Transmission of genetic disorder Huntington’s disease in normal animals

Mice transplanted with cells grown from a patient suffering from Huntington’s disease (HD) develop the clinical features and brain pathology of that patient, suggests a study published in the latest issue of Acta Neuropathologica by CHA University in Korea, in collaboration with researchers at Université Laval in Québec City, Canada.

“Our findings shed a completely new light onto our current understanding of how HD begins and develops. We believe that they will also lead to the development of a whole new range of therapies for neurodegenerative diseases of the central nervous system,” explains corresponding author of the study Jihwan Song, professor and director of Neural Regeneration and Therapy Group at the CHA Stem Cell Institute of CHA University.

The researchers have now provided further evidence for this new theory by showing that the abnormal protein coded for this genetic disorder can be transmitted to normal animals by the injection of diseased cells into their brain. “This is the first demonstration that cells carrying a genetic disease are capable of spreading into the normal mammalian brain and lead to the manifestation of behavioral abnormalities associated with the disease,” says Francesca Cicchetti, professor at the Université Laval Faculty of Medecine and researcher at Centre de recherche du CHU de Québec-Université Laval.

HD is an inherited chronic degenerative disorder of the brain characterized by major thinking and motor problems as well as psychiatric disturbances. There is no cure for HD and current treatments are of very limited efficacy. It is caused by a single gene abnormality which leads to the production of a mutant form of a protein called huntingtin (mHtt). The production of this protein in a nerve cell eventually kills it but it has long been thought that this protein cannot spread out of the cell and infect and kill neighbouring ones.

However, in recent post mortem analyses of HD patients who received transplants of non-HD tissue in an attempt to repair their brain, the researchers showed that the mHtt can be found in the graft itself. This suggests that the patient with HD transmitted the mHtt from their brain into the transplant.  Science Daily  Original web page at Science Daily


Genetic code of red blood cells discovered

Eight days. That’s how long it takes for skin cells to reprogram into red blood cells. Researchers at Lund University in Sweden, together with colleagues at Center of Regenerative Medicine in Barcelona, have successfully identified the four genetic keys that unlock the genetic code of skin cells and reprogram them to start producing red blood cells instead.

“We have performed this experiment on mice, and the preliminary results indicate that it is also possible to reprogram skin cells from humans into red blood cells. One possible application for this technique is to make personalised red blood cells for blood transfusions, but this is still far from becoming a clinical reality,” says Johan Flygare, manager of the research group and in charge of the study.

Every individual has a unique genetic code, which is a complete instruction manual describing exactly how all the cells in the body are formed. This instruction manual is stored in the form of a specific DNA sequence in the cell nucleus. All human cells — brain, muscle, fat, bone and skin cells — have the exact same code. The thing that distinguishes the cells is which chapter of the manual the cells are able to read. The research group in Lund wanted to find out how the cells open the chapter that contains instructions on how to produce red blood cells. The skin cells on which the study was based had access to the instruction manual, but how were the researchers able to get them to open the chapter describing red blood cells?

With the help of a retrovirus, they introduced different combinations of over 60 genes into the skin cells’ genome, until one day they had successfully converted the skin cells into red blood cells. The study is published in the scientific journal Cell Reports.

“This is the first time anyone has ever succeeded in transforming skin cells into red blood cells, which is incredibly exciting,” says Sandra Capellera, doctoral student and lead author of the study.

The study shows that out of 20,000 genes, only four are necessary to reprogram skin cells to start producing red blood cells. Also, all four are necessary in order for it to work.

“It’s a bit like a treasure chest where you have to turn four separate keys simultaneously in order for the chest to open,” explains Sandra.

The discovery is significant from several aspects. Partly from a biological point of view — understanding how red blood cells are produced and which genetic instructions they require — but also from a therapeutic point of view, as it creates an opportunity to produce red blood cells from the skin cells of a patient. There is currently a lack of blood donors for, for instance, patients with anemic diseases. Johan Flygare explains:

“An aging population means more blood transfusions in the future. There will also be an increasing amount of people coming from other countries with rare blood types, which means that we will not always have blood to offer them.”

Red blood cells are the most common cells in the human body, and are necessary in order to transport oxygen and carbon dioxide. Millions of people worldwide suffer from anemia — a condition in which the patient has an insufficient amount of red blood cells. Patients with chronic anemia are among the most problematic cases. They receive regular blood transfusions from different donors, which can eventually lead to the patient developing a reaction to the new blood. They simply become allergic to the donor’s blood. Finding a feasible way to make blood from an individual’s own skin cells would bring relief to this group of patients. However, further studies on how the generated blood performs in living organisms are needed.  Science Daily Original web page at Science Daily


Mobilizing mitochondria may be key to regenerating damaged neurons

Researchers at the National Institute of Neurological Disorders and Stroke have discovered that boosting the transport of mitochondria along neuronal axons enhances the ability of mouse nerve cells to repair themselves after injury. The study, “Facilitation of axon regeneration by enhancing mitochondrial transport and rescuing energy deficits,” which has been published in The Journal of Cell Biology, suggests potential new strategies to stimulate the regrowth of human neurons damaged by injury or disease.

Neurons need large amounts of energy to extend their axons long distances through the body. This energy — in the form of adenosine triphosphate (ATP) — is provided by mitochondria, the cell’s internal power plants. During development, mitochondria are transported up and down growing axons to generate ATP wherever it is needed. In adults, however, mitochondria become less mobile as mature neurons produce a protein called syntaphilin that anchors the mitochondria in place. Zu-Hang Sheng and colleagues at the National Institute of Neurological Disorders and Stroke wondered whether this decrease in mitochondrial transport might explain why adult neurons are typically unable to regrow after injury.

Sheng and his research fellow Bing Zhou, the first author of the study, initially found that when mature mouse axons are severed, nearby mitochondria are damaged and become unable to provide sufficient ATP to support injured nerve regeneration. However, when the researchers genetically removed syntaphilin from the nerve cells, mitochondrial transport was enhanced, allowing the damaged mitochondria to be replaced by healthy mitochondria capable of producing ATP. Syntaphilin-deficient mature neurons therefore regained the ability to regrow after injury, just like young neurons, and removing syntaphilin from adult mice facilitated the regeneration of their sciatic nerves after injury.

“Our in vivo and in vitro studies suggest that activating an intrinsic growth program requires the coordinated modulation of mitochondrial transport and recovery of energy deficits. Such combined approaches may represent a valid therapeutic strategy to facilitate regeneration in the central and peripheral nervous systems after injury or disease,” Sheng says. Science Daily Original web page at Science Daily


* Scientists unpack how Toxoplasma infection is linked to neurodegenerative disease

Toxoplasma gondii, a protozoan parasite about five microns long, infects a third of the world’s population. Ingested via undercooked meat or unwashed vegetables, the parasite infects 15-30 percent of the US population. In France and Brazil, up to 80 percent of the population has the infection.

Particularly dangerous during pregnancy — infection in pregnant women can cause serious congenital defects and even death of the fetus — this chronic infection has two components: the unicellular parasite, and inflammation of tissues it causes.

Working on mice (like all mammals, a natural host for this parasite), a University of California, Riverside team of biomedical scientists reports in the journal PLOS Pathogens that Toxoplasma infection leads to a disruption of neurotransmitters in the brain and postulates that it triggers neurological disease in those already predisposed to such a disease.

They note that Toxoplasma infection leads to a significant increase in glutamate — the primary and most important neurotransmitter in the brain, which transmits excitatory signals between neurons. This glutamate increase is “extracellular,” meaning outside the cell, and is strictly controlled by specialized cells in the central nervous system (brain and spinal cord), called astrocytes. Glutamate buildup is seen in traumatic brain injury as well as highly pathological and neurodegenerating diseases such as epilepsy, multiple sclerosis and amyotrophic lateral sclerosis (ALS).

One role astrocytes play is to remove extracellular glutamate, lest it increase to pathological levels that could damage neurons. This is primarily achieved using a glutamate transporter, called GLT-1, tasked with regulating extracellular glutamate. GLT-1 soaks up glutamate released by neurons and converts it back into the safer substance glutamine, which can then be used by cells for energy.

“When a neuron fires it releases glutamate into the space between itself and a nearby neuron,” explained lead researcher Emma H. Wilson, an associate professor in the Division of Biomedical Sciences in the School of Medicine, who has worked on toxoplasmosis for more than 15 years. “The nearby neuron detects this glutamate which triggers a firing of the neuron. If the glutamate isn’t cleared by GLT-1 then the neurons can’t fire properly the next time and they start to die.”

Wilson and her team found that during toxoplasma infection, astrocytes swell and are not able to regulate extracellular glutamate concentrations. Further, GLT-1 is not expressed properly. This leads to a buildup of the glutamate released from neurons and the neurons misfire.

“These results suggest that in contrast to assuming chronic Toxoplasma infection as quiescent and benign, we should be aware of the potential risk to normal neurological pathways and changes in brain chemistry,” Wilson said.

When the researchers treated the infected mice with ceftriaxone, an antibiotic known to produce beneficial results in mouse models of ALS as well as neuroprotection in a variety of central nervous system injuries, they found that GLT-1 was upregulated. This restoration of GLT-1 expression significantly reduced extracellular glutamate from pathological to normal concentrations, returning neuronal function to a normal state.

“We have shown for the first time the direct disruption of a major neurotransmitter in the brain resulting from this infection,” Wilson said. “More direct and mechanistic research needs to be performed to understand the realities of this very common pathogen.”

Next, Wilson and her colleagues will research what initiates the downregulation of GLT-1 during chronic Toxoplasma infection.

“Despite the importance of this transporter to maintaining glutamate homeostasis, there is little understanding of the mechanism that governs its expression,” Wilson said. “We’d like to know how cells, including peripheral immune cells, control the parasite in the brain. Toxoplasma infection results in the lifelong presence of parasitic cysts within the neurons in the brain. We’d like to further develop a project focused on killing the cysts, which is where the parasite hides from the immune response for the rest of the infected person’s life. Getting rid of the cyst removes the threat of reactivation of the parasite and the risk of encephalitis while also allowing us to minimize chronic inflammation in the brain.”

Mysteriously, the parasite that causes toxoplasmosis can sexually reproduce only in cats. Asexually, it can replicate and live in any mammalian cell that has a nucleus. Indeed, the parasite has been found in every mammal ever tested.

Post-infection, a competent immune system is needed to prevent parasite reactivation and encephalitis. Infected people with compromised immune systems need to be on prophylactic drugs for life. Otherwise they are at risk of cyst reactivation and death. The parasite lives in areas of the brain that have the potential to disrupt certain behaviors such as risk-seeking (infected mice will run toward cat urine instead of away from it).

The parasite is not as latent or dormant as researchers once thought. Cases of congenital infection and retinal toxoplasmosis are on the rise (the brain and retina are closely linked). People who have schizophrenia are more likely to be infected with Toxoplasma. Infection shows some correlation with Alzheimer’s disease, Parkinson’s disease and epilepsy.

