seems to be very important, because actin has two nuclear export signals (NES) into its sequence. Microinjected actin is quickly removed from the nucleus to the cytoplasm. Actin is exported at least in two ways, through exportin 1 (EXP1) and exportin 6 (Exp6).[85][86]

Specific modifications, such as SUMOylation, allows for nuclear actin retention. It was demonstrated that a mutation preventing SUMOylation causes rapid export of beta actin from the nucleus.[87]

Based on the experimental results a general mechanism of nuclear actin transport can be proposed:[87][88]

Nuclear actin exists mainly as a monomer, but can also form dynamic oligomers and short polymers.[89][90][91] Nuclear actin organization varies in different cell types. For example, in Xenopus oocytes (with higher nuclear actin level in comparison to somatic cells) actin forms filaments, which stabilize nucleus architecture. These filaments can be observed under the microscope thanks to fluorophore-conjugated phalloidin staining.[81][83]

In somatic cell nucleus however we cannot observe any actin filaments using this technique.[92] The DNase I inhibition assay, so far the only test which allows the quantification of the polymerized actin directly in biological samples, have revealed that endogenous nuclear actin occurs indeed mainly in a monomeric form.[91]

Precisely controlled level of actin in the cell nucleus, lower than in the cytoplasm, prevents the formation of filaments. The polymerization is also reduced by the limited access to actin monomers, which are bound in complexes with ABPs, mainly cofilin.[88]

Little attention is paid to actin isoforms, however it has been shown that different isoforms of actin are present in the cell nucleus. Actin isoforms, despite of their high sequence similarity, have different biochemical properties such as polymerization and depolymerization kinetic.[93] They also shows different localization and functions.

The level of actin isoforms, both in the cytoplasm and the nucleus, may change for example in response to stimulation of cell growth or arrest of proliferation and transcriptional activity.[94]

Research concerns on nuclear actin are usually focused on isoform beta.[95][96][97][98] However the use of antibodies directed against different actin isoforms allows identifying not only the cytoplasmic beta in the cell nucleus, but also:

The presence of different isoforms of actin may have a significant effect on its function in nuclear processes, especially because the level of individual isoforms can be controlled independently.[91]

Functions of actin in the nucleus are associated with its ability to polymerization, interaction with variety of ABPs and with structural elements of the nucleus. Nuclear actin is involved in:

Due to its ability to conformational changes and interaction with many proteins actin acts as a regulator of formation and activity of protein complexes such as transcriptional complex.[105]

In muscle cells, actomyosin myofibrils makeup much of the cytoplasmic material. These myofibrils are made of thin filaments of actin (typically around 7nm in diameter), and thick filaments of the motor-protein myosin (typically around 15nm in diameter).[121] These myofibrils use energy derived from ATP to create movements of cells, such as muscle contraction.[121] Using the hydrolysis of ATP for energy, myosin heads undergo a cycle during which they attach to thin filaments, exert a tension, and then, depending on the load, perform a power stroke that causes the thin filaments to slide past, shortening the muscle.

In contractile bundles, the actin-bundling protein alpha-actinin separates each thin filament by ~35nm. This increase in distance allows thick filaments to fit in between and interact, enabling deformation or contraction. In deformation, one end of myosin is bound to the plasma membrane, while the other end "walks" toward the plus end of the actin filament. This pulls the membrane into a different shape relative to the cell cortex. For contraction, the myosin molecule is usually bound to two separate filaments and both ends simultaneously "walk" toward their filament's plus end, sliding the actin filaments closer to each other. This results in the shortening, or contraction, of the actin bundle (but not the filament). This mechanism is responsible for muscle contraction and cytokinesis, the division of one cell into two.

The helical F-actin filament found in muscles also contains a tropomyosin molecule, a 40-nanometre protein that is wrapped around the F-actin helix. During the resting phase the tropomyosin covers the actins active sites so that the actin-myosin interaction cannot take place and produce muscular contraction (the interaction gives rise to a movement between the two proteins that, because it is repeated many times, produces a contraction). There are other protein molecules bound to the tropomyosin thread, these include the troponins that have three polymers: troponin I, troponin T, and troponin C.[33] Tropomyosins regulatory function depends on its interaction with troponin in the presence of Ca2+ ions.[122]

Both actin and myosin are involved in muscle contraction and relaxation and they make up 90% of muscle protein.[123] The overall process is initiated by an external signal, typically through an action potential stimulating the muscle, which contains specialized cells whose interiors are rich in actin and myosin filaments. The contraction-relaxation cycle comprises the following steps:[72]

The traditional image of actins function relates it to the maintenance of the cytoskeleton and, therefore, the organization and movement of organelles, as well as the determination of a cells shape.[74] However, actin has a wider role in eukaryotic cell physiology, in addition to similar functions in prokaryotes.

The majority of mammals possess six different actin genes. Of these, two code for the cytoskeleton (ACTB and ACTG1) while the other four are involved in skeletal striated muscle (ACTA1), smooth muscle tissue (ACTA2), intestinal muscles (ACTG2) and cardiac muscle (ACTC1). The actin in the cytoskeleton is involved in the pathogenic mechanisms of many infectious agents, including HIV. The vast majority of the mutations that affect actin are point mutations that have a dominant effect, with the exception of six mutations involved in nemaline myopathy. This is because in many cases the mutant of the actin monomer acts as a cap by preventing the elongation of F-actin.[27]

ACTA1 is the gene that codes for the -isoform of actin that is predominant in human skeletal striated muscles, although it is also expressed in heart muscle and in the thyroid gland.[141] Its DNA sequence consists of seven exons that produce five known transcripts.[142] The majority of these consist of point mutations causing substitution of amino acids. The mutations are in many cases associated with a phenotype that determines the severity and the course of the affliction.[27][142]

The mutation alters the structure and function of skeletal muscles producing one of three forms of myopathy: type 3 nemaline myopathy, congenital myopathy with an excess of thin myofilaments (CM) and Congenital myopathy with fibre type disproportion (CMFTD). Mutations have also been found that produce core myopathies).[144] Although their phenotypes are similar, in addition to typical nemaline myopathy some specialists distinguish another type of myopathy called actinic nemaline myopathy. In the former, clumps of actin form instead of the typical rods. It is important to state that a patient can show more than one of these phenotypes in a biopsy.[145] The most common symptoms consist of a typical facial morphology (myopathic faces), muscular weakness, a delay in motor development and respiratory difficulties. The course of the illness, its gravity and the age at which it appears are all variable and overlapping forms of myopathy are also found. A symptom of nemalinic myopathy is that Nemaline rods appear in differing places in Type 1 muscle fibres. These rods are non-pathognomonic structures that have a similar composition to the Z disks found in the sarcomere.[146]

The pathogenesis of this myopathy is very varied. Many mutations occur in the region of actins indentation near to its nucleotide binding sites, while others occur in Domain 2, or in the areas where interaction occurs with associated proteins. This goes some way to explain the great variety of clumps that form in these cases, such as Nemaline or Intranuclear Bodies or Zebra Bodies.[27] Changes in actins folding occur in nemaline myopathy as well as changes in its aggregation and there are also changes in the expression of other associated proteins. In some variants where intranuclear bodies are found the changes in the folding masks the nucleuss protein exportation signal so that the accumulation of actin's mutated form occurs in the cell nucleus.[147] On the other hand, it appears that mutations to ACTA1 that give rise to a CFTDM have a greater effect on sarcomeric function than on its structure.[148] Recent investigations have tried to understand this apparent paradox, which suggests there is no clear correlation between the number of rods and muscular weakness. It appears that some mutations are able to induce a greater apoptosis rate in type II muscular fibres.[36]

There are two isoforms that code for actins in the smooth muscle tissue:

ACTG2 codes for the largest actin isoform, which has nine exons, one of which, the one located at the 5' end, is not translated.[149] It is an -actin that is expressed in the enteric smooth muscle. No mutations to this gene have been found that correspond to pathologies, although microarrays have shown that this protein is more often expressed in cases that are resistant to chemotherapy using cisplatin.[150]

ACTA2 codes for an -actin located in the smooth muscle, and also in vascular smooth muscle. It has been noted that the MYH11 mutation could be responsible for at least 14% of hereditary thoracic aortic aneurisms particularly Type 6. This is because the mutated variant produces an incorrect filamentary assembly and a reduced capacity for vascular smooth muscle contraction. Degradation of the aortic media has been recorded in these individuals, with areas of disorganization and hyperplasia as well as stenosis of the aortas vasa vasorum.[151] The number of afflictions that the gene is implicated in is increasing. It has been related to Moyamoya disease and it seems likely that certain mutations in heterozygosis could confer a predisposition to many vascular pathologies, such as thoracic aortic aneurysm and ischaemic heart disease.[152] The -actin found in smooth muscles is also an interesting marker for evaluating the progress of liver cirrhosis.[153]

The ACTC1 gene codes for the -actin isoform present in heart muscle. It was first sequenced by Hamada and co-workers in 1982, when it was found that it is interrupted by five introns.[154] It was the first of the six genes where alleles were found that were implicated in pathological processes.[155]

A number of structural disorders associated with point mutations of this gene have been described that cause malfunctioning of the heart, such as Type 1R dilated cardiomyopathy and Type 11 hypertrophic cardiomyopathy. Certain defects of the atrial septum have been described recently that could also be related to these mutations.[157][158]

Two cases of dilated cardiomyopathy have been studied involving a substitution of highly conserved amino acids belonging to the protein domains that bind and intersperse with the Z discs. This has led to the theory that the dilation is produced by a defect in the transmission of contractile force in the myocytes.[29][155]

The mutations inACTC1 are responsible for at least 5% of hypertrophic cardiomyopathies.[159] The existence of a number of point mutations have also been found:[160]

Pathogenesis appears to involve a compensatory mechanism: the mutated proteins act like toxins with a dominant effect, decreasing the hearts ability to contract causing abnormal mechanical behaviour such that the hypertrophy, that is usually delayed, is a consequence of the cardiac muscles normal response to stress.[161]

Recent studies have discovered ACTC1 mutations that are implicated in two other pathological processes: Infantile idiopathic restrictive cardiomyopathy,[162] and noncompaction of the left ventricular myocardium.[163]

ACTB is a highly complex locus. A number of pseudogenes exist that are distributed throughout the genome, and its sequence contains six exons that can give rise to up to 21 different transcriptions by alternative splicing, which are known as the -actins. Consistent with this complexity, its products are also found in a number of locations and they form part of a wide variety of processes (cytoskeleton, NuA4 histone-acyltransferase complex, cell nucleus) and in addition they are associated with the mechanisms of a great number of pathological processes (carcinomas, juvenile dystonia, infection mechanisms, nervous system malformations and tumour invasion, among others).[164] A new form of actin has been discovered, kappa actin, which appears to substitute for -actin in processes relating to tumours.[165]

Three pathological processes have so far been discovered that are caused by a direct alteration in gene sequence:

The ACTG1 locus codes for the cytosolic -actin protein that is responsible for the formation of cytoskeletal microfilaments. It contains six exons, giving rise to 22 different mRNAs, which produce four complete isoforms whose form of expression is probably dependent on the type of tissue they are found in. It also has two different DNA promoters.[170] It has been noted that the sequences translated from this locus and from that of -actin are very similar to the predicted ones, suggesting a common ancestral sequence that suffered duplication and genetic conversion.[171]

In terms of pathology, it has been associated with processes such as amyloidosis, retinitis pigmentosa, infection mechanisms, kidney diseases and various types of congenital hearing loss.[170]

Six autosomal-dominant point mutations in the sequence have been found to cause various types of hearing loss, particularly sensorineural hearing loss linked to the DFNA 20/26 locus. It seems that they affect the stereocilia of the ciliated cells present in the inner ears Organ of Corti. -actin is the most abundant protein found in human tissue, but it is not very abundant in ciliated cells, which explains the location of the pathology. On the other hand, it appears that the majority of these mutations affect the areas involved in linking with other proteins, particularly actomyosin.[27] Some experiments have suggested that the pathological mechanism for this type of hearing loss relates to the F-actin in the mutations being more sensitive to cofilin than normal.[172]

However, although there is no record of any case, it is known that -actin is also expressed in skeletal muscles, and although it is present in small quantities, model organisms have shown that its absence can give rise to myopathies.[173]

Some infectious agents use actin, especially cytoplasmic actin, in their life cycle. Two basic forms are present in bacteria:

In addition to the previously cited example, actin polymerization is stimulated in the initial steps of the internalization of some viruses, notably HIV, by, for example, inactivating the cofilin complex.[178]

The role that actin plays in the invasion process of cancer cells has still not been determined.[179]

The eukaryotic cytoskeleton of organisms among all taxonomic groups have similar components to actin and tubulin. For example, the protein that is coded by the ACTG2 gene in humans is completely equivalent to the homologues present in rats and mice, even though at a nucleotide level the similarity decreases to 92%.[149] However, there are major differences with the equivalents in prokaryotes (FtsZ and MreB), where the similarity between nucleotide sequences is between 4050% among different bacteria and archaea species. Some authors suggest that the ancestral protein that gave rise to the model eukaryotic actin resembles the proteins present in modern bacterial cytoskeletons.[4][180]

Some authors point out that the behaviour of actin, tubulin and histone, a protein involved in the stabilization and regulation of DNA, are similar in their ability to bind nucleotides and in their ability of take advantage of Brownian motion. It has also been suggested that they all have a common ancestor.[181] Therefore, evolutionary processes resulted in the diversification of ancestral proteins into the varieties present today, conserving, among others, actins as efficient molecules that were able to tackle essential ancestral biological processes, such as endocytosis.[182]

Continued here:
Actin - Wikipedia

Recommendation and review posted by simmons

Beefalo, also referred to as cattalo or the American hybrid, are a fertile hybrid offspring of domestic cattle (Bos taurus), usually a male in managed breeding programs, and the American bison (Bison bison), usually a female in managed breeding programs.[1][2] The breed was created to combine the characteristics of both animals for beef production.

Beefalo are primarily cattle in genetics and appearance, with the breed association defining a full Beefalo as one with three-eighths (37.5%) bison genetics, while animals with higher percentages of bison genetics are called "bison hybrids".

Accidental crosses were noticed as long ago as 1749 in the southern English colonies of North America. Beef and bison were first intentionally crossbred during the mid-19th century.

