Mice Stressed In Simulated Weightlessness Show Organ Atrophy

A ground-based, experimental model used to simulate astronaut weightlessness in space has provided Rutgers scientists an opportunity to study the effects of stress on immune organs.



Earlier collaborative research with Japanese scientists employing this model implicated the protein osteopontin (OPN) in bone mineral loss associated with simulated weightlessness in mice. This research was made possible by the creation at Rutgers of a mouse unable to make OPN (a "knock-out" mouse). Studies with this Rutgers mouse have demonstrated that OPN likely plays a role in a variety of human problems including cancer metastasis, multiple sclerosis and other autoimmune diseases, osteoporosis and certain inflammatory responses.



The new study, which also simulated weightlessness, demonstrated that OPN is required for the atrophy of immune organs brought on by the stress resulting from hindlimb unloading - a technique employed to simulate weightless conditions by lifting the animal's body weight off its hind legs. Results were presented Sept. 3 online in the Proceedings of the National Academy of Sciences (PNAS) and in the Sept. 11 print issue.



"The bone loss seen in astronauts or bedridden patients is not a stress issue," explained David Denhardt, a professor in the Department of Cell Biology and Neuroscience at Rutgers, The State University of New Jersey. "They are experiencing a loss of weight bearing on the bones, and the loss of bone mineral is a direct result of this load reduction."



The presence of OPN, a feature common to both the bone loss and the organ atrophy, is produced by two different causes - weightlessness and stress - coincidentally related to the same laboratory conditions.



OPN is the continuing focus of Denhardt's research interests. His long-term goal is to develop an OPN antibody - a monoclonal or target-specific antibody - that will inhibit OPN function in lab mice, and ultimately, in humans. This antibody could prove useful in treating the many destructive diseases associated with OPN.



Denhardt's graduate student Kathryn Wang, a co-author on the PNAS paper, had previously conducted experiments in which the mouse was positioned in such a way as to produce hind limb unloading. This simulated weightless condition produced OPN-dependent bone loss in the hind limbs and provided a potential testing ground for possible OPN antibodies.


The specialized equipment for that experiment was supplied by another co-author on the paper, Yufang Shi, a professor in the Department of Molecular Genetics, Microbiology and Immunology at Robert Wood Johnson Medical School-University of Medicine and Dentistry of New Jersey.



Shi, an authority on stress, suggested that along with the bone loss studies, the Rutgers researchers should look at the spleen and thymus - the organs responsible for most of the animal's immune cells. If stress affects the spleen and thymus so that they atrophy, the immune system becomes impaired. People under severe stress often get sick.



The Rutgers scientists took their colleague's advice and compared the OPN-deficient knock-out mice to normal mice, with some dramatic results.



"To our astonishment and surprise, the OPN-deficient animals responded differently to the stress than the normal controls," Denhardt said. "We had no basis to expect this, but the spleen and thymus of the OPN-deficient animals remained normal whereas there was atrophy of the spleen and thymus in the normal controls. This was a novel and totally unexpected result for which we have no explanation at this time. The next phase of our research will ask what exactly is going on."



The stressed normal mice also displayed elevated levels of corticosterone - a hormone known to induce apoptosis (programmed cell death), a process evident in the spleen and thymus of these mice and a possible mechanism underlying the atrophy.



Denhardt said that their results indicate that OPN needs to be present for these stress related symptoms to occur, pointing to a whole new physiological realm in which the culprit osteopontin is causing problems.

New Nanolaser Key To Future Optical Computers And Technologies

Researchers have created the tiniest laser since its invention nearly 50 years ago, paving the way for a host of innovations, including superfast computers that use light instead of electrons to process information, advanced sensors and imaging.


Because the new device, called a "spaser," is the first of its kind to emit visible light, it represents a critical component for possible future technologies based on "nanophotonic" circuitry, said Vladimir Shalaev, the Robert and Anne Burnett Professor of Electrical and Computer Engineering at Purdue University.


Such circuits will require a laser-light source, but current lasers can't be made small enough to integrate them into electronic chips. Now researchers have overcome this obstacle, harnessing clouds of electrons called "surface plasmons," instead of the photons that make up light, to create the tiny spasers.


Findings are detailed in a paper appearing online in the journal Nature that reports on work conducted by researchers at Purdue, Norfolk State University and Cornell University.


Nanophotonics may usher in a host of radical advances, including powerful "hyperlenses" resulting in sensors and microscopes 10 times more powerful than today's and able to see objects as small as DNA; computers and consumer electronics that use light instead of electronic signals to process information; and more efficient solar collectors.


"Here, we have demonstrated the feasibility of the most critical component - the nanolaser - essential for nanophotonics to become a practical technology," Shalaev said.


The "spaser-based nanolasers" created in the research were spheres 44 nanometers, or billionths of a meter, in diameter - more than 1 million could fit inside a red blood cell. The spheres were fabricated at Cornell, with Norfolk State and Purdue performing the optical characterization needed to determine whether the devices behave as lasers.


The findings confirm work by physicists David Bergman at Tel Aviv University and Mark Stockman at Georgia State University, who first proposed the spaser concept in 2003.


"This work represents an important milestone that may prove to be the start of a revolution in nanophotonics, with applications in imaging and sensing at a scale that is much smaller than the wavelength of visible light," said Timothy D. Sands, the Mary Jo and Robert L. Kirk Director of the Birck Nanotechnology Center in Purdue's Discovery Park.


The spasers contain a gold core surrounded by a glasslike shell filled with green dye. When a light was shined on the spheres, plasmons generated by the gold core were amplified by the dye. The plasmons were then converted to photons of visible light, which was emitted as a laser.


Spaser stands for surface plasmon amplification by stimulated emission of radiation. To act like lasers, they require a "feedback system" that causes the surface plasmons to oscillate back and forth so that they gain power and can be emitted as light. Conventional lasers are limited in how small they can be made because this feedback component for photons, called an optical resonator, must be at least half the size of the wavelength of laser light.


The researchers, however, have overcome this hurdle by using not photons but surface plasmons, which enabled them to create a resonator 44 nanometers in diameter, or less than one-tenth the size of the 530-nanometer wavelength emitted by the spaser.


"It's fitting that we have realized a breakthrough in laser technology as we are getting ready to celebrate the 50th anniversary of the invention of the laser," Shalaev said.


The first working laser was demonstrated in 1960.


The research was conducted by Norfolk State researchers Mikhail A. Noginov, Guohua Zhu and Akeisha M. Belgrave; Purdue researchers Reuben M. Bakker, Shalaev and Evgenii E. Narimanov; and Cornell researchers Samantha Stout, Erik Herz, Teeraporn Suteewong and Ulrich B. Wiesner.


Future work may involve creating a spaser-based nanolaser that uses an electrical source instead of a light source, which would make them more practical for computer and electronics applications.


The work was funded by the National Science Foundation and U.S. Army Research Office and is affiliated with the Birck Nanotechnology Center, the Center for Materials Research at Norfolk State, and Cornell's Materials Science and Engineering Department.


Source
Purdue University

Isolation Of A New Gene Family Essential For Early Development

All organisms consist of a number of different cell types each producing different proteins. The nerve cells produce proteins necessary for the nerve cell function; the muscle cells proteins necessary for the muscle function and so on. All these specialised cells originate from the same cell type the embryonic stem cells. In a highly controlled process called differentiation, the stem cells are induced to become specialised cells.


Gene family helps regulate stem cell differentiation


The BRIC researchers have now identified a new gene family, which by modifying gene expression is essential for the regulation of the differentiation process. These results have been obtained by using both human and mouse stem cells, as well as by studying the devel-opment of the round worm, C. elegans.


Perspectives


The new findings are in line with a number of recent publications that support the idea that differentiation may not entirely be a "one-way process", and may have impact on the therapeutic use of stem cells for the treatment of various genetic diseases such as cancer and Alzheimers disease.


The research was carried out by a team led by Professor Kristian Helin at the new established Centre for Epigenetics at BRIC, University of Copenhagen, in cooperation with researchers at the University of Edinburgh, and the Weizmann Institute of Science, Israel.


Epigenetics


Epigenetics is a relatively new field of research but nonetheless "hot" within biotechnological and biomedical research now. With the open-ing of Centre for Epigenetics University of Copenhagen joins the re-search front internationally, e.g. the EU has initiated a research net work for epigenetics see epigenome.eu


Centre for Epigenetics is financed by the Danish Research Foundation for a period of five years as one of the eight newly established "Centres of Excellence". The centre, which consists of four research groups, is led by Professor Kristian Helin, BRIC, University of Copen-hagen.


UNIVERSITY OF COPENHAGEN

RectorВґs Office

NГёrregade 10, P.O.Box 2177

DK-1017 Copenhagen K

ku.dk

UCSD Biologists Find New Evidence For One-Way Evolution

By tracing the 30-million year history of variation in a gene found in plants such as tomatoes and tobacco, biologists at the University of California, San Diego have found new evidence to support an old idea - that some evolutionary changes are irreversible.



Their study, published this week in an early online edition of the journal Proceedings of the National Academy of Sciences, offers new support for the idea that the loss of complex traits, like eyes, wings or in this case a reproductive mechanism, is often irreversible. In other words, once lost, the traits never revert to their original state.



"This is the strongest evidence yet to support irreversibility," said Joshua Kohn, an associate professor of biology at UCSD who headed the study. "If we had not used the genetic data coding for this reproductive mechanism and only inferred the pattern of evolution based on the traits of living species, we would have come to the opposite conclusion and with high statistical support - that the trait evolved more than once."



The scientists examined existing variation in the gene used by many members of the Solanaceae family, which include tomatoes and tobacco, to recognize and reject their own pollen, thereby avoiding self-fertilization and the harmful effects of inbreeding. This ability is sometimes lost, as is the case for garden tomatoes, which can set seed by self-fertilization. Apparently, once lost, the ability to reject pollen in order to prevent self-fertilization is never regained.



Irreversible loss of complex traits, which result from the combined interaction of several genes, is an old and at times controversial scientific question. While the late evolutionary biologist Stephen Jay Gould popularized the hypothesis of irreversibility, known as Dollo's Law, studies that use current methods to reconstruct the evolution of complex traits often fail to support it. This is because it is often difficult to reconstruct characteristics of extinct ancestors with any certainty.



