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Chemical Name: (2E,4E,6E,8E)-Mono[(3R,4S,5S,6R)-5-methoxy-4-[(2R,3R)-2-methyl-3-(3-methyl-2-butenyl)oxiranyl]-1-oxaspiro[2.5]oct-6-yl] 2,4,6,8-decatetraenedioic acid ester

The technical data provided above is for guidance only. For batch specific data refer to the Certificate of Analysis. All Tocris products are intended for laboratory research use only.

Jaronski (1972) Cytochemical evidence for RNA synthesis inhibition by fumagillin. J.Antibiot. 25 327. PMID: 4630977.

Ingber et al (1990) Synthetic analogues of fumagillin that inhibit angiogenesis and suppress tumour growth. Nature 348 555. PMID: 1701033.

Lowther et al (1998) The anti-angiogenic agent fumagillin covalently modifies a conserved active-site histidine in the Escherichia coli methionine aminopeptidase. Proc.Natl.Acad.Sci.U.S.A. 95 12153. PMID: 9770455.

Rodriguez-Nieto et al (2001) A re-evaluation of fumagillin selectivity towards endothelial cells. Anticancer Res. 21 3457. PMID: 11848509.

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Keywords: Fumagillin, supplier, Methionine, aminopeptidase-2, inhibitors, Proteases, Proteinases, antiangiogenics, angiogenesis, antibiotics

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Genetics services

Genetic testing can be used to find out whether a person is carrying aspecific genetic mutation (altered gene) that causes a particular medical condition.

Itmay be carried out for anumber of reasons, including:

You will usually need to get a referral from your GP, or a specialist doctor if you have one, for genetic testing to be carried out speak to your GP or your doctor about the possibility of testing if you think you may need it.

Genetic testing usually involves having a sample of your blood or tissue taken. The sample will contain cells containing your DNA and can be tested to find out whether you are carrying a particular mutation and are at risk of developing a particular genetic condition.

In some cases, genetic testing can be carried out to see if a foetus is likely to be born with a certain genetic condition by testing samples of amniotic fluid (the fluid that surrounds the foetus in the womb) or chorionic villi cells (cells that develop into the placenta) extracted from the mother's womb using a needle.

Depending on the condition(s) being tested for, the blood or cell samples will then be tested and examined in a genetics laboratory to check fora specific gene, a certain mutation on a specific gene or any mutation on aspecific gene.

In some cases, it may be necessary to check an entire gene for mutations, using a process called gene sequencing. This has to be done very carefully, and it can take a long time compared to most other hospital laboratory tests.

Depending on the specific mutation being tested for, it can take weeks or even months for the results of genetic tests to become available. This can be because the laboratory has to gather information to help them interpret what has been found.

It is also important to realise that it is not always possible to give definite answers after genetic testing. Sometimes it is necessary to wait to see if the person being tested or other relatives do, or do not develop a condition, and other tests may need to be performed.

You can find out more about genetic testing and how it is carried out by reading the leaflet: 'What happens in a genetics laboratory?' (PDF, 1.90Mb).

If your doctor thinks genetic testing may be appropriate in your case, you will usually be referred for genetic counselling as well.

Genetic counselling is a service that provides support, information and advice about genetic conditions. It is conducted by healthcare professionals who have been specially trained in the science of human genetics (a genetic counsellor or a clinical geneticist).

What happens during genetic counselling will depend on exactly why you've been referred. It may involve:

You will be given clear, accurate information so you can decide what's best for you.

Your appointment will usually take place at your nearest NHS regional genetics centre. The British Society for Genetic Medicine has details for each of the genetics centres in the UK.

For couples at risk of having a child with a serious genetic condition, pre-implantation genetic diagnosis (PGD) may be an option.

PGD involves using in-vitro fertilisation (IVF), where eggs are removed from a woman's ovaries before being fertilised with sperm in a laboratory. After a few days, the resulting embryos can be tested fora particular genetic mutation and a maximum of two unaffected embryos are transferred into the uterus.

While PGD has the advantage of avoiding the termination of foetuses affected byserious conditions, it also has a number of drawbacks. These include the modest success rate of achieving a pregnancy after IVF, as well as the substantial financial (PGD is not always available on the NHS) and emotional burdens of the combined IVF and PGD process.

Page last reviewed: 08/08/2014

Next review due: 08/08/2016

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Genetics - Genetic testing and counselling - NHS Choices

Recommendation and review posted by Bethany Smith

Thanks to advances in science and technology, Dr. Oz says people will one day be able to live longer, healthier lives. Dr. Oz says Wake Forest University is home of one of the country's foremost tissue regeneration labs. "These are technologies that fascinate me because they could add decades to our life," he says.

What is regenerative medicine? Dr. Anthony Atala, director of Wake Forest's program, says his team is working to create cells, tissues and organs for patients who may need them. "Right now, of course, we have a limited life span because your parts are breaking down," he says. "But imagine a time in the future when, once those parts start breaking down, you can just plug a new one right in."

Watch Dr. Oz's visit to the tissue regeneration lab.

Over the years, Dr. Atala's researchers have grown nearly two dozen different types of body parts, including muscle, bones and a working heart valve. "I think if we start combining things like better prevention, better care, doing things better for your body, and just with regenerative medicine, we may push [our life spans] up to 120, 130 years," Dr. Atala says.

Published on March 24, 2009

Link:
Life Extension Technology and Tissue Regeneration

Recommendation and review posted by Bethany Smith

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Challenges in identifying the best source of stem cells ...

Recommendation and review posted by Bethany Smith

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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Induced pluripotent stem-cell therapy - Wikipedia, the ...

Recommendation and review posted by Bethany Smith

Induced pluripotent stem cells (also known as iPS cells or iPSCs) are a type of pluripotent stem cell that can be generated directly from adult cells. The iPSC technology was pioneered by Shinya Yamanakas lab in Kyoto, Japan, who showed in 2006 that the introduction of four specific genes encoding transcription factors could convert adult cells into pluripotent stem cells.[1] He was awarded the 2012 Nobel Prize along with Sir John Gurdon "for the discovery that mature cells can be reprogrammed to become pluripotent." [2]

Pluripotent stem cells hold great promise in the field of regenerative medicine. Because they can propagate indefinitely, as well as give rise to every other cell type in the body (such as neurons, heart, pancreatic, and liver cells), they represent a single source of cells that could be used to replace those lost to damage or disease.

The most well-known type of pluripotent stem cell is the embryonic stem cell. However, since the generation of embryonic stem cells involves destruction (or at least manipulation) [3] of the pre-implantation stage embryo, there has been much controversy surrounding their use. Further, because embryonic stem cells can only be derived from embryos, it has so far not been feasible to create patient-matched embryonic stem cell lines.

Since iPSCs can be derived directly from adult tissues, they not only bypass the need for embryos, but can be made in a patient-matched manner, which means that each individual could have their own pluripotent stem cell line. These unlimited supplies of autologous cells could be used to generate transplants without the risk of immune rejection. While the iPSC technology has not yet advanced to a stage where therapeutic transplants have been deemed safe, iPSCs are readily being used in personalized drug discovery efforts and understanding the patient-specific basis of disease.[citation needed]

Depending on the methods used, reprogramming of adult cells to obtain iPSCs may pose significant risks that could limit their use in humans. For example, if viruses are used to genomically alter the cells, the expression of oncogenes (cancer-causing genes) may potentially be triggered. In February 2008, scientists announced the discovery of a technique that could remove oncogenes after the induction of pluripotency, thereby increasing the potential use of iPS cells in human diseases.[4] In April 2009, it was demonstrated that generation of iPS cells is possible without any genetic alteration of the adult cell: a repeated treatment of the cells with certain proteins channeled into the cells via poly-arginine anchors was sufficient to induce pluripotency.[5] The acronym given for those iPSCs is piPSCs (protein-induced pluripotent stem cells).

iPSCs are typically derived by introducing a specific set of pluripotency-associated genes, or reprogramming factors, into a given cell type. The original set of reprogramming factors (also dubbed Yamanaka factors) are the genes Oct4 (Pou5f1), Sox2, cMyc, and Klf4. While this combination is most conventional in producing iPSCs, each of the factors can be functionally replaced by related transcription factors, miRNAs, small molecules, or even non-related genes such as lineage specifiers.

iPSC derivation is typically a slow and inefficient process, taking 12 weeks for mouse cells and 34 weeks for human cells, with efficiencies around 0.01%0.1%. However, considerable advances have been made in improving the efficiency and the time it takes to obtain iPSCs. Upon introduction of reprogramming factors, cells begin to form colonies that resemble pluripotent stem cells, which can be isolated based on their morphology, conditions that select for their growth, or through expression of surface markers or reporter genes.

Induced pluripotent stem cells were first generated by Shinya Yamanaka's team at Kyoto University, Japan, in 2006.[1] Their hypothesis was that genes important to embryonic stem cell function might be able to induce an embryonic state in adult cells. They began by choosing twenty-four genes that were previously identified as important in embryonic stem cells, and used retroviruses to deliver these genes to fibroblasts from mice. The mouse fibroblasts were engineered so that any cells that reactivated the ESC-specific gene, Fbx15, could be isolated using antibiotic selection.

Upon delivery of all twenty-four factors, colonies emerged that had reactivated the Fbx15 reporter, resembled ESCs, and could propagate indefinitely. They then narrowed their candidates by removing one factor at a time from the pool of twenty-four. By this process, they identified four factors, Oct4, Sox2, cMyc, and Klf4, which as a group were both necessary and sufficient to obtain ESC-like colonies under selection for reactivation of Fbx15.

Similar to ESCs, these first-generation iPSCs showed unlimited self-renewal and demonstrated pluripotency by contributing to lineages from all three germ layers in the context of embryoid bodies, teratomas, fetal chimeras. However, the molecular makeup of these cells, including gene expression and epigenetic marks, was somewhere between that of a fibroblast and an ESC, and the cells also failed to produce viable chimeras when injected into developing embryos.

In June 2007, the same group published a breakthrough study along with two other independent research groups from Harvard, MIT, and the University of California, Los Angeles, showing successful reprogramming of mouse fibroblasts into iPS cells. Unlike the first generation of iPS cells, these cells could produce viable chimeric mice and could contribute to the germline, the 'gold standard' for pluripotent stem cells. These cells were derived from mouse fibroblasts by retroviral-mediated expression of the same four transcription factors (Oct4, Sox2, cMyc, Klf4), but the researchers used a different marker to select for pluripotent cells. Instead of Fbx15, they used Nanog, a gene that is functionally important in ESCs. By using this different strategy, the researchers were able to create iPS cells that were more similar to ESCs than the first generation of iPS cells, and independently proved that it was possible to create iPS cells that are functionally identical to ESCs.[6][7][8][9]

Unfortunately, two of the four genes used (namely, c-Myc and KLF4) are oncogenic, and 20% of the chimeric mice developed cancer. In a later study, Yamanaka reported that one can create iPSCs even without c-Myc. The process takes longer and is not as efficient, but the resulting chimeras didn't develop cancer.[10]

Induced pluripotent cells have been made from adult stomach, liver, skin cells, blood cells, prostate cells and urinary tract cells.[11]

In November 2007, a milestone was achieved[12][13] by creating iPSCs from adult human cells; two independent research teams' studies were released one in Science by James Thomson at University of WisconsinMadison[14] and another in Cell by Shinya Yamanaka and colleagues at Kyoto University, Japan.[15] With the same principle used earlier in mouse models, Yamanaka had successfully transformed human fibroblasts into pluripotent stem cells using the same four pivotal genes: Oct3/4, Sox2, Klf4, and c-Myc with a retroviral system. Thomson and colleagues used OCT4, SOX2, NANOG, and a different gene LIN28 using a lentiviral system.

On 8 November 2012, researchers from Austria, Hong Kong and China presented a protocol for generating human iPSCs from exfoliated renal epithelial cells present in urine on Nature Protocols.[16] This method of acquiring donor cells is comparatively less invasive and simple. The team reported the induction procedure to take less time, around 2 weeks for the urinary cell culture and 3 to 4 weeks for the reprogramming; and higher yield, up to 4% using retroviral delivery of exogenous factors. Urinary iPSCs (UiPSCs) were found to show good differentiation potential, and thus represent an alternative choice for producing pluripotent cells from normal individuals or patients with genetic diseases, including those affecting the kidney.[16]

Although the methods pioneered by Yamanaka and others have demonstrated that adult cells can be reprogrammed to iPS cells, there are still challenges associated with this technology:

The table at right summarizes the key strategies and techniques used to develop iPS cells over the past half-decade. Rows of similar colors represents studies that used similar strategies for reprogramming.

One of the main strategies for avoiding problems (1) and (2) has been to use small compounds that can mimic the effects of transcription factors. These molecule compounds can compensate for a reprogramming factor that does not effectively target the genome or fails at reprogramming for another reason; thus they raise reprogramming efficiency. They also avoid the problem of genomic integration, which in some cases contributes to tumor genesis. Key studies using such strategy were conducted in 2008. Melton et al. studied the effects of histone deacetylase (HDAC) inhibitor valproic acid. They found that it increased reprogramming efficiency 100-fold (compared to Yamanakas traditional transcription factor method).[25] The researchers proposed that this compound was mimicking the signaling that is usually caused by the transcription factor c-Myc. A similar type of compensation mechanism was proposed to mimic the effects of Sox2. In 2008, Ding et al. used the inhibition of histone methyl transferase (HMT) with BIX-01294 in combination with the activation of calcium channels in the plasma membrane in order to increase reprogramming efficiency.[26] Deng et al. of Beijing University reported on July 2013 that induced pluripotent stem cells can be created without any genetic modification. They used a cocktail of seven small-molecule compounds including DZNep to induce the mouse somatic cells into stem cells which they called CiPS cells with the efficiency at 0.2% comparable to those using standard iPSC production techniques. The CiPS cells were introduced into developing mouse embryos and were found to contribute to all major cells types, proving its pluripotency.[27][28]

Ding et al. demonstrated an alternative to transcription factor reprogramming through the use of drug-like chemicals. By studying the MET (mesenchymal-epithelial transition) process in which fibroblasts are pushed to a stem-cell like state, Dings group identified two chemicals ALK5 inhibitor SB431412 and MEK (mitogen-activated protein kinase) inhibitor PD0325901 which was found to increase the efficiency of the classical genetic method by 100 fold. Adding a third compound known to be involved in the cell survival pathway, Thiazovivin further increases the efficiency by 200 fold. Using the combination of these three compounds also decreased the reprogramming process of the human fibroblasts from four weeks to two weeks. [29][30]

Another key strategy for avoiding problems such as tumor genesis and low throughput has been to use alternate forms of vectors: adenovirus, plasmids, and naked DNA and/or protein compounds.

In 2008, Hochedlinger et al. used an adenovirus to transport the requisite four transcription factors into the DNA of skin and liver cells of mice, resulting in cells identical to ESCs. The adenovirus is unique from other vectors like viruses and retroviruses because it does not incorporate any of its own genes into the targeted host and avoids the potential for insertional mutagenesis.[31] In 2009, Freed et al. demonstrated successful reprogramming of human fibroblasts to iPS cells.[32] Another advantage of using adenoviruses is that they only need to present for a brief amount of time in order for effective reprogramming to take place.

Also in 2008, Yamanaka et al. found that they could transfer the four necessary genes with a plasmid.[33] The Yamanaka group successfully reprogrammed mouse cells by transfection with two plasmid constructs carrying the reprogramming factors; the first plasmid expressed c-Myc, while the second expressed the other three factors (Oct4, Klf4, and Sox2). Although the plasmid methods avoid viruses, they still require cancer-promoting genes to accomplish reprogramming. The other main issue with these methods is that they tend to be much less efficient compared to retroviral methods. Furthermore, transfected plasmids have been shown to integrate into the host genome and therefore they still pose the risk of insertional mutagenesis. Because non-retroviral approaches have demonstrated such low efficiency levels, researchers have attempted to effectively rescue the technique with what is known as the piggyBac transposon system. The lifecycle of this system is shown below. Several studies have demonstrated that this system can effectively deliver the key reprogramming factors without leaving any footprint mutations in the host cell genome. As demonstrated in the figure, the piggyBac transposon system involves the re-excision of exogenous genes, which eliminates issues like insertional mutagenesis

In January 2014, two articles were published claiming that a type of pluripotent stem cell can be generated by subjecting the cells to certain types of stress (bacterial toxin, a low pH of 5.7, or physical squeezing); the resulting cells were called STAP cells, for stimulus-triggered acquisition of pluripotency.[34]

In light of difficulties that other labs had replicating the results of the surprising study, in March 2014, one of the co-authors has called for the articles to be retracted.[35] On 4 June 2014, the lead author, Obokata agreed to retract both the papers [36] after she was found to have committed research misconduct as concluded in an investigation by RIKEN on 1 April 2014.[37]

Studies by Blelloch et al. in 2009 demonstrated that expression of ES cell-specific microRNA molecules (such as miR-291, miR-294 and miR-295) enhances the efficiency of induced pluripotency by acting downstream of c-Myc .[38] More recently (in April 2011), Morrisey et al. demonstrated another method using microRNA that improved the efficiency of reprogramming to a rate similar to that demonstrated by Ding. MicroRNAs are short RNA molecules that bind to complementary sequences on messenger RNA and block expression of a gene. Morriseys team worked on microRNAs in lung development, and hypothesized that their microRNAs perhaps blocked expression of repressors of Yamanakas four transcription factors. Possible mechanisms by which microRNAs can induce reprogramming even in the absence of added exogenous transcription factors, and how variations in microRNA expression of iPS cells can predict their differentiation potential discussed by Xichen Bao et al.[39]

[citation needed]

The generation of iPS cells is crucially dependent on the genes used for the induction.

Oct-3/4 and certain members of the Sox gene family (Sox1, Sox2, Sox3, and Sox15) have been identified as crucial transcriptional regulators involved in the induction process whose absence makes induction impossible. Additional genes, however, including certain members of the Klf family (Klf1, Klf2, Klf4, and Klf5), the Myc family (c-myc, L-myc, and N-myc), Nanog, and LIN28, have been identified to increase the induction efficiency.

Induced pluripotent stem cells are similar to natural pluripotent stem cells, such as embryonic stem (ES) cells, in many aspects, such as the expression of certain stem cell genes and proteins, chromatin methylation patterns, doubling time, embryoid body formation, teratoma formation, viable chimera formation, and potency and differentiability, but the full extent of their relation to natural pluripotent stem cells is still being assessed.[42]

Gene expression and genome-wide H3K4me3 and H3K27me3 were found to be extremely similar between ES and iPS cells.[43][citation needed] The generated iPSCs were remarkably similar to naturally isolated pluripotent stem cells (such as mouse and human embryonic stem cells, mESCs and hESCs, respectively) in the following respects, thus confirming the identity, authenticity, and pluripotency of iPSCs to naturally isolated pluripotent stem cells:

Recent achievements and future tasks for safe iPSC-based cell therapy are collected in the review of Okano et al.[55]

The task of producing iPS cells continues to be challenging due to the six problems mentioned above. A key tradeoff to overcome is that between efficiency and genomic integration. Most methods that do not rely on the integration of transgenes are inefficient, while those that do rely on the integration of transgenes face the problems of incomplete reprogramming and tumor genesis, although a vast number of techniques and methods have been attempted. Another large set of strategies is to perform a proteomic characterization of iPS cells. The Wu group at Stanford University has made significant progress with this strategy.[56] Further studies and new strategies should generate optimal solutions to the five main challenges. One approach might attempt to combine the positive attributes of these strategies into an ultimately effective technique for reprogramming cells to iPS cells.

