Koalas selective about eucalyptus leaves at mealtime: Koalas selected leaves with more nitrogen, fewer toxins

This is a photo of a koala in a eucalyptus tree.

Koala population distribution may be influenced by eucalyptus leaf toxin and nutrient content, especially in areas with low-quality food options, according to a study published December 3, 2014 in the open-access journal PLOS ONE by Eleanor Stalenberg from The Australian National University and colleagues.

Scientists suspect that access to nutritious food plays a role in herbivore distribution and abundance, but there is still some debate over how variation in plant nutritional qualities may influence population distribution. Koalas predominantly eat eucalyptus leaves and their population density varies widely in different Australian eucalyptus forests, possibly due to variation in the nutritional quality of the eucalyptus leaves. The authors of this study sampled leaves from eight species of eucalyptus trees in forests on the far south coast of New South Wales, Australia, to investigate how leaf chemistry might influence wild koala distribution. They also measured koala tree visitation using koala faecal pellets at the base of the tree as a proxy.

They found that koalas visited trees with leaves containing higher available nitrogen--used by the body to make proteins--and avoided trees with higher leaf concentrations of a toxic chemical found exclusively in eucalypts when compared with a neighboring tree of the same species. The authors posit that plant diversity is likely important when koalas are foraging in habitats of low nutritional quality, providing a range of nutritional quality and minimizing the need to move to forests with higher quality leaves. The researchers' findings suggest that nutritional limitations play an important role in constraining leaf-eating koala populations.

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Solving a long-standing mystery, scientists identify principal protein sensor for touch

A team led by biologists at The Scripps Research Institute (TSRI) has solved a long-standing mystery in neuroscience by identifying the "mechanoreceptor" protein that mediates the sense of touch in mammals.

Mice that lack the Piezo2 ion-channel protein in their skin cells and nerve endings lose nearly all their sensitivity to ordinary light touch, but retain a mostly normal sensitivity to painful mechanical stimuli.

"We can say with certainty that Piezo2 is the principal touch sensor in mammals," said Ardem Patapoutian, professor at TSRI and investigator with Howard Hughes Medical Institute.

Patapoutian and his colleagues report their discovery in the December 4, 2014 issue of Nature.

Unraveling the Clues

By the 1980s scientists have known the identity and sequence of the main protein photoreceptor that underlies the mammalian sense of sight. Since the early 1990s they have been identifying smell and taste receptors. But the mechanoreceptor protein that mediates the sense of touch has been more elusive. "It works in very few specialized cells and isn't abundant in those cells," Patapoutian said, "and at the start we didn't have many clues about what it would look like."

Four years ago, with the help of advanced genomics techniques, Patapoutian and members of his laboratory were able to identify two mechanically activated ion-channel proteins, Piezo1 and Piezo2, in mouse cells. Physical force, enough to distort a cell membrane in which one of these ion channels was embedded, could effectively switch the ion-channel from closed to open, allowing sodium or other positively charged electrolytes to flow inward. In a sensory nerve, that could trigger an electrical nerve impulse -- thus tranducing physical force into a neural signal.

Of the two newly identified ion-channel proteins, only Piezo2 was expressed significantly in the touch-sensing neurons that are based in the dorsal root ganglia of the spine and extend their nerve processes into the skin. That led Patapoutian to focus on it as the likely transducer for the mammalian sense of touch.

Last year, Patapoutian and colleagues reported that Piezo2 works as the touch sensor on Merkel cells, specialized cells that lie at touch-sensitive nerve terminals in the skin and augment the sense of touch in mice.

One Ion Channel for One Type of Touch

In the new study, the researchers extended these findings to the touch-sensitive nerve terminals themselves. These are often shaped to detect different types and directions of force, and for extra sensitivity may be attached to other force-responsive structures such as Merkel cells or hair follicles.

To start, the scientists made use of special mice, bred in the earlier Merkel cell study led by postdoctoral fellow Seung-Hyun Woo, which produce Piezo2 linked to a fluorescent protein. That allowed them to verify, via the resulting fluorescence, that Piezo2 is expressed in a broad range of "low-threshold mechanoreceptor" nerve terminals, which are embedded in both hairy and hairless areas of mouse skin.

The next step was to delete the Piezo2 gene from mice and observe whether the animals still responded normally to touch stimuli. But mice bred without Piezo2 all died at birth. Thus, postdoctoral fellow Sanjeev S. Ranade, lead author of the paper, had to accomplish the tricky task of developing a "conditional knockout" mouse line, in which the Piezo2 gene could be almost completely deleted from already-mature mice, and just from their dorsal root ganglia sensory neurons and Merkel cells.

Electrical tests of these neurons cultured from the mice, performed by staff scientist Adrienne Dubin, showed that they lost virtually all the responsiveness to mechanical stimuli that would be required for sensing ordinary light touch. Collaborator Gary Lewin and members of his laboratory at Berlin's Max-Delbrück Center for Molecular Medicine found the same profound loss of mechanosensitivity in special tests of intact skin nerves from the mice.

The mice lacking Piezo2 in their nerve endings and Merkel cells also showed a clear behavioral difference from normal mice. "Across a range of tests, we observed a dramatic reduction in their responsiveness to ordinary light touch stimuli," said Ranade.

Remarkably, these touch-insensitive mice remained responsive to skin-applied stimuli that are normally painful, such as heat, cold and pinching. Painful mechanical sensations such as pinching are thought to be mediated by high-threshold mechanoreceptor nerve terminals, which require more force to activate. "The functions of these high-threshold mechanoreceptor nerves seemed unaffected in the Piezo2 conditional knockout mice," Patapoutian said.

The finding suggests that the detection of light, innocuous touch -- which we commonly think of as the "sense of touch" -- is mediated principally by one set of nerve ends using piezo2 ion channels. By contrast, stronger, pain-causing touch sensations appear to be mediated by a less force-sensitive set of nerve ends with their own ion channel proteins, which have yet to be discovered.

Potential Applications

Patapoutian now plans to investigate how much "crosstalk" exists between these two mechanosensitive nerve systems. It is well known that chronic pain conditions can make even light touch stimuli feel painful. "This discovery now allows us to test the relationship between touch and pain," he said.

He and his colleagues also are investigating the role of Piezo2 in other parts of the body where it is expressed, including the lungs.

Funding for the research came partly from the National Institutes of Health (R01 DE022358).

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Identifying the cellular origin of fibrosis

A Gli1 progenitor cell (red) located in a healthy kidney. During fibrosis these cells differentiate into myofibroblasts, causing scarring and organ failure.

Researchers from Brigham and Women's Hospital (BWH) have identified what they believe to be the cells responsible for fibrosis, the buildup of scar tissue. Fibrotic diseases, such as chronic kidney disease and failure, lung disease, heart failure and cirrhosis of the liver, are estimated to be responsible for up to 45 percent of deaths in the developed world.

The findings are published online in the journal Cell Stem Cell.

"Previous research indicated that myofibroblasts are the cells responsible for fibrosis," said Benjamin Humphreys, MD, PhD, senior author of the research paper and a physician scientist in the Renal Division at BWH. "But there was controversy around the origin of this cell. Identifying the origin could lead to targeted therapies for these very common diseases."

With the knowledge that fibrosis appears to radiate from blood vessels, Humphreys and colleagues examined the hedgehog signaling pathway, which normally regulates organ development but whose roles in the adult are less clear. They noticed that in adult mice, a hedgehog pathway gene called Gli1 was specifically expressed in a rare group of cells located around blood vessels in all solid organs. This pattern suggested that the cells might play a role in fibrosis. To test this hypothesis the researchers tagged this protein in tissue with varying forms of fibrosis, and found that these cells proliferated by almost 20-fold under chronic injury and turned into myofibroblasts.