The study contradicts earlier studies of complex trait evolution, which have tended to favor multiple reappearances of complex traits after these organs were lost in ancestral species. The authors suggest that traditional methods for reconstructing the history of trait evolution may be inaccurate.



Discovering irreversible change for this sexual system trait highlights the importance of considering genetic data underlying the trait when reconstructing its evolutionary history.



"Our work implies that evidence for such evolutionary change in other cases may have been missed because the current methods aren't sufficiently refined," said Boris Igic, who conducted the study while a graduate student at UCSD and is now a postdoctoral fellow at Cornell University.



While lending support to the question of unidirectional evolution, the biologists' findings also lead to new questions.



"Apparently, plants that have sex exclusively with other plants and not themselves, enjoy a greater evolutionary advantage," Igic said. "Exactly why is unclear,"



Species capable of rejecting their own pollen in favor of pollen from other individuals, harbor more genetic variation than those that self-fertilize.



"An intriguing aspect of this study is that the mechanism for ensuring cross-fertilization is very old, often lost, and never regained," Kohn said. "That it is still common despite frequent and irreversible loss implies that this trait confers an advantage to species that possess it, perhaps in terms of reduced rates of extinction."



The study was supported by a grant from the National Science Foundation.


ucsd

Very Early Indicator Of Type 2 Diabetes Is Low Levels Of PYY Hormone

It may soon be possible to take a simple blood test and predict whether or not someone has low levels of a particular molecule, predisposing them to the development of Type 2 diabetes. If the test is positive, it may then be possible to use preventative treatment, slowing down, or even halting that development.



Such is the hope of scientists and clinicians at Sydney's Garvan Institute of Medical Research who have shown conclusively that people who produce low levels of the molecule PYY have a higher risk of developing Type 2 diabetes and obesity.



The findings were published online in the prestigious International Journal of Obesity.



It is already known that the hormone PYY, which is released from the gut after a meal, creates a feeling of satiety. When PYY is in oversupply, it prevents diet-induced obesity in mice.



Professor Herbert Herzog, Director of Garvan's Neuroscience Program, and an expert on appetite, says that the new findings are important in that they show a metabolic defect before the presence of any disease or manifestation of weight gain. "We can now see that low PYY levels after eating are a very early predictor of the development of obesity and Type 2 diabetes," he said.



Professor Lesley Campbell, Director of Diabetes Services at St. Vincent's Hospital and a senior member of Garvan's Diabetes and Obesity Clinical Studies group, has been researching genetic factors in the development of Type 2 diabetes for over 10 years. Specifically, her research looks at people before they get the disease, the contributing factors, and the effects of the diabetes.



Professor Campbell has already published findings that insulin resistant people, with a family history of Type 2 diabetes, have low levels of PYY. "In earlier studies we hinted at the fact that before any of the abnormalities of diabetes are present, people already have an abnormality of satiety, marked by the lack of the secretion of this PYY hormone," she said.



"We now have published that, even earlier in the development of diabetes, people who are not yet insulin resistant show a low secretion of PYY. They have a blunted post-meal secretion of this hormone, making them less likely to feel satiety, and more likely to gain weight."



Professor Campbell's research involved elaborate testing of two groups of people, eight in each group, over a period of two years. One group had relatives with Type 2 diabetes, the other group had no family history of the disease. The groups were matched for gender, for age and for adiposity.



"It was most important to match the groups for their fatness," said Professor Campbell. "The only difference was their relatives. You assume that they are carrying the genetic burden of diabetes, which we already know to be a reality."



"Low levels of PYY at this very early pre-diabetes stage could be used as a marker, or predictor, that Type 2 diabetes is very likely to develop."



"As a clinician, I am hopeful that it will be possible to screen extensively in the future, and therefore stem the spread of this debilitating disease."







Source: Alison Heather


Research Australia

Research Into Chromosome Disorders Has Potential To Reduce Risk Of Foetal Damage

Chromosome disorders in sex cells cause infertility, miscarriage and irregular numbers of chromosomes (aneuploidy) in neonates. A new study from Karolinska Institutet published in the scientific journal Nature Genetics shows how chromosome disorders can arise when sex cells are formed.



Sex cells contain a control station for monitoring the mechanism that ensures that the correct numbers of chromosomes are distributed during cell division. Scientists have now shown that there is an alternative distribution mechanism in female sex cells that cause chromosome disorders. Aberrant chromosomes orientate themselves like normal chromosomes, and this ability to adopt double identities protects them from detection by the control centre.



"We believe that this new fundamental mechanism can help to explain why chromosome disorders are so common in female sex cells," says Professor Christer Höög, leader of the study.



The research might eventually lead to new medical treatments able to reduce the risk of foetal damage.



Over 0.3 per cent of children are born with some kind of chromosome disorder. Most develop Downs Syndrome, or obtain the wrong number of sex chromosomes and develop Turner's or Klinefelter's syndrome. Turner's syndrome only occurs in females and is caused when one of the two X chromosomes is missing. Girls with Turner's have arrested development and if no treatment is given do not enter puberty. Klinefelter's syndrome affects males, who receive an extra X chromosome. Symptoms include concentration difficulties, poor motor skills and infertility.






Publication:

"Bi-orientation of achiasmatic chromosomes in mammalian MI oocytes contributes to aneuploidy"

Anna Kouznetsova, Lisa Lister, Magnus Nordenskjöld, Mary Herbert, Christer Höög

Nature Genetics, 8 July 2007



Source: Sabina Bossi


Karolinska Institutet

Major Biofilm Dispersion Breakthrough By Binghamton University Researcher

A Binghamton University biologist's discovery of a molecule that induces the dispersion of biofilms will likely mean a sea change in health care, manufacturing, shipping and pharmaceutics over the coming years.



David Davies has found and is in the process of synthesizing a compound that will cause biofilm colonies to disperse, thus leaving individual bacteria up to 1,000 times more susceptible to disinfectants, antibiotics and immune functions. It's a discovery that will most certainly drive worldwide biofilm research in new directions and that could help put some of the most virulent cells in all of nature out of business.



Biofilms are complex aggregations of bacteria marked by the excretion of a protective and adhesive matrix. They develop almost anywhere that water and solids, or solids and gases meet, which means they are virtually everywhere. They are formed when individual microorganisms embed themselves in a gelatinous structure of their own making. When traveling alone in planktonic form, most bacteria are of small consequence and generally easy to manage, even with antibacterial hand soaps. But when they form biofilms, bacteria seem to gain super powers. In human terms the characteristic "slime" of biofilms, which comprises organic polymers that can grow to several centimeters thick and cover large areas, spells all kinds of big trouble.



Biofilms, for instance, fog your contacts, help to rot your teeth, and cause a host of diseases from cystic fibrosis and ulcers to colitis and ear infections. They are a leading cause of hospital infections and non-healing wounds, and were even at the root this past summer of corrosion that forced the replacement of 16 miles of the Alaska pipeline. As a result of that incident, 400,000 barrels a day of production from the largest oil field in the United States was suspended. The indefinite shut down, at a cost equal to 8 percent of U.S. petroleum output, led to immediate increases in the price of crude oil, and drove up fuel oil and gas prices.



Annual worldwide costs of biofilm infection and remediation are in the high billions, even according to the most modest estimates, and they are costs borne by industries and consumers worldwide. Name a manufacturing process and biofilms are probably a serious and costly issue. They have even been discovered in pipes at factories producing prepadine, the anti-bacterial, iodine-based solution that doctors swab on patients to "prep" them for surgery.



The small molecule Davies is working with appears to be one of the few known examples anywhere in nature of a communication signal that remains effective across species, family and phyla. In fact, though the evidence isn't yet in on that, Davies predicts the compound may also prove to have communicative effect even across bacterial kingdoms.
















"I consider this the Holy Grail of research in biofilms," he said. "It's a new paradigm in the way we look at how bacteria regulate their behavior."



An associate professor of biology at Binghamton University, Davies' prominence in his field was already secured when he showed in the late 1990s that bacteria "talk to one another" through cell-to-cell communication and that such signaling is key to biofilm formation. Davies discovered the molecular medium of that communication in Pseudomonas aeruginosa, a biofilm-forming microorganism that is arguably the most common organism on the planet.



The dispersion autoinducer Davies is now investigating has shown itself to be effective in dispersing biofilms containing Pseudomonas aeruginosa, Streptococcus mutans (strep), Escherichia coli (E coli) and Staphylococcus aureus (staph) whether those bacteria exist in a pure or mixed-culture biofilm.



The dispersion-inducing molecule provokes genetic and physiological changes in the biofilm bacteria, causing them to disperse and return to a planktonic state. In lay terms, Davies has discovered at the very least how to tell four of the most problematic organisms around to pack up and get out of Dodge. And in so doing, the bacteria become easier to kill than the average mosquito. Davies' feels certain his discovery will dramatically change the way infections are treated.



"I think people will start inducing dispersion to disaggregate biofilms and, then, treat them concurrently, and with significantly greater efficacy, with antibiotics."



He envisions his discovery first making its way to market as a topical treatment for cuts, lacerations and minor burns, perhaps even as an additive in adhesive bandages. But his major interest, and something he hopes to turn his attention towards in earnest in the coming year, is the area of non-healing wounds. Davies watched his diabetic great-aunt lose both of her feet to amputation after bacterial biofilm infections set in.



"If we can treat those kinds of wounds and clear up the infection, they will heal. We know that from wound debridement studies," he said. "I really think we can make a difference with these people, and if that was the only thing we did, it would be worth everything we're doing."





Contact: Gail Glover


Binghamton University

Work With Fungus Uncovering Keys To DNA Methylation

Researchers in a University of Oregon lab have shed more light on the mechanism that regulates DNA methylation, a fundamental biological process in which a methyl group is attached to DNA, the genetic material in cells of living organisms.


DNA methylation is essential for normal growth and development in plants and animals. It has been implicated in long-term memory, and irregularities in its process are associated with diseases such as cancer.


In the UO's Institute of Molecular Biology, Eric U. Selker and members of his laboratory use a quickly reproducing and easy-to-manipulate fungus, Neurospora crassa, to explore the control of DNA methylation. Neurospora is considered the simplest model organism for such research.


