Without eyes or ears, plants must rely on the interaction of molecules to determine appropriate mating partners and avoid inbreeding.  In a new study, University of Missouri researchers have identified pollen proteins that may contribute to the signaling processes that determine if a plant accepts or rejects individual pollen grains for reproduction.

Like humans, the mating game isn’t always easy for plants.  Plants rely on external factors such as wind and animals to bring them potential mates in the form of pollen grains.  When pollen grains arrive, an introduction occurs through a “conversation” between the pollen (the male part of the flower) and the pistil (the female part of the flower).  In this conversation, molecules take the place of words and allow the pollen to identify itself to the pistil.  Listening in on this molecular conversation may provide ways to control the spread of transgenes from genetically-modified crops to wild relatives, offer better ways to control fertilization between cross species, and lead to a more efficient way of growing fruit trees.

“Unlike an animal’s visual cues about mate selection, a plant’s mate recognition takes place on a molecular level,” said Bruce McClure, associate director of the Christopher S. Bond Life Sciences Center and researcher in the MU Interdisciplinary Plant Group and Division of Biochemistry.  “The pollen must, in some way, announce to the pistil its identity, and the pistil must interpret this identity.  To do this, proteins from the pollen and proteins from the pistil interact; this determines the acceptance or rejection of individual pollen grains.”

In the study, researchers used two specific pistil proteins, NaTTS and 120K, as “bait” to see what pollen proteins would bind to them.  These two pistil proteins were used because they directly influence the growth of pollen down the pistil to the ovary where fertilization takes place.

Three proteins, S-RNase-binding protein (SBP1), the protein NaPCCP and an enzyme, bound to the pistil proteins.  This action suggests that these proteins likely contribute to the signaling processes that affect the success of pollen growth.

“Our experiment was like putting one side of a Velcro strip on two pistil proteins and then screening a collection of pollen proteins to see which of the pollen proteins have the complementary Velcro strip for binding,” McClure said.  “If it sticks, it’s a good indication that the pollen proteins work with the pistil proteins to determine the success of reproduction.”

In previous studies, McClure showed that S-RNase, a protein on the pistil side, caused rejection of pollen from close relatives by acting as a cytotoxin, or a toxic substance, in the pollen tube.

For their study, the MU team used Nicotiana alata, a relative of tobacco commonly grown in home gardens as “flowering tobacco.” The study, “Pollen Proteins Bind to the C-Terminal Domain of Nicotiana Alata Pistil Arabinogalactan Proteins,” was published in the Journal of Biological Chemistry and was co-authored by McClure; Kirby N. Swatek, biochemistry graduate student; and Christopher B. Lee, post-doctoral researcher at the Bond Life Sciences Center.

Faculty from six of MU’s colleges and schools perform interdisciplinary research in the Christopher S. Bond Life Sciences Center with a vision to become a recognized world-wide center of scientific excellence and leadership in life sciences research, innovation and education.  The Center integrates the strengths of multiple, often disparate, disciplines to promote discovery that boosts the production and quality of food, improves human and animal health and enhances environmental quality.  The Center enriches the state of Missouri and its people by generating new businesses and jobs, fueling the economy through the creation and dissemination of new knowledge, and training young people to solve complex interdisciplinary problems.

The study, led by researcher Päivi Lahermo from Institute for Molecular Medicine Finland (FIMM) and University of Helsinki, Finland, and professor Juha Kere from Karolinska Institutet, Sweden, will be published in PloS ONE journal October 24th, 2008.

— The understanding of genetic variation in human populations is important not only for obtaining information on population history, but also for successful studies of genetic factors behind human diseases, says Juha Kere.

Human population genetic studies have recently gained a new powerful tool from the analysis of densely spaced single nucleotide polymorphisms (SNPs) across the whole genome.  In this study, almost 250 000 such polymorphisms were used to analyze genetic differences between the Germans, British, Eastern and Western Finns, and Swedes, based on ca.  1000 samples.

The Germans and British are genetically close to each other, which has been observed also in other recently published studies.  In contrast, the genetic distances between the Swedes and Eastern and Western Finns are larger, and the diversity in these populations is lower.

The genetic difference between Eastern and Western Finland is substantial in a European scale, and there are also clear differences between Finnish counties.

— The larger genetic distances in the north are caused by differences in population history: the northernmost parts of Europe were inhabited later than Central Europe and by fewer people, and have had smaller populations since then, says Päivi Lahermo.

Many animals live longer when raised on low calorie diets.  But now researchers at Washington University School of Medicine in St. Louis have shown that they can extend the life spans of roundworms even when the worms are well fed — it just takes a chemical that blocks their sense of smell.

Three years ago, the researchers, led by Kerry Kornfeld, M.D., Ph.D., reported they found that a class of anticonvulsant medications made the roundworm Caenorhabditis elegans live longer.  But until now, they didn’t quite know what the drugs did to give the worms their longevity.  They report their latest findings in the Oct. 24 issue of the Public Library of Science Genetics.

“We’ve learned that the drugs inhibit neurons in the worm’s head that sense chemicals in their surroundings — the neurons are like the worm’s nose,” says Kornfeld, professor of developmental biology.  “Like roundworms that are grown in a food-scarce environment, the worms exposed to the anticonvulsant ethosuximide lived longer.  But these worms ate plenty of food.  That suggests that the worms’ sensation of food is critical to controlling their metabolism and life span.”

