Labslink Research News

great tool to find conference and courses

Sat, 28 Apr 2012 02:36:59 PDT

Hey guys

Some people working at the NKI (Netherlands Cancer Institute) have setup a
search engine for scientific meetings. check the description and the website
as well, if interested...
This website, called biomeeter (www.biomeeter.com) is really well done as it
gives a nice overview of the upcoming meetings organized, and the search can
be done by field or keyword, or even by location (as it's always possible to
combine business with pleasure ;-)).
Another great characteristic of Biomeeter is that you can add yourself
meetings to the website and share the info. And last but not least: you can
get informed with an email alert about upcoming meetings in your field.
So, check it out and if you like it, spread the word in your lab and
institute!

University of Iowa, NYU biologists describe key mechanism in early embryo development

Thu, 20 Oct 2011 19:00:09 PDT

New York University and University of Iowa biologists have identified a key mechanism controlling early embryonic development that is critical in determining how structures such as appendages—arms and legs in humans—grow in the right place and at the right time. In a paper published in the journal PLoS Genetics, John Manak, an assistant professor of biology in the UI College of Liberal Arts and Sciences, and Chris Rushlow, a professor in NYU's Department of Biology, write that much research has focused on the spatial regulatory networks that control early developmental processes. However, they note, less attention has been paid to how such networks can be precisely coordinated over time. Rushlow and Manak find that a protein called Zelda is responsible for turning on groups of genes essential to development in an exquisitely coordinated fashion. "Zelda does more than initiate gene networks—it orchestrates their activities so that the embryo undergoes developmental processes in a robust manner at the proper time and in the correct order," says Rushlow, part of NYU's Center for Developmental Genetics. "Our results demonstrate the significance of a timing mechanism in coordinating regulatory gene networks during early development, and bring a new perspective to classical concepts of how spatial regulation can be achieved," says Manak, who is also assistant professor of pediatrics in the Roy J. and Lucille A. Carver College of Medicine and researcher in the UI Roy J. Carver Center for Genomics. The researchers note that their findings break new ground. "We discovered a key transcriptional regulator, Zelda, which is the long-sought-after factor that activates the early zygotic genome," says Rushlow. "Initially, the embryo relies on maternally deposited gene products to begin developing, and the transition to dependence on its own zygotic genome is called the maternal-to-zygotic transition," she adds. "Two hallmark events that occur during this transition are zygotic gene transcription and maternal RNA degradation, and interestingly, Zelda appears to be involved in both processes." The research showed that when Zelda was absent, activation of genes was delayed, thus interfering with the proper order of gene interactions and ultimately disrupting gene expression patterns, the researchers noted, adding that the consequence to the embryo of altered expression patterns is a drastic change in the body plan such that many tissues and organs are not formed properly, if at all. The researchers used Drosophila, or fruit flies, to investigate these regulatory networks. The fruit fly has the advantage of being a tractable genetic model system with a rapid developmental time, and many of the genetic processes identified in flies are conserved in humans. Additionally, pioneering fly research has led to many of the key discoveries of the molecular mechanisms underlying developmental processes in complex animals. The study brought together Rushlow, who discovered Zelda and is an expert in genetic regulatory networks in development, and Manak, a genomics expert whose laboratory focuses on how a genome is constructed and coordinately functions. "I had always wanted to work with Chris, and this was a wonderful opportunity for us to combine our complementary areas of expertise in a truly synergistic fashion," says Manak. "Our collaboration is a marvelous example of how a problem can be viewed from two different perspectives, a systems view of early gene networks and an individualistic view of single genes and single embryos, and result in novel and significant discoveries," says Rushlow.

Male-female ring finger proportions tied to sex hormones in embryo; may offer health insights

Mon, 05 Sep 2011 18:23:57 PDT

Biologists at the University of Florida have found a reason why men's ring fingers are generally longer than their index fingers — and why the reverse usually holds true for women. The finding could help medical professionals understand the origin of behavior and disease, which may be useful for customizing treatments or assessing risks in context with specific medical conditions. Writing this week in the Proceedings of the National Academy of Sciences, developmental biologists Martin Cohn, Ph.D., and Zhengui Zheng, Ph.D., of the Howard Hughes Medical Institute and the department of molecular genetics and microbiology at the UF College of Medicine, show that male and female digit proportions are determined by the balance of sex hormones during early embryonic development. Differences in how these hormones activate receptors in males and females affect the growth of specific digits. The discovery provides a genetic explanation for a raft of studies that link finger proportions with traits ranging from sperm counts, aggression, musical ability, sexual orientation and sports prowess, to health problems such as autism, depression, heart attack and breast cancer. It has long been suspected that the digit ratio is influenced by sex hormones, but until now direct experimental evidence was lacking. "The discovery that growth of the developing digits is controlled directly by androgen and estrogen receptor activity confirms that finger proportions are a lifelong signature of our early hormonal milieu," Cohn said. "In addition to understanding the basis of one of the more bizarre differences between the sexes, it's exciting to think that our fingers can tell us something about the signals that we were exposed to during a short period of our time in the womb. There is growing evidence that a number of adult diseases have fetal origins. With the new data, we've shown that that the digit ratio reflects one's prenatal androgen and estrogen activity, and that could have some explanatory power." Cohn and Zheng, also members of the UF Genetics Institute, found that the developing digits of male and female mouse embryos are packed with receptors for sex hormones. By following the prenatal development of the limb buds of mice, which have a digit length ratio similar to humans, the scientists controlled the gene signaling effects of androgen — also known as testosterone — and estrogen. Essentially, more androgen equated to a proportionally longer fourth digit. More estrogen resulted in a feminized appearance. The study uncovered how these hormonal signals govern the rate at which skeletal precursor cells divide, and showed that different finger bones have different levels of sensitivity to androgen and estrogen. Since Roman times, people have associated the hand's fourth digit with the wearing of rings. In many cultures, a proportionally longer ring finger in men has been taken as a sign of fertility. "I've been struggling to understand this trait since 1998," said John T. Manning, Ph.D., a professor at Swansea University in the United Kingdom, who was not involved in the current research. "When I read this study, I thought, thank goodness, we've attracted the attention of a developmental biologist with all the sophisticated techniques of molecular genetics and biology." In dozens of papers and two books, including the seminal "Digit Ratio" in 2002, Manning has studied the meaning of the relative lengths of second and fourth digits in humans, known to scientists as the 2D:4D ratio. "When Zheng and Cohn blocked testosterone receptors, they got a female digit ratio," Manning said. "When they added testosterone they got super male ratios, and when they added estrogen, super female ratios. And they've provided us with a list of 19 genes that are sensitive to prenatal testosterone and prenatal estrogen. "I find this completely convincing and very useful," Manning said. "We can now be more focused in our examination of the links between digit ratio and sex-dependent behaviors, diseases of the immune system, cardiovascular disorders and a number of cancers." Cohn, whose uses the tools of genetics, genomics and molecular biology to study limb development, said his lab began studying the digit ratios after Zheng became determined to find an explanation. "He suggested that the 2D:4D ratio would be an interesting question, and I have to admit to being skeptical," Cohn said. "When he came back with the initial results, I was blown away. We looked at each others hands, then got busy planning the next experiment."

Reproductive scientists create mice from 2 fathers

Thu, 09 Dec 2010 03:21:17 PDT

Using stem cell technology, reproductive scientists in Texas, led by Dr. Richard R. Berhringer at the M.D. Anderson Cancer Center, have produced male and female mice from two fathers. The study was posted today (Wednesday, December 8) at the online site of the journal Biology of Reproduction. The achievement of two-father offspring in a species of mammal could be a step toward preserving endangered species, improving livestock breeds, and advancing human assisted reproductive technology (ART). It also opens the provocative possibility of same-sex couples having their own genetic children, the researchers note. In the work reported today, the Behringer team manipulated fibroblasts from a male (XY) mouse fetus to produce an induced pluripotent stem (iPS) cell line. About one percent of iPS cell colonies grown from this XY cell line spontaneously lost the Y chromosome, resulting in XO cells. The XO iPS cells were injected into blastocysts from donor female mice. The treated blastocysts were transplanted into surrogate mothers, which gave birth to female XO/XX chimeras having one X chromosome from the original male mouse fibroblast. The female chimeras, carrying oocytes derived from the XO cells, were mated with normal male mice. Some of the offspring were male and female mice that had genetic contributions from two fathers. According to the authors, "Our study exploits iPS cell technologies to combine the alleles from two males to generate male and female progeny, i.e. a new form of mammalian reproduction." The technique described in this study could be applied to agriculturally important animal species to combine desirable genetic traits from two males without having to outcross to females with diverse traits. "It is also possible that one male could produce both oocytes and sperm for self-fertilization to generate male and female progeny," the scientists point out. Such a technique could be valuable for preserving species when no females remain. In the future, it may also be possible to generate human oocytes from male iPS cells in vitro. Used in conjunction with in vitro fertilization, this would eliminate the need for female XO/XX chimeras, although a surrogate mother would still be needed to carry the two-father pregnancy to term. Using a variation of the iPS technique, the researchers say "it may also be possible to generate sperm from a female donor and produce viable male and female progeny with two mothers." The authors also caution that the "generation of human iPS cells still requires significant refinements prior to their use for therapeutic purposes."

Marsupial embryo jumps ahead in development

Tue, 30 Nov 2010 03:17:51 PDT

Long a staple of nature documentaries, the somewhat bizarre development of a grub-like pink marsupial embryo outside the mother's womb is curious in another way. Duke University researchers have found that the developmental program executed by the marsupial embryo runs in a different order than the program executed by virtually every other vertebrate animal. "The limbs are at a different place in the entire timeline," said Anna Keyte, a postdoctoral biology researcher at Duke who did this work as part of her doctoral dissertation. "They begin development before almost any other structure in the body." Biologists have been pursuing the notion that limb development is triggered by other organ systems coming on line first, but this study shows the marsupial's limbs begin development without such triggers. "Development is probably more flexible than we might have known otherwise," said biology professor Kathleen Smith. Their study animals were gray short-tailed opossums (Monodelphis domestica) native to Brazil and Bolivia, but the same should hold true for any marsupial, Smith said. For the undeveloped embryo to be able to drag itself across the mother's belly from the birth canal to the teat, it needs a formidable pair of forelimbs. To get them, its developmental program has been rearranged to start building the forelimbs much sooner. "A lot of these genes were turned on earlier than you'd see in a mouse or a chick," Keyte said. The researchers were also able to show that the forelimbs received cells from a much larger part of the developing embryo than is normally seen in other vertebrates. What surprised the researchers was that the genetic program to establish the hind limbs also appeared to be turned on early. Gene expression sets up the pattern of where each of the four limbs will be, but the marsupial's forelimbs grow much faster than the hind limbs because the embryo devotes more of its scarce number of early cells to building those structures, Smith said. The plans are in place for the hind limbs, but not the bricks to build them. The embryo emerges from the mother with burly forearms that include bones and well developed muscles, while the hind limbs are small and rubbery. Blind, hairless and with an incomplete brain, a marsupial embryo is shockingly underdeveloped to be living outside the womb. But the system obviously works for marsupials. "There are probably 50 explanations for why marsupials develop outside the womb, and none of them are very good," Smith said. It's pretty clear however that the external development gives the female a lot more control over her reproduction. If conditions change or she runs out of food, the marsupial mother can easily terminate an external pregnancy.

Researchers insert identification codes into mouse embryos

Fri, 19 Nov 2010 03:20:18 PDT

Researchers from the Department of Cell Biology, Physiology and Immunology at Universitat Autònoma de Barcelona (UAB), in collaboration with researchers from the Institute of Microelectronics of Barcelona (IMB-CNM) of the Spanish National Research Council (CSIC), have developed an identification system for oocytes and embryos in which each can be individually tagged using silicon barcodes. Researchers are now working to perfect the system and soon will test it with human oocytes and embryos. The research, published online in Human Reproduction, represents a first step towards designing a direct labelling system of oocytes and embryos. The objective was to develop a system which minimises risks when identifying female gametes and embryos during in vitro fertilisation and embryo transfer procedures, to reduce the phases of the clinical process requiring control and supervision by two embryologists. Microscopic silicon codes, fabricated using microelectronic techniques, were employed in the research. In previous tests, researchers verified the innocuousness of silicon particles in human cells, particularly in macrophages. In the present study, the codes were microinjected into the perivitelline space of mouse embryos, located between the cell membrane and the zona pellucida, a cover which surrounds the plasma membrane of the embryo. Since the embryo exits the zona pellucida before its implantation in the uterus, this approximation should allow the embryo to free itself of the identification codes when leaving the zona pellucida. This research shows that labelled embryos develop normally in culture up to the blastocyst stage, the phase of development which precedes implantation. Researchers also studied the retention of the codes throughout the culture process, the easiness in reading the codes in a standard microscope, and their elimination when embryos free themselves from the zona pellucida. The research also verified the efficacy of the system when freezing and thawing the embryos. To make the system more viable, researchers are now working on improving the embryo's process of freeing itself from the identification code. This is the only stage of the research which presented limitations. They are currently studying whether the modification of the codes' surface could allow their direct attachment to the outer side of the zona pellucida, avoiding their microinjection into the perivitelline space. They also aim to develop an automatic code reading system. Researchers recently received authorisation from the Department of Health of the Government of Catalonia to begin testing the system with human oocytes and embryos from several fertility clinics in Spain.