The first deliberate attempts to cross breed bison with cattle was made by Colonel Samuel Bedson, warden of Stoney Mountain Penitentiary, Winnipeg, in 1880. Bedson bought eight bison from a captive herd of James McKay and inter-bred them with Durham cattle. The hybrids raised by Bedson were described by naturalist Ernest Thompson Seton:[3]

The hybrid animal is [claimed] to be a great improvement on both of its progenitors, as it is more docile and a better milker than the Buffalo, but retains its hardihood, while the robe is finer, darker and more even, and the general shape of the animal is improved by the reduction of the hump and increased proportion of the hind-quarters.

After seeing thousands of cattle die in a Kansas blizzard in 1886, Charles "Buffalo" Jones, a co-founder of Garden City, Kansas, also worked to cross bison and cattle at a ranch near the future Grand Canyon National Park, with the hope the animals could survive the harsh winters.[4] He called the result "cattalo" in 1888.[5]Mossom Boyd of Bobcaygeon, Ontario first started the practice in Canada, publishing about some of his outcomes in the Journal of Heredity.[6] After his death in 1914, the Canadian government continued experiments in crossbreeding up to 1964, with little success. For example, in 1936 the Canadian government had successfully cross-bred only 30 cattalos.[7] Lawrence Boyd continues the crossbreeding work of his grandfather on a farm in Alberta.[citation needed]

It was found early on that crossing a male bison with a domestic cow would produce few offspring, but that crossing a domestic bull with a bison cow apparently solved the problem. The female offspring proved fertile, but rarely so for the males. Although the cattalo performed well, the mating problems meant the breeder had to maintain a herd of wild and difficult-to-handle bison cows.[citation needed]

In 1965, Jim Burnett of Montana produced a hybrid bull that was fertile. Soon after, Cory Skowronek of California formed the World Beefalo Association and began marketing the hybrids as a new breed. The new name, Beefalo, was meant to separate this hybrid from the problems associated with the old cattalo hybrids. The breed was eventually set at being genetically at least five-eighths Bos taurus and at most three-eighths Bison bison.

A United States Department of Agriculture study[citation needed] found Beefalo meat, like bison meat, to be lower in fat and cholesterol than standard beef cattle. The American Beefalo Association states that Beefalo are better able to tolerate cold and need less assistance calving than cattle, while retaining domestic cattle's docile nature and fast growth rate. They damage rangeland less than cattle.[8] They also state that Beefalo meat contains 4 to 6% more protein and is more tender, flavorful, and nutritious than a standard steer.[8] Beefalo has significantly less calories, fat, and cholesterol, than beef cattle, chicken, and cod.[9]

The American Beefalo Association states that the "crossbreeds are hardier, are more economical (and less care-intensive) to nurture, and produce meat that's superior to that of the common cow."[8]

In 1983, the three main Beefalo registration groups reorganized under the American Beefalo World Registry. Until November 2008, there were two Beefalo associations, the American Beefalo World Registry[10] and American Beefalo International. These organizations jointly formed the American Beefalo Association, Inc., which currently operates as the registering body for Beefalo in the United States.[11]

Most current bison herds are genetically polluted or partly crossbred with cattle.[12][13][14][15] There are only four genetically unmixed American bison herds left, and only two that are also free of brucellosis, the Wind Cave bison herd that roams Wind Cave National Park, South Dakota; and the Henry Mountains herd in the Henry Mountains of Utah.[16] A herd on Catalina island, California is not genetically pure or self-sustaining.

Dr. Dirk Van Vuren, formerly of the University of Kansas, however, points out that "The bison today that carry cattle DNA look exactly like bison, function exactly like bison and in fact are bison. For conservation groups, the interest is that they are not totally pure."[17]

The term "cattalo" is defined by United States law as a cross of bison and cattle which have a bison appearance;[18] in Canada, however, the term is used for hybrids of all degrees and appearance. In the U.S., cattalo are regulated as "exotic animals", along with pure bison and deer.

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Beefalo - Wikipedia

Recommendation and review posted by simmons

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Heart / Circulation - Life Extension Vitamins

Recommendation and review posted by sam

Some people believe that calico cats are a breed, or that calico refers to a color of a cat. Since all cats are colored, calico refers to the pattern of how the coloring appears on the cat's coat.

According to a leading expert in Feline Genetics, Dr. Elizabeth A. Oltenacu of the Department of Animal Science at Cornell University:

"Early in its inception, a calico/tortie kitty is formed by a gene known as the white spotting factor. The white spotting factor effectively slows down the migration of cells across the kitten's body. One X-chromosome in every cell is switched off.

This is a random happenstance, and when a tortoiseshell kitten appears in the litter, you will see a mix of two colors of hair on the kitten.

In a calico kitten, the white spotting factor being present allows patches of cells with the same X chromosome shut-off to develop.

The results are patches of white, orange, and non-orange in the kitten. The more white in a calico, the larger the patches of white, orange and non-orange because the migration of cells in the embryo is slowed. Once the color is in patches, you can see the effect of the tabby genes in the orange patches."

Calico cats are overwhelmingly female. According to The Cat Fancier's Association Complete Cat Book; Persian calico cats have been accepted by CFA for years and calico Persians are always female and give birth to black-and-white or red and white bi-colored sons.

Genetically, two X chromosomes are needed to produce a calico coat, which is why the majority of calico cats are females. If the colors are black/orange upon the coat, then the cat is a calico cat. If the colors are blue/cream instead of the standard black/orange, then the cat is a muted calico.

Dr. Oltenacu further explains: "There's a gene on the X-chromosome that controls orange/non-orange color. One form (allele) determines orange, the other allele non-orange (usually black, but the actual color is determined by other genes on the autosomes). Neither form is dominant to the other, so a cat with one of each is a tortie.

It has to be female, as this requires 2 X-chromosomes. Sometimes an abnormal male is born XXY instead of the usual XY, so can be tortie.

Clearly, this male is the result of inaccurate separation of the chromosomes during egg or sperm formation. Usually, males are orange or non-orange, but not tortie as they have just one X-chromosome.

Now, if the cat also has the white-spotting gene (again autosomal, not on the sex chromosome). This will cause the color to be in patches, rather than the diffuse mix of orange and black in the tortie. Hence the calico."

If the majority of calico cats are female, then does this make male calicos valuable? For cat lovers, a calico cat, regardless of gender is valuable to the owner. Calico cats are quirky, independent, a tad stubborn and fun to be around.

It is clear that calico cats have captivated hearts of cat fanciers around the world. On October 1, 2001 the state of Maryland was so enamored with this delightful cat that they declared the calico cat as their official state cat.

The author wishes to acknowledge her great appreciation for Dr. Oltenacu's assistance in preparing this article.

Comments? Leave them using the form below. Questions? Please use the cat forums for those!

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Calico Cats - TheCatSite.com Community

Recommendation and review posted by simmons

This article is about skin in humans. For other animals, see skin.

The human skin is the outer covering of the body. In humans, it is the largest organ of the integumentary system. The skin has up to seven layers of ectodermal tissue and guards the underlying muscles, bones, ligaments and internal organs.[1] Human skin is similar to that of most other mammals. Though nearly all human skin is covered with hair follicles, it can appear hairless. There are two general types of skin, hairy and glabrous skin.[2] The adjective cutaneous literally means "of the skin" (from Latin cutis, skin).

Because it interfaces with the environment, skin plays an important immunity role in protecting the body against pathogens[3] and excessive water loss.[4] Its other functions are insulation, temperature regulation, sensation, synthesis of vitamin D, and the protection of vitamin B folates. Severely damaged skin will try to heal by forming scar tissue. This is often discolored and depigmented.

In humans, skin pigmentation varies among populations, and skin type can range from dry to oily. Such skin variety provides a rich and diverse habitat for bacteria that number roughly 1000 species from 19 phyla, present on the human skin.[5][6]

Skin has mesodermal cells, pigmentation, such as melanin provided by melanocytes, which absorb some of the potentially dangerous ultraviolet radiation (UV) in sunlight. It also contains DNA repair enzymes that help reverse UV damage, such that people lacking the genes for these enzymes suffer high rates of skin cancer. One form predominantly produced by UV light, malignant melanoma, is particularly invasive, causing it to spread quickly, and can often be deadly. Human skin pigmentation varies among populations in a striking manner. This has led to the classification of people(s) on the basis of skin color.[7]

The skin is the largest organ in the human body. For the average adult human, the skin has a surface area of between 1.5-2.0 square metres (16.1-21.5 sq ft.). The thickness of the skin varies considerably over all parts of the body, and between men and women and the young and the old. An example is the skin on the forearm which is on average 1.3mm in the male and 1.26mm in the female.[8] The average square inch (6.5cm) of skin holds 650 sweat glands, 20 blood vessels, 60,000 melanocytes, and more than 1,000 nerve endings.[9][bettersourceneeded] The average human skin cell is about 30 micrometers in diameter, but there are variants. A skin cell usually ranges from 25-40 micrometers (squared), depending on a variety of factors.

Skin is composed of three primary layers: the epidermis, the dermis and the hypodermis.[8]

Epidermis, "epi" coming from the Greek meaning "over" or "upon", is the outermost layer of the skin. It forms the waterproof, protective wrap over the body's surface which also serves as a barrier to infection and is made up of stratified squamous epithelium with an underlying basal lamina.

The epidermis contains no blood vessels, and cells in the deepest layers are nourished almost exclusively by diffused oxygen from the surrounding air[10] and to a far lesser degree by blood capillaries extending to the outer layers of the dermis. The main type of cells which make up the epidermis are Merkel cells, keratinocytes, with melanocytes and Langerhans cells also present. The epidermis can be further subdivided into the following strata (beginning with the outermost layer): corneum, lucidum (only in palms of hands and bottoms of feet), granulosum, spinosum, basale. Cells are formed through mitosis at the basale layer. The daughter cells (see cell division) move up the strata changing shape and composition as they die due to isolation from their blood source. The cytoplasm is released and the protein keratin is inserted. They eventually reach the corneum and slough off (desquamation). This process is called "keratinization". This keratinized layer of skin is responsible for keeping water in the body and keeping other harmful chemicals and pathogens out, making skin a natural barrier to infection.

The epidermis contains no blood vessels, and is nourished by diffusion from the dermis. The main type of cells which make up the epidermis are keratinocytes, melanocytes, Langerhans cells and Merkels cells. The epidermis helps the skin to regulate body temperature.

Epidermis is divided into several layers where cells are formed through mitosis at the innermost layers. They move up the strata changing shape and composition as they differentiate and become filled with keratin. They eventually reach the top layer called stratum corneum and are sloughed off, or desquamated. This process is called keratinization and takes place within weeks. The outermost layer of the epidermis consists of 25 to 30 layers of dead cells.

Epidermis is divided into the following 5 sublayers or strata:

Blood capillaries are found beneath the epidermis, and are linked to an arteriole and a venule. Arterial shunt vessels may bypass the network in ears, the nose and fingertips.

The dermis is the layer of skin beneath the epidermis that consists of epithelial tissue and cushions the body from stress and strain. The dermis is tightly connected to the epidermis by a basement membrane. It also harbors many nerve endings that provide the sense of touch and heat. It contains the hair follicles, sweat glands, sebaceous glands, apocrine glands, lymphatic vessels and blood vessels. The blood vessels in the dermis provide nourishment and waste removal from its own cells as well as from the Stratum basale of the epidermis.

The dermis is structurally divided into two areas: a superficial area adjacent to the epidermis, called the papillary region, and a deep thicker area known as the reticular region.

The papillary region is composed of loose areolar connective tissue. It is named for its fingerlike projections called papillae, that extend toward the epidermis. The papillae provide the dermis with a "bumpy" surface that interdigitates with the epidermis, strengthening the connection between the two layers of skin.

In the palms, fingers, soles, and toes, the influence of the papillae projecting into the epidermis forms contours in the skin's surface. These epidermal ridges occur in patterns (see: fingerprint) that are genetically and epigenetically determined and are therefore unique to the individual, making it possible to use fingerprints or footprints as a means of identification.

The reticular region lies deep in the papillary region and is usually much thicker. It is composed of dense irregular connective tissue, and receives its name from the dense concentration of collagenous, elastic, and reticular fibers that weave throughout it. These protein fibers give the dermis its properties of strength, extensibility, and elasticity.

Also located within the reticular region are the roots of the hair, sebaceous glands, sweat glands, receptors, nails, and blood vessels.

Tattoo ink is held in the dermis. Stretch marks from pregnancy are also located in the dermis.

The hypodermis is not part of the skin, and lies below the dermis. Its purpose is to attach the skin to underlying bone and muscle as well as supplying it with blood vessels and nerves. It consists of loose connective tissue, adipose tissue and elastin. The main cell types are fibroblasts, macrophages and adipocytes (the hypodermis contains 50% of body fat). Fat serves as padding and insulation for the body.

Human skin shows high skin color variety from the darkest brown to the lightest pinkish-white hues. Human skin shows higher variation in color than any other single mammalian species and is the result of natural selection. Skin pigmentation in humans evolved to primarily regulate the amount of ultraviolet radiation (UVR) penetrating the skin, controlling its biochemical effects.[11]

The actual skin color of different humans is affected by many substances, although the single most important substance determining human skin color is the pigment melanin. Melanin is produced within the skin in cells called melanocytes and it is the main determinant of the skin color of darker-skinned humans. The skin color of people with light skin is determined mainly by the bluish-white connective tissue under the dermis and by the hemoglobin circulating in the veins of the dermis. The red color underlying the skin becomes more visible, especially in the face, when, as consequence of physical exercise or the stimulation of the nervous system (anger, fear), arterioles dilate.[12]

There are at least five different pigments that determine the color of the skin.[13][14] These pigments are present at different levels and places.

There is a correlation between the geographic distribution of UV radiation (UVR) and the distribution of indigenous skin pigmentation around the world. Areas that highlight higher amounts of UVR reflect darker-skinned populations, generally located nearer towards the equator. Areas that are far from the tropics and closer to the poles have lower concentration of UVR, which is reflected in lighter-skinned populations.[15]

In the same population it has been observed that adult human females are considerably lighter in skin pigmentation than males. Females need more calcium during pregnancy and lactation and vitamin D which is synthesized from sunlight helps in absorbing calcium. For this reason it is thought that females may have evolved to have lighter skin in order to help their bodies absorb more calcium.[16]

The Fitzpatrick scale[17][18] is a numerical classification schema for human skin color developed in 1975 as a way to classify the typical response of different types of skin to ultraviolet (UV) light:

As skin ages, it becomes thinner and more easily damaged. Intensifying this effect is the decreasing ability of skin to heal itself as a person ages.

