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Week Ending FRIDAY April 10, 2009---------------------------News Archive

Early Treatment with Antiretrovirals Improves AIDs Survival
The first antiretroviral treatments appeared in 1996. Since then, new and better drugs have been discovered that have almost turned AIDS into a chronic disease.

Nevertheless, there is still room to improve the performance of the the therapeutic strategies used in clinical practice. This is shown by a study published in the online edition of The Lancet, suggesting that early administration of antiretroviral treatment reduces the rate of AIDS development and death in HIV-positive patients by 28%. The study analyzed information from more than 45,000 patients in Europe and North America and combined data from 15 international cohorts.

One of the cohorts is the PISCIS Catalan and Balearic cohort, coordinated by Dr. Jordi Casabona of the Centre for Epidemiologic Studies of Sexually Transmitted Diseases and AIDS in Catalonia (CEEISCAT) - Catalan Institute of Oncology (ICO), and by Dr. Josep María Miró of the Infectious Diseases Department of Hospital Clínic - IDIBAPS, University of Barcelona.

The best moment to instate antiretroviral treatment has been the subject of debate for some time. The immune system's CD4 cell count, which falls as HIV infection progresses, is one of the main tools for establishing a guideline cutoff point. Current clinical guides recommend waiting for the CD4 count to fall below 350 cells per milliliter (µL) in asymptomatic patients.

Although it was suspected that initiating treatment earlier could improve outcomes, this recommendation was maintained due to side effects associated with the drugs, making correct administration of the treatment difficult. With new families of drugs available and new, less toxic combinations, it is now possible to consider instating treatment earlier without unduly affecting the patient's quality of life.

The study published in The Lancet, in the framework of the Antiretroviral Therapy Cohort Collaboration, includes information from 15 international cohorts. Data were obtained from 21,247 patients who were followed up during the period prior to instatement of combined antiretroviral therapy and 24,444 patients who were followed up from the beginning of treatment.

Waiting to administer the combined therapy until CD4 levels had fallen to between 251 and 350 cells/µL was associated with a 28% higher rate of development of AIDS and death than beginning treatment when levels were between 351 and 450 cells/µL. The adverse effects of delaying therapy were directly linked to the drop in the CD4 count. Waiting to treat until the CD4 count was below these levels was also associated with a higher mortality rate (13%), though the effect on mortality was smaller than the combined effect on developing AIDS and death.

The conclusion of the study is that the lowest level for initiating antiretroviral therapy is 350 cells/µL.

This will soon be indicated in the clinical guides and in clinical practice. The Gesida/National AIDS Plan guides are already being drawn up and will include the recommendation to initiated treatment before the CD4 count falls below 350 cell/µL. The new recommended figure will probably be between 350 and 500 cells/µL.

International clinical guides (both European and American), which will not be updated for some months, and the SMART clinical trial also suspected that antiretroviral therapy should begin before the CD4 count falls to 350 cells/µL. Furthermore, the New England Journal of Medicine (NEJM) published identical results this month, obtained by a North American study that also involved many cohorts (NA-ACCORD). The findings of these studies will be key to helping doctors throughout the world to decide on the best time to begin antiretroviral treatment.

The Catalan and Balearic cohort PISCIS (Project for the Computerization and Clinical Epidemiological Monitoring of HIV Infection and AIDS) was created in 1998 and is currently monitoring more than 10,000 patients. Nine Catalan hospitals are taking part: Hospital Clínic, Barcelona; Hospital Universitari Germans Trias i Pujol; Hospital de Bellvitge; Corporació Parc Taulí de Sabadell; Hospital de Mataró; Hospital General de Vic; Hospital de Palamós; Hospital General de l'Hospitalet; and Hospital Alt Penedès de Vilafranca. A Balearic hospital, the Son Dureta hospital in Mallorca, is also taking part and the CEEISCAT is acting as the coordinating center.

The study published in The Lancet confirms the findings that PISCIS had already published based on Catalan and Balearic data in the journal JAIDS (J Acquir Immune Defic Syndr. 2008; 47(2):212-20), suggesting that the minimum CD4 count for beginning treatment is at the threshold of 350 cells/µL.

The Department of Health aims to potentiate this project so that it covers the largest possible number of Catalan hospitals and serves not only for clinical-epidemiologic research but also for the planning and assessment of services relating to this disease and as a source of complementary information for monitoring important aspects such as delayed diagnosis, resistance and new mortality patterns in these patients.


Chemical Compound May Stop Deadly Brain Tumors
A research team led by Yue Xiong, Ph.D., professor of biochemistry and biophysics and a member of the UNC Lineberger Comprehensive Cancer Center, has identified a compound that could be modified to treat one of the most deadly types of cancer.

They have also discovered how a particular gene mutation contributes to tumor growth.

The findings and potential treatment apply a type of brain tumor called secondary glioblastoma multiforme (GBM). GBMs are part of a larger group of brain tumors called malignant gliomas, which is the type of cancer from which Senator Edward Kennedy suffers.

A report of the research will appear in the April 10 issue of the journal Science.

In laboratory experiments with tumor cells, the researchers reversed the effects of a mutation in a gene called isocitrate dehydrogenase-1 (IDH1) by replenishing a compound called α ketoglutarate ( αKG).

“When IDH1 gene is mutated, the level of α-KG is reduced, which in turn contributes to tumor growth by helping to increase the supply of nutrients and oxygen to tumor cells. When we added the α-KG to tumor cells, the effects caused by the IDH1 mutation were reversed,” said Xiong.

Essentially, the compound helped ‘starve’ the tumor cells, stunting their growth.

“If scientists can develop α-KG into a clinical drug, it could potentially be used for treating brain tumor patients who have this specific gene mutation. The α-KG compound is already there; it only needs to be modified to be used clinically, so that may save a lot of time,” Xiong said.

Xiong is a corresponding author of the study along with Kun-Liang Guan, professor of pharmacology, at the University of California, San Diego.

Xiong and Guan helped develop the lab at Fudan University and supervise graduate student training and project development there.

Xiong and colleagues are continuing studies of other effects of the IDH1 mutation and are developing a mouse model of secondary GBM that could be used to test the potential treatment, paving the way for eventual clinical trials in humans.

The current study was supported by the National Institutes of Health, the Chinese Ministry of Education, State Key Development Programs of China, National 863 Program of China, China NSF grants, and Shanghai Key Basic Research Projects.


Life Sticks
Sticky is good. A University of California, San Diego bioengineer is the first author on an article in the journal Science that provides insights on the "stickiness of life."

The big idea is that cells, tissues and organisms hailing from all limbs of the tree of life respond to stimuli using basic biological "modules." For example, the researchers outlined similar strategies across biology for fulfilling the tasks of "sticking together" (cell-cell interactions), "sticking to their surroundings" (cell-extracellular matrix [ECM] interactions), and responding to forces.

Adam Engler, a bioengineering assistant professor from UC San Diego's Jacobs School of Engineering, is the first author of the Review article entitled "Multiscale Modeling of Form and Function" published in the 10 April issue of the journal Science. According to Engler, there is something inherent in the nature of the ever-present tasks of sticking together and responding to forces that causes common form and function to emerge.

For example, even though the cells within bacteria, fungi, sponges, nematodes and humans do not use exactly the same proteins to stick together, all of these organisms rely on fundamental components of cell-cell adhesions for survival. For this reason, the capacity to form complex multilayer organisms through cell-cell interactions is likely based on the evolutionary advantage to adhere to new environments and survive in potentially hostile environments, the authors say.

The team also described a universal need for cells, tissues, organs and organisms to respond to forces. Two examples of very different biological structures that nevertheless rely on responsiveness to forces for proper function are leg bones and breast acini. Breast acini are hollow spherical objects at the ends of breast ducts that are made of a layer of cells that secrete milk proteins. Breast acini form hollow spheres, according to Engler, because this form maximizes the surface to volume ratio. When pressure builds up, acini can hold more and more volume until they need to push the milk proteins down the duct.

"This kind of structure is conserved in a variety of dissimilar systems that respond to forces in a manner similar," said Engler. The long bones of the human skeleton are another example, where their elongated and cylindrical form optimizes the distribution of body weight while remaining very light.

Thinking Wide
Engler hopes that the observations and connections he and his coauthors make regarding the ubiquitous need for vastly different cells, tissues, organs and organisms to use common biological modules will encourage other scientists and engineers to think beyond their specific areas of specialization.

"In our Science paper, I think we have arrived at an interesting way to describe known biological processes and bring concepts together that are traditionally not considered," said Engler. "I hope this paper will encourage researchers to interact with disciplines previously assumed to be dissimilar and foster new interdisciplinary interactions like we have here at UCSD with the Institute for Engineering in Medicine."

Engler's primary appointment is in the Department of Bioengineering at UC San Diego's Jacobs School of Engineering. The Department of Bioengineering ranks 2nd in the nation for biomedical engineering, according to the latest US News rankings. The bioengineering department has ranked among the top five programs in the nation every year for the past decade.

Engler has secondary appointments in Material Science and Biomedical Sciences. He is a member of the UCSD Stem Cell Institute and the UCSD Institute for Engineering in Medicine.

Engler is a bioengineer and mechanical engineer by training. He earned a Ph.D. in mechanical engineering from the University of Pennsylvania, and went on to a post doctoral fellowship in molecular biology at Princeton University before coming to UC San Diego in 2008. He is already involved in a number of interdisciplinary collaborations at UC San Diego.

One collaboration involves Engler, Shu Chien, who is University Professor of Bioengineering and Medicine, and Director of UC San Diego's Institute of Engineering in Medicine (IEM), and materials science professor Sungho Jin from the Jacobs School of Engineering's Mechanical and Aerospace Engineering (MAE) and NanoEngineering departments. In a January 2009 paper in the journal PNAS, researchers led by this team unveiled a new way to help accelerate bone growth through the use of nanotubes and stem cells. This new finding could lead to quicker and better recovery, for example, for patients who undergo orthopedic surgery.

Engler's lab recently began a collaboration with Rick Lieber, Ph.D., Professor and Vice Chair of UC San Diego's Department of Orthopedic Surgery and Director of the National Center for Skeletal Muscle Rehabilitation Research, based at UC San Diego. Lieber is also Senior Research Career Scientist at the Veterans Affairs San Diego Health System. The team is trying to uncover the cause of unexplained lower back pain in patients with no obvious disk degeneration, pinched nerves or other known causes of lower back pain.

"No matter what your area of expertise, there is someone that has a complementary area of expertise that can really help you ask new and interesting questions," said Engler.

Interdisciplinary Research
Mathematicians, engineers and stem cell biologists have not traditionally worked together, but these kinds of interdisciplinary collaborations have been the key to developing new techniques and new disciplines, explained Engler, who told a story of how his own dabbling into interdisciplinary research led to fruitful results.