Analysis of teeth suggests modern humans mature more slowly than Neanderthals did

Tue, 16 Nov 2010 03:30:12 PDT

A sophisticated new examination of teeth from 11 Neanderthal and early human fossils shows that modern humans are slower than our ancestors to reach full maturity. The finding suggests that our characteristically slow development and long childhood are recent and unique to our own species, and may have given early humans an evolutionary advantage over Neanderthals. The research, led by scientists at Harvard University, the Max Planck Institute for Evolutionary Biology (MPI-EVA), and the European Synchrotron Radiation Facility (ESRF), is detailed in the Proceedings of the National Academy of Sciences. "Teeth are remarkable time recorders, capturing each day of growth much like rings in trees reveal yearly progress," says Tanya M. Smith, assistant professor of human evolutionary biology at Harvard. "Even more impressive is the fact that our first molars contain a tiny 'birth certificate,' and finding this birth line allows scientists to calculate exactly how old a juvenile was when it died." Compared to even early humans, other primates have shorter gestation, faster childhood maturation, younger age at first reproduction, and a shorter overall lifespan. It's been unclear exactly when, in the 6 to 7 million years since our evolutionary split from non-human primates, the life course shifted. Smith and her colleagues found that young Neanderthals' teeth growth -- a proxy for overall development -- was significantly faster than in our own species, including some of the earliest groups of modern humans to leave Africa some 90,000 to 100,000 years ago. This indicates that the elongation of childhood has been a relatively recent development. Such studies add to the growing body of evidence that subtle developmental differences exist between us and our Neanderthal cousins. The recent sequencing of the Neanderthal genome has provided tantalizing genetic clues pointing to differences in cranial and skeletal development between Neanderthals and modern humans. The current study involves some of the most famous Neanderthal children ever discovered, including the first hominin fossil, discovered in Belgium in the winter of 1829-30. This individual was previously thought, based on comparisons with modern humans, to have been four to five years old at the time of death. Now, powerful synchrotron X-rays and biological rhythms inside teeth have revealed the child was only three years old. While counting lines in teeth isn't a new method, Smith says, doing it "virtually" using synchrotron micro-computed tomography is. "These new methods present a unique opportunity to assess the origins of a fundamentally human condition: the costly yet advantageous shift from a primitive 'live fast and die young' strategy to the 'live slow and grow old' strategy that has helped to make humans one of the most successful organisms on the planet," Smith says. Humans' extended maturation may have facilitated additional learning and complex cognition, possibly giving early Homo sapiens an advantage over their Neanderthal cousins.

New insights into the development of epithelial cells

Sat, 30 Oct 2010 04:48:22 PDT

This could be important for understanding the mechanisms of various diseases. For example, Grhl2-deficient mice die early in embryonic development and display defects of neural tube closure, including spina bifida. Spina bifida is a common human congenital disease that is often associated with severe disabilities. Little is known about how the disease develops, and Grhl2 may be an important player in its pathogenesis. Furthermore, the authors hypothesize that Grhl2 may also have important functions in internal organs, such as the kidney. Epithelial cells line the renal tubular system, which in humans is several kilometers long.......> Full story

Discovery opens new window on development, and maybe potential, of human egg cells

Tue, 26 Oct 2010 03:25:47 PDT

Fertility procedures such as in vitro fertilization (IVF) require a couple and the doctor to place the risky bet that the multiple eggs they choose to fertilize will produce an embryo that will thrive in the uterus. Researchers cannot biopsy eggs directly because that would destroy them, but a new discovery by professors at Brown University and Women & Infants Hospital could lead to new insights about how eggs develop and ultimately inform judgments about how the embryos they produce will fare. The idea is to examine the genetic material the egg cells discarded when they were first forming, to see which genes they were expressing. "This opens up a whole new time of life for investigation," said Sandra Carson, professor of obstetrics and gynecology at the Warren Alpert Medical School of Brown University and director of reproductive endocrinology and infertility at Women & Infants. Oocytes, or eggs, carry half as much genetic material as other cells in the body because a sperm is supposed to donate the other half of the needed DNA. When an oocyte is formed, it casts off a copy of its DNA into a cellular byproduct called a "polar body." For years, fertility doctors have looked at the DNA in polar bodies for insight into whether the egg would thrive, but until now, nobody had ever found any copies of the oocyte's messenger RNA (mRNA), the translated messages of genetic code that are tell-tale signs of which genes are active in a cell. Moreover, no one understood how they could detect mRNA if it was there. "This research gives us a new technique that might prove useful for looking at how genes are being interpreted by the oocyte," said Peter Klatsky, a research fellow in Carson's lab, who will present the research Oct. 25 at the American Society for Reproductive Medicine annual meeting in Denver. "This may in the future allow us to ask questions about whether an egg is healthy and therefore whether or not that egg, once fertilized will develop into a healthy baby." Along with Gary Wessel, professor of molecular and cellular biology biochemistry at Brown, Klatsky and Carson reasoned that if each polar body did carry mRNA like the oocyte that spawned it, that would be the next best thing to looking for mRNA in the oocyte itself, which is too destrucive. Polar bodies, they hypothesized, could be a reliable and expendable indicator of gene expression in the egg, at least at one key stage in its development. "Our hypothesis was that along with the discarded DNA, there is cytoplasm and in that cytoplasm there could be information in the form of mRNA and that information could tell us what's going on in that oocyte," Klatsky said. In a series of experiments with donated human oocytes and polar bodies, the trio succeeded in becoming the first to detect tiny amounts of mRNA in polar bodies. Furthermore, they were able to show that the abundance of mRNA in each egg cell correlated with their ability to find it in the polar body, suggesting that what's expressed in the egg is present in the polar body. "Now that we've figured out that you can detect it, the next question is does it tell you something about the health of the egg," Klatsky said. Supporting cast of stars Achieving these results was no easy task. The amount of mRNA is so small, on the order of quadrillionths of grams, that the team had to develop a new procedure for amplifying it using polymerase chain reaction, a method of making copies of DNA. A key step was to break with tradition and not try to isolate mRNA to amplify it. Instead, Wessel said, they took steps to retool the polymerase chain reaction process to find the mRNA itself. To perfect the technique, the team practiced on sea stars (also known as starfish) that Wessel has long studied in his basic biological research on fertilization. At the single-cell level of eggs, sea stars work much like people, Wessel said, but they produce a lot more eggs and polar bodies and those are much easier to study. "Starfish have been amazingly important for understanding how oocytes develop to become fertilizable," Wessel said. "We can get a few or a dozen eggs from people each month but a starfish has about 10 million eggs." With an interest in fertility, Wessel has long kept in touch with clinicians working with humans at Women & Infants. Carson directs those efforts — Klatsky is a fellow in her division — and so they all forged a collaboration. Administrators backed them up. One measure of how risky their hypothesis was is that all $100,000 of funding for their research came from internal sources: seed grants awarded from the Office of the Provost at Brown University and from the Center of Excellence in Women's Health at Women & Infants Hospital. Now that the gamble has paid off in mRNA, the team is pushing ahead to find out whether it can inform both the basic understanding of eggs, and the ultimate promise of improving fertility treatment.

Allergies and wheezing illnesses in childhood may be determined in the womb

Tue, 26 Oct 2010 03:19:06 PDT

A child’s chances of developing allergies or wheezing is related to how he or she grew at vital stages in the womb, according to scientists from the University of Southampton.

The new research, funded by the Medical Research Council (MRC) and the British Lung Foundation, and undertaken at Southampton General Hospital, reveals that fetuses which develop quickly in early pregnancy but falter later in pregnancy are likely to go on to develop allergies and asthma as children. Scientists believe this is due to changes in the development of their immune system and lungs.

A fetus that grows too slowly in the womb is also more likely to become an infant who wheezes with common colds, possibly as a result of narrower airways in its lungs.......> Full story

Protecting embryos against microbes

Tue, 05 Oct 2010 03:23:38 PDT

Headed by the Kiel zoologist Professor Thomas Bosch, a team of scientists from Germany and Russia succeeded in deciphering the mechanisms, for the first time, with which embryos of the freshwater polyp Hydra protect themselves against bacterial colonization. The paper will be published this coming Monday (4 October 2010, press embargo 3pm US Eastern Time) in the online edition of Proceedings of the National Academy of Sciences of the United States of America (PNAS). The researchers from Kiel University found a completely different composition of bacterial colonization in Hydra embryos compared to that of adult polyps. Extensive analysis by microbiologist Sebastian Fraune and biochemist René Augustin showed that the embryos are equipped with a so-called antibacterial peptide by the mother. During the first days of development, this ensures that only certain benign bacteria settle on the embryo. "We suspect that these bacteria protect the embryo by occupying microbial habitats and keeping other, more dangerous germs away", explains Bosch. The methods of producing transgenic polyps developed in his laboratory helped the researchers to clarify if and how the bacterial population changes in an adult organism, if the polyps produce certain antibacterial peptides in higher quantities. As the scientists report in PNAS, they found that antibacterial peptides also drastically alter the composition of the bacterial colonization in adult polyps. For years, biologists had restricted the function of antibacterial peptides to killing microbes. In the meantime, there are more and more indicators that these tiny protein molecules are responsible for the composition of the bacterial colonization. Every organism – including the human body – possesses a completely individual profile of bacterial population. The microbial community is obviously already set at the time of birth by a set of antibacterial peptides. These bacteria then ensure that we stay healthy. Many diseases result from disrupted communication between man and microbe. Hydra belong to the phylum Cnidaria. Members of this phylum are over 600 million years old and were present at the beginning of animal evolution. In their original state, they preserved molecular switches which can also be found in humans in a similar form. With Hydras' practically unlimited regenerative ability and their lack of an ageing process, the old Hydra model system does not only earn a key position in modern evolutionary biology, but also provides new approaches to biomedical research. The Kiel scientists are working step by step towards the solution of this large puzzle, to clarify which bacteria perform which role.

Earlier, more accurate prediction of embryo survival enabled by Stanford research

Mon, 04 Oct 2010 03:14:12 PDT

Two-thirds of all human embryos fail to develop successfully. Now, in a new study, researchers at the Stanford University School of Medicine have shown that they can predict with 93 percent certainty which fertilized eggs will make it to a critical developmental milestone and which will stall and die. The findings are important to the understanding of the fundamentals of human development at the earliest stages, which have largely remained a mystery despite the attention given to human embryonic stem cell research. Because the parameters measured by the researchers in this study occur before any embryonic genes are expressed, the results indicate that embryos are likely predestined for survival or death before even the first cell division. Assessing these parameters in the clinic could make it easier for in vitro fertilization specialists to select embryos for transfer for a successful pregnancy. "Until recently, we've had so little knowledge about the basic science of our development," said the study's senior author Renee Reijo Pera, PhD. "In addition to beginning to understand more about our development, we're hopeful that our research will help improve pregnancy rates arising from in vitro fertilization, while also reducing the frequency of miscarriage and the need for the selective reduction of multiple embryos." Reijo Pera is a professor of obstetrics and gynecology at the medical school and the director of the Center for Human Embryonic Stem Cell Research and Education at Stanford's Institute for Stem Cell Biology and Regenerative Medicine. The study will be published online Oct. 3 in Nature Biotechnology. Postdoctoral scholar Connie Wong, PhD, and former postdoctoral scholar Kevin Loewke, PhD, are the co-first authors of the research. Loewke is currently the lead engineer at the Menlo Park, Calif., biotechnology company Auxogyn Inc. The researchers conducted their studies on a unique set of 242 frozen, one-cell human embryos from the Reproductive Medicine Center at the University of Minnesota. The embryos were created at the in vitro fertilization program at Lutheran General Hospital in Illinois over a period of several years prior to 2002, and when the clinic was closed, the patients gave their consent for their embryos to be used in research. Nowadays it's unusual to freeze embryos so soon after fertilization (about 12 to 18 hours). Instead, clinicians monitor embryonic development for three to five days in an attempt to identify those that are more likely to result in healthy pregnancies after transfer. Despite their best efforts, though, they have only about a 35 percent success rate. As a result, most women elect to transfer two or more embryos to increase the chance of a live birth. However, if multiple embryos implant and develop successfully, a woman and her physician may choose to selectively abort one or more to better the odds for the remaining embryos. Reijo Pera and her colleagues received a large grant from an anonymous donor to investigate ways to better predict embryonic developmental success within one or two days of fertilization. Not only would such an advance decrease the likelihood of miscarriage or the possible need for a selective reduction, it would also reduce the amount of time the embryo would be have to be cultured in the laboratory before transfer. (Although it's not been conclusively shown, some researchers are concerned that genetic changes may accumulate in a cultured embryo and cause subtle, long-lasting effects in the fetus.) The researchers thawed the embryos, split them into four groups and tracked their development during the first few days using time-lapse video microscopy and computer software specially designed by Loewke, a former Stanford mechanical engineering graduate student, for this study. They followed the cells through the development of a hollow ball called a blastocyst, which typically occurs within five to six days after fertilization. A blastocyst is usually an indication of a healthy embryo. They found that of the 242 embryos, 100 were able within five or six days to form normal-looking blastocysts — about the same proportion that would be expected to be successful in normal pregnancies. Because they had tracked the embryos' development so closely, they were then able to go back and identify three specific parameters collectively associated with successful blastocyst formation: the duration of first cytokinesis (the last step of a period in the cell cycle called mitosis in which the cell physically divides), the time between first and second mitoses, and the synchronicity of the second and third mitoses. All of these events occur as the embryo progresses from one cell to four cells within the first two days after fertilization. "It completely surprised me that we could predict embryonic fate so well and so early," said Reijo Pera. If an embryo's values fell within certain windows of time for the three predictive parameters, that embryo was more than 90 percent likely to go on to develop successfully into a blastocyst. When the researchers looked at the gene expression profiles of individual cells from the embryos, they found that, as had been previously shown, the embryos at first express only genes from the maternally derived egg. By roughly the third day (the eight-cell stage) they begin to express genes specific to embryonic development, and the relative proportion of embryonic to egg genes increases steadily during the next few cell divisions. Surprisingly, however, they found that not all cells in an embryo are behaving identically: While some cells may be expressing mostly maternal genes, others in the same embryo are churning out mostly embryonic genes. Similarly, not all cells in an embryo are dividing in synchrony: The researchers found embryos in which some cells were dividing on schedule while others were seemingly stuck, or paused. "We've always thought of embryos as living or dying, but in reality we find that each cell in the embryo is making decisions autonomously," said Reijo Pera. "No one has ever looked at this before." She and her colleagues found that embryos in which individual cells varied significantly in their cell-division schedules or gene-expression profiles were less likely to become successful blastocysts. Together the research indicates that the maternal RNA transcripts — that is, the molecules that carry instructions from the mother's DNA to the embryo's protein-making factories — must be actively degraded in each cell of the embryo, and that this degradation is necessary for the cells to begin to express embryonic genes. Cells that fail to execute some part of this delicate process get out of sync with their neighbors and jeopardize the life of the embryo. The whole endeavor is complicated, and may explain why human embryonic development is so precarious and unique. The research also highlights the importance of studying human embryos, which currently cannot be supported by federal funds. (Every year since 1996, Congress has approved a provision known as the Dicky-Wicker amendment that prohibits the use of federal funds for research in which a human embryo is destroyed — even ones that would otherwise be discarded.) "In mice, about 80 to 90 percent of embryos develop to the blastocyst stage. In humans, it's about 30 percent," said Reijo Pera. "In addition, about one in 100 mouse embryos are chromosomally abnormal, versus about seven out of 10 human embryos. That's why human studies like these are so important. Women, their families and their physicians want to increase the chances of having one healthy baby and avoid high-risk pregnancies, miscarriages or other adverse maternal and fetal outcomes. It's truly a women's health issue that affects the broader family." The research was funded by an anonymous donor, the March of Dimes and the Stanford Institute for Stem Cell Biology and Regenerative Medicine. The researchers have developed an automated algorithm for clinical use that could assess these time-lapse microscopy videos and determine with high accuracy which of these very early embryos would be successful by the four-cell stage. That technology has been licensed exclusively to Auxogyn Inc. by Stanford. Reijo Pera and the other coauthors of the manuscript own or have the right to purchase stock in the company.