Among other things, skin aging is noted by a decrease in volume and elasticity. There are many internal and external causes to skin aging. For example, aging skin receives less blood flow and lower glandular activity.

A validated comprehensive grading scale has categorized the clinical findings of skin aging as laxity (sagging), rhytids (wrinkles), and the various facets of photoaging, including erythema (redness), and telangiectasia, dyspigmentation (brown discoloration), solar elastosis (yellowing), keratoses (abnormal growths) and poor texture.[19]

Cortisol causes degradation of collagen,[20] accelerating skin aging.[21]

Anti-aging supplements are used to treat skin aging.

Photoaging has two main concerns: an increased risk for skin cancer and the appearance of damaged skin. In younger skin, sun damage will heal faster since the cells in the epidermis have a faster turnover rate, while in the older population the skin becomes thinner and the epidermis turnover rate for cell repair is lower which may result in the dermis layer being damaged.[22]

Skin performs the following functions:

The human skin is a rich environment for microbes.[5][6] Around 1000 species of bacteria from 19 bacterial phyla have been found. Most come from only four phyla: Actinobacteria (51.8%), Firmicutes (24.4%), Proteobacteria (16.5%), and Bacteroidetes (6.3%). Propionibacteria and Staphylococci species were the main species in sebaceous areas. There are three main ecological areas: moist, dry and sebaceous. In moist places on the body Corynebacteria together with Staphylococci dominate. In dry areas, there is a mixture of species but dominated by b-Proteobacteria and Flavobacteriales. Ecologically, sebaceous areas had greater species richness than moist and dry ones. The areas with least similarity between people in species were the spaces between fingers, the spaces between toes, axillae, and umbilical cord stump. Most similarly were beside the nostril, nares (inside the nostril), and on the back.

Reflecting upon the diversity of the human skin researchers on the human skin microbiome have observed: "hairy, moist underarms lie a short distance from smooth dry forearms, but these two niches are likely as ecologically dissimilar as rainforests are to deserts."[5]

The NIH has launched the Human Microbiome Project to characterize the human microbiota which includes that on the skin and the role of this microbiome in health and disease.[23]

Microorganisms like Staphylococcus epidermidis colonize the skin surface. The density of skin flora depends on region of the skin. The disinfected skin surface gets recolonized from bacteria residing in the deeper areas of the hair follicle, gut and urogenital openings.

Diseases of the skin include skin infections and skin neoplasms (including skin cancer).

Dermatology is the branch of medicine that deals with conditions of the skin.[2]

The skin supports its own ecosystems of microorganisms, including yeasts and bacteria, which cannot be removed by any amount of cleaning. Estimates place the number of individual bacteria on the surface of one square inch (6.5 square cm) of human skin at 50 million, though this figure varies greatly over the average 20 square feet (1.9m2) of human skin. Oily surfaces, such as the face, may contain over 500 million bacteria per square inch (6.5cm). Despite these vast quantities, all of the bacteria found on the skin's surface would fit into a volume the size of a pea.[24] In general, the microorganisms keep one another in check and are part of a healthy skin. When the balance is disturbed, there may be an overgrowth and infection, such as when antibiotics kill microbes, resulting in an overgrowth of yeast. The skin is continuous with the inner epithelial lining of the body at the orifices, each of which supports its own complement of microbes.

Cosmetics should be used carefully on the skin because these may cause allergic reactions. Each season requires suitable clothing in order to facilitate the evaporation of the sweat. Sunlight, water and air play an important role in keeping the skin healthy.

Oily skin is caused by over-active sebaceous glands, that produce a substance called sebum, a naturally healthy skin lubricant.[1] When the skin produces excessive sebum, it becomes heavy and thick in texture. Oily skin is typified by shininess, blemishes and pimples.[1] The oily-skin type is not necessarily bad, since such skin is less prone to wrinkling, or other signs of aging,[1] because the oil helps to keep needed moisture locked into the epidermis (outermost layer of skin).

The negative aspect of the oily-skin type is that oily complexions are especially susceptible to clogged pores, blackheads, and buildup of dead skin cells on the surface of the skin.[1] Oily skin can be sallow and rough in texture and tends to have large, clearly visible pores everywhere, except around the eyes and neck.[1]

Human skin has a low permeability; that is, most foreign substances are unable to penetrate and diffuse through the skin. Skin's outermost layer, the stratum corneum, is an effective barrier to most inorganic nanosized particles.[25][26] This protects the body from external particles such as toxins by not allowing them to come into contact with internal tissues. However, in some cases it is desirable to allow particles entry to the body through the skin. Potential medical applications of such particle transfer has prompted developments in nanomedicine and biology to increase skin permeability. One application of transcutaneous particle delivery could be to locate and treat cancer. Nanomedical researchers seek to target the epidermis and other layers of active cell division where nanoparticles can interact directly with cells that have lost their growth-control mechanisms (cancer cells). Such direct interaction could be used to more accurately diagnose properties of specific tumors or to treat them by delivering drugs with cellular specificity.

Nanoparticles 40nm in diameter and smaller have been successful in penetrating the skin.[27][28][29] Research confirms that nanoparticles larger than 40nm do not penetrate the skin past the stratum corneum.[27] Most particles that do penetrate will diffuse through skin cells, but some will travel down hair follicles and reach the dermis layer.

The permeability of skin relative to different shapes of nanoparticles has also been studied. Research has shown that spherical particles have a better ability to penetrate the skin compared to oblong (ellipsoidal) particles because spheres are symmetric in all three spatial dimensions.[29] One study compared the two shapes and recorded data that showed spherical particles located deep in the epidermis and dermis whereas ellipsoidal particles were mainly found in the stratum corneum and epidermal layers.[30]Nanorods are used in experiments because of their unique fluorescent properties but have shown mediocre penetration.

Nanoparticles of different materials have shown skins permeability limitations. In many experiments, gold nanoparticles 40nm in diameter or smaller are used and have shown to penetrate to the epidermis. Titanium oxide (TiO2), zinc oxide (ZnO), and silver nanoparticles are ineffective in penetrating the skin past the stratum corneum.[31][32]Cadmium selenide (CdSe) quantum dots have proven to penetrate very effectively when they have certain properties. Because CdSe is toxic to living organisms, the particle must be covered in a surface group. An experiment comparing the permeability of quantum dots coated in polyethylene glycol (PEG), PEG-amine, and carboxylic acid concluded the PEG and PEG-amine surface groups allowed for the greatest penetration of particles. The carboxylic acid coated particles did not penetrate past the stratum corneum.[30]

Scientists previously believed that the skin was an effective barrier to inorganic particles. Damage from mechanical stressors was believed to be the only way to increase its permeability.[33] Recently, however, simpler and more effective methods for increasing skin permeability have been developed. For example, ultraviolet radiation (UVR) has been used to slightly damage the surface of skin, causing a time-dependent defect allowing easier penetration of nanoparticles.[34] The UVRs high energy causes a restructuring of cells, weakening the boundary between the stratum corneum and the epidermal layer.[34][35] The damage of the skin is typically measured by the transepidermal water loss (TEWL), though it may take 35 days for the TEWL to reach its peak value. When the TEWL reaches its highest value, the maximum density of nanoparticles is able to permeate the skin. Studies confirm that UVR damaged skin significantly increases the permeability.[34][35] The effects of increased permeability after UVR exposure can lead to an increase in the number of particles that permeate the skin. However, the specific permeability of skin after UVR exposure relative to particles of different sizes and materials has not been determined.[34]

Other skin damaging methods used to increase nanoparticle penetration include tape stripping, skin abrasion, and chemical enhancement. Tape stripping is the process in which tape is applied to skin then lifted to remove the top layer of skin. Skin abrasion is done by shaving the top 5-10 micrometers off the surface of the skin. Chemical enhancement is the process in which chemicals such as polyvinylpyrrolidone (PVP), dimethyl sulfoxide (DMSO), and oleic acid are applied to the surface of the skin to increase permeability.[36][37]

Electroporation is the application of short pulses of electric fields on skin and has proven to increase skin permeability. The pulses are high voltage and on the order of milliseconds when applied. Charged molecules penetrate the skin more frequently than neutral molecules after the skin has been exposed to electric field pulses. Results have shown molecules on the order of 100 micrometers to easily permeate electroporated skin.[37]

A large area of interest in nanomedicine is the transdermal patch because of the possibility of a painless application of therapeutic agents with very few side effects. Transdermal patches have been limited to administer a small number of drugs, such as nicotine, because of the limitations in permeability of the skin. Development of techniques that increase skin permeability has led to more drugs that can be applied via transdermal patches and more options for patients.[37]

Increasing the permeability of skin allows nanoparticles to penetrate and target cancer cells. Nanoparticles along with multi-modal imaging techniques have been used as a way to diagnose cancer non-invasively. Skin with high permeability allowed quantum dots with an antibody attached to the surface for active targeting to successfully penetrate and identify cancerous tumors in mice. Tumor targeting is beneficial because the particles can be excited using fluorescence microscopy and emit light energy and heat that will destroy cancer cells.[38]

Sunblock and sunscreen are different important skin-care products though both offer full protection from the sun.[39][40]

SunblockSunblock is opaque and stronger than sunscreen, since it is able to block most of the UVA/UVB rays and radiation from the sun, and does not need to be reapplied several times in a day. Titanium dioxide and zinc oxide are two of the important ingredients in sunblock.[41]

SunscreenSunscreen is more transparent once applied to the skin and also has the ability to protect against UVA/UVB rays, although the sunscreen's ingredients have the ability to break down at a faster rate once exposed to sunlight, and some of the radiation is able to penetrate to the skin. In order for sunscreen to be more effective it is necessary to consistently reapply and use one with a higher sun protection factor.

Vitamin A, also known as retinoids, benefits the skin by normalizing keratinization, downregulating sebum production which contributes to acne, and reversing and treating photodamage, striae, and cellulite.

Vitamin D and analogs are used to downregulate the cutaneous immune system and epithelial proliferation while promoting differentiation.

Vitamin C is an antioxidant that regulates collagen synthesis, forms barrier lipids, regenerates vitamin E, and provides photoprotection.

Vitamin E is a membrane antioxidant that protects against oxidative damage and also provides protection against harmful UV rays. [42]

Several scientific studies confirmed that changes in baseline nutritional status affects skin condition. [43]

The Mayo Clinic lists foods they state help the skin: yellow, green, and orange fruits and vegetables; fat-free dairy products; whole-grain foods; fatty fish, nuts.[44]

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In 2006, Shinya Yamanaka of Kyoto University in Japan was the first to disprove the previous notion that reversible cell differentiation of mammals was impossible. He reprogrammed a fully differentiated mouse cell into a pluripotent stem cell by introducing four genes, Oct-4, SOX2, KLF4, and Myc, into the mouse fibroblast through gene-carrying viruses. With this method, he and his coworkers created induced pluripotent stem cells (iPS cells), the key component in this experiment.[1] Scientists have been able to conduct experiments that show the ability of iPS cells to treat and even cure diseases. In this experiment, tests were run on mice with inherited sickle-cell anemia. Skin cells were turned into cells containing genes that transformed the cells into iPS cells. These replaced the diseased sickled cells, curing the test mice. The reprogramming of the pluripotent stem cells in mice was successfully duplicated with human pluripotent stem cells within about a year of the experiment on the mice.[citation needed]

Sickle-cell anemia is a disease in which the body produces abnormally shaped red blood cells. Red blood cells are flexible and round, moving easily through the blood vessels. Infected cells are shaped like a crescent or sickle (the namesake of the disease). As a result of this disorder the hemoglobin protein in red blood cells is faulty. Normal hemoglobin bonds to oxygen, then releases it into cells that need it. The blood cell retains its original form and is cycled back to the lungs and re-oxygenated.

Sickle cell hemoglobin, however, after giving up oxygen, cling together and make the red blood cell stiff. The sickle shape also makes it difficult for the red blood cell to navigate arteries and causes blockages.[2] This can cause intense pain and organ damage. The sickled red blood cells are fragile and prone to rupture. When the number of red blood cells decreases from rupture (hemolysis), anemia is the result. Sickle cells die in 1020 days as opposed to the traditional 120-day lifespan of a normal red blood cell.

Sickle cell anemia is inherited as an autosomal (meaning that the gene is not linked to a sex chromosome) recessive condition.[2] This means that the gene can be passed on from a carrier to his or her children. In order for sickle cell anemia to affect a person, the gene must be inherited from both the mother and the father, so that the child has two recessive sickle cell genes (a homozygous inheritance). People who inherit one sickle cell gene from one parent and one normal gene from the other parent, i.e. heterozygous patients, have a condition called sickle cell trait. Their bodies make both sickle hemoglobin and normal hemoglobin. They may pass the trait on to their children.

The effects of sickle-cell anemia vary from person to person. People who have the disease suffer from varying degrees of chronic pain and fatigue. With proper care and treatment, the quality of health of most patients will improve. Doctors have learned a great deal about sickle cell anemia since its discovery in 1979. They know its causes, its effects on the body, and possible treatments for complications. Sickle cell anemia has no widely available cure. A bone marrow transplant is the only treatment method currently recognized to be able to cure the disease, though it does not work for every patient. Finding a donor is difficult and the procedure could potentially do more harm than good. Treatments for sickle cell anemia are generally aimed at avoiding crises, relieving symptoms, and preventing complications. Such treatments may include medications, blood transfusions, and supplemental oxygen.