Another approach is the use of iPS cells derived from patients to identify therapeutic drugs able to rescue a phenotype. For instance, iPS cell lines derived from patients affected by ectodermal dysplasia syndrome (EEC), in which the p63 gene is mutated, display abnormal epithelial commitment that could be partially rescued by a small compound[57]

An attractive feature of human iPS cells is the ability to derive them from adult patients to study the cellular basis of human disease. Since iPS cells are self-renewing and pluripotent, they represent a theoretically unlimited source of patient-derived cells which can be turned into any type of cell in the body. This is particularly important because many other types of human cells derived from patients tend to stop growing after a few passages in laboratory culture. iPS cells have been generated for a wide variety of human genetic diseases, including common disorders such as Down syndrome and polycystic kidney disease.[58][59] In many instances, the patient-derived iPS cells exhibit cellular defects not observed in iPS cells from healthy patients, providing insight into the pathophysiology of the disease.[60] An international collaborated project, StemBANCC, was formed in 2012 to build a collection of iPS cell lines for drug screening for a variety of disease. Managed by the University of Oxford, the effort pooled funds and resources from 10 pharmaceutical companies and 23 universities. The goal is to generate a library of 1,500 iPS cell lines which will be used in early drug testing by providing a simulated human disease environment.[61]

A proof-of-concept of using induced pluripotent stem cells (iPSCs) to generate human organ for transplantation was reported by researchers from Japan. Human liver buds (iPSC-LBs) were grown from a mixture of three different kinds of stem cells: hepatocytes (for liver function) coaxed from iPSCs; endothelial stem cells (to form lining of blood vessels) from umbilical cord blood; and mesenchymal stem cells (to form connective tissue). This new approach allows different cell types to self-organize into a complex organ, mimicking the process in fetal development. After growing in vitro for a few days, the liver buds were transplanted into mice where the liver quickly connected with the host blood vessels and continued to grow. Most importantly, it performed regular liver functions including metabolizing drugs and producing liver-specific proteins. Further studies will monitor the longevity of the transplanted organ in the host body (ability to integrate or avoid rejection) and whether it will transform into tumors.[62][63] Using this method, cells from one mouse could be used to test 1,000 drug compounds to treat liver disease, and reduce animal use by up to 50,000.[64]

Embryonic cord-blood cells were induced into pluripotent stem cells using plasmid DNA. Using cell surface endothelial/pericytic markers CD31 and CD146, researchers identified 'vascular progenitor', the high-quality, multipotent vascular stem cells. After the iPS cells were injected directly into the vitreous of the damaged retina of mice, the stem cells engrafted into the retina, grew and repaired the vascular vessels.[65][66]

In a study conducted in China in 2013, Superparamagnetic iron oxide (SPIO) particles were used to label iPSCs-derived NSCs in vitro. Labeled NSCs were implanted into TBI rats and SCI monkeys 1 week after injury, and then imaged using gradient reflection echo (GRE) sequence by 3.0T magnetic resonance imaging (MRI) scanner. MRI analysis was performed at 1, 7, 14, 21, and 30 days, respectively, following cell transplantation. Pronounced hypointense signals were initially detected at the cell injection sites in rats and monkeys and were later found to extend progressively to the lesion regions, demonstrating that iPSCs-derived NSCs could migrate to the lesion area from the primary sites. The therapeutic efficacy of iPSCs-derived NSCs was examined concomitantly through functional recovery tests of the animals. In this study, we tracked iPSCs-derived NSCs migration in the CNS of TBI rats and SCI monkeys in vivo for the first time. Functional recovery tests showed obvious motor function improvement in transplanted animals. These data provide the necessary foundation for future clinical application of iPSCs for CNS injury.[67]

In 2014, type O red blood cells were synthesized at the Scottish National Blood Transfusion Service from iPSC. The cells were induced to become a mesoderm and then blood cells and then red blood cells. The final step was to make them eject their nuclei and mature properly. Type O can be transfused into all patients. Each pint of blood contains about two trillion red blood cells, while some 107 million blood donations are collected globally every year. Human transfusions were not expected to begin until 2016.[68]

The first human clinical trial using autologous iPSCs is approved by the Japan Ministry Health and will be conducted in 2014 in Kobe. iPSCs derived from skin cells from six patients suffering from wet age-related macular degeneration will be reprogrammed to differentiate into retinal pigment epithelial (RPE) cells. The cell sheet will be transplanted into the affected retina where the degenerated RPE tissue has been excised. Safety and vision restoration monitoring is expected to last one to three years.[69][70] The benefits of using autologous iPSCs are that there is theoretically no risk of rejection and it eliminates the need to use embryonic stem cells.[70]

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Induced pluripotent stem cell - Wikipedia, the free ...

Recommendation and review posted by Bethany Smith

Founded in 2009 by Nobel prize winner Professor Sir Martin Evans and Ajan Reginald, former Global Head of Emerging Technologies at Roche, CTL develops life-saving and life altering regenerative medicines. CTLs team of scientists, physicians, and experienced management have discovered and developed a pipeline of world-class regenerative medicines.

Sir Martin Evans' unique expertise in discovering rare stem cells led to CTLs innovative drug discovery engine that can uniquely isolate very rare and potent tissue specific stem cells. This exceptional class of cells is then engineered into unique disease-specific cellular regenerative medicines. Each medicine is disease specific and forms part of CTLs world-class portfolio of four off the shelf blockbuster medicines all scheduled for launch before 2020.

The products in late stage clinical trials include Heartcel which regenerates the damaged heart of adults with coronary artery malformations and children with Kawasaki Disease and Bland White Garland Syndrome. In 2014, Heartcel reported unprecedented heart regeneration clinical trial results and is scheduled to launch in 2018 to treat ~400,000 patients worldwide. Myocardion is in Phase II/III trials and treats mild-moderate heart failure affecting 10 million patients worldwide. Tendoncel is the worlds first topical regenerative medicine, for early intervention of severe tendon injuries, and has completed Phase II trials. It is designed to treat the >1 million severe tendon injuries each year in the US and Europe. Skincel is for skin regeneration, and is due to complete Phase II trials in 2015. It is designed to address ulceration and wrinkles.

CTL combines world-class science and management expertise to bring life-saving regenerative medicines to market.

European Society of Gene and Cell Therapy Congress, 17-20 September 2015, Helsinki,Finland (ESGCT 2015)

4th International Conference and Exhibition on Cell & Gene Therapy, August 10-12, 2015, London (CGT 2015)

The International Society for Stem Cell Research Annual Meeting, 24th-27th June 2015, Stockholm, Sweden (ISSCR 2015)

British Society for Gene and Cell Therapy Annual Conference, 9th-11th June 2015, Strathclyde, Glasgow (BSGCT 2015)

Originally posted here:
Cell Therapy Ltd

Recommendation and review posted by Bethany Smith

A treatment for Cystic Fibrosis. A cure for AIDS. The end of cancer. That's what the newspapers promised us in the early 1990's. Gene therapy was the answer to what ailed us. Scientists had at last learned how to insert healthy genes into unhealthy people. And those healthy genes would either replace the bad genes causing diseases like CF, sickle-cell anemia and hemophilia or stimulate the body's own immune system to rid itself of HIV and some forms of cancer. A decade later, none of these treatments have come to fruition and research into gene therapy has become politically unpopular, making clinical trials hard to approve and research dollars hard to come by. But some researchers who are taking a different approach to gene therapy could be on the road to more success than ever before. - - - - - - - - - - - -

Early Promise

Almost as soon as Watson and Crick unwound the double helix in the 1950's, researchers began considering the possibility- and ethics- of gene therapy. The goals were lofty- to fix inherited genetic diseases such as Cystic Fibrosis and hemophilia forever.

Gene therapists planned to isolate the relevant gene in question, prepare good copies of that gene, then deliver them to patients' cells. The hope was that the treated cells would give rise to new generations of healthy cells for the rest of the patient's life. The concept was elegant, but would require decades of research to locate the genes that cause illnesses.

By 1990, it was working in the lab. By inserting healthy genes into cells from CF patients, scientists were able to transmogrify the sick cells as if by magic into healthy cells.

That same year, four-year-old Ashanti DeSilva became the first person in history to receive gene therapy. Dr. W. French Anderson of the National Heart, Lung and Blood Institute and Dr. Michael Blaese and Dr. Kenneth Culver, both of the National Cancer Institute, performed the historic and controversial experiment.

DeSilva suffered from a rare immune disorder known as ADA deficiency that made her vulnerable to even the mildest infections. A single genetic defect- like a typo in a novel- left DeSilva unable to produce an important enzyme. Without that enzyme, DeSilva was likely to die a premature death.

Anderson, Blaese and Culver drew the girl's blood and treated her defective white blood cells with the gene she lacked. The altered cells were then injected back into the girl, where- the scientists hoped- they would produce the enzyme she needed as well as produce future generations of normal cells.

Though the treatment proved safe, its efficacy is still in question. The treated cells did produce the enzyme, but failed to give rise to healthy new cells. DeSilva, who is today relatively healthy, still receives periodic gene therapy to maintain the necessary levels of the enzyme in her blood. She also takes doses of the enzyme itself, in the form of a drug called PEG-ADA, which makes it difficult to tell how well the gene therapy would have worked alone.

"It was a very logical approach," says Dr. Jeffrey Isner, Chief of Vascular Medicine and Cardiovascular Research at St. Elizabeth's Medical Center in Boston as well as Professor of Medicine at Tufts University School of Medicine. "But in most cases the strategy failed, because the vectors we have today are not ready for prime time." - - - - - - - - - - - - 4 pages: | 1 | 2 | 3 | 4 |

Photo: Dr. W. French Anderson

The rest is here:
Gene therapy - PBS

Recommendation and review posted by Bethany Smith

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The immune system is our safety net from germs and viruses. This complex defense system is designed to keep us alive. If we didn't have an immune system we would quickly die from the overabundance of bacteria and viruses which would completely take over the human body. The majority of our immune system is located within the digestive tract. People who suffer from poor digestion or other digestive disorders are often hit the hardest when they encounter a foreign organism. Our immune function comes from a combination of tissues, organs, proteins and vital cells.

There are a variety of autoimmune diseases that weaken the immune system. An autoimmune disease is the result of the body attacking itself. Some cells within the body become hyperactive and don't function as they should. The most common autoimmune diseases are rheumatoid arthritis, multiple sclerosis and Chron's disease. Doctors are not sure what actually causes autoimmune diseases, but it is thought that environmental and hereditary factors play a role.

Diabetes is a metabolic disorder that affects how the body uses food for energy due to insulin resistance. Diabetes affects the metabolism as well as the immune system. The disease causes the immune system to destroy insulin producing cells within the pancreas. The immune response is also much lower in people who have diabetes so they are more susceptible to getting infections that could result in the loss of a limb.

AIDS, also known as acquired immunodeficiency syndrome, is one of the most common diseases that affect the immune system. This horrible disease makes the body's defenses weaker over time. Before AIDs takes full effect, a person will first have HIV, which is the start of the progressively devastating disease. People who have the disease may even die from infectious viruses rather than the disease itself, because of their severely weak immune function. Most people know that HIV is transmitted by having unprotected sex or coming in contact with infected blood.

Hepatitis C is a virus that attacks the liver cells. The virus will rapidly multiply within the liver, causing inflammation and damage. Hepatitis C affects the immune system, causing serious liver damage leading to scarring of the liver. The virus causes the immune system to break down, making the affected person more susceptible to other infectious diseases.

Kidneys filter the blood of impurities, toxins and excess vitamins. When the kidneys are not functioning properly due to kidney disease, more toxins circulate within the blood. The excess toxins affect the immune system, making a person more tired and sluggish. A person with kidney disease will become sick more often because the immune system is weakened.

List of Immune Diseases. Immune system diseases are usually referred to as autoimmune disorders. ... Diseases That Affect the Immune System.

Lupus is an autoimmune disease that causes the immune system to attack healthy cells and ... Lupus is a disorder of the...

Diseases That Affect the Immune System; How to Clean Your Lymph System; How to Strengthen a Lymphatic System; You May Also Like....

Does Sugar Affect the Immune System?. Part of the series: Nutrition & Diets. ... Why Does Obesity Lead to Diabetes? How Does...

... including borrelia burgdorferi. Years of immune system response can damage the kidneys. ... What are the Long-Lasting Affects & Symptoms of...

For patients with a low immune system, physicians will sometimes prescribe immune-boosting medicines such as interferon, ... Disorders That Attack the Immune...

Diseases That Affect the Immune System. The immune system is our safety net from germs and viruses. This complex defense system is...

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Diseases That Affect the Immune System | eHow

Recommendation and review posted by simmons

Genetic Counseling at Summit Medical Group provides risk assessment and genetic testing for individuals and couples with family concerns such as:

If you are planning to have a baby, you might be concerned about illnesses that your child might inherit from one or both sides of your family. You can ask your health care provider about genetic counseling or genetic screening to learn more about inherited diseases.

You may have genetic testing before you get pregnant. You also can have genetic testing at your first prenatal visit and later in your pregnancy.

Most cancers are not inherited; however, in 5% to 10% of families there might be a genetic predisposition for certain cancers. A consultation with a genetic counselor can provide the opportunity to estimate the risk for cancer based on:

Our genetic counselor is experienced in risk assessment and options for families who might have a predisposition for breast/ovarian cancer, colon cancer, or any other cancer that might be inherited.

Your health care provider or board-certified genetic counselor will review your family and personal medical histories. He or she is likely to ask you about diseases, disorders, and birth defects in your families as far back as 3 generations. Your doctor or genetic counselor also will discuss the benefits and risks of testing. Both parents might have blood tests even before getting pregnant. If you are pregnant, the baby also might be tested.

Your health care provider or counselor will discuss the genetic screening results with you. If there is a problem, they will help you understand it. They will describe your choices for prevention and treatment.

Genetic testing should be accompanied with a genetic consultation.

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Genetic Counseling Center | Summit Medical Group New Jersey

Recommendation and review posted by sam

As people age, their hormone levels decline, starting in their twenties and thirties. In addition, toxins and other insults from the environment and food supply are believed to contribute to the development of hormonal imbalances.

Bioidentical hormones are hormones that are identical to those that the body makes on its own. Some are available through regular retail pharmacies. Others are only available through compounding pharmacies. The main advantages of bioidentical hormones are that they are very well tolerated and that they have no side effects when they are properly dosed and integrated in a holistic treatment plan. This cannot be said of non-bioidentical hormones, such as Premarin, PremPro, and Provera, that most physicians prescribe. We should avoid using the term hormones when we refer to these non-bioidentical chemicals. These chemicals have many known side effects, in many cases even at the recommended dosage levels. Most people do not realize that treatment with non-bioidentical chemicals cannot even be monitored properly because physicians and laboratories do not offer testing for drugs like Premarin, PremPro, and Provera. We certainly dont know what the optimal levels of horse estrogens are in human beings!

THE WILEY PROTOCOL

When I first started helping my patients with bioidentical hormone replacement therapy I used non-rhythmic, statically dosed protocols. What this meant in the context of replacement of estrogens and progesterone was that I used the same dosages of estradiol (with or without estriol and estrone) and progesterone for specified number of days in a 28- to 30-day cycle.

In February 2007 I started treating patients with the Wiley Protocol. The Wiley Protocol is different in that the dosing of estradiol and progesterone is not static. Instead, the dosages of estradiol and progesterone change cyclically, following either a womans personal cycle (if she still has a regular menstrual cycle) or the cycle of the moon (lunar cycle) if has stopped having periods or her menstrual cycle is irregular.

In a healthy young woman the levels of estradiol and progesterone are low on day 1 of the cycle. Estradiol levels rise gradually during the follicular phase, peak on day 12, and drop abruptly on day 13. After ovulation and after development of the corpus luteum the progesterone levels start rising on day 14, peak on day 21, and finally decrease gradually over the next 7 days if a woman does not get pregnant. When a woman is on the Wiley Protocol the hormone levels follow the pattern that we see in healthy young women. My patients have responded very well to this protocol, especially in cases where they did not respond to other types of hormone replacement therapy.

The Wiley Protocol has been found to be beneficial for women of all ages who experience signs and symptoms related to disorders of reproductive function. These include women with a diagnosis of PCOS (polycystic ovarian syndrome), endometriosis, uterine fibroids, PMS (premenstrual syndrome), irregular periods, painful periods, heavy periods, infertility, hot flashes, insomnia, and acne.

The main reasons that patients have responded so well is that I carefully monitor my patients signs and symptoms and hormone levels on day 12 and day 21 of the menstrual cycle.

Unlike other methods of bioidentical hormone replacement, women of all ages who follow the Wiley Protocol will have a period every month unless they dont have a uterus. More than 90% of female patients who are bioidentical hormone replacement therapy are on the Wiley Protocol because it results in superior symptom relief and because the cyclical dosing schedule makes sense to them intuitively and physiologically. For postmenopausal women who prefer not to have a menstrual period every month again I offer statically dosed therapy.

The following rhythmic, bioidentical Wiley Protocol hormones are available:

Here is information about the Wiley Protocol Face Creme from the Wiley Protocol website:

Wiley Protocol Face Creme We all yearn for a more youthful appearance and Wiley Protocol Face creme provides this option by replenishing the sub-dermal fat base which plumps up the fine lines that make us look old. There are estrogen receptors everywhere in a womans body, including in her skin. As a woman ages, she begins to lose collagen as the levels of estrogen diminish. Many dermatologists and doctors have noted that even systemic hormone therapy seems to improve the appearance of aging skin. Some studies have shown that estrogen, when applied in a cream penetrates the skin due to its small molecular size, and increases the production of collagen. Applied daily, this creme is non-greasy and absorbs quickly.

To find out more about the Wiley Protocol I recommend the following resources:

OTHER BIOIDENTICAL HORMONES

Often patients are deficient in other hormones, such as thyroid hormone, testosterone, cortisol, DHEA, and growth hormone. I offer bioidentical therapies for these hormonal imbalances as well.

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Hormone Replacement | Fred Bloem, MD Holistic Physician ...

Recommendation and review posted by Bethany Smith

Endogenous cardiac stem cells (eCSCs) are tissue-specific stem progenitor cells harboured within the adult mammalian heart.

They were first discovered in 2003 by Bernardo Nadal-Ginard, Piero Anversa and colleagues [1][2] in the adult rat heart and since then have been identified and isolated from mouse, dog, porcine and human hearts.[3][4]

The adult heart was previously thought to be a post mitotic organ without any regenerative capability. The identification of eCSCs has provided an explanation for the hitherto unexplained existence of a subpopulation of immature cycling myocytes in the adult myocardium. Indeed, recent evidence from a genetic fate-mapping study established that stem cells replenish adult mammalian cardiomyocytes lost by cardiac wear and tear and injury throughout the adult life.[5] Moreover, it is now accepted that myocyte death and myocyte renewal are the two sides of the proverbial coin of cardiac homeostasis in which the eCSCs play a central role.[6] These findings produced a paradigm shift in cardiac biology and opened new opportunities and approaches for future treatment of cardiac diseases by placing the heart squarely amongst other organs with regenerative potential such as the liver, skin, muscle, CNS. However, they have not changed the well-established fact that the working myocardium is mainly constituted of terminally differentiated contractile myocytes. This fact does not exclude, but is it fully compatible with the heart being endowed with a robust intrinsic regenerative capacity which resides in the presence of the eCSCs throughout the individual lifespan.