If roundworms sense that food is abundant, their metabolism adjusts accordingly.  Their bodies respond to promote rapid ingestion, rapid growth and rapid aging, Kornfeld explains.  In contrast, when the worms sense a shortage of food, they make “metabolic decisions” to delay growth, delay energy use and extend lifespan.

In the long term, Kornfeld’s goal is to identify compounds that could potentially delay human aging.  The research group for this project also included James Collins, Ph.D., Kim Evason, M.D., Ph.D., Chris Pickett, Ph.D., and Daniel Schneider.

Kornfeld’s lab studies C. elegans because they live only about two to three weeks, so experimental results can be obtained quickly.  In addition, the worms’ genome has been sequenced and extensively studied.

The scientists’ strategy has been to expose the roundworms to libraries of chemicals to identify compounds that delay aging and extend their lives.  That approach led to the unexpected result that some human anticonvulsants slow aging in C. elegans.

Now, further investigating the effect of one of those compounds, ethosuximide, the researchers found that it had the same life-extending effect as some well-studied genetic mutations in C. elegans.  These mutations inhibit the activity of some sensory neurons in the worm, and that helped the researchers conclude that ethosuximide also directly affected these neurons.  Roundworms treated with ethosuximide lived up to 29 percent longer than normal.

“Now we know what cells ethosuximide targets in C. elegans,” Kornfeld says.  “It’s likely that the drug prevents the nerve cells from being electrically active, but precisely how it does that is something we need to study further.  We also want to find out how the effect on the neurons is translated into an effect on the worms’ bodies to delay aging.”

Ethosuximide is used to treat seizure disorders in people.  Interestingly, a common side effect of the drug is the loss of the sense of taste.  Does that mean the ability to taste or smell food affects aging in people?  It’s probably not that simple, but it does hint at some sort of connection, Kornfeld says.  He says it’s possible that sensory perception cues have important metabolic consequences independent of what we actually eat.

“Emerging evidence suggests that core metabolic pathways that modulate lifespan in worms also modulate lifespan in vertebrates such as mice and perhaps humans,” Kornfeld says.  “Sensory pathways might also be fairly universal.  In an ancient common ancestor, these pathways might have caused metabolic adjustments that affect lifespan.  That could be reflected in our own biology.”

Clubfoot, one of the most common birth defects, has long been thought to have a genetic component.  Now, researchers at Washington University School of Medicine in St. Louis report they have found the first gene linked to clubfoot in humans.

Their research will be published in the Nov. 7 issue of the American Journal of Human Genetics.

By studying a multi-generation family with clubfoot, the scientists traced the condition to a mutation in a gene critical for early development of lower limbs called PITX1.  While other genes are also likely to be linked to clubfoot, the new finding is a first step toward improved genetic counseling and the development of novel therapies.

“To our knowledge this report is the first evidence for PITX1 mutation in human disease,” said Christina Gurnett, M.D., Ph.D., assistant professor of neurology, of pediatrics and of orthopedic surgery at the School of Medicine.  “Once we identified the mutation, we proved that all of the individuals in this family with lower extremity malformations also have the mutation.  Having large families to work with is very helpful in genetic research.”

Gurnett and her colleagues analyzed the DNA of 35 extended family members of an infant male patient of Matthew Dobbs, M.D., associate professor of orthopedic surgery at the School of Medicine and a clubfoot specialist at St. Louis Children’s Hospital and St. Louis Shriners Hospital.  The patient, the most severely affected in the family, had clubfoot in both feet, duplicated first toes and was missing the tibia in the right leg.

Gurnett and Dobbs visited the family members in their community to examine their lower limbs and to take DNA samples.  They found that 13 family members were affected: Five additional family members had clubfoot, which was more severe in the right foot in three of them.  Five others had lower limb abnormalities including flatfoot, an underdeveloped patella and hip dysplasia.

Through the genome-wide study, Gurnett and her colleagues found a region on chromosome 5 that was common to all family members affected.  From there, they identified a mutation in a gene critical for early development of lower limbs called PITX1.  The PITX1 mutation was found in all affected family members and in three carriers who showed no clinical symptoms.

Dobbs, senior author of the study, said the finding is an exciting step in developing a better understanding of the genetic basis of clubfoot, which affects about 1 in 1,000 new births.

“Clubfoot is a complex disorder meaning that more than one gene as well as environmental factors will be discovered to play a role in its etiology,” Dobbs said.  “Identifying the genes for clubfoot will allow for improved genetic counseling and may potentially lead to new and improved treatment and preventive strategies for this disorder.”

Dobbs treats children with clubfoot and other orthopedic abnormalities using the Ponseti method, a treatment that involves weekly casting and the manipulation of clubfoot soon after birth.  In 2007, Dobbs developed a new dynamic brace called the Dobbs brace for clubfoot that allows active movement, preservation of muscle strength in the foot and ankle and fewer restrictions on the child than the traditional brace.

About 80 percent of clubfoot cases are idiopathic, meaning the cause is unknown and the patient has no other birth defects.  A familial link plays a role in about 25 percent of cases.  The condition occurs in males twice as often as in females and occurs more often in the right foot.  About half of the cases affect both feet, including the bones, muscles, tendons and blood vessels.  If untreated, those affected walk on the outside of their feet, which can lead to long-term pain and disability.