As a graduate student, Engler helped put an experimental stem-cell-based surgical technique into a more appropriate mechanical context. The project began when he was approached by a surgeon puzzled by the results he was getting after injecting stem cells into damaged rat heart tissue in hopes of regenerating healthy heart tissue.

"As a matrix biologist and a mechanical engineer I said, 'Perhaps we need to look at what the host tissue is actually doing. What is being damaged and what is changing within the tissue due to the lack of oxygen?'" Engler and his collaborators found the cells in the damaged heart tissue were excreting collagen and making stiff scar tissue. "The engineer in me then analyzed the mechanical properties of the tissue and found out it was three to four times more rigid than the background healthy muscle. The biologist in me then characterized the cells in vitro and was able to show that these cells do respond to the mechanical properties of their environment."

Engler published his findings in 2006 in the high profile journal Cell and in the American Journal of Physiology. (Read New Scientist's description of Engler's findings.) One idea for improving such cell-based therapies, according to Engler, could involve injecting "smarter stem cells" that have been programmed to respond to some environmental stimuli but ignore other stimuli.


Small RNAs Play Critical Role in Male Infertility/Contraception
University of Nevada School of Medicine scientists in the Department of Physiology and Cell Biology have discovered insight into the reproductive workings of the male sex chromosome that may have significant implications for male infertility and contraception.

This important discovery has been published in Nature Genetics, one of the highest-ranking journals in the field of biomedical research based upon the impact factor.

The study findings indicate that the X chromosome in developing sperm cells encodes numerous tiny ribonucleic acids called microRNAs despite the fact that that most of genes on the X chromosomes are suppressed. This unprecedented observation implies that these small RNAs have critical roles in chromosome inactivation and also in sperm formation.

“The sex chromosome silencing in meiotic male germ cells is a well-known phenomenon, which has been termed meiotic sex chromosome inactivation. I was surprised when we first observed that numerous microRNAs were highly expressed in these cells,” said Wei Yan, M.D., Ph.D., principal investigator for the study and associate professor of physiology and cell biology at the School of Medicine.

Working in collaboration with Dr. John McCarrey, professor of molecular biology and reproductive biology at the University of Texas, San Antonio, Yan’s research group further investigated all the known X-linked microRNAs. Their data confirm that these X chromosome-derived microRNAs indeed escape the silencing effects and mange to be expressed.

“This finding opens a new avenue towards understanding the role of these small RNA species in the control of sperm production. Worldwide, one in nine couples in their reproductive age experience infertility. On the other hand, the number of unintended pregnancy is increasing yearly. Since these small RNAs are involved in the control of sperm formation, they can be causative factors in male infertility and also can be used as non-hormonal male contraceptive targets,” added Yan.

Yan’s research is focused on mammalian sperm and egg production and is funded by grants from the National Institutes of Health. Rui Song, a third year graduate student and Seungil Ro, Ph.D., an assistant professor of physiology and cell biology, co-first authored this paper. Other contributing authors include Jason D. Michaels, a third year medical student, and Chanjae Park, Ph.D., a post-doctoral researcher.

How "Silent” Mutations Influence Protein Production
Biologists at the University of Pennsylvania have revealed a hidden code that determines the expression level of a gene, providing a way to distinguish efficient genes from inefficient ones. The new research, which involved creating hundreds of synthetic green-glowing genes, provides an explanation for how a cell "knows" how much of each protein to make, providing just the right amount of protein to maintain homeostasis yet not too much to cause cell toxicity.

In the study, Penn biologists analyzed how protein levels are governed by synonymous, or silent, mutations within the protein-coding region.

Synonymous mutations do not change the amino-acid sequence of a protein, but they can nevertheless influence the amount of the protein that is produced. The researchers identified the mechanism underlying this regulation: synonymous mutations determine mRNA folding and thereby the eventual protein level. The researchers also identified a class of mutations that did not directly affect protein levels but slowed bacterial growth.

For biologists, these results fundamentally change the understanding of the role of synonymous mutations, which were previously considered evolutionarily neutral. The findings may also improve the design of therapeutic genes. Many drugs, such as insulin, are produced by transgenic cell lines. Using optimized genes will produce larger amounts of therapeutic proteins while keeping the transgenic, carrier cells healthy and fast-growing.

The human genome contains more than 20,000 genes that encode the proteins present in a human body. Some of these proteins are needed in bulk, while for others a tiny amount is sufficient and a large amount would be toxic. The question is how cells "know" how much of each protein to make.

To answer this question, Joshua B. Plotkin, senior author and the Martin Meyerson Assistant Professor in the Department of Biology in Penn's School of Arts and Sciences, and colleagues at Harvard University and the University of Edinburgh engineered a synthetic library of 154 genes that varied randomly at synonymous sites. All the genes encoded the same green fluorescent protein, enabling the researchers to easily study the effects of such mutations on protein levels when expressed in the bacterium Escherichia coli.

The silent mutations changed the amount of fluorescent protein by as much as 250-fold, without changing the properties of the protein. Codon bias, the probability that one codon of three adjacent nucleotides will code for one amino acid over another, was previously thought to be the cause for protein expression variance, but it did not correlate with gene expression in these experiments.

"At first we were stumped," Plotkin said. "How were the silent mutations influencing protein levels? Eventually, we looked at mRNA structure and discovered that this was the underlying mechanism."

The stability of mRNA folding near the ribosomal binding site explained more than half the variation in protein levels. To understand this observation, the researchers simulated the spatial arrangement of the messenger RNA molecule that carries the information from genes to proteins. They found that the inefficient genes produced tightly folded mRNA molecules that could not be accessed by the protein-making machinery. According to their analysis, mRNA folding and associated rates of translation initiation play a predominant role in shaping expression levels of individual genes, whereas codon bias influences global translation efficiency and cellular fitness.

The study, appearing in the current issue of the journal Science, was performed by Plotkin, as well as first author Grzegorz Kudla of the Department of Biology at Penn, Andrew W. Murray of the Department of Molecular and Cellular Biology at Harvard and David Tollervey of the Wellcome Trust Centre for Cell Biology at Edinburgh.

Targeting Toxic Protein in Patients with Huntington's Disease
Howard Hughes Medical Institute researchers have designed tiny RNA molecules that shut off the gene that causes Huntington's disease without damaging that gene's healthy counterpart, which maintains the health and vitality of neurons. Laboratory studies suggest that a single small interfering RNA could reduce production of the damaging Huntingtin protein in nearly half of people with the disease. Another 25 percent of patients might benefit from one of a set of four additional small interfering RNAs.

Phillip D. Zamore, an HHMI investigator at the University of Massachusetts Medical School in Worcester, and his colleagues reported their findings in an article published April 9, 2009, in the journal Current Biology.

There is no treatment for Huntington's disease, which is caused by a mutant form of the Huntingtin gene. Huntingtin is required for healthy nerve cells, but the mutant gene makes a toxic protein that contains excess amounts of the amino acid glutamine.

The key to whether the Huntingtin gene is normal or defective lies in a kind of genetic stutter: a repetitive sequence of the DNA triplet CAG, which codes for the amino acid glutamine. Stretches of CAG "repeats" appear in every human being's Huntingtin gene, but the length varies. Whereas the normal gene has a sequence of between six and 34 CAG repeats, the abnormal gene contains many more. In fact, any stretch of DNA containing more than 40 of these repeats ensures that its bearer will develop Huntington's—the greater the number of repeats, the earlier the disease strikes and the greater its ferocity. The abnormal Huntingtin protein causes movement disorders, cognitive failure, and ultimately, death. Children who have a parent with Huntington's disease have a 50 percent chance of inheriting the disease themselves.

Zamore studies how RNA interference can be used to silence genes selectively. In the 1990s, he and other scientists learned they could shut down the production of specific proteins by introducing double-stranded RNA into the cell that is identical to the RNA they wanted to turn off. These strands of RNA, known as short interfering RNA (siRNA), slice apart the original RNA, which the cell then destroys.

But nine years ago, when researcher Neil Aronin, who is also at UMass Medical School, proposed using the technique to attack Huntington's, Zamore couldn't see a way.

"I explained to him that you can't," Zamore said. The problem was that the disease gene and its healthy allele are almost identical, and Zamore told Aronin that he wouldn't be able to distinguish between the two forms of Huntingtin. "Then, as he was leaving my office, it occurred to me that you could," he recalled. The key was something called a single nucleotide polymorphism or SNP.

A SNP is any place on the genetic code that varies by a single unit. The genetic code is written with four letters, A, C, T, and G, which stand for the four nucleotides, adenosine, cytidine, thymidine, and guanosine. The pattern of these nucleotides dictates which protein is encoded by a given gene. DNA in the nucleus is transcribed as messenger RNA, which leaves the nucleus and begins making proteins based on the order of these four bases. A person's two copies of any gene may vary at these locations "simply because the two parents have different ancestries," Zamore said.

Zamore, Aronin, and their collaborators decided to look for such variation in the Huntingtin gene. It was a bit of a long shot. Even if the lab found relevant SNPs, it was likely few people would share the same polymorphisms, making drug development and testing nearly - if not completely - impossible.

Then they got lucky. The search for SNPs in the genetic material of 109 Huntington patients uncovered a single SNP carried by 48 percent of people with Huntington's. "This SNP is actually associated with the disease. We don't know why," Zamore said. That meant a single siRNA could shut off expression in the mutant Huntingtin gene – while leaving cells' healthy Huntingtin genes intact -- in almost half of all U.S. and European Huntington's patients.

"The most exciting part of the study was finding one siRNA that clearly is the top candidate for a clinical trial, where the patient population is predicted to be sufficiently large that it merits the development of a drug you could take into trial," Zamore said.

"That takes away the biggest worry we had, which was that the number of siRNAs we would have to test in order to have impact on the disease would be too large, and as a consequence the FDA would never approve any trial," he continued.

By adding an siRNA against one of two other common SNPs, Zamore says gene silencing could be effective in 75 percent of patients with Huntington's disease in the U.S. and Europe. Although the group found other SNPs, targeting more of them failed to increase the number of patients who could be helped, he said.

The next problem became developing siRNAs that could discriminate between target mRNAs and non-target. "That turned out to be frustratingly difficult," Zamore said. In tests of human cells, the siRNA sometimes sliced up the disease RNA, as it should. But sometimes it destroyed the normal Huntingtin RNA as well. To prevent this error, Zamore and his colleagues changed one more nucleotide base on the siRNA. Now, the silencing RNA was different from the healthy mRNA by two nucleotides, making it less likely to grab the good RNA.

Further research in mice will examine the efficacy of the siRNA tool. "The siRNA has to be sufficiently stable, and has to get into the right cells, and has to discriminate between the two (genes). It's incredibly expensive work," he said.