Briefly, eCSCs have been first identified through the expression of c-kit, the receptor of the stem cell factor and the absence of common hematopoietic markers, like CD45. Afterwards, different membrane markers (Sca-1, Abcg-2, Flk-1) and transcription factors (Isl-1, Nkx2.5, GATA4) have been employed to identify and characterize these cells in the embryonic and adult life.[7] eCSCs are clonogenic, self renewing and multipotent in vitro and in vivo,[8] capable of generating the 3 major cell types of the myocardium: myocytes, smooth muscle and endothelial vascular cells.[9] They express several markers of stemness (i.e. Oct3/4, Bmi-1, Nanog) and have significant regenerative potential in vivo.[10] When cloned in suspension they form cardiospheres,[11] which when cultured in a myogenic differentiation medium, attach and differentiate into beating cardiomyocytes.

In 2012, it was proposed that Isl-1 is not a marker for endogenous cardiac stem cells.[12] That same year, a different group demonstrated that Isl-1 is not restricted to second heart field progenitors in the developing heart, but also labels cardiac neural crest.[13] It has also been reported that Flk-1 is not a specific marker for endogenous and mouse ESC-derived Isl1+ CPCs. While some eCSC discoveries have been brought into question, there has been success with other membrane markers. For instance, it was demonstrated that the combination of Flt1+/Flt4+ membrane markers identifies an Isl1+/Nkx2.5+ cell population in the developing heart. It was also shown that endogenous Flt1+/Flt4+ cells could be expanded in vitro and displayed trilineage differentiation potential. Flt1+/Flt4+ CPCs derived from iPSCs were shown to engraft into the adult myocardium and robustly differentiate into cardiomyocytes with phenotypic and electrophysiologic characteristics of adult cardiomyocytes.[14]

With the myocardium now recognized as a tissue with limited regenerating potential,[15] harbouring eCSCs that can be isolated and amplified in vitro [16] for regenerative protocols of cell transplantation or stimulated to replicate and differentiate in situ in response to growth factors,[17] it has become reasonable to exploit this endogenous regenerative potential to replace lost/damaged cardiac muscle with autologous functional myocardium.

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Endogenous cardiac stem cell - Wikipedia, the free ...

Recommendation and review posted by Bethany Smith

Hematopoietic stem cell transplantation (HSCT) is the transplantation of multipotent hematopoietic stem cells, usually derived from bone marrow, peripheral blood, or umbilical cord blood. It may be autologous (the patient's own stem cells are used) or allogeneic (the stem cells come from a donor). It is a medical procedure in the field of hematology, most often performed for patients with certain cancers of the blood or bone marrow, such as multiple myeloma or leukemia. In these cases, the recipient's immune system is usually destroyed with radiation or chemotherapy before the transplantation. Infection and graft-versus-host disease are major complications of allogeneic HSCT.

Hematopoietic stem cell transplantation remains a dangerous procedure with many possible complications; it is reserved for patients with life-threatening diseases. As survival following the procedure has increased, its use has expanded beyond cancer, such as autoimmune diseases.[1][2]

Indications for stem cell transplantation are as follows:

Many recipients of HSCTs are multiple myeloma[3] or leukemia patients[4] who would not benefit from prolonged treatment with, or are already resistant to, chemotherapy. Candidates for HSCTs include pediatric cases where the patient has an inborn defect such as severe combined immunodeficiency or congenital neutropenia with defective stem cells, and also children or adults with aplastic anemia[5] who have lost their stem cells after birth. Other conditions[6] treated with stem cell transplants include sickle-cell disease, myelodysplastic syndrome, neuroblastoma, lymphoma, Ewing's sarcoma, desmoplastic small round cell tumor, chronic granulomatous disease and Hodgkin's disease. More recently non-myeloablative, "mini transplant(microtransplantation)," procedures have been developed that require smaller doses of preparative chemo and radiation. This has allowed HSCT to be conducted in the elderly and other patients who would otherwise be considered too weak to withstand a conventional treatment regimen.

A total of 50,417 first hematopoietic stem cell transplants were reported as taking place worldwide in 2006, according to a global survey of 1327 centers in 71 countries conducted by the Worldwide Network for Blood and Marrow Transplantation. Of these, 28,901 (57 percent) were autologous and 21,516 (43 percent) were allogeneic (11,928 from family donors and 9,588 from unrelated donors). The main indications for transplant were lymphoproliferative disorders (54.5 percent) and leukemias (33.8 percent), and the majority took place in either Europe (48 percent) or the Americas (36 percent).[7] In 2009, according to the World Marrow Donor Association, stem cell products provided for unrelated transplantation worldwide had increased to 15,399 (3,445 bone marrow donations, 8,162 peripheral blood stem cell donations, and 3,792 cord blood units).[8]

Autologous HSCT requires the extraction (apheresis) of haematopoietic stem cells (HSC) from the patient and storage of the harvested cells in a freezer. The patient is then treated with high-dose chemotherapy with or without radiotherapy with the intention of eradicating the patient's malignant cell population at the cost of partial or complete bone marrow ablation (destruction of patient's bone marrow function to grow new blood cells). The patient's own stored stem cells are then transfused into his/her bloodstream, where they replace destroyed tissue and resume the patient's normal blood cell production. Autologous transplants have the advantage of lower risk of infection during the immune-compromised portion of the treatment since the recovery of immune function is rapid. Also, the incidence of patients experiencing rejection (graft-versus-host disease) is very rare due to the donor and recipient being the same individual. These advantages have established autologous HSCT as one of the standard second-line treatments for such diseases as lymphoma.[9]

However, for others cancers such as acute myeloid leukemia, the reduced mortality of the autogenous relative to allogeneic HSCT may be outweighed by an increased likelihood of cancer relapse and related mortality, and therefore the allogeneic treatment may be preferred for those conditions.[10] Researchers have conducted small studies using non-myeloablative hematopoietic stem cell transplantation as a possible treatment for type I (insulin dependent) diabetes in children and adults. Results have been promising; however, as of 2009[update] it was premature to speculate whether these experiments will lead to effective treatments for diabetes.[11]

Allogeneics HSCT involves two people: the (healthy) donor and the (patient) recipient. Allogeneic HSC donors must have a tissue (HLA) type that matches the recipient. Matching is performed on the basis of variability at three or more loci of the HLA gene, and a perfect match at these loci is preferred. Even if there is a good match at these critical alleles, the recipient will require immunosuppressive medications to mitigate graft-versus-host disease. Allogeneic transplant donors may be related (usually a closely HLA matched sibling), syngeneic (a monozygotic or 'identical' twin of the patient - necessarily extremely rare since few patients have an identical twin, but offering a source of perfectly HLA matched stem cells) or unrelated (donor who is not related and found to have very close degree of HLA matching). Unrelated donors may be found through a registry of bone marrow donors such as the National Marrow Donor Program. People who would like to be tested for a specific family member or friend without joining any of the bone marrow registry data banks may contact a private HLA testing laboratory and be tested with a mouth swab to see if they are a potential match.[12] A "savior sibling" may be intentionally selected by preimplantation genetic diagnosis in order to match a child both regarding HLA type and being free of any obvious inheritable disorder. Allogeneic transplants are also performed using umbilical cord blood as the source of stem cells. In general, by transfusing healthy stem cells to the recipient's bloodstream to reform a healthy immune system, allogeneic HSCTs appear to improve chances for cure or long-term remission once the immediate transplant-related complications are resolved.[13][14][15]

A compatible donor is found by doing additional HLA-testing from the blood of potential donors. The HLA genes fall in two categories (Type I and Type II). In general, mismatches of the Type-I genes (i.e. HLA-A, HLA-B, or HLA-C) increase the risk of graft rejection. A mismatch of an HLA Type II gene (i.e. HLA-DR, or HLA-DQB1) increases the risk of graft-versus-host disease. In addition a genetic mismatch as small as a single DNA base pair is significant so perfect matches require knowledge of the exact DNA sequence of these genes for both donor and recipient. Leading transplant centers currently perform testing for all five of these HLA genes before declaring that a donor and recipient are HLA-identical.

Race and ethnicity are known to play a major role in donor recruitment drives, as members of the same ethnic group are more likely to have matching genes, including the genes for HLA.[16]

As of 2013[update], there were at least two commercialized allogeneic cell therapies, Prochymal and Cartistem.[17]

To limit the risks of transplanted stem cell rejection or of severe graft-versus-host disease in allogeneic HSCT, the donor should preferably have the same human leukocyte antigens (HLA) as the recipient. About 25 to 30 percent of allogeneic HSCT recipients have an HLA-identical sibling. Even so-called "perfect matches" may have mismatched minor alleles that contribute to graft-versus-host disease.

In the case of a bone marrow transplant, the HSC are removed from a large bone of the donor, typically the pelvis, through a large needle that reaches the center of the bone. The technique is referred to as a bone marrow harvest and is performed under general anesthesia.

Peripheral blood stem cells[18] are now the most common source of stem cells for allogeneic HSCT. They are collected from the blood through a process known as apheresis. The donor's blood is withdrawn through a sterile needle in one arm and passed through a machine that removes white blood cells. The red blood cells are returned to the donor. The peripheral stem cell yield is boosted with daily subcutaneous injections of Granulocyte-colony stimulating factor, serving to mobilize stem cells from the donor's bone marrow into the peripheral circulation.

It is also possible to extract stem cells from amniotic fluid for both autologous or heterologous use at the time of childbirth.

Umbilical cord blood is obtained when a mother donates her infant's umbilical cord and placenta after birth. Cord blood has a higher concentration of HSC than is normally found in adult blood. However, the small quantity of blood obtained from an Umbilical Cord (typically about 50 mL) makes it more suitable for transplantation into small children than into adults. Newer techniques using ex-vivo expansion of cord blood units or the use of two cord blood units from different donors allow cord blood transplants to be used in adults.

Cord blood can be harvested from the Umbilical Cord of a child being born after preimplantation genetic diagnosis (PGD) for human leucocyte antigen (HLA) matching (see PGD for HLA matching) in order to donate to an ill sibling requiring HSCT.

Unlike other organs, bone marrow cells can be frozen (cryopreserved) for prolonged periods without damaging too many cells. This is a necessity with autologous HSC because the cells must be harvested from the recipient months in advance of the transplant treatment. In the case of allogeneic transplants, fresh HSC are preferred in order to avoid cell loss that might occur during the freezing and thawing process. Allogeneic cord blood is stored frozen at a cord blood bank because it is only obtainable at the time of childbirth. To cryopreserve HSC, a preservative, DMSO, must be added, and the cells must be cooled very slowly in a controlled-rate freezer to prevent osmotic cellular injury during ice crystal formation. HSC may be stored for years in a cryofreezer, which typically uses liquid nitrogen.

The chemotherapy or irradiation given immediately prior to a transplant is called the conditioning regimen, the purpose of which is to help eradicate the patient's disease prior to the infusion of HSC and to suppress immune reactions. The bone marrow can be ablated (destroyed) with dose-levels that cause minimal injury to other tissues. In allogeneic transplants a combination of cyclophosphamide with total body irradiation is conventionally employed. This treatment also has an immunosuppressive effect that prevents rejection of the HSC by the recipient's immune system. The post-transplant prognosis often includes acute and chronic graft-versus-host disease that may be life-threatening. However, in certain leukemias this can coincide with protection against cancer relapse owing to the graft versus tumor effect.[19]Autologous transplants may also use similar conditioning regimens, but many other chemotherapy combinations can be used depending on the type of disease.

A newer treatment approach, non-myeloablative allogeneic transplantation, also termed reduced-intensity conditioning (RIC), uses doses of chemotherapy and radiation too low to eradicate all the bone marrow cells of the recipient.[20]:320321 Instead, non-myeloablative transplants run lower risks of serious infections and transplant-related mortality while relying upon the graft versus tumor effect to resist the inherent increased risk of cancer relapse.[21][22] Also significantly, while requiring high doses of immunosuppressive agents in the early stages of treatment, these doses are less than for conventional transplants.[23] This leads to a state of mixed chimerism early after transplant where both recipient and donor HSC coexist in the bone marrow space.

Decreasing doses of immunosuppressive therapy then allows donor T-cells to eradicate the remaining recipient HSC and to induce the graft versus tumor effect. This effect is often accompanied by mild graft-versus-host disease, the appearance of which is often a surrogate marker for the emergence of the desirable graft versus tumor effect, and also serves as a signal to establish an appropriate dosage level for sustained treatment with low levels of immunosuppressive agents.

Because of their gentler conditioning regimens, these transplants are associated with a lower risk of transplant-related mortality and therefore allow patients who are considered too high-risk for conventional allogeneic HSCT to undergo potentially curative therapy for their disease. The optimal conditioning strategy for each disease and recipient has not been fully established, but RIC can be used in elderly patients unfit for myeloablative regimens, for whom a higher risk of cancer relapse may be acceptable.[20][22]

After several weeks of growth in the bone marrow, expansion of HSC and their progeny is sufficient to normalize the blood cell counts and re-initiate the immune system. The offspring of donor-derived hematopoietic stem cells have been documented to populate many different organs of the recipient, including the heart, liver, and muscle, and these cells had been suggested to have the abilities of regenerating injured tissue in these organs. However, recent research has shown that such lineage infidelity does not occur as a normal phenomenon[citation needed].

HSCT is associated with a high treatment-related mortality in the recipient (1 percent or higher)[citation needed], which limits its use to conditions that are themselves life-threatening. Major complications are veno-occlusive disease, mucositis, infections (sepsis), graft-versus-host disease and the development of new malignancies.

Bone marrow transplantation usually requires that the recipient's own bone marrow be destroyed ("myeloablation"). Prior to "engraftment" patients may go for several weeks without appreciable numbers of white blood cells to help fight infection. This puts a patient at high risk of infections, sepsis and septic shock, despite prophylactic antibiotics. However, antiviral medications, such as acyclovir and valacyclovir, are quite effective in prevention of HSCT-related outbreak of herpetic infection in seropositive patients.[24] The immunosuppressive agents employed in allogeneic transplants for the prevention or treatment of graft-versus-host disease further increase the risk of opportunistic infection. Immunosuppressive drugs are given for a minimum of 6-months after a transplantation, or much longer if required for the treatment of graft-versus-host disease. Transplant patients lose their acquired immunity, for example immunity to childhood diseases such as measles or polio. For this reason transplant patients must be re-vaccinated with childhood vaccines once they are off immunosuppressive medications.

Severe liver injury can result from hepatic veno-occlusive disease (VOD). Elevated levels of bilirubin, hepatomegaly and fluid retention are clinical hallmarks of this condition. There is now a greater appreciation of the generalized cellular injury and obstruction in hepatic vein sinuses, and hepatic VOD has lately been referred to as sinusoidal obstruction syndrome (SOS). Severe cases of SOS are associated with a high mortality rate. Anticoagulants or defibrotide may be effective in reducing the severity of VOD but may also increase bleeding complications. Ursodiol has been shown to help prevent VOD, presumably by facilitating the flow of bile.

The injury of the mucosal lining of the mouth and throat is a common regimen-related toxicity following ablative HSCT regimens. It is usually not life-threatening but is very painful, and prevents eating and drinking. Mucositis is treated with pain medications plus intravenous infusions to prevent dehydration and malnutrition.

Graft-versus-host disease (GVHD) is an inflammatory disease that is unique to allogeneic transplantation. It is an attack of the "new" bone marrow's immune cells against the recipient's tissues. This can occur even if the donor and recipient are HLA-identical because the immune system can still recognize other differences between their tissues. It is aptly named graft-versus-host disease because bone marrow transplantation is the only transplant procedure in which the transplanted cells must accept the body rather than the body accepting the new cells. Acute graft-versus-host disease typically occurs in the first 3 months after transplantation and may involve the skin, intestine, or the liver. High-dose corticosteroids such as prednisone are a standard treatment; however this immuno-suppressive treatment often leads to deadly infections. Chronic graft-versus-host disease may also develop after allogeneic transplant. It is the major source of late treatment-related complications, although it less often results in death. In addition to inflammation, chronic graft-versus-host disease may lead to the development of fibrosis, or scar tissue, similar to scleroderma; it may cause functional disability and require prolonged immunosuppressive therapy. Graft-versus-host disease is usually mediated by T cells, which react to foreign peptides presented on the MHC of the host[citation needed].

Graft versus tumor effect (GVT) or "graft versus leukemia" effect is the beneficial aspect of the Graft-versus-Host phenomenon. For example, HSCT patients with either acute, or in particular chronic, graft-versus-host disease after an allogeneic transplant tend to have a lower risk of cancer relapse.[25][26] This is due to a therapeutic immune reaction of the grafted donor T lymphocytes against the diseased bone marrow of the recipient. This lower rate of relapse accounts for the increased success rate of allogeneic transplants, compared to transplants from identical twins, and indicates that allogeneic HSCT is a form of immunotherapy. GVT is the major benefit of transplants that do not employ the highest immuno-suppressive regimens.

Graft versus tumor is mainly beneficial in diseases with slow progress, e.g. chronic leukemia, low-grade lymphoma, and some cases multiple myeloma. However, it is less effective in rapidly growing acute leukemias.[27]

If cancer relapses after HSCT, another transplant can be performed, infusing the patient with a greater quantity of donor white blood cells (Donor lymphocyte infusion).[27]

Patients after HSCT are at a higher risk for oral carcinoma. Post-HSCT oral cancer may have more aggressive behavior with poorer prognosis, when compared to oral cancer in non-HSCT patients.[28]

Prognosis in HSCT varies widely dependent upon disease type, stage, stem cell source, HLA-matched status (for allogeneic HCST) and conditioning regimen. A transplant offers a chance for cure or long-term remission if the inherent complications of graft versus host disease, immuno-suppressive treatments and the spectrum of opportunistic infections can be survived.[13][14] In recent years, survival rates have been gradually improving across almost all populations and sub-populations receiving transplants.[29]

Mortality for allogeneic stem cell transplantation can be estimated using the prediction model created by Sorror et al.,[30] using the Hematopoietic Cell Transplantation-Specific Comorbidity Index (HCT-CI). The HCT-CI was derived and validated by investigators at the Fred Hutchinson Cancer Research Center (Seattle, WA). The HCT-CI modifies and adds to a well-validated comorbidity index, the Charlson Comorbidity Index (CCI) (Charlson et al.[31]) The CCI was previously applied to patients undergoing allogeneic HCT but appears to provide less survival prediction and discrimination than the HCT-CI scoring system.

The risks of a complication depend on patient characteristics, health care providers and the apheresis procedure, and the colony-stimulating factor used (G-CSF). G-CSF drugs include filgrastim (Neupogen, Neulasta), and lenograstim (Graslopin).

