Gut microbiota influences blood-brain barrier permeability

Uptake of the substance Raclopride in the brain of germ-free versus conventional mice.
Credit: Miklos Toth

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."

Source: Karolinska Institutet

Mushroom extract, AHCC, helpful in treating HPV

Judith A. Smith, Pharm.D. Credit: Image courtesy of University of Texas Health Science Center at Houston

A Japanese mushroom extract appears to be effective for the eradication of human papillomavirus (HPV), according to a pilot clinical trial at The University of Texas Health Science Center at Houston (UTHealth) Medical School.

The results were presented at the 11th International Conference of the Society for Integrative Oncology in Houston today by principal investigator Judith A. Smith, Pharm.D., associate professor in the Department of Obstetrics, Gynecology and Reproductive Sciences at the UTHealth Medical School.

Ten HPV-positive women were treated orally with the extract, AHCC (active hexose correlated compound) once daily for up to six months. Five achieved a negative HPV test result -- three with confirmed eradication after stopping AHCC -- with the remaining two responders continuing on the study.

Currently, there is no effective medicine or supplement to treat HPV, which is associated with more than 99 percent of cervical cancer cases. According to the Centers for Disease Control and Prevention, several other cancers are related to HPV, including 95 percent of anal cancer, 60 percent of oropharyngeal, 65 percent of vaginal cancer, 50 percent of vulvar cancer and 35 percent of penile cancer.

AHCC is a readily available nutritional supplement that works to improve the innate immune system. Human and preclinical studies have shown that AHCC increases the number and/or activity of Natural Killer (NK) cells, dendritic cells and cytokines, which help the body fight off infections and block tumor growth.

"The results are very encouraging," Smith said. "We were able to determine that at least three months of treatment is necessary but some need to extend that to six months. Since AHCC is a nutritional supplement with no side effects and other immune modulating benefits, we will be planning on using six months of treatment in our phase II clinical study to have consistent study treatment plan. This confirms our earlier preclinical research."

Smith is director of UTHealth's Women's Health Integrative Medicine Research Team, which focuses on the safe and effective use of nutritional and herbal supplements with pharmacologic modalities as it relates to women's health and cancer.

This research is proceeding to a randomized, double-blind, placebo-controlled Phase II clinical trial which has just begun at UTHealth, Smith said. For more information on enrolling in the trial, go to http://go.uth.edu/judithresearch.

Source: University of Texas Health Science Center at Houston

'Darting' mice may hold clues to ADHD, autism, bipolar disorder

Mice inserted with a rare human genetic variation in the dopamine transporter could lead to improvements in the diagnosis and treatment of brain disorders. Credit: Image courtesy of Vanderbilt University Medical Center

A darting mouse may hold an important clue in the development of Attention Deficit Hyperactivity Disorder (ADHD), autism and bipolar disorder, according to a study by a Vanderbilt University-led research team recently published in the Proceedings of the National Academy of Sciences.

The transgenic mouse, into which was inserted a rare human genetic variation in the dopamine transporter (DAT), could lead to improvements in the diagnosis and treatment of these all-too-common brain disorders, said Randy Blakely, Ph.D., the report's senior author.
The mutation, which has been found in people with ADHD, autism and bipolar disorder, affects the function of DAT, a protein that regulates the brain's supply of the neurotransmitter by removing excess dopamine from the synapse, or the space between nerve cells.

The DAT mutation causes the transporter to become "leaky" and spew out dopamine like "a vacuum cleaner in reverse," said Blakely, Allan D. Bass Professor of Pharmacology.

While mice with leaky DAT proteins have too much dopamine hanging around their synapses, surprisingly they aren't particularly hyperactive, possibly because DAT can still remove some of the dopamine.

But the mice exhibit an unusual "darting behavior." While their wild-type littermates are docile and quite unresponsive when researchers pick them up, those with the mutation "take off."

"Early on," Blakely said, "we could tell which ones carried the mutation by observing this response." Heightened anxiety does not appear to be the cause.

Blakely and his colleagues wonder whether this behavior is a form of "impulsivity." Rather than acting on their memories of being picked up a lot, the mice are opting for an inappropriate escape strategy.

Normal mice also stand up a lot to explore their cage. This "rearing" behavior is exacerbated by stimulant drugs. But not in these mice.

"We wonder whether this may be a sign that their behavior is driven less by searching for clues to appropriate behavior versus acting on innate impulses," Blakely said.

Other, better tests of impulsivity that evaluate premature decision-making can be applied in rodents and humans. "These tests are next on our docket," he said.

The actions of amphetamine and methylphenidate (Ritalin) are also affected by the mutation. In normal animals and people without ADHD, the stimulants flood the synapse with dopamine, eliciting hyperactivity.

But when given to the mutant animals, the drug demonstrates a "blunted" effect on both dopamine release and on locomotor activation compared to normal animals.