"We believe that this cell population is responsible for about 60 percent of all organ myofibroblasts," said Humphreys.

After identifying these cells, first author Rafael Kramann, MD, Humphreys and colleagues set out to determine whether removing these cells would lead to improvement in organ function.

Using a genetic strategy in mice, the researchers were able to ablate these Gli1 cells, while leaving other cells unharmed. In mice with kidney and cardiac fibrosis, the ablation of these cells resulted in reduction in fibrosis and rescued heart function.

"We've found that these Gli1 progenitor cells differentiate into myofibroblasts, and in fibrotic disease, when they are ablated, we can rescue organs and organ function," said Humphreys.

Researchers note that the genetic strategy employed in the preclinical model is not feasible in humans. For this reason, future research involves the exploration of drugs that could specifically target and shut off these fibrosis-causing stem cells with the hope that either an existing drug or a new drug could translate to a potential therapy for humans.

Humphreys also notes that this cell population plays a role in the aging process. "Most organs develop fibrosis as we age," he said. "Specifically, in the kidney we lose one percent of kidney function as a result of fibrosis for each year that we age. We look forward to future research, using human tissue, to confirm our findings in humans and work to develop a potential therapy."

This research was supported by the Harvard Stem Cell Institute, the National Institutes of Health, the National Institute of Diabetes and Digestive and Kidney Diseases, the American Heart Association, and the Deutsche Forschungsgemeinschaft.

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Revealed: How bacteria drill into our cells and kill them

A team of scientists has revealed how certain harmful bacteria drill into our cells to kill them. Their study shows how bacterial 'nanodrills' assemble themselves on the outer surfaces of our cells, and includes the first movie of how they then punch holes in the cells' outer membranes. The research, published in the journal eLife, supports the development of new drugs that target this mechanism, which is implicated in serious diseases. The team brings together researchers from UCL, Birkbeck, University of London, the University of Leicester, and Monash University (Melbourne).

Unlike drills from a DIY kit, which twist and grind their way through a surface, bacterial nanodrills do not contain rotating parts. Rather, they are ring-like structures (similar to an eyelet) built out of self-assembling toxin molecules. Once assembled, the toxins deploy a blade around the ring's inside edge that slices down into the cell membrane, forming a hole.
To determine how these rings are built, team member Natalya Dudkina made several thousand images of artificial cell membranes coated with toxins, using an electron microscope. Dudkina is a member of Helen Saibil's group at Birkbeck, University of London, which specialises in mapping biological structures using electron microscopy.

"Each ring was formed of around 37 copies of the toxin molecule. But aside from complete rings, we also observed arc-shaped, incomplete rings," Dudkina said. "One problem we had, though, was that our method can only record snapshots of the membrane perforation process frozen at different intermediate stages."

The solution to this was to produce a 'movie' of what happens when the toxins are placed on a cell membrane. This was carried out with atomic force microscopy (AFM) at Bart Hoogenboom's lab at the London Centre for Nanotechnology at UCL. AFM uses an ultrafine needle to feel, rather than see, a surface. This needle repeatedly scans the surface to produce a moving image that refreshes fast enough to show how the toxins move over the membrane and then cut holes in the membrane as they sink in.

"It was quite spectacular to look at," said Carl Leung, a member of Hoogenboom's lab at UCL. "After the initial assembly of the toxins into arcs and rings, they kept skating over the membrane surface. Then they stopped, sank into the membrane, and started spitting out the material they had drilled through, like sawdust when you drill holes in wood."

A big surprise for the team was that complete rings aren't needed to pierce the cell membrane: even relatively short fragments are still able to cut holes, albeit smaller ones, and hold them open, allowing bacteria to feed on the cell's contents.

Together, these findings give a detailed view of how these bacterial toxins drill holes in cell membranes. The snapshots from the electron microscopy show how the rings are structured at the start and the end of the drilling process, and the moving images from the AFM show the process as it unfolds.

The discovery supports the development of new drugs that can target bacterial nanodrills and help treat the diseases in which they are implicated. These include pneumonia, meningitis and septicaemia. Extensive research into such drugs that is ongoing at the University of Leicester, which also provided a genetically modified form of the toxin to help identify the different steps in the hole-drilling process.

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Researchers control adhesion of E. coli bacteria

A research team from Kiel University (CAU) and Goethe University Frankfurt have jointly created a synthetic surface on which the adhesion of E. coli bacteria can be controlled. The layer, which is only approximately four nanometres thick, imitates the saccharide coating (glycocalyx) of cells onto which the bacteria adhere such as during an infection. This docking process can be switched on and off using light. This means that the scientists have now made an important step towards understanding the relationship between sugar (carbohydrates) and bacterial infections. Their research results embellish the front page of the latest issue of the journal Angewandte Chemie (Applied Chemistry).

The bond between either cells and other cells or cells and surfaces is vital to organisms, for example in the development of internal organs and tissue. However, these mechanisms are also involved in illness and infections. The E. coli bacteria used in the experiment can cause urinary tract infections, meningitis, sepsis and other severe illnesses. In order to understand and treat these illnesses, researchers need to decipher the molecular processes which allow the bacteria cells to dock onto the healthy host cells.

This often happens by way of proteins, which interact with carbohydrate structures on the surface of the host cell by means of a complex fit principle (simplified: lock-and-key principle). The Kiel/Frankfurt study demonstrates for the first time that the spatial orientation of the carbohydrate structures is crucial to this process. However, in natural glycocalyx, a mere nanometre thick polysaccharide layer covering all cells, the relationships are still too complex to uncover how proteins and carbohydrates identify each other.

In Collaborative Research Center (SFB) 677 'Function by Switching', Professor Thisbe K. Lindhorst, chemist at Kiel University, and her team construct molecules which, when irradiated by light at different wavelengths, operate as biological switches. Together with the working group around the surfaces specialist Professor Andreas Terfort (Frankfurt University), the Lindhorst group has now produced a system with which the orientation of the saccharide docking points, and thus the bonding of E. coli bacteria, can be controlled. To do this, the scientists covered an extremely thin gold surface with a precisely defined saccharide covering, coupled to azobenzene. This is a hydrocarbon containing a nitrogen bridge and operating as a hinge controlled by light. The bonding properties of the saccharide coating can now be switched using this method: if the researchers irradiate their system with light with a wavelength of 365 nanometres, considerably fewer pathogenic bacteria cells can adhere to the synthetic surface. The saccharide molecules turn away from the bacteria, in a sense, and can no longer be recognised. When switched on by 450 nanometre wavelength light waves, on the other hand, the structures reorientate such that the bacteria cells can dock on once again. In this way, E. coli adhesion can be controlled.

'By employing a layer system on a solid surface, in combination with a photo-hinge, the complex dynamics of a real glycocalyx can be reduced to the principal processes and thus be better understood', explains Terfort. 'It should be possible to transfer this novel approach to other biological boundary layer systems.'

'Based on our model system, glycocalyx recognition and bonding effects can be precisely defined and investigated from a completely new angle', says Lindhorst. 'If we can learn how to influence glycocalyx in the context of the relationship between health and healing, it will lead to a revolution in medicinal chemistry.'

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The Biology of Anxious Temperament May Lie With a Problem in an Anxiety 'Off Switch'

Persistent anxiety is one of the most common and distressing symptoms compromising mental health. Most of the research on the neurobiology of anxiety has focused on the generation of increased anxiety, i.e., the processes that "turn on" anxiety.

But what if the problem lay with the "off switch" instead? In other words, the dysfunction could exist in the ability to diminish anxiety once it has begun.

