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Week Ending FRIDAY January 8 , 2010---------------------News Archive / Current News
The Visible Embryo maintains a searchable database of artcles published since 2007

Protein Critical for Activating DNA Replication

Scientists at Cold Spring Harbor Laboratory (CSHL) have discovered how a protein long known to be an essential activator of DNA replication actually triggers this process in cells.

The protein, called DDK (for Ddf4-dependent protein kinase), is an enzyme that attaches phosphate molecules to other proteins to modify their activity. The CSHL team has found that DDK performs this operation, called phosphorylation, on a protein called Mcm4, specifically within a domain that acts as a built-in brake to prevent the DNA double helix from being unwound. The phosphorylation by DDK releases this brake, thus initiating the replication of unwound DNA strands.

"As DDK is often deregulated in human cancers, this new understanding of its role in DNA replication may help shape the development of new cancer therapies," explains CSHL President Bruce Stillman, Ph.D., who co-authored the study with colleague Yi-Jun Sheu, Ph.D. "Indeed recent studies have identified DDK inhibitors and they are now in clinical trials." The report was published in Nature on 7th January.

In multicellular organisms, the duplication of the DNA in chromosomes starts at multiple sites, called origins, within the genome. For the genome to retain its integrity each time a cell divides, it's crucial that each origin "fires," or becomes active, just once and only during a timeframe in the cell cycle known as the S-phase.

A large number of proteins cooperate and interact with military precision to ensure this "once-only" condition. First, a group of proteins cluster at each origin site to form a pre-replication complex or pre-RC. The phosphorylation of some pre-RC components by DDK in turn recruits other proteins to these pre-RCs, converting them into pre-initiation complexes, or pre-ICs.

Over the last 15 years, Dr. Stillman's group has systematically uncovered many of the pre-RC and pre-IC proteins, and meticulously catalogued when and where each protein interacts with its collaborators. Having found out previously that DDK targets a multi-subunit protein complex called MCM, they've now narrowed down DDK's binding site to a domain within one of the subunits, Mcm4, where it phosphorylates a series of amino acids—protein building blocks—that otherwise inhibit Mcm4 from functioning.

The discovery of this self-inhibitory activity within Mcm4 and the finding that DDK is required to overcome it was a surprise, according to the authors. They propose that such complexity might have evolved in response to the importance of precision and accuracy of DNA replication.

"Although this is the only essential role for DDK under normal conditions, we have found that DDK takes on another task when the cell suffers DNA damage," says Dr. Stillman. In this hazardous situation, he and his colleague found, DDK activates an S-phase checkpoint mechanism that halts the DNA copying process and initiates DNA repair.

"This discovery of these distinct functions of DDK represents a key piece of the puzzle of how the initiation of DNA replication is coordinated and controlled by kinase proteins," says Dr. Stillman.

Size Zero Is Bad News For Bones

New research from the Children of the 90s project suggests that teenage girls who are too thin may be putting their bones at risk.

It has long been known that the amount of muscle in the body is related to bone growth, but this new study shows that fat mass is also important in building bone, particularly in girls.

The researchers looked at over 4,000 young people aged 15, using sophisticated scanning techniques (DXA and pCQT) that calculated the shape and density of their bones, as well as how much body fat they had.

Those with higher levels of fat tended to have larger and thicker bones. This connection was particularly marked in the girls

For example, one key measure showed that in girls, a five kilogram increase in fat mass was associated with an eight per cent increase in the circumference of the tibia (lower leg bone).

As girls tend to have higher levels of fat than boys, even when they are normal weight, these findings suggest that fat plays an important role in female bone development.

Building strong bones in youth is particularly important for women, as they are three times more likely to develop osteoporosis, and they suffer two to three times more hip fractures than men.

Jon Tobias, Professor of Rheumatology and leader of the research, said: “There is a good deal of pressure on teenage girls to be thin, but they need to be aware that this could endanger their developing skeleton and put them at increased risk of osteoporosis.

“Many people think that exercise is the key to losing weight and building strong bones at the same time – but this may only be true up to a point. If you do a good deal of low impact exercise, such as walking, you will certainly lose fat but you may not be able to put enough stress on the bones to build them significantly. To offset the detrimental effect of fat loss on your bones, it may be important to include high impact exercise as well, such as running or jumping.”

Found: Mechanism to Prevent/Treat Deadly Peroxisome Diseases

University of Alberta medical researchers have made a major breakthrough in understanding a group of deadly disorders that includes the disease made famous in the movie Lorenzo's Oil.

Because this group of diseases is inherited, the discovery could help in screening carriers and lead to prevention or an effective treatment.