Filgrastim is typically dosed in the 10 microgram/kg level for 45 days during the harvesting of stem cells. The documented adverse effects of filgrastim include splenic rupture (indicated by left upper abdominal or shoulder pain, risk 1 in 40000), Adult respiratory distress syndrome (ARDS), alveolar hemorrage, and allergic reactions (usually expressed in first 30 minutes, risk 1 in 300).[32][33][34] In addition, platelet and hemoglobin levels dip post-procedure, not returning to normal until one month.[34]

The question of whether geriatrics (patients over 65) react the same as patients under 65 has not been sufficiently examined. Coagulation issues and inflammation of atherosclerotic plaques are known to occur as a result of G-CSF injection.[33] G-CSF has also been described to induce genetic changes in mononuclear cells of normal donors.[33] There is evidence that myelodysplasia (MDS) or acute myeloid leukaemia (AML) can be induced by GCSF in susceptible individuals.[35]

Blood was drawn peripherally in a majority of patients, but a central line to jugular/subclavian/femoral veins may be used in 16 percent of women and 4 percent of men. Adverse reactions during apheresis were experienced in 20 percent of women and 8 percent of men, these adverse events primarily consisted of numbness/tingling, multiple line attempts, and nausea.[34]

A study involving 2408 donors (1860 years) indicated that bone pain (primarily back and hips) as a result of filgrastim treatment is observed in 80 percent of donors by day 4 post-injection.[34] This pain responded to acetaminophen or ibuprofen in 65 percent of donors and was characterized as mild to moderate in 80 percent of donors and severe in 10 percent.[34] Bone pain receded post-donation to 26 percent of patients 2 days post-donation, 6 percent of patients one week post-donation, and <2 percent 1 year post-donation. Donation is not recommended for those with a history of back pain.[34] Other symptoms observed in more than 40 percent of donors include myalgia, headache, fatigue, and insomnia.[34] These symptoms all returned to baseline 1 month post-donation, except for some cases of persistent fatigue in 3 percent of donors.[34]

In one metastudy that incorporated data from 377 donors, 44 percent of patients reported having adverse side effects after peripheral blood HSCT.[35] Side effects included pain prior to the collection procedure as a result of GCSF injections, post-procedural generalized skeletal pain, fatigue and reduced energy.[35]

A study that surveyed 2408 donors found that serious adverse events (requiring prolonged hospitalization) occurred in 15 donors (at a rate of 0.6 percent), although none of these events were fatal.[34] Donors were not observed to have higher than normal rates of cancer with up to 48 years of follow up.[34] One study based on a survey of medical teams covered approximately 24,000 peripheral blood HSCT cases between 1993 and 2005, and found a serious cardiovascular adverse reaction rate of about 1 in 1500.[33] This study reported a cardiovascular-related fatality risk within the first 30 days HSCT of about 2 in 10000. For this same group, severe cardiovascular events were observed with a rate of about 1 in 1500. The most common severe adverse reactions were pulmonary edema/deep vein thrombosis, splenic rupture, and myocardial infarction. Haematological malignancy induction was comparable to that observed in the general population, with only 15 reported cases within 4 years.[33]

Georges Math, a French oncologist, performed the first European bone marrow transplant in November 1958 on five Yugoslavian nuclear workers whose own marrow had been damaged by irradiation caused by a criticality accident at the Vina Nuclear Institute, but all of these transplants were rejected.[36][37][38][39][40] Math later pioneered the use of bone marrow transplants in the treatment of leukemia.[40]

Stem cell transplantation was pioneered using bone-marrow-derived stem cells by a team at the Fred Hutchinson Cancer Research Center from the 1950s through the 1970s led by E. Donnall Thomas, whose work was later recognized with a Nobel Prize in Physiology or Medicine. Thomas' work showed that bone marrow cells infused intravenously could repopulate the bone marrow and produce new blood cells. His work also reduced the likelihood of developing a life-threatening complication called graft-versus-host disease.[41]

The first physician to perform a successful human bone marrow transplant on a disease other than cancer was Robert A. Good at the University of Minnesota in 1968.[42] In 1975, John Kersey, M.D., also of the University of Minnesota, performed the first successful bone marrow transplant to cure lymphoma. His patient, a 16-year-old-boy, is today the longest-living lymphoma transplant survivor.[43]

At the end of 2012, 20.2 million people had registered their willingness to be a bone marrow donor with one of the 67 registries from 49 countries participating in Bone Marrow Donors Worldwide. 17.9 million of these registered donors had been ABDR typed, allowing easy matching. A further 561,000 cord blood units had been received by one of 46 cord blood banks from 30 countries participating. The highest total number of bone marrow donors registered were those from the USA (8.0 million), and the highest number per capita were those from Cyprus (15.4 percent of the population).[44]

Within the United States, racial minority groups are the least likely to be registered and therefore the least likely to find a potentially life-saving match. In 1990, only six African-Americans were able to find a bone marrow match, and all six had common European genetic signatures.[45]

Africans are more genetically diverse than people of European descent, which means that more registrations are needed to find a match. Bone marrow and cord blood banks exist in South Africa, and a new program is beginning in Nigeria.[45] Many people belonging to different races are requested to donate as there is a shortage of donors in African, Mixed race, Latino, Aboriginal, and many other communities.

In 2007, a team of doctors in Berlin, Germany, including Gero Htter, performed a stem cell transplant for leukemia patient Timothy Ray Brown, who was also HIV-positive.[46] From 60 matching donors, they selected a [CCR5]-32 homozygous individual with two genetic copies of a rare variant of a cell surface receptor. This genetic trait confers resistance to HIV infection by blocking attachment of HIV to the cell. Roughly one in 1000 people of European ancestry have this inherited mutation, but it is rarer in other populations.[47][48] The transplant was repeated a year later after a leukemia relapse. Over three years after the initial transplant, and despite discontinuing antiretroviral therapy, researchers cannot detect HIV in the transplant recipient's blood or in various biopsies of his tissues.[49] Levels of HIV-specific antibodies have also declined, leading to speculation that the patient may have been functionally cured of HIV. However, scientists emphasise that this is an unusual case.[50] Potentially fatal transplant complications (the "Berlin patient" suffered from graft-versus-host disease and leukoencephalopathy) mean that the procedure could not be performed in others with HIV, even if sufficient numbers of suitable donors were found.[51][52]

In 2012, Daniel Kuritzkes reported results of two stem cell transplants in patients with HIV. They did not, however, use donors with the 32 deletion. After their transplant procedures, both were put on antiretroviral therapies, during which neither showed traces of HIV in their blood plasma and purified CD4 T cells using a sensitive culture method (less than 3 copies/mL). However, the virus was once again detected in both patients some time after the discontinuation of therapy.[53]

Since McAllister's 1997 report on a patient with multiple sclerosis (MS) who received a bone marrow transplant for CML,[54] there have been over 600 reports of HSCTs performed primarily for MS.[55] These have been shown to "reduce or eliminate ongoing clinical relapses, halt further progression, and reduce the burden of disability in some patients" that have aggressive highly active MS, "in the absence of chronic treatment with disease-modifying agents".[55]

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The Relationship between Sugar and Inflammation

Scientists have long linked oedema, arthritis and inflammatory bowel disease with inflammation. Only recently the medical community has implicated the process to diabetes, certain cancers and other unsolvable degenerative conditions. The latest research links heart disease more to various inflammatory conditions than to high cholesterol. Researchers are doing their best to come up with anti-inflammatory drugs and other cures for this inflammation.

Rather than try to find a cure, it might be wise to find out what causes inflammation and stop the cause rather than look for a cure. There are many things that cause inflammation in the body: viral and bacterial infections, surgery, a bruise, a broken bone, allergies, vaccinations, high blood pressure, oestrogen therapy, smoking, obesity, chronic fatigue, and dental problems, among others.

One of the biggest offenders of inflammation is ingestion of sugar. By sugar I mean table sugar, brown sugar, raw sugar, turbinado sugar, honey (even raw), maple sugar, corn sweetener, dextrose, glucose, fructose and any other word that ends in an "ose", barley malt, rice syrup, liquid cane sugar, concentrated fruit juice and others. Don't be fooled by the name organic when it applies to sugar. Sugar is sugar, organic or not, and the following will explain exactly what can happen in the body when you eat as little as two teaspoons.

Every time a person eats as little as two teaspoons we can upset our body chemistry and disrupt homeostasis, the wonderful balance in the body needed for maintenance, repair and life itself. One of the many changes this upset body chemistry causes is for our minerals to change relationship to each other.(1)(2)

No mineral is an island: minerals can only function in relation to each other. When one of the mineral levels drops in the blood stream, it's a sure thing that other minerals cannot function as well and can become toxic or deficient.

Although calcium and phosphorus give structure to our bodies through the formation of bones and teeth, most minerals function primarily as catalysts in enzyme systems within the cells and body fluids. As enzyme catalysts, the minerals are able to help our bodies grow and maintain themselves, regulate our body processes and supply us with energy. When there are very slight changes from the normal mineral composition inside the cell, this alteration may result in profound physiological consequences, without making any appreciable difference on the total mineral makeup of the body as a whole.(3)

One of the body processes for which enzymes are important is digestion. Enzymes help us break our food down into simple product which can then move easily from the digestive tract to the bloodstream. Enzymes break down fat to fatty acids, carbohydrates to simple sugar and protein into first, polypeptides and then into amino acids. Unfortunately enzymes can not function without minerals. You can deplete the enzymes when you eat sugar. Therefore, when the enzymes cannot function well, all of the protein in the food does not digest. This protein gets into the blood stream as partially digested protein, or polypeptides.(4,5)

Dr William Philpott, in his book BRAIN ALLERGIES says, "One of the most important systemic functions of the pancreas is to supply proteolytic enzymes (enzymes from the pancreas that aid in the digestion of proteins into polypeptides and then amino acids) which act as regulatory mechanisms over inflammatory reactions in the body. Poor digestion of proteins to amino acids occurs as a consequence of insufficient pancreatic proteolytic enzymes. As a result, unusable inflammation evoking protein molecules are absorbed through the intestinal mucosa and circulate in the blood, reaching tissues in partially digested form.

The medical community rejected this concept for years. As the old saying goes, first they ignore it, then they ridicule it, then they call it their own. Well, that is just what they have done. They call it the leaky gut syndrome, gut permeability and/or food allergy. As partially digested protein molecules (peptides), the immune system, which protects us from foreign invaders, sees these protein molecules as foreign invaders and responds the only way it knows how with inflammation. Depending on where this partially digested protein goes in the body, inflammation can set in any organ or tissue.(6)

This foreign matter, or partially digested protein, is in particles too large to be utilized by the cells. They can not get into the cell and function. This form of food allergy can cause havoc in our blood stream.(7) One of the things these particles can do is cause the classic symptoms of allergy, the inflammatory response, the runny eyes, sinusitis, sneezing and scratchy throat.(8),(9) These particles can go to the joints, tissues or bones and cause arthritis.(lO),(ll). They can go to the nervous system and cause multiple sclerosis.(l2) Medical research shows that this foreign matter can go to the skin and cause psoriasis,(13) hives,(14), and eczema.(15) The inflammatory process takes place in all these diseases.

From my clinical experience, acne and water retention also are caused by food allergy. Ulcerative colitis and Crohn's disease are also caused by undigested protein.(16) The nonusable protein can go anywhere in the blood and cause problems. At this time our immune system looks at this undigested food as a foreign invader, and our immune system comes to our defence and removes this foreign protein from our blood.(l7),(l8)

When we consume sugar over and over, we weaken our body tissues, our white blood cells

and our immune system.(l9),(20) Our white cells and other tissues need protein to function optimally. The cells can not get the correct protein when it is not digested and assimilated properly.

When our body tissues and immune system are weak, we can not fend off foreign invaders. Not only are we now susceptible to degenerative diseases but also infectious diseases. Whatever infectious disease we will get depends on what bacteria or virus is in the environment, and the weakness in our genetic blueprint determines what tissue will be affected and to which degenerative disease we are susceptible.

Sugar in the amount that we eat today (over 150 lbs, or over 1/2 cup a day,) continually upsets our body chemistry, causes the inflammatory process and leads to disease. The less sugar you eat, the less inflammation, and the stronger the immune system to defend us against infectious and degenerative diseases.

So what is there left to eat that is sweet? Lots. Whole fruits are healthy foods for healthy people. Melons and berries have the least amount of sugar. A glass of grape, orange or apple juice has the same amount of sugar as a soft drink of the same ounces and is just as detrimental. So eat your fruit whole. A mashed sweet potato is also a sweet food and is great mixed with carob or coconut milk and grated coconut. Eat just a small portion for a low carb diet. Some whipped cream with vanilla is a great topper for fruits or sweet potatoes.

For more information on sugar's detrimental affects, a great sugarfree recipe and more on inflammation go to http://www.nancyappleton.com This information came from three of Dr. Appleton's books: STOPPING INFLAMMATION, LICK THE SUGAR HABIT and LICK THE SUGAR HABIT SUGAR COUNTER.

Nancy Appleton, Ph.D.

References

1. Dr. Albrech, 1897, University of Missouri, found that minerals worked in relation to each other in the soil, then later realized that this was the same in the body.

2. Eck, Paul, Analytical Research Lahs Inc., 2338 West Royal Palm Road, Suite F,Phoenix, Arizona, 85021.

3. Ashmead, Dewayne. CHELATED MINERAL NUTRITION, Huntington Beach, Calif.; International Institute of Natural Health Sciences, Inc., 1979.

4. Ratner B.G and Gruehl, H.L. "Passage of Native Proteins through the Normal Gastrointestinal Wall". JOURNAL OF CLINICAL INVESTIGATION, 1934; 13:517.

5. Warshaw, A.L., Walker, W.A. and K.J. Isselbacher. "Protein Uptake by the Intestine: Evidence for Absorption of Intact Macromolecules. GASTROENTEROLOGY, 1974;;66:987

6. Philpott, W.. BRAIN ALLERGIES. New Canaan, Conn.; Keats Publishing Inc., 1980.

7. Paganelli, R., Cavagni, G. and Francesco Pallone. "The Role of Antigenic Absorption and Circulating Immune Complexes in Food Allergy." ANNALS OF ALLERGY. 57;1986:330_336.

8.Taylor b., Norman A.P, Orgel H.A. et al., "Transient IgA Deficiency and Pathogenesis of Infantile Atopy." LANCET 1973;2:11

9. Stevens, W.J., and C.H. Bridts. "IgG_containing and IgE_containing Circulating Immune Complexes in Patients with Asthma and Rhinitis." JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY. 1979;63:297.

10. Catteral, W.E. "Rheumatoid Arthritis Is an Allergy." ARTHRITIS NEWS TODAY, 1980.

11. Darlington, L.G., Ramsey N.W. and J.R. Mansfield. "Placebo_Controlled, Blind Study of Dietary Manipulation Therapy in Rheumatoid Arthritis." LANCET, Feb. 6, l986. 236_238.

12. Jones, H.D., "Management of Multiple Sclerosis." POSTGRADUATE MEDICINE. May 1952;2:415_422.

13. Douglas, J.M.. "Psoriasis and Diet." WESTERN JOURNAL OF MEDICINE 133 (Nov. 1980)450

14. Brostoff J., Carini C., Wraith D.G. et al. "Production of IgE complexes by allergen challenge in atopic patients and the effect of sodium cromoglycate." LANCET 1979;1:1267

15. Jackson, P.G., Lessof M.H., Baker, R.W.R., et al. "Intestinal permeability in patients with eczema and food allergy." LANCET. 1981;1:1285

16. Wright, R., Truelove, S.C. "Circulating Antibodies to Dietary Proteins in Ulcerative Colitis." BRITISH MEDICAL JOURNAL. 1965;2:142

17. Kijak, E., Foust, G. and R. Steinman "Relationship of Blood Sugar Level and Leukocytic Phagocytosis." SOUTHERN CALIFORNIA STATE DENTAL

ASSOCIATION JOURNAL 32;9 (Sept.1964).

18. Sanchez, A., et al. "Role of Sugars in Human Neutrophilic Phagocytosis." AMERICA et al., AMERICAN JOURNAL OF EPIDEMIOLOGY. r1992;135(8):895_903 N JOURNAL OF CLINICAL NUTRITION. Nov. 1973. 1180_84

19. Selye, H. THE STRESS OF LIFE. San Francisco: McGraw_Hill, 1978

20. Editorial. "Depression, Stress and Immunity." LANCET I, (1987) 1467_1468.

21. PSYCHOSOMATIC MEDICINE. 49:435 & 450. (Sept._Oct. 1987).

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The Relationship between Sugar and Inflammation

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Encephalitis (from Ancient Greek , enkphalos brain,[1] composed of , en, in and , kephal, head, and the medical suffix -itis inflammation) is an acute inflammation of the brain.[2] Encephalitis with meningitis is known as meningoencephalitis. Symptoms include headache, fever, confusion, drowsiness, and fatigue. Further symptoms include seizures or convulsions, tremors, hallucinations, stroke, and memory problems.[3] In 2013 encephalitis was estimated to have resulted in 77,000 deaths, down from 92,000 in 1990.[4]

Adult patients with encephalitis present with acute onset of fever, headache, confusion, and sometimes seizures. Younger children or infants may present irritability, poor appetite and fever.[5] Neurological examinations usually reveal a drowsy or confused patient. Stiff neck, due to the irritation of the meninges covering the brain, indicates that the patient has either meningitis or meningoencephalitis.[6]

Viral encephalitis can occur either as a direct effect of an acute infection, or as one of the sequelae of a latent infection. The most common causes of acute viral encephalitis are rabies virus, HPV infection, poliovirus, and measles virus.[7] Other possible viral causes are arbovirus (St. Louis encephalitis, West Nile encephalitis virus), bunyavirus (La Crosse strain), arenavirus (lymphocytic choriomeningitis virus) and reovirus (Colorado tick virus)[8]

It can be caused by a bacterial infection, such as bacterial meningitis,[9] or may be a complication of a current infectious disease syphilis (secondary encephalitis).[10] Certain parasitic or protozoal infestations, such as toxoplasmosis, malaria, or primary amoebic meningoencephalitis, can also cause encephalitis in people with compromised immune systems. Lyme disease and/or Bartonella henselae may also cause encephalitis.[citation needed] Other bacterial pathogens, like Mycoplasma and those causing rickettsial disease, cause inflammation of the meninges and consequently encephalitis. A non-infectious cause includes acute disseminated encephalitis which is demyelinated.[11]

Limbic encephalitis is a system onset indicated by cognitive decrease, especially memory decline as a result of the involvement of the limbic system, MRI evidence indicates particularly the hippocampus. A close depiction can result from autoimmune pathologies.[12]

Autoimmune encephalitis signs are catatonia, psychosis, abnormal movements, and autonomic dysregulation. Anti-N-methyl-D-aspartate encephalitis and Rasmussen encephalitis are examples of autoimmune encephalitis; the fact that these are immune mediate changes to the treatment path.[13]

Encephalitis lethargica is identified by high fever, headache, delayed physical response, and lethargy. Individuals can exhibit upper body weakness, muscular pains, and tremors, though the cause of encephalitis lethargica is not currently known. From 1917 to 1928, an epidemic of encephalitis lethargica occurred worldwide.[14]

Diagnosing encephalitis is done via a variety of tests:[15]

Treatment (which is based on supportive care) is as follows:[16]

Vaccination is available against tick-borne[17] and Japanese encephalitis[18] and should be considered for at-risk individuals. Post-infectious encephalomyelitis complicating smallpox vaccination is avoidable as smallpox is now eradicated. Contraindication to Pertussis immunisation should be observed in patients with encephalitis.[19]

The incidence of acute encephalitis in Western countries is 7.4 cases per 100,000 population per year. In tropical countries, the incidence is 6.34 per 100,000 per year.[20] In 2013 encephalitis was estimated to have resulted in 77,000 deaths, down from 92,000 in 1990.[4] Herpes simplex encephalitis has an incidence of 24 per million population per year.[21]

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An interview with Roberto Bolli, MD.

University of Louisville cardiologist Roberto Bolli, MD, led the stem cell study that tested using patients' own heart stem cells to help their hearts recover from heart failure. Though that trial was preliminary, the results look promising -- and may one day lead to a cure for heart failure.

Here, Bolli talks about what this work means and when it might become an option for patients.

2012 WebMD, LLC. All rights reserved.

"Realistically, this will not come... for another three or four years, at least," Bolli says. "It may be longer, depending on the results of the next trial, of course."