A new report in the current issue of Biological Psychiatry by researchers at the University of Wisconsin at Madison suggests that deficits in one of the brain's off switches for anxiety, neuropeptide Y receptors, are decreased in association with anxious temperament.

To conduct their work, the researchers studied 24 young rhesus monkeys to examine expression of the neuropeptide Y system in relation to anxious temperament. Neuropeptide Y is a neurotransmitter that helps regulate the body's response to stress. Anxious temperament is a trait that presents early in life and increases the risk of developing anxiety and depressive disorders.

They found that elevated anxious temperament is associated with decreased messenger RNA expression of two neuropeptide Y receptors, Y1R and Y5R, in the central nucleus of the amygdala, a region of the brain that plays an important role in regulating fear and anxiety.

"This finding is very important as it focuses our thinking about treatment on promoting recovery after stress rather than suppressing the normal adaptive reaction to threatening situations. Fear, at times, is the best possible reaction to life events. However, persistent fear can be destructive. This new finding points us in the direction of new treatments that aim to promote resilience rather than blunting one's life experiences," said Dr. John Krystal, Editor of Biological Psychiatry.

The authors agree, with first author Dr. Patrick Roseboom noting that "extreme anxiety in children is a prominent predictor of the later development of anxiety disorders and other illnesses such as depression and substance abuse. Using young rhesus monkeys in our model of anxious temperament is critical as brain structure and function in non-human primates closely resembles that of humans."

"Identifying the molecular underpinnings of why some individuals are at-risk for developing anxiety and depression has the potential to identify new treatment targets," added Roseboom. "The current findings suggest that focusing on a system that provides resilience may be an important strategy at the molecular level."

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Sweet smell of success: Researchers boost methyl ketone production in e. coli

The research of Harry Beller (foreground) and Ee-Been Goh of the Joint BioEnergy Institute is boosting the production of methyl ketones by engineered strains of E.coli.

Two years ago, researchers at the U.S. Department of Energy's Joint BioEnergy Institute (JBEI) engineered Escherichia coli (E. coli) bacteria to convert glucose into significant quantities of methyl ketones, a class of chemical compounds primarily used for fragrances and flavors, but highly promising as clean, green and renewable blending agents for diesel fuel. Now, after further genetic modifications, they have managed to dramatically boost the E.coli's methyl ketone production 160-fold.

"We're encouraged that we could make such a large improvement in methyl ketone production with a relatively small number of genetic modifications," says Harry Beller, a JBEI microbiologist who led this study. "We believe we can further improve production using the knowledge gained from in vitro studies of our novel metabolic pathway."

Beller, who directs the Biofuels Pathways department for JBEI's Fuels Synthesis Division, and is also a senior scientist with Berkeley Lab's Earth Sciences Division, is the corresponding author of a paper describing this work in the journal Metabolic Engineering. The paper is titled "Substantial improvements in methyl ketone production in E. coli and insights on the pathway from in vitro studies." Co-authors are Ee-Been Goh, Edward Baidoo, Helcio Burd, Taek Soon Lee and Jay Keasling.

Methyl ketones are naturally occurring compounds discovered more than a century ago in the aromatic evergreen plant known as rue. Since then they've been found to be common in tomatoes and other plants, as well as insects and microorganisms. Today they are used to provide scents in essential oils and flavoring in cheese and other dairy products. Although native E. coli make virtually undetectable quantities of methyl ketones, Beller, co-author Goh and their colleagues have been able to overcome this deficiency using the tools of synthetic biology.

"In our original effort, for methyl ketone production we made two major modifications to E. coli," Beller says. "First we modified specific steps in beta-oxidation, the metabolic pathway that E. coli uses to break down fatty acids, and then we increased the expression of a native E. coli enzyme called FadM. These two modifications combined to greatly enhance the production of methyl ketones."

In their latest effort, Beller, Goh and their colleagues made further modifications that included balancing the overexpression of two other E. coli enzymes, fadR and fadD, to increase fatty acid flux into the pathway; consolidating two plasmid pathways into one; optimizing codon usage for pathway genes not native to E. coli; and knocking out key acetate production pathways. The results led to a methyl ketone titer of 3.4 grams/liter after approximately 45 hours of fed-batch fermentation with glucose. This is about 40-percent of the maximum theoretical yield for methyl ketones.

"Although the improved production is still not at a commercial level in the biofuel market, it is near a commercial level for use in flavor and fragrances, where certain methyl ketones are much more highly valued than they would be in the biofuel market," Beller says. "It may be possible for a company to sell a small percentage of methyl ketones in the flavor and fragrance market and use the profits to enhance the economic viability of the production of methyl ketones as biofuels."

The in vitro studies carried out by Beller and Goh provided insights into the pathway, some of which point to even further production gains. One key finding was the confirmation that a decarboxylase enzyme is not required for this methyl ketone pathway.

"Several different metabolic pathways have been developed in the past couple of years for methyl ketone production in E. coli, a couple of which use decarboxylase enzymes to catalyze the last step of the pathway," Beller says. "Our methyl ketone pathway is performing quite a bit better than these other pathways, but it does not include a native or added decarboxylase."

The in vitro studies also addressed concerns about the FadM enzyme being somewhat "promiscuous" in its hydrolyzing (thioesterase) activities. Beller and Goh found that FadM can act on intermediates in the methyl ketone pathway and effectively reduce the flux of carbon to the final methyl ketone products. However, they say that with some informed metabolic engineering, this need not be a problem and knowledge of the phenomenon could even be used to enhance production.

"In all likelihood, there is a sweet spot in the level of expression of the FadM enzyme that will allow for maximal production of methyl ketones without siphoning away metabolic intermediates," Beller says.

This research was supported by JBEI through the U.S. Department of Energy's Office of Science.

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Human eye can see 'invisible' infrared light

The eye can detect light at wavelengths in the visual spectrum. Other wavelengths, such as infrared and ultraviolet, are supposed to be invisible to the human eye, but Washington University scientists have found that under certain conditions, it’s possible for us to see otherwise invisible infrared light.

Any science textbook will tell you we can't see infrared light. Like X-rays and radio waves, infrared light waves are outside the visual spectrum.

But an international team of researchers co-led by scientists at Washington University School of Medicine in St. Louis has found that under certain conditions, the retina can sense infrared light after all.

Using cells from the retinas of mice and people, and powerful lasers that emit pulses of infrared light, the researchers found that when laser light pulses rapidly, light-sensing cells in the retina sometimes get a double hit of infrared energy. When that happens, the eye is able to detect light that falls outside the visible spectrum.

"We're using what we learned in these experiments to try to develop a new tool that would allow physicians to not only examine the eye but also to stimulate specific parts of the retina to determine whether it's functioning properly," said senior investigator Vladimir J. Kefalov, PhD, associate professor of ophthalmology and visual sciences at Washington University. "We hope that ultimately this discovery will have some very practical applications."

The findings are published Dec. 1 in the Proceedings of the National Academy of Sciences (PNAS) Online Early Edition. Collaborators include scientists in Cleveland, Poland, Switzerland and Norway,

The research was initiated after scientists on the research team reported seeing occasional flashes of green light while working with an infrared laser. Unlike the laser pointers used in lecture halls or as toys, the powerful infrared laser the scientists worked with emits light waves thought to be invisible to the human eye.

"They were able to see the laser light, which was outside of the normal visible range, and we really wanted to figure out how they were able to sense light that was supposed to be invisible," said Frans Vinberg, PhD, one of the study's lead authors and a postdoctoral research associate in the Department of Ophthalmology and Visual Sciences at Washington University.

Vinberg, Kefalov and their colleagues examined the scientific literature and revisited reports of people seeing infrared light. They repeated previous experiments in which infrared light had been seen, and they analyzed such light from several lasers to see what they could learn about how and why it sometimes is visible.

