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* Treating autoimmune disease without harming normal immunity

Preclinical study shows that engineered T cells can selectively target the antibody-producing cells that cause autoimmune disease.

In a study with potentially major implications for the future treatment of autoimmunity and related conditions, scientists from the Perelman School of Medicine at the University of Pennsylvania have found a way to remove the subset of antibody-making cells that cause an autoimmune disease, without harming the rest of the immune system. The autoimmune disease the team studied is called pemphigus vulgaris (PV), a condition in which a patient’s own immune cells attack a protein called desmoglein-3 (Dsg3) that normally adheres skin cells.

Current therapies for autoimmune disease, such as prednisone and rituximab, suppress large parts of the immune system, leaving patients vulnerable to potentially fatal opportunistic infections and cancers.

The Penn researchers demonstrated their new technique by successfully treating an otherwise fatal autoimmune disease in a mouse model, without apparent off-target effects, which could harm healthy tissue. The results are published in an online First Release paper in Science.

“This is a powerful strategy for targeting just autoimmune cells and sparing the good immune cells that protect us from infection,” said co-senior author Aimee S. Payne, MD, PhD, the Albert M. Kligman Associate Professor of Dermatology.

Payne and her co-senior author Michael C. Milone, MD, PhD, an assistant professor of Pathology and Laboratory Medicine, adapted the technique from the promising anti-cancer strategy by which T cells are engineered to destroy malignant cells in certain leukemias and lymphomas.

“Our study effectively opens up the application of this anti-cancer technology to the treatment of a much wider range of diseases, including autoimmunity and transplant rejection,” Milone said.

The key element in the new strategy is based on an artificial target-recognizing receptor, called a chimeric antigen receptor, or CAR, which can be engineered into patients’ T cells. In human trials, researchers remove some of patients’ T cells through a process similar to dialysis and then engineer them in a laboratory to add the gene for the CAR so that the new receptor is expressed in the T cells. The new cells are then multiplied in the lab before re-infusing them into the patient. The T cells use their CAR receptors to bind to molecules on target cells, and the act of binding triggers an internal signal that strongly activates the T cells — so that they swiftly destroy their targets.

The basic CAR T cell concept was first described in the late 1980s, principally as an anti-cancer strategy, but technical challenges delayed its translation into successful therapies. Since 2011, though, experimental CAR T cell treatments for B cell leukemias and lymphomas — cancers in which patients’ healthy B cells turn cancerous — have been successful in some patients for whom all standard therapies had failed.

B cells, which produce antibodies, can also cause autoimmunity. Payne researches autoimmunity, and a few years ago, a postdoctoral researcher in her laboratory, Christoph T. Ellebrecht, MD, took an interest in CAR T cell technology as a potential weapon against B cell-related autoimmune diseases. Soon Payne’s lab teamed up with Milone’s, which studies CAR T cell technology, in the hope of finding a powerful new way to treat these ailments.

“We thought we could adapt this technology that’s really good at killing all B cells in the body to target specifically the B cells that make antibodies that cause autoimmune disease,” said Milone.

“Targeting just the cells that cause autoimmunity has been the ultimate goal for therapy in this field,” noted Payne.

Ellebrecht was first author, the team took aim at pemphigus vulgaris. This condition occurs when a patient’s antibodies attack molecules that normally keep skin cells together. When left untreated, PV leads to extensive skin blistering and is almost always fatal, but in recent decades the condition has been treatable with broadly immunosuppressive drugs such as prednisone, mycophenolate mofetil, and rituximab.

To treat PV without causing broad immunosuppression, the Penn team designed an artificial CAR-type receptor that would direct patients’ T cells to attack only the B cells producing harmful anti-Dsg3 antibodies.

The team developed a “chimeric autoantibody receptor,” or CAAR, that displays fragments of the autoantigen Dsg3 — the same fragments to which PV-causing antibodies and their B cells typically bind, as Payne’s laboratory and others have shown in prior studies. The artificial receptor acts as a lure for the B cells that target Dsg3, bringing them into fatal contact with the therapeutic T cells.

Testing many variants, the team eventually found an artificial receptor design that worked well in cell culture, enabling host T cells to efficiently destroy cells producing antibodies to desmoglein, including those derived from PV patients. The engineered T cells also performed successfully in a mouse model of PV, killing desmoglein-specific B cells and preventing blistering and other manifestations of autoimmunity in the animals.

“We were able to show that the treatment killed all the Dsg3-specific B cells, a proof of concept that this approach works,” Payne said.

T cell therapies can be complicated by many factors. But in these experiments, the Penn scientists’ engineered cells maintained their potency despite the presence of anti-Dsg3 antibodies that might have swarmed their artificial receptors. In addition, there were no signs that the engineered T cells caused side effects by hitting the wrong cellular targets in the mice.

The team now plans to test their treatment in dogs, which can also develop PV and often die from the disease. “If we can use this technology to cure PV safely in dogs, it would be a breakthrough for veterinary medicine, and would hopefully pave the way for trials of this therapy in human pemphigus patients,” Payne said.

Also on the horizon for the Penn scientists are applications of CAAR T cell technology for other types of autoimmunity. The immune rejection that complicates organ transplants, and normally requires long-term immunosuppressive drug therapy, may also be treatable with CAAR T cell technology.

“If you can identify a specific marker of a B cell that you want to target, then in principle this strategy can work,” Payne said.

https://www.sciencedaily.com/  Science Daily

https://www.sciencedaily.com/releases/2016/06/160630144409.htm  Original web page at Science Daily

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Scientists identify mutation that causes muffs and beards to grow on chickens

The growth of long facial feathers, creating the appearance of muffs and beards on chickens, is caused by a chromosomal rearrangement affecting a gene involved in feather development, report Xiaoxiang Hu of the China Agricultural University in Beijing and colleagues, in a new study published on June 2 in PLOS Genetics.

Unusual plumage and fancy combs aren’t just interesting traits appreciated by poultry fanciers, but opportunities to explore the genetics underlying these striking variations. Scientists investigated the mutation that causes the Muffs and beard characteristic in certain chicken varieties by mapping the trait to the correct location on the chromosome and sequencing that region from chickens with and without Muffs and beard. They found that chickens with the Muffs and beard trait had three duplicated regions of chromosome 27, inserted next to one of the original gene regions. By examining changes in gene expression, they showed that one of the duplicated genes, HOXB8, which is known to function in feather development, was present at high levels in the facial skin of chickens with Muffs and beard, but not in regular chickens.

The scientists suspect that HOXB8 expression may extend the growth phase of the facial feathers, creating the characteristic bearded appearance. Other HOX gene members are linked to feather development, such as HOXC8, which is associated with a crest of feathers on top of the head. The findings present an excellent model for exploring the regulation of HOX genes in different parts of the body during development.

Dr. Guo says: “Muffs and beard in chicken is caused by a structural variation that consists of three duplicated regions on GGA27 and results in the ectopic expression of HOXB8 in facial skin. Our findings show the significance for structural variations on phenotypic diversity and a novel role for HOXB8 in feather formation. In future study, we’ll focus on the regulation of HOX genes in feather cycles.”

https://www.sciencedaily.com/ Science Daily

https://www.sciencedaily.com/releases/2016/06/160602151713.htm Original web page at Science

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Shifting bird distribution indicates a changing Arctic

Shifts in the distribution of Spectacled Eiders, a predatory bird at the top of the Bering Sea’s benthic food web, indicate possible changes in the Arctic’s marine ecosystem, according to new research in The Condor: Ornithological Applications.

Matt Sexson of the USGS Alaska Science Center and his colleagues compared recent satellite telemetry data from molting eiders with data from the mid-1990s. They found that in two of the species’ four primary molting areas, the birds have shifted their range significantly in the intervening decades, and the researchers interpret this as an indicator of ecosystem change–eiders go where their prey is, and their movements could indicate big changes in the community of bottom-dwelling, cold-water-dependent invertebrates they eat.