Scientists show Six3 gene essential for retinal development

Tue, 21 Sep 2010 03:24:45 PDT

New research led by St. Jude Children's Research Hospital investigators adds to evidence that the Six3 gene functions like a doorman in the developing brain and visual system, safeguarding the future retina by keeping the region where the eye is forming free of a signaling protein capable of disrupting the process. The findings underscore the pivotal role Six3 plays in the developing nervous system as a key regulator of the Wnt family of signaling proteins and expands on earlier work from the laboratory of Guillermo Oliver, Ph.D., member of the St. Jude Department of Genetics. Oliver is senior author of research being published in the September 20 advance online edition of the Journal of Clinical Investigation. "Our work suggests that Six3 evolved as a direct regulator of different members of the critical Wnt signaling pathway," Oliver said. The family of Wnt proteins influences the fate of different cell types by binding to receptors on the cell surface. "A few years ago we determined that very early in development Six3 is required for repressing one member of the Wnt family, a gene called Wnt1, to allow proper development of the forebrain. With this new research, we show that a few hours later Six3 is called on again, this time to repress a different Wnt family member, Wnt8b, so formation of the retina can begin." The retina is the multilayered structure lining the back of the eye. It includes light-sensing cells and the lens, both required for vision. Unlike some animals, humans cannot make new cells to replace those in the retina that are lost to age or illnesses like macular degeneration or glaucoma. Oliver said realizing the potential of stem cells or other cell-based replacement therapies to correct vision or treat blindness requires a more detailed understanding of the genes and molecular mechanisms involved in normal retinal development. In this study, investigators showed that when Six3 was switched off at a key point in mouse embryonic development the retina did not form. The association between Six3 and the retina was further strengthened when researchers found that the retinal pigmented epithelium, a cell layer outside the retina that normally nourished the retina cells, was largely unaffected by the gene's absence. The scientists went on to directly link the lack of a retina to the abnormal expansion of Wnt8b expression into a region where the forebrain normally develops. That region of the developing anterior brain is where cells undergo a process called specification, followed by differentiation to become the highly specialized cells of the retina and eye. Further analysis showed that the Six3 protein binds directly to regulatory regions of Wnt8b. "Our results conclusively demonstrated that for retinal formation to begin, the embryonic forebrain must be Wnt8b free. So the first step in the process is for Six3 to bind to and repress Wnt8b so its expression remains restricted inside its normal boundaries," Oliver explained. "Our findings provide a molecular framework to the developmental program leading to retina differentiation. The work may also be relevant for devising novel strategies aimed at characterizing and eventually treating different abnormalities in eye formation. Researchers are now working to understand the pathway activated when Six3 blocks Wnt8b. "We are focused on a very narrow window of time when specification takes place. We need to identify the critical genes that appear in that timeframe," Oliver said.

Father absence linked to earlier puberty among certain girls

Sat, 18 Sep 2010 05:04:07 PDT

Girls in homes without a biological father are more likely to hit puberty at an earlier age, according to a new study led by researchers at the University of California, Berkeley's School of Public Health. The findings, to be published Sept. 17 in the Journal of Adolescent Health, found that the absence of a biologically related father in the home predicted earlier breast and pubic hair development, but only for girls in higher income households. The findings held even after the girls' weight was taken into account. "The age at which girls are reaching puberty has been trending downward in recent decades, but much of the attention has focused on increased body weight as the primary culprit," said study lead author Julianna Deardorff, UC Berkeley assistant professor of maternal and child health. "While overweight and obesity alter the timing of girls' puberty, those factors don't explain all of the variance in pubertal timing. The results from our study suggest that familial and contextual factors – independent of body mass index – have an important effect on girls' pubertal timing." The findings came from the Cohort study of Young Girls' Nutrition, Environment and Transitions (CYGNET), an epidemiologic project headed by Lawrence Kushi, associate director of etiology and prevention research at the Kaiser Permanente Northern California Division of Research. The project is part of the UC San Francisco Bay Area Breast Cancer and the Environment Research Center (BCERC), one of four centers funded by the National Cancer Institute and the National Institute of Environmental Health Sciences. Early puberty has been linked to greater risk for breast and other reproductive cancers later in life, among other health impacts. "Although the main focus of the CYGNET Study is on environmental exposures, we are also keenly interested in the social and behavioral contexts in which maturation occurs," said Kushi. "These findings demonstrate that such factors may play important roles in the onset of puberty in girls." The link between father absence and earlier puberty in girls has been found in previous research, but most of those studies relied upon recall of the girls' first periods, and few examined the contributions of body mass index, ethnicity and income. In this new study, researchers recruited 444 girls ages 6-8 through Kaiser Permanente Northern California, and have been following them annually. Their analysis was based on the first two years of follow-up. They considered signs of puberty that occur before the start of menarche. In interviews with the girls' caregivers, the researchers asked about the residents in the girls' homes and their relationships to the children. Among the girls studied, 80 reported biological father absence at the time of recruitment. Contrary to what the researchers expected, the absence of a biologically related father was linked to earlier breast development for girls in higher income families – those having annual household incomes of $50,000 or more. Father absence predicted earlier onset of pubic hair development only in higher income African Americans families. The mechanisms behind these findings are not entirely clear, the study authors said. Evolutionary biologists have theorized that the absence of a biological father may signal an unstable family environment, leading girls to enter puberty earlier. Another theory that has been posited is that girls without a biological father in the home are exposed more to unrelated adult males – specifically, the pheromones of these males – that lead to earlier onset of puberty. However, in this study, the presence of other adult males, including stepfathers, in the home did not alter the findings. It is also unclear why father absence predicted early puberty only in higher income families, particularly for African American girls. "It's possible that in lower income families, it is more normative to rely upon a strong network of alternative caregivers," said Deardorff. "A more controversial hypothesis is that higher income families without fathers are more likely to have a single mother who works long hours and is not as available for caregiving. Recent studies have suggested that weak maternal bonding is a risk factor for early puberty." Another possibility is that higher income girls in father-absent homes may be exposed to more artificial light – which has been shown to accelerate puberty in animal studies – through television, computers and other forms of technology, according to the study authors. The researchers also suggested that higher income African American girls may be more exposed to certain beauty products, such as hair straighteners, which have estrogenic properties that could influence pubertal timing. The study adds to the debate of why girls in the United States are entering puberty at an increasingly early age. Last month, a study of 1,200 girls led by BCERC researchers at Cincinnati Children's Hospital Medical Center found that about 15 percent of the girls showed the beginnings of breast development at age 7, an increase from similar studies conducted in the 1990s. "The hunt for an explanation to this trend is significant since girls who enter puberty earlier than their peers are not only at greater risk for reproductive cancers, they are also more likely to develop asthma and engage in higher risk sexual behaviors and substance abuse, so these studies have broader relevance to women's health," said Bay Area BCERC's principal investigator Dr. Robert Hiatt, UCSF professor and co-chair of epidemiology and biostatistics, and director of population science at the campus's Helen Diller Family Comprehensive Cancer Center. "In some ways, our study raises more questions than it answers," said Deardorff. "It's definitely harder for people to wrap their minds around this than around the influence of body weight. But these findings get us away from assuming that there is a simple, clear path to the earlier onset of puberty."

New insights provide promise for development of tools to protect damaged tissues

Tue, 14 Sep 2010 03:18:57 PDT

St. Jude Children's Research Hospital investigators have identified a novel structure in cells that serves as a control switch in the body's system for eliminating damaged cells and also offers new therapeutic potential. The findings provide fresh insight into the machinery at work as cells ramp up production of p53 protein following DNA damage. The p53 protein plays a critical role in how cells respond to the stress that damages DNA. The gene that carries instructions for making p53 protein is the most commonly mutated gene in human cancers. Investigators also identified molecules that disrupt the system and reduce p53 protein levels in cells damaged by irradiation or chemotherapy. These small molecules helped cells growing in the laboratory survive better after they were damaged. The findings appear in the September 13 online edition of the journal Genes & Development. The work lays the foundation for a new approach to protecting healthy tissue using small molecules to reduce p53 protein levels in cells following damage caused by a wide range of factors, including the radiation and chemotherapy used to treat cancer or accidental exposure to dangerous chemicals or radiation, said Michael Kastan, M.D., Ph.D., director of the St. Jude Comprehensive Cancer Center and the paper's senior author. The same approach might also help ease the tissue damage that occurs as blood flow and oxygen are restored following a heart attack or stroke. "We are excited about this because we now theoretically have a way of blunting p53 induction in settings where it is detrimental," he said. The work builds on previous research from Kastan's laboratory into the mechanics of how p53 protein increases in response to cellular stress and DNA damage. Jing Chen, Ph.D., a postdoctoral fellow in Kastan's laboratory, is first author of the study. The jump in p53 protein production was widely attributed to a decrease in the breakdown of p53 inside such cells. But in 2005, Kastan and his colleagues showed that affected cells also produce more of the protein. Researchers reported that after DNA damage, a protein called RPL26 binds to a molecule called p53 messenger RNA, leading to a dramatic rise in p53 protein. Messenger RNA (mRNA) is part of the cell's protein production machinery that translates the genetic instructions inside cells into needed proteins. Efforts to better understand how RPL26 functioned led investigators to this latest discovery. Researchers showed that optimal p53 production required RPL26 to bind to a structure in mRNA not previously seen in mammalian cells. The structure forms when the ends of the normally single-stranded mRNA molecule come together and make a short region of double-stranded RNA. Those ends must obey the rules of RNA pairing and link only with a complementary molecule, or base pair, on the other strand. "We suspect we will find a whole family of stress-related proteins regulated this way," Kastan said. Investigators showed that blocking the interaction at either end of the mRNA was enough to short-circuit RPL26 binding and lead to a dramatic fall in p53 protein levels in stressed or damaged cells. Researchers used short pieces of DNA, so small they were absorbed by cells after simply being added to cell culture, to target the interactive bases and successfully disrupt formation of the double-stranded structure. Restoring the ability of the bases to bind the two ends of the mRNA restored RPL26 binding and stimulated p53 protein synthesis. Work is underway to develop a mouse model to speed efforts to find or design small molecules that target this mechanism. "We have a long way to go in terms of drug development, but the better we can define the interaction between RPL26 and the double-stranded RNA structure the more likely we will be able to develop other small molecules to specifically block that interaction," Kastan said.

Smoking damages men's sperm and also the numbers of germ and somatic cells in developing embryos

Wed, 08 Sep 2010 03:26:03 PDT

Two new studies have shed more light on how smoking may damage fertility, and give further weight to advice that mothers and fathers-to-be should stop smoking before attempting to conceive. The research is published online in Europe's leading reproductive medicine journal Human Reproduction today (Wednesday 8 September). In the first study [1], researchers found that a mother's smoking during early pregnancy dramatically reduces the numbers of germ cells (the cells that form eggs in females and sperm in males) and somatic cells (the cells that form every other part of the body) in the developing foetus. They believe that this may have an adverse effect on the fertility of the baby in later life. In the second study [2], researchers looked at specific proteins called protamines in the sperm of men who smoked and compared them with the protamines in non-smokers. Protamines play an important role in the development of sperm – they are necessary for the process that results in the formation of chromosomes during cell division – and, therefore, have an effect on subsequent male fertility. For the first study, Claus Yding Andersen, Professor of Human Reproductive Physiology at the University Hospital of Copenhagen (Denmark), and his colleagues looked at 24 embryonic testes obtained after women had undergone legal termination between 37-68 days after conception. They also took blood and urine samples and questioned the women about their lifestyle during pregnancy, including smoking and drinking habits. They found that the number of germ cells was more than halved (reduced by 55%) in the testes of embryos from mothers who smoked compared with those from the non-smoking mothers. The number of somatic cells was also reduced by more than a third (37%). The effect was dose dependent, with a greater reduction in germ and somatic cells being seen in embryos from the mothers who smoked the most. This remained the same, even after adjusting for coffee and alcohol consumption. When these results were added to their earlier work that looked at the effect of smoking on 28 female embryos, the researchers found that, overall, germ cells in the ovaries and testes of embryos exposed to smoking were reduced significantly by 41% compared with the number of germ cells in non-exposed embryos. The results also showed that germ cells were more susceptible to damage caused by smoking than somatic cells. Prof Andersen said: "As the germ cells in embryos eventually develop to form sperm in males and eggs in females, it is possible that the negative effect on the numbers of germ cells caused by maternal smoking during pregnancy may influence the future fertility of offspring. In addition, the reduction in the number of somatic cells also has the potential to affect future fertility, as somatic cells in the testes support the development of germ cells to form functional sperm. If the somatic cell number is reduced, fewer functional sperm will be produced. "These findings may provide one potential cause of the reduced fertility observed in recent years. Although the prevalence of smoking during pregnancy has declined in the last decade in developed countries, one in eight mothers continue to smoke throughout their pregnancy, and in Denmark the prevalence of smoking actually increased to 43% in 2005 among women younger than 20 at the time of delivery. This tendency is alarming, and when you take the results from this study in combination with the other known negative effects of cigarette smoke during pregnancy, it further emphasises that pregnant mothers should refrain from smoking." The first trimester is the crucial time when the sexual organs in the developing embryo are differentiating to form either testes or ovaries. "This process is very delicately regulated, with a number of hormones fluctuating. If something goes wrong at this point, just six to eight weeks after conception, it may have an impact on the function of the gonads later in life," said Prof Andersen. "Our results show that the gonads are susceptible to factors, such as cigarette smoke, just at this critical time when they start to differentiate." The authors warn that their study does not clarify whether the reduction in germ and somatic cell numbers is permanent or reflects a growth delay that might be compensated for later on. Prof Andersen said: "We would expect adverse effects to be more pronounced if the mother continues smoking throughout pregnancy, but we have only studied gonads from the first trimester and can only guess whether this effect actually will occur. So the effect on future fertility is still unknown. However, this study does indicate that smoking during pregnancy may have an adverse effect on the future reproductive ability of offspring, since both the number of germ cells and somatic cells are dramatically reduced and these are the foundations of future fertility." In the second study, researchers led by Professor Mohamed Hammadeh, head of the assisted reproductive laboratory in the Department of Obstetrics and Gynaecology at the University of the Saarland, (Homburg Saar, Germany), looked at the levels of two protamines, 1 and 2, in the sperm of 53 heavy smokers (more than 20 a day) and 63 non-smokers. P1 and P2 are necessary for proper chromatin condensation. This is the process whereby chromatin (the combination of DNA and proteins that make up chromosomes) condenses and packages up DNA into chromosomes that can fit inside cells. Poor chromatin packaging adversely affects sperm and is associated with a number of fertility problems such as lower chances of fertilisation after intercourse, poor fertilisation after IVF and ICSI (intracytoplasmic sperm injection), and a higher incidence of miscarriages. This is the first study to investigate the effect of smoking on protamines. Prof Hammadeh and his colleagues found that P2 concentrations were 14% lower in the sperm of smokers compared with non-smokers. "The concentration of P2 from smokers was 334.78 ng in every million sperm, compared with P2 concentrations of 388.8 ng per million sperm in non-smokers," said Prof Hammadeh. "This means that sperm from smokers suffer from protamine deficiency, probably caused by the cigarette smoke, and this could be a reason for incomplete or poor chromatin packaging in sperm, leading to infertility." The researchers found that the ratio of P1 to P2 was altered in smokers. "In normal, fertile men, the ratio of P1 to P2 is almost equal at 1:1. Any increase or decrease in this ratio represents some kind of infertility. In this study the ratio was significantly higher in smokers than in non-smokers, with higher levels of P1 than of P2," said Prof Hammadeh. The study also showed that levels of oxidative stress were higher in smokers than in non-smokers. Oxidative stress is an imbalance between chemically reactive molecules containing oxygen, other, unstable and highly reactive atoms called free radicals (collectively known as "reactive oxygen species"), and anti-oxidant compounds. It can cause damage to proteins, lipids and DNA. "Oxidative stress is known to cause damage to sperm DNA in a number of ways," said Prof Hammadeh. "These results suggest that induced oxidative stress by cigarette smoking may have a significant inverse effect on chromatin condensation by disrupting P2." He concluded: "Given the potential adverse effects of smoking on fertility, cancer and so on, physicians should advise infertile patients who smoke cigarettes to quit smoking. We are carrying out further research into the levels of P1 and P2 in order to find out the effect of smoking on the silencing or changing of the P2 gene in an attempt to clarify the potential mechanism behind this effect."