Blakely wonders whether stimulants like Adderall and Ritalin quell hyperactive and impulsive behaviors in some children with ADHD by reducing inappropriate dopamine leak. 
"These mice may give us much better clues as to how these drugs are acting," he said.
To that end, Blakely recently received a five-year, $2-million grant from the National Institutes of Health (NIH grant number MH109054) to pursue explorations of these mice.

"Dopamine has classically been implicated in reward and the ability to detect novelty and to respond to pleasure and to engage in effective social interactions," he continued. The darting mice thus might shed light on a much broader spectrum of behaviors.

"We've got a lot to do," he said, "a lot of needy people (to help)."

Source: Vanderbilt University Medical Center

Cold virus replicates better at cooler temperatures

Artist's rendering of a rhinovirus (stock illustration). Credit: © fotoliaxrender / Fotolia

The common cold virus can reproduce itself more efficiently in the cooler temperatures found inside the nose than at core body temperature, according to a new Yale-led study. This finding may confirm the popular yet contested notion that people are more likely to catch a cold in cool-weather conditions.

Researchers have long known that the most frequent cause of the common cold, the rhinovirus, replicates more readily in the slightly cooler environment of the nasal cavity than in the warmer lungs. However, the focus of prior studies has been on how body temperature influenced the virus as opposed to the immune system, said study senior author and Yale professor of immunobiology Akiko Iwasaki.

To investigate the relationship between temperature and immune response, Iwasaki and an interdisciplinary team of Yale researchers spearheaded by Ellen Foxman, a postdoctoral fellow in Iwasaki's lab, examined the cells taken from the airways of mice. They compared the immune response to rhinovirus when cells were incubated at 37 degrees Celsius, or core body temperature, and at the cooler 33 degrees Celsius. "We found that the innate immune response to the rhinovirus is impaired at the lower body temperature compared to the core body temperature," Iwasaki said.

The study also strongly suggested that the varying temperatures influenced the immune response rather than the virus itself. Researchers observed viral replication in airway cells from mice with genetic deficiencies in the immune system sensors that detect virus and in the antiviral response. They found that with these immune deficiencies, the virus was able to replicate at the higher temperature. "That proves it's not just virus intrinsic, but it's the host's response that's the major contributor," Iwasaki explained.

Although the research was conducted on mouse cells, it offers clues that may benefit people, including the roughly 20% of us who harbor rhinovirus in our noses at any given time. "In general, the lower the temperature, it seems the lower the innate immune response to viruses," noted Iwasaki. In other words, the research may give credence to the old wives' tale that people should keep warm, and even cover their noses, to avoid catching colds.

Yale researchers also hope to apply this insight into how temperature affects immune response to other conditions, such as childhood asthma. While the common cold is no more than a nuisance for many people, it can cause severe breathing problems for children with asthma, noted Foxman. Future research may probe the immune response to rhinovirus-induced asthma.

The study was published in the Proceedings of the National Academy of Sciences.

Source: Yale University

Heart drug may help treat ALS, mouse study shows

In the top image, cells from a mouse model of amyotrophic lateral sclerosis caused normal healthy brain cells (green) to die. But when scientists blocked an enzyme in the cells from the mouse model, more of the normal cells and their branches survived (bottom). Credit: Nature Neuroscience

Digoxin, a medication used in the treatment of heart failure, may be adaptable for the treatment of amyotrophic lateral sclerosis (ALS), a progressive, paralyzing disease, suggests new research at Washington University School of Medicine in St. Louis.

ALS, also known as Lou Gehrig's disease, destroys the nerve cells that control muscles. This leads to loss of mobility, difficulty breathing and swallowing and eventually death. Riluzole, the sole medication approved to treat the disease, has only marginal benefits in patients.

But in a new study conducted in cell cultures and in mice, scientists showed that when they reduced the activity of an enzyme or limited cells' ability to make copies of the enzyme, the disease's destruction of nerve cells stopped. The enzyme maintains the proper balance of sodium and potassium in cells.

"We blocked the enzyme with digoxin," said senior author Azad Bonni, MD, PhD. "This had a very strong effect, preventing the death of nerve cells that are normally killed in a cell culture model of ALS."

The findings appear online Oct. 26 in Nature Neuroscience.

The results stemmed from Bonni's studies of brain cells' stress responses in a mouse model of ALS. The mice have a mutated version of a gene that causes an inherited form of the disease and develop many of the same symptoms seen in humans with ALS, including paralysis and death.

Efforts to monitor the activity of a stress response protein in the mice unexpectedly led the scientists to another protein: sodium-potassium ATPase. This enzyme ejects charged sodium particles from cells and takes in charged potassium particles, allowing cells to maintain an electrical charge across their outer membranes.

Maintenance of this charge is essential for the normal function of cells. The particular sodium-potassium ATPase highlighted by Bonni's studies is found in nervous system cells called astrocytes. In the ALS mice, levels of the enzyme are higher than normal in astrocytes.