It’s easier to track marine predators than it is to track their prey, explains Sexson. “It’s tough to speculate on the connection with climate change because the data are so sparse, but we know that the north Pacific is changing,” he says. “There’s a lot of corresponding evidence that together all says something big is happening here, and eiders provide a readily available indicator that changes are occurring.”

Sexson and his colleagues spent months at a time in the remote Arctic to catch eiders on land during their breeding season, luring them into nets before making a two-hour trek back to base camp with each bird to surgically implant a satellite transmitter. “It’s a lot of hard work, but it’s a lot of fun,” Sexson says. “I used to just flip past the eiders in bird field guides, thinking I’d never see any of these. Now five years later I’m catching them and holding them. I’ve really developed a love for this group of birds–how unique they are, how beautiful they are. I’ve just become attached.”

According to the University of Maryland’s Jackie Grebmeier, an expert on Arctic marine ecosystems who was not involved with the new study, “The results of this research provide an important finding of biological response of an upper-trophic-level seabird to climate warming and sea ice retreat, another piece in the puzzle to address ecosystem change in the Pacific Arctic region.” As Arctic water warms, whole communities of animals are moving north–and there’s only so far they can go.

https://www.sciencedaily.com/  Science Daily

https://www.sciencedaily.com/releases/2016/06/160601082303.htm  Original web page at Science Daily

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* New drug clears psoriasis in clinical trials

About 80 percent of patients with moderate to severe psoriasis saw their disease completely or almost completely cleared with a new drug called ixekizumab, according to three large, long-term clinical trials led by Northwestern Medicine.

The results of these phase III trials were compiled in a paper published in the New England Journal of Medicine.

“This group of studies not only shows very high and consistent levels of safety and efficacy, but also that the great majority of the responses persist at least 60 weeks,” said Dr. Kenneth Gordon, a professor of dermatology at Northwestern University Feinberg School of Medicine and first author of the paper.

Affecting about 3 percent of the world’s population, psoriasis is an immune-mediated inflammatory disease that causes itchy, dry and red skin. It is also associated with an increased risk for depression, heart disease and diabetes, among other conditions.

Ixekizumab works by neutralizing a pathway in the immune system known to promote psoriasis.

To test the drug’s efficacy over time — and to help clinicians determine whether its benefits outweigh any risks — the three studies enrolled a total of 3,736 adult patients at more than 100 study sites in 21 countries. All participants had moderate to severe psoriasis, which is defined as covering 10 percent or more of the body. Patients were randomly assigned to receive injections of ixekizumab at various doses or a placebo over a period of more than a year.

The investigators assessed whether the drug reduced the severity of psoriasis symptoms compared to the placebo and evaluated safety by monitoring adverse events. By the 12th week, 76.4 to 81.8 percent of patients has their psoriasis classified as “clear” or “minimal” compared to 3.2% of patients on the placebo. By the 60th week, 68.7 to 78.3 percent of patients had maintained their improvement.

“Based on these findings, we expect that 80 percent of patients will have an extremely high response rate to ixekizumab, and about 40 percent will be completely cleared of psoriasis,” Gordon said. “Ten years ago, we thought complete clearance of this disease was impossible. It wasn’t something we would even try to do. Now with this drug, we’re obtaining response levels higher than ever seen before.”

Adverse events associated with ixekizumab included slightly higher rates of neutropenia (low white blood cell count), yeast infection and inflammatory bowel disease compared to the placebo. The safety of therapy longer than 60 weeks will need to be monitored in the future.

The drug has been approved by the Food and Drug Administration since the trials were completed.

https://www.sciencedaily.com/ Science Daily

https://www.sciencedaily.com/releases/2016/06/160609174808.htm Original web page at Science Daily

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Sunshine vitamin linked to improved fertility in wild animals

High levels of vitamin D are linked to improved fertility and reproductive success, a study of wild sheep has found. The study, carried out on a remote Hebridean island, adds to growing evidence that vitamin D — known as the sunshine vitamin — is associated with reproductive health.

Experts hope that further studies will help to determine the relevance of the results for other mammals, including people.

Researchers led by the University of Edinburgh measured concentrations of a marker linked to vitamin D in the blood of an unmanaged population of Soay sheep, on St Kilda. Scientists found that sheep with higher levels of vitamin D in their blood at the end of the summer went on to have more lambs in the following spring.

The study offers the first evidence that an animal’s vitamin D status is associated with an evolutionary advantage. Vitamin D is produced in the skin of sheep and other animals, including people, after exposure to sunlight. It can also be found in some foods, including certain types of plants. It is essential for healthy bones and teeth and has been linked to other health benefits.

Many studies in the lab have linked vitamin D to reproductive health in animals and humans. This is the first evidence of the link in wild animals. Scientists carried out the research as part of a long-term study on the evolution of Soay sheep. The animals have lived wild for thousands of years on the islands of St Kilda, a world Heritage site owned and managed by the National Trust for Scotland. The research is published in the journal Scientific Reports. It was funded by the Wellcome Trust and the Natural Environment Research Council.

Dr Richard Mellanby, Head of Small Animal Medicine at the University’s Royal (Dick) School of Veterinary Studies, who led the research, said: “Our study is the first to link vitamin D status and reproductive success in a wild animal population.

“Examining the non-skeletal health benefits of vitamin D in humans is challenging because people are exposed to different amounts of sunlight each day. Studying the relationship between skin and dietary sources of vitamin D — and long term health outcomes — is more straightforward in sheep living on a small island.”

http://www.sciencedaily.com/  Science Daily

http://www.sciencedaily.com/releases/2016/01/160113100557.htm  Original web page at Science Daily

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* A horse of a different color: Genetics of camouflage and the dun pattern

Most horses today are treasured for their ability to run, work, or be ridden, but have lost their wild-type camouflage: pale hair with zebra-like dark stripes known as the Dun pattern. Now an international team of scientists has discovered what causes the Dun pattern and why it is lost in most horses. The results, published in Nature Genetics, reveal a new mechanism of skin and hair biology, and provide new insight into horse domestication.

Pale hair colour in Dun horses provides camouflage as it makes a horse in the wild less conspicuous. In contrast, domestic horses, as well as many other domestic animals, have been selected over many generations to be more conspicuous, more appealing or simply different than the wild type. The pale hair colour in Dun horses does not affect all parts of the body; most Dun horses have a dark stripe along their back, and often show zebra-like leg stripes. However, the majority of domestic horses are non-dun and show a more intense pigmentation that is uniformly distributed.

“Dun is clearly one of the most interesting coat colour variants in domestic animals because it does not just change the colour but the colour pattern,” states Leif Andersson, whose group led the genetic analysis. We were really curious to understand the underlying molecular mechanism why Dun pigment dilution did not affect all parts of the body, continues Leif.

“Unlike the hair of most well studied mammals, the dilute coloured hairs from Dun horses are not evenly pigmented the whole way around. They have a section of intense pigmentation along the length of the hair, on the side that faces out from the body of the horse, whilst the rest of the hair has more or less no pigment,” explains Freyja Imsland, the lead author for the genetic analysis, and a PhD student in Andersson’s group. The hairs from the dark areas of Dun horses are in contrast intensely pigmented all around each individual hair. In spite of scientists having studied hair pigmentation in detail for a very long time, this kind of pigmentation is novel to science, and quite unlike that seen in rodents, primates and carnivores.

Genetic analysis and DNA sequencing revealed that Dun versus non-dun colour is determined by a single gene that codes for the T-box 3 (TBX3) transcription factor. In humans, inactivation of the TBX3 gene causes a constellation of birth defects known as Ulnar-Mammary Syndrome. But in horses that have lost their Dun colour, TBX3 mutations do not inactivate TBX3 protein function and instead only affect where the gene is expressed in the growing hair.