Developmental gene-environment interactions: A model for psychosis

Mon, 30 Aug 2010 03:23:12 PDT

The incidence of psychotic disorders varies greatly across places and demographic groups, as do symptoms, course, and treatment response across individuals. High rates of schizophrenia in large cities, and among immigrants, cannabis users, and traumatised individuals reflect the causal influence of environmental exposures. This, in combination with progress in the area of molecular genetics, has generated interest in more complicated models of schizophrenia aetiology that explicitly posit gene-environment interactions. Unravelling the causes of psychotic disorders Schizophrenia and related psychotic disorders have a complex aetiology. Research has attempted to determine the role of specific biological variables, such as genetic and biochemical factors and subtle changes in brain morphology. Genetic vulnerability in schizophrenia is shared in part with bipolar disorder and recent molecular genetic findings also indicate an overlap with developmental disorders such as autism (Van Os & Kapur, 2009). According to twin and family studies more than half of the vulnerability for schizophrenia is of genetic origin. However, attempts to discover genes that relate directly to psychotic disorder have been frustrating and often disappointing, and despite enormous investments, the identification of actual molecular genetic variants underlying schizophrenia liability has proven extremely difficult. This difficulty is mainly due to the phenomenon of gene-environment interaction, which is defined as genetic control of sensitivity to the environment. Exciting findings in other areas of psychiatry have motivated researchers to turn their attention to better understanding the complex ways in which genetic factors interact with non-genetic factors to produce psychosis. Biological vulnerability factors with a genetic background interact with complex physical, psychological and environmental vulnerability factors. Conceptualised in a model, gene-environment interaction proposes that genes influencing risk for schizophrenia may not do so directly (the dominant model until recently), but indirectly by making individuals more sensitive to the effects of causal environmental risk factors. The 'genotype x environmental interaction' approach differs from the linear gene-phenotype approach by positing a causal role not for either genes or environment in isolation but for their synergistic co-participation in the cause of psychosis where the effect of one is conditional on the other (Van Os et al., 2008). Gene-environment interaction seems a particularly suitable approach for understanding the development of psychosis because this phenotype is known to be associated with environmentally mediated risks, yet people display considerable heterogeneity in their response to those environmental exposures. In the framework of gene-environment interaction, research is focussing on subclinical symptoms that can be traced to prior persistence of clinically relevant symptoms. For example, in a substantial proportion of patients with bipolar disorder, onset of illness may be seen as the poor outcome of a developmentally common and usually transitory non-clinical bipolar phenotype (Tijssen et al., 2010). In schizophrenia and related psychotic disorders, the median prevalence of subclinical psychotic experiences is reported to be around 5% and the median incidence rate to be around 3%. The difference between prevalence and incidence rates, together with data from follow-up studies, indicates that approximately 75󈟆% of developmental psychotic experiences are transitory and disappear over time. There is evidence, however, that transitory developmental expression of psychosis ('psychosis proneness') may become abnormally persistent ('persistence') and subsequently clinically relevant ('impairment'), depending on the degree of environmental risk the person is additionally exposed to (Van Os et al., 2009; Dominguez et al., 2009). According to the model of psychosis proneness – persistence – impairment, genetic background factors impact on a broadly distributed and transitory population expression of psychosis during development. Hence, poor prognosis, in terms of persistence and clinical need, can be predicted by environmental exposure interacting with genetic risk. Environmental risk factors According to findings from epidemiological research, rates of schizophrenia and related psychotic disorders are substantially influenced by a spectrum of environmental risk factors with significant impact on children and adolescents growing up in European societies.

Urbanicity
Growing up in an urban area has been shown to be associated with an increased risk of developing psychotic disorder in later life (Spauwen et al., 2004). For children growing up in big cities a more than twofold risk compared to children in rural environments has been shown, independent of other risk factors. According to latest research findings up to 25% of all schizophrenia cases can be attributed to this effect.
Migration
Migration presents an increasing challenge to European countries. In immigrant populations the risk of developing psychotic disorders is much higher compared to the risk in both the host country and the country of origin. These findings point to a significant impact associated with the often problematic social interaction between migrants and majority populations.
Cannabis use
Apart from alcohol, cannabis is the most widely used drug in Europe. Although its effects were considered to be harmless compared to other drugs until recently, many studies have shown that cannabis use, in particular heavy use during adolescence, increases the risk of psychotic disorders such as schizophrenia.
Childhood victimisation
In European countries at least 15% of populations are the victims of significant abuse, neglect or bullying during childhood. Evidence from epidemiological research pointing to a link between childhood trauma and psychotic disorders is remarkably consistent in showing strong effects on disease vulnerability.

Measuring schizophrenia vulnerability caused by gene-environment interaction Given substantial gene-environment interaction underlying schizophrenia and related psychotic disorders, the most promising approach to elucidate the causes of schizophrenia is to focus on both genes and environments in the same research project. The study of gene-environment interaction is a multidisciplinary exercise involving epidemiology, psychology, psychiatry, neuroscience, neuro-imaging, pharmacology, biostatistics, and genetics. However, it has proven extremely difficult to bring together these disciplines. Now for the first time in the European Union a rational strategy of focused research collaboration has been devised with a unique, large-scale project, which aims to unravel the causes of schizophrenia and related psychotic disorders (EU-GEI project, see below). The EU-GEI project This multidisciplinary project, involving more than 7,500 patients and their families from 15 countries, is the largest effort to date to find gene-environment interactions underlying schizophrenia risk. It is designed to focus on the effects of gene-environment interactions on brain pathways and psychological vulnerability, and to elucidate how subtle, but measurable, behavioural expressions of vulnerability for psychotic disorder are mediated by cerebral and psychological pathways. Follow-up research in the project is expected to establish why, in some individuals, expression of vulnerability will never progress to overt illness, while in others, schizophrenia will manifest in clinical expression. Psychopathological experiences show essential features such as variability over time and dynamic patterns of reactivity to the environment that need to be captured for a better understanding of their underlying mechanisms. Behavioural expression of vulnerability, occasioned by gene-environment interactions, is best captured as subtle alterations in mood, perception, volition and thought in response to minor stressors in the flow of daily life. Since to date no tools exist to adequately monitor these alterations, European enterprises and start-ups in the EU-GEI project will develop new technology allowing for adequate assessment. Today a prototypic device (PSYMATE) has been designed which can be carried during the day for easy data input concerning mental state, context and activities at random moments in the stream of consciousness. This new method will enable clinicians to capture the 'film' rather than a 'snapshot' of daily life reality of patients, fuelling new research into the gene –environment – experience interplay underlying psychopathology and its treatment (Myin-Germeys et al., 2009). Clinical implications Given the evidence for detrimental effects of big cities on mental health and a wide range of somatic disorders, the impact of the increasing urbanisation and other environmental risk factors in European countries (e.g. migration) should be prioritized in scientific research. Since genetic factors impact on a rather common, transitory expression of psychosis during development, poor prognosis in terms of clinical need can be predicted by environmental exposure interacting with genetic risk. The current development of tools allowing the actual measurement of vulnerability caused by gene-environment interaction will enable clinicians to monitor, and possibly modify, vulnerability at the behavioural level. The findings of the EU-GEI project are promising with regard to preventing transition from subclinical psychosis to overt illness. Conclusion Until recently, researchers found it difficult to unveil the causes of schizophrenia and related psychotic disorders. 100 years after the modern definition of schizophrenia, research is beginning to understand the biological mechanisms underlying the symptoms of this most mysterious of mental disorders and the psychosocial factors that moderate their expression. Recent research findings in psychiatry indicate that genes are likely to influence disorder mostly indirectly, via their impact upon physiological pathways, and work by increasing the likelihood of developing a psychiatric disorder, rather than as direct causes of disorder per se (Van Os et al., 2008). A significant proportion of psychotic disorder may be understood as the rare poor outcome of a common developmental phenotype characterized by persistence of detectable subclinical psychotic experiences. The current model of gene-environment interaction is nurturing promising approaches to understand the symptoms of schizophrenia and related psychotic disorders and improve treatment.

Developmental problems: Some exist in the genes

Wed, 18 Aug 2010 03:18:16 PDT

Everyone is special in their own unique way. From a genetic point of view, no two humans are genetically identical. This means that DNA for each individual contains variants that are more or less comm. on in the overall population. Some gene variations are actually genetic deletions, where sections of DNA 'code' are missing entirely. These variants are likely to have important effects on gene function and, therefore, likely to contribute to diseases associated with that gene. But what happens when multiple genes are disrupted in a single family? A large collaborative study led by scientists based in Oxford, Bologna and Utrecht sheds some light on this complicated situation by describing the genomic characterization of a family with two rare microdeletions, in CNTNAP5 and DOCK4. Multiple members of this family were diagnosed with autism, dyslexia, and/or learning or social difficulties. The genetic analysis revealed that the CNTNAP5 deletion segregated with autism. In contrast, the DOCK4 deletion was present in multiple individuals without autism, but this gene microdeletion co-segregated with reading difficulties. "This report provides further evidence linking CNTNAP genes with autism, one of the most promising gene families in autism research," commented Dr. John Krystal, Editor of Biological Psychiatry, where this research is published. "But it also highlights how complex the connection between genes and syndromes can be, supporting the importance of DOCK4 for brain development – particularly in circuits involved in reading- but questioning its role in autism." "This is another example of the emerging theme whereby multiple rare genomic variants within a single family might, in combination, lead to the variable phenotypes associated with autism spectrum disorders," said first author Dr. Alistair Pagnamenta. Interestingly, CNTNAP5 is closely related to other genes that can influence susceptibility to autism, such as CNTNAP2, which was first identified in 2008. DOCK4 is thought to be involved in the growth and development of nerve cells in the brain. Together, these results may open up new lines of research to help understand mechanisms behind neurological disorders and brain development. The authors have noted that additional studies, which are needed to confirm these associations, are already underway.

What makes a good egg and healthy embryo?

Tue, 10 Aug 2010 03:36:28 PDT

Scientists as well as fertility doctors have long tried to figure out what makes a good egg that will produce a healthy embryo. It’s a particularly critical question for fertility doctors deciding which eggs isolated from a woman will produce the best embryos and, ultimately, babies. New research reveals healthy eggs need a tremendous amount of zinc to reach maturity and be ready for fertilization -- a finding that may ultimately help physicians assess the best eggs for fertility treatment, according to a study from Northwestern University. “Understanding zinc’s role may eventually help us measure the quality of an egg and lead to advances in fertility treatment,” said Alison Kim, a postdoctoral fellow in obstetrics and gynecology at Northwestern University Feinberg School of Medicine. “Currently we can’t predict which eggs isolated from a woman produce the best embryos and will result in a baby. Not all eggs are capable of becoming healthy embryos.“ There’s no link yet to zinc content in the egg and the nutritional status of women, but Kim plans to research that area. Kim is the lead author of a paper that will be published in the September issue of the journal Nature Chemical Biology. The article will be featured on the cover. Co-senior authors are Tom O’Halloran, director of the Chemistry of Life Processes Institute at Northwestern and associate director of basic sciences at the Robert H. Lurie Comprehensive Cancer Center of Northwestern University, and Teresa Woodruff, the Thomas J. Watkins Professor of Obstetrics and Gynecology and executive director of the Institute for Women's Health Research at Feinberg. Woodruff also is a member of the Lurie Cancer Center. Northwestern scientists, working with mice, discovered the egg becomes ravenous for zinc and acquires a 50 percent increase in the metal in order to reach full maturity before becoming fertilized. The flood of zinc appears to flip a switch so the egg can progress through the final stages of meiosis. Meiosis is when the egg sheds all but one copy of its maternal chromosomes before it can be fertilized by a sperm and become an embryo. “Zinc helps the egg exit from a holding pattern to its final critical stage of development,” said O’Halloran, the Charles E. and Emma H. Morrison Professor of Chemistry in the Weinberg College of Arts and Sciences at Northwestern. “It’s on the knife’s edge of becoming a new life form or becoming a cell that dies. It only has 24 hours. Zinc seems to be a key switch that helps control whether the egg moves forward in its development stage. “ Kim found there were approximately 60 billion zinc atoms in a mouse egg just before the egg was ready to be fertilized. She measured the zinc content of the eggs using a technique called synchrotron-based X-ray fluorescence microscopy through collaboration with the Advanced Photon Source at Argonne National Laboratory. This method allowed detection of multiple metals in single eggs using the characteristic X-ray signature of each element. Zinc levels were significantly higher in eggs than other important metals such as iron and copper. Zinc was the only metal to change significantly in concentration during the maturation process. Northwestern scientists also used small molecules to block the accumulation of zinc by the maturing egg. They found an insufficient accumulation of zinc caused all the eggs to pause prematurely at the beginning stage of meiosis. The progression of meiosis was restored by returning zinc to the eggs. Research on the role of zinc was funded by a W.M. Keck Foundation Medical Research Award, the Center for Reproductive Science through the NIH/National Institute of Child Health and Human Development and the Chemistry of Life Processes Institute at Northwestern University through NIH/National Institute of General Medicine. Use of the Advanced Photon Source at Argonne National Laboratory was supported by the Office of Basic Energy Sciences in the Office of Science of the U.S. Department of Energy.