Zamore acknowledges that even with this progress, they're a long way from a treatment for Huntington's. "The Huntington's community is very savvy about understanding that scientific progress is always plodding. It's the sum of lots of little steps. From our perspective, the most important thing is to keep taking those steps."



THURSDAY April 9, 2009---------------------------News Archive

Stem Cell Therapy Clears Cloudy Corneas
Stem cells collected from human corneas restore transparency and don't trigger a rejection response when injected into eyes that are scarred and hazy, according to experiments conducted in mice by researchers at the University of Pittsburgh School of Medicine. Their study will be published in the journal Stem Cells and appears online today.

The findings suggest that cell-based therapies might be an effective way to treat human corneal blindness and vision impairment due to the scarring that occurs after infection, trauma and other common eye problems, said senior investigator James L. Funderburgh, Ph.D., associate professor, Department of Ophthalmology. The Pitt corneal stem cells were able to remodel scar-like tissue back to normal.

"Our experiments indicate that after stem cell treatment, mouse eyes that initially had corneal defects looked no different than mouse eyes that had never been damaged," Dr. Funderburgh said.


The ability to grow millions of the cells in the lab could make it possible to create an off-the-shelf product, which would be especially useful in countries that have limited medical and surgical resources but a great burden of eye disease due to infections and trauma.

"Corneal scars are permanent, so the best available solution is corneal transplant," Dr. Funderburgh said. "Transplants have a high success rate, but they don't last forever. The current popularity of LASIK corrective eye surgery is expected to substantially reduce the availability of donor tissue because the procedure alters the cornea in a way that makes it unsuitable for transplantation."

A few years ago, Dr. Funderburgh and other University of Pittsburgh researchers identified stem cells in a layer of the cornea called the stroma, and they recently showed that even after many rounds of expansion in the lab, these cells continued to produce the biochemical components, or matrix, of the cornea. One such protein is called lumican, which plays a critical role in giving the cornea the correct structure to make it transparent.

Mice that lack the ability to produce lumican develop opaque areas of their corneas comparable to the scar tissue that human eyes form in response to trauma and inflammation, Dr. Funderburgh said. But three months after the lumican-deficient mouse eyes were injected with human adult corneal stem cells, transparency was restored.

The cornea and its stromal stem cells themselves appear to be "immune privileged," meaning they don't trigger a significant immune response even when transplanted across species, as in the Pitt experiments.

"Several kinds of experiments indicated that the human cells were alive and making lumican, and that the tissue had rebuilt properly," Dr. Funderburgh noted.

In the next steps, the researchers intend to use the stem cells to treat lab animals that have corneal scars to see if they, too, can be repaired with stem cells. Under the auspices of UPMC Eye Center's recently established Center for Vision Restoration, they plan also to develop the necessary protocols to enable clinical testing of the cells.


Human ES Cells Progress Slowly in Myelin's Direction
Scientists from the University of Wisconsin, USA, report in the journal Development (dev.biologists.org) the successful generation from human embryonic stem cells of a type of cell that can make myelin, a finding that opens up new possibilities for both basic and clinical research.

The cells the researchers made are called oligodendrocytes, which are responsible for making myelin in the central nervous system. Myelin forms an insulating sheath that surrounds nerve fibres, both protecting them and speeding up the transmission of nerve impulses. Its loss or damage has serious consequences, as is seen in the condition of multiple sclerosis, because without it nerves lose the ability to transmit impulses to each other and to function properly.

Unlike human embryonic stem (ES) cells, it's relatively easy to persuade mouse ES cells to turn into oligodendrocytes; it's often done by exposing these cells to a protein called Sonic Hedgehog, which produces oligodendrocytes in the spinal cord of developing embryos. Now Su-Chun Zhang and his co-workers show in the May issue of Development (dev.biologists.org) that treating human ES cells with this same protein also turns them into oligodendrocytes – they just take longer to do it, 14 weeks as opposed to the 2 weeks taken by mouse ES cells. They also report another difference between mouse and human ES cells: a growth factor called Fgf2 that promotes oligodendrocyte development in mouse ES cells actually stalls it in human ES cells.

As Dr Zhang reveals, these findings were quite unexpected. 'This was quite a surprise given that this is exactly how we direct mouse ES cells to become oligodendrocytes. But we have discovered an unexpected twist in the cell's response to the same external factor', explained Dr Zhang. 'It nevertheless explains why so many research groups have failed to persuade human neural stem cells to become oligodendrocytes for the past decade.'

As Dr Zhang went on to discuss, these findings are also of clinical importance. 'We are now able to generate a relatively enriched population of oligodendrocyte precursor cells that may be used to repair lost myelin sheaths. These findings also raise awareness of the direct translatability of animal studies to human biology. In this regard, the human oligodendrocytes generated from human ES cells or the generation of disease-induced pluripotent stem cells can provide a useful tool in the future for screening pharmaceuticals directly on human cells.


Vitamin D May Exacerbate Autoimmune Disease
Deficiency in vitamin D has been widely regarded as contributing to autoimmune disease, but a review appearing in Autoimmunity Reviews explains that low levels of vitamin D in patients with autoimmune disease may be a result rather than a cause of disease and that supplementing with vitamin D may actually exacerbate autoimmune disease.

Authored by a team of researchers at the California-based non-profit Autoimmunity Research Foundation, the paper goes on to point out that molecular biologists have long known that the form of vitamin D derived from food and supplements, 25-hydroxyvitamin D (25-D), is a secosteroid rather than a vitamin. Like corticosteroid medications, vitamin D may provide short-term relief by lowering inflammation but may exacerbate disease symptoms over the long-term.

The insights are based on molecular research showing that 25-D inactivates rather than activates its native receptor - the Vitamin D nuclear receptor or VDR. Once associated solely with calcium metabolism, the VDR is now known to transcribe at least 913 genes and largely control the innate immune response by expressing the bulk of the body's antimicrobial peptides, natural antimicrobials that target bacteria.

Written under the guidance of professor Trevor Marshall of Murdoch University, Western Australia, the paper contends that 25-D's actions must be considered in light of recent research on the Human Microbiome. Such research shows that bacteria are far more pervasive than previously thought – 90% of cells in the body are estimated to be non-human – increasing the likelihood that autoimmune diseases are caused by persistent pathogens, many of which have yet to be named or have their DNA characterized.

Marshall and team explain that by deactivating the VDR and subsequently the immune response, 25-D lowers the inflammation caused by many of these bacteria but allows them to spread more easily in the long-run. They outline how long-term harm caused by high levels of 25-D has been missed because the bacteria implicated in autoimmune disease grow very slowly. For example, a higher incidence in brain lesions, allergies, and atopy in response to vitamin D supplementation have been noted only after decades of supplementation with the secosteroid.

Furthermore, low levels of 25-D are frequently noted in patients with autoimmune disease, leading to a current consensus that a deficiency of the secosteroid may contribute to the autoimmune disease process. However, Marshall and team explain that these low levels of 25-D are a result, rather than a cause, of the disease process.

Indeed, Marshall's research shows that in autoimmune disease, 25-D levels are naturally down-regulated in response to VDR dysregulation by chronic pathogens. Under such circumstances, supplementation with extra vitamin D is not only counterproductive but harmful, as it slows the ability of the immune system to deal with such bacteria.

The team points out the importance of examining alternate models of vitamin D metabolism. "Vitamin D is currently being recommended at historically unprecedented doses," states Amy Proal, one of the paper's co-authors. "Yet at the same time, the rate of nearly every autoimmune disease continues to escalate."


How Tumor Cells Move
Researchers in Heidelberg discover new protein that is suppressed in particularly aggressive cancer cells / Article in Nature Cell Biology

If cancer cells lack a certain protein, it could be much easier for them to penetrate healthy body tissue, the first step towards forming metastases. Scientists at the Pharmacology Institute of the University of Heidelberg have discovered the previously unknown cell signal factor SCAI (suppressor of cancer cell invasion), which inhibits the movement and spread of tumor cells in laboratory tests. When the factor’s functioning was disrupted, the cancer cells moved much more effectively in what are known as three-dimensional matrix systems, which imitate some of the tissue properties of the human body.

“The protein is apparently suppressed in many types of tumors, e.g. breast, lung, or thyroid,” explains Dr. Robert Grosse, head of the Emmy Noether Junior Research Group funded by the German Research Association (DFG) at the Pharmacology Institute. The new factor could be an interesting starting point for research into new mechanisms for fighting cancer. The research team’s results have now been published online in the prestigious international journal Nature Cell Biology.

Tumor cells are extremely mobile and “adept” at penetrating healthy tissue to form metastases. They adapt to the consistency of the respective tissue by changing their shapes constantly and attach flexibly to surrounding tissues during movement with the help of special surface structures (receptors).

One of these receptors is what is known as b1-integrin, which is frequently formed in many tumors such as metastasizing breast cancer. “The cell signal factor SCAI controls the formation and function of b1-integrin,” says Dr. Robert Grosse. “If there is too little SCAI in tumor cells, then b1-integrin is overactive, so to speak. The cell can change more rapidly to a more aggressive form and penetrate surrounding tissue, a crucial step toward increased spreading of the tumor and the possible formation of metastases.”

In their recently published study, the Heidelberg researchers examined cells from skin cancer (melanoma) and breast cancer. In other projects, Dr. Robert Grosse’s team would like to study the function of the signal factor SCAI more closely in an animal model. “If the function of SCAI is confirmed to be decisive in the formation of especially aggressive tumor cells, this could be a promising starting point for developing new diagnostic methods or medication,” says the pharmacologist. It could also be possible to develop an agent that prevents the genetic suppression of the signal factor in cancer cells. But first the researchers need to better understand how the signal factor itself is regulated in the cell.


Scientists Identify Key Gene Protecting Against Leukemia
Researchers have identified a gene that controls the rapid production and differentiation of the stem cells that produce all blood cell types—a discovery that could eventually open the door to more streamlined treatments for leukemia and other blood cancers, in which blood cells proliferate out of control.

Additionally, in investigating the mechanisms of this gene, the scientists uncovered evidence that could lead to a protocol for bone marrow transplants that could boost the chance of a cure in some patients.

The research, led by Emmanuelle Passegué, PhD, of the University of California, San Francisco, demonstrates that the JunB gene is at the center of a complex network of molecular and environmental signals that regulate the proliferation and differentiation of hematopoietic stem cells, the multipotent, self-renewing cells that give rise to all blood cell types.

In the study published April 7, 2009, in the journal Cancer Cell, Passegué’s team studied the behavior of JunB-deficient HSCs in both the culture dish and when transplanted into mice.In every case in which engraftment of the HSCs occurred in the mice, the scientists noted a progressive expansion of the myeloidlineage, which constitutes a type of mature white blood cell that fights infection. This expansion led by 6 to 12 months post-transplantation to the development of a myeloproliferative disease, which can evolve to leukemia. The finding indicated that the proliferating JunB-deficient HSCs causes leukemia.