“Previous studies in humans and laboratory mice show that TBX3 controls several critical processes in development that affect bones, breast tissue, and cardiac conduction,” explains Greg Barsh, whose group led the tissue analysis. We were surprised to find that TBX3 also plays a critical role in skin and hair development.

The team discovered two forms of dark, non-dun colour, non-dun1 and non-dun2, caused by different mutations.

“Non-dun horses have much more vibrant colour than Dun horses. Non-dun1 horses tend to show primitive markings similar to Dun horses, whereas non-dun2 horses generally don’t show primitive markings. These primitive markings in non-dun1 horses can sometimes lead horse owners to think that their intensely pigmented non-dun1 horses are Dun,” states Freyja Imsland.

To understand how TBX3 affects hair colour, they measured TBX3 distribution in individual hairs relative to other molecules previously known to regulate pigmentation.

“In growing hairs, TBX3 mirrors the distribution of melanocytes, the cells that produce pigment,” explains Kelly McGowan, a senior scientist in the Barsh group. “Our results suggest that TBX3 affects differentiation of specific cells in the hair, creating a microenvironment that inhibits melanocytes from living in the “inner” half of the hair.”

The group speculates that the signals governing where TBX3 is expressed could help to explain zebra stripes. “The region of the body where TBX3 is expressed may account for the stripe pattern,” says McGowan, “whereas the region of the hair where TBX3 is expressed may account for colour intensity.”

The results of the present study indicates that the non-dun2 variant occurred recently most likely after domestication. In contrast, both the Dun and non-dun1 variants predate domestication, which is evident from the observation that ancient DNA from a horse that lived about 43,000 years ago, long before horses were domesticated, carried both Dun and non-dun1 variants.

“This demonstrates that horse domestication involved two different colour morphs (Dun and non-dun1) and future studies of ancient DNA will be able to reveal the geographic distribution and the abundance of the two morphs,” ends Leif Andersson.

http://www.sciencedaily.com/  Science Daily

http://www.sciencedaily.com/releases/2015/12/151221133612.htm  Original web page at Science Daily

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Articles examine relationship between skin, endocrine disorders

Two studies and an editorial published online by JAMA Dermatology examine the relationship between skin disorders and endocrine diseases.

In the first study, Dipankar De, M.D., of the Postgraduate Institute of Medical Education and Research, Chandigarh, India, and coauthors looked at the association between insulin resistance and metabolic syndrome in male patients with acne (ages 20 to 32). The study included 100 men with acne and 100 men without.

The authors report the prevalence of insulin resistance was higher among the men with acne (22 percent) compared with the healthy control patients (11 percent). The prevalence of metabolic syndrome was not statistically significant between men with acne and without. The prevalence of insulin resistance and metabolic syndrome also did not differ significantly among men when they were grouped by the severity of their acne.

A limitation of the study is its cross-sectional design because it looks at a population at a moment in time.

“These patients should be followed up to determine whether they develop conditions associated with insulin resistance,” the authors conclude.

In a second study, Kanade Shinkai, M.D., Ph.D., of the University of California, San Francisco, and coauthors identified skin features of polycystic ovary syndrome (PCOS). The study included 401 women (median age 28) with suspected PCOS. Overall, 68.8 percent of women (276 of 401) met PCOS diagnostic criteria. Most women (91.7 percent [253 of 276]) who met the criteria for PCOS had at least one skin finding.

Women who met the criteria for PCOS were more likely than women who did not meet the criteria to have acne (61.2 percent vs. 40.4 percent); hirsutism or facial and trunk hair growth (53.3 percent vs. 31.2 percent); and acanthosis nigricans (AN) or dark areas on the skin (36.9 percent vs. 20 percent).

The authors note hirsutism affects 5 percent to 15 percent of women in the general population, while AN is estimated to affect 20 percent of the U.S. population. Also, while acne is a common skin feature in women with PCOS, it did not distinguish between women suspected of having PCOS and those meeting the diagnostic criteria.

The authors note limitations to their study including a comparison group not comprised of healthy controls but of women with suspected PCOS who did not meet the diagnostic criteria.

“This study demonstrates that hirsutism and AN are the most useful cutaneous indicators of PCOS to distinguish patients most at risk for having PCOS among a suspected population,” the authors conclude.

In a related editorial, Rachel V. Reynolds, M.D., of Beth Israel Deaconess Medical Center, Boston, writes: “The findings of these two studies remind us that as dermatologists, our detective work goes beyond identifying patterns on the surface to clinch a diagnosis. Thoughtful evaluation of even the most common of skin disorders provides the opportunity to take a deeper dive into the understanding of our patients’ general physical and emotional well-being.”

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http://www.sciencedaily.com/releases/2015/12/151223130028.htm  Original web page at Science Daily

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Land use may weaken amphibians’ capacity to fight infection, disease

Human-made changes to the environment may be damaging the immune systems of a species of frog whose populations have drastically declined since the 1970s, according to a new study by researchers at Case Western Reserve University and the Holden Arboretum.

“These Blanchard’s cricket frogs have nearly gone extinct in their northern range, so we’re almost forensically trying to understand what happened,” said Mike Benard, a biology professor at Case Western Reserve. “This study suggests that changes we are making to the environment have the potential to make animals more susceptible to diseases and therefore may lead to population declines.”

Scientists found that habitat characteristics explained the differences in immune defense traits of frogs between populations. They found that the skin microbiomes ?symbiotic bacterial and fungal communities on the skin ?of frogs from disturbed sites, like residential and agricultural lands, were different from the skin microbiomes of frogs from more natural habitats. They also found natural peptide secretions–proteins frogs secrete from their skin that protect against pathogens–differed between frogs from different environments. Both changes potentially alter the amphibian’s immune defense capabilities. These findings and more are published in the journal Biological Conservation.

Research is increasingly showing that microbiomes in the gut and on the skin and antimicrobial peptides excreted by humans and other animals play important roles in fighting infection and disease.

“We’re seeing a lot of disease-related declines among amphibians, not to mention other groups of animals, such as bats plagued with white-nose syndrome and bees suffering from colony collapse disorder,” said Katherine Krynak, a postdoctoral scholar in Case Western Reserve’s Department of Biology and leader of the study. “This research shows that land use–farming or treating lawns with herbicides, pesticides and fertilizers–can influence traits that protect animals from disease.”

Blanchard’s cricket frogs are about an inch long. They had once been widely spread across Wisconsin, Michigan and northern Ohio, but now only pockets remain in this northern region.

Frogs used in the study were from ponds in various habitats: natural ponds surrounded by forest or prairie, or more disturbed ponds surrounded by houses, on farmed land or near athletic fields, parking lots and golf courses. In addition to considering the physical differences, the researchers tested water chemistry and quality in each pond.

With permission from the states of Ohio and Michigan, Krynak, Benard and David Burke, a scientist and research chair at Holden Arboretum in Kirtland, Ohio, examined samples Krynak had collected from the frogs. Krynak used Q-tip like swabs to obtain samples of the skin microbiome, and then placed the frogs in a solution that gently induced the animals to secrete the antimicrobial peptides.

Krynak and Burke then used molecular methods to examine the community of microbes on the frogs’ skin. Burke, who studies symbiotic interactions between plants and microbial communities, is also an adjunct assistant professor of biology at Case Western Reserve. Krynak and Burke also examined the amount of peptides the frogs produced and how effective the peptides were against an amphibian pathogen they cultured in the lab.

The researchers found microbiome differences between frogs that live in natural areas, such as a pond owned by the Nature Conservancy, and those in ponds surrounded by highly “managed” land, such as farmland or residential properties.

“What we’re seeing is the bacteria on the skin can vary markedly, depending on what people are doing to the environment that the frogs are living in,” Burke said.

A pond’s latitude, conductivity–a proxy for chemical runoff–and size also appear to affect the microbiome.

