Mar 14, 2014 Schematic illustrating how mechanical properties of substrates affect where YAP/TAZ protein localization in cardiac stem cells (left) and how this affects stem cell development and function (right).

Proteins associated with the regulation of organ size and shape have been found to respond to the mechanics of the microenvironment in ways that specifically affect the decision of adult cardiac stem cells to generate muscular or vascular cells.

Cell development for specific functionsso-called cell differentiationis crucial for maintaining healthy tissue and organs. Two proteins in particularthe Yes-associated protein (YAP) and WW domain-containing transcription regulator protein 1 (WWTR1 or TAZ)have been linked with control of cell differentiation in the tissues of the lymphatic, circulatory, intestinal and neural systems, as well as regulating embryonic stem cell renewal. An international collaboration of researchers has now identified that changes in the elasticity and nanotopography of the cellular environment of these proteins can affect how heart stem cells differentiate with implications for the onset of heart diseases.

Researchers at the International Center for Materials Nanoarchitectonics (MANA), National Institute for Materials Science (NIMS) collaborated with researchers in Finland, Italy, the Netherlands, Saudi Arabia and the Czech Republic in the study.

They engineered YAP and TAZ proteins that expressed green fluorescent protein so that their location within the cell could be tracked. They then prepared cell substrates from smart biomaterials displaying dynamic control of elasticity and nanostructure with temperature. "Our data provide the first evidence for YAP/TAZ shuttling activity between the nucleus and the cytoplasm being promptly activated in response to dynamic modifications in substrate stiffness or nanostructure," explain the researchers.

Observations of gene expression highlighted the key role of YAP/TAZ proteins in cell differentiation. In further investigations on the effect of substrate stiffness they also found that cell differentiation was most efficient for substrates displaying stiffness similar to that found in the heart.

The authors suggest that understanding the effects of microenvironment nanostructure and mechanics on how these proteins affect cell differentiation could be used to aid processes that maintain a healthy heart. They conclude, "These proteins are indicated as potential targets to control cardiac progenitor cell fate by materials design."

Explore further: Study identifies gene important to breast development and breast cancer

More information: Hippo pathway effectors control cardiac progenitor cell fate by acting as dynamic sensors of substrate mechanics and nanostructure. Diogo Mosqueira, et al. 2014 ACS Nano; DOI: 10.1021/nn4058984

A new study in Cell Reports identifies a gene important to breast development and breast cancer, providing a potential new target for drug therapies to treat aggressive types of breast cancer.

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Mar 14, 2014 by Brendan M. Lynch Parts of nanoinjectors from Salmonella as seen under an electron microscope. Credit: Dr. Matthew Lefebre and Professor Jorge Galan (Yale University)

If you've ever suffered the misery of food poisoning from a bacterium like Shigella or Salmonella, then your cells have been on the receiving end of "nanoinjectors"microscopic spikes made from proteins through which pathogens secrete effector proteins into human host cells, causing infection.

Many bacteria use nanoinjectors to infect millions of people around the world every year.

Today, Roberto De Guzman, associate professor of molecular biosciences at the University of Kansas, is leading a research group that is evaluating the potential of nanoinjectors as a target for a new class of antibiotics. Their work is funded by a five-year, $1.8 million grant from the National Institute of Allergy and Infectious Diseases, part of the National Institutes of Health.

"This grant will support our studies on elucidating how bacterial nanoinjectors are assembled," said De Guzman. "Nanoinjectors are protein machinery used by bacterial pathogens to inject virulence proteins into human cells to cause infectious diseases. They are nanoscale is sizethey look like needles and bacteria use them to inject virulence proteins into host cellsso I called them nanoinjectors. In microbiology, they are known as part of the type III secretion system, a protein delivery machinery."

The KU researcher said nanoinjectors are unique to pathogenic bacteria and are absolutely required for infectivity. Most people have heard of the diseases caused by bacterial pathogens that employ nanoinjectorsseveral of which have changed the course of the human experience for the worse.

"Examples are Yersinia pestis, which caused the Black Death in Europe and altered world history," said De Guzman. "Also, Pseudomonas aeruginosa, the number one cause of mortality among cystic fibrosis patients and a major source of secondary hospital infections, and Chlamydia, a major source of bacterial sexually transmitted disease."