Reporting in the Dec. 15 issue of the journal Genes & Development, Selker and Keyur K. Adhvaryu, a postdoctoral researcher in the Selker lab, document that the enzyme protein phosphatase PP1 is necessary for normal methylation of DNA.


In the nucleus of eukaryotic cells, DNA is wrapped around histone proteins to form chromatin, and one histone, H3, turns out to be critical for DNA methylation. "It was long thought that histones were simply structural proteins, but we are learning that these proteins are also informational," Selker said.


This was demonstrated in the journal Nature in 2001 by Selker and his former postdoctoral research associate Hisashi Tamaru. They found that a protein required for DNA methylation, DIM-5, is an enzyme that adds a methyl group onto lysine 9 of histone H3. "This was the first solid indication that chromatin is important for DNA methylation," Selker said.


The new paper by Adhvaryu and Selker shows that PP1 is important to remove phosphates attached to serine 10 of H3, the site immediately adjacent to the site that DIM-5 needs to methylate, leading to DNA methylation.


In an accompanying article in the same issue of Genes & Development, Wolfgang Fischle, a biochemist at the Max-Planck Institute for Biophysical Chemistry, praises the findings of Selker and Adhvaryu. He writes that there appears to be extensive "crosstalk" involved in the chemical modifications that occur on histones to influence other enzymes that interact with chromatin "Adhvaryu and Selker provide novel insights into an intricate regulatory network involving histone phosphorylation, histone methylation and DNA methylation," he noted.


"DNA methylation seems to be a luxury item in Neurospora, which means we can manipulate it as we wish, making mutants that don't do it and thereby identify important players," Selker said. "We are identifying how DNA methylation is controlled and what it does in this organism. Our assumption is that a lot of what we find in Neurospora will be applicable to other systems."


In this case, Selker said, Keyur demonstrated very nicely, in a couple different ways, that protein phosphatase PP1 is required for normal DNA methylation. "DNA methylation is involved in a silencing of invasive DNA as well as a variety of normal genes, including those on the inactive X chromosome, those subjected to imprinting, and well as tumor suppressor genes," he said, adding that methylation of the latter class of genes can lead to cancer.


The research was funded by a grant from the National Institutes of Health to Selker and in part by an American Heart Association fellowship to Adhvaryu.


About the University of Oregon


The University of Oregon is a world-class teaching and research institution and Oregon's flagship public university. The UO is a member of the Association of American Universities (AAU), an organization made up of 62 of the leading public and private research institutions in the United States and Canada. Membership in the AAU is by invitation only. The University of Oregon is one of only two AAU members in the Pacific Northwest.


-- Selker faculty Web page

-- UO department of biology


Source

Julie Brown

Director of Media Relations

University of Oregon
uoregon/

The Role Of CEP290 In Maintaining Ciliary Function Defined By Researchers

A new study in the September 6 issue of the Journal of Cell Biology helps define the role of an important ciliary protein, CEP290. The results could be applied toward targeted gene therapy in cilia-related diseases.



Mutations in human CEP290 cause cilia-related disorders that range in severity from isolated blindness to perinatal death. CEP290 mutations are known to cause Meckel syndrome, Joubert syndrome, and NPHP - the most common syndromic form of cystic kidney disease in childhood - among others.



Although the exact role of CEP290 has been unclear, a team of researchers from the University of Massachusetts Medical School and Yale University now demonstrate that CEP290 is an integral component of the ciliary "gate" that bridges the transition zone between the cilia and cytoplasm. The protein plays an important role in maintaining the structural integrity of this gate, and thus has a crucial role in maintaining ciliary function.



Source:

Rita Sullivan


Rockefeller University Press

Genome Of A Monkey - Human Malaria Parasite Surprises From Plasmodium Knowlesi Genome Sequence

Researchers have decoded the genome of a malaria parasite that has a host range from monkeys to man. Identified originally in monkeys, the parasite was first reported in a human infection just over 40 years ago.


Until recently, four species were held responsible for human malaria infections: P. falciparum, P. vivax, P. ovale, and P. malariae. P. knowlesi is increasingly recognised as the fifth and emerging human malaria parasite, which is particularly prevalent in South East Asia and can cause potentially life threatening malaria. Recent surveys suggest that many P. Knowlesi infections have been misdiagnosed by microscopy as P. malariae, resulting in gross underestimates of its prevalence.


The genome sequence reveals a dramatic example of 'molecular mimicry' that is likely to be crucial for survival and propagation of the parasite in the body. Remarkably, the team found several members of a large gene family that contain sequence signatures that closely resemble a key human gene involved in regulation of the immune system. The parasite versions of the human protein are thought to interfere with recognition of infected red blood cells.


In addition to this uniquely expanded group of genes, P. Knowlesi has a fundamentally different architecture of the genes involved in 'antigenic variation' compared to other malaria parasites. The study also emphasizes the fact that, although 80% of genes are shared among all sequenced malaria parasites, each species may have a unique set of tricks and disguises that help it to escape host responses and to keep itself ahead in the host - parasite interaction.


"P. Knowlesi has thrown up several surprises. Our study demonstrates the power of sequencing additional malaria genomes to unravel as yet undiscovered and fascinating aspects of the biology of malaria parasites" says Dr Arnab Pain, the first author in the study and the project manager at the Wellcome Trust Sanger Institute.


"Unusually, the key genes that we think help the parasite to evade detection and destruction by host defences are scattered through the genome. In the other species we have examined, these genes are most often near the tips of the chromosomes".


The phenomenon of 'antigenic variation' - where the parasite constantly changes the coat of parasitized red cells in order to avoid recognition by the host - was also first discovered in P. knowlesi. Moreover, it can be studied and grown in the lab, making it ideal to understand it's basic biology such as how it invades red cells.


Identified initially as a monkey parasite, P. knowlesi had been identified in only two cases of human infection before 2004. However, at that time, Professor Balbir Singh and colleagues developed DNA-based detection methods and examined samples from malaria patients in Malaysia. They showed that almost all cases of what was thought to be infection with the human parasite P. malariae were due to infection with the 'monkey' parasite P. knowlesi.



"Rapid and appropriate treatment is vital in cases of malaria," says Professor Balbir Singh, Director of the Malaria Research Centre at the Faculty of Medicine and Health Sciences, University Malaysia Sarawak, "but before the development of molecular detection methods, we had been hampered by our inability to distinguish between P. knowlesi and the benign P. malariae parasites by microscopy. This parasite multiplies rapidly and can cause fatal human infections, so it is vital that doctors are aware that P. knowlesi is the fifth cause of human malaria.















"The genome sequence of what has been considered to be a 'model' for human malaria becomes much more significant with our findings of the widespread distribution and high levels of human infections with P. knowlesi."



P. knowlesi is an important model for studying the way that malaria parasites interact with host cells. It is a robust species in which invasion of red blood cells can be examined in detail. The genome sequence provides an updated catalogue of proteins that might help the parasite in these first stages of infection: the team identified novel regions in the genome that help to understand the regulation of these key genes and the transport of their proteins to the red cell surface.


Switching of surface proteins is a key defence mechanism for malaria parasites, as well as being essential for successful transfer between human and mosquito host, but the mechanisms of switching remain unclear.


"This is our first view of a monkey malaria parasite genome. It brings us intrigues and surprises - as well as new resources to help in the fight against malaria," says Dr Alan Thomas, Chairman of the Department of Parasitology, Biomedical Primate Research Centre in RIJSWIJK, Netherlands. "P. knowlesi is closely related to the second-most common cause of human malaria, P. vivax. With our new understanding of the genetic architecture of both parasites, we will more efficiently translate our studies on P. knowlesi to other human parasites.


"Just as important, the genome will help in understanding human cases of knowlesi malaria."


It is thought that P. knowlesi is a zoonotic malaria parasite that is transmitted by mosquitoes of the Anopheles leucosphyrus group that feed on humans and monkeys.


The function of the majority of Plasmodium proteins remains unknown. Comparison with the other malaria parasites will help to understand the differences in pathology and the mechanisms they share in interacting with the human, monkey or mosquito hosts.


The current work is published in Nature along with a companion study, deciphering the genome of another human malaria parasite Plasmodium vivax. That study was led by scientists at the New York University School of Medicine and the J Craig Venter Institute [formerly The Institute for Genomic Research (TIGR )] of Rockville, Maryland, USA. The Sanger Institute is also sequencing the remaining two human-infecting Plasmodium species. The genome of P. falciparum was deciphered in 2002.



Publication details

Pain A (2008) The genome of the simian and human malaria parasite Plasmodium knowlesi.
Nature 455: 751 - 756


Funding


This study was funded by the Wellcome Trust through its support to the Pathogen Sequencing Unit at the Wellcome Trust Sanger Institute. Part of this work was supported by the Netherlands Organization for Scientific Research, US National Institutes of Health and European Commission Framework 6 Programmes BioMalPar and the Virimal. The work was supported by the Wellcome Trust Sanger Institute Core Sequencing and Informatics Groups.


Participating Centres


- Wellcome Trust Sanger Institute, Genome Campus, Hinxton, Cambridgeshire, UK


- Ancient DNA and Evolution Group, Department of Biology, University of Copenhagen, DK-2100 Copenhagen, Denmark


- Department of Parasitology, Biomedical Primate Research Centre, 2280 GH, Rijswijk, The Netherlands


- Machine Learning Group, Department of Engineering, University of Cambridge, Cambridge, UK


- Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK


- Emory Vaccine Center, Yerkes National Primate Research Center, Emory University, Atlanta, Georgia, USA


- School of Biological Sciences, University of Liverpool, Liverpool, UK


- Institute of Biomedical and Life Sciences and Wellcome Centre for Molecular Parasitology, University of Glasgow, Glasgow, UK


- Department of Immunology and Infectious Diseases, Harvard School of Public Health, Boston, Massachusetts, USA


- UBC Bioinformatics Centre and Department of Computer Science, University of British Columbia and Department of Medical Genetics, Vancouver, BC, Canada


- The Walter and Eliza Hall Institute of Medical Research, Melbourne, Victoria, Australia


- The Department of Medical Biology, The University of Melbourne, Parkville, Victoria, Australia


- The Weatherall Institute of Molecular Medicine, University of Oxford, John Radcliffe Hospital, Oxford, UK


The Wellcome Trust Sanger Institute, which receives the majority of its funding from the Wellcome Trust, was founded in 1992. The Institute is responsible for the completion of the sequence of approximately one-third of the human genome as well as genomes of model organisms and more than 90 pathogen genomes. In October 2006, new funding was awarded by the Wellcome Trust to exploit the wealth of genome data now available to answer important questions about health and disease.