"We experimented with laser pulses of different durations that delivered the same total number of photons, and we found that the shorter the pulse, the more likely it was a person could see it," Vinberg explained. "Although the length of time between pulses was so short that it couldn't be noticed by the naked eye, the existence of those pulses was very important in allowing people to see this invisible light."

Normally, a particle of light, called a photon, is absorbed by the retina, which then creates a molecule called a photopigment, which begins the process of converting light into vision. In standard vision, each of a large number of photopigments absorbs a single photon.

But packing a lot of photons in a short pulse of the rapidly pulsing laser light makes it possible for two photons to be absorbed at one time by a single photopigment, and the combined energy of the two light particles is enough to activate the pigment and allow the eye to see what normally is invisible.

"The visible spectrum includes waves of light that are 400-720 nanometers long," explained Kefalov, an associate professor of ophthalmology and visual sciences. "But if a pigment molecule in the retina is hit in rapid succession by a pair of photons that are 1,000 nanometers long, those light particles will deliver the same amount of energy as a single hit from a 500-nanometer photon, which is well within the visible spectrum. That's how we are able to see it."

Although the researchers are the first to report that the eye can sense light through this mechanism, the idea of using less powerful laser light to make things visible isn't new. The two-photon microscope, for example, uses lasers to detect fluorescent molecules deep in tissues. And the researchers said they already are working on ways to use the two-photon approach in a new type of ophthalmoscope, which is a tool that allows physicians to examine the inside of the eye.

The idea is that by shining a pulsing, infrared laser into the eye, doctors might be able to stimulate parts of the retina to learn more about its structure and function in healthy eyes and in people with retinal diseases such as macular degeneration.

The research was made possible, in part, by the Kefalov team's development of a tool that allowed the scientists to obtain light responses from retinal cells and photopigment molecules. That device already is commercially available and being used at several vision research centers around the world.

Funded by the National Eye Institute (NEI) and the National Institute on Aging (NIA) of the National Institutes of Health (NIH), Research to Prevent Blindness, the Norwegian Research Council, the TEAM project financed by the European Union and the Foundation for Polish Science. NIH grant numbers: R24EY021126, R01EY009339, R01EY019312, P30EY002686, P30EY011373 and R44AG043645.

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Ciliopathies lie behind many human diseases

In recent years, cilia, microscopic, tentacle-like extensions from biological cells, have risen from relative obscurity and are now considered important to the understanding of many human afflictions. In a December BioScience article, George B. Witman, of the University of Massachusetts Medical School, and Jason M. Brown, of Salem State University, describe recent discoveries involving cilia-related diseases (called "ciliopathies") and highlight "model" species that could be useful for systematic study of ciliopathies.

Cilia perform a broad range of functions, including a starring role in cell signalling. Motile ones wiggle and so move fluids within the body, including cerebrospinal fluid in the brain. In humans, cilia are found on almost every cell in the body. Because of this, ciliopathies often make themselves known as syndromes with widely varying effects on a number of tissue types. For instance, the ciliopathy Jeune asphyxiating thoracic dystrophy involves the development of abnormally short ribs, accompanied by short limbs and, occasionally, the development of extra digits.

In primary ciliary dyskinesia, motile cilia are dysfunctional and fail to beat. This can lead to bronchitis resulting from the failure to clear mucus from the sufferer's airways. Male patients with primary ciliary dyskinesia are infertile because of impaired motility of the sperm's flagellum (flagella and cilia are structurally similar).

The article's authors point to a number of other human diseases in which cilia may play a role; for example, some cancers and neurological diseases may be related to ciliopathies. Because of the limitations placed on research involving humans, the authors propose the use of model species ranging from the green alga Chlamydomonas to the house mouse to further study the role of cilia. They write, "We can anticipate that new and improved techniques will open new avenues for gaining further insight into these immensely important and ever more fascinating cell organelles."

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Restrooms: Not as unhealthy as you might think

Toilet seat samples, alone, clustered according to restroom gender, with Lactobacillus and Anaerococcus--vaginal flora--dominating ladies' room toilet seats, while the gut-associated Roseburia and Blautia, were more copious on toilet seats in men's rooms.

Microbial succession in a sterilized restroom begins with bacteria from the gut and the vagina, and is followed shortly by microbes from the skin. Restrooms are dominated by a stable community structure of skin and outdoor associated bacteria, with few pathogenic bacteria making them similar to other built environments such as your home.

The research is published ahead of print in Applied and Environmental Microbiology.

In the study, the investigators characterized the structure, function, and abundance of the microbial community, on floors, toilet seats, and soap dispensers, following decontamination of each surface. They analyzed the surfaces hourly at first, and then daily, for up to eight weeks. "We hypothesized that while enteric bacteria would be dispersed rapidly due to toilet flushing, they would not survive long, as most are not good competitors in cold, dry, oxygen-rich environments," says corresponding author Jack A. Gilbert of San Diego State University. "As such, we expected the skin microbes to take over--which is exactly what we found."

"Reproduceable successional ecology is remarkable," says Gilbert, who has conducted similar studies of the home, and the hospital. "Most systems have the potential to have multiple outcomes. The restroom surfaces, though, were remarkably stable, always ending up at the same endpoint."

Indeed, the communities associated with each surface became more similar in species and abundance within five hours following initial sterilization, and the resulting late-successional surface community structure remained stable for the remainder of the 8 weeks' sampling. Floor communities showed a rapid reduction in abundance of Firmicutes and Bacteroidetes, while the relative abundance of Proteobacteria, Cyanobacteria, and Actinobacteria declined over the course of a day. Cyanobacteria are likely derived from dietary plant biomass or from plant material tracked in from outdoors.

Toilet seat samples, alone, clustered according to restroom gender, with Lactobacillus and Anaerococcus--vaginal flora--dominating ladies' room toilet seats, while the gut-associated Roseburia and Blautia, were more copious on toilet seats in men's rooms.

Ultimately, skin and outdoor-associated taxa comprised 68-98 percent of cultured communities, with fecal taxa representing just 0-15 percent of these. And out-door-associated taxa predominated in restrooms prior to sterilization, as well as in long-term post-sterilization communities, suggesting that over the long term, human-associated bacteria need to be dispersed in restrooms in order to be maintained there.

Overall, the research suggests that the restroom is no more healthy or unhealthy than your home, says Gilbert."A key criterion of of healthy or unhealthy might be the presence or relative abundance of pathogens. While we found cassettes associated with methicillin-resistant Staphylococcus aureus (MRSA) the predominant Staph organisms didn't harbor those genes, so MRSA may be there but it is very rare." Restrooms, he says, are not necessarily unhealthy, but classifying them as healthy would not necessarily be accurate.

The research, he says, is very important for understanding the environmental ecology of the built environment, and will likely help in building restrooms and buildings generally that are healthier for humans.

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Duality in the human genome

Every human being possesses a cis and trans mutations in a 60:40 ratio. In the cis configuration two mutations occur in one and the same genetic copy. The corresponding protein becomes incapacitated, but the second copy and the protein remain unaffected. In the trans configuration, however, both copies of the gene are mutated and produce two damaged proteins.

Humans don't like being alone, and their genes are no different. Together we are stronger, and the two versions of a gene -- one from each parent -- need each other. Scientists at the Max Planck Institute for Molecular Genetics in Berlin have analysed the genetic makeup of several hundred people and decoded the genetic information on the two sets of chromosomes separately. In this relatively small group alone they found millions of different gene forms. The results also show that genetic mutations do not occur randomly in the two parental chromosome sets and that they are distributed in the same ratio in everyone.