During the first step of the experiment, skin cells (also known as fibroblasts) were collected from infected test mice and put in a culture. The fibroblasts were reprogrammed by infecting them with retroviruses that contained genes common to embryonic stem cells. These genes were the same four used by Yamanaka (Oct-4, SOX2, KLF4, and Myc) in his earlier study. The investigators were trying to produce cells with the potential to differentiate into any type of cell needed (i.e. pluripotent stem cells). As the experiment continued, the fibroblasts multiplied into identical copies of iPS cells. The cells were then treated to form the mutation needed to reverse the anemia in the mice. This was accomplished by restructuring the DNA containing the defective globin gene into DNA with the normal gene through the process of homologous recombination. The iPS cells then differentiated into blood stem cells, or hematopoietic stem cells. The hematopoietic cells were injected back into the infected mice, where they proliferate and differentiate into normal blood cells, curing the mice of the disease.[3][4][verification needed]

To determine whether the mice were cured from the disease, the scientists checked for the usual symptoms of sickle cell disease. They examined the blood for mean corpuscular volume (MCV) and red cell distribution width (RDW) and urine concentration defects. They also checked for sickled red blood cells. They examined the DNA through gel electrophoresis, checking for bands that display an allele that causes sickling. Compared to the untreated mice with the disease, which they used as a control, "the treated animals had marked increases in RBC counts, healthy hemoglobin, and packed cell volume levels".[5]

Researchers examined "the urine concentration defect, which results from RBC sickling in renal tubules and consequent reduction in renal medullary blood flow, and the general deteriorated systemic condition reflected by lower body weight and increased breathing."[5] They were able to see that these parts of the body of the mice had healed or improved. This indicated that "all hematological and systemic parameters of sickle cell anemia improved substantially and were comparable to those in control mice."[5] They cannot say if this will work in humans because a safe way to inject the genes for the induced pluripotent cells is still needed.[citation needed]

The reprogramming of the induced pluripotent stem cells in mice was successfully duplicated in humans within a year of the successful experiment on the mice. This reprogramming was done in several labs and it was shown that the iPS cells in humans were almost identical to original embryonic stem cells (ES cells) that are responsible for the creation of all structures in a fetus.[1] An important feature of iPS cells is that they can be generated with cells taken from an adult, which would circumvent many of the ethical problems associated with working with ES cells. These iPS cells also have potential in creating and examining new disease models and developing more efficient drug treatments.[6] Another feature of these cells is that they provide researchers with a human cell sample, as opposed to simply using an animal with similar DNA, for drug testing.

One major problem with iPS cells is the way in which the cells are reprogrammed. Using gene-carrying viruses has the potential to cause iPS cells to develop into cancerous cells.[1] Also, an implant made using undifferentiated iPS cells, could cause a teratoma to form. Any implant that is generated from using these iPS cells would only be viable for transplant into the original subject that the cells were taken from. In order for these iPS cells to become viable in therapeutic use, there are still many steps that must be taken.[5][7]

In the future, researchers hope that induced pluripotent cells may be used to treat other diseases. Pluripotency is a crucial part of disease treatment because iPS cells are capable of differentiation in a way that is very similar to embryonic stem cells which can grow into fully differentiated tissues. iPS cells also demonstrate high telomerase activity and express human telomerase reverse transcriptase, a necessary component in the telomerase protein complex. Also, iPS cells expressed cell surface antigenic markers expressed on ES cells. Also, doubling time and mitotic activity are cornerstones of ES cells, as stem cells must self-renew as part of their definition. As said, iPS cells are morphologically similar to embryonic stem cells. Each cell has a round shape, a large nucleolus and a small amount of cytoplasm. One day, the process may be used in practical settings to provide a fundamental way of regeneration.

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The pituitary gland produces a number of hormones, which are released into the blood to control other glands in the body (thyroid, adrenal, ovary or testicles). If the pituitary is not producing one or more of these hormones, the condition is called hypopituitarism. If all the hormones produced by the anterior pituitary are decreased, the condition is called panhypopituitarism. Hypopituitarism is most often caused by large benign tumors of the pituitary gland, or of the brain in the region of the hypothalamus. Pituitary underactivity may be caused by the direct pressure of the tumor mass on the normal pituitary or by the effects of surgery or radiotherapy used to treat the pituitary tumors.

Less frequently, hypopituitarism can be caused by infections in or around the brain (such as meningitis) or by severe blood loss, by head injury, or by other rare diseases. Some of the clinical features that may be associated with hypopituitarism include excessive tiredness and decreased energy, irregular periods (oligomenorrhea) or loss of normal menstrual function (amenorrhea), impotence (in men), infertility, increased sensitivity to cold, constipation, dry skin, low blood pressure and lightheadedness upon standing (postural hypotension). Treatment of hypopituitarism consists of long-term hormone replacement therapy, since pituitary hormone deficits are rarely reversed after tumor removal.

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Induced stem cells (iSC) are stem cells derived from somatic, reproductive, pluripotent or other cell types by deliberate epigenetic reprogramming. They are classified as either totipotent (iTC), pluripotent (iPSC) or progenitor (multipotentiMSC, also called an induced multipotent progenitor celliMPC) or unipotent(iUSC) according to their developmental potential and degree of dedifferentiation. Progenitors are obtained by so-called direct reprogramming or directed differentiation and are also called induced somatic stem cells.

Three techniques are widely recognized:[1]

In 1895 Thomas Morgan removed one of a frog's two blastomeres and found that amphibians are able to form whole embryos from the remaining part. This meant that the cells can change their differentiation pathway. In 1924 Spemann and Mangold demonstrated the key importance of cellcell inductions during animal development.[20] The reversible transformation of cells of one differentiated cell type to another is called metaplasia.[21] This transition can be a part of the normal maturation process, or caused by an inducement.

One example is the transformation of iris cells to lens cells in the process of maturation and transformation of retinal pigment epithelium cells into the neural retina during regeneration in adult newt eyes. This process allows the body to replace cells not suitable to new conditions with more suitable new cells. In Drosophila imaginal discs, cells have to choose from a limited number of standard discrete differentiation states. The fact that transdetermination (change of the path of differentiation) often occurs for a group of cells rather than single cells shows that it is induced rather than part of maturation.[22]

The researchers were able to identify the minimal conditions and factors that would be sufficient for starting the cascade of molecular and cellular processes to instruct pluripotent cells to organize the embryo. They showed that opposing gradients of bone morphogenetic protein (BMP) and Nodal, two transforming growth factor family members that act as morphogens, are sufficient to induce molecular and cellular mechanisms required to organize, in vivo or in vitro, uncommitted cells of the zebrafish blastula animal pole into a well-developed embryo.[23]

Some types of mature, specialized adult cells can naturally revert to stem cells. For example, "chief" cells express the stem cell marker Troy. While they normally produce digestive fluids for the stomach, they can revert into stem cells to make temporary repairs to stomach injuries, such as a cut or damage from infection. Moreover, they can make this transition even in the absence of noticeable injuries and are capable of replenishing entire gastric units, in essence serving as quiescent "reserve" stem cells.[24] Differentiated airway epithelial cells can revert into stable and functional stem cells in vivo.[25]

After injury, mature terminally differentiated kidney cells dedifferentiate into more primordial versions of themselves and then differentiate into the cell types needing replacement in the damaged tissue[26] Macrophages can self-renew by local proliferation of mature differentiated cells.[27][28] In newts, muscle tissue is regenerated from specialized muscle cells that dedifferentiate and forget the type of cell they had been. This capacity to regenerate does not decline with age and may be linked to their ability to make new stem cells from muscle cells on demand.[29]

A variety of nontumorigenic stem cells display the ability to generate multiple cell types. For instance, multilineage-differentiating stress-enduring (Muse) cells are stress-tolerant adult human stem cells that can self-renew. They form characteristic cell clusters in suspension culture that express a set of genes associated with pluripotency and can differentiate into endodermal, ectodermal and mesodermal cells both in vitro and in vivo.[30][31][32][33][34]

Other well-documented examples of transdifferentiation and their significance in development and regeneration were described in detail.[35][36]

Induced totipotent cells can be obtained by reprogramming somatic cells with somatic-cell nuclear transfer (SCNT). The process involves sucking out the nucleus of a somatic (body) cell and injecting it into an oocyte that has had its nucleus removed[3][5][37][38]

Using an approach based on the protocol outlined by Tachibana et al.,[3] hESCs can be generated by SCNT using dermal fibroblasts nuclei from both a middle-aged 35-year-old male and an elderly, 75-year-old male, suggesting that age-associated changes are not necessarily an impediment to SCNT-based nuclear reprogramming of human cells.[39] Such reprogramming of somatic cells to a pluripotent state holds huge potentials for regenerative medicine. Unfortunately, the cells generated by this technology, potentially are not completely protected from the immune system of the patient (donor of nuclei), because they have the same mitochondrial DNA, as a donor of oocytes, instead of the patients mitochondrial DNA. This reduces their value as a source for autologous stem cell transplantation therapy, as for the present, it is not clear whether it can induce an immune response of the patient upon treatment.

Induced androgenetic haploid embryonic stem cells can be used instead of sperm for cloning. These cells, synchronized in M phase and injected into the oocyte can produce viable offspring.[40]

These developments, together with data on the possibility of unlimited oocytes from mitotically active reproductive stem cells,[41] offer the possibility of industrial production of transgenic farm animals. Repeated recloning of viable mice through a SCNT method that includes a histone deacetylase inhibitor, trichostatin, added to the cell culture medium,[42] show that it may be possible to reclone animals indefinitely with no visible accumulation of reprogramming or genomic errors[43] However, research into technologies to develop sperm and egg cells from stem cells raises bioethical issues.[44]

Such technologies may also have far-reaching clinical applications for overcoming cytoplasmic defects in human oocytes.[3][45] For example, the technology could prevent inherited mitochondrial disease from passing to future generations. Mitochondrial genetic material is passed from mother to child. Mutations can cause diabetes, deafness, eye disorders, gastrointestinal disorders, heart disease, dementia and other neurological diseases. The nucleus from one human egg has been transferred to another, including its mitochondria, creating a cell that could be regarded as having two mothers. The eggs were then fertilised and the resulting embryonic stem cells carried the swapped mitochondrial DNA.[46] As evidence that the technique is safe author of this method points to the existence of the healthy monkeys that are now more than four years old and are the product of mitochondrial transplants across different genetic backgrounds.[47]

In late-generation telomerase-deficient (Terc/) mice, SCNT-mediated reprogramming mitigates telomere dysfunction and mitochondrial defects to a greater extent than iPSC-based reprogramming.[48]

Other cloning and totipotent transformation achievements have been described.[49]

Recently some researchers succeeded to get the totipotent cells without the aid of SCNT. Totipotent cells were obtained using the epigenetic factors such as oocyte germinal isoform of histone.[50] Reprogramming in vivo, by transitory induction of the four factors Oct4, Sox2, Klf4 and c-Myc in mice, confers totipotency features. Intraperitoneal injection of such in vivo iPS cells generates embryo-like structures that express embryonic and extraembryonic (trophectodermal) markers.[51]

iPSc were first obtained in the form of transplantable teratocarcinoma induced by grafts taken from mouse embryos.[52] Teratocarcinoma formed from somatic cells.[53]Genetically mosaic mice were obtained from malignant teratocarcinoma cells, confirming the cells' pluripotency.[54][55][56] It turned out that teratocarcinoma cells are able to maintain a culture of pluripotent embryonic stem cell in an undifferentiated state, by supplying the culture medium with various factors.[57] In the 1980s, it became clear that transplanting pluripotent/embryonic stem cells into the body of adult mammals, usually leads to the formation of teratomas, which can then turn into a malignant tumor teratocarcinoma.[58] However, putting teratocarcinoma cells into the embryo at the blastocyst stage, caused them to become incorporated in the inner cell mass and often produced a normal chimeric (i.e. composed of cells from different organisms) animal.[59][60][61] This indicated that the cause of the teratoma is a dissonance - mutual miscommunication between young donor cells and surrounding adult cells (the recipient's so-called "niche").

In August 2006, Japanese researchers circumvented the need for an oocyte, as in SCNT. By reprograming mouse embryonic fibroblasts into pluripotent stem cells via the ectopic expression of four transcription factors, namely Oct4, Sox2, Klf4 and c-Myc, they proved that the overexpression of a small number of factors can push the cell to transition to a new stable state that is associated with changes in the activity of thousands of genes.[7]

Reprogramming mechanisms are thus linked, rather than independent and are centered on a small number of genes.[62] IPSC properties are very similar to ESCs.[63] iPSCs have been shown to support the development of all-iPSC mice using a tetraploid (4n) embryo,[64] the most stringent assay for developmental potential. However, some genetically normal iPSCs failed to produce all-iPSC mice because of aberrant epigenetic silencing of the imprinted Dlk1-Dio3 gene cluster.[18]

An important advantage of iPSC over ESC is that they can be derived from adult cells, rather than from embryos. Therefore, it became possible to obtain iPSC from adult and even elderly patients.[9][65][66]

Reprogramming somatic cells to iPSC leads to rejuvenation. It was found that reprogramming leads to telomere lengthening and subsequent shortening after their differentiation back into fibroblast-like derivatives.[67] Thus, reprogramming leads to the restoration of embryonic telomere length,[68] and hence increases the potential number of cell divisions otherwise limited by the Hayflick limit.[69]

However, because of the dissonance between rejuvenated cells and the surrounding niche of the recipient's older cells, the injection of his own iPSC usually leads to an immune response,[70] which can be used for medical purposes,[71] or the formation of tumors such as teratoma.[72] The reason has been hypothesized to be that some cells differentiated from ESC and iPSC in vivo continue to synthesize embryonic protein isoforms.[73] So, the immune system might detect and attack cells that are not cooperating properly.