Nevertheless, Wilson notes that infection is no cause for major worry. “We have been living with this parasite for a long time,” she said. “It does not want to kill its host and lose its home. The best way to prevent infection is to cook your meat and wash your hands and vegetables. And if you are pregnant, don’t change the cat litter.” Science Daily Original web page at Science Daily


Resistance mechanism of aggressive brain tumors revealed

Brain tumors subject to therapy can become resistant to it through interactions with their tumor microenvironment rather than because of anything intrinsic about the tumor itself, a new study in mice suggests.

The resistance mechanism outlined in the study involves a particular enzyme and can be overcome using other drugs that target this newly identified signaling pathway. Glioblastoma multiforme (GBM) is a common and aggressive type of adult brain tumor; current standard treatment only minimally prolongs survival.

Macrophages, types of white blood cell that ingest debris, are found in abundance in GMB tumors, and tend to express high levels of colony stimulating factor-1 (CSF-1).

Daniela Quail et al. showed that inhibiting CSF-1 with a drug called BLZ945 caused tumor regression in mice; however, the majority of GBM tumors ultimately developed resistance to BLZ945, a phenomenon of interest as cancer drugs targeting CSF-1 are currently in clinical trials in multiple settings.

Further investigation revealed that GMB recurrence correlated with elevated activity of a tumor enzyme called PI3-K, which was in turn driven by an environmental influence, macrophage-secreted IGF-1. Mice that were treated with BLZ945 plus a PI3-K or IGF-1 inhibitor benefited from significantly longer survival than control mice, the researchers showed.

By implanting BLZ945-resistant tumors into naïve mice, Quail et al. demonstrated that GBM tumors use this this PI3-K/IGF-1 mechanism to manipulate the surrounding microenvironment to their advantage.

Thus, they say, tumors can also develop resistance through microenvironment-dependent mechanisms, independent of the tumor itself. Whether the findings will translate to a human model of glioma remains to be seen.  Science Daily  Original web page at Science Daily


Making virus sensors cheap and simple: New method detects single viruses in urine

Scientists at The University of Texas at Austin have developed a new method to rapidly detect a single virus in urine, as reported this week in the journal Proceedings of the National Academy of Sciences.

While the technique presently works on just one virus, scientists say it could be adapted to detect a range of viruses that plague humans, including Ebola, Zika and HIV.

“The ultimate goal is to build a cheap, easy-to-use device to take into the field and measure the presence of a virus like Ebola in people on the spot,” says Jeffrey Dick, chemistry graduate student and co-lead author of the study. “While we are still pretty far from this, this work is a leap in the right direction.”

The new method is highly selective, meaning it is only sensitive to one type of virus, filtering out possible false negatives due to other viruses or contaminants.

There are two other commonly used methods for detecting viruses in biological samples, but they have drawbacks: one requires a much higher concentration of viruses and the other requires samples to be purified to remove contaminants. The new method, however, can be used with urine straight from a person or animal.

The other co-authors are Lauren Strawsine, a postdoctoral fellow in chemistry, Jason Upton, an assistant professor of molecular biosciences and Allen Bard, professor of chemistry and director of the Center for Electrochemistry.

The researchers demonstrated their new technique on a virus that belongs to the same family as the herpes virus, called murine cytomegalovirus (MCMV). To detect individual viruses, the team places an electrode–a wire that conducts electricity, in this case, one that is thinner than a human cell–in a sample of mouse urine. They then add to the urine some special molecules made up of enzymes and antibodies that naturally stick to the virus of interest. When all three stick together and then bump into the electrode, there’s a spike in electric current that can be easily detected.

The researchers say their new method still needs refinement. For example, the electrodes become less sensitive over time because a host of other naturally occurring compounds stick to them, leaving less surface area for viruses to interact with them. To be practical, the process will also need to be engineered into a compact and rugged device that can operate in a range of real world environments. Science Daily Original web page at Science Daily


Citizen scientists can help protect endangered species

Lay people can help scientists conserve the protected Florida fox squirrel and endangered species just by collecting data, a new University of Florida Institute of Food and Agricultural Sciences study shows.

So-called citizen scientists did a commendable job collecting information on the fox squirrel, according to the study. Until this study, the conservation and management of fox squirrels in Florida was constrained by a lack of reliable information on the factors influencing its distribution. But with this research, which combines sightings and photos of fox squirrels by everyday citizens and professional ecologists, scientists now know they can get help from citizen scientists in conserving the fox squirrel population.

“When citizens are used in research to find animals across large scales, such as the state of Florida, they provide lots of information that is generally useful for conservation efforts,” said Bob McCleery, a UF/IFAS associate professor of wildlife ecology and conservation. “We showed that data collected by citizens has a considerable amount of biases, but it is equal, if not better, than data collected by trained professionals. Additionally, regardless of its bias, citizen-collected data provided reliable predictions of fox squirrel occurrence and helped understand fox squirrel habitat relationships.”

McCleery supervised a thesis conducted by Courtney Tye, a now-deceased master’s student in the UF/IFAS wildlife ecology and conservation department. For the study, Tye and her colleagues put up a website,, for citizen scientists and professional ecologists to post where they had spotted Sherman fox squirrels and to post photos of the animals.

They collected 4,222 sightings of fox squirrels from 66 of 67 counties in 194 days in 2011 to 2012. Of those locations, 73 percent came from citizens and 27 percent from natural resource professionals.

Researchers examined their findings in four data sets, including citizens only and professionals only, to check for bias. Citizen science is increasingly used in ecology and conservation, yet researchers remain concerned about the value of such data, the study says. The UF/IFAS researchers say their results illustrate that citizen science data do not show sample bias to lower the predictive ability of their models.

“It is these kinds of synergies between citizens and professionals that are going to be increasingly necessary to generate the information we need to develop conservation strategies for the planet’s growing biodiversity crisis,” the study said.

According to the Florida Fish and Wildlife Conservation Commission, the fox squirrel may be found throughout Florida in open woods and mangrove swamps. Of the four subspecies in Florida, two are listed as protected: Sherman’s Fox Squirrel and the Big Cypress Fox Squirrel. The findings are published online in the Journal of Applied Ecology.  Science Daily Original web page at Science Daily


* How brain connects memories across time

Neuroscientists boost ability of aging brain to recapture links between related memories. Using a miniature microscope that opens a window into the brain, UCLA neuroscientists have identified in mice how the brain links different memories over time. While aging weakens these connections, the team devised a way for the middle-aged brain to reconnect separate memories.

The findings, which were published in the advance online edition of Nature, suggest a possible intervention for people suffering from age-related memory problems.

“Until now, neuroscientists have focused on how the brain creates and stores single memories,” said principal investigator Alcino Silva, a professor of neurobiology at the David Geffen School of Medicine at UCLA. “We wanted to explore how the brain links two memories and whether the passage of time affects the strength of the connection.”

“In the real world, memories don’t happen in isolation,” said first author Denise Cai, a researcher in Silva’s lab. “Our past experiences influence the creation of new memories and help us predict what to expect and make informed decisions in the future.”

In an intricate experiment, the UCLA team tested in young and middle-aged mice whether the brain linked memories of experiences separated by five hours versus seven days.

The lab used a miniature microscope, called a Miniscope, which was developed by UCLA neuroscientists Dr. Peyman Golshani, Baljit Khakh and Silva with funding from the presidential BRAIN Initiative and the Geffen School. The instrument’s powerful camera allowed the scientists to peer into the brains of young and observe their cells in action. The tiny, head-mounted microscope illuminated the animals’ neurons firing as the mice moved freely in their natural environments.

For 10 minutes at a time, each mouse was placed in three boxes, all unique in terms of fragrance, shape, lighting and flooring. A week’s time separated placement in the first and second boxes. Only five hours separated time spent in the second and third boxes, where the mouse later received a small shock to the foot.

Two days later, the team returned each mouse to all three boxes. As expected, the mice froze with fear when it recognized the inside of the third box.

“The mouse also froze in the second box, where no shock occurred,” Silva observed. “This suggests that the mouse transferred its memory of the shock in the third box to its experience in the second box five hours earlier.”

When Silva and Cai examined the animals’ brains, the neural activity confirmed their hypothesis.

“The same brain cells that recorded the mouse’s shock in the third box also encoded its memory of the second box a few hours earlier,” Cai said. “We saw 20 percent more overlap in the neural circuits that recorded the animal’s experiences in the memories that unfolded closer in time.”

In other words, says Silva, “The memories became interrelated in how they were encoded and stored by the brain, such that the recall of one memory triggered the recall of another memory related in time.”

Based on an earlier Silva finding, the team knew that a cell is most likely to encode a memory when it’s aroused and ready to fire. Neuroscientists refer to this condition as excitability.

“The excitable brain is already warmed up,” Silva said. “It’s like stretching your muscles before exercise or revving your car engine before you drive.”

Suspecting that aging weakens neurons’ ability to fully excite, the UCLA researchers conducted a similar experiment in middle-aged mice. They introduced each of the mice to two boxes, five hours apart, and administered a foot shock in the second box.

When they returned the animals to the boxes two days later, the results could not have been more clear-cut.

“The older mice froze only in the box where they had received a shock,” Cai explained. “They did not react in the first box.”

A glimpse into the Miniscopes confirmed that the brains of the mice did not connect the two memories; each memory was encoded on its own neural circuit.

Next the team focused on boosting the older animals’ ability to link memories. Cai used a biological tool to excite neurons in a tiny part of the hippocampus — the memory center of the brain — before introducing the mice to the first box.

She stimulated the same cells before placing the mice in the first box and the second box, where they received a foot shock two days later.

“The proof in the pudding arrived when we reintroduced the middle-aged mice to the first box,” Silva said. “The animals froze — they now linked the shock that happened in the second box to the first. This suggests that increased excitability had reversed their age-related inability to link memories.”

Cai and Silva are currently testing an FDA-approved drug’s effect on the ability of middle-aged mice to connect memories.  Science Daily Original web page at Science Daily


Putting the brakes on cell’s ‘engine’ could give flu, other vaccines a boost

A relatively unknown molecule that regulates metabolism could be the key to boosting an individual’s immunity to the flu — and potentially other viruses — according to research reported today in the journal Immunity.

The study, led by University of Vermont (UVM) College of Medicine doctoral student Devin Champagne and Mercedes Rincon, Ph.D., a professor of medicine and an immunobiologist, discovered that a protein called methylation controlled J — or MCJ — can be altered to boost the immune system’s response to the flu.

Metabolism is a crucial function that helps keep cells alive. It plays a role in a range of bodily processes — from the conversion of food into energy to the ability to fight off infection. MCJ is the part of the cell that produces energy and enables metabolism.

“It’s the engine of the cell,” says Rincon, who adds that previously, researchers assumed that the mitochondria were constantly active.

She and Champagne discovered that MCJ acts as a braking system in the mitochondria, slowing these organelles down. Without MCJ, the mitochondria are hyperactive.