The amount of natural peptide secretions produced from the frogs’ skin also varied across sites and was influenced by both the size of the pond and the conductivity of the water. Some of the skin secretions have been shown to fight off fungal infections, Krynak said. But in petri dishes in the lab, the growth rate of chytrid fungus, which has been linked to devastating population declines in amphibians worldwide, climbed with increasing Blanchard’s cricket frog natural peptide secretions.

The researchers will further investigate why higher concentrations of peptides appear to allow the killer fungus to grow faster in this species.

“This pattern suggests that in areas where land use increases the amount of the peptides these frogs produce, this particular pathogen could have devastating effects” Krynak said.

The team will also look more directly at how the environment interacts with a population’s genes, changing the expression of traits. “Not only may the environment be altering traits now, but it may be dampening the ability of a population to adapt in the future,” Krynak said.

They are also experimentally isolating factors such as how a commonly used and commercially available glyphosate-based herbicide may alter these immune defense traits.

Environmental alteration of defense traits may explain why different amphibian populations show different levels of resistance to infection and disease.

Krynak said there’s a strong chance that the environment is affecting these traits in other amphibians and wildlife in general.”By improving our understanding of the factors influencing immune defense traits capabilities, we are given the opportunity to make changes to our land management practices to better protect wildlife health” she said “and in all likelihood, our own health as a consequence.”

http://www.sciencedaily.com/  Science Daily

http://www.sciencedaily.com/releases/2015/12/151216140525.htm  Original web page at Science Daily

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* Hypoallergenic dogs don’t have lower household allergen levels than other dogs, study finds

Contrary to popular belief, so-called hypoallergenic dogs do not have lower household allergen levels than other dogs.

That’s the conclusion of a study by Henry Ford Hospital researchers who sought to evaluate whether hypoallergenic dogs have a lower dog allergen in the home than other dogs. Hypoallergenic dogs are believed to produce less dander and saliva and shed less fur.

The findings are to be published online this month in the American Journal of Rhinology and Allergy.

“We found no scientific basis to the claim hypoallergenic dogs have less allergen,” says Christine Cole Johnson, Ph.D., MPH, chair of Henry Ford’s Department of Public Health Sciences and senior author of the study.

“Based on previous allergy studies conducted here at Henry Ford, exposure to a dog early in life provides protection against dog allergy development. But the idea that you can buy a certain breed of dog and think it will cause less allergy problems for a person already dog-allergic is not borne out by our study.

This is believed to be the first time researchers measured environmental allergen associated with hypoallergenic dogs. Previous studies analyzed hair samples from only a handful of dogs in a small number of breeds

Henry Ford researchers analyzed dust samples collected from 173 homes one month after a newborn was brought home. The dust samples were collected from the carpet or floor in the baby’s bedroom and analyzed for the dog allergen Can f 1. Only homes with one dog were involved in the study. Sixty dog breeds were involved in the study, 11 of which are considered hypoallergenic dogs

Based on public web site claims of hypoallergenic breeds, dogs were classified as hypoallergenic using one of four “schemes” based on their breed for comparing allergen levels. Scheme A compared purebred hypoallergenic dogs to purebred non-hypoallergenic dogs; Scheme B compared purebred and mixed breed dogs with at least one hypoallergenic parent to purebred non-hypoallergenic dogs; Scheme C compared purebred and mixed breed dogs with at least one hypoallergenic parent to purebred and mixed breed dogs with no known hypoallergenic component; Scheme D compared only purebred dogs identified as hypoallergenic by the American Kennel Club to all other dogs.

Researchers found that the four schemes yielded no significant differences in allergen levels between hypoallergenic dogs and non-hypoallergenic dogs. In homes where the dog was not allowed in the baby’s bedroom, the allergen level for hypoallergenic dogs was slightly higher compared to allergen levels of non-hypoallergenic dogs.

While researchers acknowledged limitations in their study — the amount of time the dog spent in the baby’s bedroom was not recorded and the size of its sample did not allow looking at specific breeds — they say parents should not rely on dog breeds classified as hypoallergenic.

http://www.sciencedaily.com/  Science Daily

http://www.sciencedaily.com/releases/2011/07/110707161738.htm  Original web page at Science Daily

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New technique offers model for studying disease, progress toward cell therapy

A highly efficient method has been developed for making kidney structures from stem cells that are derived from skin taken from patients. The kidney structures formed could be used to study abnormalities of kidney development, chronic kidney disease, the effects of toxic drugs, and be incorporated into bioengineered devices to treat patients with acute and chronic kidney injury, say scientists.

Investigators at Brigham and Women’s Hospital (BWH) and the Harvard Stem Cell Institute (HSCI) have established a highly efficient method for making kidney structures from stem cells that are derived from skin taken from patients. The kidney structures formed could be used to study abnormalities of kidney development, chronic kidney disease, the effects of toxic drugs, and be incorporated into bioengineered devices to treat patients with acute and chronic kidney injury. In the longer term, these methods could hasten progress toward replacing a damaged or diseased kidney with tissue derived from a patient’s own cells. These results were published in Nature Biotechnology this week.

“Kidneys are the most commonly transplanted organs, but demand far outweighs supply,” said co-corresponding author Ryuji Morizane, MD, PhD, associate biologist in BWH’s Renal Division. “We have converted skin cells to stem cells and developed a highly efficient process to convert these stem cells into kidney structures that resemble those found in a normal human kidney. We’re hopeful that this finding will pave the way for the future creation of kidney tissues that could function in a patient and eliminate the need for transplantation from a donor.”

Chronic kidney disease (CKD) affects 9 to11 percent of the U.S. adult population and is a serious public health problem worldwide. Central to the progression of CKD is the gradual and irreversible loss of nephrons, the individual functional units of the kidney. Patients with end-stage kidney disease benefit from treatments such as dialysis and kidney transplantation, but these approaches have several limitations, including the limited supply of compatible organ donors.

While the human kidney does have some capacity to repair itself after injury, it is not able to regenerate new nephrons. In previous studies, researchers have successfully differentiated stem cells into heart, liver, pancreas or nerve cells by adding certain chemicals, but kidney cells have proved challenging. Using normal kidney development as a roadmap, the BWH investigators developed an efficient method to create kidney precursor cells that self assemble into structures which mimic complex structures of the kidney. The research team further tested these organoids — three-dimensional organ structures grown in the lab — and found that they could be used to model kidney development and susceptibility of the kidney tissue to therapeutic drug toxicity. The kidney structures also have the potential to facilitate further studies of how abnormalities occur as the human kidney develops in the uterus and to establish models of disease where they can be used to test new therapies.

“This new finding could hasten progress to model human disease, find new therapeutic agents, identify patient-specific susceptibility to toxicity of drugs and may one day result in replacement of human kidney tissue in patients with kidney disease from cells derived from that same patient,” said author Joseph V. Bonventre, chief of BWH’s Renal Division and Chief of BWH’s Division of Biomedical Engineering. “This approach is especially attractive because the tissues obtained would be ‘personalized’ and, because of their genetic identity to the patient from whom they were derived, this approach may ultimately lead to tissue replacement without the need for suppression of the immune system.”

http://www.sciencedaily.com/  Science Daily

http://www.sciencedaily.com/releases/2015/10/151016142633.htm  Original web page at Science Daily

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* Bacteria could contribute to development of wound-induced skin cancer