New insights into how stem cells determine what tissue to become

Mon, 02 Aug 2010 04:56:49 PDT

Within 24 hours of culturing adult human stem cells on a new type of matrix, University of Michigan researchers were able to make predictions about how the cells would differentiate, or what type of tissue they would become. Their results are published in the Aug. 1 edition of Nature Methods. Differentiation is the process of stem cells morphing into other types of cells. Understanding it is key to developing future stem cell-based regenerative therapies. "We show, for the first time, that we can predict stem cell differentiation as early as Day 1," said Jianping Fu, an assistant professor in mechanical engineering and biomedical engineering who is the first author on the paper. "Normally, it takes weeks or maybe longer to know how the stem cell will differentiate. Our work could speed up this lengthy process and could have important applications in drug screening and regenerative medicine. Our method could provide early indications of how the stem cells are differentiating and what the cell types they are becoming under a new drug treatment." In this study, Fu and his colleagues examined stem cell mechanics, the slight forces the cells exert on the materials they are attached to. These traction forces were suspected to be involved in differentiation, but they have not been as widely studied as the chemical triggers. In this paper, the researchers show that the stiffness of the material on which stem cells are cultivated in a lab does, in fact, help to determine what type of cells they turn into. "Our research confirms that mechanical factors are as important as the chemical factors regulating differentiation," Fu said. "The mechanical aspects have, until now, been largely ignored by stem cell biologists." The researchers built a novel type of stem cell matrix, or scaffold, whose stiffness can be adjusted without altering its chemical composition, which cannot be done with conventional stem cell growth matrices, Fu said. The new scaffold resembles an ultrafine carpet of "microposts," hair-like projections made of the elastic polymer polydimethylsiloxane---a key component in Silly Putty, Fu said. By adjusting the height of the microposts, the researchers were able to adjust the rigidity of the matrix. In this experiment, the engineers used human mesenchymal stem cells, which are found in bone marrow and other connective tissues such as fat. The stem cells differentiated into bone when grown on stiffer scaffolds, and into fat when grown on more flexible scaffolds. Once the researchers observed the cells differentiating according to the mechanical stiffness of the substrate, they decided to measure the cellular traction forces throughout the culturing process to see if they could predict how the cells would differentiate. Using a technique called fluorescent microscopy, the researchers measured the bending of the microposts in order to quantify the traction forces. "Our study shows that if the stem cells determine to differentiate into one cell type then their traction forces can be much greater than the ones that do not differentiate, or that differentiate into another cell type," Fu said. "We prove that we can use the evolution of the traction force as early indicators for stem cell differentiation." The new matrix---manufactured through an inexpensive molding process---is so cheap to make that the researchers are giving it away to any interested scientists or engineers. "We think this toolset provides a newly accessible, practical methodology for the whole community," Fu said.

'Runaway' development implicated in loss of function of the aging brain

Tue, 20 Jul 2010 05:10:45 PDT

The brain undergoes rapid growth and development in the early years of life and then degenerates as we progress into old age, yet little is known about the biological processes that distinguish brain development and aging. In a report published online today in Genome Research (http://www.genome.org), researchers have identified a gene regulatory link between changes in the young and aging brain, describing "runaway" development as a potentially significant factor in age-related loss of function. The brain grows and changes dramatically during the early years of life, with some developmental processes extending well into adulthood. In later years, the brain undergoes destructive changes, such as a drop in brain volume, synapse loss, and cognitive decline. While brain development and aging are areas of intense research, they are traditionally studied separately, and little is known about the boundaries between the two processes. Underlying brain development is the complex and coordinated process of gene regulation. "In development, many genes are turned on and off by regulators, such as transcription factors and microRNAs." said Mehmet Somel, postdoctoral researcher at the Shanghai Institutes for Biological Sciences. "The question is, do all of these regulatory processes cease once adulthood is reached, or are they still active in aging?" Somel and an international team of researchers addressed this question by investigating messenger RNA (mRNA), microRNA, and protein expression changes in the prefrontal cortex of humans and rhesus macaque monkeys over the life span of each species. The prefrontal cortex is believed to be involved in functions such as complex behavior, personality, and decision-making. The group found that distinct patterns of gene regulation in the prefrontal cortex do not stop at maturity, instead persisting into old age, a phenomenon that was observed for many different functional processes. One particularly striking example was the down-regulation of genes related to neuronal function. Previous work has shown that neuronal genes gradually lose activity with age, attributed to an accumulation of damage in neuronal cells over a lifetime. Somel and colleagues have now shown that this process begins as early as three to four years of age, suggesting that these changes may be normal developmental regulation that continues long into old age. While this regulation is likely to be beneficial during development, at old age continuation of the gene regulation, or "runaway" development, might be detrimental. Interestingly, they found the runaway neuronal development to be conserved in macaques, but it occurs an accelerated rate. Because the regulatory processes progress much faster, the authors suggest that this could be a significant contributor toward limiting the life span of macaques to only about one-third that of humans. The authors caution that aging is a very complex process stemming from many contributing factors, but explain that their work suggests runaway development may be a significant contributor to age-related decline. Why has evolution not eliminated such a potentially harmful process? Philipp Khaitovich of the Shanghai Institutes for Biological Sciences and senior author of the study explained that detrimental effects experienced during old age could spread throughout and fix within populations, especially when those effects are beneficial early in life. "Evolutionarily, species are optimized to reproduce and ensure survival of the next generation, not to live as long as possible as individuals," said Khaitovich. "In fact, long lifespan precludes rapid genetic adaptations to changing environment." Khaitovich added that as they now begin to understand the biological consequences of this evolutionary feature, researchers may find ways to shift the balance from early reproduction to individual longevity and enhanced health at old age.

Study sheds light on how psychiatric risk gene disrupts brain development

Thu, 15 Jul 2010 03:20:45 PDT

Scientists are making progress towards a better understanding of the neuropathology associated with debilitating psychiatric illnesses like bipolar disorder and schizophrenia. New research, published by Cell Press in the July 15 issue of the journal Neuron, reveals mechanisms that connect a known psychiatric risk gene to disruptions in brain cell proliferation and migration during development. A research group led by Dr. Li-Huei Tsai from the Massachusetts Institute of Technology had recently discovered that the psychiatric risk gene, Disrupted in Schizophrenia-1 (DISC1), is an essential regulator of the proliferation of early brain cells (known as neural progenitor cells) via inhibition of a molecule called GSK3? and modulation of the Wnt signaling pathway. Disruptions in the Wnt pathway, which is critical for embryonic development, have previously been linked with developmental defects and with various human diseases. "Our recent finding was particularly interesting because one of the actions of lithium, the most common mood disorder drug, is to inhibit GSK3?." explains Dr. Tsai. "Although DISC1 was one of the first psychiatric illness risk genes to be identified and we know that it plays a key role in brain development, the mechanisms by which DISC1 is regulated remain unknown." In this study, Dr. Tsai and colleagues built on earlier work and investigated how DISC1 is regulated during cortical development by looking for novel DISC1-interacting proteins. The researchers discovered a key interaction between DISC1 and a protein called Dixdc1 which is the mammalian version of a nonmammalian Wnt signaling molecule. Dixdc1 and DISC1 interacted to regulate neural progenitor proliferation via modulation of Wnt/GSK3? signaling. Interestingly, although DISC1 and Dixdc1 were both essential for neural migration, the Wnt/GSK3? pathway was not required for migration. It appears as if Dixdc1 integrates DISC1 into Wnt-dependent and -independent signaling pathways. "Our findings identify the novel Wnt signaling pathway gene, Dixdc1, as a critical regulator of DISC1 function during cortical development. This discovery suggests that Dixdc1 and DISC1 are involved in Wnt signaling at many levels in the nervous system and that mutations in DISC1 likely contribute to disease pathology by disrupting Wnt signaling during neural development and in the adult brain," concludes Dr. Tsai. "Future studies are needed to determine whether other candidate psychiatric risk genes also interact with Wnt signaling."

Digital embryo gains wings

Mon, 05 Jul 2010 03:13:50 PDT

The scientists at the European Molecular Biology Laboratory (EMBL) in Heidelberg, Germany, who 'fathered' the Digital Embryo have now given it wings, creating the Fly Digital Embryo. In work published today in Nature Methods, they were able to capture fruit fly development on film, and were the first to clearly record how a zebrafish's eyes and midbrain are formed. The improved technique will also help to shed light on processes and organisms, which have so far been under-studied because they could not be followed under a microscope. "Non-transparent samples like the fruit fly embryo scatter light, so the microscope picks up a mixture of in-focus and out-of-focus signal– good and bad information, if you like," says Ernst Stelzer, whose group carried out the project at EMBL. "Our new technique enables us to discriminate between that good and bad information, so it allows us to record organisms which have so far been poorly studied, because of their unfortunate optical properties." Philipp Keller, who co-led and conducted the work, and Ernst Stelzer overcame the difficulties caused by thick, opaque samples, by shining patterns of light on them, instead of the usual continuous light sheet. This generates an image with alternating light and dark stripes, unless the light bounces off the sample and changes direction, in which case this stripy pattern will be blurred. By taking multiple images of different phases of the light pattern, and combining them, a computer can filter out the effects of scattered light and generate an accurate image of the sample, thus enabling scientists to record images that were previously unobtainable. By combining this approach with imaging along different angles, the scientists were able to obtain three-dimensional movies of the developing fruit fly embryo in spite of the fact that it is almost opaque. The EMBL scientists were also able to extend their recordings of zebrafish development to an unprecedented level. They took around one million images to capture the first three days of zebrafish development from three different angles, generating films in which the formation of the animal's eyes and midbrain are clearly visible. "Of course, getting such good images is nice for the human observer, but it's particularly crucial for computational analyses, like tracking cell movements and divisions as we do in the Digital Embryo," says Philipp Keller, now at the Janelia Farm Research Campus of the Howard Hughes Medical Institute in Ashburn, VA, USA.

Breakthrough in understanding cell development

Thu, 01 Jul 2010 03:17:57 PDT

How do plants and animals end up with right number of cells in all the right places? For the first time, scientists have gained an insight into how this process is co-ordinated in plants. An international team, including Cardiff University's School of Biosciences and Duke University in the USA, have linked the process of cell division with the way cells acquire their different characteristics. A protein called Short-root, already known to play a part in determining what cells will become, was also found to control cell division. The researchers report their findings on July 1 in the journal Nature. The discovery may have implications for animals and improve our understanding of what happens when organs are deformed. The research team had already studied the molecular-level events that determine how particular cells in plants develop into different types. These events involve Short-root and another protein, Scarecrow. Researchers also had a good understanding of the factors which allow cells to go through their cycle and divide into two daughter cells. "What was missing was a connection between the two," according to Dr Rosangela Sozzani, a postdoctoral researcher at the Duke Institute for Genome Sciences and Policy, North Carolina, who was lead author of the new study. The research team combined a number of experimental techniques and technologies to produce a dynamic view of the genetic events that Short-root and its partner Scarecrow set into motion within a single type of cell in Arabidopsis plants. They found that at the very same time that cells divide, Short-root and Scarecrow switch on the gene cyclin D6. Cyclin D6 is one of a family of genes that govern cell growth and division. Professor Jim Murray, who led the Cardiff University involvement in the discovery, said: "Not only does this finding have practical significance to our understanding of how plants develop, this may also be a fundamental process which is relevant to animals as well. For example, we already know that cyclin D6 is present in humans. We also know that disruption of this process can lead to tumours or badly-formed organs, so it is vital that we know more about it."

Yale scientists implant regenerated lung tissue in rats

Fri, 25 Jun 2010 03:46:25 PDT

A Yale University-led team of scientists reports that it has achieved an important first step in regenerating fully functional lung tissue that can exchange gas, which is the key role of the lungs. Their paper appears in the June 24 issue of Science Express. Lung disease accounts for around 400,000 deaths each year in the United States. Lung tissue is difficult to regenerate because it does not generally repair or regenerate beyond the microscopic level. The only current way to replace damaged adult lung tissue is to perform lung transplantation, which is highly susceptible to organ rejection and infection and achieves only 10% to 20% survival at 10 years. The Yale team's goal was to see if it was possible to successfully implant tissue-engineered lungs, cultured in vitro, that could serve the lung's primary function of exchanging oxygen and carbon dioxide. They took adult rat lungs and first removed their existing cellular components, preserving the extracellular matrix and hierarchical branching structures of the airways and vascular system to use later as scaffolds for the growth of new lung cells. They then cultured a combination of lung-specific cells on the extracellular matrix, using a novel bioreactor designed to mimic some aspects of the fetal lung environment. Under the fetal-like conditions of the bioreactor, the cells repopulated the decellularized matrix with functional lung cells. When implanted into rats for short intervals of time (45-120 minutes), the engineered lungs exchanged oxygen and carbon dioxide similarly to natural lungs. Lead author Laura Niklason, M.D., Ph.D., professor and vice-chair of the Departments of Anesthesiology and Biomedical Engineering at Yale University and a member of Yale Medical Group, said, "We succeeded in engineering an implantable lung in our rat model that could efficiently exchange oxygen and carbon dioxide, and could oxygenate hemoglobin in the blood. This is an early step in the regeneration of entire lungs for larger animals and, eventually, for humans." The team found that the mechanical characteristics of the engineered lungs were similar to those of native tissues and, when implanted, were capable of participating in gas exchange. "Seeded and cultured epithelium displays remarkable hierarchical organization within the lung matrix, while seeded endothelial cells efficiently repopulate the lung vasculature, Niklason said. The Yale team says this is an important first step, but a great deal more research must be done to see if fully functional lungs can be regenerated in vitro, implanted and sustained in their functioning. Niklason says that for this technology to be applicable to patients, it is likely that years of research with adult stem cells will be needed to repopulate lung matrices and produce fully functional lungs.