Wellcome Trust Sanger Institute


The Wellcome Trust is the largest independent charity in the UK and the second largest medical research charity in the world. It funds innovative biomedical research, in the UK and internationally, spending around ВЈ500 million each year to support the brightest scientists with the best ideas. The Wellcome Trust supports public debate about biomedical research and its impact on health and wellbeing.


Wellcome Trust

Cocaine's Effects On Brain Metabolism May Contribute To Abuse

Many studies on cocaine addiction - and attempts to block its addictiveness - have focused on dopamine transporters, proteins that reabsorb the brain's "reward" chemical once its signal is sent. Since cocaine blocks dopamine transporters from doing their recycling job, it leaves the feel-good chemical around to keep sending the pleasure signal. Now a new study conducted at the U.S. Department of Energy's Brookhaven National Laboratory suggests that cocaine's effects go beyond the dopamine system. In the study, cocaine had significant effects on brain metabolism, even in mice that lack the gene for dopamine transporters.



"In dopamine-transporter-deficient mice, these effects on metabolism are clearly independent of cocaine's effects on dopamine," said Brookhaven neuroscientist Panayotis (Peter) Thanos, who led the research. "These metabolic factors may be a strong regulator of cocaine use and abuse, and may also suggest new avenues for addiction treatments." The study will appear in the May 2008 issue of the journal Synapse, and will be available online on Monday, February 18, 2008.



The scientists used positron emission tomography, or PET scanning, to measure brain metabolism in dopamine-transporter deficient mice (known as DAT knockouts) and in littermates that had normal dopamine transporter levels. In this technique, the scientists administer a radioactively labeled form of sugar (glucose) - the brain's main "fuel" - and use the PET scanner to track its site-specific concentrations in various brain regions. They tested the mice before and after cocaine administration, and compared the results to mice treated with saline instead of the drug.



Before any treatment, mice lacking dopamine transporters had significantly higher metabolism in the thalamus and cerebellum compared with normal mice. This elevated metabolism may be linked to chronically high levels of dopamine in the DAT knockout mice. It also suggests that dopamine levels may play an important role in modulating glucose levels in these brain areas, which play important roles integrating sensory information, learning, and motor function.



Interestingly, DAT knockout mice have been suggested as an animal model for attention-deficit hyperactivity disorder (ADHD). Elevated metabolism due to persistent elevated dopamine levels may be a factor contributing to the symptoms of ADHD, Thanos said.



After the scientists administered cocaine, whole brain metabolism decreased in both groups of mice, but more significantly in normal mice than in DAT knockouts. The scientists were able to detect this reduction in metabolism in a wide range of brain regions in the normal mice, suggesting that these decreases in metabolism are somehow associated with the blockade of dopamine transporters by cocaine.



The scientists also observed a reduction in metabolism in the thalamus region in the DAT knockout mice. This effect may likely be due to the effect of cocaine on other neurotransmitter systems, for example, norepinepherine or serotonin.
















In summary, cocaine exposure has an effect on regional brain activity, which is mostly driven by dopamine action and to a secondary degree norepinephrine or serotonin. These results also support the idea that the thalamus and the cerebellum play key roles in cocaine's mechanism of effect on sensory input, learning, and motor function. This is particularly of interest in better understanding the mechanism of cocaine addiction as well as the neurobiology of ADHD.







The research was funded by The National Institute on Alcohol Abuse and Alcoholism Intramural Research Program at the National Institutes of Health and by the Office of Biological and Environmental Research within the U.S. Department of Energy's (DOE) Office of Science. DOE has a long-standing interest in research on brain chemistry gained through brain-imaging studies. Brain-imaging techniques such as PET are a direct outgrowth of DOE's support of basic physics and chemistry research.



All research involving laboratory animals at Brookhaven National Laboratory is conducted under the jurisdiction of the Lab's Institutional Animal Care and Use Committee in compliance with the Public Heath Service (PHS) Policy on Humane Care and Use of Laboratory Animals, the U.S. Department of Agriculture's Animal Welfare Act, and the National Academy of Sciences' Guide for the Care and Use of Laboratory Animals. This research has enhanced understanding of a wide array of human medical conditions including cancer, drug addiction, Alzheimer's and Parkinson's diseases, and normal aging and has led to the development of several promising treatment strategies.



For further information on Peter Thanos' lab and research visit bnl/thanoslab.



One of ten national laboratories overseen and primarily funded by the Office of Science of the U.S. Department of Energy (DOE), Brookhaven National Laboratory conducts research in the physical, biomedical, and environmental sciences, as well as in energy technologies and national security. Brookhaven Lab also builds and operates major scientific facilities available to university, industry and government researchers. Brookhaven is operated and managed for DOE's Office of Science by Brookhaven Science Associates, a limited-liability company founded by the Research Foundation of State University of New York on behalf of Stony Brook University, the largest academic user of Laboratory facilities, and Battelle, a nonprofit, applied science and technology organization.



Source: Karen McNulty Walsh


DOE/Brookhaven National Laboratory

Upright Walking May Have Begun In The Trees

By observing wild orangutans, a research team has found that walking on two legs may have arisen in relatively ancient, tree-dwelling apes, rather than in more recent human ancestors that had already descended to the savannah, as current theory suggests.



These findings appear in the 1 June 2007 issue of the journal Science, published by AAAS, the nonprofit science society.



Upright walking, or bipedalism, has long been considered a defining feature of humans and our closest ancestors. One of the most popular explanations, known as the savannah hypothesis, suggests that the ancestors to chimps, gorillas and humans descended from the trees and began walking on the ground on all fours.



Over time, this four-legged gait would have evolved into the "knuckle-walking" that chimps and gorillas still use today and then into upright, two-legged walking in humans.



Paleontologists have conventionally used signs of bipedalism as key criteria for distinguishing early human, or "hominin," fossils from those of other apes. But, this distinction is complicated by recent fossil evidence that some early hominins, including Lucy (Australopithecus afarensis), lived in woodland environments, while even earlier forms such as Millennium Man (Orrorin) appear to have lived in the forest canopy and moved on two legs.



"Our findings blur the picture even further," said Robin Crompton of the University of Liverpool in Liverpool, Great Britain, who is one of the study's authors. "If we're right, it means you can't rely on bipedalism to tell whether you're looking at a human or other ape ancestor. It's been getting more and more difficult for us to say what's a human and what's an ape, and our work makes that much more the case."



Crompton and his colleagues, Susannah Thorpe and Roger Holder of the University of Birmingham in Birmingham, Great Britain, came to their conclusions by observing wild orangutans in Sumatra, Indonesia. Orangutans spend almost their whole lives in trees, making them useful models for how our ancestors moved around several million years ago.



To collect the data, Thorpe spent a year living in the Sumatran rainforest and recording virtually every move the orangutans made. Then, she and her colleagues used these observations to test the hypothesis that bipedalism would have benefited tree-dwelling ape ancestors.



Because these ancestors were probably fruit-eaters, as orangutans are, they would have needed a way to navigate the thin, flexible branches at the tree's periphery, where the fruit typically is. Moving on two legs and using their arms primarily for balance, or "hand-assisted bipedalism," may have helped them travel on these branches.



The researchers analyzed nearly 3,000 examples of observed orangutan movement, and found that the orangutans were more likely to use hand-assisted bipedalism when they were on the thinnest branches. When bipedal, the animals also tended to grip multiple branches with their long toes.
















On medium-sized branches, the orangutans used their arms more to support their weight, changing their moving style to incorporate hanging. They only tended to walk on all fours when navigating the largest branches, the researchers found.



Hand-assisted bipedalism may have offered several advantages that allowed our arboreal ancestors to venture onto thin branches. They could have gripped multiple branches with their toes and distributed their center of gravity more effectively, while keeping one or both of their long arms free to reach for fruits and other supports.



Orangutans also keep their legs straight while standing on bending branches, the authors report. The exact benefit of the straight legs is still unclear, but when humans run on springy surfaces, we also keep our weight-bearing legs relatively straight, so this may have an energy-related advantage.



"Our results suggest that bipedalism is used to navigate the smallest branches where the tastiest fruits are, and also to reach further to help cross gaps between trees," said Thorpe.



The authors propose an evolutionary scenario that begins as other researchers have envisioned. Somewhere toward the end of the Miocene epoch (24 to 5 million years ago), climate in East and Central Africa became alternately wetter and drier, and the rainforest grew increasingly patchy. Apes living in the forest canopy would have begun to encounter gaps between trees that they could not cross at the canopy level.



The Science authors suggest that early human ancestors responded to this by abandoning the high canopy for the forest floor, where they remained bipedal and began eating food from the ground or smaller trees. The ancestors of chimps and gorillas, on the other hand, became more specialized for vertical climbing between the high canopy and the ground and thus developed knuckle-walking for crossing from one tree to another on the ground.



"Our conclusion is that arboreal bipedalism had very strong adaptive benefits. So, we don't need to explain how our ancestors could have gone from being quadrupedal to being bipedal," Thorpe said.



Observations of orangutan movement should be useful for conservation efforts, according to Thorpe. These animals are seriously endangered, primarily due to habitat destruction.



"If you can understand how they cross gaps in the forest, you can learn about effects that living in logged or degraded habitat would have on their locomotion. These could affect energy levels, for example, if they have to go to the ground, which is incredibly risky because the Sumatran tiger is down there licking its lips. The Sumatran orangutan population is predicted to be extinct in the next decade if habitat degradation continues. Our research further highlights the need for protecting these animals," she said.







"Origin of Human Bipedalism as an Adaptation for Locomotion on Flexible Branches," by Thorpe et al. This research was supported by The Leverhulme Trust, The Royal Society, The L.S.B. Leakey Foundation and The Natural Environment Research Council.



A related Perspective entitled "Walking on Trees," by Paul O'Higgins of the University of York and Sarah Elton of the University of Hull, discusses the study.