The study, published in Nature Communications, highlights an innate sensing of bacteria by immune cells in the formation of skin tumours. This molecular process could tip the balance between normal wound repair and tumour formation in some patients, according to researchers. Although an association between tissue damage, chronic inflammation and cancer is well established, little is known about the underlying cause. Epidermolysis Bullosa (EB), for instance, is one of several rare inherited skin conditions associated with chronic wounding and increased risk of tumours. However, this study — funded primarily by the Medical Research Council (MRC) and the Wellcome Trust — is the first to demonstrate that bacteria present on the skin can contribute to the development of skin tumours. Researchers found that when mice with chronic skin inflammation are wounded they develop tumours at the wound site, with cells of the immune system required for this process to take place. They discovered that the underlying signalling mechanism involves a bacterial protein, flagellin, which is recognised by a receptor (Toll-like receptor 5) on the surface of the immune cells. Although the direct relevance to human tumours is yet to be tested, researchers have shown that a protein called HMGB1 — found to be highly expressed in mice with chronic skin inflammation — is increased in human patients with Epidermolysis Bullosa (EB). The study found a reduction in HMGB1 levels in mice when the TLR-5 receptor was removed from immune cells. This raises the possibility of future treatments aimed at reducing levels of the flagellin bacterial protein on the skin surface, or targeting the TLR-5 receptor. Professor Fiona Watt, lead author and Director of the Centre for Stem Cells and Regenerative Medicine at King’s College London, said: ‘These findings have broad implications for various types of cancers and in particular for the treatment of tumours that arise in patients suffering from chronic ulcers or skin blistering diseases. ‘In the context of chronic skin inflammation, the activity of a particular receptor in white blood cells, TLR-5, could tip the balance between normal wound repair and tumour formation.’ Professor Watt added: ‘Our findings raise the possibility that the use of specific antibiotics targeting bacteria in wound-induced malignancies might present an interesting clinical avenue.’

http://www.sciencedaily.com/  Science Daily

http://www.sciencedaily.com/releases/2015/01/150109084723.htm Original web page at  Science Daily

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* Acute psychological stress promotes skin healing in mice

Brief, acute psychological stress promoted healing in mouse models of three different types of skin irritations, in a study led by UC San Francisco researchers. The scientists found that healing was brought about by the anti-inflammatory effects of glucocorticoids — steroid hormones — produced by the adrenal glands in response to stress. “Under chronic stress, these same naturally-occurring steroids damage the protective functions of normal skin and inhibit wound healing, but during shorter intervals of stress, they are beneficial for inflammatory disorders and acute injury in both mice and humans,” said senior investigator Peter Elias, MD, a UCSF professor of dermatology based at the San Francisco VA Medical Center (SFVAMC). “We believe that our findings explain why this otherwise harmful component of the stress response has been preserved during human evolution,” he said. The study was published online in the Journal of Investigative Dermatology on August 7, 2014, in advance of print publication in the journal. The scientists studied mouse models of three types of common skin irritations: irritant contact dermatitis, caused by exposure to an irritant such as a soap or solvent; acute allergic contact dermatitis, of the sort caused by poison ivy or poison oak; and atopic dermatitis, or eczema. After exposure to irritants on a small patch of skin on one ear, one group of mice was returned to its regular cages, while another group was put in a stressful situation — being placed in very small enclosures for 18 hours a day over the course of four days. The researchers found that the stressed mice showed significantly reduced inflammation and faster healing in all three types of skin irritation. When stressed mice were simultaneously given mifepristone, which blocks steroid action, all of the healing benefits of stress disappeared. “This demonstrated the central role of internal steroids in providing these benefits,” said Elias. He noted that other researchers have recently proposed that psychological stress has a potential role in promoting healing, “but that work has focused on the immune system rather than glucocorticoids as the responsible, beneficial mediator.” According to Elias, the study provides a clue to an evolutionary puzzle: why, over millions of years, humans have preserved the tendency to produce steroids under stress. Previous research by Elias’s laboratory and others has demonstrated that prolonged exposure to steroids harms both the structure and function of skin and other organs.

“Our ancestors did not have an arsenal of pharmaceutical steroids available to treat acute illnesses or injuries,” Elias observed. “This safe, effective internal anti-inflammatory system provides just the correct amount of steroids to promote healing, over a time interval that is too short to cause harm.” Elias emphasized that the study did not look at the implications for human medical treatments. However, he contrasted the “substantial benefits” seen from modest increases in glucocorticoid levels brought on by short-term stress with the “adverse effects that we see all too commonly” with steroid therapy. Elias speculated that those negative effects could be the result of “overly aggressive treatment — too high doses, and perhaps for unnecessarily prolonged treatment intervals.” He said that while his research team did not study other kinds of inflammatory disorders, “the same benefits of psychological stress should accrue in any acute illness or injury.”

http://www.sciencedaily.com/  Science Daily

http://www.sciencedaily.com/releases/2014/08/140807104309.htm  Original web page at Science Daily

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* Key cells in touch sensation identified: Skin cells use new molecule to send touch information to the brain

In a study published in the April 6 online edition of the journal Nature, a team of Columbia University Medical Center researchers led by Ellen Lumpkin, PhD, associate professor of somatosensory biology, solve an age-old mystery of touch: how cells just beneath the skin surface enable us to feel fine details and textures. Touch is the last frontier of sensory neuroscience. The cells and molecules that initiate vision — rod and cone cells and light-sensitive receptors — have been known since the early 20th century, and the senses of smell, taste, and hearing are increasingly understood. But almost nothing is known about the cells and molecules responsible for initiating our sense of touch. This study is the first to use optogenetics — a new method that uses light as a signaling system to turn neurons on and off on demand — on skin cells to determine how they function and communicate. The team showed that skin cells called Merkel cells can sense touch and that they work virtually hand in glove with the skin’s neurons to create what we perceive as fine details and textures. “These experiments are the first direct proof that Merkel cells can encode touch into neural signals that transmit information to the brain about the objects in the world around us,” Dr. Lumpkin said. The findings not only describe a key advance in our understanding of touch sensation, but may stimulate research into loss of sensitive-touch perception.

Several conditions — including diabetes and some cancer chemotherapy treatments, as well as normal aging — are known to reduce sensitive touch. Merkel cells begin to disappear in one’s early 20s, at the same time that tactile acuity starts to decline. “No one has tested whether the loss of Merkel cells causes loss of function with aging — it could be a coincidence — but it’s a question we’re interested in pursuing,” Dr. Lumpkin said. In the future, these findings could inform the design of new “smart” prosthetics that restore touch sensation to limb amputees, as well as introduce new targets for treating skin diseases such as chronic itch. The study was published in conjunction with a second study by the team done in collaboration with the Scripps Research Institute. The companion study identifies a touch-activated molecule in skin cells, a gene called Piezo2, whose discovery has the potential to significantly advance the field of touch perception. “The new findings should open up the field of skin biology and reveal how sensations are initiated,” Dr. Lumpkin said. Other types of skin cells may also play a role in sensations of touch, as well as less pleasurable skin sensations, such as itch. The same optogenetics techniques that Dr. Lumpkin’s team applied to Merkel cells can now be applied to other skin cells to answer these questions. “It’s an exciting time in our field because there are still big questions to answer, and the tools of modern neuroscience give us a way to tackle them,” she said.

http://www.sciencedaily.com/  Science Daily

April 29, 2014

http://www.sciencedaily.com/releases/2014/04/140406162249.htm  Original web page at Science Daily

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Scientists reprogram skin cells into insulin-producing pancreas cells

A cure for type 1 diabetes has long eluded even the top experts. Not because they do not know what must be done — but because the tools did not exist to do it. But now scientists at the Gladstone Institutes, harnessing the power of regenerative medicine, have developed a technique in animal models that could replenish the very cells destroyed by the disease. The team’s findings, published online in the journal Cell Stem Cell, are an important step towards freeing an entire generation of patients from the life-long injections that characterize this devastating disease. Type 1 diabetes, which usually manifests during childhood, is caused by the destruction of ß-cells, a type of cell that normally resides in the pancreas and produces a hormone called insulin. Without insulin, the body’s organs have difficulty absorbing sugars, such as glucose, from the blood. Once a death sentence, the disease can now be managed with regular glucose monitoring and insulin injections. A more permanent solution, however, would be to replace the missing ß-cells. But these cells are hard to come by, so researchers have looked towards stem cell technology as a way to make them. “The power of regenerative medicine is that it can potentially provide an unlimited source of functional, insulin-producing ß-cells that can then be transplanted into the patient,” said Dr. Ding, who is also a professor at the University of California, San Francisco (UCSF), with which Gladstone is affiliated. “But previous attempts to produce large quantities of healthy ß-cells — and to develop a workable delivery system — have not been entirely successful. So we took a somewhat different approach.”