Bonni's group found that the increase in sodium-potassium ATPase led the astrocytes to release harmful factors called inflammatory cytokines, which may kill motor neurons.

Recent studies have suggested that astrocytes may be crucial contributors to neurodegenerative disorders such as ALS, and Alzheimer's, Huntington's and Parkinson's diseases. For example, placing astrocytes from ALS mice in culture dishes with healthy motor neurons causes the neurons to degenerate and die.

"Even though the neurons are normal, there's something going on in the astrocytes that is harming the neurons," said Bonni, the Edison Professor of Neurobiology and head of the Department of Anatomy and Neurobiology.

How this happens isn't clear, but Bonni's results suggest the sodium-potassium ATPase plays a key role. When he conducted the same experiment but blocked the enzyme in ALS astrocytes using digoxin, the normal motor nerve cells survived. Digoxin blocks the ability of sodium-potassium ATPase to eject sodium and bring in potassium.

In mice with the mutation for inherited ALS, those with only one copy of the gene for sodium-potassium ATPase survived an average of 20 days longer than those with two copies of the gene. When one copy of the gene is gone, cells make less of the enzyme.

"The mice with only one copy of the sodium-potassium ATPase gene live longer and are more mobile," Bonni said. "They're not normal, but they can walk around and have more motor neurons in their spinal cords."

Many important questions remain about whether and how inhibitors of the sodium-potassium ATPase enzyme might be used to slow progressive paralysis in ALS, but Bonni said the findings offer an exciting starting point for further studies.

Source: Washington University School of Medicine

A lab in your pocket: Using CAD to load dozens of tests on a lab-on-a-chip

Two computer-generated configurations for routing a droplet through multiple lab-on-a-chip diagnostic tests, many more than are currently possible using manual methods. The software was developed by Michigan Tech's Shiyan Hu and Chen Liao. The figure is reproduced with permission of IEEE Transactions on NanoBioscience. Credit: Chen Liao and Shiyan Hu

When you get sick, your physician may take a sample of your blood, send it to the lab and wait for results. In the near future, however, doctors may be able to run those tests almost instantly on a piece of plastic about the size of credit card.

These labs-on-a-chip would not only be quick -- results are available in minutes -- but also inexpensive and portable. They could be used miles from the nearest medical clinic to test for anything from HIV to diabetes. But as powerful as they may be, they could be far better, says Shiyan Hu, an associate professor of electrical and computer engineering at Michigan Technological University.

Generally, a lab-on-a-chip (LOC) can run no more than a test or two. That's because the chips are designed manually, says Hu. If the LOC were made using computer-aided design, you could run dozens of tests with a single drop of blood.

"In a very short time, you could test for many conditions," he said. "This really would be an entire lab on a chip."

With PhD student Chen Liao, Hu has taken the first step. "We have developed software to design the hardware," he said. Their work focuses on routing the droplet of blood or other fluid through each test on the chip efficiently while avoiding any chip contamination.

"It has taken us four years to do the software, but to manufacture the LOC would be inexpensive," Hu said. "The materials are very cheap, and the results are more accurate than a conventional lab's."

Ultimately, Hu aims to fabricate their own biochip using their software.

Their work was featured on the cover of the March edition of IEEE Transactions on Nanobiosciences and described in the article "Physical-Level Synthesis for Digital Lab-On-a-Chip Considering Variation, Contamination, and Defect." Liao was partially supported by an A. Richard Newton Graduate Scholarship, awarded by the Design Automation Conference.

Source: Michigan Technological University

Software models more detailed evolutionary networks from genetic data

Phylogenetic networks depict the movement of genetic sequences from one species to another as a means of showing where horizontal gene transfer may have taken place. Software by scientists at Rice University aims to reveal far more about species’ evolutionary histories than traditional tree models are able to. Credit: Luay Nakhleh/Rice University

The tree has been an effective model of evolution for 150 years, but a Rice University computer scientist believes it's far too simple to illustrate the breadth of current knowledge.

Rice researcher Luay Nakhleh and his group have developed PhyloNet, an open-source software package that accounts for horizontal as well as vertical inheritance of genetic material among genomes. His "maximum likelihood" method, detailed this month in the Proceedings of the National Academy of Sciences, allows PhyloNet to infer network models that better describe the evolution of certain groups of species than do tree models.

"Inferring" in this case means analyzing genes to determine their evolutionary history with the highest probability -- the maximum likelihood -- of connections between species. Nakhleh and Rice colleague Christopher Jermaine recently won a $1.1 million National Science Foundation grant to analyze evolutionary patterns using Bayesian inference, a statistics-based technique to estimate probabilities based on a data set.