In 2001 scientists announced the successful decoding of the first human genome. Since then, thousands more have been sequenced. The price of a genetic analysis will soon fall below the 1,000 dollar mark. Given this rapid pace of development, it's easy to forget that the technology used only reads a mixed product of genetic information. The analytical methods commonly employed do not take into account the fact that every person has two sets of genetic material. "So they are ignoring an essential property of the human genome. However, it's important to know, for example, how mutations are distributed between the two chromosome sets," says Margret Hoehe from the Max Planck Institute for Molecular Genetics, who carried out the study.

Hoehe and her team have developed molecular genetic and bioinformatic methods that make it possible to sequence the two sets of chromosomes in a human separately. The researchers decoded the maternal and paternal parts of the genome in 14 people and supplemented their analysis with the genetic material of 372 Europeans from the 1000 Genomes Project. "Fourteen people may not sound like a lot, but given the technical challenge, it is an unprecedented achievement," says Hoehe.

The results show that most genes can occur in many different forms within a population: On average, about 250 different forms of each gene exist. The researchers found around four million different gene forms just in the 400 or so genomes they analysed. This figure is certain to increase as more human genomes are examined. More than 85 percent of all genes have no predominant form which occurs in more than half of all individuals. This enormous diversity means that over half of all genes in an individual, around 9,000 of 17,500, occur uniquely in that one person -- and are therefore individual in the truest sense of the word.

The gene, as we imagined it, exists only in exceptional cases. "We need to fundamentally rethink the view of genes that every schoolchild has learned since Gregor Mendel's time. Moreover, the conventional view of individual mutations is no longer adequate. Instead, we have to consider the two gene forms and their combination of variants," Hoehe explains. When analysing genomes, scientists should therefore examine each parental gene form separately, as well as the effects of both forms as a pair.

According to the researchers, mutations of genes are not randomly distributed between the parental chromosomes. They found that 60 percent of mutations affect the same chromosome set and 40 percent both sets. Scientists refer to these as cis and trans mutations, respectively. Evidently, an organism must have more cis mutations, where the second gene form remains intact. "It's amazing how precisely the 60:40 ratio is maintained. It occurs in the genome of every individual -- almost like a magic formula," says Hoehe. The 60:40 distribution ratio appears to be essential for survival. "This formula may help us to understand how gene variability occurs and how it affects gene function."

Some of the many variants that alter the genome also have an effect at the protein level. The researchers have now identified a set of 4,000 genes that are altered by mutations so that their proteins occur especially frequently in two different forms in humans. These genes mainly control signal transmission between cells, the immune system and gene activity. This dual gene and protein arrangement has the advantage that it allows the activity of genes to be more flexibly adjusted and altered. By using the more favourable variant, the body is better able to adapt to changes in its own processes and to environmental conditions. If the duality of genes goes awry and the wrong protein form is used, this can trigger pathogenic mechanisms. This is probably why those 4,000 genes include many disease genes.

These findings will change the interpretation of genetic analyses and the prediction of diseases. Moreover, individualised medicine cannot ignore the "dual nature" of human genomes. "Our investigations at the protein level have shown that 96 percent of all genes have at least 5 to 20 different protein forms. This results in tremendous individual diversity in possible interactions between genes, and shows how daunting the challenge is to develop individually tailored therapies," says Hoehe.

So far, researchers have estimated the risk of disease only by the presence or absence of mutations. However, there is evidence that in cancer, for example, the severity and course of the disease is determined by the wrong distribution of a mutation. The location of mutations therefore needs to be considered in the diagnosis, prediction and prevention of diseases in future.

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Clue to why females live longer than males

A study from the University of Exeter has found that male flies die earlier than their female counterparts when forced to evolve with the pressures of mate competition and juvenile survival. The results could help researchers understand the mechanisms involved in aging.

The research, published in the journal Functional Ecology, used populations of the fly Drosophila simulans that had evolved under different selection regimes. The study shows that mate competition (sexual selection), along with survival (natural selection), is tougher on male aging than it is on females reducing their lifespan by about a third.

Some species, like the flies in this study, age quickly over a number of days while others -- including some trees and whales -- age slowly across centuries.

Professor David Hosken from Biosciences at the University of Exeter said: "We found dramatic differences in the effects of sexual and natural selection on male and female flies. These results could help explain the sex differences in lifespan seen in many species, including humans, and the diverse patterns of aging we observe in nature."

The flies were subjected to elevated or relaxed sexual and natural selection and left to evolve in these conditions. To elevate sexual selection groups of males were housed with single females. A stressful temperature was used to elevate natural selection.

Males court females by singing, dancing and smelling good but their efforts come at considerable cost and this cost is amplified when they also have to cope with stressful temperatures.

The results of the study showed that under relaxed sexual and natural selection, male and female flies had very similar lifespans -- around 35 days. However males that evolved under elevated sexual selection and elevated natural selection had a much shorter lifespan -- just 24 days -- and died seven days earlier than females under the same conditions.

Both sexual selection and natural selection were found to affect lifespan but their effects were greatest on males. The findings show that the sexes can respond differently to the same selection regimes.

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Breast cancer vaccine shows promise in small clinical trial

A breast cancer vaccine developed at Washington University School of Medicine in St. Louis is safe in patients with metastatic breast cancer, results of an early clinical trial indicate. Preliminary evidence also suggests that the vaccine primed the patients' immune systems to attack tumor cells and helped slow the cancer's progression.

The study appears Dec. 1 in Clinical Cancer Research.

The new vaccine causes the body's immune system to home in on a protein called mammaglobin-A, found almost exclusively in breast tissue. The protein's role in healthy tissue is unclear, but breast tumors express it at abnormally high levels, past research has shown.

"Being able to target mammaglobin is exciting because it is expressed broadly in up to 80 percent of breast cancers, but not at meaningful levels in other tissues," said breast cancer surgeon and senior author William E. Gillanders, MD, professor of surgery. "In theory, this means we could treat a large number of breast cancer patients with potentially fewer side effects.

"It's also exciting to see this work progress from identifying the importance of mammaglobin-A, to designing a therapeutic agent, manufacturing it and giving it to patients, all by investigators at Washington University," he added.

The vaccine primes a type of white blood cell, part of the body's adaptive immune system, to seek out and destroy cells with the mammaglobin-A protein. In the smaller proportion of breast cancer patients whose tumors do not produce mammaglobin-A, this vaccine would not be effective.

In the new study, 14 patients with metastatic breast cancer that expressed mammaglobin-A were vaccinated. The Phase 1 trial was designed mainly to assess the vaccine's safety. According to the authors, patients experienced few side effects, reporting eight events classified as mild or moderate, including rash, tenderness at the vaccination site and mild flu-like symptoms. No severe or life-threatening side effects occurred.

Although the trial was designed to test vaccine safety, preliminary evidence indicated the vaccine slowed the cancer's progression, even in patients who tend to have less potent immune systems because of their advanced disease and exposure to chemotherapy.

"Despite the weakened immune systems in these patients, we did observe a biologic response to the vaccine while analyzing immune cells in their blood samples," said Gillanders, who treats patients at Siteman Cancer Center at Barnes-Jewish Hospital and Washington University. "That's very encouraging. We also saw preliminary evidence of improved outcome, with modestly longer progression-free survival."

Of the 14 patients who received the vaccine, about half showed no progression of their cancer one year after receiving the vaccine. In a similar control group of 12 patients who were not vaccinated, about one-fifth showed no cancer progression at the one-year follow-up. Despite the small sample size, this difference is statistically significant.

Based on results of this study, Gillanders and his colleagues are planning a larger clinical trial to test the vaccine in newly diagnosed breast cancer patients, who, in theory, should have more robust immune systems than patients who already have undergone extensive cancer therapy.