The American Association for the Advancement of Science (AAAS) is the world's largest general scientific society, and publisher of the journal Science (sciencemag/).
AAAS was founded in 1848, and serves 262 affiliated societies and academies of science, reaching 10 million individuals. Science has the largest paid circulation of any peer-reviewed general science journal in the world, with an estimated total readership of 1 million. The nonprofit AAAS (aaas/) is open to all and fulfills its mission to "advance science and serve society" through initiatives in science policy; international programs; science education; and more. For the latest research news, log onto EurekAlert!, eurekalert/, the premier science-news Web site, a service of AAAS.



Contact: Natasha Pinol


aaas/
American Association for the Advancement of Science

Competition, Loss Of Selfishness Mark Shift To Supersociety

How social or altruistic behavior evolved has been a central and hotly debated question, particularly by those researchers engaged in the study of social insect societies - ants, bees and wasps. In these groups, this question of what drives altruism also becomes critical to further understanding of how ancestral or primitive social organizations (with hierarchies and dominance fights, and poorly developed division of labor) evolve to become the more highly sophisticated networks found in some eusocial insect collectives termed "superorganisms."



In a paper published online before print by the Proceedings of the National Academy of Sciences (PNAS), a pair of researchers from Cornell University and Arizona State University propose a model, based on tug-of-war theory, that may explain the selection pressures that mark the evolutionary transition from primitive society to superorganism and which may bring some order to the conflicted thinking about the roles of individual, kin, and group selection that underlie the formation of such advanced eusocial groups.



A superorganism ultimately emerges as a result of intergroup competition according to findings by theoretician H. Kern Reeve of Cornell University's Department of Neurobiology and Behavior and professor Bert Hölldobler of Arizona State University's School of Life Sciences and Center for Social Dynamics and Complexity.



Reeve and Hölldobler's model is unique in that it is comprised of two interlocked nested tug-of-war theories. The first piece describes the tug of war over resource shares within a group or colony (intragroup competition), and the second piece incorporates the effects of a tug-of-war between competing colonies (intergroup competition).



According to Hölldobler, the path to colonial supergiant is first paved by the maximization of the inclusive fitness of each individual of the society. How this might arise, he believes, is that competition that might exist between individuals in the same society diminishes as the incipient colonial society becomes larger, better organized and contains better division of labor and ultimately, cohesiveness.



"Such societies in turn produce more reproductive offspring each year than neighboring societies that are less organized. Thus, genes or alleles that code for such behaviors will be propagated faster," Hölldobler says.



The second piece of the model takes into account that "as the colonial organization of one group rises, there is a coincident rise in discrimination against members of other societies of the same species." Hölldobler notes that the competition between societies soon becomes a major force reinforcing the evolutionary process: "In this way the society or insect colony becomes the extended phenotype of the collective genome of the society."



Hölldobler believes that this model developed with Reeve goes further than others in explaining the evolutionary transition from hierarchical organizations to superorganism, "as it also demonstrates how the target of selection shifts from the individual and kin to group selection."



Such a nested tug-of-war model, he says, might also be applied "equally well to the analysis of the evolution of other animal societies" and give insight into the evolution of cooperation in non-human and human primates, in addition to such things as collectives of cells and the formation of bacterial films.







Hölldobler is the Pulitzer Prize winning author (1991, non-fiction) of "The Ants," co-authored with Edward O. Wilson, Harvard Professor Emeritus. Hölldobler's research on the evolution of social organizations for this tiny, formidable insect has taken him around the world, led to the authorship of more than 300 articles and has garnered many international awards, including the Treviranus Medal, U.S. Senior Scientist Prize and Werner Heisenberg-Medal of the Alexander von Humboldt Foundation, and the Gottfried Wilhelm Leibniz Prize, some of the most prestigious science prizes given in Europe. He has been elected to the National Academy of Sciences, the American Academy of Arts and Sciences, the American Philosophical Society, and the former Alexander Agassiz Professor of Zoology of Harvard University, and Professor Emeritus, University of Würzburg, Germany. In addition to being a professor in the School of Life Sciences and the Center for Social Dynamics and Complexity in the College of Liberal Arts and Sciences at ASU, he is also Cornell University's Andrew D. White Professor at Large.



Arizona State University

College of Liberal Arts and Sciences

School of Life Sciences

Tempe, Arizona USA

sols.asu



Contact: Margaret Coulombe


Arizona State University

NIST Issues First Reference Material For Tissue Engineering

The National Institute of Standards and Technology (NIST) last week issued its first reference materials to support the new and growing field of tissue engineering for medicine. The new NIST materials are samples of a typical tissue scaffold material that have been measured and documented by NIST for three different degrees of porosity.



Three-dimensional tissue scaffolds, under development for some years, are biodegradable materials that are meant to be implanted in the body to provide a structurally sound framework for the patient's cells to implant and grow, in time repairing damaged tissue. The scaffolds are meant to be absorbed gradually by the body and replaced by normal tissue. Today they are used most commonly to help repair damaged bone, but other applications being studied.



In addition to biocompatibility and biodegradability, successful 3-D tissue scaffolds have a number of physical requirements. Porosity or pore size is one key factor. The pores in the scaffold must be large enough to permit cells to infuse the structure and receive nutrients, but healthy cell growth also depends on the cell's immediate surroundings. If the pores are too large or spaced too far apart, cells will be unable to build the proper connections.



The three new NIST reference materials are disks approximately 20 millimeters across and 5 millimeters high formed of crisscrossed layers polyester struts approximately 200 micrometers in diameter. Varying the spacing of the struts in each layer resulted in three different average porosities for the disks: 47 percent (average strut spacing of 200 micrometers), 60 percent (300 micrometers), and 69 percent (450 micrometers). These span the common range of pore sizes typically required for tissue engineering applications.



The biodegradable polymer, polycaprolactone, originally was used for sutures, and was chosen for being relatively strong and stable when not exposed to water or sunlight. The material has been approved by the Food and Drug Administration for use in tissue engineering implants, but the NIST reference materials are not meant for use in the body.



The release of these reference materials culminates a multi-year effort involving input from the FDA, the National Institutes of Health and ASTM Working Group WK6507 "Reference Scaffolds for Tissue Engineering."



RM 8395 - Tissue Engineering Reference, Scaffold (200 micrometer spacing)


RM 8396 - Tissue Engineering Reference, Scaffold (300 micrometer spacing)


RM 8397 - Tissue Engineering Reference, Scaffold (450 micrometer spacing)



Source:
Michael Baum


National Institute of Standards and Technology (NIST)

Dr H.P. Heineken Prize For Biochemistry And Biophysics Awarded To Jack Szostak

The Royal Netherlands Academy of Arts and Sciences has awarded the 2008 Dr H.P. Heineken Prize for Biochemistry and Biophysics to Professor Jack W. Szostak, Howard Hughes Medical Institute, Harvard Medical School and the Department of Molecular Biology, Massachusetts General Hospital, Boston, Massachusetts, United States, for 'his highly original insights into the fundamental processes of life'.


The topic


Biochemist Jack Szostak has been responsible for a series of scientific breakthroughs. Each discovery has concerned the fundamental processes of life and evolution. For example, he is one of the forefathers of today's genetic research with 'knockout mice', genetically engineered mice in which one or more genes have been turned off. This method, which has played a major role in many areas of biomedical research, can be traced back to the early 1980s, when Szostak first aired his revolutionary ideas about the crucial function of telomeres, the specialised DNA sequences at the tips of chromosomes, in cell division. His ideas were later proven correct. Szostak and Elizabeth Blackburn (Heineken Prize for Medicine, 2004) conducted pioneering research on telomeres, which have turned out to play a key role in cancer prevention.


Szostak has also developed new techniques to control the evolution of biological molecules. Known as in vitro selection, this technique has recently made it possible to evolve a new enzyme that does not occur in nature.


Today, Szostak is focusing on the origins of life. He has already shown that minerals may have acted as a catalyst for assembling the building blocks of the first cell structures.


The laureate


Jack Szostak (1952) was only nineteen when he was awarded his B.S. in cell biology at McGill University in Montreal, Canada. He obtained his PhD in biochemistry at Cornell University (Ithaca, New York, USA), where he worked as a research assistant until 1979. He then moved to Harvard Medical School, where he has been a professor with the Department of Genetics since 1988. In that same year, he accepted an appointment with the Department of Molecular Biology at Boston's Massachusetts General Hospital, where he became an Alex Rich Distinguished Investigator in 2000. In 1998, Szostak became an Investigator at the Howard Hughes Medical Institute at Massachusetts General Hospital.



Szostak has been granted numerous patents and is a member of several American academies and the American Association for the Advancement of Science (AAAS). His previous awards include the 2006 Albert Lasker Award for Basic Medical Research (together with Elizabeth Blackburn and others). Szostak is praised on all sides for his versatility and originality.


Examples of key publications


- Szostak, J.W, Blackburn, E.H., Cloning yeast telomeres on linear plasmid vectors. In: Cell 1982; 29: 245-55


- Szostak, J.W., Orr-Weaver, T.L., Rothstein, R.J., Stahl, F.J., The double-strand-break repair model for recombination. In: Cell 1983; 33: 25-35


- Murray, A.W., Szostak , J.W., Construction of artificial chromosomes in yeast. In: Nature 1983; 305: 189-193


- Roberts, R.W., Szostak, J.W., RNA-peptide fusions for the in vitro selection of peptides and proteins. In: Proc. Natl. Acad. Sci. USA 1997; 94: 12297-12302


- Seelig, B., Szostak, J.W., Selection and evolution of enzymes from a partially randomized non-catalytic scaffold. In: Nature 2007; 448: 828-831.


The prize


The Dr H.P. Heineken Prize for Biochemistry and Biophysics (named for Alfred Heineken's father) is the oldest of the Heineken Prizes and was established in 1964. Previous winners include Christian de Duve (Nobel Prize for Medicine 1974), Piet Borst, Michael Berridge, Paul Nurse (Nobel Prize for Medicine 2001), Andrew Fire (Nobel Prize for Medicine 2006) and Sir Alec Jeffreys. The jury was chaired by Rob Kaptein.