One of the major challenges to generating large quantities of ß-cells is that these cells have limited regenerative ability; once they mature it’s difficult to make more. So the team decided to go one step backwards in the life cycle of the cell. The team first collected skin cells, called fibroblasts, from laboratory mice. Then, by treating the fibroblasts with a unique ‘cocktail’ of molecules and reprogramming factors, they transformed the cells into endoderm-like cells. Endoderm cells are a type of cell found in the early embryo, and which eventually mature into the body’s major organs — including the pancreas. “Using another chemical cocktail, we then transformed these endoderm-like cells into cells that mimicked early pancreas-like cells, which we called PPLC’s,” said Gladstone Postdoctoral Scholar Ke Li, PhD, the paper’s lead author. “Our initial goal was to see whether we could coax these PPLC’s to mature into cells that, like ß-cells, respond to the correct chemical signals and — most importantly — secrete insulin. And our initial experiments, performed in a petri dish, revealed that they did.” The research team then wanted to see whether the same would occur in live animal models. So they transplanted PPLC’s into mice modified to have hyperglycemia (high glucose levels), a key indicator of diabetes.

“Importantly, just one week post-transplant, the animals’ glucose levels started to decrease gradually approaching normal levels,” continued Dr. Li. “And when we removed the transplanted cells, we saw an immediate glucose spike, revealing a direct link between the transplantation of the PPLC’s and reduced hyperglycemia.” But it was when the team tested the mice eight weeks post-transplant that they saw more dramatic changes: the PPLC’s had given rise to fully functional, insulin-secreting ß-cells. “These results not only highlight the power of small molecules in cellular reprogramming, they are proof-of-principle that could one day be used as a personalized therapeutic approach in patients,” explained Dr. Ding. “I am particularly excited about the prospect of translating these findings to the human system,” said Matthias Hebrok, PhD, one of the study’s authors and director of the UCSFDiabetesCenter. “Most immediately, this technology in human cells could significantly advance our understanding of how inherent defects in ß-cells result in diabetes, bringing us notably closer to a much-needed cure.”

http://www.sciencedaily.com/  Science Daily March 4, 2014

http://www.sciencedaily.com/releases/2014/02/140206133640.htm  Original web page at Science Daily

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Surprising discovery: Skin communicates with liver

Researchers from the University of Southern Denmark have discovered that the skin is capable of communicating with the liver. The discovery has surprised the scientists, and they say that it may help our understanding of how skin diseases can affect the rest of the body. Professor Susanne Mandrup and her research group in collaboration with Nils Færgeman’s research group at the Department of Biochemistry and Molecular Biology at the University of Southern Denmark was actually studying something completely different when they made the groundbreaking discovery: That the skin, which is the body’s largest organ, can “talk” to the liver. “We have showed that the skin affects the metabolism in the liver, and that is quite a surprise,” say Susanne Mandrup and Ditte Neess, a former student in the Mandrup research group and now laboratory manager in Professor Nils Færgeman’s group. The phenomenon was observed in the researcher’s laboratory mice. The Mandrup and Færgeman groups work with so-called knock-out mice, in which a specific fat binding protein called acyl CoA binding protein has been removed (knocked out). Some knock-out mice produced by the researchers had a strange greasy fur, and they had difficulties being weaned from their mother. In the weaning period they gained less weight and showed a failure to thrive. Analyses also showed that the mice accumulated fat in the liver at weaning.

“At first we thought that the fat accumulation in the liver was linked with the fact that the gene was missing in the liver of the knock-out mice. But this was ruled out by a series of studies, and we had to find another explanation,” says Ditte Neess. She and her colleagues took another look at the rumpled and weak knock-out mice. Their fur was greasy, and they had a leaky skin from which they lost more water than normal mice. “When they lose water, they also lose heat. We therefore asked ourselves whether this water and heat loss could be the reason why the mice accumulated fat in the liver and became weak when weaned from their mother,” says Ditte Neess. To clarify this, the researchers made some mice that lacked the fat binding protein only in the skin. Similar to the full knockouts these mice had difficulties after weaning and accumulated fat in the liver. So this showed that the lack of the fat-binding protein in the skin was sufficient to induce accumulation of fat in the liver. To get to the bottom of how a defect in the skin “talks” to the liver, the researchers decided to cover the mice with Vaseline. This would prevent water evaporating from the skin and thus stopping the heat loss. As a result the fat accumulation in the liver disappeared. But as Vaseline contains fat, that could theoretically be absorbed by the skin or ingested by the mice, the researchers were a little unsure if there were side effects from the Vaseline. A student proposed to cover the mice with liquid latex, which she found in a local sex shop. Having covered the mice in blue latex the researchers saw that fat accumulation in the liver again disappeared. “We believe that the leaking of water from the skin makes the mice feel cold, and that this leads to breaking down of fat in their adipose (fat) tissue. The broken down fat is then moved to the liver. The mice move energy from the tissues to the liver,” Susanne Mandrup and Ditte Neess explain.

Science Daily
January 7, 2014

Original web page at Science Daily

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More than skin deep: New layer to the body’s fight against infection

The layers of skin that form the first line of defense in the body’s fight against infection have revealed a unanticipated secret. The single cell type that was thought to be behind the skin’s immune defense has been found to have a doppelganger, with researchers from the Walter and Eliza Hall Institute showing the cells, despite appearing identical, are actually two different types. Institute scientists Dr Michael Chopin, Dr Stephen Nutt and colleagues from the institute’s Molecular Immunology division have been investigating Langerhans cells, the immune cells that provide the first line of defense against attacks through the skin. Until recently, scientists believed that, because they looked identical, all Langerhans cells were also genetically identical and had the same function. However Dr Nutt said the research team, with collaborators from the National Institutes of Health, US, have shown this is not the case. “Langerhans cells are produced and found in the skin and are quite unique among immune cells because they do not have a definite lifespan, they can last for a lifetime,” Dr Nutt said. “They are only replaced when necessary, such as when the skin is damaged by a burn or a cut. When that happens, new Langerhans cells have to be produced by the bone marrow. These cells look the same, so it was always thought that they were genetically the same and their function was the same. We have shown that this isn’t the case.” This surprise finding, published today in the Journal of Experimental Medicine, could have repercussions for developing and refining therapies for skin infections and skin cancers.

Although Langerhans cells were discovered nearly 150 years ago, Dr Chopin said there were still a lot of gaps in our knowledge about how they develop and their role in responding to foreign invaders. Dr Chopin said the research team was initially trying to understand the role of Langerhans cells. “Not everything that makes contact with the skin is harmful, so it is important the immune system doesn’t overreact,” he said. “We were trying to find out whether Langerhans cells were there to activate an immune response to invaders, or to suppress the immune system to prevent it from overreacting. “While designing the experiment, we found that the genes that define the Langerhans cells that are produced in the skin were different to those of Langerhans cells that came from bone marrow. In essence we now know that there are two different types of Langerhans cells where we thought there was one. We now need to find out if they behave differently as well.” Dr Nutt said the research could explain why some promising new drugs have not had the desired effect in the clinic. “Some clinical trials of drugs that were designed to help boost Langerhans cells in response to infections have not responded as the researchers expected,” Dr Nutt said. “Our finding may help explain why these drugs didn’t work outside the laboratory and our current research may provide guidance in developing therapeutics to treat skin infections or skin cancer.”