Richard Rachubinski, in the Faculty of Medicine & Dentistry, is an expert on structures in cells called peroxisomes which are involved in breaking down fatty acids. They are vital for humans. Babies born with a peroxizome disorder do not typically survive longer than a year because of impaired metabolism.

In his latest study, Rachubinski found another clue in the search to understand the peroxisome and the disorders caused by its malfunction. He and his team discovered that a protein family thought to be only involved in the early stages of making peroxisomes is actually crucial in ensuring peroxisomes transfer into other cells after they divide.

All cells of the body must have peroxisomes to survive. These proteins are found in every living being, so they provide a universal mechanism not only for how peroxisomes are made but also for how peroxisomes are maintained in cells to keep them alive as they divide.

One peroxisome disorder is adrenoleukodystrophy, or ALD, the disease a boy named Lorenzo Odone suffered from. His parents' fight for a cure was made into the movie.

30,000-year-old Child's Teeth Shed New Light on Human Evolution

The teeth of a 30,000-year-old child are shedding new light on the evolution of modern humans, thanks to research from the University of Bristol published this week in PNAS.

The teeth are part of the remarkably complete remains of a child found in the Abrigo do Lagar Velho, Portugal and excavated in 1998-9 under the leadership of Professor João Zilhão of the University of Bristol.

Classified as a modern human with Neanderthal ancestry, the child raises controversial questions about how extensively Neanderthals and modern human groups of African descent interbred when they came into contact in Europe.

‘Early modern humans’, whose anatomy is basically similar to that of the human race today, emerged over 50,000 years ago and it has long been the common perception that little has changed in human biology since then.

When considering the biology of late archaic humans such as the Neanderthals, it is thus common to compare them with living humans and largely ignore the biology of the early modern humans who were close in time to the Neanderthals.

With this in mind, an international team, including Professor Zilhão, reanalysed the dentition of the Lagar Velho child (all of its deciduous – milk – teeth and almost all of its permanent teeth) to see how they compared to the teeth of Neanderthals, later Pleistocene (12,000-year-old) humans and modern humans.

Employing a technique called micro-tomography which uses x-rays to create cross-sections of 3D-objects, the researchers investigated the relative stages of formation of the developing teeth and the proportions of crown enamel, dentin and pulp in the teeth.

They found that, for a given stage of development of the cheek teeth, the front teeth were relatively delayed in their degree of formation. Moreover, the front teeth had a greater volume of dentin and pulp but proportionally less enamel than the teeth of recent humans.

The teeth of the Lagar Velho child thus fit the pattern evident in the preceding Neanderthals, and contrast with the teeth of later Pleistocene (12,000-year-old) humans and living modern humans.

Professor Zilhão said: “This new analysis of the Lagar Velho child joins a growing body of information from other early modern human fossils found across Europe (in Mladeč in the Czech Republic, Pes¸tera cu Oase and Pes¸tera Muierii in Romania, and Les Rois in France) that shows these ‘early modern humans’ were ‘modern’ without being ‘fully modern’. Human anatomical evolution continued after they lived 30,000 to 40,000 years ago.”


THURSDAY January 7, 2010---------------------News Archive / Current News
The Visible Embryo maintains a searchable database of artcles published since 2007

Triggering the Embryo to Develop

The DNA contained within each one of our cells is exactly the same, yet produces different results – skin cells, heart cells, brain cells – performing very different functions. Now, a protein complex has been found that "erases" the instructions on sperm DNA - allowing embryos to develop into the different cell types needed for our body's configuration.



The ultimate fate of cells is encoded not just in the DNA, but in specific chemical modifications that overlay the DNA structure. These modifications, called epigenetic markers, are stable and consistently carried in our genomes - except when the sperm meets the egg. Then they are erased completely.

Researchers at the UNC School of Medicine have discovered a protein complex that appears to play a significant role in erasing epigenetic instructions in sperm DNA. The complex essentially creates a blank slate for the differentiation of all cell types in a new embryo.

The protein complex – called elongator – might prove valuable in changing cell fate, such as converting cancer cells to normal cells. It may be able to reactivate tumor suppressor genes by removing the epigenetic modifiers that often prevent tumor suppressors from curbing the proliferation of cancer cells.

The discovery may also have implications for stem cell research by providing a tool to quickly reprogram adult cells to embryonic stem cells. The results of the study appear on-line in the Jan. 6, 2010 issue of the journal Nature.

"The implications of such research have always been clear, and that is why for years researchers have tried to identify a factor responsible for erasing these epigenetic markers," said senior author Yi Zhang, Ph.D., Howard Hughes Medical Institute Investigator and Kenan Distinguished Professor of biochemistry and biophysics at UNC. He is also a member of the UNC Lineberger Comprehensive Cancer Center.