Little is understood about alcohol's effect on fetal development, Georgetown researchers say

Wed, 16 Jun 2010 03:17:53 PDT

It's long been known that alcohol use in pregnancy can lead to children with mental retardation and birth defects, but researchers who study fetal alcohol syndrome (FAS) have not made definitive progress on preventing the disorder, detecting it early, or effectively treating it, say researchers from Georgetown University Medical Center. In the issue of Developmental Neuroscience, four first-year medical students at Georgetown University School of Medicine looked into the science and clinical treatment of FAS, and found that although there is much ongoing study, no new medical strategies exist to change the grim outcome that can occur when a fetus is exposed to alcohol. "Although there is a lot of research in the field to determine how alcohol acts on the developing brain, there is not much translation into the clinic," says Sahar Ismail, now a second year medical student. "What surprised us the most was the lack of sensitive and specific diagnostic tools to identify children with FAS, given its prevalence and harmful effects on the child, family, and society." Working with her on the study were medical students Stephanie Buckley, Ross Budacki, and Ahmad Jabbar – each student contributed equally. Their study was a project for the Sexual Development and Reproduction Module under directorship of G. Ian Gallicano, PhD, an associate professor in the Department of Biochemistry and Molecular & Cellular Biology. "This is a very important review, because it combed the research literature on FAS, and concluded that nothing has changed clinically," Gallicano says. "Not every woman who drinks alcohol will have a child with FAS, but because so much remains unknown, women are still advised not to drink any time during pregnancy." Even the question of whether alcohol is a teratogen (a chemical that causes nervous system abnormalities) in the first days or weeks of pregnancy – when a woman may not know she is pregnant – has not been answered fully, says Ismail. Mouse studies show alcohol can have detrimental effects at any stage of fetal development, but "only so much can be concluded about humans from mouse studies," she says. "All we can say now is that there is no safe period to drink." What is clear, however, is that alcohol is the leading cause of preventable mental retardation, the researchers say. FAS is relatively uncommon, affecting .2 to 1.5 live births in every 1,000, but fetal alcohol spectrum disorders (FASD), the less severe form of FAS, is much more common and has a broad range of the same symptoms, they say. "Taken together, both FAS and FASD, are more common than the public realizes but are entirely preventable," Ismail says. The study authors say FAS research shows: Alcohol can have a range of effects on the baby but the fetal brain is particularly at risk because of its complex blood networks. Alcohol is carried from the mother to the child through blood that flows through the umbilical cord. Many factors influence the severity of alcohol's effects, such as maternal genetics, increased maternal age, history of alcohol abuse, poor prenatal care. In the genetics realm, for example, researchers have found that women with a more efficient enzyme that breaks down alcohol have a decreased risk of giving birth to a child with FAS. Alcohol can cause dramatic and irreversible effects on the fetus, such as developmental delay, head and facial irregularities, seizures, hyperactivity, attention deficits, cognitive deficits, learning and memory impairments, poor psychosocial functioning, facial irregularities, and motor coordination deficits. However, the exact developmental phases in which alcohol has these specific effects on the fetus are not entirely known Based on animal studies, consumption of alcohol during the times in animals that correspond to the first 2-3 weeks in human brain growth are detrimental to the brain. But much remains unknown about alcohol's vast mechanism in growth development in humans, most importantly on neurogenesis. It is very important to identify FAS early in life in order to provide the child with the appropriate counseling and guidance as early as possible. But, at this point, there is no treatment or specific and sensitive diagnostic tools to diagnose FAS early in pregnancy or early after birth. Still, the authors say there is ongoing research aimed at devising better diagnostic tools for FAS. These include a panel of genes that are altered in a developing fetus and a kit to examine a newborn's stool for telltale chemicals. Research is underway to find biomarkers that can inform physicians if a pregnant woman is using, or chronically abusing, alcohol. One marker, for example, can be detected in a woman's bloodstream for at least 28 days after alcohol use. Other researchers are studying biomarkers in amniotic fluid that can distinguish between high-risk and low-risk pregnancies. Still, the authors say there is comparatively little investigation on these ideas. Prevention of FAS is an important goal primarily because so little is understood about the adverse effects that alcohol has on the developing fetus. Current prevention programs focus on educating potential mothers at risk for conceiving a child with FAS. However, potentially powerful approaches are being studied in animals, such as the use of agents to protect the developing brain early in pregnancy or to treat brain malformations caused by alcohol exposure. Although there is vast research in this area, clinical strategies to reverse the effects of alcohol are not foreseeable in the near future, the authors say.

Study sheds light into the nature of embryonic stem cells

Wed, 26 May 2010 03:42:58 PDT

New insight into what stem cells are and how they behave could help scientists to grow cells that form different tissues. A study at the University of Edinburgh has shown that embryonic stem cells consist of cells that switch back and forth between precursors of different cell types. This may be linked to their potential to become any cell type in the body. The findings could help scientists catch embryonic stem cells at exactly the right point when they are primed to differentiate into cells that form specific tissues. The study indicates that embryonic stem cells are not a single cell type as previously thought, but comprise a mixture of different cell types from the early embryo that can transform themselves from one type to another. Scientists previously thought that embryonic stem cells were only able to become the embryonic precursors for adult cells, a property known as pluripotency. The researchers have now found that they can also turn into cells associated with the placenta. These cells – known as the primitive endoderm - form the yolk sac that helps provide nutrients to the early embryo. The study, published in the journal PLoS Biology, also shows that embryonic stem cells are able to alternate and transform themselves between cells that create the primitive endoderm and founder embryonic cells, which will go onto form tissues in the body. Although cells in early embryonic development switch back and forth between these two different cells, signals received from surrounding cells and the embryonic environment allow them to quickly fix on becoming one specific cell type. However, in the laboratory embryonic stem cells are grown in a dish away from the embryo and as a result exist in a captured state where their identity does not become fixed. Scientists hope that better understanding of how embryonic stem cells change will enable them create an environment to encourage growth of specific cells. Dr Josh Brickman, from the University's Medical Research Council Centre for Regenerative Medicine, said: "This study changes our view of what embryonic stem cells are and how they behave. Knowing that embryonic stem cells can switch between different founder cell types could help us isolate cells at a point in time when they are primed to become specific cells. This could improve the ability to produce specific cells in the laboratory."

Stem-cell disruption induces skull deformity, UR study shows

Wed, 26 May 2010 03:39:09 PDT

University of Rochester Medical Center scientists discovered a defect in cellular pathways that provides a new explanation for the earliest stages of abnormal skull development in newborns, known as craniosynostosis. Mutations of the WNT and FGF signaling pathways set off a cascade of events that regulate bone formation at the stem cell level, according to the article, published May 25, 2010, in the journal Science Signaling. “Our work contributes to the overall knowledge of the complex system that controls the stem cell fate,” said lead author Wei Hsu, Ph.D., associate professor of Biomedical Genetics and Oncology, and an investigator in the URMC Center for Oral Biology. “More specifically, we found that when a certain type of stem cell goes awry, it leads to a new mechanism for craniosynostosis.” Abnormal head shape due to craniosynostosis affects about one in 2,500 individuals. It can restrict normal brain growth and result in neurodevelopment delays and elevated intracranial pressure. The chief cause, which is already known, is a defect in osteoblasts, the type of cells most important for the making of bone. But until now scientists did not know about a second mechanism for craniosynostosis, a result of a disruption among the earliest forms of cells. Hsu’s lab made the discovery in a study in mice, which have the same skull structure as humans. Eight bones make up the cranium. Initially these individual plates of skull bone are separated by gaps called sutures. In humans the bone plates gradually fuse together, starting at birth and ending in people’s 30s. Two key events takes place during the first 18 months of life that are critical to the proper formation of bone. The first, called intramembranous ossification, is responsible for final development of the skull bones, jaw-bones and collarbones. The other process, called endochondral ossification, controls development of the long bones in the body. During intramembranous ossification a type of stem cell – the mesenchymal cell – must transform into bone-forming osteoblast cells, which deposit the bone matrix. The majority of bone is made after the matrix hardens and entraps the osteoblasts. Hsu’s group discovered that the WNT and FGF signaling pathways determine the fate of the mesenchymal stem cells. And, when these pathways are altered, the mesenchymal cells change to chondrocytes and end up inducing endochondral ossification instead of intramembranous ossification. As a result of this switch, the skull sutures close prematurely. While endochrondal ossification is essential to the development of cartilage and long bones, it has not been shown to play a role in normal skull development. Hsu’s research, therefore, implies that endochondral ossification is a culprit for skull deformities. “There have been some reports of peculiar chondrocytes present in prematurely closed sutures,” Hsu said, “and based on our research it is reasonable to believe they might be there for a reason.” Alterations of the mesenchymal stem cells also have been associated with osteoarthritis, osteoporosis and osteoponia, and mutations in either the WNT or FGF pathways are often detected in skeletal disorders and cancer. Thus, additional research might shed light on the complex properties of stem cells, and how they are transformed during the disease process, Hsu said. The National Institutes of Health funded the research. Co-authors are Takamitsu Maruyama and Anthony J. Mirando from the URMC Department of Biomedical Genetics and Center for Oral Biology; and Chu-Xia Deng, of the NIH

Caltech-led team first to directly measure body temperatures of extinct vertebrates

Tue, 25 May 2010 03:54:46 PDT

Was Tyrannosaurus rex cold-blooded? Did birds regulate their body temperatures before or after they began to grow feathers? Why would evolution favor warm-bloodedness when it has such a high energy cost? Questions like these—about when, why, and how vertebrates stopped relying on external factors to regulate their body temperatures and began heating themselves internally—have long intrigued scientists. Now, a team led by researchers at the California Institute of Technology (Caltech) has taken a critical step toward providing some answers. Reporting online this week in the early edition of the Proceedings of the National Academy of Sciences (PNAS), they describe the first method for the direct measurement of the body temperatures of large extinct vertebrates—through the analysis of rare isotopes in the animals' bones, teeth, and eggshells. "This is not quite like going back in time and sticking a thermometer up a creature's back end," says John Eiler, Robert P. Sharp Professor of Geology and professor of geochemistry at Caltech. "But it's close." Studying the mechanisms of and changes in temperature regulation in long-extinct animals requires knowing what their body temperatures were in the first place. But the only way scientists have had to study temperature regulation in such creatures was to make inferences based on what is known about their anatomy, diet, or behavior. Until now. The technique the team has developed to measure body temperature in extinct vertebrates looks at the concentrations of two rare isotopes—carbon-13 and oxygen-18. "These heavy isotopes like to bond, or clump together, and this clumping effect is dependent on temperature," says Caltech postdoctoral scholar Robert Eagle, the paper's first author. "At very hot temperatures, you get a more random distribution of these isotopes, less clumping. At low temperatures, you find more clumping." In living creatures, this clumping can be seen in the crystalline lattice that makes up bioapatite—the mineral from which bone, tooth enamel, eggshells, and other hard body parts are formed. "When the mineral precipitates out of the blood—when you create bone or tooth enamel—the isotopic composition is frozen in place and can be preserved for millions of years," he adds. In addition, work in Eiler's lab has "defined the relationship between clumping and temperature," says Eagle, "allowing measurements of isotopes in the lab to be converted into body temperature." The method is accurate to within one or two degrees of difference. "A big part of this paper is an exploration of what sorts of materials preserve temperature information, and where," notes Eiler. To do this, the team looked at bioapatite from animals whose form of body-temperature regulation is already known. "We know, for instance, that mammals are warm-blooded; all the bioapatite in their bodies was formed at or near 37 degrees centigrade," says Eagle. After showing proof of concept in living animals, the team looked at those no longer roaming the earth. For instance, the team was able to analyze mammoth teeth, finding body temperatures of between 37 and 38 degrees—exactly as expected. Going back even further in time, they looked at 12-million-year-old fossils from a relative of the rhinoceros, as well as from a cold-blooded member of the alligator family tree. "We found we could measure the expected body temperature of the rhino-like mammal, and could see a temperature difference between that and the alligator relative, of about 6 degrees centigrade," Eagle says. There are, however, limitations to this sort of temperature sleuthing. For one, the information that the technique provides is only a snapshot of a particular time and place, Eiler says, and not a lifelong record. "When we look at tooth enamel, for instance, what we get is a record of the head temperature of the animal when the tooth grew," he notes. "If you want to know what his big-toe temperature was two years later, too bad." And, of course, the technique relies on the quality of the fossils available for testing. While teeth tend to withstand the rigors of burial and time, eggshells are "fragile and prone to recrystallization during burial," says Eiler. Finding good specimens can be difficult. But the rewards are worth the effort. "The main reason to do this sort of work is because gigantic land animals are intrinsically fascinating," Eiler says. "We want to look at where warm-bloodedness emerged, and where it didn't emerge. And this technique will help us to reconstruct food webs. In the distant past, dinosaurs and other large animals were the crown of the food web; we'll be able to figure out how they went about their business." Now that they've pinned down an accurate paleothermometer, the research team has gone further back in time, and has begun looking at the body temperatures of vertebrates about whom less is known. "Before mammals and birds," says Eagle, "we have no good idea what physiology these ancient creatures had." First up? Dinosaurs, of course. "We're looking at eggshells and teeth to see whether the most conspicuous dinosaur species were warm- or cold-blooded," says Eiler. In addition, he says, the researchers would like to apply their approach to better understand some key evolutionary transitions. "Take birds, for instance," Eiler says. "Were they warm-blooded before or after they started to fly? Before or after they developed feathers? We want to take small birds and track their body temperature through time to see what we can learn." Finally, they hope to get a peek at the paleoclimate, through the body-temperature data derived from ancient cold-blooded animals. "With this method, we can track changes in body temperature as a proxy for changes in air or water temperature."