In the T cells of the body’s immune system, specifically the CD8 T cells that fight viruses and infections, metabolism helps ensure that those bug-fighting cells remain active and don’t tire out. When a virus attacks, CD8 cells detect and kill it while leaving the healthy cells intact.

MCJ controls the metabolism of the CD8 cells. It prevents the mitochondria from generating too much energy and making the CD8 cells so overactive that they kill healthy cells.

A vaccine, such as a flu shot, trains the CD8 cells to identify that virus and destroy it. With a good vaccine, the CD8 cells will “remember” and protect against that virus for a long time.

“The metabolism of immune cells is very important,” explains Rincon. “It is critical to determining effective protection against infection, but also if vaccines will work,” she says.

For their study, Champagne and Rincon generated mutant mice without MCJ and infected both normal mice and mice lacking MCJ with flu virus — imitating a vaccine, so the animals’ CD8 cells would learn to recognize the bug. After four weeks, they took the CD8 cells from the infected mice and injected those cells into other mice. One group received normal CD8 cells; the other group got cells without MCJ.

The researchers gave those new mice very high doses of the same flu virus. The mice with normal CD8 cells all died from the virus, indicating that the “educated” CD8 cells did poorly in protection. In contrast, the mice injected with MCJ-deficient CD8 cells had proper protection and all survived.

Champagne and Rincon concluded that with normal MCJ levels, CD8 cells are not as efficient in fighting virus because their mitochondrial metabolism is not strong enough, so the removal of MCJ (the “mitochondrial brake”) can improve the CD8 cells protection capability — and thus the efficacy of a vaccine.

“Nothing has been shown to do what this protein does,” says Rincon. “Suppressing MCJ will enhance your immune response and protection from an influenza virus and, most likely, protection from other threatening viruses.”

The researchers are now testing potential therapies for fatty liver disease by eliminating MCJ in liver cells. That action speeds up the metabolism process of breaking down lipids and converting fat into energy, thus reducing the presence of the disease, which affects 15 to 20 percent of humans, Rincon says. Science Daily Original web page at Science Daily


Early-life stress causes digestive problems and anxiety in rats

Traumatic events early in life can increase levels of norepinephrine — the primary hormone responsible for preparing the body to react to stressful situations — in the gut, increasing the risk of developing chronic indigestion and anxiety during adulthood, a new study in American Journal of Physiology — Gastrointestinal and Liver Physiology reports.

Functional dyspepsia, also known as indigestion with no clear origin, affects an estimated 25 to 40 percent of adults. The most common symptoms include pain or discomfort in the upper abdomen, upset stomach, bloating and feeling full quickly while eating. Because the symptoms cannot be pinpointed to a cause, such as an ulcer or gastritis, functional dyspepsia is challenging to treat and many patients continue to experience symptoms years after diagnosis.

How functional dyspepsia develops is not well understood. Population studies have reported that early-life trauma — including abuse, psychological stress and gastrointestinal infections from sources such as contaminated food and water — increases the risk of developing functional dyspepsia in adulthood. Patients with functional dyspepsia also have a higher prevalence of anxiety, but whether functional dyspepsia and anxiety are linked is a contentious issue.

A research team from the University of Texas Medical Branch at Galveston reported in a previous study that inducing inflammation in the colon — such as what occurs during gastrointestinal infections — of neonatal rats caused gut hypersensitivity when the rats became adults. The researchers found that colon inflammation did so by increasing levels of stress hormone norepinephrine. Norepinephrine is produced in nerves all over the body. When stimulated, the nerves release norepinephrine into the blood stream, which affects cells in the surrounding area. This new study aimed to explain the increase in norepinephrine and determine whether rats were more susceptible to anxiety after having colon inflammation as newborns.

The researchers induced inflammation in the colons of 10-day-old rats. After six to eight weeks, the adult rats were evaluated for stomach hypersensitivity and anxiety-like behavior. The researchers found that colon inflammation increased the levels of tyrosine hydroxylase, a protein that makes norepinephrine, in the nerves in the upper abdomen. The nerves released more norepinephrine, increasing levels of norepinephrine in the upper abdomen. The rats also displayed anxiety-like behavior.

The study shows that increased norepinephrine release in the upper abdomen increases stomach sensitivity and susceptibility to anxiety-like behaviors in rats. “Our findings extend the clinical observations that adverse early-life experiences are risk factors for the development of functional dyspepsia symptoms,” says Sushil Sarna, PhD, of University of Texas Medical Branch at Galveston and lead investigator of the team.

The research group will continue to study the link between functional dyspepsia, anxiety and early-life stress. Anxiety worsens the symptoms of functional dyspepsia, but whether it causes or is a result of functional dyspepsia remains to be investigated, according to Sarna. The experimental method used in this study can be used to answer these questions, Sarna says. The research team is also working to identify potential targets for treating the condition and finding biomarkers to diagnose and evaluate the severity of functional dyspepsia symptoms.  Science Daily  Original web page at Science Daily


Experimental drug against hepatitis C slows down Zika virus infection in mice

Virologists from KU Leuven, Belgium, have shown that an experimental antiviral drug against hepatitis C slows down the development of Zika in mice. The research team was led by Professor Johan Neyts from the Laboratory of Virology and Chemotherapy.

“The Zika virus is transmitted by the tiger mosquito. Roughly twenty percent of the people who are infected actually get sick,” explains Professor Neyts. “The most common symptoms, which last about a week, are fever, fatigue, joint and muscle pain, rash, and red eyes. A small number of infected people go on to develop Guillain-Barré Syndrome, which causes muscle weakness and temporary paralysis. In some cases, the patient needs to be put on a ventilator.”

“The biggest cause for concern is that pregnant women with the infection can pass on the virus to the fetus,” Neyts continues. “As a result, some babies are born with microcephaly, a disorder of the central nervous system whereby the child’s skull and brain are too small. In severe cases, these children grow up with serious physical and mental disabilities.”

Following explosive outbreaks of the virus on islands in the Pacific, the virus spread quickly to South and Central America and the Caribbean in 2015 and 2016. Earlier this year, the World Health Organisation declared the state of emergency to contain the epidemic as quickly as possible. After all, there is currently no vaccine or antiviral drug available to prevent or treat an infection.

“As the Zika virus is related to the hepatitis C virus, we examined whether some inhibitors of the hepatitis C virus also prevent the multiplication of the Zika virus in human cells. We have identified at least one experimental drug that is effective against the Zika virus.”

Next, the researchers needed to assess whether the inhibitor also provides protection in lab animals. “We used mice with a defect in their innate immune system. When these mice are infected with the Zika virus, they develop a number of the symptoms that we also see in human patients. Treating the infected mice with the hepatitis C virus inhibitor resulted in a clear delay in virus-induced symptoms.”

“The experimental hepatitis C inhibitor is not very powerful yet,” Neyts concludes. “Nevertheless, our study opens up important new possibilities. We can now start testing the effectiveness of other promising virus inhibitors and vaccines against the Zika virus.” Science Daily Original web page at Science Daily


Stress affects males, females differently

How does stress — which, among other things, causes our bodies to divert resources from non-essential functions — affect the basic exchange of materials that underlies our everyday life? Weizmann Institute of Science researchers investigated this question by looking at a receptor in the brains of mice, and they came up with a surprising answer. The findings, which recently appeared in Cell Metabolism, may in the future aid in developing better drugs for stress-related problems and eating disorders.

Dr. Yael Kuperman began this study as part of her doctoral research in the lab of Prof. Alon Chen of the Department of Neurobiology. Dr. Kuperman, presently a staff scientist in the Veterinary Resources Department, Prof. Chen, and research student Meira Weiss focused on an area of the brain called the hypothalamus, which has a number of functions, among them helping the body adjust to stressful situations, controlling hunger and satiety, and regulating blood glucose and energy production.

When stress hits, cells in the hypothalamus step up production of a receptor called CRFR1. It was known that this receptor contributes to the rapid activation of a stress-response sympathetic nerve network — increasing heart rate, for example. But since this area of the brain also regulates the body’s exchange of materials, the team thought that the CRFR1 receptor might play a role in this, as well.

Prof. Chen and his group characterized the cells in a certain area of the hypothalamus, finding that the receptor is expressed in around half of the cells that arouse appetite and suppress energy consumption. These cells comprise one of two main populations in the hypothalamus — the second promotes satiety and the burning of energy. “This was a bit of a surprise,” says Dr. Kuperman, “as we would instinctively expect the receptor to be expressed on the cells that suppress hunger.”

To continue investigating, the researchers removed the CRFR1 receptor in mice from just the cells that arouse appetite in the hypothalamus, and then observed how this affected the animals’ bodily functions. At first, the team did not see any significant changes, confirming that this receptor is saved for stressful situations. But when they exposed the mice to stress — cold or hunger — they got another surprise.

When exposed to cold, the sympathetic nervous system activates a unique type of fat called brown fat, which produces heat to maintain the body’s internal temperature. When the receptor was removed, the body temperature dropped dramatically — but only in the female mice. Their temperatures failed to stabilize even afterward the stressor was removed, while male mice showed hardly any change.

Fasting produced a similarly drastic response in the female mice. Normally, when food is scarce, the brain sends a message to the liver to produce glucose, conserving a minimum level in the blood. But when food was withheld from female mice missing the CRFR1 receptor, the amount of glucose their livers produced dropped significantly. In hungry male CRFR1-deficient mice, the result was similar to the effects of exposure to cold: the exchange of materials in their bodies was barely affected.

“We discovered that the receptor has an inhibitory effect on the cells, and this is what activates the sympathetic nervous system,” says Dr. Kuperman.

Among other things — revealing exactly how this receptor works and how it contributes to the stress response — the findings show that male and female bodies may exhibit significant differences in the ways that materials are exchanged under stress. Indeed, the fact that the receptor suppresses hunger in females may help explain why women are much more prone to eating disorders than men.

Because drugs can enter the hypothalamus with relative ease, the findings could be relevant to the development of treatments for regulating hunger or stress responses, including anxiety disorders or depression. Indeed, several pharmaceutical companies have already begun developing psychiatric drugs to block the CRFR1 receptor. The scientists caution, however, that because the cells are involved in the exchange of materials, blocking the receptor could turn out to have such side effects as weight gain. Science Daily  Original web page at Science Daily


* How prions kill neurons: New culture system shows early toxicity to dendritic spines

Prion diseases are fatal and incurable neurodegenerative conditions of humans and animals. Yet, how prions kill nerve cells (or neurons) remains unclear. A study published on May 26, 2016 in PLOS Pathogens describes a system in which to study the early assault by prions on brain cells of the infected host.

Some of the earliest and potentially most critical changes in prion-infected brains occur at the connections (synapses) between neurons, and specifically at so-called dendritic spines. Dendritic spines are protrusions on the post-synaptic branches of a neuron that receive signals from other neurons. However, to date there has been no experimentally tractable model system in which the early degenerative changes caused by prions can be studied in cell culture.