"If we give the vaccine to patients at the beginning of treatment, the immune systems should not be compromised like in patients with metastatic disease," Gillanders said. "We also will be able to do more informative immune monitoring than we did in this preliminary trial. Now that we have good evidence that the vaccine is safe, we think testing it in newly diagnosed patients will give us a better idea of the effectiveness of the therapy."

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Gut microbiota influences blood-brain barrier permeability

A new study in mice, conducted by researchers at Sweden's Karolinska Institutet together with colleagues in Singapore and the United States, shows that our natural gut-residing microbes can influence the integrity of the blood-brain barrier, which protects the brain from harmful substances in the blood. According to the authors, the findings provide experimental evidence that our indigenous microbes contribute to the mechanism that closes the blood-brain barrier before birth. The results also support previous observations that gut microbiota can impact brain development and function.

The blood-brain barrier is a highly selective barrier that prevents unwanted molecules and cells from entering the brain from the bloodstream. In the current study, being published in the journal Science Translational Medicine, the international interdisciplinary research team demonstrates that the transport of molecules across the blood-brain barrier can be modulated by gut microbes -- which therefore play an important role in the protection of the brain.

The investigators reached this conclusion by comparing the integrity and development of the blood-brain barrier between two groups of mice: the first group was raised in an environment where they were exposed to normal bacteria, and the second (called germ-free mice) was kept in a sterile environment without any bacteria.

"We showed that the presence of the maternal gut microbiota during late pregnancy blocked the passage of labeled antibodies from the circulation into the brain parenchyma of the growing fetus," says first author Dr. Viorica Braniste at the Department of Microbiology, Tumor and Cell Biology at Karolinska Institutet. "In contrast, in age-matched fetuses from germ-free mothers, these labeled antibodies easily crossed the blood-brain barrier and was detected within the brain parenchyma."

The team also showed that the increased 'leakiness' of the blood-brain barrier, observed in germ-free mice from early life, was maintained into adulthood. Interestingly, this 'leakiness' could be abrogated if the mice were exposed to fecal transplantation of normal gut microbes. The precise molecular mechanisms remain to be identified. However, the team was able to show that so-called tight junction proteins, which are known to be important for the blood-brain barrier permeability, did undergo structural changes and had altered levels of expression in the absence of bacteria.

According to the researchers, the findings provide experimental evidence that alterations of our indigenous microbiota may have far-reaching consequences for the blood-brain barrier function throughout life.

"These findings further underscore the importance of the maternal microbes during early life and that our bacteria are an integrated component of our body physiology," says Professor Sven Pettersson, the principal investigator at the Department of Microbiology, Tumor and Cell Biology. "Given that the microbiome composition and diversity change over time, it is tempting to speculate that the blood-brain barrier integrity also may fluctuate depending on the microbiome. This knowledge may be used to develop new ways for opening the blood-brain-barrier to increase the efficacy of the brain cancer drugs and for the design of treatment regimes that strengthens the integrity of the blood-brain barrier."

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Notre Dame biologist leads sequencing of the genomes of malaria-carrying mosquitoes

Nora Besansky, O'Hara Professor of Biological Sciences at the University of Notre Dame and a member of the University's Eck Institute for Global Health, has led an international team of scientists in sequencing the genomes of 16 Anopheles mosquito species from around the world. Anopheles mosquitoes are responsible for transmitting human malaria parasites that cause an estimated 200 million cases and more than 600 thousand deaths each year. However, of the almost 500 different Anopheles species, only a few dozen can carry the parasite and only a handful of species are responsible for the vast majority of transmissions. Besansky and her fellow researchers investigated the genetic differences between the deadly parasite-transmitting species and their harmless (but still annoying) cousins.

Two papers published in today's (Nov. 27) editions of Science Express, an electronic publication of the journal Science in advance of print, describe detailed genomic comparisons of these mosquitoes and the deadliest of them all, Anopheles gambiae. These results offer new insights into how these species are related to each other and how the dynamic evolution of their genomes may contribute to their flexibility to adapt to new environments and to seek out human blood. These newly sequenced genomes represent a substantial contribution to the scientific resources that will advance our understanding of the diverse biological characteristics of mosquitoes, and help to eliminate diseases that have a major impact on global public health.

Malaria parasites are transmitted to humans by only a few dozen of the many hundreds of species of Anopheles mosquitoes, and of these, only a handful are highly efficient disease-vectors. Thus, although about half the world's human population is at risk of malaria, most fatalities occur in sub-Saharan Africa, home of the major vector species, Anopheles gambiae. Variation in the ability of different Anopheles species to transmit malaria -- known as "vectorial capacity" -- are determined by many factors, including feeding and breeding preferences, as well as their immune responses to infections. Much of our understanding of many such processes derives from the sequencing of the Anopheles gambiae genome in 2002, which was led by Notre Dame researchers and which has since facilitated many large-scale functional studies that have offered numerous insights into how this mosquito became highly specialized in order to live amongst and feed upon humans.

Until now, the lack of such genomic resources for other Anopheles limited comparisons to small-scale studies of individual genes with no genome-wide data to investigate key attributes that impact the mosquito's ability to transmit parasites. To address these questions, researchers sequenced the genomes of 16 Anopheles species.

"We selected species from Africa, Asia, Europe, and Latin America that represent a range of evolutionary distances from Anopheles gambiae, a variety of ecological conditions, and varying degrees of vectorial capacity," Besansky said.

DNA sequencing and assembly efforts at the Broad Institute were funded by NHGRI and led by Daniel Neafsey, with samples obtained from mosquito colonies maintained through BEI Resources at the United States Centres for Disease Control and Prevention, and wild-caught or laboratory-reared mosquitoes from scientists in Africa, India, Iran, Melanesia and Southeast Asia.

"Getting enough high-quality DNA samples for all species was a challenging process and we had to design and apply novel strategies to overcome the difficulties associated with high levels of DNA sequence variations, especially from the wild-caught sample," Neafsey said.

With genome sequencing complete, scientists from around the world contributed their expertise to examine genes involved in different aspects of mosquito biology including reproductive processes, immune responses, insecticide resistance, and chemosensory mechanisms. These detailed studies involving so many species were facilitated by large-scale computational evolutionary genomic analyses led by Robert Waterhouse from the University of Geneva Medical School and the Swiss Institute of Bioinformatics.

The researchers carried out interspecies gene comparisons with the Anopheles and other insects, to identify equivalent genes in each species and highlight potentially important differences.

"We used similarities to genes from Anopheles gambiae and other well-studied organisms such as the fruit fly to learn about the possible functions of the thousands of new genes found in each of the Anopheles genomes," Waterhouse said.

Examining gene evolution across the Anopheles revealed high rates of gene gain and loss, about five times higher than in fruit flies. Some genes, such as those involved in reproduction or those that encode proteins secreted into the mosquito saliva, have very high rates of sequence evolution and are only found in subsets of the most closely-related species.

"These dynamic changes," Neafsey said, "may offer clues to understanding the diversification of Anopheles mosquitoes; why some breed in salty water while others need temporary or permanent pools of fresh water, or why some are attracted to livestock while others will only feed on humans."

The newly available genome sequences also provided conclusive evidence of the true relations amongst several species that are very closely related to Anopheles gambiae but nevertheless show quite different traits that affect their vectorial capacity.

"The question of the true species phylogeny has been a highly contentious issue in the field," Besansky said. "Our results show that the most efficient vectors are not necessarily the most closely-related species, and that traits enhancing vectorial capacity may be gained by gene flow between species."