To build networks that account for all of the genetic connections between species, the software infers the probability of variations that phylogenetic trees can't illustrate, such as horizontal gene transfers. These transfers circumvent simple parent-to-offspring evolution and allow genetic variations to move from one species to another by means other than reproduction.

Biologists want to know when and how these transfers happened, but tree structures conceal such information. "When horizontal transfer occurs, as with the hybridization of two species, the tree model becomes inadequate to describe the evolutionary history, and networks that incorporate horizontal gene transfer become the more appropriate model," Nakhleh said.

Nakhleh's Java-based software accounts for incomplete lineage sorting, in which clues to gene evolution that don't match the established lineage of species appear in the genetic record.

"We are the first group to develop a general model that will allow biologists to estimate hybridization while accounting for all these complexities in evolution," Nakhleh said.

Most existing programs for phylogenetics (the study of evolutionary relationships) ignore such complexities. "They end up overestimating the amount of hybridization," Nakhleh said. 

"They start seeing lots of complexities in the data and say, 'Oh, it's complex here; it must be hybridization,' and end up inferring too much. Our method acknowledges that part of the complexity has nothing to do with hybridization; it has to do with other random processes that happened during evolution."

The Rice researchers used two data sets to test the new program. One, a computer-generated set of data that mimics a realistic model of evolution, allowed them to evaluate the accuracy of the program. The second involved multiple genomes of mice found across Europe and Asia. "There have been stories about mice hybridizing," Nakhleh said. "Now that we have the first method to allow for systematic analysis, we ran it on a very large amount of data from five mouse samples and we detected hybridization" -- most notably in the presence of a genetic signal from a mouse in Kazakhstan that found its way to mice in France and Germany, he said.

Nakhleh hopes evolutionary biologists will use PhyloNet to take a fresh look at the massive amount of genomic data collected over the past few decades. "The exciting thing for me about this is that biologists can now systematically go through lots of data they have generated and check to see if there has been hybridization."

Source: Rice University

What bank voles can teach us about prion disease transmission and neurodegeneration

This image shows accumulation of misfolded, toxic prion protein (brown staining) in the brain of a transgenic mouse expressing bank vole PrP and challenged with human variant Creutzfeldt-Jakob disease (vCJD) prions. Credit: Image courtesy of Dr. Joel Watts

When cannibals ate brains of people who died from prion disease, many of them fell ill with the fatal neurodegenerative disease as well. Likewise, when cows were fed protein contaminated with bovine prions, many of them developed mad cow disease. On the other hand, transmission of prions between species, for example from cows, sheep, or deer to humans, is -- fortunately -- inefficient, and only a small proportion of exposed recipients become sick within their lifetimes.

A study published on April 3rd in PLOS Pathogens takes a close look at one exception to this rule: bank voles appear to lack a species barrier for prion transmission, and their universal susceptibility turns out to be both informative and useful for the development of strategies to prevent prion transmission.
Prions are misfolded, toxic versions of a protein called PrP, which in its normal form is present in all mammalian species that have been examined. Toxic prions are "infectious"; they can induce existing, properly folded PrP proteins to convert into the disease-associated prion form. Prion diseases are rare, but they share features with more common neurodegenerative diseases like Alzheimer's disease.

Trying to understand the unusual susceptibility of bank voles to prions from other species, Stanley Prusiner, Joel Watts, Kurt Giles and colleagues, from the University of California in San Francisco, USA, first tested whether the susceptibility is an intrinsic property of the voles' PrP, or whether other factors present in these rodents make them vulnerable.

The scientists introduced into mice the gene that codes for the normal bank vole prion protein, thereby generating mice that express bank vole PrP, but not mouse PrP. When these mice get older, some of them spontaneously develop neurologic illness, but in the younger ones the bank vole PrP is in its normal, benign folded state. The scientists then exposed young mice to toxic misfolded prions from 8 different species, including human, cattle, elk, sheep, and hamster.

They found that all of these foreign-species prions can cause prion disease in the transgenic mice, and that the disease develops often more rapidly than it does in bank voles. The latter is likely because the transgenic mice express higher levels of bank vole PrP than are naturally present in the voles.

The results show that the universal susceptibility of bank voles to cross-species prion transmission is an intrinsic property of bank vole PrP. Because the transgenic mice develop prion disease rapidly, the scientists propose that the mice will be useful tools in studying the processes by which toxic prions "convert" healthy PrP and thereby destroy the brain. And because that process is similar across many neurodegenerative diseases, better understanding prion disease development might have broader implications.

Source:  PLOS

Genetic factors behind surviving or dying from Ebola shown in mouse study

In an emerging disease research lab at the University of Washington, Chris Williams, a research scientist who specializes in microbiology laboratory robotics, programs a piece of equipment that can be programmed to performs many lab tasks. Credit: Brian Donohue

A newly developed mouse model suggests that genetic factors are behind the mild-to-deadly range of reactions to the Ebola virus.