David Harris, from Boston University School of Medicine, USA, and colleagues have argued that the availability of a neuronal culture system susceptible to the toxic effects of prions is crucial for understanding the underlying mechanisms and for potentially identifying drugs that block neurodegeneration. In this study, they report such a system, which reproduces acute prion neurotoxicity through degeneration of dendritic spines on cultured hippocampal neurons.

The researchers started by culturing neurons isolated from the hippocampus (a brain region involved in learning and memory) of mice. These neurons can be maintained in culture for three weeks, during which time they develop mature dendrites studded with spines, which contain chemical receptors that receive signals from neighboring neurons.

When the cultured neurons were exposed to brain extracts from mice with prion disease (which are known to contain large amounts of infectious prions), they showed rapid and dramatic changes: Within hours, there was severe retraction of spines, reducing their overall density and the size of the remaining ones. These changes in spines occurred without large-scale destruction of the neurons, suggesting that they represented very early events that would affect the functioning of the neurons prior to their actual death. When the researchers used three different kinds of purified prion preparations, they saw similar dendritic spine retraction in the cultures.

It is known that the development of prion disease involves an alteration of the normal cellular prion protein (designated PrPC), such that it assumes an abnormal shape (designated PrPSc). The resulting PrPSc is toxic to neurons, and it can propagate an infection by corrupting the shape of additional molecules of PrPC in a kind of chain-reaction.

To test whether the effects of PrPSc in their cell cultures depended on the neurons’ normal PrPC, the researchers generated cultures of hippocampal neurons from mice that were genetically engineered to lack PrPC. These cultures, they found, were resistant to toxic prion exposure, i.e., they did not show any of the changes in dendritic spines seen in neurons from normal mice containing PrPC.

Finally, the researchers tested neurons from transgenic mice expressing mutant PrPC molecules that were missing a specific region that is thought to interact with toxic prions. And indeed, the researchers found that these neurons–just like neurons without any PrPC–were immune to prion toxicity.

The researchers summarize their results as follows: “We describe a new system that is capable of reproducing acute prion neurotoxicity, based on PrPSc-induced degeneration of dendritic spines on cultured hippocampal neurons.” The system, they state, “provides new insights into the mechanisms responsible for prion neurotoxicity, and it provides a platform for testing potential therapeutic agents.”

Because “dendritic spine loss is a common theme in many neurodegenerative conditions, including Alzheimer’s, Huntington’s, and Parkinson’s diseases, and has been suggested to contribute to clinical symptoms in patients,” the researchers also suggest that their system allows for “direct comparisons between pathogenic mechanisms involved in prion diseases and other neurodegenerative disorders.” Science Daily Original web page at Science Daily


Mimicking deep sleep brain activity improves memory

It is not surprising that a good night’s sleep improves our ability to remember what we learned during the day. Now, researchers at the RIKEN Brain Science Institute in Japan have discovered a brain circuit that governs how certain memories are consolidated in the brain during sleep. Published in the May 26 issue of Science magazine, the study shows how experimentally manipulating the identified neural connection during non-REM sleep (deep sleep) can prevent or enhance memory retention in mice.

The team led by Masanori Murayama studied the long-known phenomenon of memory consolidation during sleep by building off their recent study on tactile perception in which they found that perceiving texture requires signaling within a neural circuit from higher-level motor-related brain regions back to lower-level touch-related sensory areas. They reasoned that the same “top-down” pathway might also consolidate memories of textures. Explains Murayama, “There is a long standing hypothesis that top-down input is crucial for memory consolidation and that during sleep, neurons in sensory regions activated during the initial experience can “reactivate” by unknown pathways. We found such reactivation of the top-down pathway is critical for mice to encode memories of their tactile experiences.”

The researchers developed a task to assess memory retention that relies on the natural inclination of mice to spend more time investigating new items in their environment. First they allowed mice to explore objects in two rooms with smooth floors, then they changed one of the smooth floors to a textured floor and again allowed the mice to explore. With normal sleep, mice spent more time exploring the room with the textured floor, showing that they remembered the smooth room and were less interested in it. Typically, this behavior was observed as long as the second exploration occurred within two days.

To examine whether the top down circuit was responsible for memory consolidation during sleep, they manipulated the mice in several ways. First, they showed that sleep deprivation immediately following the first tactile experience caused mice to explore the textured room less often on the second exploration, indicating that they did not remember the smooth room. Next, they inactivated the top-down neural pathway during non-REM sleep shortly after the first exploration and found that during the second exploration, mice performed as if they had been sleep deprived. Silencing the top-down pathway when mice were awake or during non-REM sleep at later times had no effect on performance, indicating that memory consolidation happened in the first bout of non-REM sleep after the experience.

The importance of top-down circuit activation in non-REM sleep suggested that memory consolidation might involve synchronous slow wave brain activity between the two brain regions that is characteristic of non-REM sleep. To test this, they artificially applied synchronous or asynchronous activity in the higher and lower regions of the circuit during non-REM sleep after the first tactile experience. Mice with asynchronous activation were unable to consolidate memories, but synchronous activation allowed them to retain a strong memory of the smooth floor for at least 4 days or twice as long as normal. The synchronous treatment even rescued the typical lack of memory retention in sleep-deprived mice.

“Our findings on sleep deprivation are particularly interesting from a clinical perspective,” says Murayama. “Patients who suffer from sleep disorders often have impaired memory functions. Our findings suggest a route to therapy using transcortical magnetic or direct-current stimulation to top down cortical pathways to reactivate sleep-deprived neurons during non-REM sleep. Our next step is to test this in mouse models of sleep-disorders.  Science Daily  Original web page at Science Daily


* Alternative odor receptors discovered in mice

Smell in mammals turns out to be more complex than we thought. Rather than one receptor family exclusively dedicated to detecting odors, a study in mice reports that a group of neurons surrounding the olfactory bulb use an alternative mechanism for catching scents. These “necklace” neurons, as they’re called, use this newly discovered olfactory detection system to respond to odors that elicit instinctive responses, such as pheromones and the smell of seeds and nuts. Harvard researchers report the finding May 26 in Cell.

“Our work suggests that mammalian mechanisms for smell are not monolithic in terms of mechanism or logic, but rather can take many forms and can be mediated by multiple types of receptors,” says senior author Sandeep Robert Datta, a neurobiologist at Harvard Medical School. “These findings revise our canonical view of how animals probe the chemical environment.”

Nobel Prize-winning work back in 1991 showed that, in mammals, each sensory neuron in the main olfactory system expresses one type of G-protein coupled receptor (GPCR), which is specialized to detect a specific type of odor. The pattern of activity of all sensory neurons in the olfactory system allows us to distinguish between different odors present in the environment. This one-GPCR-per-neuron pattern also exists in the vomeronasal olfactory system, which is specialized for recognizing pheromones, suggesting a common and general logic for processing smell. Yet, a third olfactory system consisting of necklace neurons, so-called due to the unique circular pattern of their projections to the brain, also responds to diverse odors. It has not been clear which receptors are expressed by these neurons and what role they play in odor perception.

In the new study, Datta and his team discovered that necklace neurons in mice do not express GPCRs, unlike all other types of olfactory sensory neurons in mammals. Rather, these neurons express the MS4A class of proteins, which were previously not known to play a role in odor perception. Moreover, each necklace neuron expresses multiple types of MS4A receptors, in stark contrast to the one-receptor-per-neuron rule that organizes insect and other mammalian olfactory systems. These receptors respond to fatty acids that are specifically found in nuts and seeds, as well as a pheromone known to be aversive to mice.

“This discovery strongly suggests that the brain must be interpreting information from these receptors using a very different strategy from the one used by the brain to discriminate most odors,” Datta says. “We speculate–but don’t have the evidence to back this idea yet–that the MS4As are used as a kind of alert system for the brain, letting it know that something of real importance is out there in the world, but not telling the brain explicitly what that thing is.”

By analyzing differences between Ms4a genes across mammalian species, the researchers found that the evolution of these genes preceded the advent of the mammalian receptors for taste and for pheromones. “The fact that the MS4As have been preserved for at least 400 million years suggests that these receptors play a crucial role in enabling animals to interact with the olfactory environment,” Datta says.

In humans, MS4A receptors have previously been found in the intestines, lung cells, and even sperm cells. Based on the pattern of expression of MS4A receptors in different tissues, and the type of odors they detect, Datta suspects that MS4A molecules represent an ancient mechanism for sensing ethologically salient small molecules in the environment. “It is possible that this is the main function of the MS4As across species, and that the olfactory function of the MS4As is actually more recently evolved,” Datta says.

For now, it is not clear whether MS4As in humans serve as odor receptors. In future studies, Datta and his team will examine whether MS4A proteins act as a primordial odor receptor across species. “This would be incredibly interesting, as it would suggest that many animals have a kind of hidden nose we were unaware of buried within their main olfactory system,” Datta says.

Because the MS4A proteins are expressed on many cells in the body, the researchers will also test whether they detect cues that are generated by the body itself. “If so, this would suggest that one reason that the Ms4As are so widespread across evolution is that they are generally well suited to the detection of small molecules in the environment, regardless of whether that environment is the external or the internal world,” Datta says.  Science Daily Original web page at Science Daily


Mouse models of Zika in pregnancy show how fetuses become infected

Two mouse models of Zika virus infection in pregnancy have been developed by a team of researchers at Washington University School of Medicine in St. Louis. In them, the virus migrated from the pregnant mouse’s bloodstream into the placenta, where it multiplied, then spread into the fetal circulation and infected the brains of the developing pups.

The models provide a basis to develop vaccines and treatments, and to study the biology of Zika virus infection in pregnancy. The research is published May 11 in Cell.

“This is the first demonstration in an animal model of in utero transmission of Zika virus, and it shows some of the same outcomes we’ve been seeing in women and infants,” said co-senior author Michael Diamond, MD, PhD, a professor of medicine, molecular microbiology and pathology and immunology. “This could be used in vaccine trials, to find out whether vaccinating the mother can protect against uterine infection. You also could test therapeutics, once the mother got infected, to see if they could arrest the transmission to the fetus or prevent damage to the fetus.”

Since mice with normal immune systems are able to fight off Zika infection, Diamond and colleagues weakened the mice’s immune systems before infecting them with the virus.

In one model, the researchers genetically modified mice to lack a molecule called interferon alpha receptor that plays a key role in the immune response to viral infections. In the other model, they injected mice with antibodies against the molecule.

The scientists infected pregnant mice with Zika virus about a week after conception and examined their placentas and fetuses six to nine days later. Both mouse models reflected some of the key aspects of human Zika infection. In the mice, as in humans, the virus crossed from the mother’s bloodstream into the fetus’s and infected the developing brain, where damage to neurons was observed.

Microcephaly — which is marked by abnormally small heads, the most striking result of human infection — was not observed in either model. This may be due to differences in how mouse and human brains develop.

“Unlike in humans, a significant amount of neurodevelopment in mice actually occurs after birth, especially in the cerebral cortex, which is the part of the brain damaged in microcephaly,” Diamond said.