Because an increasing number of pathogens have evolved strains that are unaffected by antibiotics now on the market, De Guzman said that new approaches in drug development are necessaryand nanoinjectors could present a worthwhile target.

"The problem is that all of these pathogens have developed resistance to current antibiotics," he said. "Further, antibiotics are not as profitable as other drugs, so pharmaceutical companies have disfavored developing them. Hence, there is a dearth of new antibiotics in the pipeline. We're in for a perfect storm when the age of antibiotics is no longer assured."

A major factor in NIH awarding this grant to KU is a $1.9 million nuclear magnetic resonance or NMR spectrometeressentially a huge magnetthat the university bought in 2004 through a bond approved by the Kansas Legislature.

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Nasty nanoinjectors pose a new target for antibiotic research

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The Nobel Prize-winning head of a Japanese institute whose scientists' work on stem cells was hailed as a game-changer in the field of medical biology called the lead researcher's handling of the data "extremely sloppy" and "irresponsible".

Two papers published in the journal Nature in January detailed a simple way to reprogram mature animal cells back into an embryonic-like state that allows them to generate many types of tissue, offering hope for a simpler way to replace damaged cells or grow new organs in humans.

But other scientists have been unable to replicate the research's results since then and there have been indications of problems with its data and images.

"The problem here is one immature researcher collected a huge amount of research data, and her handling of data was extremely sloppy and irresponsible," president of Japanese research institute RIKEN Ryoji Noyori told a news conference.

"I would like to offer my apology for the Nature articles, having brought into question the credibility of the science community," said Noyori, bowing deeply.

Noyori, who won a Nobel prize for chemistry in 2001, was referring to Haruko Obokata, 30, a lead author of the papers who became an instant celebrity in Japan after they were published.

A written statement from Obokata and two other RIKEN researchers made available at the news conference said they are discussing the possible withdrawal of the papers with other co-authors.

Another scientist on the team, Teruhiko Wakayama of the University of Yamanashi, has already called for the papers to be withdrawn.

"It is no longer clear what's right," Wakayama told public broadcaster NHK on Monday.

The news conference was called to release the interim findings of investigation on the controversy by a panel of experts from within and outside RIKEN.

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PUBLIC RELEASE DATE:

14-Mar-2014

Contact: Dr. Lachlan Jolly lachlan.jolly@adelaide.edu.au 61-881-616-363 University of Adelaide

Research from the University of Adelaide has confirmed that a gene linked to intellectual disability is critical to the earliest stages of the development of human brains.

Known as USP9X, the gene has been investigated by Adelaide researchers for more than a decade, but in recent years scientists have begun to understand its particular importance to brain development.

In a new paper published online in the American Journal of Human Genetics, an international research team led by the University of Adelaide's Robinson Research Institute explains how mutations in USP9X are associated with intellectual disability. These mutations, which can be inherited from one generation to the next, have been shown to cause disruptions to normal brain cell functioning.

Speaking during Brain Awareness Week, senior co-author Dr Lachlan Jolly from the University of Adelaide's Neurogenetics Research Program says the USP9X gene has shed new light on the mysteries of brain development and disability.

Dr Jolly says the base framework for the brain's complex network of cells begins to form at the embryo stage.

"Not surprisingly, disorders that cause changes to this network of cells, such as intellectual disabilities, epilepsy and autism, are hard to understand, and treat," Dr Jolly says.

"By looking at patients with severe learning and memory problems, we discovered a gene - called USP9X - that is involved in creating this base network of nerve cells. USP9X controls both the initial generation of the nerve cells from stem cells, and also their ability to connect with one another and form the proper networks," he says.

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Researchers at Virginia Tech and the Massachusetts Institute of Technology have used a computer-aided design tool to create genetic languages to guide the design of biological systems.

Known as GenoCAD, the open-source software was developed by researchers at the Virginia Bioinformatics Institute at Virginia Tech to help synthetic biologists capture biological rules to engineer organisms that produce useful products or health-care solutions from inexpensive, renewable materials.

GenoCAD helps researchers in the design of protein expression vectors, artificial gene networks, and other genetic constructs, essentially combining engineering approaches with biology.

Synthetic biologists have an increasingly large library of naturally derived and synthetic parts at their disposal to design and build living systems. These parts are the words of a DNA language and the "grammar" a set of design rules governing the language.

It has to be expressive enough to allow scientists to generate a broad range of constructs, but it has to be focused enough to limit the possibilities of designing faulty constructs.