The presentation ceremony


The Heineken Prizes are presented every other year during an extraordinary meeting of the Royal Netherlands Academy of Arts and Sciences. This year the meeting will be held on Thursday 2 October at the Beurs van Berlage Building in Amsterdam.

massgeneral

Researchers From CIC BioGUNE Have Found A Way To Treat Ischemic Pathologies

A team of researchers from CIC bioGUNE from the Cellular Biology and Stem Cell Unit, alongside a team from Paris' Cardiovascular Research Centre (INSERM U970) have developed a new area of research which looks extremely promising as regards the development of new therapeutic responses to ischemic pathologies and cardiovascular diseases in general. The results of this research project, which was initiated in 2005 and is supported by Bizkaia:Xede and the Basque Government's Etortek programme, were published in the prestigious scientific journal Circulation.



By activating a protein called HIF, the strategy is to stimulate revascularisation and the repair of the damaged organ following ischemia caused by the obstruction of a blood vessel preventing normal blood flow. These obstructions occur, for example, in the event of thrombosis in a limb, myocardial infarction or a stroke. In this sense, it is important to highlight the fact that cardiovascular diseases are the principal cause of death throughout the world (in the European Union, they account for 40% of all deaths, a figure equivalent to 2 million deaths per year).



In general, cells tend to respond to the lack of oxygen caused by poor blood flow by activating HIF. However, in the case of an ischemic pathology, HIF is not sufficiently activated.



Dr Berra, Cellular Biology and Stem Cell Unit's leader, stated that they decided to over-produce HIF following ischemia as an attractive therapeutic alternative. For their research purposes, they used an ischemic model provoked in a mouse leg through ligation of the femoral artery. In other words, they closed off the femoral artery and stopped the blood flow to the limb. When this happens, the leg develops necrosis and after a time, the mouse dies.



The aim was to artificially help stimulate the production of HIF after the femoral artery had been closed off. And they saw that when they did this, the mouse's leg revascularised and no longer entered into a degenerative process.



How is this high level of HIF production achieved? HIF is a protein which, when not required, degrades constitutively and this degradation is regulated by enzymes called PHDs.



These enzymes hydroxylate HIF and, as a result of this hydroxylation, the protein degrades. Therefore, when these enzymes are inhibited, HIF cannot degrade and so accumulates. To inhibit PHDs, they use siRNAs, explains Dr Berra.



Source:
Oihane Lakar


Elhuyar Fundazioa

Changes In Brain Mechanisms For Cocaine Addicts Revealed By Computer Model

About 2 million Americans currently use cocaine for its temporary side-effects of euphoria, which have contributed to making it one of the most dangerous and addictive drugs in the country. Cocaine addiction, which can cause severe biological and behavioral problems, is very difficult to overcome. Now, University of Missouri researchers Ashwin Mohan and Sandeep Pendyam, doctoral students in the Department of Electrical and Computer Engineering, are utilizing computational models to study how the brain's chemicals and synaptic mechanisms, or connections between neurons, react to cocaine addiction and what this could mean for future therapies.



"With cocaine addiction, addicts don't feel an urge to revolt because there is a strong connection in the brain from the decision-making center to the pleasure center, which overwhelms other normal rewards and is why they keep seeking it," Pendyam said. "By using computational models, we're targeting the connection in the brain that latches onto the pleasure center and the parameters that maintain that process."



Glutamate is the major chemical released in the synaptic connections in the brain; the right amount present determines the activity of those connections. Using the computational model, MU researchers found that in an addict's brain excessive glutamate produced in the pleasure center makes the brain's mechanisms unable to regulate themselves and creates permanent damage, making cocaine addiction a disease that is more than just a behavioral change.



"Our model showed that the glutamate transporters, a protein present around these connections that remove glutamate, are almost 40 percent less functional after chronic cocaine usage," Mohan said. "This damage is long lasting, and there is no way for the brain to regulate itself. Thus, the brain structure in this context actually changes in cocaine addicts."



Mohan and Pendyam, in collaboration with MU professor Satish Nair, professor of electrical and computer engineering, and Peter Kalivas, professor and chair of the neuroscience department at the Medical University of South Carolina, found that the parameters of the brain that activate the pleasure center's connections beyond those that have been discovered must undergo alteration in order for addicts to recover. This novel prediction by the computer model was confirmed based on experimental studies done on animal models by Kalivas' laboratory.



"The long-term objective of our research is to find out how some rehabilitative drugs work by devising a model of the fundamental workings of an addict's brain," said Mohan, who will attend Washington University in St. Louis for his postdoctoral fellowship. "Using a systems approach helped us to find key information about the addict's brain that had been missed in the past two decades of cocaine addiction research."



Moham and Pendyam's research has been published in Neuroscience and as a book chapter in New Research on Neuronal Network from Nova Publishers.



Source:
Kelsey Jackson


University of Missouri-Columbia

Scientists At J. Craig Venter Institute Publish Draft Genome Sequence From Aedes Aegypti, Mosquito Responsible For Yellow Fever, Dengue Fever

The fight against
yellow fever and dengue fever was advanced today by an international team
of researchers led by Vishvanath Nene, Ph.D. of the J. Craig Venter
Institute who sequenced the Aedes aegypti genome, the mosquito that carries
these deadly diseases. The research was published in the journal "Science."



This research is the first characterization of the approximately 1.38
billion base pairs of DNA of the Ae. aegypti genome. From this sequence,
the team showed that this mosquito species has an estimated 15, 419 protein
encoding genes.



Since both the sequence of the fruit fly, Drosophila melanogaster
(sequenced in 1999 and published in 2000) and another mosquito species,
Anopheles gambiae, (sequenced and published in 2002) were available,
researchers were able to compare these insects to Ae. aegypti to ascertain
biological differences between the species.



An. gambiae diverged on the evolutionary tree from the fruit fly about
250 million years ago, and the two mosquito species diverged from one
another approximately 150 million years ago. Genomic comparisons revealed
greater differences between the fruit fly and the mosquito species, than
between the two mosquito species.



An important finding from this analysis is the discovery of certain
proteins and genes unique to the Ae. aegypti. These proteins and genes,
among many things, infer robustness to the insect. A more thorough analysis
of these genes and proteins may lead to improved means to eradicate the
mosquito and thereby stop the spread of yellow and dengue fevers.



Another key discovery was that almost 50 percent of the genome
consisted of transposable elements. These are movable pieces of DNA that
cause mutations and can affect genome size. The researchers showed that
likely due to these elements the gene length and the intergenic regions of
Ae. aegypti are 4-6 times larger than those of An. gambiae and the fruit
fly.



"With more than half a million cases of dengue fever which is endemic
in at least 100 countries and more than 30,000 deaths from yellow fever
each year, clearly understanding the biology of the vector for these two
worldwide killers is essential to eradicating these diseases," said Dr.
Nene, principal investigator. "By having the genomic code of this species
of mosquito we now have a key tool that will aid in the study of aspects of
biology specific to Aedes aegypti. This will to help identify pathways
which permit these mosquitoes to transmit viruses. Interfering with the
function of critical mosquito molecules could lead to effective control of
this prolific pest and the devastating diseases associated with it."




The scientists concluded that this draft genome will enable continued
and more refined genomic maps of this disease vector. And, with other
ongoing genome sequencing and analysis projects of related mosquito
species, the spectrum of knowledge about these disease carriers grows, as
does the potential to eliminate the associated diseases that kill millions
each year.



This work was mainly funded by contracts from the United States
National Institutes of Health's National Institute of Allergy and
Infectious Diseases (NIAID). This research was first undertaken at The
Institute for Genomic Research (TIGR), a legacy organization of the J.
Craig Venter Institute, and in collaboration with The Broad Institute and
VectorBase, a NIAID bioinformatics resource center. TIGR became part of the
JCVI in October 2006.



About the J. Craig Venter Institute



The J. Craig Venter Institute is a not-for-profit research institute
dedicated to the advancement of the science of genomics; the understanding
of its implications for society; and communication of those results to the
scientific community, the public, and policymakers. Founded by J. Craig
Venter, Ph.D., the JCVI is home to approximately 500 scientists and staff
with expertise in human and evolutionary biology, genetics,
bioinformatics/informatics, information technology, high-throughput DNA
sequencing, genomic and environmental policy research, and public education
in science and science policy. The legacy organizations of the JCVI are:
The Institute for Genomic Research (TIGR), The Center for the Advancement
of Genomics (TCAG), the Institute for Biological Energy Alternatives
(IBEA), the Joint Technology Center (JTC), and the J. Craig Venter Science
Foundation. The JCVI is a 501 (c)(3) organization. For additional
information, please visit JCVI.


J. Craig Venter Institute

JCVI

Bird Brains Suggest How Vocal Learning Evolved

Though they perch far apart on the avian family tree, birds with the ability to learn songs use similar brain structures to sing
their tunes. Neurobiologists at Duke University Medical Center now have an explanation for this puzzling likeness.



In all three groups of birds with vocal learning abilities - songbirds, parrots and hummingbirds - the brain structures for singing and learning
to sing are embedded in areas controlling movement, the researchers discovered. The team also found that areas in charge of movement share many
functional similarities with the brain areas for singing. This suggests that the brain pathways used for vocal learning evolved out of the brain
pathways used for motor control.



These ancient pathways, which power limb and body movements, constrained both the location and circuitry of structures for learning and imitating
sounds, theorizes senior author Erich Jarvis, Ph.D., associate professor of neurobiology. The findings may also help solve the riddle of why humans
talk with our hands and voice, but chimps can talk only with their hands.



"In its most specialized way, spoken language is the ability to control the learned movements of our larynx," Jarvis said. "It's possible that human
language pathways have also evolved in ways similar to these birds. Perhaps the evolution of vocal learning brain areas for birds and humans exploited
a universal motor system that predates the split from the common ancestor of birds and mammals."



The results appear in the March 12, 2008 edition of the journal PLoS ONE. The research was funded by the National Science Foundation and a National
Institutes of Health Pioneer Award to Jarvis. The collaborative study was co-led by Henrik Mouritsen of the University of Oldenburg in Germany, who
was supported by the VolkswagenStiftung, and first author Gesa Feenders, now a postdoctoral researcher at the University of Newcastle, UK.



"This innovative research exemplifies the bold thinking and creative approaches fostered by the NIH Director's Pioneer Award," said National
Institutes of Health Director Elias A. Zerhouni, M.D. "The discovery that vocal learning brain pathways are embedded in the parts of the brain that
control body movement offers unexpected insights on the origins of spoken language and could open up new approaches to understanding vocalization
disorders in humans."