A small molecule called MitoBloCK-6 can force the pluripotent stem cells to die by triggering apoptosis (via cytochrome c release across the mitochondrial outer membrane) in human pluripotent stem cells, but not in differentiated cells. Shortly after differentiation, daughter cells became resistant to death. When MitoBloCK-6 was introduced to differentiated cell lines, the cells remained healthy. The key to their survival, was hypothesized to be due to the changes undergone by pluripotent stem cell mitochondria in the process of cell differentiation. This ability of MitoBloCK-6 to separate the pluripotent and differentiated cell lines has the potential to reduce the risk of teratomas and other problems in regenerative medicine.[74]

In 2012 other small molecules (selective cytotoxic inhibitors of human pluripotent stem cellshPSCs) were identified that prevented human pluripotent stem cells from forming teratomas in mice. The most potent and selective compound of them (PluriSIn #1) inhibits stearoyl-coA desaturase (the key enzyme in oleic acid biosynthesis), which finally results in apoptosis. With the help of this molecule the undifferentiated cells can be selectively removed from culture.[75][76] An efficient strategy to selectively eliminate pluripotent cells with teratoma potential is targeting pluripotent stem cell-specific antiapoptotic factor(s) (i.e., survivin or Bcl10). A single treatment with chemical survivin inhibitors (e.g., quercetin or YM155) can induce selective and complete cell death of undifferentiated hPSCs and is claimed to be sufficient to prevent teratoma formation after transplantation.[77] However, it is unlikely that any kind of preliminary clearance,[78] is able to secure the replanting iPSC or ESC. After the selective removal of pluripotent cells, they re-emerge quickly by reverting differentiated cells into stem cells, which leads to tumors.[79] This may be due to the disorder of let-7 regulation of its target Nr6a1 (also known as Germ cell nuclear factor - GCNF), an embryonic transcriptional repressor of pluripotency genes that regulates gene expression in adult fibroblasts following micro-RNA miRNA loss.[80]

Teratoma formation by pluripotent stem cells may be caused by low activity of PTEN enzyme, reported to promote the survival of a small population (0,1-5% of total population) of highly tumorigenic, aggressive, teratoma-initiating embryonic-like carcinoma cells during differentiation. The survival of these teratoma-initiating cells is associated with failed repression of Nanog as well as a propensity for increased glucose and cholesterol metabolism.[81] These teratoma-initiating cells also expressed a lower ratio of p53/p21 when compared to non-tumorigenic cells.[82] In connection with the above safety problems, the use iPSC for cell therapy is still limited.[83] However, they can be used for a variety of other purposes - including the modeling of disease,[84] screening (selective selection) of drugs, toxicity testing of various drugs.[85]

It is interesting to note that the tissue grown from iPSCs, placed in the "chimeric" embryos in the early stages of mouse development, practically do not cause an immune response (after the embryos have grown into adult mice) and are suitable for autologous transplantation[86] At the same time, full reprogramming of adult cells in vivo within tissues by transitory induction of the four factors Oct4, Sox2, Klf4 and c-Myc in mice results in teratomas emerging from multiple organs.[51] Furthermore, partial reprogramming of cells toward pluripotency in vivo in mice demonstrates that incomplete reprogramming entails epigenetic changes (failed repression of Polycomb targets and altered DNA methylation) in cells that drive cancer development.[87]

Determining the unique set of cellular factors that is needed to be manipulated for each cell conversion is a long and costly process that involved much trial and error. As a result, this first step of identifying the key set of cellular factors for cell conversion is the major obstacle researchers face in the field of cell reprogramming. An international team of researchers have developed an algorithm, called Mogrify(1), that can predict the optimal set of cellular factors required to convert one human cell type to another. When tested, Mogrify was able to accurately predict the set of cellular factors required for previously published cell conversions correctly. To further validate Mogrify's predictive ability, the team conducted two novel cell conversions in the laboratory using human cells and these were successful in both attempts solely using the predictions of Mogrify.[89][90][91] Mogrify has been made available online for other researchers and scientists.

By using solely small molecules, Deng Hongkui and colleagues demonstrated that endogenous "master genes" are enough for cell fate reprogramming. They induced a pluripotent state in adult cells from mice using seven small-molecule compounds.[17] The effectiveness of the method is quite high: it was able to convert 0.02% of the adult tissue cells into iPSCs, which is comparable to the gene insertion conversion rate. The authors note that the mice generated from CiPSCs were "100% viable and apparently healthy for up to 6 months". So, this chemical reprogramming strategy has potential use in generating functional desirable cell types for clinical applications.[92][93]

In 2015th year a robust chemical reprogramming system was established with a yield up to 1,000-fold greater than that of the previously reported protocol. So, chemical reprogramming became a promising approach to manipulate cell fates.[94]

The fact that human iPSCs capable of forming teratomas not only in humans but also in some animal body, in particular in mice or pigs, allowed to develop a method for differentiation of iPSCs in vivo. For this purpose, iPSCs with an agent for inducing differentiation into target cells are injected to genetically modified pig or mouse that has suppressed immune system activation on human cells. The formed teratoma is cut out and used for the isolation of the necessary differentiated human cells[95] by means of monoclonal antibody to tissue-specific markers on the surface of these cells. This method has been successfully used for the production of functional myeloid, erythroid and lymphoid human cells suitable for transplantation (yet only to mice).[96] Mice engrafted with human iPSC teratoma-derived hematopoietic cells produced human B and T cells capable of functional immune responses. These results offer hope that in vivo generation of patient customized cells is feasible, providing materials that could be useful for transplantation, human antibody generation and drug screening applications. Using MitoBloCK-6[74] and/or PluriSIn # 1 the differentiated progenitor cells can be further purified from teratoma forming pluripotent cells. The fact, that the differentiation takes place even in the teratoma niche, offers hope that the resulting cells are sufficiently stable to stimuli able to cause their transition back to the dedifferentiated (pluripotent) state and therefore safe. A similar in vivo differentiation system, yielding engraftable hematopoietic stem cells from mouse and human iPSCs in teratoma-bearing animals in combination with a maneuver to facilitate hematopoiesis, was described by Suzuki et al.[97] They noted that neither leukemia nor tumors were observed in recipients after intravenous injection of iPSC-derived hematopoietic stem cells into irradiated recipients. Moreover, this injection resulted in multilineage and long-term reconstitution of the hematolymphopoietic system in serial transfers. Such system provides a useful tool for practical application of iPSCs in the treatment of hematologic and immunologic diseases.[98]

For further development of this method animal in which is grown the human cell graft, for example mouse, must have so modified genome that all its cells express and have on its surface human SIRP.[99] To prevent rejection after transplantation to the patient of the allogenic organ or tissue, grown from the pluripotent stem cells in vivo in the animal, these cells should express two molecules: CTLA4-Ig, which disrupts T cell costimulatory pathways and PD-L1, which activates T cell inhibitory pathway.[100]

See also: US 20130058900 patent.

In the near-future, clinical trials designed to demonstrate the safety of the use of iPSCs for cell therapy of the people with age-related macular degeneration, a disease causing blindness through retina damaging, will begin. There are several articles describing methods for producing retinal cells from iPSCs[101][102] and how to use them for cell therapy.[103][104] Reports of iPSC-derived retinal pigmented epithelium transplantation showed enhanced visual-guided behaviors of experimental animals for 6 weeks after transplantation.[105] However, clinical trials have been successful: ten patients suffering from retinitis pigmentosa have had their eyesight restoredincluding a woman who had only 17 percent of her vision left.[106]

Chronic lung diseases such as idiopathic pulmonary fibrosis and cystic fibrosis or chronic obstructive pulmonary disease and asthma are leading causes of morbidity and mortality worldwide with a considerable human, societal and financial burden. So there is an urgent need for effective cell therapy and lung tissue engineering.[107][108] Several protocols have been developed for generation of the most cell types of the respiratory system, which may be useful for deriving patient-specific therapeutic cells.[109][110][111][112][113]

Some lines of iPSCs have the potentiality to differentiate into male germ cells and oocyte-like cells in an appropriate niche (by culturing in retinoic acid and porcine follicular fluid differentiation medium or seminiferous tubule transplantation). Moreover, iPSC transplantation make a contribution to repairing the testis of infertile mice, demonstrating the potentiality of gamete derivation from iPSCs in vivo and in vitro.[114]

The risk of cancer and tumors creates the need to develop methods for safer cell lines suitable for clinical use. An alternative approach is so-called "direct reprogramming" - transdifferentiation of cells without passing through the pluripotent state.[115][116][117][118][119][120] The basis for this approach was that 5-azacytidine - a DNA demethylation reagent - can cause the formation of myogenic, chondrogenic and adipogeni clones in the immortal cell line of mouse embryonic fibroblasts[121] and that the activation of a single gene, later named MyoD1, is sufficient for such reprogramming.[122] Compared with iPSC whose reprogramming requires at least two weeks, the formation of induced progenitor cells sometimes occurs within a few days and the efficiency of reprogramming is usually many times higher. This reprogramming does not always require cell division.[123] The cells resulting from such reprogramming are more suitable for cell therapy because they do not form teratomas.[120] For example, Chandrakanthan et al., & Pimanda describe the generation of tissue-regenerative multipotent stem cells (iMS cells) by treating mature bone and fat cells transiently with a growth factor (platelet-derived growth factorAB (PDGF-AB)) and 5-Azacytidine. These authors claim that: "Unlike primary mesenchymal stem cells, which are used with little objective evidence in clinical practice to promote tissue repair, iMS cells contribute directly to in vivo tissue regeneration in a context-dependent manner without forming tumors" and so "has significant scope for application in tissue regeneration."[124][125][126]

Originally only early embryonic cells could be coaxed into changing their identity. Mature cells are resistant to changing their identity once they've committed to a specific kind. However, brief expression of a single transcription factor, the ELT-7 GATA factor, can convert the identity of fully differentiated, specialized non-endodermal cells of the pharynx into fully differentiated intestinal cells in intact larvae and adult roundworm Caenorhabditis elegans with no requirement for a dedifferentiated intermediate.[127]

The cell fate can be effectively manipulated by epigenome editing. In particular, by directly activating of specific endogenous gene expression with CRISPR-mediated activator. When dCas9 (that has been modified so that it no longer cuts DNA, but still can be guided to specific sequences and to bind to them) is combined with transcription activators, it can precisely manipulate endogenous gene expression. Using this method, Wei et al., enhanced the expression of endogenous Cdx2 and Gata6 genes by CRISPR-mediated activators, thus directly converted mouse embryonic stem cells into two extraembryonic lineages, i.e., typical trophoblast stem cells and extraembryonic endoderm cells.[128] An analogous approach was used to induce activation of the endogenous Brn2, Ascl1, and Myt1l genes to convert mouse embryonic fibroblasts to induced neuronal cells.[129] Thus, transcriptional activation and epigenetic remodeling of endogenous master transcription factors are sufficient for conversion between cell types. The rapid and sustained activation of endogenous genes in their native chromatin context by this approach may facilitate reprogramming with transient methods that avoid genomic integration and provides a new strategy for overcoming epigenetic barriers to cell fate specification.

Another way of reprogramming is the simulation of the processes that occur during amphibian limb regeneration. In urodele amphibians, an early step in limb regeneration is skeletal muscle fiber dedifferentiation into a cellulate that proliferates into limb tissue. However, sequential small molecule treatment of the muscle fiber with myoseverin, reversine (the aurora B kinase inhibitor) and some other chemicals: BIO (glycogen synthase-3 kinase inhibitor), lysophosphatidic acid (pleiotropic activator of G-protein-coupled receptors), SB203580 (p38 MAP kinase inhibitor), or SQ22536 (adenylyl cyclase inhibitor) causes the formation of new muscle cell types as well as other cell types such as precursors to fat, bone and nervous system cells.[130]

The researchers discovered that GCSF-mimicking antibody can activate a growth-stimulating receptor on marrow cells in a way that induces marrow stem cells that normally develop into white blood cells to become neural progenitor cells. The technique[131] enables researchers to search large libraries of antibodies and quickly select the ones with a desired biological effect.[132]

Schlegel and Liu[133] demonstrated that the combination of feeder cells[134][135][136] and a Rho kinase inhibitor (Y-27632) [137][138] induces normal and tumor epithelial cells from many tissues to proliferate indefinitely in vitro. This process occurs without the need for transduction of exogenous viral or cellular genes. These cells have been termed "Conditionally Reprogrammed Cells (CRC)". The induction of CRCs is rapid and results from reprogramming of the entire cell population. CRCs do not express high levels of proteins characteristic of iPSCs or embryonic stem cells (ESCs) (e.g., Sox2, Oct4, Nanog, or Klf4). This induction of CRCs is reversible and removal of Y-27632 and feeders allows the cells to differentiate normally.[133][139][140] CRC technology can generate 2106 cells in 5 to 6 days from needle biopsies and can generate cultures from cryopreserved tissue and from fewer than four viable cells. CRCs retain a normal karyotype and remain nontumorigenic. This technique also efficiently establishes cell cultures from human and rodent tumors.[133][141][142]

The ability to rapidly generate many tumor cells from small biopsy specimens and frozen tissue provides significant opportunities for cell-based diagnostics and therapeutics (including chemosensitivity testing) and greatly expands the value of biobanking.[133][141][142] Using CRC technology, researchers were able to identify an effective therapy for a patient with a rare type of lung tumor.[143] Engleman's group[144] describes a pharmacogenomic platform that facilitates rapid discovery of drug combinations that can overcome resistance using CRC system. In addition, the CRC method allows for the genetic manipulation of epithelial cells ex vivo and their subsequent evaluation in vivo in the same host. While initial studies revealed that co-culturing epithelial cells with Swiss 3T3 cells J2 was essential for CRC induction, with transwell culture plates, physical contact between feeders and epithelial cells is not required for inducing CRCs and more importantly that irradiation of the feeder cells is required for this induction. Consistent with the transwell experiments, conditioned medium induces and maintains CRCs, which is accompanied by a concomitant increase of cellular telomerase activity. The activity of the conditioned medium correlates directly with radiation-induced feeder cell apoptosis. Thus, conditional reprogramming of epithelial cells is mediated by a combination of Y-27632 and a soluble factor(s) released by apoptotic feeder cells.[145]

Riegel et al.[146] demonstrate that mouse ME cells isolated from normal mammary glands or from mouse mammary tumor virus (MMTV)-Neuinduced mammary tumors, can be cultured indefinitely as conditionally reprogrammed cells (CRCs). Cell surface progenitor-associated markers are rapidly induced in normal mouse ME-CRCs relative to ME cells. However, the expression of certain mammary progenitor subpopulations, such as CD49f+ ESA+ CD44+, drops significantly in later passages. Nevertheless, mouse ME-CRCs grown in a three-dimensional extracellular matrix gave rise to mammary acinar structures. ME-CRCs isolated from MMTV-Neu transgenic mouse mammary tumors express high levels of HER2/neu, as well as tumor-initiating cell markers, such as CD44+, CD49f+ and ESA+ (EpCam). These patterns of expression are sustained in later CRC passages. Early and late passage ME-CRCs from MMTV-Neu tumors that were implanted in the mammary fat pads of syngeneic or nude mice developed vascular tumors that metastasized within 6 weeks of transplantation. Importantly, the histopathology of these tumors was indistinguishable from that of the parental tumors that develop in the MMTV-Neu mice. Application of the CRC system to mouse mammary epithelial cells provides an attractive model system to study the genetics and phenotype of normal and transformed mouse epithelium in a defined culture environment and in vivo transplant studies.