Gurnett said some clinical characteristics of the family members with the PITX1 mutation suggest that the genetic defect may be linked to idiopathic clubfoot.  First, the majority of the affected family members had clubfoot, but no other abnormalities.  Second, there were five females who carried the gene but did not have clubfoot, which supports the lower incidence of clubfoot in females.  Third, clubfoot affects the right foot more frequently, a hallmark of mutations in PITX1.

Previous studies had shown a relation between PITX1 and the development of hindlimbs in other vertebrates.  In mice, a loss of PITX1 leads to shorter femur length and fewer digits on the right foot than on the left.  An alteration of the gene in a developing chick wing changes it so that it looks more like a leg.  In vertebrates such as the manatee and stickleback fish, an alteration has resulted in evolutionary changes in the development of the pelvis.

“It’s our job to prove that this is going to be important for many kids with clubfoot,” Gurnett said.  “Until now, we didn’t know whether clubfoot was a muscle, nerve, spinal cord or brain problem.  Now, we have an idea that clubfoot may result from mutations of genes that are involved in early limb development.”

Gurnett said she and her colleagues will take the finding back to the lab to look for other factors involved in the pathway or how environmental effects may influence the gene.  She and Dobbs, who have been studying the genetics of clubfoot for a decade, plan to investigate the frequency of PITX1 gene mutations in other families with clubfoot.

New research continues to link tart cherries, one of today’s hottest “Super Fruits,” to lowering risk factors for heart disease. In addition to lowering cholesterol and reducing inflammation, the study being presented by University of Michigan researchers at next week’s American Dietetic Association annual meeting, found that a cherry-enriched diet lowered body weight and fat – major risk factors for heart disease.In the study, at-risk, obese rats that were fed a cherry-enriched diet saw significant decreases in body weight and fat (especially the important “belly” fat with known risk for heart disease) while maintaining lean muscle mass. After twelve weeks, the cherry-fed rats had 14 percent lower body fat compared to the other rats who did not consume cherries (cherry-fed rats were approximately 54% body fat; rats eating the Western diet alone were 63% body fat). The researchers suggested cherry consumption could have an effect on important fat genes and genetic expression. According to the American Heart Association, being overweight or obese, in particular when the weight is concentrated in the middle, is a major risk factor for heart disease . Nearly two out of three Americans are overweight.

The animals were fed a “Western diet,” characterized by high fat and moderate carbohydrate – in line with the typical American diet – with or without added whole tart cherry powder, as 1 percent of the diet. The study was funded by the Cherry Marketing Institute, which provided an unrestricted grant to the University of Michigan to conduct the research and was not directly involved in the design, conduct or analysis of the project.

“Heart disease is the number one killer of Americans today, so it’s important we continue researching ways people can improve their diet to help reduce key risk factors,” said study co-author Dr. Steven F. Bolling, a cardiac surgeon at the University of Michigan Cardiovascular Center who also heads the U-M Cardioprotection Research Laboratory, where the study was performed. “We know excess body fat increases the risk for heart disease. This research gives us one more support point suggesting that diet changes, such as including cherries, could potentially lower heart disease risk.”

Cherry-enriched diets in the study also reduced total cholesterol levels by about 11 percent and two known markers of inflammation – commonly produced by abdominal fat and linked to increased risk for heart disease. Inflammation marker TNF-alpha was reduced by 40 percent and interleukin 6 (IL-6) was lowered by 31 percent. In their genetic analysis, the researchers found that the cherry-enriched diets reduced the genes for these two inflammation compounds, suggesting a direct anti-inflammation effect. While inflammation is a normal process the body uses to fight off infection or injury, according to recent science, a chronic state of inflammation could increase the risk for diseases and may be especially common for those who are overweight or obese, at least in part because of excess weight around the middle. Researchers say the animal study is encouraging and will lead to further clinical studies in humans to explore the link between diet, weight, inflammation and lowering heart disease risk.

The Power of Eating Red

Tart cherries, frequently sold as dried, frozen or juice, contain powerful antioxidants known as anthocyanins, which provide the bright, rich red color. Studies suggest these colorful plant compounds may be responsible for cherries’ anti-inflammatory properties and other health benefits.

This new research is the latest linking this red hot “Super Fruit” to protection against heart disease and inflammation. In fact, research suggests the red compounds in cherries that deliver the anti-inflammatory benefits may also help ease the pain of arthritis and gout.

Researchers have put forward a simple model of development and gene regulation that is capable of explaining patterns observed in the distribution of morphologies and body plans (or, more generally, phenotypes). The study, by Elhanan Borenstein of the Santa Fe Institute and Stanford University and David Krakauer of the Santa Fe Institute was published in this month’s issue of PLoS Computational Biology.

Nature truly displays a bewildering variety of shapes and forms. Yet, with all its magnificence, this diversity still represents only a tiny fraction of the endless ’space’ of possibilities, and observed phenotypes actually occupy only small, dense patches in the abstract phenotypic space. Borenstein and Krakauer demonstrate that the sparseness of variety in nature can be attributed to the interactions between multiple genes and genetic controls involved in the development of organisms – a much simpler explanation than previously suggested.

Borenstein and Krakauer further integrated their model with phylogenetic dynamics, allowing developmental plans to evolve over time. They showed that this hybrid developmental-phylogenetic model reproduces patterns that are observed in the fossil record, including increasing variation between taxonomic groups, accompanied by decreasing variation within groups. This pattern is consistent with the Cambrian radiation associated with a rapid proliferation of highly disparate, multicellular animals, and suggests that much of the variation seen today is as a result of simpler genetic controls dating from much earlier in evolutionary time.