Like traffic lights, which limit speed, direct the flow of vehicles and prevent accidents, JunB curtails both the rate at which HSCs are proliferating and the rate of differentiation toward the myeloid lineage that ultimately results in leukemia. The striking analogy inspired the image for the cover of Cancer Cell’s April 7 issue.

Without JunB, HSCs lose their ability to respond to signals from the protein receptors Notch and TGF-beta, which reside on the cells’ surface and play critical roles in determining cell fate.

“By uncovering this mechanism, we might one day be able to determine the difference between normal HSCs and leukemic stem cells in gene regulatory networks. This could allow us to develop more targeted therapies. These kinds of therapeutic applications are still down the road, but they can happen very quickly in the blood/leukemia field,” says Passegué.

Passegué’s study represents a turnabout from other research, which has demonstrated that mutated HSC that cause leukemia burn out at a faster rate than normal HSCs. In contrast, this study shows that JunB does not effect the cells’ potential for unlimited self-renewal.

The researchers demonstrated this by treating both JunB-deficient mice and control mice with the powerful chemotherapy drug 5-FU, which was given to deplete regenerating HSCs. As expected, JunB-deficient mice consistently displayed higher levels of myeloid lineage than the control group, indicating constant regeneration of a myeloproliferative disease from JunB-deficient HSCs that persisted after treatment. When researchers compared survival rates of the animals during several cycles of treatment, they found little difference between the two groups, indicating that JunB-deficient HSCsdo not exhaust faster than the control HSCs.

In tracking the differences between the JunB-deficient mice and the control group, it became apparent to the researchers that purity of HSCs was a key factor in determining the success of engraftment. Initially, the scientists were struck by the disparity in engraftment between the JunB-deficient HSCs and the control HSCs. But with the use of SLAM cells, a highly purified HSC population, they found that the two groups displayed in fact identical engraftment.

This finding may have important ramifications for patients undergoing bone marrow transplants, for leukemia, lymphoma, multiple myeloma and certain cancers.

“Currently, patients undergoing bone marrow transplants may not be getting enough of the quiescent transplanted HSCs that are optimal for successful engraftment,” says Passegué. Using a highly purified HSC population could be more beneficial.”

Research was funded by grants from the Concern Foundation, UCSF Research Evaluation and Allocation Committee and the NIH.

Key Protein in Cellular Respiration Discovered
Many diseases derive from problems with cellular respiration, the process through which cells extract energy from nutrients.

Researchers at Karolinska Institutet have now discovered a new function for a protein in the mitochondrion - popularly called the cell's power station - that plays a key part in cell respiration.

Cellular respiration depends on proteins synthesised outside the mitochondrion and imported into it, and on proteins synthesised inside the mitochondrion from its own DNA. Researchers at Karolinska Institutet have now shown that a specific gene (Tfb1m) in the cell's nucleus codes for a protein (TFB1M) that is essential to mitochondrial protein synthesis. If TFB1M is missing, mitochondria are unable to produce any proteins at all and cellular respiration cannot take place.

The scientists believe that the study represents a breakthrough in the understanding of how mitochondrial protein synthesis is regulated, and thus increases the chances of one day finding a treatment for mitochondrial disease, something which is currently unavailable.

Did a Nickel Famine Trigger the “Great Oxidation Event”?
The Earth’s original atmosphere held very little oxygen. This began to change around 2.4 billion years ago when oxygen levels increased dramatically during what scientists call the “Great Oxidation Event.”

The cause of this event has puzzled scientists, but researchers writing in Nature* have found indications in ancient sedimentary rocks that it may have been linked to a drop in the level of dissolved nickel in seawater.

“The Great Oxidation Event is what irreversibly changed surface environments on Earth and ultimately made advanced life possible,” says research team member Dominic Papineau of the Carnegie Institution’s Geophysical Laboratory. “It was a major turning point in the evolution of our planet, and we are getting closer to understanding how it occurred.”


The researchers, led by Kurt Konhauser of the University of Alberta in Edmonton, analyzed the trace element composition of sedimentary rocks known as banded-iron formations, or BIFs, from dozens of different localities around the world, ranging in age from 3,800 to 550 million years. Banded iron formations are unique, water-laid deposits often found in extremely old rock strata that formed before the atmosphere or oceans contained abundant oxygen. As their name implies, they are made of alternating bands of iron and silicate minerals. They also contain minor amounts of nickel and other trace elements.


Nickel exists in today’s oceans in trace amounts, but was up to 400 times more abundant in the Earth’s primordial oceans. Methane-producing microorganisms, called methanogens, thrive in such environments, and the methane they released to the atmosphere might have prevented the buildup of oxygen gas, which would have reacted with the methane to produce carbon dioxide and water. A drop in nickel concentration would have led to a “nickel famine” for the methanogens, who rely on nickel-based enzymes for key metabolic processes. Algae and other organisms that release oxygen during photosynthesis use different enzymes, and so would have been less affected by the nickel famine. As a result, atmospheric methane would have declined, and the conditions for the rise of oxygen would have been set in place.


The researchers found that nickel levels in the BIFs began dropping around 2.7 billion years ago and by 2.5 billion years ago was about half its earlier value. “The timing fits very well. The drop in nickel could have set the stage for the Great Oxidation Event,” says Papineau. “And from what we know about living methanogens, lower levels of nickel would have severely cut back methane production.”


What caused the drop in nickel? The researchers point to geologic changes that were occurring during the interval. During earlier phases of the Earth’s history, while its mantle was extremely hot, lavas from volcanic eruptions would have been relatively high in nickel. Erosion would have washed the nickel into the sea, keeping levels high. But as the mantle cooled, and the chemistry of lavas changed, volcanoes spewed out less nickel, and less would have found its way to the sea.


“The nickel connection was not something anyone had considered before,” says Papineau. “It’s just a trace element in seawater, but our study indicates that it may have had a huge impact on the Earth's environment and on the history of life.”


*Kurt O. Konhauser, Ernesto Pecoits, Stefan V. Lalonde, Dominic Papineau, Euan G. Nisbet, Mark E. Barley, Nicholas T. Arndt, Kevin Zahnle & Balz S. Kamber, Oceanic nickel depletion and a methanogen famine before the Great Oxidation Event, scheduled for publication in Nature on 09 April, 2009.



WENESDAY April 8, 2009---------------------------News Archive

Too Much Protein, Eaten Along with Fat, May Lead to Insulin Resistance
A clue about the blood chemistry of obese people who develop insulin resistance, a precursor to diabetes, has been confirmed in animal studies at the Duke University Medical Center.

Obese people have been found to harbor proteins called branched-chain amino acids (BCAAs) at far higher levels than non-obese people. The suspicion has been that these amino acids, in combination with a high-fat diet, contribute to insulin resistance.

The team found that the BCAA signature in obese humans consisted of the branched-chain amino acids themselves, plus a cluster of several products related to the body's breakdown processes for BCAA.

"In the case of the amino acids, we also are finding increased levels of their metabolic breakdown products, which suggests the whole system for handling the amino acid metabolic process has been overloaded," said senior author Christopher Newgard, PhD, director of the Sarah W. Stedman Nutrition and Metabolism Center and W. David and Sarah W. Stedman Distinguished Professor at Duke.

"Our rat studies show that this overload causes changes at the cellular level that can lead to insulin resistance."

To determine whether the BCAA signature in obese humans might signal that their intake is harmful, the scientists performed a feeding study in rats that showed an independent contribution of BCAAs to insulin resistance.

"These findings, however, would need to be confirmed in studies with people before any dietary recommendations could be issued," said Laura Svetkey, MD, director of the Duke Hypertension Center, director of clinical research at the Sarah W. Stedman Nutrition and Metabolism Center, and co-senior author of the study, published in Cell Metabolism.

"Insulin resistance occurred in animals with a diet high in the branched-chain amino acids, but only if they were ingested along with a high level of fat in the diet," Newgard said.

Because obese humans tend to ingest high-fat diets, the combination of high-BCAA and high-fat intake might contribute to insulin resistance in obese humans, but additional studies are needed. BCAAs constitute as much as 25 percent of amino acids in dietary protein, and are particularly enriched in diets high in animal (meat) proteins.

"I want to be clear that our animal data suggest that there is nothing wrong with obtaining protein from sources that are high in branched-chain amino acids, as long as you are not eating beyond what your energy needs are," said Newgard, who is a professor of pharmacology and cancer biology and professor of medicine at Duke.

"If you add a lot of unneeded protein to a fatty diet, perhaps that's where you get into problems. The ancient Greeks were right: everything in moderation."

Insulin resistance happens when insulin, released by the beta cells in the pancreas, doesn't work normally to stimulate glucose uptake into tissues.

Rats on a high-fat diet gained substantially more weight than rats that ate BCAAs with high-fat chow or those that ate standard chow. However, the rats eating the high-fat diet with BCAA became as insulin resistant as rats fed a high-fat only diet, even though they weren't eating as much.

To make sure that the BCAAs and not high fat contributed to insulin resistance, the researchers let animals feed freely on the standard chow, high-fat, or high fat with BCAA diets, and added a fourth group of rats fed a high-fat chow diet in an amount that matched the lower rate of food intake in the high-fat BCAA group. Studies showed clear insulin resistance in the high-fat and high-fat with BCAA groups, but not in the rats eating less of the high fat chow or those eating standard chow. This proved that moderate fat intake was not a cause of insulin resistance.

The researchers also showed that BCAAs contributed to insulin resistance by chronically activating mTOR, a signaling protein that regulates cell growth and survival and that functions as a sensor of cellular nutrient and energy levels. When the rats had the drug rapamycin, which blocks mTOR, their insulin resistance was reversed.

Next the team will study what happens when obese people who have insulin resistance lose weight and "whether there is a parallel improvement in the BCAA metabolic signature in the blood," Newgard said.

Svetkey added, "We also need to study the relationship between dietary intake of BCAA and insulin resistance in humans, and whether changing dietary patterns, beyond weight control, can improve matters."

The study was supported by a sponsored research agreement from Glaxo SmithKline and NIH grants. Authors Jie An, James Bain, Michael Muehlbauer, Robert D. Stevens, Lillian Lien, Andrea Haqq, Michelle Arlotto, Olga Ilkayeva, Brett Wenner, David Millington and Mark D. Butler are with the Sarah W. Stedman Nutrition and Metabolism Center. Lillian Lien, Svati Shah, Cris Slentz, William Yancy Jr. and Gerald Musante are with the Duke Department of Medicine. Jie An is with the Duke Department of Pharmacology and Cancer Biology. Andrea Haqq and David Millington are with the Duke Department of Pediatrics. James Rochon and Dianne Gallup are with the Duke Department of Biostatistics and Informatics. Howard Eisenson is with Duke Community and Family Medicine, and Richard Surwit is the Duke Department of Psychiatry.