Epigenetic markers are chemical tags attached to the genomes of each cell, determining which genes will be turned on or off, thus determining what cell type will be produced. One way this comes about is through DNA methylation, a process by which methyl groups attach to cytosines - in the Watson-Crick DNA double helix model, a Cytosine forms three hydrogen bonds with Guanine - and alter the pattern into becomming a particular cell.

During fertilization, the father's genome derived from the sperm is demethylated quickly before cell division, while the maternal genome is demethylated passively.

"Several previous studies have identified factors that can perform gene-specific DNA demethylation, but ours is the first to link a protein complex to global DNA demethylation that correlates to germ cell to somatic cell transition," Zhang said.

The scientists set out to discover the factor that orchestrates this demethylation. By creating a green fluorescent tag that has affinity to non-methylated DNA, they were able to "watch" the demethylation process under the microscope.

After they "knocked down" possible candidate genes in mouse zygotes, only the loss of the elongator gene prevented the accumulation of the fluorescent tags in the paternal genome, indicating that it was needed for demethylation to occur.

Zhang says the identification of this gene could have implications for stem cell research, which up until this point has only been possible using two major approaches. One way scientists reprogram adult cell nuclei is by transferring them into an egg, which contains factors that wipe away all epigenetic markers. The other way is to express several critical stem cell factors in adult somatic cells, which coax the cells back to their virginal stem cell state. The first approach involves the use of embryos, which raises ethical concerns; the second involves retroviruses, which can cause cancer and are thus not considered safe.

"But there could be another way," says Zhang. "Many of the genes that are active in stem cells are not active in adult cells because they are methylated. If elongator can catalyze global demethylation, it could be the critical ingredient to these reprogramming cocktails, enabling us to generate stem cells quickly and safely."

Now Zhang and his colleagues are conducting more experiments to prove that the protein does possess true demethylase activity. It will be a difficult task, Zhang says, because they still do not know all the subunits of the elongator protein complex. At the same time, the researchers are actively investigating the effects of the protein on reprogramming and its implications for furthering stem cell research.

Silencing Brain Cells Using Colored Light

New tools show potential for treating brain disorders.

Neuroscientists at MIT have developed a powerful new class of tools to reversibly shut down brain activity using different colors of light. When targeted to specific neurons, these tools could potentially lead to new treatments for the abnormal brain activity associated with disorders such as chronic pain, epilepsy, brain injury, and Parkinson's disease.

The tools work on the principle that such disorders might be best treated by silencing, rather than stimulating, brain activity. These "super silencers" exert exquisite control over the timing of the shutdown of overactive neural circuits – an effect that's impossible with existing drugs or other conventional therapies.

"Silencing different sets of neurons with different colors of light allows us to understand how they work together to implement brain functions," explains Ed Boyden, senior author of the study, to be published in the Jan. 7 issue of Nature. "Using these new tools, we can look at two neural pathways and study how they compute together. These tools will help us understand how to control neural circuits, leading to new understandings and treatments for brain disorders – some of the biggest unmet medical needs in the world." Boyden is the Benesse Career Development Professor in the MIT Media Lab and an associate member of the McGovern Institute for Brain Research at MIT.

Boyden's super silencers are developed from two genes found in different natural organisms such as bacteria and fungi. These genes, called Arch and Mac, encode for light-activated proteins that help the organisms make energy. When neurons are engineered to express Arch and Mac, researchers can inhibit their activity by shining light on them. Light activates the proteins, which lowers the voltage in the neurons and safely and effectively prevents them from firing. In this way, light can bathe the entire brain and selectively affect only those neurons sensitized to specific colors of light. Neurons engineered to express Arch are specifically silenced by yellow light, while those expressing Mac are silenced by blue light.

"In this way the brain can be programmed with different colors of light to identify and possibly correct the corrupted neural computations that lead to disease," explains co-author Brian Chow, postdoctoral associate in Boyden's lab.

In 2005, Boyden, in collaboration with investigators at Stanford University and the Max Planck Institute, introduced the first such "optogenetic" technique, so called because it combines the use of optics with gene delivery. The 2005 tool, now widely used, involves a light-activated ion channel, ChR2, which allows light to selectively turn on neurons in the brain.

Two years later, Boyden demonstrated that halorhodopsin, another light-sensitive protein, could inhibit the activity of neurons when illuminated. "But the genomic diversity of the world suggested that more powerful tools were out there waiting to be discovered," Boyden says. His group accordingly screened a diverse set of microbial light-sensitive proteins, and found the new multicolor silencers. The newly discovered tools are much better than the old. Arch-expressing neurons were switched off with greater precision and recovered faster than halorhodopsin-expressing neurons, allowing researchers to manipulate different neurons with different colors of light.