The findings presented in this study also bear directly on issues of convergence (when very different organisms independently evolve similar features). By including a model of development, rather different genotypes can produce very similar phenotypes. Consequently, convergent evolution, which the vast space of genotypes would suggest to be rare, is allowed to become much more common.

One of the paradoxical implications of this study has been to show how innovations in development that lead to an overall increase in the number of accessible phenotypes, can lead to a reduction in selective variance. In other words, while the potential for novel phenotypes increases, the fraction of space these phenotypes occupies tends to contract. They concluded that “The theory presented in our paper complements the view of development as a key component in the production of endless forms and highlights the crucial role of development in constraining (as well as generating) biotic diversity.”

When reaching for an object, the brain prepares neural commands sent to the target muscles to minimize energy expenditure, according to a study published in PLoS Computational Biology by neuroscientists and mathematicians from the INSERM and ENSTA.

How the human brain organizes and controls our actions is a crucial question in life sciences. In recent decades, an important theoretical advance has been the use of computational models and the assumption that the brain behaves like an optimal controller. In most studies, an optimality criterion is chosen a priori and assumed to produce smooth and harmonious movements, as those recorded experimentally. Most existing models, however, fail to explain how our interactions with the external environment are integrated into optimization processes.

In particular, gravity is one of the constraints that permanently act upon the movements of living organisms. The simple observation of vertical arm movements reveals that muscle activity when moving upwards differs from when moving downwards. This led the authors to surmise that the brain takes advantage of gravitational force during movement, trying to optimize energy consumption. The discovery of this biological rule has resulted from the use of a hypothetical-deductive mathematical method which predicted short periods of muscle inactivation and direction-dependent hand kinematics. These predictions have been verified experimentally using human volunteers. Moreover, they have demonstrated a necessary and sufficient condition of optimal control for arm movements which is a novelty in motor control studies.

The authors explain how the brain plans movements by integrating biological and environmental constraints and the method may be of potential value for understanding motor dysfunction and guiding subsequent rehabilitation programs. Moreover, it opens the prospect of studying brain functions by a cooperative interaction of mathematicians and neuroscientists. Interestingly, the paper is a clear demonstration that mathematical principles and theories, formerly used for understanding the non-living world, are now used for understanding how biological organisms integrate these laws.

One of the smallest dinosaur skulls ever discovered has been identified and described by a team of scientists from London, Cambridge and Chicago. The skull would have been only 45 millimeters (less than two inches) in length. It belonged to a very young Heterodontosaurus, an early dinosaur. This juvenile weighed about 200 grams, less than two sticks of butter.

In the Fall issue of the Journal of Vertebrate Paleontology, the researchers describe important findings from this skull that suggest how and when the ornithischians, the family of herbivorous dinosaurs that includes Heterodontosaurus, made the transition from eating meat to eating plants.

“It’s likely that all dinosaurs evolved from carnivorous ancestors,” said study co-author Laura Porro, a post-doctoral student at the University of Chicago. “Since heterodontosaurs are among the earliest dinosaurs adapted to eating plants, they may represent a transition phase between meat-eating ancestors and more sophisticated, fully-herbivorous descendents.”

“This juvenile skull,” she added, “indicates that these dinosaurs were still in the midst of that transition.”

Heterodontosaurus lived during the Early Jurassic period (about 190 million years ago) of South Africa. Adult Heterodontosaurs were turkey-sized animals, reaching just over three feet in length and weighing around five to six pounds.

Because their fossils are very rare, Heterodontosaurus and its relatives (the heterodontosaurs) are poorly understood compared to later and larger groups of dinosaurs.

“There were only two known fossils of Heterodontosaurus, both in South Africa and both adults,” said Porro, who is completing her doctoral dissertation on feeding in Heterodontosaurus under the supervision of David Norman, researcher at the University of Cambridge and co-author of the study. “There were rumors of a juvenile heterodontosaur skull in the collection of the South African Museum,” she said, “but no one had ever described it.”

As part of her research, Porro visited the Iziko South African Museum, Cape Town, to examine the adult fossils. When she was there, she got permission to “poke around” in the Museum’s collections. While going through drawers of material found during excavations in the 1960s, she found two more heterodontosaur fossils, including the partial juvenile skull.

“I didn’t recognize it as a dinosaur at first,” she said, “but when I turned it over and saw the eye looking straight at me, I knew exactly what it was.”

“This discovery is important because for the first time we can examine how Heterodontosaurus changed as it grew,” said the study’s lead author, Richard Butler of the Natural History Museum, in London. “The juvenile Heterodontosaurus had relatively large eyes and a short snout when compared to an adult,” he said, “similar to the differences we see between puppies and fully-grown dogs.”

A specialist on the mechanics of feeding, Porro was particularly interested in the new fossil’s teeth. Heterodontosaurs, which means “different-toothed lizards,” have an unusual combination of teeth, with large fang-like canines at the front of their jaws and worn, molar-like grinding teeth at the back. In contrast, most reptiles have teeth which change little in shape along the length of the jaw.