Indira Mysorekar, PhD, co-senior author of the study and postdoctoral fellow Bin Cao, PhD, co-first author, found the virus in the placenta at 1,000 times the concentration in the maternal blood, suggesting that it had not just migrated to the placenta, but multiplied there.

In the genetically-modified mice, Zika infection caused the death of most of the fetuses, and the remaining fetuses were much smaller than normal. The placentas showed damage: They were shrunken, with a reduced number of blood vessels. Such placentas would be unable to supply enough oxygen and nutrients to a developing fetus, a condition known as placental insufficiency, which causes abnormally slow fetal growth and, in severe cases, fetal death.

Placental insufficiency, abnormally small fetuses and miscarriages have been reported in pregnant women infected with Zika virus, as well.

In both models, the virus also was detected in the fetal brain. The researchers observed cell death in the brains of infected fetuses, but there were no obvious abnormalities in the overall structure of the brain.

In the model in which mice were injected with antibodies, the effect of Zika infection was less severe. The fetuses survived, although some were smaller than normal. Diamond and colleagues plan to use this model to study whether prenatal Zika virus infection causes long-term neurological problems in pups born without obvious brain damage.

Not all babies born to women infected with Zika during pregnancy develop microcephaly; some seem healthy at birth. But it is unknown whether such babies will face developmental or intellectual challenges as they grow up.

Diamond and Mysorekar, an associate professor of obstetrics and gynecology, and of pathology and immunology, also want to identify the molecules the virus latches onto to get into and through the placenta, so they can block them. Zika’s greatest health threat is to developing fetuses; if that threat can be eliminated, the public health emergency would be significantly lessened.

“For years, we’ve been studying transplacental infections and what prevents them,” Mysorekar said. “It’s gratifying to be able to apply all that expertise to something that’s suddenly become very important around the world.”  Science Daily Original web page at Science Daily


Early life stress accelerates maturation of key brain region in male mice

Intuition is all one needs to understand that stress in early childhood can create lifelong psychological troubles, but scientists have only begun to explain how those emerge in the brain. They have observed, for example, that stress incurred early in life attenuates neural growth. Now a study in male mice exposed to stress shows that a particular region, the hippocampus, hits many developmental milestones early — essentially maturing faster in response to stress.

The findings, the first to track and report signs of stress-related early maturation in a brain region throughout mouse development, may lend some neuroscientific credence to the expression that children facing early adversity have to “grow up too fast.”

Lead author Kevin Bath, assistant professor of cognitive, linguistic and psychological sciences at Brown University, said he became curious about whether some brain regions were maturing faster because he and other researchers had made observations in humans and rodents all suggesting that certain traits — such as fear-driven learning and memory, sexual development and neural connectivity among some brain regions — were accelerated, rather than stunted, after early life stress (ELS). Some of these qualities, particularly memory and emotion regulation, involve the hippocampus.

“There were a number of different indicators that [early maturation] might be happening,” Bath said. “We wanted to carefully assess this and look at a number of different markers of not only growth, but also maturation of these animals, and to measure it not only at the behavioral level but also at the neuromolecular level.”

The study, co-authored by Brown graduate students Gabriela Manzano-Nieves and Haley Goodwill, appears online in the journal Hormones and Behavior.

The experimental stress introduced to the mice in the study was a period of fragmented maternal care — a condition comparable to one that might affect a child growing up in an economically challenged, single-parent household, for example.

At four days of age, pups and their mothers were moved from standard cages to ones where the materials available to the mother for nest building were inadequate. Food and water remained plentiful, but the mother responded anxiously and would frequently depart to search for anything that might work as nesting material. Pups therefore received less consistent and attentive care from their harried and distracted mothers than experimental controls who were never moved from standard cages. After just a week of exposure to this manipulation (a significant span of time for mice who mature from birth to adulthood in just eight weeks), the mice returned to cages with everything they needed.

By then, however, the effects of the ELS were underway. Bath and his co-authors made several measurements in mice aged four to 50 days (when mice reach young adulthood) to track how development in the hippocampus varied between mice with ELS and the unstressed controls.

What they found — from counting specific populations of cells, to measuring behavior, to gene expression — was that the hippocampus appeared to mature significantly faster in the ELS mice during their seven weeks from birth to early adulthood.

Based upon measures of gene expression and counting cells, the team saw that parvalbumin interneurons developed about a week early, attaining an abundance by day 21 in ELS mice that was not seen in control mice until day 28. In other measurements, the teams saw that developmental changes in synaptic receptor subunits that are important for developmental changes in learning occurred about nine days ahead of schedule. They also found that myelination, a key developmental process for neural communication, also started more than a week early.

They also looked at a behavioral trait controlled by the hippocampus. Mice can be conditioned to associate shocks with a particular location, such that they will freeze in fear when they come back to that place. But for about a week during the maturation of the hippocampus, that freezing behavior temporarily disappears, Bath has found. In the new study, he saw that this was still the case, but the temporary suspension of the fear response happened a week earlier in ELS mice than in control mice.

Also, in their study, the team confirmed the findings of previous researchers showing overall reduced neural growth.

The results showing reduced growth but faster hippocampus maturation appear to support an evolution-based hypothesis that mice — and perhaps people, too — interpret ELS as a cue to adapt brain development to match a world where long-term survival seems unlikely, Bath said.

“In the case of development, the stress may be providing a signal about the hospitability of the environment,” Bath said.

Rather than invest for the long run in optimally refined systems in the cortex for learning rules and suppressing emotional responses, mice may instead invest in accelerating the maturation of more primal systems, such as the hippocampus, to support short-term priorities. The priority, Bath speculates, becomes racing to survive long enough to reproduce at least once.

“The evolutionary push is for you to pass on your genes,” Bath said. “We hypothesize that stress drives a reallocation of developmental resources from development of the full brain to development of limbic structures that are important for reproduction.”

To know for sure — and to get hints about how mental health practitioners can help people who have experienced early life stress — much more work is needed, Bath said. He’s pursuing several lines of research including studying female mice, given observations that females are twice as prone as males to develop problems in response to stress, and that human girls who have experienced early life stress undergo menarche earlier. He’s also tracking the behavioral implications of accelerated maturational traits (e.g. the early abundance of parvalbumin interneurons), measuring whether maturation is accelerated or delayed in other areas in the brain, and looking at the genetic mechanisms underlying the accelerated maturation to understand why some humans are resilient to ELS exposure.  Science Daily  Original web page at Science Daily


Researchers one step closer to understanding regeneration in mammals

A long-standing question in biology is why humans have poor regenerative ability compared to other vertebrates? While tissue injury normally causes us to produce scar tissue, why can’t we regenerate an entire digit or piece of skin? A group of University of Kentucky researchers is one step closer to answering these questions after studying a unique mammal, and its ears.

The team’s new findings come on the heels of UK Assistant Professor of Biology Ashley Seifert’s landmark discovery in 2012 that two species of African spiny mice found in Kenya could regenerate damaged skin. The group built on this work to show that a third species of spiny mouse, Acomys cahirinus, could completely close four millimeter ear holes and regenerate the missing tissue. Their recent work examined repair of ear holes across a number of different mammals and revealed that regeneration appears to be a unique trait.

While three species of wild African spiny mice and New Zealand white rabbits were capable of regenerating ear tissue, outbred laboratory mice and inbred strains such as the MRL healer mice failed to do so and instead healed the wounds by scarring.

“First we need to understand how mammalian regeneration works in a natural setting, then comes the potential to create therapeutic treatments for humans,” said Thomas Gawriluk, postdoctoral scholar and co-lead author of the study.

This new study suggests that genetic factors underlie variation in regenerative ability. Unlike many previous assumptions that there is a magic bullet for regeneration, like the presence of a specific gene, the group’s comprehensive genetic analysis shows that it is a complex trait. Importantly, cellular and molecular analysis by Seifert’s group has now demonstrated that spiny mice regenerate ear tissue by forming a blastema. Methodical demonstration of a blastema was important to place spiny mice in the context of regeneration in other vertebrates.

“These findings show that tissue regeneration in African spiny mice is similar to that described for other vertebrate regenerators like salamanders and zebrafish, giving us a powerful framework to understand mammalian regeneration,” said Seifert.

Rigorous examination of this mammalian model is the first stage in figuring out molecular mechanisms that govern regenerative processes, which could have a significant impact on regenerative medicine for humans. Many regeneration biologists believe that inducing a blastema in humans would be a major step towards stimulating tissue regeneration.

“The regenerative healing response of the spiny mouse is truly remarkable and Dr. Seifert’s new work provides clear evidence that regenerative capabilities have evolved among rodents,” said Ken Muneoka, professor at Texas A&M University and a pioneer in the field of regeneration. “The spiny mouse represents one of only a handful of regeneration models in mammals that can be used to uncover basic strategies to enhance the regenerative capacity of humans.”  Science Daily

://  Original web page at Science Daily


* Cells carry ‘memory’ of injury, which could reveal why chronic pain persists

A new study from King’s College London offers clues as to why chronic pain can persist, even when the injury that caused it has gone. Although still in its infancy, this research could explain how small and seemingly innocuous injuries leave molecular ‘footprints’ which add up to more lasting damage, and ultimately chronic pain.

All of us are likely to know someone who suffers from persistent pain — it is a very common condition, which can be caused by sports injuries, various diseases and the process of ageing. Treatment options are limited and doctors are often unable to offer anything more than partial relief with painkillers, leaving their patients resigned to suffering.

While chronic pain can have many different causes, the outcome is often the same: an overly sensitive nervous system which responds much more than it normally would. However, a question still remains as to why the nervous system should remain in this sensitive state over long periods of time, especially in instances where the underlying injury or disease has gone.

Researchers from King’s sought to answer this question by examining immune cells in the nervous system of mice, which are known to be important for the generation of persistent pain.

In the study, published today in Cell Reports, they found that nerve damage changes epigenetic marks on some of the genes in these immune cells. Epigenetics is the process that determines which gene is expressed and where. Some epigenetic signals have direct functional consequences, while others are just primers: flags that indicate a potential to act or be modified.

The cells examined in this King’s study still behaved as normal, but the existence of these novel epigenetic marks may mean that they carry a ‘memory’ of the initial injury.

Dr Franziska Denk, first author of the study, from the Wolfson Centre for Age Related Diseases at the Institute of Psychiatry, Psychology & Neuroscience (IoPPN), King’s College London, said: ‘We are ultimately trying to reveal why pain can turn into a chronic condition. We already knew that chronic pain patients have nerves that are more active, and we think this is probably due to various proteins and channels in those nerves having different properties.

However, it is unclear why these nerves should remain in this overactive, highly sensitive state, even when the initial injury or disease has gone: the back pain from two years ago that never quite went away or the joints that are still painful despite your rheumatoid arthritis being in remission.’

Dr Denk added: ‘We want to know why these proteins and channels should maintain their altered function over such a long period of time. Cells have housekeeping systems by which the majority of their content are replaced and renewed every few weeks and months — so why do crucial proteins keep being replaced by malfunctioning versions of themselves? Our study is the very first step towards trying to answer this question by exploring the possibility that changes in chronic pain may persist because of epigenetics. We hope that future research in this area could help in the search for novel therapeutic targets.’