Larger studies are needed to confirm the procedure's safety and effectiveness. If those succeed, it could be "the biggest advance in cardiovascular medicine in my lifetime," Bolli says.

A total of 20 patients took part in the initial study.

All of them experienced significant improvement in their heart failure and now function better in daily life, according to Bolli. "The patients can do more, there's more ability to exercise, and the quality of life improves markedly," Bolli says.

Bolli's team published its findings on how the patients were doing one year after stem cell treatment in November 2011 in the Lancet, a British medical journal.

Each patient was infused with about 1 million of his or her own cardiac stem cells, which could eventually produce an estimated 4 trillion new cardiac cells, Bolli says. His team plans to follow each patient for two years after their stem cell procedure.

Keep in mind that this was a phase I study. Those focus on safety more than effectiveness.

The results were "much more striking" than past stem cell trials to heal the heart, Bolli says.

This trial was the first in the world to use stem cells derived from the heart. Earlier studies used stem cells gleaned from different bodily sources, including bone marrow, adipose (fat) tissue, and circulating blood. Those showed either no improvement or only modest gains in a patient's left ventricular ejection fraction, a measure of the heart's pumping ability.

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Abstract

The exploitation of male sterility systems has enabled the commercialization of heterosis in rice, with greatly increased yield and total production of this major staple food crop. Hybrid rice, which was adopted in the 1970s, now covers nearly 13.6 million hectares each year in China alone. Various types of cytoplasmic male sterility (CMS) and environment-conditioned genic male sterility (EGMS) systems have been applied in hybrid rice production. In this paper, recent advances in genetics, biochemistry, and molecular biology are reviewed with an emphasis on major male sterility systems in rice: five CMS systems, i.e., BT-, HL-, WA-, LD- and CW- CMS, and two EGMS systems, i.e., photoperiod- and temperature-sensitive genic male sterility (P/TGMS). The interaction of chimeric mitochondrial genes with nuclear genes causes CMS, which may be restored by restorer of fertility (Rf) genes. The PGMS, on the other hand, is conditioned by a non-coding RNA gene. A survey of the various CMS and EGMS lines used in hybrid rice production over the past three decades shows that the two-line system utilizing EGMS lines is playing a steadily larger role and TGMS lines predominate the current two-line system for hybrid rice production. The findings and experience gained during development and application of, and research on male sterility in rice not only advanced our understanding but also shed light on applications to other crops.

Male reproductive development in plants involves several major developmental stages in series and along several cell lineage pathways, which include specification of stamen primordia, production of sporogenous cells, development of tapetum and microspore mother cells (MMCs), meiosis, formation of free haploid microspores, degeneration of tapetum and release of mature pollen grains (Goldberg et al. [1993]). Arrest of any of these steps can result in male sterility (MS), the failure to produce or release functional pollen grains. The phenotypic manifestations of MS may range from the complete absence of male organs, abnormal sporogenous tissues, to the inability of anther to dehisce or of pollen to germinate on compatible stigma (Chase et al. [2010]).

Evolutionarily, MS has been a subtle means by which plants prevent self-pollination and increase genetic diversity (Hanson [1991]). Over the past century, MS has facilitated the use of heterosis (or hybrid vigor) in crop production. Utilization of heterosis, the superior performance that the first generation (F1) hybrid demonstrates over its two parental lines, depends on the cost-effective production of hybrid seeds. Rice is a staple food crop for more than half of the worlds population; the use of heterosis in rice is second only to that in corn, among crop plants, and has played a significant role in further increasing rice yield after the first Green Revolution (Li et al. [2007]).

The success of hybrid rice has greatly promoted the search for and study of MS in rice. Several articles have recently reviewed the key genes and networks that determine male reproductive development, including the differentiation of sporophytic cells (Xing et al. [2011]; Feng et al. [2013]), specification of tapetum and microsporocyte cells (Zhang and Yang [2014]), and biosynthesis and regulation of sporopollenin and pollen exine development (Ariizumi and Toriyama [2011]; Liu and Fan [2013]). Mutations in such genes often result in MS in different forms, e.g. knockout mutation of CAP1, which encodes L-arabinokinase, resulted in collapsed abnormal pollens (Ueda et al. [2013]), and microsporeless anthers resulted from null mutations of MSCA1 in corn (Chaubal et al. [2003]) and MIL1 in rice (Hong et al. [2012]). As reviewed recently by Guo and Liu ([2012]) and Wang et al. ([2013b]), more than 40 MS genes have been cloned in rice. Shortly after the publication of these two reviews, several more rice fertility/sterility-related genes were reported, including genes underpinning tapetum function and hence pollen development (Liu and Fan [2013]; Ji et al. [2013]), genes required for the development of the anther and pollen (Moon et al. [2013]; Niu et al. [2013a], [b]), and genes for pollen germination and pollen tube growth (Huang et al. [2013b]). Clearly, the list is expected to grow in the near future. Although identifying genes and pathways is necessary in order to understand the underlying mechanisms in the development of the male reproductive system, not all MS mutations have practical use in hybrid crop production. This paper aims to analyze different MS systems that have been explored in hybrid rice production and summarize the latest understanding of their genetics, biochemistry, and biology. We also describe the dynamics of different MS systems in hybrid rice production in China over the past 30years.

Commercialization of any hybrid crop can only be achieved if reasonably priced technical solutions to hybrid seed production are available. In rice, hybrid seed production was first attempted using chemical hybridizing agent in the 1970s, but this approach was no longer used after MS systems became available. In order for an MS system to be workable for hybrid seed production, it must meet the following prerequisites: (1) complete and stable MS during hybrid seed production; (2) no substantial negative effect on MS and hybrid plants; (3) ability to multiply MS seeds through an intermediate genetic line (maintainer) or under particular environmental conditions; (4) ability to fully achieve fertility in hybrids. Therefore, although a number of MS systems have been generated during the past 40years, only those that met these requirements were adopted in hybrid production. So far, two distinct systems have been utilized in hybrid rice production: cytoplasmic male sterility (CMS) and environment-conditioned genic male sterility (EGMS).

Numerous CMS systems with different cytoplasm/nucleus combinations have been generated through backcross breeding. The cytoplasm and nucleus of CMS lines may originate from two different species, two different subspecies (indicajaponica), or two cultivars (indicaindica) (Virmani [1994]; Cheng et al. [2007]; Fujii et al. [2010]; Huang et al. [2013a],[b]). According to the China Rice Data Center (http://www.ricedata.cn/variety/ webcite), a total of 13 types of CMS lines have been used in developing hybrid cultivars, constituting an annual growing area of more than ~6800ha in at least 1year from 1983 to 2012 (data before 1983 are unavailable). The cytoplasm and nucleus sources of these 13 different CMS types are summarized in Table1, with BT-CMS and Dian1-CMS used in japonica and other systems used in indica hybrid rice production.

Table 1. Major male sterility systems utilized in hybrid rice production in China1

Both BT-CMS and Dian1-CMS contain indica cytoplasm and a japonica nucleus, whereas indica hybrid rice cultivars contain cytoplasm of diverse origins, including O. rufipogon (e.g., WA-CMS), various indica cultivars (e.g., GA-CMS, ID-CMS), and one japonica genotype (i.e., K-CMS) (Table1). It is not difficult to develop japonica CMS lines using cytoplasm from O. rufipogon or other indica lines, but such CMS has no practical use because no restorer lines have been identified in japonica rice.

WA-CMS lines are the most widely deployed lines in hybrid rice production (see below). Pollen abortion in WA-CMS occurs relatively early during microspore development, mainly at the uninucleate stage (Luo et al. [2013]), resulting in amorphous aborted pollen grains (Figure1). The pollen abortion is determined by the genotype of sporophytic tissues, not by the genotype of the pollen itself. That is, aborted pollens are only produced in plants with homozygous rf (restorer of fertility) gene (s) and CMS factor (s), but not in plants that are heterozygous at the Rf locus (Figure1, pollen fertility of F1 plants). All other CMS types of indica rice, except for HL-CMS, are similar to WA-CMS and are classified as WA-CMS-like types (Table1).

Figure 1. A schematic presentation of the five well-studied rice CMS types. Abbreviations for cytoplasm sources are RWA for wild-abortive Oryza rufipogon, RRA for red-awned O. rufipogon, and RW1 for Chinese wild rice (O. rufipogon) accession W1; IBT and ILD for indica Boro-II type and Lead rice, respectively. Nucleus sources are either indica (I) or japonica (J).

Pollen development in HL-CMS lines is arrested at the binucleate stage while that of BT-CMS arrested at the trinucleate stage. In contrast to the irregular morphology in WA-CMS, the pollen grains in both HL- and BT-CMS are spherical, and are unstainable or stainable, respectively, in I2-KI solution (Li et al. [2007]). Due to their deficiency in starch accumulation, pollen grains of BT-CMS is stained lighter than normal pollen grains (Figure1; Wang et al. [2006]); the intensity of staining, however, can be rather dark in some BT-CMS lines, almost indiscriminate from that of fertile pollen grains (Li et al. [2007]). Furthermore, unlike in WA-CMS, the MS of the BT- and HL-CMS lines is genetically controlled by gametophytic tissue (i.e., the haploid microspores; hence, only half of the pollen grains in F1 plants are viable) (Figure1). Dian1-CMS lines are very similar to BT-CMS in terms of pollen abortion and fertility restoration; they are classified as BT-like CMS (Table1).

The other MS system that is widely used in hybrid rice breeding is the EGMS system, which includes the photoperiod-sensitive genic male sterility (PGMS) and temperature-sensitive genic male sterility (TGMS) lines. PGMS lines are male-sterile under natural long day conditions and male fertile under natural short day conditions (Ding et al. [2012a]), whereas TGMS lines are sterile at high temperatures and fertile at lower temperatures (Xu et al. [2011]). Some lines, such as Peiai 64S, are male sterile under both long day and high temperature conditions and are referred to as P/TGMS lines (Zhou et al. [2012]).

The majority (>95%) of the EGMS lines utilized in hybrid rice production in China were derived from three independent progenitor lines, i.e., PGMS line Nongken 58S (NK58S) and TGMS lines Annong S-1 and Zhu 1S (Si et al. [2012]; Table1). Many lines derived from NK58S were P/TGMS or even TGMS (e.g., Guangzhan 63S), but the underlying mechanism leading to such dramatic changes has yet to be revealed (Lu [2003]).

Two other CMS types have the potential to be utilized in hybrid rice production. LD-CMS was obtained by Watanabe et al. ([1968]) by performing a backcross of the japonica variety Fujisaka 5 to the Burmese rice cultivar Lead Rice, giving it indica cytoplasm and a japonica nucleus (Figure1). The pollen grains of LD-CMS can be slightly stained with I2-KI, but they cannot germinate on stigmas (Figure1). The other CMS type is CW-CMS, which has the cytoplasm of O. rufipogon and a japonica nucleus. It produces morphologically normal pollen grains that can be stained darkly with I2-KI but lacks the ability to germinate (Figure1; Fujii and Toriyama [2005]). Both LD-CMS and CW-CMS are gametophytically controlled and hence half of the pollen grains of F1 plants are viable (Figure1).

A novel type of EGMS rice, known as rPGMS (reverse PGMS), may also be useful in hybrid rice system. This rice shows normal male fertility under long day conditions (>13.5h) but is male sterile under short day conditions (<12.5h). It can be used in a two-line hybrid system by producing hybrid seeds in the tropics and subtropics (e.g., Sanya, Hainan) and multiplying seeds of rPGMS lines under long day conditions (e.g., summer season in Shanghai) (Zhang et al. [2013]).

The CMS is controlled by the interaction of cytoplasmic factors (now widely identified as mitochondrial genetic factors) and nuclear genes (Chen and Liu [2014]). As shown in Figure1, most CMS genes and their corresponding Rf genes have already been identified.

The genetic factors conditioning BT-, HL-, and WA-CMS are all chimeric genes, probably as a result of the rearrangement of the mitochondrial genome (Figure1). The BT-CMS gene, a mitochondrial open reading frame, orf79, was the first CMS gene identified (Akagi et al. [1994]) and subsequently cloned (Wang et al. [2006]) in rice. It is co-transcribed with a duplicated atp6 and hence is also known as B-atp6-orf79 (Figure1). Mitochondrial DNA analysis suggested that orf79 may also be responsible for Dian1-CMS (Luan et al. [2013]).

In HL-CMS lines, a chimeric ORF defined as atp6-orfH79 is the gene conditioning MS (Figure1). Although nucleotide sequences of orfH79 and orf79 share 98% identity, the intergenic regions between atp6-orfH79 and B-atp6-orf79 are significantly different, suggesting that atp6-orfH79 and B-atp6-orf79 diverged from a common ancestor (Yi et al. [2002]; Peng et al. [2010]; Hu et al. [2012]).

Two differentially expressed transcripts, one of them containing the ribosomal protein gene rpl5, were identified by examining the transcripts of the whole mitochondrial genomes of a WA-CMS line, Zhenshan 97A and of its maintainer, Zhenshan 97B (Liu et al. [2007]). The same group recently used rpl5 to probe the rearranged region in the mitochondrial genome and identified the WA-CMS gene, named WA352 (Wild Abortive 352), which is comprised of three rice mitochondrial genomic segments (orf284, orf224, and orf288) and one segment of unknown origin (Figure1), and encodes a 352-residue putative protein with three transmembrane segments (Luo et al. [2013]).

Previous work by Bentolila and Stefanov ([2012]), constituting the complete sequencing of male-fertile and male-sterile mitochondrial genomes, identified a WA-CMS-specific ORF, orf126, as a plausible candidate for the WA-CMS causative gene. This result is consistent with that of Luo et al. ([2013]) because orf126 is indeed part of WA352. Independently, Das et al. ([2010]) also identified rearrangements around the regions of atp6 and orfB. According to Luo et al. ([2013]), the atp6 locus is rearranged and directly linked to WA352, which is less than 20kb away from orfB in WA-CMS. Therefore, the results of these studies all corroborate one another.

The CMS gene that conditions LD-CMS has yet to be determined, but a B-atp6-orf79-like structure (L-atp6-orf79) was identified as the candidate (Figure1). In the mitochondrion of LD-CMS, there is only one copy of atp6 linked with orf79, which is different from BT-CMS and HL-CMS, the mitochondria of which retain a normal atp6 (N-atp6) in its origin position (Itabashi et al. [2009]).

No B-atp6-orf79-like structure was identified in the mitochondrion of CW-CMS, and the cytoplasmic factor (s) conditioning pollen sterility has yet to be determined (Fujii et al. [2010]).

It has been well documented that CMS can be restored by one or two Rf genes. A total of six Rf genes (Rf1a, Rf1b, Rf2, Rf4, Rf5 and Rf17) have been cloned (Figure1), and all except Rf17 are dominant.

Two fertility restoration genes, Rf1a and Rf1b, both encoding proteins containing pentatricopeptide repeat (PPR) motifs, were identified as being able to restore the fertility of BT-CMS (Kazama and Toriyama [2003]; Akagi et al. [2004]; Komori et al. [2004]; Wang et al. [2006]). Both Rf1a and Rf1b are located in the classical Rf1 locus. The rf1a allele differs from Rf1a due to a frameshift mutation that results in a truncated putative protein of 266 amino acids (Komori et al. [2004]; Wang et al. [2006]). A single-nucleotide polymorphism (SNP) of A1235-to-G causes the missense mutation of Rf1b to rf1b by substituting Asn412 for Ser (Wang et al. [2006]).

MS of HL-CMS can be restored by either Rf5 or Rf6, producing 50% normal pollen grains in F1 plants (Figure1). When both Rf5 and Rf6 are present, F1 plants may have 75% normal pollen grains (Huang et al. [2012]). Recently, the Rf5 gene was cloned and was identified to be the same gene as Rf1a or Rf1, which encodes the PPR protein PPR791 (Hu et al. [2012]). Sequencing of Rf5 and rf5 identified a single nucleotide T791-to-A alteration at the fourth PPR motif, which results in a nonsense mutation (TAT to TAA) in the HL-CMS line (Hu et al. [2012]).

WA-CMS can be restored by either Rf3 or Rf4, located on chromosome 1 and 10, respectively (Figure1). Numerous attempts have been made to delimit and ultimately clone the two genes without much success (Ahmadikhah and Karlov [2006]; Ngangkham et al. [2010]; Suresh et al. [2012]). The breakthrough was not made until very recently by Tang et al. ([2014]), who finally cloned the Rf4 gene, which also encodes a PPR protein.

Pollen fertility of LD-CMS can be restored by either Rf1 or Rf2; the latter has already been cloned (Figure1; Itabashi et al. [2009], [2011]). The Rf2 gene encodes a mitochondrial glycine-rich protein; replacement of isoleucine by threonine at amino acid 78 of the RF2 protein causes functional loss of the rf2 allele (Itabashi et al. [2011]). The CW-CMS is restored by a single nuclear gene, Rf17, which is a retrograde-regulated male sterility (rms) gene (Figure1; Fujii and Toriyama [2009]). Contrary to this finding, the same group suggested in earlier reports that two other genes, DCW11 and OsNek3, were related to pollen sterility in CW-CMS rice (Fujii and Toriyama [2008]; Fujii et al. [2009]). It is now evident that diversified mechanisms have been evolved for restoring fertility in CMS with multilayer interactions between the mitochondrial and nucleus genes (Chen and Liu [2014]).

In addition to the three major CMS types (i.e., WA-, BT-, and HL-CMS), several other CMS types were bred independently and have different cytoplasm and nucleus sources (Table1). Further studies revealed that both cytoplasm and nuclear genetic determinants are almost identical among some of them; hence, they may be classified into a common group.

First, the fertility restoration of Dian1-CMS is identical to that of BT-CMS, i.e., restorer lines of the latter are equally effective for the former, although Rf-D1 (t) was assigned for Dian1-CMS (Tan et al. [2004]). Subsequent cloning and characterization suggested that Rf-D1 is highly similar to Rf1a and has only one nucleotide difference (Zhu et al. [2009]).

Second, nine CMS types are classified as WA-like CMS (Table1) on the basis of the following observations: (1) WA352 is also identified in the GA-, D-, DA-, ID-, K-, and Y-CMS lines (Luo et al. [2013]); (2) Rf3 and Rf4 are effective for restoring the fertility of D-, DA-, ID-, GA-, Y-, and WA-CMS (Sattari et al. [2008]; Cai et al. [2014]); (3) these nine CMS types possess common mitotype-specific sequences that differ from fertile genotypes and from other CMS systems (e.g., BT-CMS, HL-CMS) (Xie et al. [2014]); and (4) they have identical or highly similar mitochondrial DNA (Luan et al. [2013]). However, we should not exclude the possibility that differences exist in their mitochondrial genomes. For example, Xu et al. ([2013]) recently indicated that male sterile cytoplasm has a marked effect on DNA methylation, which is enhanced to a much greater extent in WA- and ID-CMS than in G- and D-CMS.

Third, restorer lines containing Rf4 can often restore the fertility of BT-CMS and HL-CMS (but the opposite is not true). This effect might be explained by the following considerations: (1) Plants with Rf4 may also possess Rf1a and Rf1b. (2) The Rf4 allele has more functions than Rf1, and Rf4 itself has the ability to restore the fertility of both WA-CMS and BT-CMS. Notably, the recent cloning of Rf4 reveals that it also encodes a PPR protein, with high amino acid sequence identity with Rf1a of BT-CMS (Tang et al. [2014]).