"Multicolor silencing dramatically increases the complexity with which you can study neural circuits," says co-author Xue Han, postdoctoral researcher in Boyden's lab. "We will use these tools to parse out the neural mechanisms of cognition."

How they did it: MIT researchers loaded the Arch and Mac genes into viruses that inserted their genetic cargo into mouse neurons. Optical fibers attached to lasers flashed light onto the neurons, and electrodes measured the resulting neural activity.

Next steps: Boyden's team recently demonstrated the efficacy of ChR2 in monkeys with no apparent side effects. Determining whether Arch and Mac are safe and effective in monkeys will be a critical next step toward the potential use of these optical silencing tools in humans. Boyden plans to use these super silencers to examine the neural circuits of cognition and emotion and to find targets in the brain that, when shut down, could relieve pain and treat epilepsy. His group continues to mine the natural world for new and even more powerful tools to manipulate brain cell activity – tools that, he hopes, will empower scientists to explore neural circuits in ways never before possible.

WEDNESDAY January 6, 2010---------------------News Archive / Current News
The Visible Embryo maintains a searchable database of artcles published since 2007

"Mental Health" Gene Has Different Effects Depending on Activation Before or After Birth

Scientists have long eyed mutations in a gene known as DISC1 as a possible contributor to schizophrenia and mood disorders, including depression and bipolar disorder. Now, new research led by Johns Hopkins researchers suggests that disturbing this gene during prenatal periods, postnatal periods or both may have different effects in mice, leading to separate types of brain or mood disorders.

The findings, reported online Jan. 5 in Molecular Psychiatry, could eventually help researchers treat mental illness in people or even prevent it.

To manipulate DISC1 expression during different periods, the researchers, led by Associate Professor Mikhail Pletnikov, M.D., Ph.D., crafted a novel mouse model in which a mutant form of the gene could be turned off by feeding the animals small amounts of the antibiotic doxycycline in their food.

The animals could get the drug directly by eating it or through their mothers during gestation. Withdrawing doxycycline turned this gene on. (All the animals also carried the normal DISC1 gene, which wasn't affected by the drug.)

Using this model, Pletnikov's team generated four groups of mice: those that expressed mutant DISC1 prenatally (Pre), those that expressed mutant DISC1 postnatally (Post), those that expressed it during both periods (Pre+Post), and those that never expressed it (NO).

When the mice were about 2 months old, the researchers put the animals through a battery of behavioral tests designed to measure characteristics similar to schizophrenia and depression in humans, such as abnormal social interactions and heightened aggression under stress, comparing these animals with "control" animals that didn't express the mutant gene.

When the researchers examined the brains of the mice, they found significant differences between animals in different groups. Those in the Prenatal group (those mice having DISC1 prenatally) had significantly smaller brain volume than the other 3 groups. Mice in the Postnatal (expressed mutant DISC1 after birth) and Pre&Postnatal (mice that expressed it during both periods) groups had significantly larger lateral ventricles and decreased content of dopamine, a pleasure-producing brain chemical, in the frontal cortex. Both female and male mice in the Prenatal, Postnatal and Pre+Postnatal groups had fewer neurons that produce GABA, a brain chemical that regulates nerve cell firing, than mice in the NO (those that never expressed it) group.

The researchers say both the behavioral and physiological findings suggest that expressing mutant DISC1 at different time points during fetal or early childhood development can lead to different outcomes.

While selective prenatal expression led to smaller brain volumes but mild behavioral effects, pre- and postnatal expression led to behaviors and brain alterations in male mice similar to schizophrenic humans, and postnatal expression produced abnormalities in female mice similar to depression.

The researchers aren't sure why the animals varied according to sex. However, Pletnikov notes, schizophrenia and depression also vary between the sexes in humans, with schizophrenia more prevalent in males and depression more prevalent in females. He and his team plan to study these sex-related differences in future studies.

The team also plans to try to narrow the time periods in which mutant DISC1 is turned on in their model to study particular stages, such as early postnatal development, sexual maturity, adulthood and aging, since triggers at each of these stages might bring on mental illness.

The goal, says Pletnikov, is to use these findings to develop new therapies to treat psychiatric disorders.

"Right now," he says, "we cannot treat or reverse all the abnormalities associated with schizophrenia or major mood disorders, but our research gives us hope that we can eventually target some of these abnormalities that are currently considered incurable. If we catch these problems early enough, we may someday be able to prevent schizophrenia or depression from developing."