Growth Factor TGF-B Helps Maintain Health of Retinal Blood Vessels
Scientists at the University of Michigan have developed a method of gene delivery that appears safe for regenerating tooth-supporting gum tissue—a discovery that assuages one of the biggest safety concerns surrounding gene therapy research and tissue engineering.

Gene therapy is an accepted, viable therapeutic concept, but safety is a major hurdle, said William Giannobile, professor at the U-M School of Dentistry. The most notable incident highlighting the safety concerns of gene therapy research and treatment occurred several years ago when a teenager died when given the adenovirus during a gene therapy clinical trial at the University of Pennsylvania.

The U-M therapy also uses the adenovirus, Giannobile said, but the big difference in the U-M approach lies in the local application and much lower dose. Instead of injecting the genes into the blood vessels, where they can then travel through the bloodstream and result in unexpected and sometimes fatal reactions, U-M scientists put the genes on a localized area, directly on the tissue during surgery much like a paste.

"What the U-M study showed is (the topical method) is very well contained and doesn't distribute throughout the body," said Giannobile, who also directs the Michigan Center for Oral Health Research and has an appointment at the U-M College of Engineering's Department of Biomedical Engineering. "This approach alleviates the safety concern about negative reactions within the body.


"When the teenager died, it got into his bloodstream and he reacted to it. It was tragic. This is the first study of periodontal disease therapy that demonstrates the distribution of these genes is very safe, suggesting that it could be used in the clinic for clinical application.

"Our study doesn't look at all the safety concerns, but certainly this is very important to the field. The two clinical applications to date where it shows potential are periodontal disease and diabetic wounds. Maybe the reason for this is that both diseases result from a compromised or a defective healing environment."

The next step for the U-M team is to use the new gene delivery approach in human clinical trials, Giannobile said. The planning stages for these studies will commence in the next year.


Adult Brain Processes Fractions 'Effortlessly'
Mathematical value intuited without calculation; findings may impact math education

Although fractions are thought to be a difficult mathematical concept to learn, the adult brain encodes them automatically without conscious thought, according to new research in the April 8 issue of The Journal of Neuroscience. The study shows that cells in the intraparietal sulcus (IPS) and the prefrontal cortex — brain regions important for processing whole numbers — are tuned to respond to particular fractions. The findings suggest that adults have an intuitive understanding of fractions and may aid in the development of new teaching techniques.

“Fractions are often considered a major stumbling block in math education,” said Daniel Ansari, PhD, at the University of Western Ontario in Canada, an expert on numerical cognition in children and adults who was not affiliated with the study. “This new study challenges the notion that children must undergo a qualitative shift in order to understand fractions and use them in calculations. The findings instead suggest that fractions are built upon the system that is employed to represent basic numerical magnitude in the brain,” Ansari said.

The study authors, Simon Jacob, MD, and Andreas Nieder, PhD, at the University of Tübingen in Germany, scanned the brains of adult participants as they watched fractions flashed on a screen. The researchers used a technique called functional MRI adaptation (fMRA) to identify brain regions that adapt - or show decreased activity - to the same stimulus presented over and over again.

When the researchers rapidly and repeatedly presented study participants with fractions that equaled approximately 1/6, they found decreased activation in the IPS and prefrontal cortex. Then, the researchers showed the participants fractions that deviated from 1/6. The more the fraction differed from 1/6, the greater the activity in IPS cells. The rapid presentation of each fraction and small variations in fraction value ensured that study participants directly processed the fractions, rather than calculating their values.

These findings suggest that fractions automatically activate the IPS and prefrontal cortex in adults. The researchers found that distinct groups of cells in these brain regions responded to different fraction values. Moreover, the cells responded the same way, whether fractions were presented as either numbers (1/4) or words (one-fourth).

The study builds on previous findings showing that human babies and nonhuman primates understand proportions.

“These experiments change the way we should think about fractions,” said study author Jacob. “We have shown that our highly-trained brains represent fractions intuitively, a result that could influence the teaching of arithmetic and mathematics in schools,” he said.

Future research will determine whether children process fractions the same way as adults, who may have learned to do so through experience.

The research was supported by the German Research Foundation (Deutsche Forschungsgemeinschaft) and the International Human Frontier Science Program Organization.


Rhythmic Genomics - Yeast Metronome and the Walk of Life
New genome sequence information from the humble baker's yeast has revealed surprising variation in a set of genes that can be thought of as nature's oldest clock. In a paper published in Genome Research scientists show how ribosomal RNA genes that are essential to all Earth's organisms provide insight into how genomes maintain their integrity on their evolutionary journey.

Ribosomal RNA sequence changes have been ticking away like clockwork for over 3 billion years, maybe even pre-dating the origin of the DNA world itself. However, even the slightest changes in sequence of these genes can be fatal. It is vital to conserve the important genetic 'cogs' to make sure cells function correctly. However, significant changes do occur, contrary to expectation, and yet the yeast somehow still survives.

Furthermore, when two yeasts hybridise the clocks appear to re-set, apparently overwriting each others' rhythm and eliminating unwanted variations on the theme. This provides clues as to how key motifs are conserved and allows us to track the evolutionary history of hybrids.

Steve James, lead researcher at the Institute of Food Research (IFR), said "I have sequenced these genes to selectively identify yeast species for over 15 years and had no idea they would turn out to be so variable."

Rob Davey, computational biologist at the National Collection of Yeast Cultures (NCYC), said "we can use new computer techniques to model the changes mathematically and really get to grips with what orchestrates the variation in these important cell housekeepers."

Ian Roberts, Curator of NCYC, said "Yeasts are everywhere around us in nature and industry. This extra level of detail allows us to resolve important differences between yeasts and gain maximum benefits from their use in food, drink and healthcare."

This work was carried out in collaboration with the Wellcome Trust Sanger Institute and the Massachusetts Institute of Technology. The IFR is an institute of the Biotechnology and Biological Sciences Research Council (BBSRC).

Is Love at First Sight Real? Geneticists Offer Tantalizing Clues
Research published in the journal Genetics shows that the reproductive outcome of a mated pair depends on pre-existing gene expression in the female and on the male with whom she mates

Leave it to geneticists to answer a question that has perplexed humanity since the dawn of time: does love at first sight truly exist?

According to a study published in the April 2009 issue of the journal GENETICS, a team of scientists from the United States and Australia discovered that at the genetic level, some males and females are more compatible than others, and that this compatibility plays an important role in mate selection, mating outcomes, and future reproductive behaviors. In experiments involving fruit flies, the researchers found that before mating, females experience what amounts to "genetic priming," making them more likely to mate with certain males over others.

"Our research helps to shed light on the complex biochemistry involved in mate selection and reproduction," said Mariana Wolfner, Professor of Developmental Biology at Cornell University and the senior scientist involved in the study. "These findings may lead to ways to curb unwanted insect populations by activating or deactivating genes that play a role in female mating decisions," she added.

To reach their conclusions, scientists mated two different strains of fruit fly females to males either from their own strain or to males from the other strain. They noted the males with which females of each strain tended to mate and then examined whether the females showed differences in behavior soon after mating and in reproduction-related activities, such as how many offspring were produced and how many sperm were stored. They also examined the females' RNA to compare the genes expressed in females mated to males of different strains. They found that despite observed differences in mating behaviors and reproduction activities in females mated to different strains of males, there were only negligible mating-dependent differences in gene expression between the groups. This suggests that genetic changes involved in mate choice and reproduction were in place before mating began.

"It appears that females really do care about the character of their consorts," said Mark Johnston, Editor-in-Chief of the journal GENETICS, "but they may not have as much control over our choice of mates as they'd like to think."

Gene Therapy Appears Safe to Regenerate Gum Tissue
Results from a new study identify a biomarker that may be useful for predicting the outcome of treatment for neuroblastoma, the most common cancer in young children

The research, published by Cell Press in the April 7th issue of the journal Cancer Cell, also provides new information about the molecular signals that are involved in the progression of this often devastating pediatric cancer.

Retinoic acid (RA) is a metabolite of Vitamin A that has important influences over the processes of growth and differentiation. RA mediates gene expression by interacting with retinoic acid receptors (RARs) that, in the presence of RA, switch from repressing target genes to activating them. Because many targets of RA induce differentiation or cell death, RA is used as a therapeutic agent in many cancers, including neuroblastoma.

"Many neuroblastoma patients exhibit aggressive tumors with poor clinical outcome," explains senior study author Dr. Rene Bernards from The Netherlands Cancer Institute. "While some of these aggressive tumors exhibit increased expression of the MYCN oncogene, little is known about the other genetic factors that control neuroblastoma progression." Dr. Bernards and colleagues performed a genome-wide RNA interference screen to search for additional components of the RA signaling pathway that might be linked to neuroblastoma.

The researchers identified ZNF423 as a critical cofactor of RA-induced differentiation. Reduced expression of ZNF423 was led to a growth advantage and resistance to RA differentiation in neuroblastoma cells while increased expression of ZNF423 led to growth inhibition and enhanced differentiation. The researchers went on to show that ZNF423 interacts with the RAR?/RXR? nuclear receptor that is necessary for activation in response to retinoids.

Importantly, low expression levels of ZNF423 were associated with poor disease outcome in neuroblastoma patients, suggesting that the gene might be useful as a prognostic biomarker. "Expression levels of ZNF423 could significantly affect responses to both endogenous and pharmacological concentrations of RA in cancer patients, which may in turn influence the outcome of neuroblastoma," offers Dr. Bernards. "Therefore, ZNF423 may be a useful biomarker for predicting responses to RA-based therapies, which are increasingly being used to treat neuroblastoma."


Wild Chimpanzees Exchange Meat for Sex on a Long-Term Basis
Wild female chimpanzees copulate more frequently with males who share meat with them over long periods of time, according to a study led by researchers from the Max Planck Institute for Evolutionary Anthropology in Germany, published in the open-access, peer-reviewed journal PLoS ONE April 8.

How females choose their mating partners and why males hunt and share meat with them are questions that have long puzzled scientists. Evidence from studies on human hunter-gatherer societies suggest that men who are more successful hunters have more wives and a larger number of offspring. Studies on wild chimpanzees, humans' closest living relative, have shown that male hunters frequently share meat with females who did not participate in the hunt. One of the hypotheses proposed to explain these findings is the meat-for-sex hypothesis, whereby males and females exchange meat for mating access. However, there has been little evidence in both humans and chimpanzees to support it.


In recent research conducted in the Taï National Park, Côte d'Ivoire, Cristina M. Gomes and Christophe Boesch show that females copulate more frequently with males who share meat with them on at least one occasion, compared with males who never share meat with them, indicating that sharing meat with females improves a males' mating success. Although males were more likely to share meat with females who had sexual swellings (i.e., estrous females), excluding all sharing episodes with estrous females from the analysis, did not alter the results. This indicates that short term exchanges alone (i.e., within the estrous phase of the female) cannot account for the relationship between sharing meat and mating success.