Rice is a short-day plant; short day length accelerates panicle initiation and promotes flowering, but long day length delays or inhibits development. Likewise, relatively high temperatures promote rice growth and development. This reaction of plants to photoperiod and temperature is described as the first photoperiod/temperature reaction (FPTR, Yuan et al. [1993]). The P/TGMS lines described in this paper are those in which the male reproductive system responds to both day length and temperature, in the so-called second photoperiod/temperature reaction (SPTR).

Different EGMS lines may have very different fertility responses to photoperiod and temperature. Cheng et al. ([1996]) classified EGMS lines into three types: PGMS lines respond to either photoperiod or photoperiod-and-temperature, but not to temperature alone; TGMS lines respond to temperature, but not to photoperiod; P/TGMS lines are characterized by responding to photoperiod-and-temperature for their fertility transition.

During the past 20years, a number of EGMS lines have been identified that show genic MS under different conditions: long day (PGMS) or short day (reverse PGMS, rPGMS), high temperature (TGMS) or low temperature (rTGMS), and either long day or high temperature. In all these cases, the pollen fertility of EGMS systems is sporophytically controlled by nuclear gene (s), and the loci that control PGMS or TGMS, including rPGMS or rTGMS, have been mapped to different chromosomes (Si et al. [2012]; Sheng et al. [2013]; Zhang et al. [2013]). These mappings include PGMS genes: pms1, pms2, pms3; rPGMS genes: rpms1, rpms2, csa; TGMS genes: tms1, tms2, tms3, tms4, tms5, tms6, tms6(t), tms9; and P/TGMS genes: p/tms12-1, pms1(t). Some of these genes may be allelic and two of them, pms3 (p/tms12-1) (Ding et al. [2012a]; Zhou et al. [2012]) and csa (Zhang et al. [2013]), have been cloned.

NK58S, the first PGMS, was identified in 1973 from a Nongken58 population. It exhibits complete MS when growing under long days (day length more than 13h), but complete or partial fertility under short days (day length less than 13h) (Zhang and Yuan [1989]). However, Peiai 64S, developed from a cross between NK58S and Peiai 64 followed by backcrossing with Peiai 64, showed MS under both long day and high temperature conditions (Luo et al. [1992]). W6154S, also derived from NK58S, is a TGMS line. Zhang et al. ([1994]) identified two genes underlying the PGMS of NK58S. A study on the allelism of gene (s) for P/TGMS lines further showed that there were allelic male sterile genes between NK58S and its derivatives W6154S and Peiai 64S, but male sterile genes from the latter two are nonallelic, suggesting that NK58S has at least two genes underpinning its PGMS (Li et al. [2003]). Two recent independent studies identified the identical causative SNP for both the PGMS of NK58S (pms3, Ding et al. [2012a]) and the TGMS of Peiai 64S (p/tms12-1, Zhou et al. [2012]), although the identity of the locus containing the SNP was different (see below).

An rPGMS gene, carbon starved anther (csa), was recently cloned and may be potentially useful for diversification of the two-line hybrid rice system (Zhang et al. [2013]).

Several spontaneous TGMS mutants have been independently identified in breeding programs; more TGMS lines were selected in the progenies derived from NK58S (Si et al. [2012]). Genetic analyses indicated that the TGMS trait is under the control of single recessive genes. Among the fine-mapped TGMS genes, those of Annong S-1 (tms5), Guangzhan 63S (ptgms2-1), and Zhu 1S (tms9) are all located on chromosome 2. Whereas tms5 and ptgms2-1 were delimited to a partially overlapped region, tms9 was fine-mapped to a different segment near that of ptgms2-1/tms5 (Sheng et al. [2013]). Candidate genes were proposed for tms5 (OsNAC6; Yang et al. [2007]) and ptgms2-1 (a ribonuclease Z homolog, RNZ; Xu et al. [2011]), but none were suggested for tms9 (Sheng et al. [2013]). Our recent study, however, demonstrated that Annong S-1, Guangzhan 63S and Zhu 1S carry allelic TGMS genes (i.e. tms5, ptgms2-1, and tms9 are allelic), and further characterization of more than 300 non-EGMS and EGMS lines suggested that an identical nonsense mutation of the RNZ gene, i.e. RNZm.conditions the TGMS of Guangzhan 63S, Zhu 1S, Annong S-1, and a number of other TGMS lines (Zhang et al. [2014]).

Anther development in rice occurs over 14 stages (Zhang and Wilson [2009]), and the specification, development, and degradation of the anther are tightly regulated by various genes and pathways. Dysfunction of any gene may result in MS (Suzuki [2009]; Wilson and Zhang [2009]; Ariizumi and Toriyama [2011]; Feng et al. [2013]).

The development of pollen and degradation of the endothecium, middle layer, and tapetal cells are illustrated in Figure2. The tapetum is the nursing tissue inside the anther and plays a crucial role in the formation and development of pollen grains (Suzuki [2009]; Ariizumi and Toriyama [2011]). In wild-type plants, tapetum undergoes cellular degeneration by programmed cell death (PCD) and completely disappears by the time the mature pollen grains form. PCD is often observed in anther tissues by terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling (TUNEL) assay. Slight differences have been reported regarding the commencement of tapetal PCD in rice: One group (Ji et al. [2013]; Luo et al. [2013]) detected PCD as early as stage 8a (the dyad stage), whereas others (Li et al. [2006]; Ding et al. [2012a]) observed the earliest PCD occurring at stage 8b (the tetrad stage) or noted that it peaked at stage 9 (young microspore stage). The correct timing of tapetal PCD is important, and premature or delayed PCD is often associated with MS. Unlike most other rice MS mutants, which have delayed tapetal PCD (Li et al. [2006]; Ji et al. [2013]), certain EGMS and WA-CMS rice have premature tapetal PCD (Ding et al. [2012a]; Luo et al. [2013]; Figure2).

Figure 2. A schematic presentation of anther and pollen development in wild type (WT) rice, wild-abortive CMS (WA-CMS) rice, temperature- and photoperiod -sensitive genic male sterile (TGMS and PGMS) rice. Stage demarcation and developmental features of WT rice are adopted from Zhang and Wilson ([2009]); those of WA-CMS, TGMS and PGMS are according to Luo et al. ([2013]), Ku et al. ([2003]), and Ding et al. ([2012a]), respectively. Dots represent the DNA fragmentations detected by TUNNEL assay in tapetal cells undergoing programmed cell death. AP, aborted pollen; BP, binucleate pollen; E, epidermis; En, endothecium; ML, middle layer; T, tapetum; MMC, microspore mother cell; MC, meiotic cell; DY, dyad; Td: tetrad; MP, mature pollen.

The TGMS lines of Annong S-1, Xian 1S, and Guangzhan 63S have empty anthers (Ku et al. [2003]; Peng et al. [2010]; Xu et al. [2011]). Premature tapetal PCD initiates as early as the microspore mother cell (MMC) stage (stage 6) and continues until the tapetal cells are completely degraded in Annong S-1 grown under high temperature conditions (Ku et al. [2003]). The premature tapetal PCD resulted in early degradation of the tapetum, causing a decline in the supply of nutrition and other components (e.g. sporopollenin) to microspores, which were ruptured around stage 9. Consequently, no pollen grains were seen in the pollen sac in TGMS lines (Figure2).

Analysis of the PGMS line NK58S grown under long-day conditions demonstrated that tapetal PCD was already apparent at stage 7 and became intense from stage 8a to stage 9, much earlier than in NK58 (Ding et al. [2012a]). The premature tapetal PCD in NK58S resulted not only in pollen abortion but also incomplete degradation of tapetal cells at later stages (Figure2).

The different timings of premature tapetal PCD in TGMS and PGMS lines entail distinct consequences on pollen development in these two types (i.e., no pollen is formed in the pollen sac in TGMS lines and pollen abortion occurs in PGMS lines) (Figure2). However, it remains unclear whether the premature tapetal PCD is induced under MS-inducing conditions, because neither the PGMS gene nor the TGMS gene is involved directly or indirectly in any known PCD pathway.

In WA-CMS line Zhenshan 97A, tapetal PCD was also observed as early as stage 7 (Figure2), although it was not detected until stage 8a in its maintainer line Zhenshan 97B (Luo et al. [2013]). Tapetal PCD in WA-CMS rice started at the same stage as in PGMS rice, however, TUNEL assay indicated that DNA fragmentation only persisted to stage 9 in tapetal cells. Degradation of tapetal cells started as early as stage 8b, at which stage cytological observation showed debris was leaking from tetrads or tapetal cells. Consequently, tapetal cells degraded earlier than in wild type rice, and abnormal development of microspores could already be seen at stage 9 (Luo et al. [2013]; Figure2). The molecular mechanism leading to premature tapetal PCD in WA-CMS rice is well explained (see below).

In the BT-CMS system, CMS is known to be caused by a cytotoxic peptide, ORF79, encoded by a mitochondrial dicistronic gene B-atp6-orf79. ORF79 is a transmembrane protein; it is toxic to Escherichia coli (Wang et al. [2006]) and is also toxic to plant regeneration when it targets the mitochondria (Kojima et al. [2010]). ORF79 is accumulated specifically in microspores, despite its constitutive expression (Wang et al. [2006]), which provides a tight correlation between its accumulation and the phenotype of gametophytic MS. The molecular mechanism that regulates the expression of ORF79 and the way in which it causes the arrest of microspore development at the trinucleate stage are unknown.

BT-CMS is restored by two related PPR motif genes, Rf1a and Rf1b, by blocking ORF79 production through distinct modes of mRNA silencing: endonucleolytic cleavage of the dicistronic B-atp6-orf79 mRNA by RF1A and degradation by RF1B. In the presence of these two restorers, the Rf1a gene has an epistatic effect over the Rf1b gene in mRNA processing (Wang et al. [2006]). Further studies suggested that the RF1 protein mediates cleavage of the dicistronic mRNA by binding to the intergenic region, and the processed orf79 transcripts are degraded and unable to associate with ribosome. As a result, the orf79 expression is drastically reduced due to the processing of atp6-orf79 transcripts (Kazama et al. [2008]).

The mitochondrial dicistronic gene atp6-orfH79 is responsible for HL-CMS (Peng et al. [2010]), as proposed by Wang et al. ([2002]). Transcripts of orf79 and orfH79 differ in only five nucleotides, each of which results in distinctly different codon (Peng et al. [2010]). Like orf79, orfH79 is constitutively expressed; however, accumulation of ORFH79 is not limited to microspores as it is for orf79 in BT-CMS. Rather, it is accumulated mainly in the mitochondria in both vegetative and reproductive tissues, preferentially in sporogenous cells and root tips (Peng et al. [2010]). ORFH79 impairs mitochondrial function through its interaction with P61, a subunit of electron transport chain (ETC) complex III in HL-CMS rice (Wang et al. [2013a]). The interaction of ORFH79 and P61 significantly reduces the activity of ETC III through an as-yet-unknown mechanism, impairs the electron transport efficiency, and down-regulates the production of ATP. Concomitantly, more reactive oxygen species (ROS) are produced accompanying increased electron leakage from the ETC (Wang et al. [2013a]). The observations of increased ROS and preferential accumulation of ORFH79 in sporogenous cells are in accordance with a study that detected PCD in microspores of the HL-CMS line Yuetai A (Li et al. [2004]).

Unlike the RF1A-binding to B-atp6-orfH79 transcript, RF5 (the same protein of RF1A) is unable to bind to atp6-orfH79 transcript directly, due to its divergent intergenic region. Instead, a RF5s partner protein, GRP162, can bind to the atp6-orfH79 through an RNA recognition motif. These two proteins interact physically with each other in the so-called restoration of fertility complex (RFC), which can cleave atp6-orfH79 at a site 1169 nucleotides away from the atp6 start codon (Hu et al. [2012]). Additional components are predicted to participate in the RFC, because neither RF5 nor GRP162 can cleave the mRNA; it remains to be determined which factor of the RFC possesses the capacity as an endoribonuclease to process atp6-orfH79.

Another gene, Rf6, can also restore the fertility of HL-CMS, but little is known regarding its identity or the mechanism leading to fertility restoration (Huang et al. [2012]).

MS in WA-CMS rice is caused by WA352, which interacts with a nuclear-encoded integral protein of the inner mitochondrial membrane, OsCOX11. COX11 proteins are essential for the assembly of cytochrome c oxidase; they display high levels of conservation among eukaryotes and play a role in hydrogen peroxide degradation (Banting and Glerum [2006]). A significantly increased amount of ROS was observed in the tapetum of WA-CMS line Zhenshan 97A, but not in its maintainer, at the MMC stage (Luo et al. [2013]). Hence, it is assumed that the elevation of ROS in WA-CMS line, as a result of the interaction of WA352 with OsCOX11, prevents the normal function of OsCOX11 in H2O2 degradation. The excessive amount of ROS could further affect the mitochondrial membrane permeability and promote Cyt c release into the cytosol, triggering PCD (Luo et al. [2013]).

Both OsCOX11 and WA352 are constitutively expressed; however, while OsCOX11 protein is accumulated in all tissues, WA352 protein was detected only in anthers, not in leaves. In the anthers, WA352 was observed mainly in tapetal cells at the MMC stage and diminished after the meiotic prophase I stage. The tissue specificity and accumulation duration of WA352 are in good accordance with the occurrence of tapetal PCD as detected by TUNEL assay, the earliest PCD being observed as early as stage 7 of anther development (Figure2; Luo et al. [2013]). However, it is not known why WA352 only accumulates in tapetal cells at the MMC stage. Further studies are needed to uncover the molecular mechanism and genetic factor (s) regulating time-specific protein accumulation.

WA-CMS can be restored by either Rf3 or Rf4 (Figure1). The amounts of WA352 transcripts in the Rf4-carrying lines with WA-CMS cytoplasm were decreased to ~2025% of those in the WA-CMS line without Rf4, but were not affected in the Rf3-carrying lines. WA352 was undetectable in either Rf3- or Rf4-carrying young anthers (Luo et al. [2013]). These observations suggest different mechanisms of male fertility restoration be deployed by the two Rf genes: RF4 may cleave the WA352 transcript and RF3 may suppress its translation. In this regard, RF4 may function like that of RF1B, which mediates the degradation of atp6-orf79 mRNA, whereas RF3s mode of action would be distinctly different from those of RF1A and RF1B (see above).

Fertility of the LD-CMS can be restored by either Rf1 or Rf2 (Figure2). Although LD-CMS rice also possesses a chimeric atp6-orf79 dicistronic gene, L-atp6-orf79 (Figure2), the CMS in LD-cytoplasm is not caused by the accumulation of ORF79. The induction and restoration of LD-CMS are different from those in BT-CMS (Itabashi et al. [2009]). The Rf2 gene has already been cloned and is known to encode a mitochondrial glycine-rich protein, but the mechanism of CMS restoration has yet to be determined (Itabashi et al. [2011]).

As in LD-CMS, the cytoplasmic genetic factor that causes MS in CW-CMS has not been identified. However, its restorer of fertility gene, Rf17, is known to encode a 178-aa mitochondrial protein of unknown function. Rf17 is considered to be an rms gene, because its expression is regulated by the cytoplasmic genotype. The low expression of RMS in a restorer line of CW-CMS, probably due to a SNP in its promoter region, is speculated to restore compatibility between the nucleus and mitochondria, leading to male fertility (Fujii and Toriyama [2009]).

As mentioned above, a noncoding RNA was recently identified to underpin the PGMS of NK58S (pms3) and TGMS of Peiai 64S (p/tms12-1), with a common CG SNP as the causative element of P/TGMS (Ding et al. [2012a]; Zhou et al. [2012]). However, the functional element of this locus and its role in P/TGMS development were elucidated quite differently by the two groups.

Ding et al. ([2012a]) showed that the locus encodes a long noncoding RNA (lncRNA) designated LDMAR (long day-specific male fertility associated RNA), and they argued that a sufficient amount of LDMAR is essential for male fertility under long day conditions. The low abundance of LDMAR transcripts, rather than the CG SNP, is responsible for the PGMS of NK58S, because overexpression of the LDMAR transcript of NK58S restored the fertility of NK58S under long day conditions. They indicated that the low expression of LDMAR in NK58S is due to increased methylation in the promoter region, compared with NK58 (Ding et al. [2012a]). In a later study, they identified in the promoter region of LDMAR a siRNA called Psi-LDMAR, which is more abundant in NK58S than its wild type line (Ding et al. [2012b]). They suggested that the enhanced methylation in the LDMAR promoter region induced by the greatly enriched PsiLDMAR repressed the expression of LDMAR. However, several puzzles remain: First, as the authors noted, Psi-LDMAR is produced mainly in leaves, but regulation of fertility should reside in panicles (Ding et al. [2012b]); Second, the role of the CG SNP in increasing methylation of the promoter directly, or indirectly through the generation of Psi-LDMAR, was not addressed.

After identifying the lncRNA locus, Zhou et al. ([2012]) further narrowed down its functional form to a small, 21-nt RNA, designated as osa-smR5864w and osa-smR5864m for the wild-type and mutant allele, respectively. The small RNA may be a product of a 136-nt intermediate precursor. They speculated that osa-smR5864w may be the functional form and regulate male development under sterility-inducing conditions by cross-talking between the genetic networks and environmental conditions. However, no gene known to be involved in anther and pollen development has been shown to be the target of osa-smR5864w.

In addition to offering different explanations for the functional identity of the lncRNA locus, Ding et al. ([2012a]) and Zhou et al. ([2012]) made the following different observations: (1) LDMAR is expressed in all tissues and is relatively higher in panicles, whereas osa-smR5864w is mainly expressed in panicles; (2) Expression of LDMAR in NK58 is significantly higher under long days than under short days, and is significantly higher in NK58 than in NK58S under any day length, while expression of osa-smR5864w is almost independent of growing conditions. Consequently, Ding et al. ([2012a]) argued that occurrence of PGMS under long day resulted from lower expression of LDMAR rather than from the CG SNP; Zhou et al. ([2012]) inferred that it was the function rather than the amount of osa-smR5864w that determined PGMS in NK58S and TGMS in Peiai 64S.

Further studies will verify which hypothesis is correct, but the authors of this review are inclined to agree with Zhou et al. ([2012]) for the following reasons. (1) The functional importance of the CG SNP is explained in osa-smR5864w and osa-smR5864m, but it is very speculative in LDMAR. (2) The spatial expression of osa-smR5864w is more relevant to its function than is the spatial expression of LDMAR. (3) The possibility that LDMAR is a precursor of small RNA was not excluded. Indeed, Ding et al. ([2012a]) predicted and verified by RT-PCR that three small RNAs could be processed from a stem-loop structure involving 145 bases of LDMAR, and the smRNA-1 with the CG SNP is exactly the same as osa-smR5864.

The RNase Z enzyme is a highly conserved single-chain endoribonuclease that is expressed in all living cells. There are two classes of RNase Z proteins, long RNase ZL and short RNase ZS (Vogel et al. [2005]). RNase Z catalyzes the hydrolysis of a phosphodiester bond, producing 3-hydroxy and 5-phospho termini as it participates in tRNA maturation by cleaving off a 3 trailer sequence (Mayer et al. [2000]). The first RNase Z gene was cloned from Arabidopsis (Schiffer et al. [2002]); studies of homologous genes in various species have revealed that RNase Z could cleave a broader spectrum of substrates, including coding and noncoding RNAs (Xie et al. [2013]).