This bizarre suite of teeth has led to debate over what heterodontosaurs ate. Some scientists think heterodontosaurs were omnivores who used their differently-shaped teeth to eat both plants and small animals. Others contend that heterodontosaurs were herbivores who ate only plants and that the canines were sexually dimorphic–present only in males, as in living warthogs. In that scenario, the canines could have been used as weapons by rival males in disputes over mates and territories.

Porro and colleagues found that the juvenile already had a fully-developed set of canines.

“The fact that canines are present at such an early stage of growth strongly suggests that this is not a sexually dimorphic character because such characters tend to appear later in life,” said Butler.

Instead, the researchers suspect that the canines were used as defensive weapons against predators, or for adding occasional small animals such as insects, small mammals and reptiles to a diet composed mainly of plants–what the authors refers to as “occasional omnivory.”

The study created a new mystery, however. With the aid of X-rays and CT scans, Porro found a complete lack of replacement teeth in the adult and juvenile skulls.

Most reptiles, including living crocodiles and lizards, replace their teeth constantly throughout their lives, so that sharp, unworn teeth are always available. The same was true for dinosaurs. Most mammals, on the other hand, replace their teeth only once during their lives, allowing the upper and lower teeth to develop a tight, precise fit.

Heterodontosaurus was more similar to mammals, not only in the specialized, variable shape of its teeth but also in replacing its teeth slowly, if at all, and developing tight tooth-to-tooth contact. “Tooth replacement must have occurred during growth,” the authors conclude, “however, evidence of continuous tooth replacement appears to be absent, in both adult and juvenile specimens.”

Amoebas glide toward their prey with the help of a protein switch that controls a molecular compass, biologists at the University of California, San Diego have discovered.

Their finding, detailed in this week’s issue of the journal Current Biology, is important because the same molecular switch is shared by humans and other vertebrates to help immune cells locate the sites of infections.

The amoeba Dictyostelium finds bacteria by scent and moves toward its meal by assembling a molecular motor on its leading edge. The active form of a protein called Ras sets off a cascade of signals to start up that motor, but what controlled Ras was unknown.

Richard Firtel, professor of biology along with graduate student Sheng Zhang and postdoctoral fellow Pascale Charest tested seven suspect proteins by disrupting their genes. One called NF1, which matches a human protein, proved critical to chemical navigation.

NF1 turns Ras off. Without this switch mutant amoebas extended false feet called pseudopodia in all directions and wandered aimlessly as Ras flickered on and off at random points on their surfaces. “You have to orient Ras in order to drive your cell in the right direction,” Firtel said.

In contrast, normal amoebas with working versions of NF1 elongate in a single direction and head straight for the most intense concentration of bacterial chemicals, the team reports.

The biochemical components of the system match those found in vertebrate immune cells called neutrophils that hunt down bacterial invaders, suggesting that the switch might be a key navigational control for many types of cells, Firtel said. “The pathway and responses are very similar and so are the molecules.”

Scientists at the Gladstone Institute of Neurological Disease (GIND) have identified a new strategy to destroy amyloid-beta (AB) proteins, which are widely believed to cause Alzheimer’s disease (AD). Li Gan, PhD, and her coworkers discovered that the activity of a potent AB-degrading enzyme can be unleashed in mouse models of the disease by reducing its natural inhibitor cystatin C (CysC).

All of us produce AB proteins in the brain. However, in most people, the proteins never build up to dangerous levels because they are cleared away by enzymes that destroy them. Previously Dr. Gan’s laboratory had shown that cathepsin B (CatB) is such an AB-degrading enzyme. In the latest issue of the journal Neuron, the researchers report a highly effective approach to promote CatB-mediated clearance of AB .

“Many groups have developed drugs to block the production of AB, but the efficacy and safety of this approach remains to be demonstrated in clinical trials,” said GIND Director Lennart Mucke, MD “By identifying an effective strategy to enhance the removal of AB, this research provides a very promising alternative or complementary therapeutic avenue.”

High levels of AB in the brain may result from overproduction of AB or from an inability to eliminate it from the brain. While most work has focused on the first option, the latter has been problematic. For example, efforts to develop a vaccine that would trigger the immune system to eliminate AB have shown limited success and resulted in adverse side effects.

“Our strategy to harness the activity of a powerful AB-degrading enzyme takes advantage of the brain’s own defense system to remove the toxic AB build-up,” said Dr. Gan. “In principle, one could boost the activity of CatB by expressing more of it in the brain or by reducing the activity of CysC, its natural inhibitor. We focused on the latter strategy because it has greater long-term therapeutic potential.”

Many enzymes that degrade proteins are kept in check by regulators called protease inhibitors. The activity of CatB is regulated by the protease inhibitor CysC. By reducing CysC activity, the scientists were able to unleash the AB-degrading power of CatB, effectively preventing the build-up of AB in mouse models of AD.

To examine the impact of this manipulation on brain function, Dr. Gan’s team measured brain cell activities that relate closely to learning and memory. Increasing CatB activity by lowering CysC levels prevented AB-induced deficits in those cellular activities. The investigators also tested the modified AD mice for learning and memory in a water maze. Higher levels of CatB activity improved the ability of AD to learn the maze and to retain the new information. Increasing CatB activity also prevented the premature mortality that is typically seen in these Alzheimer models.

“Our results suggest that CysC reduction has major therapeutic potential,” Dr. Gan said. “The next step will be to develop pharmacological approaches to inhibit CysC in the human brain.”

A new study looking at unprotected intercourse within gay couples when each partner has established HIV-infection found a correlation between anti-HIV immune response and sexual activity.