Jarvis and his colleagues examined bird species with vocal learning skills and some without: garden warblers, zebra finches, budgerigars (parrots),
Anna's hummingbirds and ring doves. Their technique involved observing and manipulating bird behavior, then recording which genes were active in the
birds' brains when the birds were moving and singing in certain ways.



"When we use this behavioral molecular mapping approach, we get gene expression patterns in the brain that light up like MRI images," Jarvis said. The
study is the first to map the parts of the forebrain that control movement in birds. The forebrain is the largest part of the brain, and includes the
pathways for thought, learning and perception.
















While all birds vocalize, for most of them these sounds are genetically hardwired. Only songbirds, parrots and hummingbirds have the ability to learn
songs. This type of vocal learning is similar to the way that humans learn to speak, Jarvis said.



"Based on the data, we think that the brain has a pre-existing substrate, namely a forebrain motor pathway, that led to the evolution of similar vocal
learning pathways in three different bird families," Jarvis said.



The connection between movement and vocal learning also extends to humans, Jarvis suggests. Human brain structures for speech also lie adjacent to,
and even within, areas that control movement. "We can make a plausible argument that in humans, our spoken language areas also evolved out of
pre-existing motor pathways," he said. These pathways, he believes, date back to the common ancestor of reptiles, birds and mammals, creatures called
stem amniotes that lived about 300 million years ago.



The results from birds are consistent with the hypothesis that spoken language was preceded by gestural language, or communication based on movements
(one of several competing explanations for the origin of spoken language), Jarvis adds. Both humans and chimps gesture with the limbs while
communicating, and young children gesture even before they begin talking. "Gesturing is something that goes along naturally with speech. The brain
areas used for gesturing may have been co-opted and used for speech," Jarvis said.



Co-authors on the study include Miriam Liedvogel, University of Oxford, UK; Manuela Zapka, University of Oldenburg, Germany; Miriam Rivas, Haruhito
Horita and Erina Hara, Duke; and Kazuhira Wada, Hokkaido University, Japan.



Molecular Mapping of Movement-Associated Areas in the Avian Brain: A Motor Theory for Vocal Learning Origin
Feenders G, Liedvogel M, Rivas M, Zapka M, Horita H, et al. (2008)

PLoS ONE 3(3): e1768. doi:10.1371/journal.pone.0001768
Please click here to view article online


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Single Factor Converts Adult Stem Cells Into Embryonic-Like Stem Cells

The simple recipe scientists earlier discovered for making adult stem cells behave like embryonic-like stem cells just got even simpler. A new report in the February 6th issue of the journal Cell, a Cell Press publication, shows for the first time that neural stem cells taken from adult mice can take on the characteristics of embryonic stem cells with the addition of a single transcription factor. Transcription factors are genes that control the activity of other genes.



The discovery follows a 2006 report also in the journal Cell that showed that the introduction of four ingredients could transform differentiated cells taken from adult mice into "induced pluripotent stem cells" (iPS) with the physical, growth, and genetic characteristics typical of embryonic stem cells (medicalnewstoday/articles/49405.php). Pluripotent refers to the ability to differentiate into most other cell types. The same recipe was later shown to work with human skin cells as well (medicalnewstoday/articles/89503.php).



Subsequent studies found that the four-ingredient recipe could in some cases be pared down to just two or three essential ingredients, said Hans Schöler of the Max Planck Institute for Molecular Biomedicine in Germany. "Now we've come down to just one that is sufficient. In terms of the biology, it's really quite amazing."



The discovery sheds light on centuries-old questions about what distinguishes the embryonic stem cells that give rise to egg and sperm from other body cells, Schöler said. It might also have implications for the use of reprogrammed stem cells for replacing cells lost to disease or injury.



Other researchers led by Shinya Yamanaka showed that adult cells could be reprogrammed by adding four factors - specifically Oct4, Sox2, Klf4, and c-Myc. Recently, Schöler and his colleagues demonstrated that Oct4 and Klf4 are sufficient to induce pluripotency in neural stem cells.



By omitting Klf4 in the new study, they have now established that Oct4 is the "driving force" behind the conversion of the neural stem cells into iPS cells. The lone transcription factor is not only essential, but it is also sufficient to make neural stem cells pluripotent.



Those cells, which Schöler's team calls "1F iPS" can differentiate into all three germ layers. Those primary germ layers in embryos eventually give rise to all the body's tissues and organs. Not only can those cells efficiently differentiate into neural stem cells, heart muscle cells, and germ cells, they show, but they are also capable of forming tumors when injected under the skin of nude mice. Those tumors, or teratomas, contain tissue representing all three germ layers. When injected into mouse embryos, the 1F iPS cells also found their way into the animals' developing organs and were able to be transmitted through the germ line to the next generation, they report.
















The results show that adult stem cells can be made pluripotent without c-Myc and Klf4, both of which are "bona fide" oncogenes that can help turn normal cells into cancer cells, Schöler said. Limiting the number of factors is also a bonus because it means fewer genes must be inserted into the genome, where they can potentially have detrimental effects.



"Strikingly, Oct4 alone is sufficient to induce pluripotency in neural stem cells, which demonstrates its crucial role in the process of reprogramming…" the researchers concluded. "Future studies will show whether other sources of neural stem or progenitor cell populations such as mouse or human bone marrow-derived mesenchymal stem cells or dental pulp can be reprogrammed to iPS cells and whether expression of Oct4 can be induced by non-retroviral means, a prerequisite for the generation of iPS cells of therapeutic value."







The researchers include Jeong Beom Kim, Max Planck Institute for Molecular Biomedicine, Munster, Germany; Vittorio Sebastiano, Max Planck Institute for Molecular Biomedicine, Munster, Germany; Guangming Wu, Max Planck Institute for Molecular Biomedicine, Munster, Germany; Marcos J. Arauzo-Bravo, Max Planck Institute for Molecular Biomedicine, Munster, Germany; Philipp Sasse, University of Bonn, Bonn, Germany; Luca Gentile, Max Planck Institute for Molecular Biomedicine, Munster, Germany; Kinarm Ko, Max Planck Institute for Molecular Biomedicine, Munster, Germany; David Ruau, RWTH Aachen University Medical School, Aachen, Germany; Mathias Ehrich, SEQUENOM Inc., San Diego, CA; Dirk van den Boom, SEQUENOM Inc., San Diego, CA; Johann Meyer, Hannover Medical School, Hannover, Germany; Karin Hubner, Max Planck Institute for Molecular Biomedicine, Munster, Germany; Christof Bernemann, Max Planck Institute for Molecular Biomedicine, Munster, Germany; Claudia Ortmeier, Max Planck Institute for Molecular Biomedicine, Munster, Germany; Martin Zenke, RWTH Aachen University Medical School, Aachen, Germany; Bernd K. Fleischmann, University of Bonn, Bonn, Germany; Holm Zaehres, Max Planck Institute for Molecular Biomedicine, Munster, Germany; and Hans R. Scholer, Max Planck Institute for Molecular Biomedicine, Munster, Germany.



Source: Cathleen Genova


Cell Press

Schering-Plough Extends Antibody Alliance With MorphoSys - Third Extension With Major Pharmaceutical Company After Landmark Deal With Novartis

MorphoSys AG (FSE: MOR; Prime Standard Segment, TecDAX) announced that Schering-Plough Corporation has decided to extend the current collaboration between the two companies for one year. The collaboration, announced in May 2006, has a maximum term of 5 years until 2011 and may be extended by Schering-Plough after each single year.


Under the agreement, Schering-Plough will continue to have access to MorphoSys's proprietary antibody library HuCAL GOLD at its research site in Palo Alto, California, the location of Schering-Plough Biopharma, an affiliate of Schering-Plough Research Institute. Furthermore, the contract provides Schering-Plough with the option to develop and commercialize HuCAL-derived therapeutic antibodies, in which case MorphoSys would receive exclusive license fees, milestone payments, as well as royalties. Under the extended agreement MorphoSys continues to receive annual user fees for access to its HuCAL platform. Further financial details were not disclosed.


"Today's news is yet another clear signal that our HuCAL technology will continue to form the basis of antibody-based drug development programs at a number of leading pharmaceutical companies," commented Dr. Simon Moroney, Chief Executive Officer of MorphoSys. "We are very pleased with Schering-Plough's decision to continue using our HuCAL GOLD technology for their antibody development programs."


About MorphoSys


MorphoSys is a publicly traded biotechnology company focused on the generation of fully human antibodies as a means to discover and develop innovative antibody-based drugs against life-threatening diseases. MorphoSys's goal is to establish HuCAL as the technology of choice for antibody generation in research, diagnostics and therapeutic applications. The Company currently has therapeutic and research alliances with the majority of the world's largest pharmaceutical companies including Boehringer Ingelheim, Centocor/Johnson & Johnson, Novartis, Pfizer and Roche. Within these partnerships, more than 50 therapeutic antibody programs are ongoing in which MorphoSys participates through exclusive license and milestones payments as well as royalties on any end products. Additionally, MorphoSys is active in the antibody research market through its AbD Serotec business unit. The business unit has operations in Germany (Munich), the U.S. (Raleigh, NC) and U.K. (Oxford). For further information please visit morphosys/


HuCAL and HuCAL GOLD are registered trademarks of MorphoSys AG


This communication contains certain forward-looking statements concerning the MorphoSys group of companies. The forward-looking statements contained herein represent the judgment of MorphoSys as of the date of this release and involve risks and uncertainties. Should actual conditions differ from the Company's assumptions, actual results and actions may differ from those anticipated. MorphoSys does not intend to update any of these forward-looking statements as far as the wording of the relevant press release is concerned.

morphosys/

End To Fat-Free Diets A Possibility

A new study in mice raises a tantalizing possibility - that humans may one day be able to eat any kind of fat they want without raising their risk of heart disease.



"We deleted an enzyme in mice and they could eat any type of fat and not get heart disease," said Lawrence Rudel, Ph.D., a professor of comparative medicine. "If you're a mouse, it's great. Of course, we don't know yet if it will be the same in humans."



Rudel's findings are reported online by Arteriosclerosis, Thrombosis and Vascular Biology and will appear in a future print issue.



The study involved deleting a gene in the mice that causes production of ACAT2, an enzyme that alters the molecular structure of cholesterol so that it can be transported to the body's cells.