In plants, RNase Z is described using a prefix for the species, followed by TRZ (e.g., AthTRZ and OsaTRZ are the RNase Z genes in Arabidopsis and rice, respectively) (Fan et al. [2011]). The rice genome has three RNase Z genes: OsaTRZ1 (LOC_Os02g12290) and OsaTRZ2 (LOC_Os09g30466) encoding RNase ZS, and OsaTRZ3 (LOC_Os01g13150) encoding RNase ZL (Fan et al. [2011]). OsaTRZ2 contributes to chloroplast biogenenesis and homozygous OsaTRZ2 mutants are albino with deficient chlorophyll content due to the arrest of chloroplast development at an early stage (Long et al. [2013]). As indicated above, a nonsense mutation of OsaTRZ1 (RNZm) could be responsible for the TGMS traits in rice (Zhang et al. [2014]). Although it is unclear how this mutation leads to TGMS, the following observations in other species suggest a logical pathway by which the RNZm mutation could result in TGMS. First, the Arabidopsis genome has four RNase Z genesAthTRZ1 and AthTRZ2 for RNase ZS, and AthTRZ3 and AthTRZ4 for RNase ZLbut only the chloroplast-localized AthTRZ2 is essential. Deletions of the other three are not lethal (Canino et al. [2009]), suggesting that the null mutation of OsaTRZ1 will also not be lethal for rice development, a phenomenon that fits RNZm mutants. Second, it has been proven that conditional knockout at gametogenesis of Drosophila RNZ leads to thinner testes and lack of post-meiotic germ cells (Xie et al. [2013]), a phenomenon similar to that observed in TGMS rice: premature degeneration of tapetal cells and lack of pollen in the pollen sac (Figure2).

Because the function of TRZ genes has been assigned recently, very limited references are available for a thorough judgment of the possible functions of OsaTRZ1 and its involvement in male gametophyte formation. Further studies are needed to unveil the molecular mechanism of TGMS and to elucidate the functions and working mechanisms of TRZ1 genes in plants in general and in rice in particular.

Epigenetic regulation has recently been identified to play an important role in gene expression. DNA methylation is known to play a role in fertility transformation of rice P/TGMS (Ding et al. [2012b]). In addition, Chen et al. ([2014]) further observed that the DNA methylation level of P/TGMS line Peiai 64S was lower under low temperatures and short-day conditions (associated with fertility) than under high temperatures and long-day conditions (associated with sterility), suggesting that DNA methylation may be involved in the sterilityfertility transition of Peiai 64S in two different environmental profiles. Similarly, Xu et al. ([2013]) detected DNA methylation sites that were specific to CMS lines or maintainer lines (B lines), implying a specific relationship between DNA methylation at these sites and male-sterile cytoplasm, as well as a relationship with MS. Furthermore, Xu et al. ([2013]) demonstrated that DNA methylation was markedly affected by male-sterile cytoplasms (i.e., WA- and ID-type cytoplasms affected methylation to a much greater degree than did G- and D-type cytoplasms, although there were few differences at the DNA level). Therefore, studies on epigenetic regulation may increase our understanding of the mechanisms regulating MS and restoration.

Since the first WA-CMS-based hybrid rice was commercialized in the 1970s in China, several hundred CMS and EGMS lines have been developed, and some of them are currently or were once used in rice production. Although it is known that WA-CMS is the most widely used CMS in China (Cheng et al. [2007]) and in India (Khera et al. [2012]), so far no report has documented the dynamic changes of different MS systems in rice production. The China Rice Data Center (http://www.ricedata.cn/ webcite) has kept records of the annual planting area of rice cultivars grown in areas of at least ~6800ha from 1983 to the present day. Therefore, we are able to analyze the growing areas under hybrid rice cultivation over the past 20years (19832012). The following is the information extracted from the original data.

Two-line system hybrid rice was not commercialized until 1993; however, it has since played a steadily larger role in hybrid rice production (Figure3a). In 2012, two-line system hybrid rice already covered a total growing area of ~3.3 million ha, about one-third of the total hybrid rice growing area (~10 million ha) (Figure3a) (Note: only the hybrids that had been grown in areas more than 50,000ha were included in Figure3).

Figure 3. Planting areas covered by different types of hybrid rice in China (19832012).a, Hybrids based on BT-, HL-, and WA-CMS lines as well as EGMS (environment-conditioned genic male sterility). b, Hybrids based on different CMS types with similar features to WA-CMS. For definition of different CMS types see Table1. Note the data were composed of hybrid rice cultivars that had grown in more than 50,000ha (1983 to 2012) in this figure, cultivars with less growing area were not included.

In order to avoid the genetic vulnerability such as the crop failure of hybrid corn based on T-CMS in the 1970s, Chinese rice breeders from the very beginning have been trying to develop new types of CMS lines and to diversify the cytoplasm sources of these lines. Hence, ~15 new CMS sources other than WA-CMS have been developed and deployed in hybrid rice production. These sources may be classified into three primary groups: BT- and BT-like CMS, HL-CMS, and WA- and WA-like CMS (Table1).

BT-CMS-based japonica hybrid rice was successfully developed in the 1970s, only a few years after WA-CMS-based indica hybrids. However, the planting area was very limited compared with the latter (Figure3a). Within the BT- and BT-like category, Dian1-CMS hybrids are steadily replacing BT-CMS hybrids; the former now comprise ~90% of cultivation (data not shown).

Within the WA-CMS and the WA-CMS-like categories, there are more than a dozen subtypes of CMS lines. Although WA-CMS still dominates among the subtypes, its absolute dominance has been diminishing since the mid-1990s, and now it represent less than 55% of the total CMS-based hybrid rice (Figure3b). Indeed, this category represents almost the same proportion of all CMS rice because BT- and HL-CMS have a very low percentage of the total CMS (Figure3a).

CMS was used initially in the development of hybrid rice in the so-called three-line hybrid system, but EGMS is becoming more popular in hybrid rice production since the two-line hybrid system, in which the EGMS lines are used, has advantages of a wider range of restoring lines, more freely combinations and simple breeding program. CMS is conditioned by chimeric recombinant mitochondrial genes; the fertility of CMS lines may be restored by Rf genes. EGMS is underpinned by genes for non-coding RNA, transcriptional factors and RNA-processing enzymes. Different MS systems for rice have undergone dynamic changes in practical application in China.

B line: Maintainer line

CMS: Cytoplasmic male sterility

csa: Carbon starved anther

EGMS: Environment-conditioned genic male sterility

ETC: Electron transport chain

F1: First generation

FPTR: First photoperiod/temperature reaction

LDMAR: Long day specific male fertility associated RNA

lncRNA: Long non-coding RNA

lncRm: lncR with C-to-G SNP that underpins the PGMS phenotype

MMCs: Microspore mother cells

MS: Male sterility

NK58: Nongken58

P/TGMS: Photoperiod-and temperature-sensitive genic male sterility

PCD: Programmed cell death

PGMS: Photoperiod-sensitive genic male sterility

PPR: Pentatricopeptide repeat

Rf: Restorer of fertility gene

RFC: Restoration of fertility complex

RMS: Retrograde-regulated male steriity

RNZ: Ribonuclease Z homolog

RNZm: OsaTRZ1 carrying a null mutation that underpins the TGMS phenotype

ROS: Reactive oxygen species

rPGMS: Reverse PGMS

rTGMS: Reverse TGMS

SNP: Single-nucleotide polymorphism

SPTR: Second photoperiod/temperature reaction

TGMS: Temperature-sensitive genic male sterility

TUNEL: Terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling

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Workable male sterility systems for hybrid rice: Genetics ...

Recommendation and review posted by Bethany Smith

While age is a major risk factor for osteoarthritis of the knee, young people can get it, too. For some individuals, it may be hereditary. For others, osteoarthritis of the knee can result from injury or infection or even from being overweight. Here are answers to your questions about knee osteoarthritis, including how it's treated and what you can do at home to ease the pain.

Osteoarthritis, commonly known as wear-and-tear arthritis, is a condition in which the natural cushioning between joints -- cartilage -- wears away. When this happens, the bones of the joints rub more closely against one another with less of the shock-absorbing benefits of cartilage. The rubbing results in pain, swelling, stiffness, decreased ability to move and, sometimes, the formation of bone spurs.

Osteoarthritis is the most common type of arthritis. While it can occur even in young people, the chance of developing osteoarthritis rises after age 45. According to the Arthritis Foundation, more than 27 million people in the U.S. have osteoarthritis, with the knee being one of the most commonly affected areas. Women are more likely to have osteoarthritis than men.

The most common cause of osteoarthritis of the knee is age. Almost everyone will eventually develop some degree of osteoarthritis. However, several factors increase the risk of developing significant arthritis at an earlier age.

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Genetic Counseling and Evaluation for BRCA1/2 Testing Cancer Genetic Counseling

Genetic counseling by a suitably trained health care provider is important to help women make informed decisions about genetic testing. In a genetic counseling session for breast and ovarian cancer, the health care provider will typically collect a detailed family and medical history and discuss the following questions:

Following the genetic counseling session, a woman may decide she does not want BRCA1/2 testing, or she may learn that testing is not appropriate for her circumstances. For a woman who chooses to undergo BRCA1/2 testing, counseling can help her better understand the meaning of her test results.In addition, the careful evaluation of family history performed as part of a genetic consultation, may identify other, less common hereditary causes of cancer.

Several medical options are available for managing breast and ovarian cancer risk in women who have BRCA1/2 mutations. These options have risks and benefits and should be discussed with a health care provider knowledgeable about medical management for women with BRCA1/2 mutations.

The most effective option for preventing cancer from developing is undergoing surgery to remove the breasts and ovaries.

Other available options may reduce the chance of developing cancer, or improve the likelihood of detecting it earlier, but the effectiveness of these options is less certain.

BRCA1/2 test results can provide important information for family members.

Understanding and coping with a strong family history of breast or ovarian cancer can be challenging for individuals and families.Genetic counselors can help by providing information, resources, and support to families both with and without BRCA1/2 mutations.

Learn more about family history risk categories

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Genetic Counseling and Evaluation for BRCA1/2 Testing

Recommendation and review posted by sam

Precertification requirements

The Genetic Testing and Counseling Program includes a precertification requirement and medical necessity review for certain Tier 1 and all Tier 2 genetic testing codes. Three additional CPT codes (81210, 81300 and 81301) have been added to the precertification list beginning September 16, 2013. This will help ensure that individuals receive cost-effective care that is covered under their benefit plans.

For a complete, up-to-date list of services that require precertification of coverage, health care professionals should log in to our Cigna for Health Care Professionals website at CignaforHCP.com and click on "Precertification Policies" under "Popular Links." Once there, please see the "Master Precertification Policy" document.

Precertification requests may be submitted on the Cigna for Health Care Professionals website (CignaforHCP.com) or by calling the Cigna Customer Service Center at 1.800.88Cigna (882.4462).

As part of the updated precertification requirements, beginning September 16, 2013, individuals with Cigna-administered coverage will be required to receive pre-testing genetic counseling from an independent board-certified genetic counselor or clinical geneticist for three hereditary conditions breast and ovarian cancer (BRCA), colorectal cancer syndromes, and Long QT syndrome in order for precertification to be approved. This will provide these individuals with the opportunity to become fully informed about these complex genetic tests.

Prior to requesting precertification for these three conditions, ordering physicians should refer their patients with Cigna-administered coverage (and whose benefit plan requires precertification for outpatient procedures) to a participating independent board-certified genetic counselor or clinical geneticist for genetic counseling. This genetics professionals role will not only be to provide pre- and post-testing genetic counseling for individuals, but also to provide support to the ordering physician and help facilitate the overall testing process.

An independent genetics professional is one who is not employed by any clinical or genetic laboratory. Requiring that individuals receive services from an independent genetics professional ensures that there is no conflict of interest between the genetics professional and the facility that performs the tests.

For more information about how to find a genetic counselor, please review the information in the "Find a participating independent board-certified genetic counselor or clinical geneticist" section below.

Health care professionals and their patients can find a participating independent board-certified genetic counselor or clinical geneticist four different ways:

Please contact genetic counselors prior to receiving services to confirm that theyparticipate in Cigna's network.

To help ensure that individuals have ready access to genetics experts and expedited services, we have established a relationship with InformedDNA. InformedDNA is a nationwide network of participating independent board-certified genetic counselors who deliver services via telephone or web. Day, evening, and weekend appointments are available for individuals by telephone at home, and consultations for patients with urgent surgical or treatment decisions are scheduled within 24-48 hours of referral.

Once the ordering physician refers their patient to an independent board-certified genetic counselor or clinical geneticist, we will typically receive the clinical documentation for the counseling directly from the genetics professional.

In order to help genetic counselors and clinical geneticists facilitate their reviews, we will provide them with a form that will help them to clearly and efficiently make their recommendation regarding the proposed test. We will then use that recommendation and clinical documentation as part of our decision to approve or deny the precertification request.

Each precertification decision will be handled as follows:

We will do everything possible to help individuals receive the care they need as soon as they need it. We understand that many tests, especially the BRCA test, may be urgent. Thats why customers have access to many board certified-genetic counselors and clinical geneticists in our network.

Additionally, to help ensure that individuals have efficient access to genetics experts and expedited services, they can contact InformedDNA at 1.800.975.4819.

If a health care professional does not have Internet access to view these updates or if they would like additional information about our Genetic Testing and Counseling Program, they should contact their local Market Medical Executive or call Cigna Customer Service at 1.800.88Cigna (882.4462).

Customers can contact Customer Service at the telephone number on the back of their ID card for additional information about this program, or if they need help finding a participating independent board-certified genetic counselor.

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Recommendation and review posted by sam

Partners HealthCare Personalized Medicine (formerly known as the Partners HealthCare Center for Personalized Genetic Medicine or PCPGM) is a division of Partners HealthCare, an integrated health care system founded by Brigham and Womens and Massachusetts General Hospital, both Harvard-affiliated teaching hospitals, and the largest independent hospital recipients of National Institute of Health (NIH) research funding in the United States.

Partners Personalized Medicine was founded in 2001 by Partners HealthCare and Harvard Medical School (HMS) as the Harvard-Partners Center for Genetics and Genomics. The center was launched before completion of the Human Genome Project as an early commitment to, and in recognition of, the potential for genomic knowledge to dramatically improve health care. This mission, to better understand and harness the unique genetic and genomic makeup of individuals to improve their health, continues today.

As a part of the Partners HealthCare system, and through its affiliation with Harvard Medical School, Partners Personalized Medicine is uniquely positioned to leverage the talent and resources of Partners HealthCare system and impact the research and clinical activities of one of the largest and most transformative health care systems in the country.

Partners Personalized Medicine brings together scientists, clinicians, genetic counselors and information scientists from Partners hospitals and Harvard Medical School who collaborate to:

In this way, the Partners Personalized Medicine plays a crucial role in helping to ensure that the Partners HealthCare system fulfills its mission of delivering high quality and efficient patient care, advancing clinical care through research discoveries, and educating the next generation of scientists and care givers who can bring that care to our local and global community.

Partners Personalized Medicine comprises four areas that work together and with you to provide you with industry leading personalized medicine services:

The investigative and clinical work of Partners Personalized Medicine is backed by a world-class,information technology infrastructure that includes GeneInsight Suite and GIGPAD. These and other applications developed by and utilized by the divisionare critical to managing the data intensive and rapid pace of genetic testing and research.

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Hormone Replacement Therapy For Weight Loss

There is a definite case to be made for the role of hormones in weight management. When our hormones are out of balance, we can experience weight gain and sluggishness that leads to less exercise. This reduction in our physical activity can compound the problem by resulting in more weight gain. Luckily, this is a fight you may be able to win by simply changing a few bad habits. Ultimately, learning how to balance your hormones can help you lose weight.

First Stop: Stress Many people find that, when under stress, they eat more. While this propensity to over indulge could be the result of an emotional issue, it is more often a result of the hormone Cortisol. Cortisol is released by your body when you have the need for adrenaline; this is often referred to as, fight or flight. If you were in a physically dangerous position and needed extra energy to fight someone or flee from something, the release of some of your stored glucose as a result of Cortisol would give you the energy to punch or run. After a release of Cortisol, you find yourself hungry and exhausted.

In todays society, stress most often comes from work or family situations and, while your body still releases the Cortisol to help you fight or flee- you dont actually need it. Everyday stressful situations are not resolved my punching your boss in the face or running away from paperwork. So now, you have the exhaustion after the Cortisol is released and the hunger afterward- but no actual glucose burned from physical activity.

Next Stop: Metabolism Your thyroid is a tricky beast. It is a small gland in your throat that produces two hormones (Thyroxine and Triiodothyronine) which work to increase your metabolism and help you burn more calories throughout the day. When the thyroid doesnt work properly, your metabolism could slow and you could find yourself suddenly gaining a large amount of weight- even without making any changes to your diet. Youll also feel sluggish, leaving no energy for exercise.

Last Stop: Insulin Insulin is yet another hormone that can cause you to gain weight. When your pancreas doesnt produce enough insulin, then the food your body breaks down into glucose gets stored as fat. Switching to a higher protein diet and cutting out simple carbohydrates while adding exercise to your daily routine can help you win this battle.

Understanding your bodys relationship with hormones can help you lose weight in a safe way and can impact your health in other positive ways.

When people feel bad, many times they chalk it up to a bad day or a dietary imbalance. Of course, you might suffer from a vitamin or mineral deficiency, but many times people eat well enough to prevent this from happening. Another cause could be a chronic condition or disease, but again if you are getting regular checkups at the doctors office, these should be spotted rather quickly. One of the most common conditions that is also rarely self-diagnosed accurately, is having low testosterone.

Although testosterone is usually seen as a male hormone, the truth is that both males and females need it. Testosterone is a common hormone in both sexes used for muscle and bone strength and is essential to maintain high energy levels. Women produce less testosterone after menopause and often have to supplement their bodies during this time. Estrogen boosters also reduce testosterone levels in women (the same goes for men, but men rarely supplement with estrogen).

Some common low testosterone symptoms are fatigue, difficulty gaining or maintaining muscle, depression, and loss of strength. More than four million men suffer from low testosterone levels, largely in part because many either dont seek treatment or dont understand the condition. Low testosterone is a problem that is generally believed to occur among older men, however men in their 30s and 40s also suffer from low testosterone levels.

The reason that athletes take steroids, which include testosterone among other hormones, is that they help reduce body fat, improve muscle growth, and improve energy levels. A testosterone deficiency can have the opposite effect, which usually goes hand in hand with depression.

Our Physicianscan prescribe hormone replacement therapy to increase the testosterone levels in your body so that you dont have to suffer from mood swings, irritability, and a lack of energy. If you are active, then any sort of physical exercise can deplete your testosterone levels, leaving you constantly fatigued and unable to heal. If you think you have any of these symptoms, it is important that you talk to a doctor as soon as possible.

You can ask your doctor for a blood test, where you can find out for certain if you suffer from low testosterone. A blood test is quick and easy and you can usually have your results back within a few days. Sometimes, you can have aspot reading so that you can start hormone replacement therapy immediately.

There has long been a cult of mystique around the advent of menopause in women. Women, differentiated from men by their ability to have children and menstruate, lose that ability when they grow older. Suddenly they are in a state of flux no longer of child bearing age, yet still in this day and age healthy and often vital. Now women live long, healthy and active lives after menopauseand they want to feel good, vital and happy while doing so. That is where hormone replacement therapy comes in.

Bioidentical hormone therapy (sometimes called bioidentical hormone replacement therapy or BHRT) is basically the term for the treatment of the hormone deficiencies caused when a women goes through menopause. Bioidentical hormone therapy uses molecules that are endogenous to the hormones already found in the human body, hence the term bioidentical.