A different approach to CRC is to inhibit CD47a membrane protein that is the thrombospondin-1 receptor. Loss of CD47 permits sustained proliferation of primary murine endothelial cells, increases asymmetric division and enables these cells to spontaneously reprogram to form multipotent embryoid body-like clusters. CD47 knockdown acutely increases mRNA levels of c-Myc and other stem cell transcription factors in cells in vitro and in vivo. Thrombospondin-1 is a key environmental signal that inhibits stem cell self-renewal via CD47. Thus, CD47 antagonists enable cell self-renewal and reprogramming by overcoming negative regulation of c-Myc and other stem cell transcription factors.[147] In vivo blockade of CD47 using an antisense morpholino increases survival of mice exposed to lethal total body irradiation due to increased proliferative capacity of bone marrow-derived cells and radioprotection of radiosensitive gastrointestinal tissues.[148]

Differentiated macrophages can self-renew in tissues and expand long-term in culture.[27] Under certain conditions macrophages can divide without losing features they have acquired while specializing into immune cells - which is usually not possible with differentiated cells. The macrophages achieve this by activating a gene network similar to one found in embryonic stem cells. Single-cell analysis revealed that, in vivo, proliferating macrophages can derepress a macrophage-specific enhancer repertoire associated with a gene network controlling self-renewal. This happened when concentrations of two transcription factors named MafB and c-Maf were naturally low or were inhibited for a short time. Genetic manipulations that turned off MafB and c-Maf in the macrophages caused the cells to start a self-renewal program. The similar network also controls embryonic stem cell self-renewal but is associated with distinct embryonic stem cell-specific enhancers.[28]

Hence macrophages isolated from MafB- and c-Maf-double deficient mice divide indefinitely; the self-renewal depends on c-Myc and Klf4.[149]

Indirect lineage conversion is a reprogramming methodology in which somatic cells transition through a plastic intermediate state of partially reprogrammed cells (pre-iPSC), induced by brief exposure to reprogramming factors, followed by differentiation in a specially developed chemical environment (artificial niche).[150]

This method could be both more efficient and safer, since it does not seem to produce tumors or other undesirable genetic changes and results in much greater yield than other methods. However, the safety of these cells remains questionable. Since lineage conversion from pre-iPSC relies on the use of iPSC reprogramming conditions, a fraction of the cells could acquire pluripotent properties if they do not stop the de-differentation process in vitro or due to further de-differentiation in vivo.[151]

A common feature of pluripotent stem cells is the specific nature of protein glycosylation of their outer membrane. That distinguishes them from most nonpluripotent cells, although not white blood cells.[152] The glycans on the stem cell surface respond rapidly to alterations in cellular state and signaling and are therefore ideal for identifying even minor changes in cell populations. Many stem cell markers are based on cell surface glycan epitopes including the widely used markers SSEA-3, SSEA-4, Tra 1-60 and Tra 1-81.[153] Suila Heli et al.[154] speculate that in human stem cells extracellular O-GlcNAc and extracellular O-LacNAc, play a crucial role in the fine tuning of Notch signaling pathway - a highly conserved cell signaling system, that regulates cell fate specification, differentiation, leftright asymmetry, apoptosis, somitogenesis, angiogenesis and plays a key role in stem cell proliferation (reviewed by Perdigoto and Bardin[155] and Jafar-Nejad et al.[156])

Changes in outer membrane protein glycosylation are markers of cell states connected in some way with pluripotency and differentiation.[157] The glycosylation change is apparently not just the result of the initialization of gene expression, but perform as an important gene regulator involved in the acquisition and maintenance of the undifferentiated state.[158]

For example, activation of glycoprotein ACA,[159] linking glycosylphosphatidylinositol on the surface of the progenitor cells in human peripheral blood, induces increased expression of genes Wnt, Notch-1, BMI1 and HOXB4 through a signaling cascade PI3K/Akt/mTor/PTEN and promotes the formation of a self-renewing population of hematopoietic stem cells.[160]

Furthermore, dedifferentiation of progenitor cells induced by ACA-dependent signaling pathway leads to ACA-induced pluripotent stem cells, capable of differentiating in vitro into cells of all three germ layers.[161] The study of lectins' ability to maintain a culture of pluripotent human stem cells has led to the discovery of lectin Erythrina crista-galli (ECA), which can serve as a simple and highly effective matrix for the cultivation of human pluripotent stem cells.[162]

Cell adhesion protein E-cadherin is indispensable for a robust pluripotent phenotype.[163] During reprogramming for iPS cell generation, N-cadherin can replace function of E-cadherin.[164] These functions of cadherins are not directly related to adhesion because sphere morphology helps maintaining the "stemness" of stem cells.[165] Moreover, sphere formation, due to forced growth of cells on a low attachment surface, sometimes induces reprogramming. For example, neural progenitor cells can be generated from fibroblasts directly through a physical approach without introducing exogenous reprogramming factors.

Physical cues, in the form of parallel microgrooves on the surface of cell-adhesive substrates, can replace the effects of small-molecule epigenetic modifiers and significantly improve reprogramming efficiency. The mechanism relies on the mechanomodulation of the cells' epigenetic state. Specifically, "decreased histone deacetylase activity and upregulation of the expression of WD repeat domain 5 (WDR5)a subunit of H3 methyltranferaseby microgrooved surfaces lead to increased histone H3 acetylation and methylation". Nanofibrous scaffolds with aligned fibre orientation produce effects similar to those produced by microgrooves, suggesting that changes in cell morphology may be responsible for modulation of the epigenetic state.[166]

Substrate rigidity is an important biophysical cue influencing neural induction and subtype specification. For example, soft substrates promote neuroepithelial conversion while inhibiting neural crest differentiation of hESCs in a BMP4-dependent manner. Mechanistic studies revealed a multi-targeted mechanotransductive process involving mechanosensitive Smad phosphorylation and nucleocytoplasmic shuttling, regulated by rigidity-dependent Hippo/YAP activities and actomyosin cytoskeleton integrity and contractility.[167]

Mouse embryonic stem cells (mESCs) undergo self-renewal in the presence of the cytokine leukemia inhibitory factor (LIF). Following LIF withdrawal, mESCs differentiate, accompanied by an increase in cellsubstratum adhesion and cell spreading. Restricted cell spreading in the absence of LIF by either culturing mESCs on chemically defined, weakly adhesive biosubstrates, or by manipulating the cytoskeleton allowed the cells to remain in an undifferentiated and pluripotent state. The effect of restricted cell spreading on mESC self-renewal is not mediated by increased intercellular adhesion, as inhibition of mESC adhesion using a function blocking anti E-cadherin antibody or siRNA does not promote differentiation.[168] Possible mechanisms of stem cell fate predetermination by physical interactions with the extracellular matrix have been described.[169][170]

A new method has been developed that turns cells into stem cells faster and more efficiently by 'squeezing' them using 3D microenvironment stiffness and density of the surrounding gel. The technique can be applied to a large number of cells to produce stem cells for medical purposes on an industrial scale.[171][172]

Cells involved in the reprogramming process change morphologically as the process proceeds. This results in physical difference in adhesive forces among cells. Substantial differences in 'adhesive signature' between pluripotent stem cells, partially reprogrammed cells, differentiated progeny and somatic cells allowed to develop separation process for isolation of pluripotent stem cells in microfluidic devices,[173] which is:

Stem cells possess mechanical memory (they remember past physical signals)with the Hippo signaling pathway factors:[174] Yes-associated protein (YAP) and transcriptional coactivator with PDZ-binding domain (TAZ) acting as an intracellular mechanical rheostatthat stores information from past physical environments and influences the cells' fate.[175][176]

Stroke and many neurodegenerative disorders such as Parkinson's disease, Alzheimer's disease, amyotrophic lateral sclerosis need cell replacement therapy. The successful use of converted neural cells (cNs) in transplantations open a new avenue to treat such diseases.[177] Nevertheless, induced neurons (iNs), directly converted from fibroblasts are terminally committed and exhibit very limited proliferative ability that may not provide enough autologous donor cells for transplantation.[178] Self-renewing induced neural stem cells (iNSCs) provide additional advantages over iNs for both basic research and clinical applications.[118][119][120][179][180]

For example, under specific growth conditions, mouse fibroblasts can be reprogrammed with a single factor, Sox2, to form iNSCs that self-renew in culture and after transplantation can survive and integrate without forming tumors in mouse brains.[181] INSCs can be derived from adult human fibroblasts by non-viral techniques, thus offering a safe method for autologous transplantation or for the development of cell-based disease models.[180]

Neural chemically induced progenitor cells (ciNPCs) can be generated from mouse tail-tip fibroblasts and human urinary somatic cells without introducing exogenous factors, but - by a chemical cocktail, namely VCR (V, VPA, an inhibitor of HDACs; C, CHIR99021, an inhibitor of GSK-3 kinases and R, RepSox, an inhibitor of TGF beta signaling pathways), under a physiological hypoxic condition.[182] Alternative cocktails with inhibitors of histone deacetylation, glycogen synthase kinase and TGF- pathways (where: sodium butyrate (NaB) or Trichostatin A (TSA) could replace VPA, Lithium chloride (LiCl) or lithium carbonate (Li2CO3) could substitute CHIR99021, or Repsox may be replaced with SB-431542 or Tranilast) show similar efficacies for ciNPC induction.[182] Zhang, et al.,[183] also report highly efficient reprogramming of mouse fibroblasts into induced neural stem cell-like cells (ciNSLCs) using a cocktail of nine components.

Multiple methods of direct transformation of somatic cells into induced neural stem cells have been described.[184]

Proof of principle experiments demonstrate that it is possible to convert transplanted human fibroblasts and human astrocytes directly in the brain that are engineered to express inducible forms of neural reprogramming genes, into neurons, when reprogramming genes (Ascl1, Brn2a and Myt1l) are activated after transplantation using a drug.[185]

Astrocytesthe most common neuroglial brain cells, which contribute to scar formation in response to injurycan be directly reprogrammed in vivo to become functional neurons that formed networks in mice without the need of cell transplantation.[186] The researchers followed the mice for nearly a year to look for signs of tumor formation and reported finding none. The same researchers have turned scar-forming astrocytes into progenitor cells called neuroblasts that regenerated into neurons in the injured adult spinal cord.[187]

Without myelin to insulate neurons, nerve signals quickly lose power. Diseases that attack myelin, such as multiple sclerosis, result in nerve signals that cannot propagate to nerve endings and as a consequence lead to cognitive, motor and sensory problems. Transplantation of oligodendrocyte precursor cells (OPCs), which can successfully create myelin sheaths around nerve cells, is a promising potential therapeutic response. Direct lineage conversion of mouse and rat fibroblasts into oligodendroglial cells provides a potential source of OPCs. Conversion by forced expression of both eight[188] or of the three[189] transcription factors Sox10, Olig2 and Zfp536, may provide such cells.

Cell-based in vivo therapies may provide a transformative approach to augment vascular and muscle growth and to prevent non-contractile scar formation by delivering transcription factors[115] or microRNAs[14] to the heart.[190] Cardiac fibroblasts, which represent 50% of the cells in the mammalian heart, can be reprogrammed into cardiomyocyte-like cells in vivo by local delivery of cardiac core transcription factors ( GATA4, MEF2C, TBX5 and for improved reprogramming plus ESRRG, MESP1, Myocardin and ZFPM2) after coronary ligation.[115][191] These results implicated therapies that can directly remuscularize the heart without cell transplantation. However, the efficiency of such reprogramming turned out to be very low and the phenotype of received cardiomyocyte-like cells does not resemble those of a mature normal cardiomyocyte. Furthermore, transplantation of cardiac transcription factors into injured murine hearts resulted in poor cell survival and minimal expression of cardiac genes.[192]

Meanwhile, advances in the methods of obtaining cardiac myocytes in vitro occurred.[193][194] Efficient cardiac differentiation of human iPS cells gave rise to progenitors that were retained within infarcted rat hearts and reduced remodeling of the heart after ischemic damage.[195]

The team of scientists, who were led by Sheng Ding, used a cocktail of nine chemicals (9C) for transdifferentiation of human skin cells into beating heart cells. With this method, more than 97% of the cells began beating, a characteristic of fully developed, healthy heart cells. The chemically induced cardiomyocyte-like cells (ciCMs) uniformly contracted and resembled human cardiomyocytes in their transcriptome, epigenetic, and electrophysiological properties. When transplanted into infarcted mouse hearts, 9C-treated fibroblasts were efficiently converted to ciCMs and developed into healthy-looking heart muscle cells within the organ.[196] This chemical reprogramming approach, after further optimization, may offer an easy way to provide the cues that induce heart muscle to regenerate locally.[197]

In another study, ischemic cardiomyopathy in the murine infarction model was targeted by iPS cell transplantation. It synchronized failing ventricles, offering a regenerative strategy to achieve resynchronization and protection from decompensation by dint of improved left ventricular conduction and contractility, reduced scarring and reversal of structural remodelling.[198] One protocol generated populations of up to 98% cardiomyocytes from hPSCs simply by modulating the canonical Wnt signaling pathway at defined time points in during differentiation, using readily accessible small molecule compounds.[199]

Discovery of the mechanisms controlling the formation of cardiomyocytes led to the development of the drug ITD-1, which effectively clears the cell surface from TGF- receptor type II and selectively inhibits intracellular TGF- signaling. It thus selectively enhances the differentiation of uncommitted mesoderm to cardiomyocytes, but not to vascular smooth muscle and endothelial cells.[200]

One project seeded decellularized mouse hearts with human iPSC-derived multipotential cardiovascular progenitor cells. The introduced cells migrated, proliferated and differentiated in situ into cardiomyocytes, smooth muscle cells and endothelial cells to reconstruct the hearts. In addition, the heart's extracellular matrix (the substrate of heart scaffold) signalled the human cells into becoming the specialised cells needed for proper heart function. After 20 days of perfusion with growth factors, the engineered heart tissues started to beat again and were responsive to drugs.[201]

Reprogramming of cardiac fibroblasts into induced cardiomyocyte-like cells (iCMs) in situ represents a promising strategy for cardiac regeneration. Mice exposed in vivo, to three cardiac transcription factors GMT (Gata4, Mef2c, Tbx5) and the small-molecules: SB-431542 (the transforming growth factor (TGF)- inhibitor), and XAV939 (the WNT inhibitor) for 2 weeks after myocardial infarction showed significantly improved reprogramming (reprogramming efficiency increased eight-fold) and cardiac function compared to those exposed to only GMT.[202]

See also: review[203]

The elderly often suffer from progressive muscle weakness and regenerative failure owing in part to elevated activity of the p38 and p38 mitogen-activated kinase pathway in senescent skeletal muscle stem cells. Subjecting such stem cells to transient inhibition of p38 and p38 in conjunction with culture on soft hydrogel substrates rapidly expands and rejuvenates them that result in the return of their strength.[204]

In geriatric mice, resting satellite cells lose reversible quiescence by switching to an irreversible pre-senescence state, caused by derepression of p16INK4a (also called Cdkn2a). On injury, these cells fail to activate and expand, even in a youthful environment. p16INK4a silencing in geriatric satellite cells restores quiescence and muscle regenerative functions.[205]

Myogenic progenitors for potential use in disease modeling or cell-based therapies targeting skeletal muscle could also be generated directly from induced pluripotent stem cells using free-floating spherical culture (EZ spheres) in a culture medium supplemented with high concentrations (100ng/ml) of fibroblast growth factor-2 (FGF-2) and epidermal growth factor.[206]

Unlike current protocols for deriving hepatocytes from human fibroblasts, Saiyong Zhu et al., (2014)[207] did not generate iPSCs but, using small molecules, cut short reprogramming to pluripotency to generate an induced multipotent progenitor cell (iMPC) state from which endoderm progenitor cells and subsequently hepatocytes (iMPC-Heps) were efficiently differentiated. After transplantation into an immune-deficient mouse model of human liver failure, iMPC-Heps proliferated extensively and acquired levels of hepatocyte function similar to those of human primary adult hepatocytes. iMPC-Heps did not form tumours, most probably because they never entered a pluripotent state.