People exposed to Ebola vary in how the virus affects them. Some completely resist the disease, others suffer moderate to severe illness and recover, while those who are most susceptible succumb to bleeding, organ failure and shock.

In earlier studies of populations of people who have contracted Ebola, these differences are not related to any specific changes in the Ebola virus itself that made it more or less dangerous; instead, the body's attempts to fight infection seems to determine disease severity.

In the Oct. 30 edition of Science, scientists describe strains of laboratory mice bred to test the role of an individual's genetic makeup in the course of Ebola disease. Systems biologists and virologists Angela Rasmussen and Michael Katze from the Katze Laboratory at the University of Washington Department of Microbiology led the study in collaboration with the National Institutes of Health's Rocky Mountain Laboratories in Montana and University of North Carolina at Chapel Hill.

Research on Ebola prevention and treatment has been hindered by the lack of a mouse model that replicates the main characteristics of human Ebola hemorrhagic fever. The researchers had originally obtained this genetically diverse group of inbred laboratory mice to study locations on mouse genomes associated with influenza severity.

The research was conducted in a highly secure, state-of-the-art biocontainment safety level 4 laboratory in Hamilton, Mont. The scientists examined mice that they infected with a mouse form of the same species of Ebola virus causing the 2014 West Africa outbreak. The study was done in full compliance with federal, state, and local safety and biosecurity regulations. This type of virus has been used several times before in research studies. Nothing was done to change the virus.

Interestingly, conventional laboratory mice previously infected with this virus died, but did not develop symptoms of Ebola hemorrhagic fever.

In the present study, all the mice lost weight in the first few days after infection. Nineteen percent of the mice were unfazed. They not only survived, but also fully regained their lost weight within two weeks. They had no gross pathological evidence of disease. Their livers looked normal.

Eleven percent were partially resistant and less than half of these died. Seventy percent of the mice had a greater than 50 percent mortality. Nineteen percent of this last group had liver inflammation without classic symptoms of Ebola, and thirty-four percent had blood that took too long to clot, a hallmark of fatal Ebola hemorrhagic fever in humans. Those mice also had internal bleeding, swollen spleens and changes in liver color and texture.

The scientists correlated disease outcomes and variations in mortality rates to specific genetic lines of mice.

"The frequency of different manifestations of the disease across the lines of these mice screened so far are similar in variety and proportion to the spectrum of clinical disease observed in the 2014 West African outbreak," Rasmussen said.

While acknowledging that recent Ebola survivors may have had immunity to this or a related virus that saved them during this epidemic, Katze said, "Our data suggest that genetic factors play a significant role in disease outcome."

In general, when virus infection frenzied the genes involved in promoting blood vessel inflammation and cell death, serious or fatal disease followed. On the other hand, survivors experienced more activity in genes that order blood vessel repair and the production of infection-fighting white blood cells.

The scientists note that certain specialized types of cells in the liver could also have limited virus reproduction and put a damper on systemic inflammation and blood clotting problems in resistant mice. Susceptible mice had widespread liver infection, which may explain why they had more virus in their bodies and poorly regulated blood coagulation. The researchers also noticed that spleens in the resistant and susceptible mice took alternate routes to try to ward off infection.

"We hope that medical researchers will be able to rapidly apply these findings to candidate therapeutics and vaccines," Katze said. They believe this mouse model can be promptly implemented to find genetic markers, conduct meticulous studies on how symptoms originate and take hold, and evaluate drugs and that have broad spectrum anti-viral activities against all Zaire ebolaviruses, including the one responsible for the current West African epidemic.

Source: University of Washington Health Sciences/UW Medicine

Teeth, sex and testosterone reveal secrets of aging in wild mouse lemurs

A brown mouse lemur in the wild. Mouse lemurs, weighing a mere 30 to 80 grams, are the world's smallest primates. Credit: Jukka Jernvall

Mouse lemurs can live at least eight years in the wild -- twice as long as some previous estimates, a long-term longitudinal study finds.

PLOS ONE published the research on brown mouse lemurs (Microcebus rufus) led in Madagascar by biologist Sarah Zohdy, a post-doctoral fellow in Emory's Department of Environmental Sciences and the Rollins School of Public Health. Zohdy conducted the research while she was a doctoral student at the University of Helsinki.

"It's surprising that these tiny, mouse-sized primates, living in a jungle full of predators that probably consider them a bite-sized snack, can live so long," Zohdy says. "And we found individuals up to eight years of age in the wild with no physical symptoms of senescence like some captive mouse lemurs start getting by the age of four."

It is likely that starvation, predation, disease and other environmental stressors reduce the observed rate of senescence in the wild, Zohdy notes, but a growing body of evidence also suggests that captive conditions may affect mental and physical function.