According to Gomes, "Our results strongly suggest that wild chimpanzees exchange meat for sex, and do so on a long-term basis. Males who shared meat with females doubled their mating success, whereas females, who had difficulty obtaining meat on their own, increased their caloric intake, without suffering the energetic costs and potential risk of injury related to hunting."

She adds, "Previous studies might not have found a relationship between mating success and meat sharing because they focused on short-term exchanges; or perhaps because in those groups access to females was driven by male coercion so females rarely chose their mating partners."

Boesch concluded, "Our findings add to the ever-growing evidence suggesting that chimpanzees can think in the past and the future and that this influences their present behavior."

"These findings are bound to have an impact on our current knowledge about relationships between men and women; and similar studies will determine if the direct nutritional benefits that women receive from hunters in human hunter-gatherer societies could also be driving the relationship between reproductive success and good hunting skills," concludes Gomes.



TUESDAY April 7, 2009---------------------------News Archive

New Way to See Single RNA Molecules Inside Living Cells
Biomedical engineers have developed a new type of probe that allows them to visualize single ribonucleic acid (RNA) molecules within live cells more easily than existing methods. The tool will help scientists learn more about how RNA operates within living cells

Techniques scientists currently use to image these transporters of genetic information within cells have several drawbacks, including the need for synthetic RNA or a large number of fluorescent molecules. The fluorescent probes developed at the Georgia Institute of Technology circumvent these issues.

"The probes we designed shine bright, are small and easy to assemble, bind rapidly to their targets, and can be imaged for hours. These characteristics make them a great choice for studying the movement and location of RNA inside a single cell and the interaction between RNA and binding proteins," said Philip Santangelo, an assistant professor in the Wallace H. Coulter Department of Biomedical Engineering at Georgia Tech and Emory University.

Details of the probe production process and RNA imaging strategy were published online in the journal Nature Methods on April 6. In addition to Santangelo, Georgia Tech graduate student Aaron Lifland, Emory University associate professor Gary Bassell and Vanderbilt University professor James Crowe Jr. also contributed to this research. This research was funded by new faculty support from Georgia Tech.

I
n the study, the probes – produced by attaching a few small fluorescent molecules called fluorophores to a modified nucleic acid sequence and combining the sequences with a protein – exhibited single-molecule sensitivity and allowed the researchers to target and follow native RNA and non-engineered viral RNA in living cells.

"The great thing about these probes is that they recognize RNA sequences and bind to them using the same base pairing most people are familiar with in regards to DNA," explained Santangelo. "By adding only a few probes that would bind to a region of RNA, we gained the ability to distinguish a targeted RNA molecule from a single unbound probe because the former lit up two or three times brighter."

For their experiments, the team used a bacterial toxin to transport the probes into living cells – a delivery technique that when combined with the high affinity of the probes for their targets, required significantly fewer probes than existing techniques. The toxin created several tiny holes in the cell membrane that allowed the probes to enter the cell's cytoplasm.

The researchers tested the sensitivity of conventional fluorescence microscopy to image individual probes inside a cell. Previous studies showed that these techniques were able to image an accumulation of probes inside a cell, but the current study demonstrated that individual probes without cellular targets could be observed homogenously distributed in the cytoplasm with no localization or aggregation.

With single-molecule sensitivity accomplished, the researchers investigated whether they could visualize individual RNA molecules using the probes. To do this, they simultaneously delivered probes designed to target a human messenger RNA (mRNA) sequence region and a probe designed with no target in the human genome. They were able to image unbound probes of both types as well as individual RNA molecules that had attached to the former probes.

The imaging technique also allowed the researchers to observe a process called dynamic RNA-protein co-localization, which is the joining of RNA molecules and RNA binding proteins in a single cell.

"We observed substantial transient interactions between proteins and viral RNA molecules that I don't think had ever been seen before with non-engineered RNA," noted Santangelo. "We saw one of the proteins move into a viral RNA granule and reside within it for over a minute before it was released, and we also saw another protein that appeared to dock with a viral RNA granule."

Santangelo is currently trying to improve the probes by making them smaller and brighter, while also using them to investigate viral pathogenesis and other biological phenomena.

"We are excited to use this imaging strategy to study how single viral RNAs travel from the nucleus of a cell to a virus assembly site, how mRNAs are regulated by location and time, and RNA trafficking in neurons," added Santangelo.

Gutsy Germs Succomb to Baby Broccoli
A small, pilot study in 50 people in Japan suggests that eating two and a half ounces of broccoli sprouts daily for two months may confer some protection against a rampant stomach bug that causes gastritis, ulcers and even stomach cancer.

Citing their new “demonstration of principle” study, a Johns Hopkins researcher and an international team of scientists caution that eating sprouts containing sulforaphane did not cure infection by the bacterium Helicobacter pylori (H. pylori). They do not suggest that eating this or any amount of broccoli sprouts will protect anyone from stomach cancer or cure GI diseases.
However, the study does show that eating a daily dose of broccoli sprouts reduced by more than 40 percent the level of HpSA, a highly specific measure of the presence of components of H. pylori shed into the stool of infected people. There was no HpSA level change in control subjects who ate alfalfa sprouts. The HpSA levels returned to pretreatment levels eight weeks after people stopped eating the broccoli sprouts, suggesting that although they reduce H. pylori colonization, they do not eradicate it.

“The highlight of the study is that we identified a food that, if eaten regularly, might potentially have an effect on the cause of a lot of gastric problems and perhaps even ultimately help prevent stomach cancer,” says Jed W. Fahey, M.S., Sc.D., an author of the paper who is a nutritional biochemist in the Lewis B. and Dorothy Cullman Cancer Chemoprotection Center at the Johns Hopkins University School of Medicine.

In the new report, the team also shows that when H. pylori-infected mice sipped broccoli-sprout smoothies for eight weeks, there was up to a fourfold increase in the activity of two of these key enzymes that protect cells against oxidative damage. In addition, the number of Helicobacter bacteria in the mice’s stomachs decreased by almost a hundredfold it did not change in infected control animals that drank plain water. The researchers also noted a greater than 50 percent reduction in inflammation of the primary target of this bacterium – the body of the stomach – in treated mice but not in controls.

In a related experiment, the team fed the same dose of broccoli sprouts for the same amount of time to H. pylori-infected mice that had been genetically engineered to lack the Nrf2 gene that activates protective enzymes. “These knock-out mice didn’t respond,” Fahey says, which confirms previous findings for a role of Nrf2 in protection against H. pylori-induced inflammation and gastritis.


Classified a carcinogen by the World Health Organization, H. pylori is a gastrointestinal tract germ that manages to thrive in the lining of the stomach despite the strength of natural acids there that rival that of car batteries. Afflicting several billion people – roughly half of the world’s population – this corkscrew-shaped bacterium has long been associated with stomach ulcers, which now are frequently cured by antibiotics. Research strongly suggests that the bacteria also are linked to high rates of stomach cancer in some countries, that strains resistant to standard antibiotics are prevalent, and that multiple courses of standard antibiotics do not always eliminate the infection.

Working in Japan where there is high incidence of chronic H. pylori-infection, the research team gave 25 H. pylori-infected subjects two and a half ounces (70 grams) per day of broccoli sprouts for two months. Another 25 infected people consumed an equivalent amount of alfalfa sprouts which, although rich in phytochemicals, don’t contain sulforaphane.

The researchers assessed the severity of Helicobacter infection at the start of the study, after four and eight weeks of treatment, and again eight weeks after intervention was stopped. They used breath tests to assess colonization by H. pylori bacteria and blood tests to judge the severity of inflammation in the stomach lining; in addition, they looked for antigens in stool samples to help determine the extent of the infections.

“We know that a dose of a couple ounces a day of broccoli sprouts is enough to elevate the body’s protective enzymes,” Fahey says. “That is the mechanism by which we think a lot of the chemoprotective effects are occurring.

“What we don’t know is whether it’s going to prevent people from getting stomach cancer. But the fact that the levels of infection and inflammation were reduced suggests the likelihood of getting gastritis and ulcers and cancer is probably reduced.”

In disclosure of a potential conflict of interest, Fahey is a cofounder of, but holds no equity in, a company that is licensed by The Johns Hopkins University to produce broccoli sprouts. A portion of the proceeds is used to help support cancer research, but no such funds were provided to support this study.

“It’s exciting that a chronic bacterial infection that poses great hazards to hundreds of millions of people globally can be ameliorated by a specific dietary strategy,” says Paul Talalay, M.D., John Jacob Abel Distinguished Service Professor of Pharmacology and Experimental Therapeutics and director of the Lewis B. and Dorothy Cullman Cancer Chemoprotection Center at Johns Hopkins’ Institute for Basic Biomedical Sciences.

Talalay directs the lab where, in 1992, his team discovered the health-promoting properties of sulforaphane. A longtime proponent of cancer prevention and chemoprotection, Talalay eats fresh broccoli sprouts regularly, as does Fahey.

“I like them,” Fahey says. “I eat them all the time, but not every day. Variety is the spice of life: I eat blueberries on the other days.”

In addition to Fahey, the authors of the paper are Akinori Yanaka, Atsushi Fukumoto, Mari Nakayama and Souta Inoue, Tokyo University of Science, Japan; Masayuki Yamamoto, Songhua Zhang, Masafumi Tauchi, Hideo Suzuki and Ichinosuke Hyodo, University of Tsukuba, Japan.


New Technique Invented to Reveal Pancreatic Stem Cells
Wanted: stems cells. Just like those absconders chased by police all over the world, everybody can tell about their good deeds but none really knows how to recognize them

Yet, as of today, thanks to a study just published in the Proceedings of the National Accademy of Sciences (PNAS) and authored by Nobel Laureate for Medicine in 2007 Mario Capecchi and by the researcher from the Catholic University of Rome Eugenio Sangiorgi, we now know how to reveal the stem cells camouflaged in the pancreas.

A stem cell is a cell capable of generating all the other cells constituting the same tissue (sometimes also called "adult stem cell").

"Reading the newspapers sometimes one would doubt it – says Sangiorgi – but we don't know many things about stem cells. It might look odd, but for instance we don't have a method to distinguish a priori between a stem cell and any other cell in the same tissue. We can only infer that a cell really is a stem cell by observing its behaviour".

In other words, when a researcher encounters a tissue, it's not immediately possible to identify with certainty and thus isolate a stem cell. In some case, like in the meadows, we now know where they are located and how to single them out – and hence we have been capable of successful life saving transplants for many years. But in the case of the pancreas, as in that of many other tissues, until some years ago we doubted that these special cells were even present there.