This study substantially improves our understanding of the process of gene flow between closely related species -- a process believed to have occurred from Neanderthals to the ancestors of modern humans -- and how it may affect the evolution of common and distinct biological characteristics of mosquitoes such as ecological flexibility and vectorial capacity.

These two very different evolutionary timescales -- spanning all the Anopheles or focusing on the subset of very closely-related species -- offer distinct insights into the processes that have moulded these mosquito genomes into their present-day forms. Their dynamic evolutionary profiles may represent the genomic signatures of an inherent evolvability that has allowed Anopheles mosquitoes to quickly exploit new human-generated habitats and become the greatest scourge of humankind.

Besansky's research focuses primarily on African vectors of human malaria: the anopheline mosquitoes known as Anopheles gambiae and Anopheles funestus.

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Mindfulness treatment as effective as CBT for depression, anxiety

Group mindfulness treatment is as effective as individual cognitive behavioral therapy (CBT) in patients with depression and anxiety, according to a new study from Lund University in Sweden and Region Skåne. This is the first randomized study to compare group mindfulness treatment and individual cognitive behavioral therapy in patients with depression and anxiety in primary health care.

The researchers, led by Professor Jan Sundquist, ran the study at 16 primary health care centres in Skåne, a county in southern Sweden. They trained two mindfulness instructors, from different occupational groups, at each primary health care centre during a 6-day training course.

In spring 2012, patients with depression, anxiety or reactions to severe stress were randomized to either structured group mindfulness treatment with approximately 10 patients per group, or regular treatment (mainly individual CBT). Patients also received a private training programme and were asked to record their exercises in a diary. The treatment lasted 8 weeks. General practitioner and mindfulness instructor Ola Schenström designed the mindfulness training programme and model for training instructors.

A total of 215 patients were included in the study. Before and after treatment, the patients in the mindfulness and regular treatment groups answered questionnaires that estimated the severity of their depression and anxiety. Self-reported symptoms of depression and anxiety decreased in both groups during the 8-week treatment period. There was no statistical difference between the two treatments.

"The study's results indicate that group mindfulness treatment, conducted by certified instructors in primary health care, is as effective a treatment method as individual CBT for treating depression and anxiety," says Jan Sundquist. "This means that group mindfulness treatment should be considered as an alternative to individual psychotherapy, especially at primary health care centres that can't offer everyone individual therapy."

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New substance overcomes treatment-restistance in leukemia

Haematologists from Goethe University Frankfurt, working with a Russian pharmaceutical company, have developed a new active substance that effectively combats the most aggressive forms of Philadelphia chromosome-positive leukemia.

The chances of patients with Philadelphia chromosome-positive leukemia (Ph+) being cured has greatly increased in recent years. Nevertheless, a high percentage of patients have developed resistance to available medication. But now, haematologists from Goethe University Frankfurt, working with a Russian pharmaceutical company, have developed a new active substance that effectively combats the most aggressive forms of Philadelphia chromosome-positive leukemia, both in vitro and in vivo. They have reported this in the current edition of the specialist journal 'Leukemia'.

Patients with the Philadelphia chromosome develop chronic myelogenous leukemia (CML) or acute lymphatic leukemia (Ph+ ALL). These are the first types of leukemia that are able to be treated due to the development of targeted molecular therapy. Selective kinase inhibitor active substances act directly on the cancer-inducing gene BCR/ABL. However, after a while, the treatment becomes ineffective for many patients -- either due to BCR/ABL mutations or due to other mechanisms that are as yet unknown. At present, there is only one substance, Ponatinib, which is able to overcome nearly all clinical resistance. Unfortunately, Ponatinib can only be used with extreme caution due to some of its life-threatening side-effects.
Moscow-based company Fusion Pharma has developed an innovative kinase inhibitor, PF-114 with the aim of having the same effect on Ph+ leukemia as Ponatinib, but with reduced side-effects. In the current edition of 'Leukemia', the team led by Dr. Afsar Mian, Professor. Oliver Ottoman and lecturer Dr. Martin Ruthardt from the Haematology Department of Medical Clinic II, have reported that PF-114 is as effective as Ponatinib against resistant Ph+ leukemia.

"These results provide the basis for the administration of PF-114 in treatment-resistant patients with Ph+ leukemia. The favourable efficacy and good side effect profile now need to be further tested on patients in clinical phase I studies," explained Dr. Ruthardt. "PF-114 would not have reached this level of development without our colleagues in Frankfurt. On the basis of this data, in the first half of 2015, we will be able to start international phase I studies," explains Dr. Ghermes Chilov, CEO of Fusion Pharma, the company that financed the project.

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Love at first smell: Can birds choose mates by their odors?

Mate choice is often the most important decision in the lives of humans and animals. Scientists at the Konrad Lorenz Institute of Ethology at the Vetmeduni Vienna have found the first evidence that birds may choose their mate through odor. The researchers compared the preen gland chemicals of black-legged kittiwakes with genes that play a role in immunity. Kittiwakes that smell similarly to each other also have similar genes for immunity. Since the birds prefer to mate with unrelated mates, the scientists have now found the likely mechanism by which they recognize relatedness. The scientists published their findings in Nature's Scientific Reports.

It has long been understood that reproducing with close relatives may have profoundly negative effects on offspring. It is therefore not surprising that biologists have discovered in some species that breeding individuals have evolved ways to detect their genetic similarity with those of prospective partners. Over 20 years ago it was discovered that female mice were able to choose unrelated over related males as mates. Females achieved this by comparing the smell of the urine of each male and comparing it with their own odors. Amazingly, the urine odors reflected the genetic composition of each mouse. More specifically, the odors were correlated with a special group of genes called the "major histocompatiabilty complex," or MHC, which helps individuals resist diseases. Thus, by pairing with MHC-dissimilar mates, breeders produce offspring with a more diverse collection of disease-resistant genes.

This discovery in mice was followed by similar findings in other mammals. More recently it has been shown that birds in several species also avoid breeding with MHC-similar mates. This poses a mystery. Whereas smell is a very well developed sense in mammals, it has long been thought that birds lack such keen olfactory abilities. Although a growing body of research is showing that birds can discriminate odors more than previously thought, none had shown that birds can do as mammals and use odor to compare their MHC composition with that of prospective mates. This mystery appears to have been solved by a group of researchers from Austria and France. Team leader Richard H. Wagner and behavioral geneticist Wouter van Dongen of the Konrad Lorenz Institute of Ethology, a part of the Veterinary Medicine University Vienna, have been collabortating with French colleagues on a long-term study of a cliff-nesting gull, the black-legged kittiwake, breeding in Anchorage Bay, Alaska.

When birds groom themselves with their bills, they spread chemical compounds from their preen glands throughout their plumage. These chemicals produce odors that appear to be unique to each individual, providing an olfactory fingerprint. The team suspected that, just as in mammals, these odors may be used by kittiwakes to assess their relatedness to other individuals.

To test this idea, the researchers collected both DNA samples and preen gland odor samples from nesting kittiwakes. The project then entailed two kinds of laboratory work: while Sarah Leclaire at the University of Toulouse conducted the analyses of the preen gland chemicals to characterise the odor signatures of each individual, van Dongen analyzed the MHC of the kittiwakes in the Vienna lab. The team had previously discovered that kittiwakes avoided pairing with relatives, but the mechanism by which the birds recognized their relatedness to each other had remained unknown until now. Their new finding is that individual kittiwakes that smell similarly to each other (i.e. have similar preen gland chemicals) also have similar MHC genes. Closer relatives therefore have more similar odors than distantly related individuals. This suggests that birds may be able to compare their own odor with those of potential mates, and to choose unrelated individuals as breeding partners. Quips ornithologist Wagner, "the more research that is performed on smell, the more it appears that anything mammals can do, birds can do too." The new findings, moreover, open the door for further work linking mate choice and disease-resistance in birds.