"Regardless of the type of fatty acid in the diet, even trans fat, no atherosclerosis occurs if the ACAT2 enzyme isn't present," said Rudel. "Our research in animals tells us that ACAT2 is a potential treatment target to protect people against heart disease."



Groups of female mice with and without the ACAT2 gene were fed six different diets enriched with one of these types of fat: fish oil, flax seed oil, polyunsaturated fat from vegetable oil, saturated fat, trans-monounsaturated fat and cis-monounsaturated fat, such as in olive oil.



Fish oil, flax seed oil and polyunsaturated fats are considered "healthy" fats. Saturated fat - found in meats, milk and cheeses, coconut oil, palm oil and palm kernel oil - is considered a main cause of high cholesterol.



There are two types of monounsaturated fatty acids, "cis" and "trans," which are named according to their shapes. Trans-fatty acids are formed when vegetable oil is treated to make it less likely to go rancid and are found in many fried foods, baked goods and potato chips. Cis monounsaturated fat is naturally occurring and is particularly high in canola and olive oil. Recently, the U.S. Food and Drug Administration has required that levels of trans-fats be listed on food labels.



After 20 weeks on the diets, the mice that had the active ACAT2 enzyme and were fed saturated fat and both types of monounsaturated fat had higher levels of cholesterol and more atherosclerosis than the mice that were fed polyunsaturated fats. All of the mice without the ACAT2 enzyme were protected against atherosclerosis, which is the buildup of fatty deposits in the blood vessels that can lead to heart attacks and strokes.



"Regardless of the diet fed, the mice without ACAT2 were protected from atherosclerosis," said Rudel.



Eliminating ACAT2 did not interfere with the normal processing of cholesterol. ACAT2 is one of three enzymes that can change cholesterol into a form that can be more easily carried in blood. Studies in both mice and monkeys show that when cholesterol is altered by ACAT2, it is more likely to build up in blood vessel walls and cause atherosclerosis.



Rudel hopes to get funding to repeat the study in monkeys.



"If it works in monkeys, it would be proof of concept that it could work in humans," he said.



He also hopes the research will lead to a drug that can inhibit the enzyme's actions in humans. Currently, there is a compound that can block ACAT2, but it must be injected so isn't quite as practical as a drug. He is collaborating with a pharmaceutical company that is working to find a compound that could be taken orally.



Scientists already know that humans produce ACAT2 in the liver and that women have lower levels than men. Research has shown that estrogen can lower ACAT2 production, which may partly explain why women are less likely than men to get heart disease during their estrogen-producing years.



"All of these findings tell us that a potential treatment for protecting against heart disease is a compound that decreases ACAT2 activity," said Rudel.






The research was funded by a grant from the National Heart Lung and Blood Institute. Co-researchers were Thomas Bell, Ph.D., who worked on the the project for his doctoral degree, Kathryn Kelley, B.S., Martha Wilson, Ph.D., and Janet Sawyer, M.S., all with Wake Forest.



Contact: Shannon Koontz



About Wake Forest University Baptist Medical Center: Wake Forest Baptist is an academic health system comprised of North Carolina Baptist Hospital and Wake Forest University Health Sciences, which operates the university's School of Medicine. The system comprises 1,282 acute care, psychiatric, rehabilitation and long-term care beds and is consistently ranked as one of "America's Best Hospitals" by U.S. News & World Report.



Contact: Karen Richardson


Wake Forest University Baptist Medical Center

Tiny RNAs Play A Big Role In Controlling Genes

A study by researchers at the Yale Stem Cell Center for the first time demonstrates that piRNAs, a recently discovered class of tiny RNAs, play an important role in controlling gene function, it was reported in Nature.



Haifan Lin, director of the stem cell center and professor of cell biology at Yale School of Medicine, heads the laboratory that originally identified piRNAs. Derived mostly from so-called "junk DNA," piRNAs had escaped the attention of generations of geneticists and molecular biologists until last year when Lin's team discovered them in mammalian reproductive cells, and named them.



The lab's current work suggests that piRNAs have crucial functions in controlling stem cell fate and other processes of tissue development.



In this study Lin and his Ph.D. student, Hang Yin, discovered more than 13,000 Piwi-associated piRNAs in fruit flies. One particular piRNA, they found, forms a complex with the protein known as Piwi, which then binds to chromatin, a strategic region in the genome that regulates the activity of the gene. Chromatin's role is to package DNA so that it will fit into the cell, to strengthen the DNA to allow cell division, and to serve as a mechanism to control gene expression.



"This is important in maintaining self-renewal of stem cells," Lin said. "These small RNAs might provide new tools to harness the behavior of stem cells and other biological processes related to diseases."



"This finding revealed a surprisingly important role for piRNAs, as well as junk DNA, in stem cell division," Lin said. "It calls upon biologists to look for answers beyond the one percent of the genome with protein coding capacity to the vast land of junk DNA, which constitutes 99 percent of the genome."







This research was supported by the Mather's Foundation and the National Institutes of Health.



Nature: Advance Online Publication doi:10.1038/nature06263



Source: Jacqueline Weaver


Yale University

Ticking Of Body's 24-Hour Clock Turns Gears Of Metabolism And Aging

All animals, including humans, have an internal 24-hour clock or circadian rhythm that creates a daily oscillation of body temperature, brain activity, hormone production and metabolism. Studying mice, researchers at Washington University School of Medicine in St. Louis and Northwestern University found how the biological circadian clock mechanism communicates with processes that govern aging and metabolism.


Reported March 19, 2009 through advance online publication in Science, their findings can potentially explain why the waning of the circadian rhythm with age could contribute to age-related disorders such as insulin resistance and type 2 diabetes.


"Our study establishes a detailed scheme linking metabolism and aging to the circadian rhythm," says one of the lead authors, Shin-ichiro Imai, M.D., Ph.D., who researches aging at Washington University School of Medicine. "This opens the door to new avenues for treating age-related disorders and ways to restore a healthy daily circadian rhythm. It could also yield new interventions to alleviate metabolic disorders such as obesity and diabetes."


Imai, associate professor of medicine and of developmental biology, focuses on the molecular mechanisms of aging and longevity. Earlier, he demonstrated that a gene called SIRT1 was at the center of a network that regulates aging. A form of the gene is found in every organism on earth, and seven forms of the gene exist in humans.


SIRT1 has a broad reach, influencing glucose breakdown and production, cholesterol metabolism, fat burning and insulin sensitivity. Basically, the gene coordinates metabolic reactions throughout the body and manages the body's response to nutrition.


Interestingly, increasing the activity of proteins related to SIRT1 extends the life span of organisms such as yeast, worms and flies. SIRT1 is activated when calories are restricted below normal, which has been shown to extend the life spans of some laboratory animals. "Under nutritional scarcity, SIRT1 may delay aging and extend life span to assure survival until food becomes more readily available," Imai explains.


Imai's collaborator in the current study, Joseph Bass, M.D., Ph.D., assistant professor of medicine and neurobiology at Northwestern University, earlier demonstrated that interfering with the circadian clock of mice led to metabolic complications including obesity and type 2 diabetes.


Now their joint research, led by Kathryn Moynihan Ramsey, Ph.D., at Northwestern and Jun Yoshino, M.D., Ph.D., and Cynthia S. Brace, both at Washington University, has linked the circadian clock to SIRT1 through a key metabolite that serves as the energy currency of the body.















As a result, they have defined a biochemical mechanism by which the body's metabolic and nutritional status can directly drive the oscillation of the body's daily clock as well as influence aging and longevity. This new information points potentially to innovative ways to correct metabolic disorders and improve health as people age.


Studying laboratory mice, the researchers found a daily oscillation of the metabolite NAD (nicotinamide adenine dinucleotide), an important compound that is the body's way of exchanging energy and moving it where it's needed. Previously, scientists believed the amount of NAD in the body's cells stayed fairly constant.


"Seeing this striking abnormality in the NAD levels was like discovering the cause of a disease in a patient after running a blood test," Bass says.


Importantly, the researchers found that this NAD rhythm was linked to the daily rise and fall of the activity of "clock" genes, the genes that serve as the gears that run the body's internal clock. They discovered that the clock genes directly interact with a biochemical process that produces NAD.


NAD is required for SIRT1 to function, suggesting that SIRT1 activity increased and decreased along with NAD oscillation in the mice. Since SIRT1 is known to inhibit the clock genes, the cycle of its activity feeds back into the clock mechanism.


Studying the mice under controlled conditions of light and dark, the researchers established the details of the NAD-SIRT1-clock gene loop and showed that it functions in liver and fat cells. "We showed that this feedback cycle is driven by NAD," Imai says. "Because NAD levels reflect nutrition and energy levels, NAD's link to the circadian and aging mechanisms makes them sensitive to the nutritional status of the organism."


Next, Imai and members of his laboratory will look at whether manipulating components of the NAD biochemical pathway could have therapeutic effects on metabolism through insulin secretion and insulin sensitivity as well as on health in aging individuals.


Ramsey KM, Yoshino J, Brace CS, Abrassart D, Kobayashi Y, Marcheva B, Hong HK, Chong JL, Buhr ED, Lee C, Takahashi JS, Imai S, Bass J. Circadian clock feedback cycle through NAMPT-mediated NAD biosynthesis. Science. March 19, 2009 (advance online publication).


Takahasi is a cofounder of ReSet Therapeutics Inc., and he and Bass are members of its scientific advisory board. Bass is an advisor and receives support from Amylin Pharmaceuticals. Imai holds a patent related to this research.


Funding from the National Institute of Diabetes and Digestive and Kidney Diseases, The National Institute on Aging, the Ellison Medical Foundation, the Longer Life Foundation, the National Institutes of Health, Chicago Biomedical Consortium Searle Funds, the Juvenile Diabetes Research Foundation, the Japan Research Foundation for Clinical Pharmacology, Keio University Medical Science Fund and the Howard Hughes Medical Institute supported this research.


Washington University School of Medicine's 2,100 employed and volunteer faculty physicians also are the medical staff of Barnes-Jewish and St. Louis Children's hospitals. The School of Medicine is one of the leading medical research, teaching and patient care institutions in the nation, currently ranked third in the nation by U.S. News & World Report. Through its affiliations with Barnes-Jewish and St. Louis Children's hospitals, the School of Medicine is linked to BJC HealthCare.


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