Study results showed that individuals who had regular unprotected receptive anal intercourse with partners with significant levels of HIV in their blood showed a stronger anti-HIV immune response. In addition, the magnitude of anti-HIV specific immune response correlated with their exposure to HIV through sex.

Published in the October 24th, 2008 issue of PLoS Pathogens, the study paper is authored by a research team from UCSF and the Gladstone Institute for Virology and Immunology.

The researchers found no evidence of systemic superinfection (re-infection with another strain of HIV) in the receptive partners, whose virus had been successfully suppressed through antiretroviral therapy for at least five months. In a comparison group of HIV-infected couples in which both partners’ viruses had been suppressed by therapy, researchers did not find the same strength of immune responses correlations or the same correlations with sexual exposure.

“We found HIV-specific immune responses in the treatment-suppressed partners that correlated with the level and route of exposure. The individuals with no detectable virus who were on antiretroviral therapy and who were exposed to HIV through receptive intercourse with a partner with detectable virus, had the stronger anti-HIV immune responses in comparison to individuals exposed to partners whose virus was also suppressed by antiretroviral therapy, where no effect was seen,” said study lead author, Christian B. Willberg, PhD, post-doctoral fellow in the UCSF Division of Experimental Medicine.

Notwithstanding the intriguing HIV specific findings, the findings also reveal an important general mechanism occurring in infectious diseases.

“We found that immune responses to chronic viral infections are influenced not only by the chronic infection existing in an individual or host, but also by exposures to exogenous virus from outside the individual or host,” said study co-senior author, Douglas F. Nixon, MD, PhD, professor of medicine in the UCSF Division of Experimental Medicine.

The investigators were unable to determine from these findings whether there is any benefit from this type of repeated exposure to HIV—i.e., a type of therapeutic vaccination for HIV-infected patients with suppressed virus. Some HIV patients on antiretroviral regimens lose many of their HIV-specific immune responses over time due to the successful suppression of viral replication by therapy.

“Indeed, our hypothesis had been that in the context of these waning anti-HIV responses among the suppressed partners and the expected level of exposure from repeated unprotected receptive intercourse, we would find evidence of superinfection. While we did not find systemic super-infection, we cannot exclude limited or localized superinfections in the gut. And, antiretroviral therapy may have been the factor that prevented superinfection in these patients,” said study co-senior author Robert M. Grant, MD, MPH, senior investigator at the Gladstone Institute of Virology and Immunology and associate professor of medicine at UCSF.

The study involved 49 HIV-infected gay men from the San Francisco Positive Partners Program study—a cohort of couples in which both partners are HIV-positive that began enrolling participants in 2000. Viral suppression in this study meant viral loads less than 50 copies. Among those participants whose virus had not been suppressed, the lowest viral load was 9,420 copies.

The team that designed this study benefited from its unique multidisciplinary composition. Immunologists working with social researchers were able to design a study that managed to distinguish between different levels of viral suppression and different patterns of sexual contacts and correlate the immunological aspects with the behavioral variables.

“We call the interaction between these two scientific communities together: ’social immunology’. It may be true that patterns of social activities shape immune responses generally, as we observed for people with HIV having contact with other HIV infected persons. Obviously more study is needed and we would like to see whether social immunology will continue to offer important insights,” said Grant.

“While we have not found a case of superinfection in our cohort of chronically infected HIV couples, a handful of cases of superinfection verified by linkage to a known partner’s virus have been reported in chronically infected HIV patients. It is also important to stress, these findings do not address the negative consequences of acquiring other sexually transmitted diseases through engaging in unprotected sex or the potentially positive consequences that unprotected sex may have in partnerships where both individuals are HIV-positive,” said study co-author, J. Jeff McConnell, MA, director of the Positive Partners study at the Gladstone Institute for Virology and Immunology.

As the first globally co-ordinated plan for the planet’s gravest health threats is hatched by government ministers from around the world this weekend, a new report sets out a 10-point plan for this new, globalised approach to infectious diseases such as avian flu.

Ministers of health and agriculture will formulate a global plan to prepare for, and respond to, the threat of avian flu and other emerging infectious diseases at the International Ministerial Conference on Avian and Pandemic Influenza in Sharm el Sheikh, Egypt (October 24-26). The plan - called the One World, One Health initiative - aims for an unprecedented integration of animal, human and ecosystem health issues to fight the threat of the avian flu virus, H5N1.

A new report by Professor Ian Scoones and Paul Forster of the ESRC STEPS Centre at the UK’s Institute of Development Studies lays out 10 key recommendations for One World, One Health, based on analysis of lessons learned from the massive $2bn international response to the avian flu over the past five years, during which time 245 people have died.

According to the report - The International Response to Highly Pathogenic Avian Influenza: Science, Policy and Politics - ministers need to rethink current ideas in order to achieve an effective, equitable and resilient international plan of response to emerging diseases.

The recommendations include rethinking disease surveillance, redefining health security, new responses to uncertainty and ignorance, emphasising access and equity as well as questions of organisational architecture and governance.

“The One World, One Health initiative is a radical departure from the conventional sectoral approaches to health. It is essential, but presents many challenges. We have identified 10 challenges for the way ahead, and urge ministers to rethink rather than repackage their measures. One World One Health needs to be more than ‘old wine in new bottles’,” said Professor Ian Scoones, IDS Fellow and co-director of the ESRC STEPS Centre.