Professor Stephen McMahon from the IoPPN at King’s College London said: ‘This research raises many interesting questions: do neurons also acquire epigenetic footprints as a result of nerve injury? Do these molecular footprints affect the function of proteins? And are they ultimately the reason that chronic pain persists in patients over such long periods of time?

‘The last question is particularly hard to answer, because to study epigenetics we need access to pure cell populations. Obviously, many of these are only accessible in postmortem tissue. However, colleagues at King’s are already doing this in psychiatry, through studies such as the The PsychENCODE project, so it is possible.’

Dr Giovanna Lalli, Neuroscience & Mental Health Senior Portfolio Developer at the Wellcome Trust, which part-funded the study, said: ‘People develop chronic pain for a huge variety of reasons. We therefore need an equally diverse range of treatments to tackle the different root causes.

‘The clues from this study, suggesting epigenetic changes may be involved in pain persisting, will hopefully lead us to better understand the mechanisms underlying chronic pain.’  Science Daily  Original web page at Science Daily


Mice with genetic defect for human stuttering offer new insight into speech disorder

Mice that vocalize in a repetitive, halting pattern similar to human stuttering may provide insight into a condition that has perplexed scientists for centuries, according to a new study by researchers at Washington University School of Medicine in St. Louis and the National Institutes of Health.

The researchers created mice with a mutation in a gene associated with stuttering in humans, and found that they vocalized in an abnormal pattern reminiscent of human stuttering. The animal model of stuttering can help scientists understand the molecular and neurological basis of the disorder, and potentially develop treatments. The research is published online April 14, 2016 in Current Biology.

Once thought to be caused by nervousness, stress or even bad parenting, stuttering is now recognized as primarily biological in origin, although anxiety can exacerbate the condition.

Some people who stutter have a mutation in a gene called Gnptab (for N-acetylglucosamine-1-phosphate transferase alpha and beta). With Dennis Drayna, PhD, and colleagues at the National Institute on Deafness and Other Communication Disorders, the researchers created mice with a corresponding mutation in the same gene and studied their vocalizations for evidence of abnormalities similar to human stuttering.

“Speech is obviously a unique human capacity, but the patterns of speech are built out of a lot of building blocks that are much simpler,” said Tim Holy, PhD, an associate professor of neurosciences and the paper’s senior author. “You have to be able to control the timing of your breath and the fine muscles in your tongue and mouth. You have to be able to initiate movement. Those kinds of things may be shared all the way from mice to people.”

Mice make complex sounds all the time, at pitches too high for the human ear to detect.

“Pups spontaneously vocalize when they are taken from their mom,” said first author Terra Barnes, PhD, a senior scientist in Holy’s lab. “Mice vocalize when they’re in pain, when they meet another mouse or to attract a mate.”

A key characteristic of stuttering is the presence of hesitations that break up the smooth flow of speech. Barnes and colleagues developed an algorithm to analyze the length of pauses in the spontaneous vocalizations of 3- to 8-day-old mouse pups. They found that mice carrying the mutation exhibited longer pauses than those without the mutation.

The researchers applied the same algorithm to recordings of people talking, some of whom stuttered and some did not. The algorithm accurately distinguished people who speak fluently from people who stutter.

The scientists also found that the syllables vocalized by mice with the mutation were less random than those of mice without the mutation. In other words, similar to people who stutter, the mice with the mutation repeated the same syllables more often.

“We found abnormalities that mimic some features of human stuttering,” said Barnes.

Other than in their vocalizations, the mice with the mutation were normal. Co-author David Wozniak, PhD, professor of psychiatry at Washington University, and colleagues put the mice through a battery of tests — to check their balance, strength, coordination, movement initiation, spatial learning, memory, sociability and more — and found no substantial differences between mice with and without the mutation. In this respect, the mice with the mutation are like people who stutter — indistinguishable from nonstutterers in all but speech.

“One of the things we find scientifically interesting about stuttering is that it is so precisely limited to speech,” said Holy. “It’s a very clean defect in an incredibly complex task.”

It is not clear how the gene relates to speech. It is known to be involved in the pathway that degrades molecules inside the cell. Mutations that cause total loss of function result in serious metabolic diseases called mucolipidosis II/III, but the mutations associated with stuttering appear to preserve much of the known function of these genes.

“It’s kind of crazy that this gene that’s involved in digesting the garbage in your cells is somehow linked to something so specific as stuttering,” said Holy. “It could be that the protein has many functions and this mutation affects only one of them. Or the mutation could very mildly compromise the function of the protein, but there’s a set of cells in the brain that is exquisitely sensitive, and if you ever so slightly compromise the function in those cells you get the observable behavioral deficit.”

Now that researchers have a mouse model of stuttering, they are developing ideas to explore the disorder further. “We’re coming up with lots of studies we can do to figure this out,” said Barnes.  Science Daily  Original web page at Science Daily


Researchers show ‘dirty mice’ could clean up immune system research

Scientists at the University of Minnesota have developed a new way to study mice that better mimics the immune system of adult humans and which could significantly improve ways to test potential therapeutics. Published online in the journal Nature, the researchers describe the limitations of laboratory mice for immunology research and reveal the benefits of what they are calling “dirty mice.”

“Standard lab mice don’t reflect important features of the adult human immune system. We wanted to know whether this is because lab animals are shielded from microbes that normal mice encounter in the wild,” said Stephen Jameson, Ph.D., co-senior author, professor in the Department of Laboratory Medicine and Pathology and member of the Center for Immunology, University of Minnesota. “Lab mice remain critical for basic immunology research, but it was important to find a better way to model the complex immune system of adult humans.”

To do so, the group caught mice in barns or purchased them at pet stores and carefully compared their immune system to that of humans. The free-living, or dirty, mice better mirrored immune cell types and tissue distribution found in adult humans. In contrast, the immune system in lab mice which are sheltered from natural microbial exposure were more strongly matched with newborn humans.

When genetically homogenous lab mice were co-housed with dirty mice this restored more normal microbial experience and allowed the immune system of the lab mice to adapt and better recapitulate the adult human immune system.

“This model could provide an important addition to basic research into immunology and the many biological processes and diseases that are impacted by inflammation,” said David Masopust, Ph.D., co-senior author, associate professor in the Department of Microbiology and Immunology and member of the Center for Immunology, University of Minnesota. “Utilizing this model to test vaccinations and therapeutics for cancer or transplantation may better predict how these will perform in humans.”

The use of standard lab mice has led to numerous breakthroughs in biomedical research, including studies that led to recent advances in cancer immunotherapy. However, this study shows the immune system in lab mice may not be fully normalized without a more complete microbial exposure. Hence these so-called dirty mice offer a substantial advance over current models, providing increased translational potential for human disease and better therapeutic models without sacrificing established and powerful research tools.  Science Daily  Original web page at Science Daily


* Stem cell therapy reverses age-related osteoporosis in mice

Imagine telling a patient suffering from age-related (type-II) osteoporosis that a single injection of stem cells could restore their normal bone structure. This week, with a publication in STEM CELLS Translational Medicine, a group of researchers from the University of Toronto and The Ottawa Hospital suggest that this scenario may not be too far away.

Osteoporosis affects over 200M people worldwide and, unlike post-menopausal (type-I) osteoporosis, both women and men are equally susceptible to developing the age-related (type-II) form of this chronic disease. With age-related osteoporosis, the inner structure of the bone diminishes, leaving the bone thinner, less dense, and losing its function. The disease is responsible for an estimated 8.9 M fractures per year worldwide. Fractures of the hip–one of the most common breaks for those suffering from type-II osteoporosis–lead to a significant lack of mobility and, for some, can be deadly.

But how can an injection of stem cells reverse the ravages of age in the bones? Professor William Stanford, senior author of the study, had in previous research demonstrated a causal effect between mice that developed age-related osteoporosis and low or defective mesenchymal stem cells (MSCs) in these animals.

“We reasoned that if defective MSCs are responsible for osteoporosis, transplantation of healthy MSCs should be able to prevent or treat osteoporosis,” said Stanford, who is a Senior Scientist at The Ottawa Hospital and Professor at the University of Ottawa.

To test that theory, the researchers injected osteoporotic mice with MSCs from healthy mice. Stem cells are “progenitor” cells, capable of dividing and changing into all the different cell types in the body. Able to become bone cells, MSCs have a second unique feature, ideal for the development of human therapies: these stem cells can be transplanted from one person to another without the need for matching (needed for blood transfusions, for instance) and without being rejected.

After six months post-injection, a quarter of the life span of these animals, the osteoporotic bone had astonishingly given way to healthy, functional bone.

“We had hoped for a general increase in bone health,” said John E. Davies, Professor at the Faculty of Dentistry and the Institute of Biomaterials & Biomedical Engineering (IBBME) at the University of Toronto, and a co-author of the study. “But the huge surprise was to find that the exquisite inner “coral-like” architecture of the bone structure of the injected animals–which is severely compromised in osteoporosis–was restored to normal.”

The study could soon give rise to a whole new paradigm for treating or even indefinitely postponing the onset of osteoporosis. Currently there is only one commercially available therapy for type-II osteoporosis, a drug that maintains its effectiveness for just two years.

And, while there are no human stem cell trials looking at a systemic treatment for osteoporosis, the long-range results of the study point to the possibility that as little as one dose of stem cells might offer long-term relief.

“It’s very exciting,” said Dr. Jeff Kiernan, first author of the study. A graduate from IBBME who is beginning a Postdoctoral Fellowship at The Ottawa Hospital with the Centre for Transfusion Research, Kiernan pursued the research for his doctoral degree.

“We’re currently conducting ancillary trials with a research group in the U.S., where elderly patients have been injected with MSCs to study various outcomes. We’ll be able to look at those blood samples for biological markers of bone growth and bone reabsorption,” he added.

If improvements to bone health are observed in these ancillary trials, according to Stanford, larger dedicated trials could follow within the next 5 years.  Science Daily  Original web page at Science Daily


Vitamin stops the aging process of organs

Nicotinamide riboside (NR) is pretty amazing. It has already been shown in several studies to be effective in boosting metabolism. And now a team of researchers at EPFL’s Laboratory of Integrated Systems Physiology (LISP), headed by Johan Auwerx, has unveiled even more of its secrets. An article written by Hongbo Zhang, a PhD student on the team, was published today in Science and describes the positive effects of NR on the functioning of stem cells. These effects can only be described as restorative.

As mice, like all mammals, age, the regenerative capacity of certain organs (such as the liver and kidneys) and muscles (including the heart) diminishes. Their ability to repair them following an injury is also affected. This leads to many of the disorders typical of aging.

Hongbo Zhang wanted to understand how the regeneration process deteriorated with age. To do so, he teamed up with colleagues from ETH Zurich, the University of Zurich and universities in Canada and Brazil. Through the use of several markers, he was able to identify the molecular chain that regulates how mitochondria — the “powerhouse” of the cell — function and how they change with age. The role that mitochondria play in metabolism has already been amply demonstrated, “but we were able to show for the first time that their ability to function properly was important for stem cells,” said Auwerx.