Hammerhead shark study shows cascade of evolution affected size, head shape

Wed, 19 May 2010 03:18:29 PDT

The ancestor of all hammerhead sharks probably appeared abruptly in Earth's oceans about 20 million years ago and was as big as some contemporary hammerheads, according to a new study led by the University of Colorado at Boulder. But once the hammerhead evolved, it underwent divergent evolution in different directions, with some species becoming larger, some smaller, and the distinctive hammer-like head of the fish changing in size and shape, said CU-Boulder Professor Andrew Martin of the ecology and evolutionary biology department. Sporting wide, flattened heads known as cephalofoils with eyeballs bulging at each end, hammerhead sharks are among the most recognizable fish in the world. The bizarre creatures range in length from about 3 feet up to 18 feet and cruise warm waters around the world, Martin said. In the new study, scientists focused on the DNA of eight species of hammerhead sharks to build family "gene trees" going back thousands to millions of generations. In addition to showing that small hammerheads evolved from a large ancestor, the team showed that the "signature" cephalofoils of hammerheads underwent divergent evolution in different lineages over time, likely due to selective environmental pressures, said Martin. The team used both mitochondrial DNA passed from mother to offspring and nuclear DNA -- which is commonly used in forensic identification -- to track gene mutations. The researchers targeted four mitochondrial genes and three nuclear genes, which they amplified and sequenced for the study. "These techniques allowed us to see the whole organism evolving through time," Martin said. "Our study indicates the big hammerheads probably evolved into smaller hammerheads, and that smaller hammerheads evolved independently twice." A paper on the subject was published in this month's issue of Molecular Phylogenetics and Evolution. Led by former CU-Boulder ecology and evolutionary biology undergraduate student Douglas Lim, co-authors included Martin and University of South Florida researchers Philip Motta and Kyle Mara. Lim is currently a student at the University of Colorado School of Medicine. The National Science Foundation funded the study. The researchers sampled hammerheads from across the globe -- including the waters of the southeast United States now under siege by the Gulf oil spill -- as well as Australia, Panama, Hawaii, Trinidad and South Africa. Most of the hammerhead DNA was obtained at local markets, where the peddling of sharks and other fish is common practice. The team sequenced the DNA of the sharks, constructing a "phylogenetic" tree that shows how all of the species are related and when each species originated, said Martin. The hammerhead ancestor probably lived in the Miocene epoch about 20 million years ago. The team found that two divergent lineages of small sharks about 3 to 4 feet long originated independently at separate times in the past. One of the species, the winghead shark, now lives in the warm waters north of Australia and the other, the bonnethead shark, inhabits the Caribbean and tropical eastern Pacific Ocean. One reason for the "incredible shrinking shark" over the eons may be the process of neoteny -- the ability of some adult sharks to retain juvenile traits -- or their ability to achieve sexual maturity at earlier ages, Martin said. "As the sharks became smaller, they may have begun investing more energy into reproductive activities instead of growth." While the cephalofoils appear to provide "lift" to large hammerheads as they cruise through the water -- much like the wing of an airplane -- smaller hammerheads don't appear to gain an advantage in lift, but may gain other attributes. "It looks like they sacrifice locomotion advantages for prey detection and visualization," he said. Another advantage hammerheads may gain from larger cephalofoils is an increased number of electrical sensors in their flattened noses and heads that can detect extremely weak electrical emissions from molecules associated with potential prey. "Hammerheads appear to be able to triangulate on their prey, which is remarkable," said Martin. Small sharks are highly variable in the size and shape of their cephalofoils, said Martin. The winghead shark, for example, has a laterally expanded head that is about half the size of its roughly 4-foot body length. At the other end of the spectrum is the bonnethead shark, about 3 feet long but which has the smallest cephalofoil of all hammerhead species -- a protrusion that resembles the head of a shovel, Martin said. Martin said that hammerheads are an ideal biological study subject in part because of some important similarities to humans. Both have slow growth rates, mature late in life, give live birth and have relatively few offspring. While hammerheads may have a dozen or more pups, other oceanic fish regularly lay millions of eggs. Hammerheads generally live for about 30 years, he said. While hammerhead sharks appear intimidating, attacks on humans are extremely rare, said Martin. Hammerheads have relatively small mouths facing downward that are used to grab food like fish, shellfish, shrimp, squid, octopuses and stingrays. "If you see a hammerhead, I'd say grab your camera and jump into the water," said Martin. "Hammerheads are special fish, and there is nothing that remotely resembles them anywhere on the planet," said Martin. Unfortunately, hammerheads -- like most shark species -- are on the decline. In addition to being overfished, sharks often are the victims of a technique known as finning, in which fishermen catch them, cut off their fins for use in delicacy soups, and return them to the water to die, Martin said. Shark meat also is used for fertilizer and to make pet food. There currently are 233 shark species on the International Union for the Conservation of Nature's "Red List of Threatened Species," and 12 shark species are classified as critically endangered. A study led by Virginia Tech showed the great hammerhead, scalloped hammerhead and smooth hammerhead species declined by an average of 90 percent from 1981 to 2005. "Their situation is generally pretty dire," Martin said. A 2005 study by Martin and his colleagues on scalloped hammerheads indicated females tend to breed in the specific ocean regions where they were born, while males tended to move around more widely. A previous study by Martin's team also showed that male great white sharks roam Earth's oceans much more widely than females, a finding with implications for future conservation strategies for the storied and threatened fish.

New information on the development of the brain

Sat, 15 May 2010 04:34:22 PDT

With their French colleagues, researchers at the University of Helsinki have found a mechanism in the memory centre of newborn that adjusts the maturation of the brain for the information processing required later in life. The study was published this week in an American science magazine The Journal of Neuroscience. The brain cells in the brain of a newborn are still quite loosely interconnected. In the middle of chaos, they are looking for contact with each other and are only later able to operate as interactive neural networks. Many cognitive operations, such as attention, memory, learning and certain states of sleep are based on rhythmic interactions of neural networks. For a long time the researchers have been interested in finding the stage in the development of the brain in which the functional characteristics and interconnections are sufficiently developed for these subtle brain functions. Key players in this maturation process include a type of nerve cells called interneurones, and recent research sheds light on their functional development. The researchers have noticed that the activeness of the interneurones change dramatically during early development. In the memory centre of the brain they found a mechanism which adjusts changes in the activeness of interneurones. The interneurones nerve cells are kind of controller cells. In the nervous system of a newborn they promote the creation of nerve cell contacts, and on the other hand they prevent premature rhythmic activity of neural networks. During development the controlling role will change, and the result is that the neural network becomes more efficiently rhythmic. This can be seen, for example, in the strengthening of the EEG signal during sleep. The mechanism adjusting the activity of the interneurones is related to the development phase which prepares the brain to process and handle information needed later in life. The finding may also offer more detailed means to intervene in the electric disorders of developing neural networks, such as epilepsy.

Scripps Research team provides groundbreaking new understanding of stem cells

Mon, 03 May 2010 03:29:48 PDT

In findings that could one day lead to new therapies, researchers from The Scripps Research Institute have described some striking differences between the biochemistry of stem cells versus mature cells. The study, led by Scripps Research Associate Professor Sheng Ding and Senior Director of the Scripps Research Center for Mass Spectrometry Gary Siuzdak, was published in an advance, online edition of the prestigious journal Nature Chemical Biology on May 2, 2010. In the research, the team used a unique approach to better understand stem cells, which have the ability to change or "differentiate" into adult cell types (such as hair cells, skin cells, nerve cells). Understanding how stem cells mature opens the door for scientists and physicians to manipulate the process to meet the needs of patients, potentially treating such intractable conditions as Parkinson's disease and spinal injury. "In the past, scientists trying to understand stem cell biology focused on genes and proteins," said Ding. "In our study, we looked at stem cell regulation in a different way—on the biochemical level, on a functional level. With metabolomics profiling, we were able to look at naturally occurring small molecules and how they control cell fate on a completely different level." The new paper describes parts of the stem cell "metabolome"— the complete set of substances ("metabolites") formed in metabolism, including all naturally occurring small molecules, biofluids, and tissues. The scientists then compared this profile to those of more mature cells, specifically of nerve cells and heart cells. When the results were tallied, the scientists had found about 60 previously unidentified metabolites associated with the progression of stem cells to mature cells, as well as an unexpected pattern in the chemistry that mirrored the cells' increasing biological maturity. Ripe for Discovery The study of metabolomics is relatively new, having emerged only over the past decade or so. "One of the most interesting aspects of metabolomics is how little we know," commented Siuzdak. "We don't know what the vast majority of metabolites are, or what they do. It is an area ripe for discovery." Research in metabolomics is made possible by a variety of special techniques and equipment. In the current study, the team used liquid chromatography-mass spectrometry (LCMS), which draws on two more traditional techniques to provide scientists with the ability to chemically analyze virtually any molecular species. The group then analyzed the resulting data using an open-access bioinformatics platform XCMS, a now-popular technique developed by Siuzdak and colleagues described in a 2006 article in the journal Analytical Chemistry. The XCMS software allows researchers to identify and assess metabolite and peptide features that show significant change between sample groups—in this case mouse stem cells versus mature cells. The most difficult part of untargeted metabolomics studies is analyzing the results and characterizing metabolites, according to Research Associate Oscar Yanes of the Siuzdak lab, the new paper's first author. Nevertheless, Yanes shifted though the data on stem cells and identified an unexpected pattern: stem cell metabolites had highly unsaturated structures compared with mature cells, and levels of highly unsaturated molecules decreased as the stem cells matured. Highly unsaturated molecules, which contain little hydrogen, can easily react and change into many other different types of molecules. "The study reveals an astounding cellular strategy," commented Yanes. "The capacity of embryonic stem cells to generate a whole spectrum of cell types characteristic of different tissues (a phenomenon referred to as plasticity) is mirrored at the metabolic level." "We were not expecting these results," said Siuzdak, "although in retrospect it makes sense that stem cells (which can form almost any cell) have metabolites that are chemically flexible." Confirming their observations, the researchers found that by chemically blocking the usual route to saturation—oxidation—they were able to prevent stem cells' normal progress into mature heart and nerve cells. Conversely, when specific oxidized metabolites were introduced into the culture, stem cell differentiation was promoted. Ding notes the study also provides a new perspective on fatty acids similar to those found in fish oil and other nutriceuticals. "In the past, people focused on the fact that fatty acids were important to create cell membranes, the scaffolding of our cells," said Ding. "But in our study, we show that different fatty acids don't just play a role in constituting cell membranes, but also have functions in directing cell fate."

New method reveals how individual nerve cells process visual input

Fri, 30 Apr 2010 03:38:01 PDT

Pioneering a novel microscopy method, neuroscientist Arthur Konnerth and colleagues from the Technische Universitaet Muenchen (TUM) have shown that individual neurons carry out significant aspects of sensory processing: specifically, in this case, determining which direction an object in the field of view is moving. Their method makes it possible for the first time to observe individual synapses, nerve contact sites that are just one micrometer in size, on a single neuron in a living mammalian brain. Focusing on neurons known to play a role in processing visual signals related to movement, Konnerth's team discovered that an individual neuron integrates inputs it receives via many synapses at once into a single output signal -- a decision, in essence, made by a single nerve cell. The scientists report these results in the latest issue of the journal Nature. Looking ahead, they say their method opens a new avenue for exploration of how learning functions at the level of the individual neuron. When light falls on the retina of the human eye, it hits 126 million sensory cells, which transform it into electrical signals. Even the smallest unit of light, a photon, can stimulate one of these sensory cells. As a result, enormous amounts of data have to be processed for us to be able to see. While the processing of visual data starts in the retina, the finished image only arises in the brain or, to be more precise, in the visual cortex at the back of the cerebrum. Scientists working with Arthur Konnerth -- professor of neurophysiology at TUM and Carl von Linde Senior Fellow at the TUM Institute for Advanced Study -- are interested in a certain kind of neuron in the visual cortex that fires electrical signals when an object moves in front of our eyes -- or the eyes of a mouse. When a mouse is shown a horizontal bar pattern in motion, specific neurons in its visual cortex consistently respond, depending on whether the movement is from bottom to top or from right to left. The impulse response pattern of these "orientation" neurons is already well known. What was not previously known, however, is what the input signal looks like in detail. This was not easy to establish, as each of the neurons has a whole tree of tiny, branched antennae, known as dendrites, at which hundreds of other neurons "dock" with their synapses. To find out more about the input signal, Konnerth and his colleagues observed a mouse in the act of seeing, with resolution that goes beyond a single nerve cell to a single synapse. They refined a method called two-photon fluorescence microscopy, which makes it possible to look up to half a millimeter into brain tissue and view not only an individual cell, but even its fine dendrites. Together with this microscopic probe, they conducted electrical signals to individual dendrites of the same neuron using tiny glass pipettes (patch-clamp technique). "Up to now, similar experiments have only been carried out on cultured neurons in Petri dishes," Konnerth says. "The intact brain is far more complex. Because it moves slightly all the time, resolving individual synaptic input sites on dendrites was extremely difficult." The effort has already rewarded the team with a discovery. They found that in response to differently oriented motions of a bar pattern in the mouse's field of vision, an individual orientation neuron receives input signals from a number of differently oriented nerve cells in its network of connections but sends only one kind of output signal. "And this," Konnerth says, "is where things get really exciting." The orientation neuron only sends output signals when, for example, the bar pattern moves from bottom to top. Evidently the neuron weighs the various input signals against each other and thus reduces the glut of incoming data to the most essential information needed for clear perception of motion. In the future, Konnerth would like to extend this research approach to observation of the learning process in an individual neuron. Neuroscientists speculate that a neuron might be caught in the act of learning a new orientation. Many nerve endings practically never send signals to the dendritic tree of an orientation neuron. Presented with visual input signals that represent an unfamiliar kind of movement, formerly silent nerve endings may become active. This might alter the way the neuron weighs and processes inputs, in such a way that it would change its preferred orientation; and the mouse might learn to discern certain movements better or more rapidly. "Because our method enables us to observe, down to the level of a single synapse, how an individual neuron in the living brain is networked with others and how it behaves, we should be able to make a fundamental contribution to understanding the learning process," Konnerth asserts. "Furthermore, because here at TUM we work closely with physicists and engineers, we have the best possible prospects for improving the spatial and temporal resolution of the images."