How Leukemia Protein 'Bookmarks' Genes

Each cell inherits genes from its parent as well as epigenetic information – basically an instruction manual that specifies which genes should be activated or "expressed," when and to what extent.

Cold Spring Harbor Laboratory (CSHL) scientist Chris Vakoc, M.D., Ph.D., and his team have now discovered how some of these epigenetic instructions get transferred from one generation of cells to the next.

The scientists report that newly formed cells inherit the knowledge of which genes to turn on right away due to a helpful protein "bookmarking" these genes during the division from their parent cell. Their findings appear in the December 24th issue of Molecular Cell.

The bookmarking protein, called Mixed Lineage Leukemia or MLL, is notorious for triggering leukemia when the encoding gene becomes mutated. MLL mutations occur in about 10% of leukemia cases.

"We now have a clearer picture of what MLL normally does in healthy cells to help gene expression information to travel from parent cells to daughter cells," said Vakoc. "These findings may help us understand how mutated MLL subverts inheritance mechanisms in leukemic cells."

During cell division or "mitosis," all gene activity is temporarily shut down. The dividing cell's chromosomes—the X-shaped coils of DNA—condense into tight clumps and expel most proteins that cling to DNA.

Vakoc's team was surprised to find, however, that unlike other chromosome-bound molecules, the MLL protein stays tethered to chromosomes during mitosis. Genome-wide surveys that compared MLL's chromosomal binding sites before and during division—the first comparison of its kind—revealed a second twist.

During division, the scientists found, MLL abandoned some of the genes that it was previously shackled to. Instead, for the duration of mitosis, MLL shifted to a new set of genes. The team discovered that this set constitutes all the most active genes before division triggers a blackout on all gene activity.

The MLL triggered genes quickly reactivate to their previous high activity levels when division ends. "By seeking out and bookmarking this cohort of highly-expressed genes during division, MLL delivers a post-mitotic kick that helps turn genes back on," explains Vakoc.

In support of this idea, his team found that when MLL was depleted, the reactivation of these genes was delayed and they "kicked" on more slowly. By staying tethered to these genes, MLL provides a beacon to which other proteins can home to, thereby jump-starting gene activity.

Vakoc is now exploring how the mutations that increase the activity of MLL in leukemia affect gene reactivation in new cells and how this might contribute to the abnormal cell proliferation seen in leukemia.

TUESDAY January 5, 2010---------------------News Archive / Current News
The Visible Embryo maintains a searchable database of artcles published since 2007

An Excuse to Eat Bacon and Eggs When Pregnant

New epigenetic study in the FASEB Journal shows a link between maternal diet and brain development in gestating mice.

If you're pregnant and looking for an excuse to eat bacon and eggs, now you've got one: a new research study published in the January 2010 print issue of the FASEB Journal by a team of University of North Carolina researchers shows that choline plays a critical role in helping fetal brains develop regions associated with memory. Choline is found in meats, including pork, as well as chicken eggs.

"Our study in mice indicates that the diet of a pregnant mother, especially choline in that diet, can change the epigenetic switches that control brain development in the fetus" said Steven Zeisel, the senior scientist involved in the work and a senior member of the FASEB Journal's editorial board. "Understanding more about how diet modifies our genes could be very important for assuring optimal development."

Zeisel and colleagues made this discovery by feeding two groups of pregnant mice different diets during the window of time when a fetus develops its hippocampus, that part of the brain responsible for memory. The first group received no choline while the other received choline (1.1g/Kg). The group that received no choline had changes in epigenetic marks on the proteins (histones) that wrap genes in cells responsible for the creation of new brain cells (neural progenitor cells). Then, by isolating these cells from the developing brains and growing them in cell culture, the scientists determined the expression of genes for two proteins that regulate neuronal cell creation and maturation. These two proteins (G9a and Calb1) were changed in the brains of fetuses whose mothers were fed low choline diets.

"We may never be able to call bacon a health food with a straight face, but the emerging field of epigenetics is already making us rethink those things that we consider healthful and unhealthful," said Gerald Weissmann, MD, Editor-in-Chief of the FASEB Journal. "This is yet another example showing that good prenatal nutrition is vitally important throughout a child's entire lifetime."

The Agricultural Research Service's Nutrient Data Laboratory makes a database available to the public in an effort to help them get healthful amounts of choline in their diets. The database provides researchers and consumers with the means to estimate daily choline intake from consumption of more than 400 different foods and can be accessed here.

The Agricultural Research Service says that "experts suggest that an adequate choline intake is 425 milligrams a day for women and 550 milligrams a day for men. Top sources of choline include meat, nuts, and eggs."