Over the last decade, the avian flu virus, H5N1, has spread across most of Asia and Europe and parts of Africa. In some countries – including Indonesia, China, Vietnam, Bangladesh, Nigeria and Egypt – the disease has become endemic. Although 245 deaths have been reported since 2003 there has, as yet, been no human pandemic. But somewhere, some time, a new emerging infectious disease will have major impacts, given changing disease ecologies and patterns of urbanisation and climate change.

A major international response, backed by over $2bn of public money, has affected the livelihoods and businesses of millions. Markets have been restructured, surveillance and poultry vaccination campaigns implemented, and over two billion birds have died or been culled. Simultaneously substantial investment has been made in human and animal health systems and developing drugs and vaccines.

In many countries pandemic contingency and preparedness plans have been devised. Yet coordination at country level has been found wanting; rivalries between professions and organisations persist; and funding and capacities for an effective and equitable global responses to a pandemic remain weak.

The themes addressed in this report are being explored as part of a project on avian influenza policy responses in Cambodia, Indonesia, Thailand and Vietnam, in collaboration with the UN Food and Agriculture Organisation. They are central to the ESRC STEPS Centre’s research programme on ecology, politics, policy and pathways to sustainability.

VIB researchers at Ghent University have discovered the substance that governs the formation of root offshoots in plants, and how it works. Root offshoots are vitally important for plants – and for farmers. Plants draw the necessary nutrients from the soil through their roots. Because they do this best with a well-branched root system, plants must form offshoots of their roots at the right moment. The VIB researchers describe how this process is controlled in the prominent professional journal Science. A key player in this process is a protein called ACR4. Depending on the signals that it receives from its environment, this protein triggers the formation of a root offshoot. Now that we know the control mechanism, we can begin to stimulate plant roots to form more, or fewer, offshoots. This can lead to a more ecological agriculture and to the production of better crops at the same time. An efficient network

It is difficult to overstate the importance of plants in our lives − they are responsible for our oxygen and for food, clothing, energy, and countless other things. And in turn, the importance of a plant’s roots is unquestionable: they provide the plant with necessary nutrients and moisture. The more the roots are subdivided, in breadth and depth, the better they can do their work. So, a well-coordinated, controlled formation of root offshoots is crucial to a plant. But, until now, how a plant determines when and where an offshoot should be formed was unknown.

Asymmetric cell division

The presence of stem cells is very important in the development of plants and animals. Stem cells are cells that can transform themselves into various types of cells. In animals, tissues and organs are formed before birth; but in fully-grown plants, stem cells continue to play a major role in the formation of new organs or tissues, such as root offshoots.

These stem cells are found inside the root, and several of them will induce the formation of an offshoot. These ‘root-founder’ cells undergo an asymmetric cell division. In contrast to the usual cell division, which gives rise to two identical cells, asymmetric cell division produces two different cells: a stem cell that is identical to the original cell, and a cell that is ready to become a specialized cell – in this case, a secondary root cell.

The decisive signal

With the aid of the mouse-ear cress (Arabidopsis thaliana), a frequently used model plant, Ive De Smet and Valya Vassileva in Tom Beeckman’s group have been studying how a plant determines which cells will trigger offshoots. To do this, the VIB researchers in Ghent have employed a special technology that makes it possible to make synchronous offshoots develop at different moments. This allowed them to isolate the cells that induce the formation of offshoots. They found out which genes are active in these cells and compared them with the genes that are crucial to normal cell division. In this way, the researchers identified a specific set of genes that control asymmetric cell division and send the signal for the formation of offshoots.

ACR4: control over asymmetric division

The researchers then examined one of these genes more closely. The ACR4 gene contains the DNA code for a receptor, a protein that is often located on the exterior of a cell to pick up signals from the outside and transmit them to the controlling mechanisms within the cell. When the researchers disrupted the function of ACR4 in plant cells, the precisely orchestrated asymmetric cell division was also disturbed. From this finding, De Smet and Vassileva inferred that ACR4 plays a key role in the creation of offshoots. Because the protein has a receptor function, triggering the formation of offshoots depends on its reaction to signals from the environment.

Desired or undesired

With this research, the scientists have discovered a fundamental mechanism − fundamental for the plant, and very important for plant-breeders as well. This new knowledge enables us to promote, or retard, the formation of offshoots − both activities are useful in a large number of applications.

Promoting an extensive root system helps plants absorb nutrients more readily, and thus they need less fertilizer. Such plants can also grow more easily in dry or infertile soils. Furthermore, plants with a well-developed root system are more firmly anchored in the soil and can be used to counteract erosion.

On the other hand, slowing down secondary root formation can be advantageous in tuberous plants, like potatoes or sugar beets. This enables these food crops to invest all their energy in the production of nutrients. Fewer root offshoots also makes it easier for farmers to harvest these crops.

Plant research with medical possibilities?

This plant research sheds light on the control of asymmetric cell division − and this kind of cell division is similar to the cell division of stem cells in animals, too. So, these results can also provide greater insight into how animal stem cells specialize.

For example, irregular cell division plays a role in the development of various types of cancer, and similar control mechanisms might underlie this process as well. This is clearly an important area for future research.