You often hear about hormone replacement therapy for women, but bioidentical hormone replacement therapy is different in one supremely important way it uses human hormones, not the animal or synthetic hormones that are so often used in other popular and conventional forms of hormone replacement therapy.

Bioidentical hormone therapy uses many types of hormones, but the two major hormones used in bioidentical hormone therapy are estradiol and progesterone. Both of these hormones are available in FDA-approved forms.

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Hormone Replacement Therapy - Ideal Physician Weight Loss

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What is a Gene? Look closely at the chromosomes and you'd see that each is made of bundles of looping coils. If you unraveled these coils, you'd have a six-foot long double strand of deoxyribonucleic acid-DNA. A more+ How Do Genes Work? Genes are often called the blueprint for life, because they tell each of your cells what to do and when to do it: be a muscle, make bone, carry nerve signals, and so on. And how do genes orchestrate more+ Why We are Different Biologists use two fancy words to describe the relationship between your genes and your physical traits. The first word is genotype. Your genotype is your genes for a given trait. In most cases, more+ Mutations and Disease DNA is constantly subject to mutations, accidental changes in its code. Mutations can lead to missing or malformed proteins, and that can lead to disease. We all start out our lives with some more+ Genetic Testing Have you ever had your genes tested? Probably not. DNA testing is still pretty limited, although it is becoming more and more common, especially for fetuses and newborns. Many prospective parents, more+ Making Medicines Not long ago, if you were diabetic, the insulin your doctor prescribed would have come from a pig. If you required human growth hormone, it would have come from human cadavers, a source that is more+ New Therapies Many of the worst diseases around are caused by glitches in our genes, and the therapies for these diseases often involve a lifetime of drugs (and their nasty side effects) that help but don't really more+ Ethics The new possibilities created by genetics have brought with them new questions about what is right. An example: genetic testing is, for now, optional. But many medical tests that start out as more+

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About Genetics | Understanding Genetics

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Last update 23andMe returns with FDA-approved genetic health tests, 15 hours ago

Genetic testing company 23andMe is reintroducing some health screening tools that federal regulators forced off the market more than two years ago, due to concerns about their accuracy and interpretation by customers.

Genetic ancestry, as well as facial characteristics, may play an important part in who we select as mates, according to an analysis from UC San Francisco, Microsoft Research, Harvard, UC Berkeley and Tel Aviv University.

(Medical Xpress)A large team of researchers affiliated with multiple institutions in several European countries has found new genetic variants that put heavy drinkers at higher risk of developing cirrhosis of the liver. ...

Researchers at King's College London have identified a new gene linked to nerve function, which could provide a treatment target for 'switching off' the gene in people with neurodegenerative diseases such as Parkinson's disease.

Never before have scientists been able to make scores of simultaneous genetic edits to an organism's genome. But now, in a landmark study by George Church and his team at the Wyss Institute for Biologically Inspired Engineering ...

Eczema - an itchy dry-skin condition - affects an estimated one in five children and one in 12 adults in the UK. Genes play an important role in determining how likely we are to develop eczema but the majority of the genes ...

Genes involved in schizophrenia and obesity have been highlighted in a new UCL study, which could lead to a better understanding of the DNA variants which affect risk of these conditions and aid the development of improved ...

We've known for years that the Huntingtin protein (Htt) is responsible for Huntington's disease, a neurodegenerative disorder that diminishes a person's mental and physical abilities.

Using two complementary analytical approaches, scientists at Whitehead Institute and Broad Institute of MIT and Harvard have for the first time identified the universe of genes in the human genome essential for the survival ...

The proposed Regulation on In Vitro Diagnostic Medical Devices (IVDs) negotiations, currently at the stage of tripartite negotiations between the Council (representing Member State governments), the European Parliament, and ...

A coalition of leukemia researchers led by scientists from UC San Francisco has discovered surprising genetic diversity in juvenile myelomonocytic leukemia (JMML), a rare but aggressive childhood blood cancer.

In the kidney, injured cells can be kicked into reparative mode by a gene called Sox9, according to a new paper published in Cell Reports.

University of Otago researchers working with zebrafish have published a study providing new insights into the causes of the congenital heart defects associated with a rare developmental disorder.

The team behind the Deciphering Developmental Disorders (DDD) Study, one of the world's largest nationwide rare disease genome-wide sequencing initiatives, have developed a novel computational approach to identify genetic ...

The whimsically named sonic hedgehog gene, best known for controlling embryonic development, also maintains the normal physiological state and repair process of an adult healthy lung, if damaged, according to new research ...

A research group at Tohoku Medical Megabank Organization (ToMMo) has successfully constructed a Japanese population reference panel (1KJPN), from the genome information of 1,070 individuals who had participated in the cohort ...

Walt Whitman's famous line, "I am large, I contain multitudes," has gained a new level of biological relevance.

Research indicates for the first time that mutations within the DNA sequence of mitochondria impact on the energy producing capacity of these cells, with significant effects on fertility and life expectancy - and remarkably ...

A new test detects virtually any virus that infects people and animals, according to research at Washington University School of Medicine in St. Louis, where the technology was developed.

An international team of scientists from the 1000 Genomes Project Consortium has created the world's largest catalog of genomic differences among humans, providing researchers with powerful clues to help them establish why ...

Scientists have calculated more precise measurements of heritabilitythe influence of underlying genesin nine autoimmune diseases that begin in childhood. The research may strengthen researchers' abilities to better ...

Published today in Nature, the findings detail a new gene locus that can explain why, in communities where everyone is constantly exposed to malaria, some children develop severe malaria and others don't. Now, researchers ...

In recent years, University of Utah biologists showed that when wild-type mice compete in seminatural "mouse barns" for food, territory and mates, they can suffer health problems not revealed by conventional toxicity tests ...

An international study of nearly 70,000 women has identified more than forty regions of the human genome that are involved in governing at what age a woman goes through the menopause. The study, led by scientists at the Universities ...

Cells of multicellular organisms contain identical genetic material (the genome) yet can have drastic differences in their structural arrangements and functions. This variation of the distinct cell types comes from the differential ...

Using a genome-wide association study, EPFL scientists have identified subtle genetic changes that can cause substantial differences to how we fight viral infections.

Mitochondria are not only the power plants of our cells, these tiny structures also play a central role in our physiology. Furthermore, by enabling flexible physiological responses to new environments, mitochondria have helped ...

A genetic variant near the KLF14 gene regulates hundreds of genes that govern how and where women's bodies store fat, which affects their risk of developing Type 2 diabetes, according to research presented at the American ...

Progeria, a premature aging disease, is the research focus of Roland Foisner's team at the Max F. Perutz Laboratories of the University of Vienna and the Medical University of Vienna. Children suffering from progeria die ...

Tourists spending a recuperative holiday on the Italian coast may be envious of the regenerative abilities of locally found flatworm Macrostomum lignano. Named for its discovery near the Italian beach town of Lignano Sabbiadoro, ...

Some research has suggested that omega-3 fatty acids, abundant in fish oils, can relieve inflammation in Crohn's disease. But a new study using software developed by Duke scientists hints that we should be paying closer attention ...

A 'gene signature' that could be used to predict the onset of diseases, such as Alzheimer's, years in advance has been developed in research published in the open access journal Genome Biology.

An international team of scientists led from Sweden's Karolinska Institutet has for the first time mapped all the genes that are activated in the first few days of a fertilized human egg. The study, which is being published ...

A single stem cell has the potential to generate an animal made of millions of different types of cells. Some cancers contain stem-like but abnormal cells that can act like mini factories to rapidly churn out not only more ...

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Genetics News - Genetics Science, Genetics Technology, Genetics

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History of the Department

On the following page is a brief history of the department, along with a video entitled The First 48 Years of the Department of Genetics at the University of Pennsylvania. On the subsequent page there are four additional videos: The Billingham Chairmanship and Transplantation Immunology (Clyde Barker and David Gasser), The Mellman Chairmanship and Cytogenetics (Beverly Emanuel and David Gasser), The Mellman Chairmanship and Maternal/Fetal Medicine (Michael Mennuti and David Gasser), and The Kazazian Chairmanship (Haig Kazazian and David Gasser). Read and view more about the department...

The Department of Genetics hosts a different speaker every Monday of the academic year, with invitees ranging from postdoctoral researchers to prominent scientists presenting a broad array of current, genetics-related research. Our series is cosponsored with the Department of Cell and Developmental Biology and the Institute for Regenerative Medicine. Click here to view the schedule.

Congratulations to Dr. Janine Lamonica from the Zhou lab for receiving a two-year postdoctoral fellowship from the International Rett Syndrome Foundation!

We are pleased to announce that this year's Tom Kadesch Prize in Genetic Research has been awarded to Judy I-Ting Wang. Read more about Ms. Wang, the Kadesch Prize, and the Symposium...

Zhaolan Zhou, Dan Rader, Judy Wang, Alex Kadesch, Becca Mueller

We are pleased to announce the recruitment of Golnaz Vahedi, Ph.D.Golnaz received her Ph.D. in Computational Biology from Texas A&M in 2009, where she studied gene regulatory networks applying Boolean probabilistic modeling and other methods. After developing her interest in regulatory networks controlling gene expression, Golnaz joined Dr. John OSheas laboratory at the National Institutes of Health in 2009. During her postdoctoral training Dr. Vahedi made seminal findings in the area of epigenetic and transcription factor control of cell fate in the immune system. Golnaz will join the Department as a tenure track Assistant Professor on May 1, 2015. Her arrival is expected to further strengthen and expand the Department's capacities in the computational and bioinformatics aspects of immunogenetics.

Yoseph Barash In silico to in vivo splicing analysis using splicing code models. Gazzara MR, Vaquero-Garcia J, Lynch KW, Barash Y. Methods. S1046-2023(13)00444-1, 2013.

AVISPA: a web tool for the prediction and analysis of alternative splicing. Barash Y, Vaquero-Garcia J, Gonzlez-Vallinas J, Xiong HY, Gao W, Lee LJ, Frey BJ. Genome Biol. 14(10):R114, 2013.

Maja Bucan From Mouse to Human: Evolutionary Genomics Analysis of Human Orthologs of Essential Genes. Georgi B, Voight BF, Bucan M PLoS Genet. 2013. 9(5): e1003484.

Genomic View of Bipolar Disorder Revealed by Whole Genome Sequencing in a Genetic Isolate Georgi B, Craig D, Kember RL, Liu W, Lindquist I, Nasser S, Brown C, Egeland JA, Paul SM, Bucan M PLoS Genet 10(3): e1004229. doi:10.1371/journal.pgen.1004229, 2014.

Doug Epstein Divergent roles for Wnt/-catenin signaling in epithelial maintenance and breakdown during semicircular canal formation. Rakowiecki S,Epstein DJ. Development 140(8):1730-9, 2013.

Inhibition of Sox2-dependent activation of Shh in the ventral diencephalon by Tbx3 is required for formation of the neurohypophysis. Trowe MO, Zhao L, Weiss AC, Christoffels V,Epstein DJ, Kispert A. Development 140(11):2299-309, 2013.

Arupa Ganguly Parental nutrient intake and risk of retinoblastoma resulting from new germline RB1 mutation. Bunin GR, Li Y, Ganguly A, Meadows AT, Tseng M. Cancer Causes Control. 2013 Feb;24(2):343-55. doi: 10.1007/s10552-012-0120-x. Epub 2012 Dec 8.

A case-control study of paternal occupational exposures and the risk of childhood sporadic bilateral retinoblastoma. Abdolahi A, van Wijngaarden E, McClean MD, Herrick RF, Allen JG, Ganguly A, Bunin GR. Occup Environ Med. 2013 Jun;70(6):372-9. doi: 10.1136/oemed-2012-101062. Epub 2013 Mar 16.

Genomic profile of 320 uveal melanoma cases: chromosome 8p-loss and metastatic outcome. Ewens KG, Kanetsky PA, Richards-Yutz J, Al-Dahmash S, De Luca MC, Bianciotto CG, Shields CL, Ganguly A. Invest Ophthalmol Vis Sci. 2013 Aug 23;54(8):5721-9. doi: 10.1167/iovs.13-12195.

Dominant form of congenital hyperinsulinism maps to HK1 region on 10q. Pinney SE, Ganapathy K, Bradfield J, Stokes D, Sasson A, Mackiewicz K, Boodhansingh K, Hughes N, Becker S, Givler S, Macmullen C, Monos D, Ganguly A, Hakonarson H, Stanley CA. Horm Res Paediatr. 2013;80(1):18-27. doi: 10.1159/000351943. Epub 2013 Jul 13.

Enhanced Sensitivity for Detection of Low-Level Germline Mosaic RB1 Mutations in Sporadic Retinoblastoma Cases Using Deep Semiconductor Sequencing. Chen Z, Moran K, Richards-Yutz J, Toorens E, Gerhart D, Ganguly T, Shields CL, Ganguly A. Hum Mutat. 2013 Nov 26. doi: 10.1002/humu.22488. [Epub ahead of print]

David Gasser Focal segmental glomerulosclerosis is associated with a PDSS2 haplotype and, independently, with a decreased content of coenzyme Q10. Gasser DL, Winkler CA, Peng M, An P, McKenzie LM, Kirk GD, Shi Y, Xie LX, Marbois BN, Clarke CF and Kopp JB. Am J Physiol Renal Physiol 305(8): F1228-F1238, 2013.

Yugong Ho An -regulatory pathway establishes the definitive chromatin conformation at the Pit-1 locus Ho Y, Cooke NE, Liebhaber SA. Mol Cell Biol. In Press.

Stephen Liebhaber An -regulatory pathway establishes the definitive chromatin conformation at the Pit-1 locus Ho Y, Cooke NE, Liebhaber SA. Mol Cell Biol. In Press.

TissueSpecific CTCF Occupancy andBoundary Function at the Human Growth HormoneLocus Tsai, Y-C, Cooke, NE, and Liebhaber, SA Nucleic Acids Research. 42: 4906-21., 2014.

Specific enrichment of the RNA-bindingproteins PCBP1 and PCBP2 in chief cells of the murinegastric mucosa Ghanem,LR, Chatterji, P, and Liebhaber, SA Gene Expression Patterns. 14:78-87, 2014. Autonomous Actions of theHumanGrowth Hormone Long-Range Enhancer Yoo, EJ, Brown, CD., Tsai, Y-C, Cooke, NE, and Liebhaber, SA Nucleic Acids Research. 2015.

Julia I-Ju Leu Structural basis for the inhibition of HSP70 and DnaK chaperones by small-molecule targeting of a C-terminal allosteric pocket. Leu JI, Zhang P, Murphy ME, Marmorstein R, George DL ACS Chem Biol. 9(11): 2508-16, 2014.

Crystal structure of the stress-inducible human heat shock protein 70 substrate-binding domain in complex with peptide substrate. Zhang P, Leu JI, Murphy ME, George DL, Marmorstein R PLoS One. 9(7): e103518, 2014.

Meera Sundaram A cell non-autonomous role for Ras signaling in C. elegans neuroblast delamination Parry, J. M. and Sundaram, M. V. Development 141: 4279-4284, 2014.

Sarah Tishkoff Higher frequency of genetic variants conferring increased risk for ADRs for commonly used drugs treating cancer, AIDS and tuberculosis in persons of African descent. Aminkeng F, Ross CJ, Rassekh SR, Brunham LR, Sistonen J, Dube MP, Ibrahim M, Nyambo TB, Omar SA, Froment A, Bodo JM, Tishkoff S, Carleton BC, Hayden MR. The Pharmacogenomics Journal J. doi: 10.1038/tpj. 2013.

Comparison Between Southern Blots and qPCR Analysis of Leukocyte Telomere Length in the Health ABC Study. Elbers CC, Garcia ME, Kimura M, Cummings SR, Nalls MA, Newman AB, Park V, Sanders JL, Tranah GJ, Tishkoff SA, Harris TB, Aviv A. The journals of gerontology. Series A, Biological sciences and medical sciences, published online ahead of print, 2013.

Patterns of nucleotide and haplotype diversity at ICAM-1 across global human populations with varying levels of malaria exposure. Gomez F, Tomas G, Ko WY, Ranciaro A, Froment A,Ibrahim M, Lema G, Nyambo TB, Omar SA, Wambebe C, Hirbo JB, Rocha J, Tishkoff SA. Human Genetics 132(9): 987-99, 2013.

Identifying Darwinian selection acting on different human APOL1 variants among diverse African populations. Ko WY, Rajan P, Gomez F,Scheinfeldt L, An P, Winkler CA, Froment A, Nyambo TB, Omar SA, Wambebe C, Ranciaro A, Hirbo JB, Tishkoff SA. American Journal of Human Genetics 93(1): 54-66, 2013.

Great ape genetic diversity and population history. Prado-Martinez J, Sudmant PH, Kidd JM, Li H, Kelley JL, Lorente-Galdos B, Veeramah KR, Woerner AE, O'Connor TD, Santpere G, Cagan A, Theunert C, Casals F, Laayouni H, Munch K, Hobolth A, Halager AE, Malig M, Hernandez-Rodriguez J, Hernando-Herraez I, Prfer K, Pybus M, Johnstone L, Lachmann M, Alkan C, Twigg D, Petit N, Baker C, Hormozdiari F, Fernandez-Callejo M, Dabad M, Wilson ML, Stevison L, Camprub C, Carvalho T, Ruiz-Herrera A, Vives L, Mele M, Abello T, Kondova I, Bontrop RE, Pusey A, Lankester F, Kiyang JA, Bergl RA, Lonsdorf E, Myers S, Ventura M, Gagneux P, Comas D, Siegismund H, Blanc J, Agueda-Calpena L, Gut M, Fulton L, Tishkoff SA, Mullikin JC, Wilson RK, Gut IG, Gonder MK, Ryder OA, Hahn BH, Navarro A, Akey JM, Bertranpetit J, Reich D, Mailund T, Schierup MH, Hvilsom C, Andrs AM, Wall JD, Bustamante CD, Hammer MF, Eichler EE, Marques-Bonet T. Nature. 499(7459):471-5. 2013. Origin and differential selection of allelic variation at TAS2R16 associated with salicin bitter taste sensitivity in Africa. Campbell MC, Ranciaro A, Zinshteyn D, Rawlings-Goss R, Hirbo JB, Thompson SI, Woldemeskel D, Froment A, Rucker JB, Omar SA, Bodo J-M, Nyambo T, Belay G, Drayna D, Breslin PAS, Tishkoff SA. Molecular Biology and Evolution, Advanced online publication. 2013.

Zhaolan (Joe) Zhou Cellular origins of auditory event-related potential deficits in Rett syndrome Goffin D, Brodkin ES, Blendy JA, Siegel SJ and Zhou Z Nature Neuroscience. 17(6): 804-806, 2014.

Yoseph Barash has been awarded an R01 from the National Institute on Aging. Title: Modeling Splicing in normal tissues and neurodegenerative disease R01 AG046544-01A1

Joe Zhou has been awarded an R01 from the NINDS. Title: Understanding the Pathogenic Mechanisms of Rett Syndrome R01-NS081054

Donna George has been awarded a P01 from the NCI. Title: Targeted Therapies in Melanoma 2P01 CA114046-06

John Murray has been awarded an R01 from the NIH. Title: Mechanisms integrating lineage history with fate specification in C. elegans 1R01GM105676-01A1

Casey Brown has been awarded an R01 from the NIMH. Title: Identification and validation of cell specific eQTLs by Bayesian modeling 1-R01-MH101822-01

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Department of Genetics || University of Pennsylvania

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