Protein Key to Being Male, Key in Wound Healing

A molecular receptor pivotal to the action of male hormones such as testosterone also plays a crucial role in the body’s ability to heal, report scientists in the December issue of the Journal of Clinical Investigation.

In studies in mice, scientists at the University of Rochester Medical Center found that the androgen receptor – delays wound healing. When scientists used an experimental compound to block the receptor, wounds healed much more quickly.

Scientists say that while the results in mice offer new insights into a potential new way to help the body heal faster, they stress that more research must be done before considering whether to explore the treatment in people whose wounds are slow to heal.

“This is a very interesting observation,” said Edward Messing, M.D., a urologist and surgeon at the University of Rochester Medical Center who was not involved in the study. “For people at the marginal end of health – the elderly, or people who have impaired healing for other reasons, such as diabetes – maybe blocking the androgen receptor in certain cells could speed up wound healing and help prevent infections.”

Chawnshang Chang, Ph.D., director of the George Whipple Laboratory for Cancer Research and a widely recognized expert on the androgen receptor led the research.

The work explains how a sex hormone is one of the most important and pervasive forces in inflammation. Inflammation is crucial for allowing the body to heal from wounds and to fight off invaders. But when our inflammatory response goes beyond what’s necessary, or if it occurs in the wrong time or place, it hurts our health and can be deadly.

By identifying the androgen receptor as a key player in at least one form of inflammation, the work opens a new window for scientists investigating differences between the genders when it comes to autoimmune or inflammatory diseases.

“Many inflammatory diseases, such as atherosclerosis and asthma, manifest themselves differently in the genders, indicating that sexual hormones could be involved. We’ve found that the androgen receptor plays a role regulating the inflammatory response in wound healing. It will be very interesting to see if the receptor plays a similar role in other diseases,” said Lai.

To block the receptor and speed healing, the team used a synthetic chemical compound (ASC-J9) loosely based on a compound found in curry that can shut down the receptor selectively. ASC-J9 is being tested in Phase II trials as a treatment for severe acne by San Diego-based AndroScience Corp., a biotech company founded by Chang and colleagues. Both Chang and the University of Rochester own a stake in the company, which has licensed several of Chang’s research findings.

For the current study funded by the National Cancer Institute, Chang and colleagues studied several different types of cells involved in wound healing. The team created different types of mice, turning off the androgen receptor in certain cell types while leaving it functional in other cells - then applied ASC-J9 to block the activity of the androgen receptor and studied the effects.

The team found that the androgen receptor spurs white blood cells known as macrophages to produce a chemical messenger called TNF-alpha, which in turn stimulates the body’s inflammatory response. The receptor also plays a role recruiting macrophages to the site of injury. When the team blocked the receptor, there were fewer macrophages and less TNF-alpha at the wound site, and the wound healed much more quickly.

“It is a surprise that the androgen receptor is involved in wound healing in so many ways,” said Chang, who is a faculty member in the departments of Pathology and Urology and the James P. Wilmot Cancer Center. “People have suspected that the receptor plays a role in wound healing, but it’s new that it plays a direct role guiding circulating macrophages to the area.”

Shutting off the interaction between the androgen receptor and androgen hormones like testosterone is a goal in several areas of medicine. The action is taken by doctors most commonly to treat patients with advanced prostate cancer. For some patients, doctors prescribe “chemical castration” and shut down the body’s supply of hormones like testosterone. This causes severe, systemic side effects that can include impotence, loss of libido, osteoporosis, and fatigue.

Messing, a surgeon who regularly treats men with prostate cancer, says that the ability to turn off the effects of androgens in just the tissues necessary is a challenge but holds great promise.

“Currently there is no way of preventing androgens in your body from reaching just one particular wound or one specific part of the body,” said Messing. “To stop them anywhere, you need to turn off androgens throughout the body, which has severe and unpleasant side effects, particularly in men. Turning off the androgen receptor only where you want to, and nowhere else, could lead to new treatments for diseases like prostate cancer and for speeding wound healing.”

MONDAY January 4, 2010---------------------News Archive / Current News
The Visible Embryo maintains a searchable database of artcles published since 2007

Determining Ethnic Origin of Stem Cell Lines

Stem cells more representative of the US and world populations could lead to more accurate research and safer, more effective therapies.

While the majority of the Yoruba live in western Nigeria, there are also substantial indigenous Yoruba communities in the Republic of Benin, Brazil, Cuba, Haiti, USA, Trinidad and Tobago, Guyana, Jamaica, Antigua and Barbuda, Bahamas,Barbados, Dominica, Grenada, Puerto Rico, Ghana and Togo.An international team of scientists led by researchers at The Scripps Research Institute has developed a straightforward technique to determine the ethnic origin of stem cells.