Science Daily
December 10, 2013

Original web page at Science Daily

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Progression of aggressive skin cancers in mice

The c-Fos oncogene has traditionally been linked to cellular activities related to cancer, such as cell division, differentiation — conversion from one cell type to another — or survival. Any alteration of these activities can set off the development of tumours, which has made c-Fos an important target for the understanding and treatment of cancer. A study led by Erwin Wagner, head of the F-BBVA-CNIO Cancer Cell Biology Programme and of the Genes, Development and Disease Group, has revealed a novel mechanism in which c-Fos is able to promote skin cancer: an increase in c-Fos expression in the skin stimulates the immune system, which induces the appearance of squamous cell carcinomas (SCCs), one of the most aggressive skin cancers. Another important result from this study is the observation in mice of a decrease in the progression of SCCs by using anti-inflammatory drugs, which block the immune response induced by c-Fos. The conclusions are published in the latest issue of the journal Genes and Development, and are featured on its cover. The classic way of looking at inflammatory immune response, which is more than 100 years old, asserts that defence mechanisms protect the organism when faced with neoplasms. This vision has given way over the last few years to new evidence that suggests chronic inflammation favours the proliferation and survival of tumour cells, thus increasing susceptibility to cancer.

“We know that there are cancers, like pancreatic, liver or colon cancer, in which the inflammatory component plays a very important role in the development of the disease,” says Juan Guinea-Viniegra, a researcher from Wagner’s team. Furthermore, inflammatory skin diseases, such as lupus or chronic ulcers, predispose patients to develop tumours, although for now the mechanisms responsible for this phenomenon had not been discovered. The research sheds light on this question for the first time. Eva Briso, first author of the study says: “We have discovered that mice that have higher c-Fos expression in the skin promote the recruitment of immune cells, known as CD4+T, leading to the development of skin lesions and carcinogenesis.” Briso adds that when mice were treated with anti-inflammatory drugs that specifically blocked CD4+T cell-mediated immune response, tumours decreased. Furthermore, the researchers analysed samples from nearly a hundred patients with SCCs, in which they found that up to 75% of the tumours displayed increased c-Fos expression, as well as an increase in inflammatory activity. These results open up the possibility of using anti-inflammatory drugs as a means of treating patients with this pathology. “If we find molecules that in patients are able to block this immune response, we could think about a new specific therapy for this disease,” says Wagner. Squamous cell carcinoma is a very aggressive type of skin cancer that can invade other tissues and form metastasis. It affects 16 out of every 100,000 people in Europe and is the type of skin cancer most related to sun exposure. Due to the few biological and molecular data available on the disease, the standard treatment is reduced to surgery and radiotherapy.

Science Daily
October 15, 2013

Original web page at Science Daily

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Salamanders under threat from deadly skin-eating fungus

A new species of fungus that eats amphibians’ skin has ravaged the fire salamander population in the Netherlands, bringing it close to regional extinction. Fire salamanders, recognisable by their distinctive yellow and black skin patterns, have been found dead in the country’s forests since 2010. The population has fallen to around 10 individuals, less than four per cent of its original level, but what has been killing them has been a mystery until now. Scientists from Ghent University, Imperial College London, Vrije Universiteit Brussel and the Dutch conservation group Ravon have isolated a new species of fungus from the dead animals and found that it can rapidly kill fire salamanders. They have named the fungus Batrachochytrium salamandrivorans, the second part meaning “salamander-eating,” and report their findings today in the Proceedings of the National Academy of Sciences. Fungi are increasingly recognised as important threats to biodiversity. A species related to the new fungus, Batrachochytrium dendrobatidis (Bd), has plagued amphibian populations across the globe and is thought to have wiped out more than 200 species worldwide. It causes the disease chytridiomycosis, which the International Union for the Conservation of Nature has called the single most devastating infectious disease in vertebrate animals.

The study’s lead author, Professor An Martel from the University of Ghent, said: “In several regions, including northern Europe, amphibians appeared to be able to co-exist with Bd. It is therefore extremely worrying that a new fungus has emerged that causes mass mortalities in regions where amphibian populations were previously healthy.” Co-author Professor Matthew Fisher, from Imperial College London, said: “It is a complete mystery why we are seeing this outbreak now, and one explanation is that the new salamander-killing fungus has invaded the Netherlands from elsewhere in the world. We need to know if this is the case, why it is so virulent, and what its impact on amphibian communities will be on a local and global scale. Our experience with Bd has shown that fungal diseases can spread between amphibian populations across the world very quickly. We need to act urgently to determine what populations are in danger and how best to protect them.” The fungus can be passed between salamanders by direct contact, and possibly by indirect contact although this hasn’t been proven. It invades the animal’s skin, eventually destroying it completely. In tests, the fungus was not able to infect midwife toads, which have been threatened by chytridiomycosis, but whether other species might be vulnerable is unknown. The scientists have brought surviving salamanders into captivity to protect the remaining population in the Netherlands. To aid further studies, they have also developed a diagnostic tool that enables the new fungus to be quickly identified. They tested 100 salamanders from Belgium, where the population has remained healthy, but so far there is no sign that the fungus has spread beyond the Netherlands.

Science Daily
September 17, 2013

Original web page at Science Daily

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Tide is turning in skin cancer battle

A decade ago there was little doctors could do to help a patient with advanced-stage melanoma. “I’ve been doing this for 30 years, and now is by any measure the most exciting time for melanoma research,” said Brian Nickoloff, director of the Nicholas V. Perricone, M.D., Division of Dermatology and Cutaneous Sciences at Michigan State University’s College of Human Medicine. In the research journal Laboratory Investigation, Nickoloff and colleagues outline recent advances that have put melanoma at the forefront of cancer research, raising hopes that scientists and clinicians may have cornered the deadliest of all skin cancers. “In the past melanoma outsmarted us, but now we’re starting to outsmart melanoma,” said Nickoloff, who also is director of cutaneous oncology at Van Andel Research Institute in Grand Rapids and a member of the Stand Up to Cancer Dream Team for melanoma research. “Go back 10 years and you’ll see we had almost nothing to offer patients with advanced disease, but now we’re definitely getting the upper hand on this cancer.” Melanoma is really a catch-all term for the most virulent types of skin cancer. The disease’s complexity is staggering — melanoma tumors have more mutations per cell than any other type of cancer — but new diagnostic tools such as DNA sequencing are helping scientists sort through troves of data to decode each tumor’s “fingerprint.”

And while the list of known mutations that cause melanoma keeps growing, researchers can target most of them by blocking a handful of the “signaling pathways” that control normal cell function and can cause tumors to form and spread. Meanwhile, about 100 new drugs with melanoma in their sights are in development, and new combinations of drugs show promise for blocking cancer-causing signaling pathways. Still, optimism about such progress is tempered by the fact that someone dies from melanoma every hour. Besides being deadly, melanoma is one of the fastest growing cancers worldwide. Melanoma also is unusual among cancers in how often it develops in young people; it is one of the leading causes of cancer-related deaths in 25- to 29-year-old women. Science’s rapid progress in understanding and treating melanoma must be coupled with prevention efforts to educate people about the dangers of sun exposure and artificial tanning, Nickoloff said. “It’s entirely preventable,” he said. “Nobody should die from advanced-stage melanoma.”

Science Daily
August 6, 2013

Original web page at Science Daily

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Multi-sensory organs in crocodylian skin sensitive to touch, heat, cold, environment

Previously misunderstood multi-sensory organs in the skin of crocodylians are sensitive to touch, heat, cold, and the chemicals in their environment, finds research in BioMed Central’s open access journal EvoDevo. These sensors have no equivalent in any other vertebrate. Crocodylians, the group that includes crocodiles, gharials, alligators and caimans, have particularly tough epidermal scales consisting of keratin and bony plates for added protection. On the head, these scales are unusual because they result from cracking of the hardened skin, rather than their shape being genetically determined. The scales have sensors known as dome pressure receptors (DPR) or Integumentary Sensory organs (ISOs) with fingertip sensitivity. Researchers from the University of Geneva investigated ISOs in Nile crocodiles (Crocodylus niloticus) and the spectacled caiman (Caiman crocodilus) to find out exactly what these micro-organs can ‘see and how they are formed.’. ISOs appear on the head of the developing caiman and crocodile embryos before the skin starts to crack and form scales. Nile crocodiles additionally develop ISOs all over their body. In both animals the ISOs contain mechano-, thermo-, and chemo-sensory receptor-channels giving them the combined ability to detect touch, heat/cold and chemical stimuli, but not salinity. Nile crocodiles have separate salt glands on their tongues which help regulate osmolarity in hyper-saline environments.