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Genomes of malaria-carrying mosquitoes sequenced

Anopheles mosquito.

Nora Besansky, O'Hara Professor of Biological Sciences at the University of Notre Dame and a member of the University's Eck Institute for Global Health, has led an international team of scientists in sequencing the genomes of 16 Anopheles mosquito species from around the world.

Anopheles mosquitoes are responsible for transmitting human malaria parasites that cause an estimated 200 million cases and more than 600 thousand deaths each year. However, of the almost 500 different Anopheles species, only a few dozen can carry the parasite and only a handful of species are responsible for the vast majority of transmissions. Besansky and her fellow researchers investigated the genetic differences between the deadly parasite-transmitting species and their harmless (but still annoying) cousins.

Two papers published in today's (Nov. 27) editions of Science Express, an electronic publication of the journal Science in advance of print, describe detailed genomic comparisons of these mosquitoes and the deadliest of them all, Anopheles gambiae. These results offer new insights into how these species are related to each other and how the dynamic evolution of their genomes may contribute to their flexibility to adapt to new environments and to seek out human blood. These newly sequenced genomes represent a substantial contribution to the scientific resources that will advance our understanding of the diverse biological characteristics of mosquitoes, and help to eliminate diseases that have a major impact on global public health.

Malaria parasites are transmitted to humans by only a few dozen of the many hundreds of species of Anopheles mosquitoes, and of these, only a handful are highly efficient disease-vectors. Thus, although about half the world's human population is at risk of malaria, most fatalities occur in sub-Saharan Africa, home of the major vector species, Anopheles gambiae. Variation in the ability of different Anopheles species to transmit malaria -- known as "vectorial capacity" -- are determined by many factors, including feeding and breeding preferences, as well as their immune responses to infections. Much of our understanding of many such processes derives from the sequencing of the Anopheles gambiae genome in 2002, which was led by Notre Dame researchers and which has since facilitated many large-scale functional studies that have offered numerous insights into how this mosquito became highly specialized in order to live amongst and feed upon humans.

Until now, the lack of such genomic resources for other Anopheles limited comparisons to small-scale studies of individual genes with no genome-wide data to investigate key attributes that impact the mosquito's ability to transmit parasites. To address these questions, researchers sequenced the genomes of 16 Anopheles species.

"We selected species from Africa, Asia, Europe, and Latin America that represent a range of evolutionary distances from Anopheles gambiae, a variety of ecological conditions, and varying degrees of vectorial capacity," Besansky said.

DNA sequencing and assembly efforts at the Broad Institute were funded by NHGRI and led by Daniel Neafsey, with samples obtained from mosquito colonies maintained through BEI Resources at the United States Centres for Disease Control and Prevention, and wild-caught or laboratory-reared mosquitoes from scientists in Africa, India, Iran, Melanesia and Southeast Asia.

"Getting enough high-quality DNA samples for all species was a challenging process and we had to design and apply novel strategies to overcome the difficulties associated with high levels of DNA sequence variations, especially from the wild-caught sample," Neafsey said.

With genome sequencing complete, scientists from around the world contributed their expertise to examine genes involved in different aspects of mosquito biology including reproductive processes, immune responses, insecticide resistance, and chemosensory mechanisms. These detailed studies involving so many species were facilitated by large-scale computational evolutionary genomic analyses led by Robert Waterhouse from the University of Geneva Medical School and the Swiss Institute of Bioinformatics.

The researchers carried out interspecies gene comparisons with the Anopheles and other insects, to identify equivalent genes in each species and highlight potentially important differences.

"We used similarities to genes from Anopheles gambiae and other well-studied organisms such as the fruit fly to learn about the possible functions of the thousands of new genes found in each of the Anopheles genomes," Waterhouse said.
Examining gene evolution across the Anopheles revealed high rates of gene gain and loss, about five times higher than in fruit flies. Some genes, such as those involved in reproduction or those that encode proteins secreted into the mosquito saliva, have very high rates of sequence evolution and are only found in subsets of the most closely-related species.

"These dynamic changes," Neafsey said, "may offer clues to understanding the diversification of Anopheles mosquitoes; why some breed in salty water while others need temporary or permanent pools of fresh water, or why some are attracted to livestock while others will only feed on humans."

The newly available genome sequences also provided conclusive evidence of the true relations amongst several species that are very closely related to Anopheles gambiae but nevertheless show quite different traits that affect their vectorial capacity.

"The question of the true species phylogeny has been a highly contentious issue in the field," Besansky said. "Our results show that the most efficient vectors are not necessarily the most closely-related species, and that traits enhancing vectorial capacity may be gained by gene flow between species."

This study substantially improves our understanding of the process of gene flow between closely related species -- a process believed to have occurred from Neanderthals to the ancestors of modern humans -- and how it may affect the evolution of common and distinct biological characteristics of mosquitoes such as ecological flexibility and vectorial capacity.

These two very different evolutionary timescales -- spanning all the Anopheles or focusing on the subset of very closely-related species -- offer distinct insights into the processes that have moulded these mosquito genomes into their present-day forms. Their dynamic evolutionary profiles may represent the genomic signatures of an inherent evolvability that has allowed Anopheles mosquitoes to quickly exploit new human-generated habitats and become the greatest scourge of humankind.

Besansky's research focuses primarily on African vectors of human malaria: the anopheline mosquitoes known as Anopheles gambiae and Anopheles funestus.

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Fragile X study offers hope of new autism treatment

People affected by a common inherited form of autism could be helped by a drug that is being tested as a treatment for cancer, according to researchers from the University of Edinburgh and McGill University.

Fragile X Syndrome is the most common genetic cause of autism spectrum disorders. It affects around 1 in 4,000 boys and 1 in 6,000 girls. Currently, there is no cure.

The scientists, who have identified a chemical pathway that goes awry in the brains of Fragile X patients, say a cancer drug candidate could reverse their behavioural symptoms. The researchers have found that a naturally occurring anti-fungal called cercosporamide can block the pathway and improve sociability in mice with the condition.

The team identified a key molecule -- eIF4E -- that drives excess protein production in the brains of Fragile X patients. This can cause behavioural symptoms that include learning difficulties. It can also lead to more serious intellectual disabilities, delays in speech and language development and problems with social interactions.

"We found that eIF4E regulates the production of an enzyme called MMP-9, which breaks down and re-orders the connections between brain cells called synapses," says Nahum Sonenberg, McGill professor in the Faculty of Medicine and the Goodman Cancer Research Centre and co-author of the study, "Excess MMP-9 disrupts communication between brain cells, leading to changes in behaviour."

The team found that treatment with cercosporamide blocks the activity of eIF4E, and therefore reduces the amounts of MMP-9, and reverses the behavioural symptoms in mice with a version of Fragile X Syndrome. The new findings suggest that it could have a use as a treatment for patients with Fragile X Syndrome. The study is published in the journal Cell Reports.

Findings open door to targeted treatments

McGill post-doctoral student and a co-first author of the study Arkady Khoutorsky said that "the enzyme MMP-9 has been implicated before in Fragile X Syndrome. What's new in our research is the demonstration that the symptoms of the disease can be controlled by manipulating eIF4E activity with available drug candidates."
"Our findings open the door to targeted treatments for Fragile X Syndrome," says Christos Gkogkas, of the University of Edinburgh's Patrick Wild Centre for Research into Autism, Fragile X Syndrome and Intellectual Disabilities. "By designing treatments that block just this pathway, it is hoped that we can limit the potential side-effects and develop therapies that are more efficient than general treatment approaches."

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