The Scripps Research scientists initiated the study - published in the January 2010 edition of the prestigious journal Nature Methods - because the availability of genetically diverse cell lines for cell replacement therapy and drug development could have important medical consequences. Research has shown that discordance between the ethnic origin of organ donors and recipients can influence medical outcomes for tissue transplantation, and that the safety and effectiveness of specific drugs can vary widely depending on ethnic background.

Drummers from the Kwara tribe of Nigeria; also known as the Yoruba people.The team's analysis of a variety of human embryonic stem cell lines currently in use in research laboratories around the world found that these cells originated largely from Caucasian and East Asian populations, with little representation from populations originating in Africa. In response to these results, the scientists used skin cells from an individual of West African Yoruba heritage to create a new stem cell line, the first to carry the genetic profile of this ethnic group.

"Ethnic origin is a critical piece of information that should come with every cell line," said Scripps Research Professor Jeanne Loring, Ph.D., who is senior author of the paper. "Everyone who works with stem cells should be doing this kind of analysis."

"Knowing that a big push in the future is using these lines in the clinic and in drug development, there's a need to have an ethnically diverse population of cells," added Louise Laurent, M.D., Ph.D., assistant professor at the University of California, San Diego (UCSD) and research associate at Scripps Research, who is first author of the paper with Caroline Nievergelt, Ph.D., also an assistant professor at UCSD.

Greater diversity in cell samples would set the stage for more broadly relevant research by labs in academia and industry, more robust results on the safety and efficacy of potential therapies, and more successful tissue transplants.

The Promise of Stem Cells

Normally, cells develop from stem cells into a myriad of increasingly more specialized cell types during early development and throughout a lifetime. In humans and other mammals, these developmental events are usually irreversible. This means that when tissues are damaged or cells are lost, the body has limited means by which to replenish them.

Having a source of stem cells would be useful in many medical situations because these cells are "pluripotent," having the ability to become any of the body's cell types. Pluripotent stem cells would potentially provide physicians with the ability to replace or repair damaged tissues throughout the body. For example, pluripotent stem cells could be differentiated into the damaged cell type and transplanted.

Much research on pluripotent stem cells to date has been conducted on human embryonic stem cells, which are harvested from discarded embryos (those created but not used for the purposes of in vitro fertilization, a technique to help couples conceive). However, recently another source of pluripotent stem cells has come onto the scene. These cells—called induced pluripotent stem cells—are created by taking a sample of skin cells or another type of differentiated cell and using chemicals and molecular biology techniques to coax them back into a pluripotent state.

The current analysis included 47 human embryonic stem cell lines collected from labs located around the world—including Korea, Australia, and Finland. The analysis also included five induced pluripotent stem cell lines.

Ancestors Forgotten and Remembered

To determine the ethnic origins of the stem cell lines and to link them to genetic "signatures" that might affect medical outcomes, the scientists drew on previous research from the International HapMap Project, published in the journal Nature in 2003. This research linked single-letter alterations in the genetic code—known as single nucleotide polymorphisms, or SNPs—with people of known ethnic origins. This data provided a way to identify the ethnic heritage of a donor of any cell.

Laurent noted that simply asking cell donors about their ethnic heritage does not provide accurate data. "There's often an ancestor from a different area who a person doesn't know about," she said.

The technology used for the new study, known as SNP genotyping, uses microarrays, which are easily available, inexpensive, and relatively straight forward for scientists to use.

When the Scripps Research scientists applied the technique to the embryonic stem cell lines, they found that Caucasians were especially well represented among the samples, followed by East Asians. Cells of some mixed heritage were also common. Notably lacking from the samples were cell lines representing African heritage.

In addition, the authors found that the country in which a cell line was generated did not necessarily predict the ethnicity of the donor.

In creating a new pluripotent stem cell line from an individual with a West African Yoruba background, the scientists generated a line that contains distinct genetic markers for disease risk and drug metabolism.

"There's not a lot of value in making a new pluripotent stem cell line now unless it has something new to offer," said Loring. "I think that increasing ethnicity and genetic diversity is an important reason for generating new lines."

The data generated by the study—which Loring describes as the foundation of a new database of human pluripotent stem cell genetic information—will be available for other researchers to access for studies on specific genes, stem cell transplantation, and other topics.

Sealed With a Platelet, Treating Newborn PDA

The fetal heart has distinctive features allowing the fetus to obtain oxygen through the placenta rather than through its lungs.

Before birth, a blood vessel called the ductus arteriosus (DA) allows blood to bypass the fetal lungs and connect the pulmonary artery - which later will supply blood to the lungs - with the aorta. The ductus arteriosus is a small duct which normally closes a day or two after birth, but in some newborns remains open and can lead to complications.