‘Global change, environment and natural resources management, sustainable development, poverty reduction, and environment and human health, are some of the major scientific research challenges currently being tackled by ICSU.  But these issues cannot be solved without understanding the impact of people on these issues and the impact of these issues on people—that is, social science,’ said Anne Whyte, a member of ICSU’s Committee on Scientific Planning and Review (CSPR) and a former Director General for Environment and Natural Resources of the International Development Research Centre (IDRC) in Canada.  The report, ‘Enhancing Involvement of Social Sciences in ICSU’, identifies social sciences as being essential for the implementation of the ICSU Strategic Plan 2006-2011.  Recommendations in the report include: that ICSU continue to encourage the participation of social sciences on its committees, task forces and collaborative research initiatives; stimulate more social sciences unions to join ICSU; and to work with the International Social Sciences Council (ISSC) as a key partner in strengthening international social science of relevance for implementing ICSU’s Strategic Plan.  Whyte said, ‘ICSU’s mission is to strengthen international science for the benefit of society.  To do this, the natural and social sciences must be fully involved; working together to provide knowledge to solve global challenges.’ Heide Hackmann, Secretary-General of the International Social Sciences Council (ISSC) agreed, ‘High quality social scientific knowledge is becoming necessary knowledge for policymakers, business and community leaders, and natural scientists alike.  In this environment the ISSC has taken on the challenge of becoming the major global social scientific player alongside, and in collaboration with, ICSU in addressing key global challenges’.  But it’s not all smooth sailing.  There are barriers that must be overcome: natural and social scientists speak different languages; many institutions are not equipped to deal with interdisciplinary research; and there is resistance among some scientists from both sides of the table.  ‘The key to success is that natural and social scientists must work together on research agenda setting.  One field cannot merely provide services for the other—they both must be involved in setting research goals.  And you need to choose the right people,’ said Roberta Balstad of the Center for Research on Environmental Decisions, at Columbia University in New York, and a member of CSPR.  Over the years, ICSU has actively involved the social sciences, particularly through its global environmental change programmes.  The Earth System Science Partnership (ESSP) successfully integrates natural and social sciences in order to investigate how changes in the Earth System affect global and regional sustainability.  And new ICSU programmes, such as ‘Integrated Research on Disaster Risk’ and ‘Ecosystem Change and Human Well-being’, have involved both the natural and social sciences from the earliest planning stages.  ‘Indeed, it could be argued that ICSU is at a point in its history where it is increasingly dependent on social science to fulfil its mission.  Thus, better integration of the social sciences into ICSU is no longer an option, it is a necessity,’ said Balstad.

Depressed pregnant women have twice the risk of preterm delivery than pregnant women with no symptoms of depression, according to a new study by the Kaiser Permanente Division of Research.  The study is published online in the Oxford University Press’s journal Human Reproduction on behalf of the European Society of Human Reproduction and Embryology.

The study found that pregnant women with symptoms of depression have an increased risk of preterm delivery, and that the risk grows with the severity of the depressive symptoms.  These findings also provide preliminary evidence that social and reproductive risk factors, obesity, and stressful events may exacerbate the depression-preterm delivery link, according to the researchers.

Because the majority of the women in the study did not use anti-depressants, the study provides a clear look at the link between depression and preterm delivery.

The study -which is among the first to examine depression and pre-term delivery in a representative and diverse population in the United States -looked at 791 pregnant Kaiser Permanente members in San Francisco city and county from October 1996 through October 1998.

Researchers interviewed the women around their 10th week of pregnancy and found that 41 percent of the women reported significant or severe depressive symptoms.  The women with less severe depressive symptoms had a 60 percent higher risk of preterm delivery -defined as delivery at less than 37 completed weeks of gestation -compared with women without significant depressive symptoms, and the women with severe depressive symptoms had more than twice the risk.

“Preterm delivery is the leading cause of infant mortality, and yet we don’t know what causes it.  What we do know is that a healthy pregnancy requires a healthy placenta, and that placental function is influenced by hormones, which are in turn influenced by the brain,” said lead author Dr. De-Kun Li, a reproductive and perinatal epidemiologist at Kaiser Permanente’s Division of Research in Oakland.

“This study adds to emerging evidence that depression during early pregnancy may interfere with the neuroendocrine pathways and subsequently placental function.  The placenta and neuroendocrine functions play an important role in maintaining the health of a pregnancy and determining the onset of labor,” Li explained.

“Post-partum depression has been extensively studied and discussed by the public, but depression during pregnancy is significantly under-recognized and under-diagnosed.  Clinicians should pay close attention to depression during pregnancy to catch it early,” Li said.  “If prenatal depression is indeed as prevalent as reported in this and other studies and doubles the risk of preterm delivery, then bringing depression to the forefront of prenatal care could lead to a significant reduction of preterm deliveries.”

In addition to being the leading cause of infant mortality and morbidity, preterm delivery is also the leading medical expenditure for infants, with estimated annual cost of about $26 billion in the United States alone.  Presently, other than a prior history of preterm delivery and some pregnancy complications, very little is known for its risk factors and origins.

“The key strengths of this study are that it ascertained the depressive symptoms early in pregnancy, long before the preterm delivery occurred, therefore avoiding recall bias.  In addition, the study was not clouded by antidepressant use because only 1.5 percent of the study population was prescribed antidepressants and we could exclude them in the analyses,” Li said.  “Considering the increased use of antidepressants among pregnant women, this study’s findings may provide a rare opportunity to evaluate the effect of depression on risk of preterm delivery without the entanglements of antidepressants.”