How chimps deal with death: Studies offer rare glimpses

Tue, 27 Apr 2010 03:49:41 PDT

Two studies in the April 27th issue of Current Biology, a Cell Press publication, offer rare glimpses into the ways that chimpanzees deal with the deaths of those closest to them. In one case, researchers describe the final hours and moment of death of an older female chimp living in a small group at a UK safari park as captured on video. In the other, researchers observed as two chimpanzee mothers in the wild carried their infants' mummified remains for a period of weeks after they were lost to a respiratory epidemic. "Several phenomena have at one time or another been considered as setting humans apart from other species: reasoning ability, language ability, tool use, cultural variation, and self-awareness, for example, but science has provided strong evidence that the boundaries between us and other species are nowhere near to being as clearly defined as many people used to think," said James Anderson of the University of Stirling in reference to his observations of the safari park chimps. "The awareness of death is another such psychological phenomenon. The findings we've described, along with other observations of how chimpanzees respond to dead and dying companions, indicate that their awareness of death is probably more highly developed than is often suggested. It may be related to their sense of self-awareness, shown through phenomena such as self-recognition and empathy towards others.".......> Full story

Singapore Scientists Make Breakthrough Findings on Early Embryonic Development

Sun, 25 Apr 2010 04:45:29 PDT

Scientists at the Genome Institute of Singapore (GIS) have recently generated significant single cell expression data crucial for a detailed molecular understanding of mammalian development from fertilization to embryo implantation, a process known as the preimplantation period. The knowledge gained has a direct impact on clinical applications in the areas of regenerative medicine and assisted reproduction. This study, published in Developmental Cell on April 20, 2010, is the first of its kind to apply single cell gene expression analysis of many genes to hundreds of cells in a developmental system. Using the new BioMark microfluidic technology and the mouse preimplantation embryo as a model, the scientists were able to study the expression of 48 genes from individual cells and applied this to analyze over 600 individual cells from the 1-cell to the 64-cell stage of preimplantation development. This high throughput single cell research methodology provides the scientists with the ability to detect dynamic patterns in cellular behaviour, which is unprecedented in the field. Significantly, the findings of the study resolves some of the arguments pertaining to cellular differentiation events and places fibroblast growth factor signalling as the primary event in the later cell fate decisions........> Full story

Newly discovered RNA steers brain development

Thu, 15 Apr 2010 03:35:01 PDT

How does the brain work? This question is one of the greatest scientific mysteries, and neurobiologists have only recently begun to piece together the molecular building blocks that enable human beings to be "thinking" animals. One fundamental property of the mammalian brain is that it continues to develop after birth, and one of the biggest drivers of the formation of new links between neurons is experience. Every time a baby sticks her finger on a pin or laughs in response to an adult's embellished gestures, a cascade of genetic activity is triggered in her brain that results in new, and perhaps even lifelong, synaptic connections. New research from the lab of Michael Greenberg, Nathan Marsh Pusey professor and chair of neurobiology at HMS, in collaboration with bioinformatics specialist and neuroscientist Gabriel Kreiman, assistant professor of ophthalmology at Children's Hospital, Boston, has found that a particular set of RNA molecules widely considered to be no more than a genomic oddity are actually major players in brain development—and are essential for regulating the process by which neurons absorb the outside world into their genetic machinery. "This discovery may inform disorders of cognition such as autism spectrum disorders," says Greenberg. "It's incredibly important to know all about the brain's genetic regulatory mechanisms in order to think more deeply about how to develop therapies for treating these sorts of conditions."......> Full story

New tool developed for DNA research

Wed, 07 Apr 2010 03:40:04 PDT

Luminescent markers are an indispensable tool for researchers working with DNA. But the markers are troublesome. Some tend to destroy the function and structure of DNA when inserted. Others emit so little light, that they can barely be detected in the hereditary material. So researchers have been asking for alternative markers.
Now a PhD student at Department of Chemistry at the University of Copenhagen has developed a tool in collaboration with researchers at Chalmers Technical University, which could solve both problems: A tool that you might call a molecular gauge.PhD student Soren Preus has investigated the properties of the two luminescent so called DNA base analogues tCO and tCnitro trying to determine whether they could measure the structure of DNA without disrupting it. His scrutiny has shown that the function of DNA is unimpeded by the insertion of the molecular gauge. And even better: One base analogue is very efficient at emitting light, and the other very good at receiving it. And because you can provoke transport of light-energy between the two luminescent markers they are usable for a measuring technique known as FRET or Fluorescence Resonance Energy Transfer......> Full story

Notch Protein: Opposing Functions of Key Molecule in Development of Organisms

Mon, 05 Apr 2010 03:47:19 PDT

Scientists headed by ICREA researcher Marco Milán, at the Institute for Research in Biomedicine (IRB Barcelona), reveal a surprising new function of Notch protein that contrasts with the one known to date. Found in the cell membrane, this protein activates a signalling pathway that regulates the expression of genes that make the cell divide, grow, migrate, specialise or die. Notch activity is required for the correct development of organisms and for the maintenance of tissues in adults. When Notch acts at an incorrect time or in an incorrect context, it can give rise to the generation of tumours, among these leukaemia, breast cancer, colon cancer, skin cancer, lung cancer and renal carcinomas. "The same pathways responsible for the development and growth of organisms are involved in the transformation of healthy cells into cancerous ones," says Marco Milán, so "all new data on the modulation of Notch activity, the first step in the chain, may be relevant for the design of effective therapies." Marco Milán's group has now discovered that the presence of Notch proteins in the cell membrane is also required to inactivate the pathway.......> Full story

Chemical competition: Research identifies new mechanism regulating embryonic development

Wed, 10 Mar 2010 03:45:41 PDT

A Princeton University-led research team has discovered that protein competition over an important enzyme provides a mechanism to integrate different signals that direct early embryonic development. The work suggests that these signals are combined long before they interact with the organism's DNA, as was previously believed, and also may inform new therapeutic strategies to fight cancer. The fought-over enzyme, known as the mitogen-activated protein kinase (MAPK), is found in all complex organisms, ranging from yeast to humans. MAPK signaling pathways, or chemical networks that involve the enzyme, are critical for normal development, and defects in these pathways can lead to severe developmental disorders and cancer. During early embryonic development, a single undifferentiated cell becomes a complex and highly specialized organism containing a variety of different cell types arranged in very precise patterns.......> Full story

Model may offer better understanding of embryonic development

Wed, 10 Mar 2010 03:42:48 PDT

A mathematical model developed at Purdue University can predict complex signaling patterns that could help scientists determine how stem cells in an embryo later become specific tissues, knowledge that could be used to understand and treat developmental disorders and some diseases. During embryonic development, proteins attach to cell receptors and start a cascade of reactions. Understanding those reactions is difficult, however, because feedback signals go back out to the proteins or other molecules along the cascade, constantly changing the reaction pattern. The outcomes of those reactions and the feedback mechanisms - or inputs - are known because they can be observed, but how the inputs lead to the outputs isn't understood. "We want to understand how stem cells become tissue-specific so that we can manipulate that process to create cells that could be used to treat injuries and diseases," said David Umulis, a Purdue assistant professor of agricultural and biological engineering. "Using a model approach, we can simulate these complex signaling patterns to get a better handle on the process." .......> Full story

Roving ‘Sonic hedgehog’ gene may change scientists’ understanding of limb growth

Wed, 10 Mar 2010 03:24:31 PDT

Sonic hedgehog, a gene that plays a crucial rule in the positioning and growth of limbs, fingers and toes, has been confirmed in an unexpected place in the embryos of developing mice — the layer of cells that creates the skin. Named for a video game character, Sonic hedgehog describes both a gene and the protein it produces in the body. Its study is important to increase understanding of human birth defects. It was thought to be exclusively present in the cell layer that builds bone and muscle, called the mesoderm. But University of Florida Genetics Institute researchers have discovered that Sonic hedgehog is also at work in mice limb buds in what is known as the ectoderm, the cell layer that gives rise to the skin in vertebrates.......> Full story

Canine morphology: Hunting for genes and tracking mutations

Tue, 02 Mar 2010 03:44:22 PDT

Why do domestic dogs vary so much in size, shape, coat texture, color and patterning? Study of the dog genome has reached a point where the molecular mechanisms governing such variation across mammalian species are becoming understood. In an essay published in the March 2, 2010 issue of PLoS Biology, National Human Genome Research Institute (NHGRI) researchers discuss advances in understanding the genomic mechanisms controlling canine morphology. There are more than 300 dog breeds in the world, including 170 recognized by the American Kennel Club. All are members of the species Canis familiaris. The authors review unique features of the canine genome that make it particularly good for genetic studies, and they show that breeds can be divided into five major groups derived from groups of ancient forebears. "Study of variation in the dog species......> Full story

Genes associated with early tooth development identified

Fri, 26 Feb 2010 04:02:00 PDT

Several genes affect tooth development in the first year of life, according to the findings of a study conducted at Imperial College London, the University of Bristol in the UK and the University of Oulu in Finland. The research, published February 26 in the open-access journal PLoS Genetics, shows that the teeth of babies with certain genetic variants tend to appear later and that these children have a lower number of teeth by age one. Additionally, those children whose teeth develop later are more likely to need orthodontic treatment. The research, led by Professor Marjo-Riitta Jarvelin of the School of Public Health at Imperial College London, scanned the entire genetic code of 6,000 individuals from the Northern Finland Birth Cohort (NFBC1966) and the Avon Longitudinal Study on Parents and Children (ALSPAC), UK, both of which track participants from mother's early pregnancy until adulthood. The researchers identified five genes associated with both the first tooth eruption and the number of teeth at age one. They also found that one of the identified genes was associated with a 35% increased risk of requiring orthodontic treatment by the age of 30 years.......> Full story

Unpacking condensins' function in embryonic stem cells

Tue, 23 Feb 2010 04:11:09 PDT

Regulatory proteins common to all eukaryotic cells can have additional, unique functions in embryonic stem (ES) cells, according to a study in the February 22 issue of the Journal of Cell Biology. If cancer progenitor cells—which function similarly to stem cells—are shown to rely on these regulatory proteins in the same way, it may be possible to target them therapeutically without harming healthy neighboring cells. The new study, by Thomas Fazzio and Barbara Panning (University of California, San Francisco) finds that two chromatin regulatory proteins essential for ES cell survival, Smc2 and Smc4, together form the heart of the condensin complexes that promote chromosome condensation in mitosis and meiosis. Because somatic cells lacking condensins continue to proliferate with relatively minor mitotic defects, Fazzio and Panning wondered why ES cells died in the absence of Smc2 or Smc4......> Full story

Chubby birds get there faster

Thu, 18 Feb 2010 03:40:25 PDT

Small migratory birds, like the garden warbler, must make stopovers on their journeys to their breeding grounds. When they have crossed extensive ecological barriers, such as deserts or oceans, they must land to replenish their fat reserves. A researcher from the Max Planck Institute for Ornithology in Seewiesen and a team of Italian colleagues measured the duration of the stopovers made by garden warblers on an island off the Italian coast. There they observed that fat birds usually move on the night of their arrival, while thin birds interrupt their journey for an average of almost two days......> Full story

New study suggests stem cells sabotage their own DNA to produce new tissues

Tue, 16 Feb 2010 03:56:41 PDT

A new study from the Ottawa Hospital Research Institute (OHRI) and the University of Ottawa suggests that stem cells intentionally break their own DNA as a way of regulating tissue development. The study, published in Proceedings of the National Academy of Science (PNAS), could dramatically change how researchers think about tissue development, stem cells and cancer. Human cells contain 46 strands of DNA that code for all our genes. Certain chemicals and UV light can break these strands into pieces, a process that has traditionally been considered a bad thing, leading to cell death or diseases such as cancer if the damage is not repaired quickly.......> Full story

Scientists Discover Molecular Pathway For Organ Tissue Regeneration And Repair

Tue, 16 Feb 2010 03:20:28 PDT

Scientists have discovered a molecular pathway that works through the immune system to regenerate damaged kidney tissues and may lead to new therapies for repairing injury in a number of organs. The findings, reported in this week's Proceedings of the National Academy of Sciences (PNAS), come from collaborative research led by Cincinnati Children's Hospital Medical Center and the Brigham & Women's Hospital of Harvard Medical School.......> Full story

Virus-free technique enables scientists to easily make stem cells pluripotent, moving closer to possible human therapies

Wed, 10 Feb 2010 08:22:26 PDT

Tiny circles of DNA are the key to a new and easier way to transform stem cells from human fat into induced pluripotent stem cells for use in regenerative medicine, say scientists at the Stanford University School of Medicine. Unlike other commonly used techniques, the method, which is based on standard molecular biology practices, does not use viruses to introduce genes into the cells or permanently alter a cell's genome. Full story

Cell fate in the balance

Mon, 08 Feb 2010 14:53:32 PDT

Differentiation of an embryonic stem cell (ESC) requires both suppression of self-renewal and activation of a specific differentiation pathway. The small non-coding RNAs known as microRNAs (miRNAs) are emerging as important players in the orchestration of cell fate. Now the prominent miRNA, let-7, is shown to be responsible for suppressing the self-renewal program in ESCs. This inhibition can be reversed by a family of ESC-regulating (ESCC) miRNAs that regulate the cell cycle, suggesting that the interplay between let-7 and ESCC miRNAs provides a mechanism capable of dictating cell fate. Full story

Gene That Improves Quality Of Reprogrammed Stem Cells Identified By Singapore Scientists

Mon, 08 Feb 2010 03:40:00 PDT

Scientists from the Genome Institute of Singapore (GIS), a biomedical research institute of the Agency for Science, Technology and Research (A*STAR), have discovered a genetic molecule, called Tbx3, which greatly improves the quality of stem cells that have been reprogrammed from differentiated cells (stem cells reprogrammed from differentiated cells are known as induced pluripotent stem cells or iPS cells). The study was published on 7 February 2010 in the prestigious journal Nature. Using a series of genomic experiments that examines the process of reprogramming, the scientists discovered that Tbx3 significantly improved the quality of the iPS cells created. Interestingly, this gene is also crucial for many aspects of early developmental processes in mammals........> Full story