Every time your heart beats, it pumps blood through the pulmonary artery and into your lungs where it soaks up oxygen before returning the blood to the pulmonary vein in the heart. With the next beat, it pumps the blood through the aorta to provide oxygen to all of the body.

During fetal development, the lungs are bathed in amniotic fluid and the fetus is supplied with oxygen via the placenta. As a baby takes its first breaths, the ductus arteriosus begins to close allowing normal pulmonary circulation to take place. The compression of uterine contractions also helps close the ductus arteriosus. However it does not always close, causing a condition known as Patent Ductus Arteriosus (PDA). Untreated PDA initially can cause breathing difficulties - but can lead to congestive heart failure, a particularly common and serious condition for preterm infants.

Dr Steffen Massberg and Dr Katrin Echtler in Munich knew from previous research that the release of cytokines is associated with the closing of the ductus arteriosus. Cytokines indicate an inflammatory response when tissue is damaged. Platelets are the irregularly-shaped blood cells crucial to blood clotting that are then recruited to the damaged tissue. Studying this process in mice, the researchers observed that within the first hour after birth, cells lining the ductus arteriosus detach themselves, thus providing new attachment sites for platelets. The platelets then quickly accumulate to form a plug to stop blood flow and block PDA.

When two proteins that are required for platelet adhesion and activation were removed, the researchers found the ductus arteriosus failed to close in the newborn mice. The role of platelets was not confined to the initial blocking of the ductus arteriosus; Dr Echtler and her colleagues also found that platelets attract specialized precursor cells required for a more permanent closure.

Examining samples of ductus arteriosus taken from newborn infants during heart surgery, Massberg and Echtler observed the same modifications to the lining of the human ductus arteriosus and the same platelet accumulation as seen in mice. With this strong association between low platelet counts and PDA and uncovering the key process of platelet recruitment, it may now be possible to create a less invasive treatment for PDA than surgery.


New Techniques Tell Ancient from Modern Humans

DNA that is left in the remains of long-dead plants, animals, or humans allows a direct look into the history of evolution. So far, studies of this kind on ancestral members of our own species have been hampered by scientists' inability to distinguish the ancient DNA from modern-day human DNA contamination.

Now, research by Svante Pääbo from The Max-Planck Institute for Evolutionary Anthropology in Leipzig, published online on December 31st in Current Biology - a Cell Press publication - overcomes this hurdle and shows how it is possible to directly analyze DNA from a member of our own species who lived around 30,000 years ago.

DNA - the hereditary material contained in the nuclei and mitochondria of all body cells - is a hardy molecule and can persist, conditions permitting, for several tens of thousands of years. Such ancient DNA provides scientists with unique possibilities to directly glimpse into the genetic make-up of organisms that have long since vanished from the Earth. Using ancient DNA extracted from bones, the biology of extinct animals, such as mammoths, as well as of ancient humans, such as the Neanderthals, has been successfully studied in recent years.

The ancient DNA approach could not be easily applied to ancient members of our own species. This is because the ancient DNA fragments are multiplied with special molecular probes that target certain DNA sequences. These probes, however, cannot distinguish whether the DNA they recognize comes from the ancient human sample or was introduced much later, for instance by the archaeologists who handled the bones. Thus, conclusions about the genetic make-up of ancient humans of our own species were fraught with uncertainty.

Using the remains of humans that lived in Russia about 30,000 years ago, Pääbo and his colleagues now make use of the latest DNA sequencing (i.e., reading the sequence of bases that make up the DNA strands) techniques to overcome this problem. These techniques, known as "second-generation sequencing," enable the researchers to "read" directly from ancient DNA molecules, without having to use probes to multiply the DNA. Moreover, they can read from very short sequence fragments that are typical of DNA ancient remains because over time the DNA strands tend to break up.

By contrast, DNA that is younger and only recently came in contact with the sample would consist of much longer fragments. This and other features, such as the chemical damage incurred by ancient as opposed to modern DNA, effectively enabled the researchers to distinguish between genuine ancient DNA molecules and modern contamination.

"We can now do what I thought was impossible just a year ago – determine reliable DNA sequences from modern humans - but this is still possible only from very well-preserved specimens," says Pääbo.

The application of this technology to the remains of members of our own species that lived tens of thousands of years ago now opens a possibility to address questions about the evolution and prehistory of our own species that were not possible with previous methods, for instance whether the humans living in Europe 30,000 years ago are the direct ancestors of present-day Europeans or whether they were later replaced by immigrants that brought new technology such as farming with them.













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