These results establish the feasibility of significant liver repopulation of mice with human hepatocytes generated in vitro, which removes a long-standing roadblock on the path to autologous liver cell therapy.

Cocktail of small molecules, Y-27632, A-83-01 (a TGF kinase/activin receptor like kinase (ALK5) inhibitor), and CHIR99021 (potent inhibitor of GSK-3), can convert rat and mouse mature hepatocytes in vitro into proliferative bipotent cells - CLiPs (chemically induced liver progenitors). CLiPs can differentiate into both mature hepatocytes and biliary epithelial cells that can form functional ductal structures. In long-term culture CLiPs did not lose their proliferative capacity and their hepatic differentiation ability, and can repopulate chronically injured liver tissue.[208]

Complications of Diabetes mellitus such as cardiovascular diseases, retinopathy, neuropathy, nephropathy and peripheral circulatory diseases depend on sugar dysregulation due to lack of insulin from pancreatic beta cells and can be lethal if they are not treated. One of the promising approaches to understand and cure diabetes is to use pluripotent stem cells (PSCs), including embryonic stem cells (ESCs) and induced PCSs (iPSCs).[209] Unfortunately, human PSC-derived insulin-expressing cells resemble human fetal cells rather than adult cells. In contrast to adult cells, fetal cells seem functionally immature, as indicated by increased basal glucose secretion and lack of glucose stimulation and confirmed by RNA-seq of whose transcripts.[210]

An alternative strategy is the conversion of fibroblasts towards distinct endodermal progenitor cell populations and, using cocktails of signalling factors, successful differentiation of these endodermal progenitor cells into functional beta-like cells both in vitro and in vivo.[211]

Overexpression of the three transcription factors, PDX1 (required for pancreatic bud outgrowth and beta-cell maturation), NGN3 (required for endocrine precursor cell formation) and MAFA (for beta-cell maturation) combination (called PNM) can lead to the transformation of some cell types into a beta cell-like state.[212] An accessible and abundant source of functional insulin-producing cells is intestine. PMN expression in human intestinal "organoids" stimulates the conversion of intestinal epithelial cells into -like cells possibly acceptable for transplantation.[213]

Adult proximal tubule cells were directly transcriptionally reprogrammed to nephron progenitors of the embryonic kidney, using a pool of six genes of instructive transcription factors (SIX1, SIX2, OSR1, Eyes absent homolog 1(EYA1), Homeobox A11 (HOXA11) and Snail homolog 2 (SNAI2)) that activated genes consistent with a cap mesenchyme/nephron progenitor phenotype in the adult proximal tubule cell line.[214] The generation of such cells may lead to cellular therapies for adult renal disease. Embryonic kidney organoids placed into adult rat kidneys can undergo onward development and vascular development.[215]

As blood vessels age, they often become abnormal in structure and function, thereby contributing to numerous age-associated diseases including myocardial infarction, ischemic stroke and atherosclerosis of arteries supplying the heart, brain and lower extremities. So, an important goal is to stimulate vascular growth for the collateral circulation to prevent the exacerbation of these diseases. Induced Vascular Progenitor Cells (iVPCs) are useful for cell-based therapy designed to stimulate coronary collateral growth. They were generated by partially reprogramming endothelial cells.[150] The vascular commitment of iVPCs is related to the epigenetic memory of endothelial cells, which engenders them as cellular components of growing blood vessels. That is why, when iVPCs were implanted into myocardium, they engrafted in blood vessels and increased coronary collateral flow better than iPSCs, mesenchymal stem cells, or native endothelial cells.[216]

Ex vivo genetic modification can be an effective strategy to enhance stem cell function. For example, cellular therapy employing genetic modification with Pim-1 kinase (a downstream effector of Akt, which positively regulates neovasculogenesis) of bone marrowderived cells[217] or human cardiac progenitor cells, isolated from failing myocardium[218] results in durability of repair, together with the improvement of functional parameters of myocardial hemodynamic performance.

Stem cells extracted from fat tissue after liposuction may be coaxed into becoming progenitor smooth muscle cells (iPVSMCs) found in arteries and veins.[219]

The 2D culture system of human iPS cells[220] in conjunction with triple marker selection (CD34 (a surface glycophosphoprotein expressed on developmentally early embryonic fibroblasts), NP1 (receptor - neuropilin 1) and KDR (kinase insert domain-containing receptor)) for the isolation of vasculogenic precursor cells from human iPSC, generated endothelial cells that, after transplantation, formed stable, functional mouse blood vessels in vivo, lasting for 280 days.[221]

To treat infarction, it is important to prevent the formation of fibrotic scar tissue. This can be achieved in vivo by transient application of paracrine factors that redirect native heart progenitor stem cell contributions from scar tissue to cardiovascular tissue. For example, in a mouse myocardial infarction model, a single intramyocardial injection of human vascular endothelial growth factor A mRNA (VEGF-A modRNA), modified to escape the body's normal defense system, results in long-term improvement of heart function due to mobilization and redirection of epicardial progenitor cells toward cardiovascular cell types.[222]

RBC transfusion is necessary for many patients. However, to date the supply of RBCs remains labile. In addition, transfusion risks infectious disease transmission. A large supply of safe RBCs generated in vitro would help to address this issue. Ex vivo erythroid cell generation may provide alternative transfusion products to meet present and future clinical requirements.[223][224] Red blood cells (RBC)s generated in vitro from mobilized CD34 positive cells have normal survival when transfused into an autologous recipient.[225] RBC produced in vitro contained exclusively fetal hemoglobin (HbF), which rescues the functionality of these RBCs. In vivo the switch of fetal to adult hemoglobin was observed after infusion of nucleated erythroid precursors derived from iPSCs.[226] Although RBCs do not have nuclei and therefore can not form a tumor, their immediate erythroblasts precursors have nuclei. The terminal maturation of erythroblasts into functional RBCs requires a complex remodeling process that ends with extrusion of the nucleus and the formation of an enucleated RBC.[227] Cell reprogramming often disrupts enucleation. Transfusion of in vitro-generated RBCs or erythroblasts does not sufficiently protect against tumor formation.

The aryl hydrocarbon receptor (AhR) pathway (which has been shown to be involved in the promotion of cancer cell development) plays an important role in normal blood cell development. AhR activation in human hematopoietic progenitor cells (HPs) drives an unprecedented expansion of HPs, megakaryocyte- and erythroid-lineage cells.[228] See also Concise Review:[229][230] The SH2B3 gene encodes a negative regulator of cytokine signaling and naturally occurring loss-of-function variants in this gene increase RBC counts in vivo. Targeted suppression of SH2B3 in primary human hematopoietic stem and progenitor cells enhanced the maturation and overall yield of in-vitro-derived RBCs. Moreover, inactivation of SH2B3 by CRISPR/Cas9 genome editing in human pluripotent stem cells allowed enhanced erythroid cell expansion with preserved differentiation.[231] (See also overview.[230][232])

Platelets help prevent hemorrhage in thrombocytopenic patients and patients with thrombocythemia. A significant problem for multitransfused patients is refractoriness to platelet transfusions. Thus, the ability to generate platelet products ex vivo and platelet products lacking HLA antigens in serum-free media would have clinical value. An RNA interference-based mechanism used a lentiviral vector to express short-hairpin RNAi targeting 2-microglobulin transcripts in CD34-positive cells. Generated platelets demonstrated an 85% reduction in class I HLA antigens. These platelets appeared to have normal function in vitro[233]

One clinically-applicable strategy for the derivation of functional platelets from human iPSC involves the establishment of stable immortalized megakaryocyte progenitor cell lines (imMKCLs) through doxycycline-dependent overexpression of BMI1 and BCL-XL. The resulting imMKCLs can be expanded in culture over extended periods (45 months), even after cryopreservation. Halting the overexpression (by the removal of doxycycline from the medium) of c-MYC, BMI1 and BCL-XL in growing imMKCLs led to the production of CD42b+ platelets with functionality comparable to that of native platelets on the basis of a range of assays in vitro and in vivo.[234] Thomas et al., describe a forward programming strategy relying on the concurrent exogenous expression of 3 transcription factors: GATA1, FLI1 and TAL1. The forward programmed megakaryocytes proliferate and differentiate in culture for several months with megakaryocyte purity over 90% reaching up to 2x105 mature megakaryocytes per input hPSC. Functional platelets are generated throughout the culture allowing the prospective collection of several transfusion units from as few as one million starting hPSCs.[235] See also overview[236]

A specialised type of white blood cell, known as cytotoxic T lymphocytes (CTLs), are produced by the immune system and are able to recognise specific markers on the surface of various infectious or tumour cells, causing them to launch an attack to kill the harmful cells. Thence, immunotherapy with functional antigen-specific T cells has potential as a therapeutic strategy for combating many cancers and viral infections.[237] However, cell sources are limited, because they are produced in small numbers naturally and have a short lifespan.

A potentially efficient approach for generating antigen-specific CTLs is to revert mature immune T cells into iPSCs, which possess indefinite proliferative capacity in vitro and after their multiplication to coax them to redifferentiate back into T cells.[238][239][240]

Another method combines iPSC and chimeric antigen receptor (CAR)[241] technologies to generate human T cells targeted to CD19, an antigen expressed by malignant B cells, in tissue culture.[242] This approach of generating therapeutic human T cells may be useful for cancer immunotherapy and other medical applications.

Invariant natural killer T (iNKT) cells have great clinical potential as adjuvants for cancer immunotherapy. iNKT cells act as innate T lymphocytes and serve as a bridge between the innate and acquired immune systems. They augment anti-tumor responses by producing interferon-gamma (IFN-).[243] The approach of collection, reprogramming/dedifferentiation, re-differentiation and injection has been proposed for related tumor treatment.[244]

Dendritic cells (DC) are specialized to control T-cell responses. DC with appropriate genetic modifications may survive long enough to stimulate antigen-specific CTL and after that be completely eliminated. DC-like antigen-presenting cells obtained from human induced pluripotent stem cells can serve as a source for vaccination therapy.[245]

CCAAT/enhancer binding protein- (C/EBP) induces transdifferentiation of B cells into macrophages at high efficiencies[246] and enhances reprogramming into iPS cells when co-expressed with transcription factors Oct4, Sox2, Klf4 and Myc.[247] with a 100-fold increase in iPS cell reprogramming efficiency, involving 95% of the population.[248] Furthermore, C/EBPa can convert selected human B cell lymphoma and leukemia cell lines into macrophage-like cells at high efficiencies, impairing the cells' tumor-forming capacity.[249]

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Recommendation and review posted by Bethany Smith

If you are feeling out of balance, tired and overwhelmed, or your quality of life is being compromised by the symptoms of aging, don't despair. Your body and hormones are simply trying to give you a wake-up call. There is plenty you can do to feel energetic, vibrant and healthy again.

The medical team at Westcoast Women's Clinic are specially trained hormone physicians and experts in helping women achieve optimal health and wellness during their midlife years, which can range from their late-30s to mid-60s.

We also offer programs for Young Women and Male patients to optimize hormone health.

Our Comprehensive Hormone Health Program includes state-of-the-art hormone testing, bioidentical hormone therapy, mind/body medicine, nutritional supplements and lifestyle modifications. Every treatment program is fully customized, from the bioidentical hormones to the physical, emotional and spiritual recommendations, to help ensure individual success.

Our Hormone Health program is an effective way to manage:

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West Coast Womens Clinic - Vancouver Womens Health Clinic

Recommendation and review posted by Bethany Smith

Causes of pituitary insufficiency include pituitary adenomas or other intrasellar and parasellar tumors, inflammatory and infectious destruction, surgical removal, radiation-induced destruction of pituitary tissue, traumatic brain injury (TBI), subarachnoid hemorrhage, and postpartum pituitary necrosis (Sheehan syndrome). Similar diseases originating in the hypothalamus or pituitary stalk may also result in pituitary insufficiency.

Pituitary tumors, or adenomas, are the most common cause of hypopituitarism in adults, although traumatic brain injury as a cause is being more frequently recognized.

Hypopituitarism resulting from pituitary adenomas is due to impaired blood flow to the normal tissue, compression of normal tissue, or interference with the delivery of hypothalamic hormones via the hypothalamus-hypophysial portal system.

In primary pituitary destruction, the anterior pituitary is destroyed, causing a deficiency in some or all pituitary hormones, including prolactin. Disease involving the hypothalamus or pituitary stalk may cause pituitary hormone deficiency with an elevated serum prolactin. Pituitary tumors, or adenomas, can be secretory or nonsecretory. Approximately 30% of all macroadenomas larger than 10 mm produce at least 1 hormone.