"Together with Professor Capecchi, we had already designed in the past a novel way to mark the stem cells in a tissue: a sort of little flag, capable of helping us to effectively label the cells we were looking for", explains Sangiorgi. In order to achieve this, Capecchi and Sangiorgi used a molecular switch, that is a piece of DNA, which activates itself once the mouse under scrutiny takes a special drug. When the switch is "on", a special fluorescent protein is produced (and, as a matter of fact, the study about this type of proteins won the Nobel Prize in Chemistry last October). The luminous cells are indeed the long-sought stem cells.

"In order to understand that these are really stem cells, we need only to wait", comments Sangiorgi. "A normal cell is sooner or later destined to die. A stem cell, instead, retains its capacity to renew itself and replicate. Thus, if we can still observe, many months later, that a cell is still alive, that means it is indeed a stem cell – or a cell derived directly from the division of a stem cell".

In the newly published article, Sangiorgi and Capecchi have shown with their technique that a particular subset of the pancreatic cells, the so-called acinar cells, are indeed stem cells. The truly interesting aspect of their results is that these cells also produce important digestive enzymes.

"So far, a stem cell was really looked upon as a sort of General, in charge of all the other cells, but really doing nothing: an undifferentiated cell, but with no specific task other than generating new tissue. Acinar cells, on the other hand, despite being proved stem cells, have a well defined task in the pancreas. They are like soldiers doing their job, but also capable – when necessary – of taking over the reins of the government", tells Sangiorgi with a metaphor.

The work of Capecchi and Sangiorgi paves the way to an extension of the definition of the stem cell, which will lead to a more detailed study on the proliferation mechanisms at the root of the success of these cells – and of their potential danger.

"Thanks to their extraordinary reproductive power – Sangiorgi, in fact, explains – these cells might even turn out to be carcinogenic. But if we are capable of constructing an effective instrument like ours in order to isolate and study them even in other organs, we can study their properties and give many answers about the way they work. One of the things we would like to understand is if also in vivo these types of cells – somehow eternal – are more tumour-sensitive – for instance because they tend to accumulate all the potential environmental risk factors throughout their very long life".

Eugenio Sangiorgi has been collaborating with Mario Capecchi for many years: "I already admired him a great deal before he won the Nobel Prize", he says. "The nicest thing about him is that – even at 72 – he keeps working in active research and continues being as enthusiastic as a child, always full of new ideas".

How the Retina Works: Like a Multi-Layered Jigsaw Puzzle
About 1.25 million neurons in the retina - each of which views the world only through a small jagged window called a receptive field - collectively form the seamless picture we rely on to navigate our environment. Receptive fields fit together like pieces of a puzzle, preventing "blind spots" and excessive overlap that could blur our perception of the world, according to researchers at the Salk Institute for Biological Studies.

In the April 7 issue of the journal Public Library of Science, Biology, the scientists say their findings suggest that the nervous system operates with higher precision than previously appreciated and that apparent irregularities in individual cells may actually be coordinated and finely tuned to make the most of the world around us.

Previously, the observed irregularities of individual receptive fields suggested that the collective visual coverage might be uneven and irregular, potentially posing a problem for high-resolution vision. "The striking coordination we found when we examined a whole population indicated that neuronal circuits in the retina may sample the visual scene with high precision, perhaps in a manner that approaches the optimum for high-resolution vision," says senior author E.J. Chichilnisky, Ph.D., an associate professor in the Systems Neurobiology Laboratories.

All visual information reaching the brain is transmitted by retinal ganglion cells. Each of the 20 or so distinct ganglion cell types is thought to transmit a complete visual image to the brain, because the receptive fields of each type form a regular lattice covering visual space. However, within each regular lattice, the individual cells' receptive fields have irregular and inconsistent shapes, which could potentially result in patchy coverage of the visual field.

To understand how the visual system overcomes this problem, postdoctoral researcher and first author Jeffrey L. Gauthier, Ph.D., used a microscopic electrode array to record the activity of ganglion cells in isolated patches of retina, the tissue lining the back of the eye.

After monitoring hundreds of ganglion cells over several hours, he distinguished between different cell types based on their light response properties. "Often people record from many cells simultaneously but they don't know which cell belongs to which type," says Gauthier. Without this information, he says, he wouldn't have been able to observe that the receptive fields of neighboring cells of a specific type interlock, complementing each others' irregular shapes.

"The receptive fields of all four cell types we examined were precisely coordinated," he says, "but we saw no coordination between cells of different types, emphasizing the importance of clearly distinguishing one cell type from another when studying sensory encoding by a population of neurons."

Biomarker Associated With Poor Outcome in Neurobalstoma
Results from a new study identify a biomarker that may be useful for predicting the outcome of treatment for neuroblastoma, the most common cancer in young children

The research, published by Cell Press in the April 7th issue of the journal Cancer Cell, also provides new information about the molecular signals that are involved in the progression of this often devastating pediatric cancer.

Retinoic acid (RA) is a metabolite of Vitamin A that has important influences over the processes of growth and differentiation. RA mediates gene expression by interacting with retinoic acid receptors (RARs) that, in the presence of RA, switch from repressing target genes to activating them. Because many targets of RA induce differentiation or cell death, RA is used as a therapeutic agent in many cancers, including neuroblastoma.

"Many neuroblastoma patients exhibit aggressive tumors with poor clinical outcome," explains senior study author Dr. Rene Bernards from The Netherlands Cancer Institute. "While some of these aggressive tumors exhibit increased expression of the MYCN oncogene, little is known about the other genetic factors that control neuroblastoma progression." Dr. Bernards and colleagues performed a genome-wide RNA interference screen to search for additional components of the RA signaling pathway that might be linked to neuroblastoma.

The researchers identified ZNF423 as a critical cofactor of RA-induced differentiation. Reduced expression of ZNF423 was led to a growth advantage and resistance to RA differentiation in neuroblastoma cells while increased expression of ZNF423 led to growth inhibition and enhanced differentiation. The researchers went on to show that ZNF423 interacts with the RAR?/RXR? nuclear receptor that is necessary for activation in response to retinoids.

Importantly, low expression levels of ZNF423 were associated with poor disease outcome in neuroblastoma patients, suggesting that the gene might be useful as a prognostic biomarker. "Expression levels of ZNF423 could significantly affect responses to both endogenous and pharmacological concentrations of RA in cancer patients, which may in turn influence the outcome of neuroblastoma," offers Dr. Bernards. "Therefore, ZNF423 may be a useful biomarker for predicting responses to RA-based therapies, which are increasingly being used to treat neuroblastoma."



MONDAY April 6, 2009---------------------------News Archive

Gum Disease a Potential Risk for Gestational Diabetes
A new study by NYU dental researchers has uncovered evidence that pregnant women with periodontal (gum) disease face an increased risk of developing gestational diabetes even if they don't smoke or drink, a finding that underscores how important it is for all expectant mothers – even those without other risk factors – to maintain good oral health

The study, led by Dr. Ananda P. Dasanayake, Professor of Epidemiology & Health Promotion at New York University College of Dentistry in collaboration with the Faculty of Dental Sciences at the University of Peradeniya, Sri Lanka, eliminated smoking and alcohol use among a group of 190 pregnant women in the South Asian island nation of Sri Lanka, where a combination of cultural taboos and poverty deter the majority of women from smoking and drinking. The findings support an earlier study led by Dr. Dasanayake that found evidence that pregnant women with periodontal disease are more likely to develop gestational diabetes than pregnant women with healthy gums.

That study, which followed 256 women at New York's Bellevue Hospital Center through their first six months of pregnancy, showed that 22 of the women developed gestational diabetes. Those women had significantly higher levels of periodontal bacteria and inflammation than the other women in the study. The findings were published in the April 2008 issue of the Journal of Dental Research.

More than one-third of the women in the new study, which was conducted over the course of one year, reported having bleeding gums when they brushed their teeth. The women were given a dental examination and a glucose challenge test, which is used specifically to screen for gestational diabetes. According to Dr. Dasanayake, those women found to have the greatest amount of bleeding in their gums also had the highest levels of glucose in their blood. Dr. Dasanayake, who presented the findings today at the annual meeting of the International Association for Dental Research in Miami, said that he expected the final data to show that between 20 and 30 of the women had developed gestational diabetes.

Gestational diabetes is characterized by an inability to transport glucose - the main source of fuel for the body - to the cells during pregnancy. The condition usually disappears when the pregnancy ends, but women who have had gestational diabetes are at a greater risk of developing the most common form of diabetes, known as Type 2 diabetes, later in life. Asians, Hispanics, and Native Americans are at the highest risk for developing gestational diabetes. All of the women in the Sri Lanka study were of Asian origin, while 80 percent of the New York study subjects were Hispanic.

"In addition to its potential role in preterm delivery, evidence that gum disease may also contribute to gestational diabetes suggests that women should see a dentist if they plan to get pregnant, and after becoming pregnant," Dr. Dasanayake said. "Treating gum disease during pregnancy has been shown to be safe and effective in improving women's oral health and minimizing potential risks."

Chemically Created DNA Walker Mimics Role of Cell’s Transportation System
Chemists at New York University and Harvard University have created a bipedal, autonomous DNA “walker” that can mimic a cell’s transportation system

The device, which marks a step toward more complex synthetic molecular motor systems, is described in the most recent issue of the journal Science. For a video demonstration of the walker, please click here.

Two fundamental components of life’s building blocks are DNA, which encodes instructions for making proteins, and motor proteins, such as kinesin, which are part of a cell’s transportation system. In nature, single strands of DNA-each containing four molecules, or bases, attached to backbone-self-assemble to form a double helix when their bases match up. Kinesin is a molecular motor that carries various cargoes from one place in the cell to another. Scientists have sought to re-create this capability by building DNA walkers.

Earlier versions of walkers, which move along a track of DNA, did not function autonomously, thereby requiring intervention at each step. A challenge these previous devices faced was coordinating the movement of the walker’s legs so they could move in a synchronized fashion without falling off the track.

To create a walker that could move on its own, the NYU and Harvard researchers employed two DNA “fuel strands” (purple and green in the above video). These fuel strands push the walker (blue) along a track of DNA, thereby allowing the walker and the fuel strands to function as a catalytic unit. The forward progress of the system is driven by the fact that more base pairs are formed every step-a process that creates the energy necessary for movement.

As the walker moves along the DNA track, it forms base pairs. Simultaneously, the fuel strands move the walker along by binding to the track and then releasing the walker’s legs, thereby allowing the walker to take “steps”.

T
he track’s length is 49 nanometers - if the track was one meter long, an actual meter, enlarged proportionally, would be the approximate diameter of the earth.

The walker was created in the laboratory of NYU Chemistry Professor Nadrian Seeman, one of the article’s co-authors. The paper’s other authors were Tosan Omabegho, a doctoral candidate at Harvard’s School of Engineering and Applied Sciences, and Ruojie Sha, a senior research associate in the NYU Chemistry Department.