Under normal conditions, these stem cells, reacting to signals sent by the body, regenerate damaged organs by producing new specific cells. At least in young bodies. “We demonstrated that fatigue in stem cells was one of the main causes of poor regeneration or even degeneration in certain tissues or organs,” said Hongbo Zhang.

This is why the researchers wanted to “revitalize” stem cells in the muscles of elderly mice. And they did so by precisely targeting the molecules that help the mitochondria to function properly. “We gave nicotinamide riboside to 2-year-old mice, which is an advanced age for them,” said the researcher. “This substance, which is close to vitamin B3, is a precursor of NAD+, a molecule that plays a key role in mitochondrial activity. And our results are extremely promising: muscular regeneration is much better in mice that received NR, and they lived longer than the mice that didn’t get it.”

Parallel studies have revealed a comparable effect on stem cells of the brain and skin. “This work could have very important implications in the field of regenerative medicine,” said Auwerx. “We are not talking about introducing foreign substances into the body but rather restoring the body’s ability to repair itself with a product that can be taken with food.” This work on the aging process also has potential for treating diseases that can affect — and be fatal — in young people, like muscular dystrophy (myopathy).

So far, no negative side effects have been observed following the use of NR, even at high doses. But caution remains the byword when it comes to this elixir of youth: it appears to boost the functioning of all cells, which could include pathological ones. Further in-depth studies are required. Science Daily  Original web page at Science Daily


* New hope for spinal cord injuries

Stem cells have been used successfully, for the first time, to promote regeneration after injury to a specialized band of nerve fibres that are important for motor function.

Researchers from Hokkaido University in Japan together with an international team of scientists implanted specialized embryonic stem cells into the severed spinal cords of rats. The stem cells, called neural progenitor cells, were taken from rat embryos and directed to develop as spinal cord tissue. The implants, or “grafts,” promoted extensive regeneration of the severed nerve fibres, with the rats showing improvement in their ability to move their forelimbs. The team also used grafts of human neural stem cells in injured rats with similar results, demonstrating the potential of the success of this method across species.

The corticospinal tract (CST) is a band of nerve fibres that travels from the brain, through the brain stem and into the spinal cord. This structure is very important for motor function in humans. Injuries to the CST can result in paralysis. Much research has been done, with some progress, on using stem cells to regenerate other bands of nerve fibres in the spinal cord. But these have involved small gaps between the severed nerves in the presence of bands of bridging tissue. Lesions to nerve fibres located in the CST, however, and those involving large gaps and no bands of bridging tissue have proven largely resistant to regeneration.

The success of this current trial, reported in Nature Medicine, is promising for the future treatment of humans with severe spinal cord injuries. But much work remains to be done before it can be translated into clinical treatments. Further research is required to determine the best cell type to be used for grafting and for establishing safe grafting methods.  Science Daily  Original web page at Science Daily


Towards a new theory of sleep

Why do animals sleep? Even though slumber consumes about a third of the day for many life forms, we know very little about why it’s needed. The need for sleep remains one of the great mysteries of biology.

A leading theory posits that sleep may provide the brain with an opportunity to “rebalance” itself. In this model, waking experiences are associated with powerful processes of learning and development that, over time, result in the saturation of our brains’ ability to strengthen connections. Not only would this prevent further learning, but this unbounded increase in connectivity would destabilize the brain, leading to “overexcitation” of neural networks. A leading theory suggests that the core function of sleep is “neuronal homeostasis,” the processes whereby neurons self-tune their excitability to restore balanced activity to brain circuits.

Brand new research conducted in the lab of Brandeis neurobiologist Gina Turrigiano suggests this theory isn’t true. In a paper published in the March 24th issue of the journal Cell, the Turrigiano lab showed that when the activity of neurons is suppressed in rats, homeostatic rebalancing doesn’t occur during sleep; instead, it happened exclusively when animals were awake and active.

This research poses as many questions as it answers. For example, why is homeostasis inhibited during sleep? Turrigiano suggests that homeostatic plasticity may interfere with a sleep-dependent process that strengthens memories. Using behavioral states such as sleep and wake to temporally segregate distinct forms of plasticity may alleviate this interference problem.

Gina Turrigiano is the Joseph J. Levitan Chair in Visual Sciences at Brandeis, and was elected to the National Academy of Sciences in 2013. In 2000, at the age of 37, she won a MacArthur Fellowship, or ‘genius’ award. Her groundbreaking work has focused on the cellular processes that allow neuronal circuits in the brain to change and adapt. Her lab has played a major role in identifying the key mechanisms underlying homeostatic plasticity, or a neuron’s ability to dynamically seek stability despite changes induced by learning or development.

This latest research in Cell, led by postdoctoral fellow Keith Hengen, broke new ground as it explored neuronal homeostasis in the context of freely behaving rats (most research in the past has relied upon cell cultures or anesthetized animals). In this work, rats with occlusion of vision from one eye were observed over nine days during sleep and wake periods. Electrodes inserted in the animals’ visual cortex recorded the firings of many individual neurons; these neurons were then followed for nine days, producing a total of six terabytes of data. Algorithms developed in Turrigiano’s lab with the help of Brandeis assistant professor Steven Van Hooser enabled the analysis of these enormous and complex datasets.

Turrigiano expects these computational methods to open new avenues of research for her lab, enabling far longer observation of rats’ brains and with greater precision.  Science Daily  Original web page at Science Daily


* New microscope controls brain activity of live animals

For the first time, researchers have developed a microscope capable of observing — and manipulating — neural activity in the brains of live animals at the scale of a single cell with millisecond precision. By allowing scientists to directly control the firing of individual neurons within complex brain circuits, the device could ultimately revolutionize how neuroscience is done and lead to new insights about healthy brain functioning and neurological disorders.

“With this new microscope, we believe we will soon be able to treat the brain as the keyboard of a piano, so to speak, and write in a sequence of activity that is needed to understand or correct brain function,” said Hillel Adesnik, Ph.D., assistant professor of neurobiology at the University of California, Berkeley, who led the research team. “After more refinements, this instrument may be able to function as a sort of Rosetta Stone to help us crack the neural code.”

Adesnik will present this research at the American Association of Anatomists Annual Meeting during Experimental Biology 2016.

To process inputs, store information and issue commands, the brain’s neurons communicate with each other through on-off electrical signals akin to the ones and zeroes used to encode information in computer programming. Although scientists have long been able to observe these signals with various imaging techniques, without understanding the “syntax” of how that digital code translates into information, the brain’s communication system has been essentially indecipherable.

“If you want to learn a language, you need a dictionary, and if you want to understand how a machine works, you need to know its parts,” said Adesnik. “We wanted to develop a technology that can offer a general approach to understand the basic syntax of neural signals, so that we can begin to understand what a given brain circuit is doing and perhaps what’s gone wrong with that in the case of a disease.”

The best way to learn that syntax, Adesnik said, is to not simply read the information, but to actually write it by making small tweaks in the code, inputting the new code back into the brain and seeing how it alters a perception or behavior. The new microscope, which Adesnik’s team developed by combining and building upon several existing technologies developed by other researchers, is the first to be able to handle and transmit information at a spatial and temporal scale that is truly relevant to manipulating brain activity.

“The brain is an enormous collection of single cells, and cells right next to each other could be doing entirely different things,” Adesnik said. “The resolution of our technique is key, because if you aren’t looking at a single cell you could be scrambling your code, so to speak, and you won’t be able to correctly interpret it. By overcoming the last technological hurdles to get to that single cell resolution, and at the same time getting to the temporal scale that cells operate at, we have developed a prototype microscope that achieves the level of detail needed to actually understand the neural code.”

The tool they have devised is essentially a microscope that points into the brain of a live mouse, zooms in on a few thousand cells and uses sophisticated lasers to manipulate electrical signals between individual neurons.

Since the lasers can penetrate brain tissue but not skull, the research team implanted small glass windows into the skulls of the mice used to test the instrument. When positioned atop the window, the microscope uses two different types of high-powered infrared lasers to create a 3-dimensional holographic pattern in a specific area of interest within the brain. Because the research is done in mice genetically modified to have neurons that respond to light — a technique called optogenetics — the hologram induces the neurons to send electrical signals in a specific pattern that is pre-determined by the researchers.

“We’re adapting holographic display technology, optogenetics and sensory biology and behavior into one complete system that allows an all-optical approach to image and manipulate the nervous system,” said Adesnik. “We’ve essentially put a lot of disparate existing pieces together to achieve something nobody had yet achieved.”

So far, the team has conducted preliminary tests of the instrument by mapping the effects of small perturbations, such as wiggling a whisker, and then creating holograms that induce the neurons to fire in the same — or slightly different — patterns. In a series of tests that are still underway, they are working with mice trained to push a specific lever when they see a certain shape in order to develop holograms that “trick” the mouse into seeing, for example, a circle where none exists, or to make the mouse perceive a square as a circle. In the near future, the team hopes to apply the microscope to studies of memory formation.

Once it is further tested and refined, the most immediate applications for the microscope are likely to be in basic research, but Adesnik said it is conceivable that its core technology could one day be adapted for therapeutic use, for example, to correct neurological problems in a high-tech form of brain surgery. Such an application is still a long way off, however, and applying the device in human beings would require overcoming a whole new set of technological challenges.  Science Daily  Original web page at Science Daily


Genetic elements that drive regeneration uncovered

If you trace our evolutionary tree way back to its roots — long before the shedding of gills or the development of opposable thumbs — you will likely find a common ancestor with the amazing ability to regenerate lost body parts.

Lucky descendants of this creature, including today’s salamanders or zebrafish, can still perform the feat, but humans lost much of their regenerative power over millions of years of evolution.

In an effort to understand what was lost, researchers have built a running list of the genes that enable regenerating animals to grow back a severed tail or repair damaged tissues. Surprisingly, they have found that genes important for regeneration in these creatures also have counterparts in humans. The key difference might not lie in the genes themselves but in the sequences that regulate how those genes are activated during injury.

A Duke study appearing April 6 in the journal Nature has discovered the presence of these regulatory sequences in zebrafish, a favored model of regeneration research. Called “tissue regeneration enhancer elements” or TREEs, these sequences can turn on genes in injury sites and even be engineered to change the ability of animals to regenerate.

“We want to know how regeneration happens, with the ultimate goal of helping humans realize their full regenerative potential,” said Kenneth D. Poss, Ph.D., senior author of the study and professor of cell biology at Duke University School of Medicine. “Our study points to a way that we could potentially awaken the genes responsible for regeneration that we all carry within us.”

Over the last decade, researchers have identified dozens of regeneration genes in organisms like zebrafish, flies, and mice. For example, one molecule called neuregulin 1 can make heart muscle cells proliferate and others called fibroblast growth factors can promote the regeneration of a severed fin. Yet, Poss says, what has not been explored are the regulatory elements that turn these genes on in injured tissue, keep them on during regeneration, and then turn them off when regeneration is done.