MIT's Oliver Purcell, a postdoctoral associate, and Timothy Lu, an associate professor in the Department of Electrical Engineering and Computer Science, have developed a language detailed in ACS Synthetic Biology describing how to design a broad range of synthetic transcription factors for animals, plants, and other organisms with cells that contain a nucleus.

Meanwhile, Sakiko Okumoto, an assistant professor of plant pathology, physiology, and weed science at the Virginia Tech College of Agriculture and Life Sciences, and Amanda Wilson, a software engineer with the Synthetic Biology Group at the Virginia Bioinformatics Institute, developed a language describing design rules for expressing genes in the chloroplast of microalgae Their work was published in the Jan. 15 issue of Bioinformatics.

"Just like software engineers need different languages like HTML, SQL, or Java to develop different kinds of software applications, synthetic biologists need languages for different biological applications," said Jean Peccoud, an associate professor at the Virginia Bioinformatics Institute, and principal investigator of the GenoCAD project. "From its inception, we envisioned GenoCAD as a framework allowing users to capture their expertise of a particular domain in languages that they could use themselves or share with others."

The researchers said encapsulating current knowledge by defining standards will become increasingly important as the number and complexity of components engineered by synthetic biologists increases.

They propose that grammars are a first step toward the standardization of a broad range of synthetic genetic parts that could be combined to develop innovative products.

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Washington, March 14 : Scientists have linked autism and intellectual disability in newborn males with genetic changes that could result from harmful environmental factors, a study said.

An analysis of 100 million US medical records said that autism and intellectual disability rates are correlated at the county level with incidence of genital malformations in newborn males, an indicator of possible congenital exposure to harmful environmental factors such as pesticides.

Autism rates - after adjustment for gender, ethnic, socioeconomic and geopolitical factors - jump by 283 percent for every one percent increase in frequency of malformations in a county.

The intellectual disability rates increase 94 percent.

Slight increases in autism and intellectual disability rates are also seen in wealthier and more urban counties.

The study, published by scientists from the University of Chicago March 13 in PLOS Computational Biology, confirmed the dramatic effect of diagnostic standards, reported Science Daily.

Incidence rates for autism and intellectual disability on a per-person basis decrease by roughly 99 percent in states with stronger regulations on diagnosis of these disorders.

"Autism appears to be strongly correlated with rate of congenital malformations of the genitals in males across the country," said study author Andrey Rzhetsky, Ph.D, professor of genetic medicine and human genetics at the University of Chicago.

"This gives an indicator of environmental load and the effect is surprisingly strong."

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University of Washington researchers have created a line of human embryonic stem cells with the ability to develop into a far broader range of tissues than most existing cell lines.

"These cells will allow us to gain a much greater understanding of normal embryonic development and have the real potential for use in developing ways to grow new tissues and organs for transplantation," said Carol Ware, a professor of comparative medicine. She is the lead author of a paper describing the new cell line.

The findings are reported in the March 10 issue of the journal Proceedings of the National Academy of Sciences. The cells, called nave embryonic stem cells, normally appear at the earliest stages of embryonic development. They retain the ability to turn into any of all the different types of cells of the human body -- a capacity called "pluripotency."

Researchers had been able to develop nave cells using mouse embryonic stem cells, but to create naive human embryonic stem cells has required inserting a set of genes that force the cells to behave like naive cells.

While these transgenic cells are valuable research tools, the presence of artificially introduced genes meant the cells will not develop as normal embryonic cells would nor could they be safely used to create tissues and organs for transplantation.

In an article, Ware and her colleagues from the UW Institute for Stem Cell and Regenerative Medicine describe how they successfully created a line of nave human embryonic stem cells without introducing an artificial set of genes.

They first took embryonic stem cells that are slightly more developed, called primed stem cells, and grew them in a medium that contained factors that switched them back -- or "reverse toggled" them -- to the nave state. They then used the reverse toggled cells to develop a culture medium that would keep them in the nave state and create a stable cell line for study and research.

While the "reverse toggled" cells are much easier to create and will prove valuable research tools, Ware said, the cells that were directly derived from embryos are the more important advance because they are more likely to behave, grow and develop as embryonic cells do in nature.

The new cell line is called Elf1: "El" for the Ellison Foundation, a major supporter of the lab's work; "f" for female, the sex of the stem cell; and "1" for first.

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