Nicotine May Have More Profound Impact Than Thought
Brown University researchers have identified 55 proteins that interact with a receptor in mice known previously to bind with nicotine. The findings, detailed in an April 3 article in the Journal of Proteome Research, could have broad implications for future treatments for nicotine addiction, the search for new drug targets and treatments for diseases such as schizophrenia.

Nicotine isn’t just addictive. It may also interfere with dozens of cellular interactions in the body, new Brown University research suggests.

Conversely, the data could also help scientists develop better treatments for various diseases. Pharmaceutical companies rely on basic research to identify new cellular interactions that can, in turn, serve as targets for potential new drugs.

“It opens several new lines of investigation,” said lead author Edward Hawrot, professor of molecular science, molecular pharmacology, physiology and biotechnology at Brown University.

Hawrot’s research is highlighted in a paper published April 3 in the Journal of Proteome Research. He and a team that included graduate students William Brucker and Joao Paulo set out to provide a more basic understanding of how nicotine affects the process of cell communication through the mammalian nervous system.

The Brown University researchers looked specifically at the alpha-7 nicotinic acetylcholine receptor in mouse brain tissue. A very similar receptor exists in humans. The alpha-7 receptor is the most enigmatic of the so-called “nicotinic” receptors, so named because nicotine binds to them when it is introduced into the body. Most receptors are on the surface of cells and are sensitive to small signaling molecules such as the neurotransmitter acetylcholine, which is the naturally occurring signal the body uses to activate alpha-7 receptors.

Their discovery: 55 proteins were found to interact with the alpha-7 nicotinic receptor. Scientists had not previously known of those connections.

“This is called a “nicotinic” receptor and we think of it as interacting with nicotine, but it likely has multiple functions in the brain,” Hawrot said. “And in various, specific regions of the brain this same alpha-7 receptor may interact with different proteins inside neurons to do different things.”

One in particular - the G alpha protein - was among the most unexpected proteins to be identified in the study, as it is usually associated with a completely different class of receptors (the eponymous G-protein coupled receptors (GPCRs).

This finding is significant because G alpha proteins are involved in many different biochemical and signaling processes throughout the brain and the rest of the body. body.

An example of the importance of G alpha proteins: 40 percent of all currently used therapeutic drugs target a member of the large GPCR family of receptors.

The new finding suggests that the alpha-7 receptors have a much broader role in the body than previously suspected and that the newly identified associated proteins could also be affected when nicotine binds to the alpha-7 receptor.

Nicotine may affect bodily processes - and perhaps the actions of other commonly used drugs - more broadly than was previously thought.

This advance could lead to the development of new treatments to combat smoking addiction. At the same time, the finding could also have future implications for diseases such as schizophrenia, Hawrot said.

Recent genetic studies have suggested that some cases of schizophrenia are associated with deletions where a block of genes, including the gene for the alpha-7 receptor, is missing. Hawrot said the connection, while not conclusive, offers hope for new strategies in the development of treatments for those suffering from the disorder.

To conduct their study, Hawrot’s lab looked at mice genetically engineered by other researchers to lack the alpha-7 nicotinic acetylcholine receptor. Those mice were compared with normal mice, so the difference in receptor-associated proteins could be highlighted.

Grants from the National Institutes of Health and the Rhode Island Research Alliance helped support the study.

Scientists Show How a Neuron Gets its Shape
Ask a simple question, get a simple answer: When Abraham Lincoln was asked how long a man’s legs should be, he absurdly replied, “Long enough to reach the ground.” Now, by using a new microscopy technique to watch the growth of individual neurons in the microscopic roundworm Caenorhabditis elegans, Rockefeller University researchers are turning another deceptively simple question on its head. They asked, “How long should a worm’s neurons be?” And the worms fired back, “Long enough to reach their targets.”

The researchers’ surprising result: Rather than growing like the branches of a tree - extending outward - certain neurons work backward from their destination, dropping anchor and stretching their dendrites behind them as they crawl away. The work, led by Shai Shaham, head of the Laboratory of Developmental Genetics, and Maxwell Heiman, a research associate in the lab, not only addresses an age-old question of how neurons get their shape, but is also changing the way scientists think about the genetic program that wires the brain and allows it to grow throughout development.
Grounded. Live footage of transparent C. elegans embryos shows how a developing sensory neuron gets its shape. After the neuron drops anchor at the tip of the worm’s nose, the cell body crawls away, stretching the dendrite out behind it as it goes.

“When I came to the lab, I thought that you would build a brain just like you would a house,” says Heiman. “The cell would measure the distance between its cell body and its target and then specify a dendrite of that length. Now, I’m not thinking about that kind of physical map at all. I think of a connectivity map, where what’s programmed are these connections among neurons and between neurons and their anchoring points.”

Since they were interested in how neurons get their shapes, Heiman and Shaham used a chemical to randomly mutate genes and then screened through thousands of animals for ones whose neurons were shaped abnormally. They specifically looked at a group of 12 sensory neurons whose dendritic tips converge at the worm’s nose in a sensory organ called the amphid. These dendritic tips collect information from the outside environment and give the worm cues on how to react to it.

Two genes, called dex-1 and dyf-7, caught their attention. If the animals had a mutation in either one of these genes, Heiman and Shaham saw that even though the cell migrated normally away from the tip of the nose, the dendrite didn’t stay anchored. Instead, it dragged along behind the cell body, resulting in an abnormally short dendrite. When they looked at the function of the proteins, the researchers found that they form a matrix to which the dendrites are anchored. Without the matrix to anchor the neuron, the dendrites didn’t form properly.

The two proteins, it turns out, are very similar to proteins that anchor the hair cells that detect sound waves in the human ear. “That was our second surprise,” says Heiman. “That there is this evolutionary relationship between a sensory organ in a worm and a sensory organ in humans. In the case of the worm, the anchor is being used to resist the force of cell migration. In our ear, it is the same anchor but it is being used for a completely different purpose.”

The scientists’ theory that the brain is wired based on connectivity (not absolute distance) provides an explanation of how the brain grows in proportion to the growth of an organism. “As the worm grows, its dendrites get longer and longer and the position of cell bodies change as they move farther away from a synapse,” says Shaham. “But what stays the same are these connections.”

Model System Reveals Cell Communication Via Amino Acids
MGH study identifies a novel mode of interaction between cells

A team of researchers from the Massachusetts General Hospital Center for Engineering in Medicine (MGH-CEM) has found the first evidence of cell-to-cell communication by amino acids, the building blocks of proteins, rather than by known protein signaling agents such as growth factors or cytokines. Their report will appear in an upcoming issue of the FASEB Journal and has been released online.

"We were taken by complete surprise," says Rohit Jindal, PhD, a postdoctoral fellow at MGH-CEM and the paper's lead author. "Past reports have implicated various growth factors and the extracellular matrix proteins secreted by other cell types in regulating hepatocyte behavior, but to the best of our knowledge, this is the first evidence that cells can communicate by changing local amino acid concentrations."

The authors describe the development of a three-dimensional model of liver tissue in which hepatocytes (liver cells) are embedded in a layer of collagen and covered with a layer of endothelial cells – the cells that line blood vessels, which permeate the liver. In this model system liver cells recovered their metabolic activity much faster than in previous models – in two days instead of a week or longer. The fundamental discovery was that the amino acid proline was responsible for this enhanced recovery. A building block of collagen, proline was secreted by the endothelial layer of the liver model, taken up by hepatocytes and used to synthesize new collagen, leading to faster recovery of hepatocyte activity.

"Identifying this amino-acid-mediated communication points to the importance of considering changes in metabolism while evaluating cell-to-cell communication," says Martin Yarmush, MD, PhD, director of the MGH-CEM and the paper's senior author. "Metabolic factors are gaining prominence in our understanding of a number of diseases, and establishing the contribution of different cell types to the metabolic milieu could provide new drug targets in the treatment of liver disease." Yarmush is the Helen Andrus Benedict Professor of Surgery and Bioengineering at Harvard Medical School (HMS).

Co-author Yaakov Nahmias, PhD, of MGH-CEM, adds, "It's not currently clear whether this mechanism occurs in living animals, but it could contribute to active liver remodeling during liver development or regeneration." Additional co-authors of the FASEB Journal paper are Arno Tilles, MD, and Francois Berthiaume, PhD, both of the MGH-CEM. The work was supported by grants from the National Institutes of Health and Shriners Hospitals for Children.

Malfunction of Respiratory Epithelium Cause of Allergy?
One reason for the development of allergy may be malfunction of the respiratory epithelium, which allows allergens to bind to, enter and travel through the epithelium. Two studies by Finnish research groups on this subject have recently been published in two international biomedical journals (1) Allergy, and (2) Journal of Allergy and Clinical Immunology

Research on the mechanisms of allergy has focused on the understanding of aberrant immunoresponses. Only lately the role of epithelium as the first line of defense against allergens has been realized. So far, we do not know why and how allergens are transported through the epithelium.

The research groups of the Helsinki University and Helsinki University Central Hospital in collaboration with several other Finnish research groups aimed to clarify what happens in the epithelium immediately after allergen exposure, before the allergic reaction develops. They used birch pollen allergen (Bet v 1) exposure and showed that this allergen binds to, enters and travels through conjunctival and nasal epithelium of allergic patients but not of healthy subjects within one minute after the exposure. An allergic reaction developed when the allergen reached mast cells under the basement membrane.

During the research it became evident that during spring, in allergic patients the birch pollen allergen Bet v 1 changed the expression of hundreds of genes of the nasal epithelium compared to samples taken during winter; and of these genes several were connected with protein transport and regulation of cytoskeleton. An astonishing finding was that the immune response of in healthy controls to pollen exposure was strong, and hundreds of genes changed their expression during winter and spring; however, many of these genes were related to the function of the immune response.

"We were able to describe a mechanism whereby birch pollen allergen Bet v 1 travels through the epithelium of allergic patients but not of healthy subjects. This kind of transport mechanisms are used by several viruses and bacteria when invading the epithelium and infecting patients", explains Professor Risto Renkonen (Haartman Institute, University of Helsinki and HUSLAB, Helsinki, Finland).

A systems biological approach was used in these studies, where data obtained concomitantly by several different methods is collected into a massive data warehouse allowing one to start analyzing the roles of different proteins and their networks in the pathogenesis of allergic reactions.

Reductionistic analyses, i.e., work focusing on one or only a few molecules are gradually replaced by systems approaches. The ability to discover new, etiologically relevant disease mechanisms is the major motivation for unbiased explorative approaches. The drawback of such top-down experiments is that they are very expensive and produce much more raw data than hypothesis-derived approaches thus generating an overflow of data. However, the urgent need to develop in silico data managing and analysis environments has been recognized by several research groups and biocompanies.


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