In this study, Poss and his colleagues wanted to determine whether or not these important stretches of DNA exist, and if so, pinpoint their location. It was already well known that small chunks of sequence, called enhancer elements, control when genes are turned on in a developing embryo. But it wasn’t clear whether these elements are also used to drive regeneration.

First, lead study author Junsu Kang, Ph.D., a postdoctoral fellow in the Poss lab, looked for genes that were strongly induced during fin and heart regeneration in the zebrafish. He found that a gene called leptin b was turned on in fish with amputated fins or injured hearts. Kang scoured the 150,000 base pairs of sequence surrounding leptin b and identified an enhancer element roughly 7,000 base pairs away from the gene.

He then whittled the enhancer down to the shortest required DNA sequence. In the process, Kang discovered that the element could be separated into two distinct parts: one that activates genes in an injured heart, and, next to it, another that activates genes in an injured fin. He fused these sequences to two regeneration genes, fibroblast growth factor and neuregulin 1, to create transgenic zebrafish whose fins and hearts had superior regenerative responses after injury.

Finally, the researchers tested whether these “tissue regeneration enhancer elements” or TREEs could have a similar effect in mammalian systems like mice. Collaborator Brian L. Black, PhD, of the University of California, San Francisco attached one TREE to a gene called lacZ that produces a blue color wherever it is turned on. Remarkably, he found that borrowing these elements from the genome of zebrafish could activate gene expression in the injured paws and hearts of transgenic mice.

“We are just at the beginning of this work, but now we have an encouraging proof of concept that these elements possess all the sequences necessary to work with mammalian machinery after an injury,” said Poss. He suspects there may be many different types of TREEs: those that turn on genes in all tissues; those that turn on genes only in one tissue like the heart; and those that are active in the embryo as it develops and then are reactivated in the adult as it regenerates.

Eventually, Poss thinks that genetic elements like these could be combined with genome-editing technologies to improve the ability of mammals, even humans, to repair and regrow damaged or missing body parts.

“We want to find more of these types of elements so we can understand what turns on and ultimately controls the program of regeneration,” said Poss. “There may be strong elements that boost expression of the gene much higher than others, or elements that activate genes in a specific cell type that is injured. Having that level of specificity may one day enable us to change a poorly regenerative tissue to a better one with near-surgical precision.”  Science Daily  Original web page at Science Daily


New mouse model to aid testing of Zika vaccine, therapeutics

A research team at Washington University School of Medicine in St. Louis has established a mouse model for testing of vaccines and therapeutics to battle Zika virus.

The mouse model mimics aspects of the infection in humans, with high levels of the virus seen in the mouse brain and spinal cord, consistent with evidence showing that Zika causes neurological defects in human fetuses. Interestingly, the researchers detected the highest levels of the virus in the testes of male mice, a finding that supports clinical data indicating the virus can be sexually transmitted. The new research is published April 5 in Cell Host &Microbe.

“Now that we know the mice can be vulnerable to Zika infection, we can use the animals to test vaccines and therapeutics — and some of those studies are already underway — as well as to understand the pathogenesis of the virus,” said senior author Michael Diamond, MD, PhD, a professor of medicine at Washington University.

The new model of Zika virus infection, along with another recently identified by scientists at the University of Texas Medical Branch, are the first to be developed since 1976. The earlier models were not as clinically relevant because the infections were generated by injecting the virus directly into the brain. In the new models, infection occurs via the skin, much like the bite of the mosquito that spreads the virus.

The ongoing Zika virus outbreak in Latin America and the Caribbean has created an urgent need for identifying small animal models as a first step toward developing vaccines and treatments to fight the infection. The infection has been linked to microcephaly, a condition in which infants are born with unusually small heads and brain damage. In adults, the virus is thought to be related to rare cases of Guillian-Barré syndrome, an illness that can cause temporary paralysis.

For the new study, researchers in Diamond’s laboratory, led by first author Helen Lazear, PhD, now at the University of North Carolina at Chapel Hill, tested five strains of the Zika virus in the mice: the original strain acquired from Uganda in 1947; three strains that circulated in Senegal in the 1980s; and the French Polynesian strain, which caused infections in 2013 and is nearly identical to the strain causing the current outbreak. All yielded similar results in the animals, suggesting that there may not be much difference in the pathogenicity between individual strains, at least in this mouse model. Tests with the viral strains from the current Zika outbreak are ongoing.

Because Zika typically has trouble establishing infections in mice, the researchers used animals that were genetically altered so that they could not produce interferon, a key immune system signaling molecule, thus dampening the animals’ immune response to the virus.

“If you take away interferon, the Zika virus replicates quite well in the mouse and goes to the sites that we see it causing disease in humans,” said Diamond, an expert in viral immunology. He also is a professor of molecular microbiology and of pathology and immunology.

The immune-deficient mice lost weight, became lethargic and died within 10 days of infection. In contrast, normal laboratory mice included in the study only developed severe symptoms of Zika infection if they were infected soon after birth, under one week of age, before their immune systems were developed.

That finding parallels what is seen in humans. “It appears that pregnant women infected with Zika can pass the virus to babies in utero and that newborns also may be susceptible to infection,” said Diamond, also an associate director of the university’s Center for Human Immunology and Immunotherapy Programs. “Other than in infants, we don’t really see severe disease in most people with Zika, except for a small fraction who develop Guillian-Barré.”

He was inspired to pursue Zika research after a meeting at the National Institutes of Health (NIH) in June 2015, where Brazilian scientists described accounts of a rise in birth defects related to a local Zika outbreak. He returned to St. Louis and shifted several members of his lab to studying Zika, including developing mouse models of the disease.

As new clinical information becomes available about the virus in humans, Diamond has pivoted his research to investigate suspected links in mice.

“We looked for evidence of Zika in the mouse testes mostly as an afterthought, due to mounting evidence of sexual transmission and were surprised that viral levels were the highest we saw in any tissue,” Diamond noted. “We are now doing subsequent tests to determine how long those viral levels are sustained, which could help us estimate the length of time Zika can be transmitted sexually.”  Science Daily Original web page at Science Daily


A real Peter Rabbit tale: Biologists find key to myxoma virus/rabbit coevolution

A naturally-occurring mutation in a rabbit-specific virus — related to the smallpox virus — weakens the virus and may give insight to understanding pathogen evolution, according to a Kansas State University study.

“Our findings may help scientists predict which viruses can pose threats to humans,” said Stefan Rothenburg, assistant professor in the Division of Biology and principal investigator for the study. “It is a big step toward understanding the molecular basis of host-virus interaction.”

Rothenburg; microbiology doctoral students Chen Peng, China, and Sherry Haller, Topeka; and collaborators from the University of Florida, recently published a study in the Proceedings of the National Academy of Sciences of the United States of America about the function of an immune-regulating protein from myxoma virus, called M156. According to Rothenburg, M156 inhibits an antiviral protein from the host in a species-specific fashion. The researchers also characterized a loss-of-function mutation in M156 that makes the once severe virus weaker.

“We are still very ignorant when it comes to predicting which viruses pose threats to humans and animals,” Rothenburg said. “We don’t fully understand the molecular mechanisms. This is why it is important to study a very well established host-virus system like myxoma virus in the European rabbit as a model for human viruses and why understanding this mutation is important.”

Myxoma virus was intentionally released in Australia in the 1950s to control invasive rabbits. At that time, the mortality rate of virus infection was nearly 100 percent and the release led to a huge decrease in the European rabbit population. According to Rothenburg, within a few years, two things happened that stunned scientists at the time: Myxoma virus mutated to become weaker, or attenuated, and the rabbits evolved to become more resistant to the virus.

“These two phenomena together led to a rebound of the rabbit population,” Rothenburg said. “The scientists found that the naturally evolved weakening of the virus is actually beneficial for the virus because infected rabbits lived longer and were able to better transmit the virus.”

Rothenburg further said that on the population level, this is probably the best-known example for a host-virus coevolution in nature, but it lacked a molecular explanation until this study.

M156 normally inhibits a rabbit’s virus-defense factor called protein kinase R, or PKR. Peng and colleagues found that a single mutation causes the virus’s protein to fail at inhibiting the rabbit’s PKR and makes the virus weaker.

“The virus has an evolutionary advantage to maintain this mutation because it is found in more than 50 percent of the Australian virus isolates,” Peng said.

The researchers found that only rabbit PKR was inhibited by M156 but not PKR from other mammals, which may contribute to the reason why myxoma virus only causes disease in rabbits. According to Rothenburg, the interaction of the host and virus proteins is like a lock and a key where the lock is PKR and the virus inhibitor is the key. If either lock or key change, the virus cannot establish an active infection in the host, he said.

Rothenburg’s next step is to look at myxoma strains that were illegally released in Europe for the same purpose — to see if there are mutations in PKR inhibitors with similar effects. In addition, the Rothenburg lab is using the knowledge gained from the current study to modify myxoma virus with the goal to enhance the virus’s oncolytic activity and to expand the spectrum of cancer forms that can be destroyed by myxoma virus.

“Our findings are important because we can use the gained knowledge for examining pathogens that concern human health,” Rothenburg said. “Those include viruses such as influenza or Ebola viruses, which can jump from animals into the human population and also counteract their hosts’ immune system, including the inhibition of PKR. Investigating species-specific interactions might yield valuable information about which viruses pose future threats.”   Science Daily  Original web page at Science Daily


Blood-brain barrier breakthrough reported by researchers

Cornell researchers have discovered a way to penetrate the blood brain barrier (BBB) that may soon permit delivery of drugs directly into the brain to treat disorders such as Alzheimer’s disease and chemotherapy-resistant cancers.

The BBB is a layer of endothelial cells that selectively allow entry of molecules needed for brain function, such as amino acids, oxygen, glucose and water, while keeping others out.

Cornell researchers report that an FDA-approved drug called Lexiscan activates receptors — called adenosine receptors — that are expressed on these BBB cells.

“We can open the BBB for a brief window of time, long enough to deliver therapies to the brain, but not too long so as to harm the brain. We hope in the future, this will be used to treat many types of neurological disorders,” said Margaret Bynoe, associate professor in the Department of Microbiology and Immunology in Cornell’s College of Veterinary Medicine. Bynoe is senior author of the study, which appears in The Journal of Clinical Investigation.

Bynoe’s team was able to deliver chemotherapy drugs into the brains of mice, as well as large molecules, like an antibody that binds to Alzheimer’s disease plaques, according to the paper.

The lab also engineered a BBB model using human primary brain endothelial cells. They observed that Lexiscan opened the engineered BBB in a manner similar to its actions in mice.

Because Lexiscan is an FDA-approved drug,”the potential for a breakthrough in drug delivery systems for diseases such as Alzheimer’s disease, Parkinson’s disease, autism, brain tumors and chemotherapy-resistant cancers is not far off,” Bynoe said.  Science Daily  Original web page at Science Daily