Hypothalamic disease involves destruction of the hypothalamus. This causes a deficiency or loss of hypothalamic regulatory hormone input to the pituitary, which leads to the loss of anterior pituitary hormone secretion, with an elevated serum prolactin level. Loss of antidiuretic hormone (ADH) may have concomitant diabetes insipidus.

Hypersecretion of the secretory pituitary tumor hormone is suggestive of an adenoma. Another indication of a pituitary adenoma is a deficiency in some pituitary hormones with concomitant hyperprolactinemia. Normally, dopamine, produced in the hypothalamus, inhibits prolactin secretion by the anterior pituitary. Compressing the pituitary stalk decreases the inhibitory effect of dopamine and increases prolactin levels.

Longstanding target gland disease may result in hyperplasia of the relevant pituitary cell secreting the tropic hormone, the level of which would be elevated, with an enlarged pituitary gland simulating a mass. Although uncommon, this may appear to be a pituitary adenoma, but the target gland is not hyperfunctioning.

Another common intracranial tumor is craniopharyngioma, a squamous cell tumor that arises from remnants of the Rathke pouch. One third of these tumors extend into the sella, while approximately two thirds remain suprasellar.

Sheehan syndrome occurs with a large volume of postpartum hemorrhage. During pregnancy, the pituitary gland enlarges due to hyperplasia and hypertrophy of the lactotroph cells, which produce prolactin. The hypophyseal vessels, which supply the pituitary, constrict in response to decreasing blood volume, and subsequent vasospasm occurs, causing necrosis of the pituitary gland. The degree of necrosis correlates with the severity of the hemorrhage.

As many as 30% of women experiencing postpartum hemorrhage with hemodynamic instability may develop some degree of hypopituitarism. These patients can develop adrenal insufficiency, hypothyroidism, amenorrhea, diabetes insipidus, and an inability to breastfeed (an early symptom). Lymphocytic hypophysitis occurs most commonly in the postpartum state and may appear as Sheehan syndrome with postpartum hypopituitarism.

Pituitary apoplexy denotes the sudden destruction of the pituitary tissue resulting from infarction or hemorrhage into the pituitary. The most likely cause of the apoplexy is brain trauma; however, it can occur in patients with diabetes mellitus, pregnancy, sickle cell anemia, blood dyscrasias or anticoagulation, or increased intracranial pressure. Apoplexy usually spares the posterior pituitary and solely affects the anterior pituitary. In patients with such underlying diseases, Sheehan syndrome can occur with lesser degrees of postpartum hemorrhage or hypotension.

Head trauma from a motor vehicle accident, a fall, or a projectile can cause hypopituitarism by direct damage to the pituitary or by injuring the pituitary stalk or the hypothalamus. Hypopituitarism may occur immediately, or it may develop months or years later. Recovery is uncommon. Many studies show an incidence of 15-40%, [2] but a study by Kokshoorn et al found the incidence of posttraumatic hypopituitarism to be low. [3]

Other causes of hypopituitarism include empty sella syndrome and infiltrative diseases. Empty sella syndrome occurs when the arachnoid herniates into the sella turcica through an incompetent sellar diaphragm and flattens the pituitary against bone, but resulting pituitary insufficiency is uncommon. Infiltrative diseases, such as Wegener granulomatosis and sarcoidosis, can cause destruction of the anterior pituitary. Lymphocytic hypophysitis is an autoimmune destructive disease that may be directed towards the pituitary or its stalk.

Physiologic or psychological states can influence the hypothalamus by impairing synthesis and secretion of regulating hormones. For example, poor nutrition may impair the hypothalamic secretion of gonadotropin-releasing hormone (GnRH), resulting in reversible pituitary gonadotropin deficiency. Medications may affect measured hormone levels, such as opioids decreasing serum LH and testosterone.

The degree of hormone deficiency varies greatly and depends on the extent of the process and its location. Some functional causes include emotional disorders, changes in body weight, habitual exercise, anorexia, bulimia, congestive heart failure (CHF), renal failure, and certain medications.

Hypopituitarism occurs in adult patients after cranial radiotherapy performed to treat nonpituitary tumors. Thus, patients who undergo cranial radiotherapy should be periodically assessed for pituitary functions. [4]

Additional causes of hypopituitarism include the following:

With regard to item 9 above, in a study of 435 patients, Fatemi et al found evidence that the likelihood of hypopituitarism development after transsphenoidal adenoma removal is higher when the tumor is larger than 20 mm. [6] In contrast, some with hypopituitarism prior to adenomectomy may have improved pituitary function following surgery, if the cause of the hypopituitarism was increased suprasellar pressure resulting from the mass itself.

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Hypopituitarism (Panhypopituitarism): Background ...

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Durham, NC A new study appearing in the current issue of STEM CELLS Translational Medicine indicates that stem cells harvested from fat (adipose) are more potent than those collected from bone marrow in helping to modulate the bodys immune system.

The finding could have significant implications in developing new stem-cell-based therapies, as adipose tissue-derived stem cells (AT-SCs) are far more plentiful in the body than those found in bone marrow and can be collected from waste material from liposuction procedures. Stem cells are considered potential therapies for a range of conditions, from enhancing skin graft survival to treating inflammatory bowel disease.

Researchers at the Leiden University Medical Centers Department of Immunohematology and Blood Transfusion in Leiden, The Netherlands, led by Helene Roelofs, Ph.D., conducted the study. They were seeking an alternative to bone marrow for stem cell therapies because of the low number of stem cells available in marrow and also because harvesting them involves an invasive procedure.

Adipose tissue is an interesting alternative since it contains approximately a 500-fold higher frequency of stem cells and tissue collection is simple, Dr. Roelofs said.

Moreover, Dr. Sara M. Melief added, 400,000 liposuctions a year are performed in the U.S. alone, where the aspirated adipose tissue is regarded as waste and could be collected without any additional burden or risk for the donor.

For the study, the team used stem cells collected from the bone marrow and fat tissue of age-matched donors. They compared the cells ability to regulate the immune system in vitro and found that the two performed similarly, although it took a smaller dose for the AT-SCs to achieve the same effect on the immune cells.

When it came to secreting cytokines the cell signaling molecules that regulate the immune system the AT-SCs also outperformed the bone marrow-derived cells.

This all adds up to make AT-SC a good alternative to bone marrow stem cells for developing new therapies, Dr. Roelofs concluded.

Cells from bone marrow and from fat were equivalent in terms of their potential to differentiate into multiple cell types, said Anthony Atala, M.D., editor of STEM CELLS Translational Medicine and director of Wake Forest Institute for Regenerative Medicine. The fact that the cells from fat tissue seem to be more potent at suppressing the immune system suggest their promise in clinical therapies.

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Stem cells from fat outperform those from bone marrow in ...

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An isolated cardiac muscle cell, beating

Cardiac muscle (heart muscle) is an involuntary, striated muscle that is found in the walls and histological foundation of the heart, specifically the myocardium. Cardiac muscle is one of three major types of muscle, the others being skeletal and smooth muscle. These three types of muscle all form in the process of myogenesis. The cells that constitute cardiac muscle, called cardiomyocytes or myocardiocytes, predominantly contain only one nucleus, although populations with two to four nuclei do exist.[1][2][pageneeded] The myocardium is the muscle tissue of the heart, and forms a thick middle layer between the outer epicardium layer and the inner endocardium layer.

Coordinated contractions of cardiac muscle cells in the heart pump blood out of the atria and ventricles to the blood vessels of the left/body/systemic and right/lungs/pulmonary circulatory systems. This complex mechanism illustrates systole of the heart.

Cardiac muscle cells, unlike most other tissues in the body, rely on an available blood and electrical supply to deliver oxygen and nutrients and remove waste products such as carbon dioxide. The coronary arteries help fulfill this function.

Cardiac muscle has cross striations formed by rotating segments of thick and thin protein filaments. Like skeletal muscle, the primary structural proteins of cardiac muscle are myosin and actin. The actin filaments are thin, causing the lighter appearance of the I bands in striated muscle, whereas the myosin filament is thicker, lending a darker appearance to the alternating A bands as observed with electron microscopy. However, in contrast to skeletal muscle, cardiac muscle cells are typically branch-like instead of linear.

Another histological difference between cardiac muscle and skeletal muscle is that the T-tubules in the cardiac muscle are bigger and wider and track laterally to the Z-discs. There are fewer T-tubules in comparison with skeletal muscle. The diad is a structure in the cardiac myocyte located at the sarcomere Z-line. It is composed of a single T-tubule paired with a terminal cisterna of the sarcoplasmic reticulum. The diad plays an important role in excitation-contraction coupling by juxtaposing an inlet for the action potential near a source of Ca2+ ions. This way, the wave of depolarization can be coupled to calcium-mediated cardiac muscle contraction via the sliding filament mechanism. Cardiac muscle forms these instead of the triads formed between the sarcoplasmic reticulum in skeletal muscle and T-tubules. T-tubules play critical role in excitation-contraction coupling (ECC). Recently, the action potentials of T-tubules were recorded optically by Guixue Bu et al.[3]

The cardiac syncytium is a network of cardiomyocytes connected to each other by intercalated discs that enable the rapid transmission of electrical impulses through the network, enabling the syncytium to act in a coordinated contraction of the myocardium. There is an atrial syncytium and a ventricular syncytium that are connected by cardiac connection fibres.[4] Electrical resistance through intercalated discs is very low, thus allowing free diffusion of ions. The ease of ion movement along cardiac muscle fibers axes is such that action potentials are able to travel from one cardiac muscle cell to the next, facing only slight resistance. Each syncytium obeys the all or none law.[5]

Intercalated discs are complex adhering structures that connect the single cardiomyocytes to an electrochemical syncytium (in contrast to the skeletal muscle, which becomes a multicellular syncytium during mammalian embryonic development). The discs are responsible mainly for force transmission during muscle contraction. Intercalated discs consist of three different types of cell-cell junctions: the actin filament anchoring adherens junctions, the intermediate filament anchoring desmosomes , and gap junctions. They allow action potentials to spread between cardiac cells by permitting the passage of ions between cells, producing depolarization of the heart muscle. However, novel molecular biological and comprehensive studies unequivocally showed that intercalated discs consist for the most part of mixed-type adhering junctions named area composita (pl. areae compositae) representing an amalgamation of typical desmosomal and fascia adhaerens proteins (in contrast to various epithelia).[6][7][8] The authors discuss the high importance of these findings for the understanding of inherited cardiomyopathies (such as arrhythmogenic right ventricular cardiomyopathy).

Under light microscopy, intercalated discs appear as thin, typically dark-staining lines dividing adjacent cardiac muscle cells. The intercalated discs run perpendicular to the direction of muscle fibers. Under electron microscopy, an intercalated disc's path appears more complex. At low magnification, this may appear as a convoluted electron dense structure overlying the location of the obscured Z-line. At high magnification, the intercalated disc's path appears even more convoluted, with both longitudinal and transverse areas appearing in longitudinal section.[9]

In contrast to skeletal muscle, cardiac muscle requires extracellular calcium ions for contraction to occur. Like skeletal muscle, the initiation and upshoot of the action potential in ventricular cardiomyocytes is derived from the entry of sodium ions across the sarcolemma in a regenerative process. However, an inward flux of extracellular calcium ions through L-type calcium channels sustains the depolarization of cardiac muscle cells for a longer duration. The reason for the calcium dependence is due to the mechanism of calcium-induced calcium release (CICR) from the sarcoplasmic reticulum that must occur during normal excitation-contraction (EC) coupling to cause contraction. Once the intracellular concentration of calcium increases, calcium ions bind to the protein troponin, which allows myosin to bind to actin and contraction to occur.

Until recently, it was commonly believed that cardiac muscle cells could not be regenerated. However, a study reported in the April 3, 2009 issue of Science contradicts that belief.[10] Olaf Bergmann and his colleagues at the Karolinska Institute in Stockholm tested samples of heart muscle from people born before 1955 who had very little cardiac muscle around their heart, many showing with disabilities from this abnormality. By using DNA samples from many hearts, the researchers estimated that a 4-year-old renews about 20% of heart muscle cells per year, and about 69 percent of the heart muscle cells of a 50-year-old were generated after he or she was born.

One way that cardiomyocyte regeneration occurs is through the division of pre-existing cardiomyocytes during the normal aging process.[11] The division process of pre-existing cardiomyocytes has also been shown to increase in areas adjacent to sites of myocardial injury. In addition, certain growth factors promote the self-renewal of endogenous cardiomyocytes and cardiac stem cells. For example, insulin-like growth factor 1, hepatocyte growth factor, and high-mobility group protein B1 increase cardiac stem cell migration to the affected area, as well as the proliferation and survival of these cells.[12] Some members of the fibroblast growth factor family also induce cell-cycle re-entry of small cardiomyocytes. Vascular endothelial growth factor also plays an important role in the recruitment of native cardiac cells to an infarct site in addition to its angiogenic effect.

Based on the natural role of stem cells in cardiomyocyte regeneration, researchers and clinicians are increasingly interested in using these cells to induce regeneration of damaged tissue. Various stem cell lineages have been shown to be able to differentiate into cardiomyocytes, including bone marrow stem cells. For example, in one study, researchers transplanted bone marrow cells, which included a population of stem cells, adjacent to an infarct site in a mouse model. Nine days after surgery, the researchers found a new band of regenerating myocardium.[13] However, this regeneration was not observed when the injected population of cells was devoid of stem cells, which strongly suggests that it was the stem cell population that contributed to the myocardium regeneration. Other clinical trials have shown that autologous bone marrow cell transplants delivered via the infarct-related artery decreases the infarct area compared to patients not given the cell therapy.[14]

Occlusion (blockage) of the coronary arteries by atherosclerosis and/or thrombosis can lead to myocardial infarction (heart attack), where part of the myocardium is injured due to ischemia (not receiving enough oxygen). This occurs because coronary arteries are functional end arteries - i.e. there is almost no overlap in the areas supplied by different arteries (anastomoses) so that if one fails, others cannot adequately perfuse the region, unlike in other tissues.

Certain viruses lead to myocarditis (inflammation of the myocardium). Cardiomyopathies are inherent diseases of the myocardium, many of which are caused by genetic mutations.

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Recommendation and review posted by sam