"We focused on wild mouse lemurs because we want to know what happens naturally when a primitive primate is exposed to all of the extrinsic and intrinsic mortality factors that shaped them as a species," Zohdy says. "Comparing longevity data of captive and wild mouse lemurs may help us understand how the physiological and behavioral demands of different environments affect the aging process in other primates, including humans."

The study determined ages of wild mouse lemurs in Madagascar's Ranomafana National Park through a dental mold method that had not previously been used with small mammals. In addition to the high-resolution tooth-wear analysis for aging, fecal samples underwent hormone analysis.

The researchers found no difference between the longevity of male and female mouse lemurs, unlike most vertebrates where males tend to die first.

"And even more interestingly, we found no difference in testosterone levels between males and females," Zohdy says. Mouse lemurs are female dominant, which may explain why their testosterone levels are on a par with males.

"While elevated male testosterone levels have been implicated in shorter lifespans in several species, this is one of the first studies to show equivalent testosterone levels accompanying equivalent lifespans," Zohdy says.

A co-author of the study is primatologist Patricia Wright of the Centre ValBio Research Station in Madagascar and Stony Brook University. Other institutions involved in the study include Colorado State University, Duke University and the University of Arizona, Tucson.
Mouse lemurs, found only on the island of Madagascar, are the world's smallest primates. They are among nearly 100 species of lemurs that arrived in Madagascar some 65 million years ago, perhaps floating over from mainland Africa on mats of vegetation.

Mouse lemurs weigh a mere 30 to 80 grams but in captivity they live six times longer than mammals of similar body size, such as mice or shrews. Captive gray mouse lemurs (Microcebus murinus) can live beyond age 12. By age four, however, they can start exhibiting behavioral and neurologic degeneration. In addition to slowing of motor skills and activity levels, reduced memory capacity and sense of smell, the captive four-year-olds can start developing gray hair and cataracts, Zohdy says.

The wild brown mouse lemurs in the study were trapped, marked and released during the years 2003 to 2010. A total of 420 dental impressions were taken from the lower-right mandibular tooth rows of 189 unique individuals. Over the course of seven years, 270 age estimates were calculated. For 23 individuals captured three or more times during the duration of the study, the regression slopes of wear rates were calculated and the mean slope was used to calculate ages for all individuals.

"We found that wild brown mouse lemurs can live at least eight years," Zohdy says. "In the population that we studied, 16 percent lived beyond four years of age. And we found no physical signs of senescence, such as graying hair or cataracts, in any wild individual."

Limitations of the study include the inability to document gradual physiological symptoms of senescence in the wild. "Our results do not provide information about wild brown mouse lemurs that can be directly compared to senescence in captive gray mouse lemurs," Zohdy says. "Further research, using identical measures of senescence, will help to reveal whether patterns of physiological senescence occur consistently across the genus and in both captive and wild conditions."

Another confounding factor Zohdy cites is "the Sleeping Beauty effect," the fact that wild mouse lemurs hibernate for half the year, possibly boosting their life span.
"We now know that mouse lemurs can live a relatively long time in the wild," she says, "but we don't know the exact mechanisms behind why they live so long."

Source: Emory Health Sciences

Controlling genes with your thoughts

Thoughts control a near-infrared LED, which starts the production of a molecule in a reaction chamber. Credit: Martin Fussenegger et al., Copyright ETH Zurich

It sounds like something from the scene in Star Wars where Master Yoda instructs the young Luke Skywalker to use the force to release his stricken X-Wing from the swamp: Marc Folcher and other researchers from the group led by Martin Fussenegger, Professor of Biotechnology and Bioengineering at the Department of Biosystems (D-BSSE) in Basel, have developed a novel gene regulation method that enables thought-specific brainwaves to control the conversion of genes into proteins -- called gene expression in technical terms.

"For the first time, we have been able to tap into human brainwaves, transfer them wirelessly to a gene network and regulate the expression of a gene depending on the type of thought. Being able to control gene expression via the power of thought is a dream that we've been chasing for over a decade," says Fussenegger.

A source of inspiration for the new thought-controlled gene regulation system was the game Mindflex, where the player wears a special headset with a sensor on the forehead that records brainwaves. The registered electroencephalogram (EEG) is then transferred into the playing environment. The EEG controls a fan that enables a small ball to be thought-guided through an obstacle course.

Wireless Transmission to Implant

The system, which the Basel-based bioengineers recently presented in the journal Nature Communications, also makes use of an EEG headset. The recorded brainwaves are analysed and wirelessly transmitted via Bluetooth to a controller, which in turn controls a field generator that generates an electromagnetic field; this supplies an implant with an induction current.

A light then literally goes on in the implant: an integrated LED lamp that emits light in the near-infrared range turns on and illuminates a culture chamber containing genetically modified cells. When the near-infrared light illuminates the cells, they start to produce the desired protein.

Thoughts Control Protein Quantity

The implant was initially tested in cell cultures and mice, and controlled by the thoughts of various test subjects. The researchers used SEAP for the tests, an easy-to-detect human model protein which diffuses from the culture chamber of the implant into the mouse's bloodstream.

To regulate the quantity of released protein, the test subjects were categorised according to three states of mind: bio-feedback, meditation and concentration. Test subjects who played Minecraft on the computer, i.e. who were concentrating, induced average SEAP values in the bloodstream of the mice. When completely relaxed (meditation), the researchers recorded very high SEAP values in the test animals. For bio-feedback, the test subjects observed the LED light of the implant in the body of the mouse and were able to consciously switch the LED light on or off via the visual feedback. This in turn was reflected by the varying amounts of SEAP in the bloodstream of the mice.

New Light-sensitive Gene Construct

"Controlling genes in this way is completely new and is unique in its simplicity," explains Fussenegger. The light-sensitive optogenetic module that reacts to near-infrared light is a particular advancement. The light shines on a modified light-sensitive protein within the gene-modified cells and triggers an artificial signal cascade, resulting in the production of SEAP. Near-infrared light was used because it is generally not harmful to human cells, can penetrate deep into the tissue and enables the function of the implant to be visually tracked.

The system functions efficiently and effectively in the human-cell culture and human-mouse system. Fussenegger hopes that a thought-controlled implant could one day help to combat neurological diseases, such as chronic headaches, back pain and epilepsy, by detecting specific brainwaves at an early stage and triggering and controlling the creation of certain agents in the implant at exactly the right time.

Source: ETH Zurich

Genetically identical ants help unlock the secrets of larval fate

Cerapachys biroi ants, native to Asia and introduced globally on tropical and subtropical islands, have no queens and have minimal genetic variation, making them ideal for research on social behavior. Credit: Image courtesy of Rockefeller University

A young animal's genes are not the only genes that determine its fate. The genetic identity of its caretakers matters too. Researchers suspect the interaction between the two can sway the fate of the young animal, but this complex dynamic is difficult to pin down in lab experiments.

However, social insect researchers have found a solution. Rockefeller University's Daniel Kronauer, head of the Laboratory of Insect Social Evolution, and his colleagues are developing a species of small raider ants as a model organism in order to ask questions about the relationships between genes, social behavior and evolution.

In a pair of recent papers, the researchers first explain the unique, and potentially useful, biology of this 2.5-millimeter-long ant. Then, in work with collaborators at the University of Paris 13, they put it to work exploring the interaction between the larvae and their nursemaids, and the influence on the young ants' reproductive success as adults.

Clonal raider ants, the species Cerapachys biroi, reproduce by cloning, and they live in colonies of as many as a few hundred nearly genetically identical workers. This makes these ants ideal for studies testing how a particular genetic makeup responds to different conditions, the researchers write in Current Biology. With the help of collaborators at BGI China, researchers in Kronauer's lab have sequenced the clonal raider ant's genome. This is an important step toward using the ant in the sorts of experiments conducted for years in traditional model organisms, such as mice and fruit flies.

"We have shown that colony mates are extremely closely related to one another, with all of the individuals in a colony being essentially genetically identical. This gives us precise control in experiments because we don't need to account for individual genetic variation," says Peter Oxley, a postdoc in the laboratory who led work establishing the clonal raider ant as a promising new model organism.

In the second study, one of the first to make use of the clonal raider ant, a team led by Serafino Teseo of the University of Paris 13 used the unique aspects of the ants' biology to test the indirect role genes play in shaping the future identity of larvae and whole colonies by looking at the interaction between larvae and adults. They did so by observing the success of two ant clones, A and B, in pure colonies or mixed together into chimeric colonies. They also swapped broods, so A adults raised B larvae and vice versa.

It turned out that A and B larvae developed differently depending on whether A or B nurses raised them. Left alone, pure A colonies produced the most young after six generations, making them more successful than B. However, in mixed colonies, B did better because its larvae more frequently turned into large adults that specialize in egg-laying rather than smaller, foraging-focused individuals.

The researchers suspect an indirect genetic effect -- specifically, a social influence. To begin to tease apart the dynamic, they had adults from one clone raise larvae from the other. Again, B did better when raised by A nurses than any of the other combinations. The results were published in Nature Communications.

The B colony's strategy of favoring reproduction over foraging when raised by A colony nurses smacks of social parasitism, in which one organism exploits another's social behavior for its own benefit. "This doesn't mean B is a parasite in the making, just that uncoupling the normal interaction between larvae and their nearly identical adult nursemaids reveals the presence of this mechanism," Kronauer says.

The study shows that, in social species, genetic makeup alone does not provide enough information to predict social behavior. Instead, interactions between social partners, such as larvae and their caregivers, are crucial determinants and can lead to surprising outcomes.

Source: Rockefeller University

A fraction of the global military spending could save the planet's biodiversity, say experts: Only one in four protected areas is well managed

This image shows Murchison Falls National Park in Uganda. A fundamental step-change involving an increase in funding and political commitment is urgently needed to ensure that protected areas deliver their full conservation, social and economic potential, according to an article published today in Nature by experts from Wildlife Conservation Society, the University of Queensland, and the IUCN World Commission on Protected Areas (WCPA). Credit: Julie Larsen Maher, copyright WCS

A fundamental step-change involving an increase in funding and political commitment is urgently needed to ensure that protected areas deliver their full conservation, social and economic potential, according to an article published today in Nature by experts from Wildlife Conservation Society, the University of Queensland, and the IUCN World Commission on Protected Areas (WCPA).

The paper, The performance and potential of protected areas, comes ahead of the IUCN World Parks Congress 2014 -- a once-in-a-decade global forum on protected areas opening next week in Sydney, Australia.

According to the authors, allocating US$45 -- $76 billion to protected areas annually -- just 2.5% of the global annual military expenditure -- could help adequately manage those areas, ensuring their potential contribution to the well-being of the planet is fully met.

Many threatened species, such as the Asian elephant, the tiger, and all rhinoceros species, as well as numerous plants, reptiles and amphibians, survive thanks to protected areas. Well-managed marine protected areas contain more than five times the total large fish biomass and 14 times the shark biomass compared with fished areas.

"Protected areas offer us solutions to some of today's most pressing challenges" says Dr James Watson of the Wildlife Conservation Society and The University of Queensland and lead author of the study. "But by continuing with 'business as usual', we are setting them up for failure. A step-change in the way we value, fund, govern and manage those areas is neither impossible nor unrealistic and would only represent a fraction of what the world spends annually on defense."

According to the latest data, protected areas cover around 15% of land and 3% of oceans. Experts warn, however, that despite the significant increase in their coverage over the past century, this is still short of the global 2020 targets to protect at least 17% of land and 10% of oceans. Many ecosystems remain poorly conserved because protected areas do not always encompass the most important areas for biodiversity.

In addition, the vast majority of existing protected areas that are well placed do not have sufficient resources to be effective, with some studies finding as few as one quarter of them are being effectively managed. Growing threats from climate change and the escalating poaching crisis place additional pressures on protected areas globally.

"Some of the most iconic protected areas, such as Ecuador's Galapagos National Park, are undergoing significant degradation, partly due to an inability to manage them effectively," says Professor Marc Hockings of The University of Queensland,co-author of the study and member of the IUCN WCPA. "But governments cannot be solely responsible for ensuring that protected areas fulfill their potential. We need to find new, innovative ways to fund and manage them, actively involving government, business and community groups."

The paper also highlights an alarming increase in governments -- in both developing and developed countries -- backtracking on their commitments through funding cuts and changes in policy. A recent global analysis has documented 543 instances where protected areas saw their status downgraded or removed altogether.

For example, recent cuts to the Parks Canada budget have reduced conservation spending by 15%¬. In Uganda, active oil exploration and development is occurring inside many protected areas, including Murchison Falls National Park. In Indonesia, in 2010, mining permits were issued inside 481,000 hectares of protected areas and in the Virgin Komi Forests in Russia, significant boundary changes have been made to reserves such as the Yugyd Va National Park to allow mining. The Arabian Oryx Sanctuary in Oman was removed from the World Heritage List after the government reduced the size of the reserve by 90% to allow for oil and gas extraction.

"There is a fundamental need for an increase in support of global protected areas, including better recognition, funding, planning and enforcement" says Nigel Dudley, co-author of the paper, from Equilibrium Research and The University of Queensland, member of the IUCN WCPA. "It is government's responsibility to step up but there is also the need for the wider community to take collective responsibility for protected areas."

Protected areas conserve biodiversity and sustain a large proportion of the world's poorest people by providing them with food, water, shelter and medicine. They play a key part in climate change mitigation and adaptation and bolster national economies through tourism revenues. In Rwanda, for example, tourism revenue from visits to see mountain gorillas inside Volcanoes National Park is now the country's largest source of foreign exchange, raising US$200 million annually. In Australia, the 2012-2013 budget for the Great Barrier Reef Marine Park Authority was approximately AUS$50 million, but tourism to the reef was worth more than A$5.2 billion annually to the Australian economy.

"The growth of the modern global protected area movement over the last 100 years is arguably the greatest conservation achievement," says Julia Marton-Lefèvre, IUCN Director General. "It is also increasingly important for livelihoods and global security. The key now is for countries to recognize the return on investment that protected areas offer and realize that those places are fundamental to the future of life on earth. This is exactly what we hope to achieve at the upcoming IUCN World Parks Congress."

Effective management of protected areas, the threats they face and the solutions they offer to today's global challenges will be discussed at the IUCN World Parks Congress taking place in Sydney from 12 to 19 November 2014.

Source: Wildlife Conservation Society