This means that they can detect surface pressure waves allowing them to quickly find prey even in the dark. The thermal sensitivity help them to maintain body temperature by moving between basking in the sun and cooling in the water, and the chemical sensors may help them to detect suitable habitats. Prof Michel Milinkovitch, who led this study explained, “ISO sensors are remarkable because not only are they able to detect many different types of physical and chemical stimuli, but because there is no equivalent in any other vertebrates. It is this transformation of a diffuse sensory system, such as we have in our own skin, into ISO which has allowed crocodilians to evolve a highly armored yet very sensitive skin.”

Science Daily
July 23, 2013

Original web page at Science Daily

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Doctors in veterinary, human medicine team to give burned horse a second chance

The unlikely pairing of an equine veterinarian and a burn surgeon is providing a second chance at a normal life for a horse that was doused in flammable liquid and set on fire late last summer. The Ohio State University doctors and their teams have partnered to perform two skin graft procedures on the American Paint Horse named Northstar, who suffered severe burns to almost half of his body when the abuse occurred. The same instruments used in a typical human burn surgery were used for the horse’s grafting procedures. The clinicians removed ultrathin sheets of skin from Northstar’s chest and expanded them with a meshing tool before placing the grafts across an enormous wound spanning the horse’s back. When he arrived in Columbus on Sept. 5, Northstar had exposed bone at the base of his neck as a result of the burns. Skin damage extended from his neck to the base of his tail and along both of his sides. No suspect has been identified in the case. The doctors’ collaboration — not to mention the unusual size of the back wound — has provided a rare learning experience for both clinicians and their colleagues. “There’s been a lot of trial and error with the challenges of how to bandage him, what the most appropriate antiseptic is for cleaning the wound bed, and the biology of burned tissue in a horse,” said Samuel Hurcombe, assistant professor of veterinary clinical sciences and the leader of Northstar’s care team.

Veterinary experts got the healing off to a good start with relentless wound management, a series of smaller skin grafts and the implantation of cell cultures in the wound bed. These procedures were performed to bring top-layer skin tissue to the central area of the expansive wound bed on Northstar’s neck and shoulders, where all his skin had burned away. To address the large wound across the horse’s back, Hurcombe consulted longtime trauma and burn surgeon Larry Jones at Ohio State’s Wexner Medical Center. The two observed one another’s surgeries and studied human- and veterinary-medicine journal articles before teaming to accelerate Northstar’s care. Jones, associate professor of clinical surgery and director of the Burn Center at the medical center, led the two larger skin graft surgeries. Early on, he encountered a significant challenge: how deep to set the tool that would peel off the donor skin. “We want to take the top layer of skin but we also need a portion of the second layer, the dermis,” he said. After Jones consulted with Hurcombe and the two conducted more research, “I knew I had to take a graft that’s about twice as thick as one I would take if I were operating on a human.”

The team then ran the graft through a mesher that cut holes in the graft skin and allowed for expansion of the graft to about four times its original size. “When the graft takes, the holes will fill in from skin cells growing from the edges,” Jones said. They dressed the wounds with bandages containing medical-grade silver, which functions as an antibiotic, to speed healing of the grafts and the donor sites. At this stage of the horse’s recovery, more than half of the initial wound is healed, with the repair resulting from both the various skin grafting procedures and normal closure along the edges of the damaged skin. Northstar will likely undergo a series of additional sheet graft surgeries to completely heal the wound. Multiple grafts are often required for extensive human burn injuries, as well. “It’s a slow process but even in the time we’ve been caring for him, he has made remarkable progress,” said Hurcombe, a specialist in equine emergency and critical care. “From a welfare standpoint, his psychology is great and after what he’s gone through, the fact that he is still so trusting of people is pretty amazing.” While he initially appeared to be a dark horse for recovery, Northstar persevered through weeks of daily cleansing and removal of dead and infected tissue followed by the application of antiseptics, honey, aloe and silver sulfadiazine cream, a common human burn treatment, to his damaged tissue.

In yet another application of human medicine in veterinary care, the team has treated Northstar with gabapentin (sold under the brand name Neurontin), a medication used for neuropathic pain in humans, to treat the severe itching and nerve-related pain that is typical in burn patients as they recover. Northstar, who turned 7 in January, is a “young, naughty boy” and would love nothing more than to toss himself to the ground and roll on his back to scratch that persistent itch, Hurcombe said. So the horse is gently tethered to keep him standing and he wears a cradle that immobilizes his neck several hours throughout the day. He is also covered in bandages and wears what is called a full-body “sleazy” covering that is typically seen on show horses. The clinicians hope that Northstar will have a complete layer of skin coverage by his 8th birthday. The road ahead is a long one, both physicians acknowledge. The location of his back wound is a tricky one to treat because even with secure bandages from his neck to his tail, the horse anatomy in the location of the burn is such that Northstar’s every movement slightly disturbs the grafted areas. “His skin graft take is a little less than what I am used to in humans,” Jones noted. “But as Dr. Hurcombe reminds me, considering his hospital bed is in a barn, he is doing very well. “I view Northstar in the same way as I do any of my other patients. I just want him to get better and go on and live his life as a horse.”

Northstar’s owners live in northwestern Pennsylvania, where police have investigated the burning incident as a criminal case. “All the owners want is for him to be happy, pain-free and able to live his life with his pasture mates,” Hurcombe said. “He is bright and alert, he interacts with people and he can eat and drink and do all the things that a horse can normally do as far as function. And he has been telling us through his behaviors that he wants to live.”

Science Daily
July 9, 2013

Original web page at Science Daily

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Gene associated with eczema in dogs identified

A novel gene associated with canine atopic dermatitis has been identified by a team of researchers led by professors Kerstin Lindblad-Toh, Uppsala university and Åke Hedhammar, SLU, Sweden. The gene encodes a protein called plakophilin 2, which is crucial for the formation and proper functioning of the skin structure, suggesting an aberrant skin barrier as a potential risk factor for atopic dermatitis. Details appeared recently in the open-access journal PLoS Genetics. Atopic dermatitis (or eczema) is an inflammatory, relapsing non-contagious skin disease affecting about 10-30 percent of the human population. It is not only humans that suffer from the disease: about 3-10 percent of dogs are also affected. The skin of a patient with atopic dermatitis becomes easily irritated by various allergens such as certain types of food, pollens or house mites. Such irritation causes very strong itching which leads to scratching, redness and flaky skin that becomes vulnerable to bacterial and yeast infections. To-date, despite many scientific efforts, little has been known about the genetics of the disease. In their study, researchers from Uppsala University, SLU and Broad Institute, compared DNA samples from a large group of German shepherd dogs affected by atopic dermatitis with DNA coming from healthy dogs to reveal the specific DNA segment associated with the disease.

“With the help of pet owners, we have managed to collect a unique set of DNA samples from sick and healthy dogs which allowed us to gain insight into atopic dermatitis genetics,” said first author Katarina Tengvall, Uppsala University. Purebred dogs such as German shepherds have been selected for specific physical features for several generations. Selection led to an inadvertent enrichment for disease-risk genes in certain breeds. Moreover, the resulting architecture of canine DNA makes it easier to pinpoint segments that carry these disease risk-genes. This helped the researchers to reveal the genetics of atopic dermatitis. They found a region associated with the atopic dermatitis containing the gene PKP-2, which encodes Plakophilin-2, a protein involved in the formation and maintaining of the proper skin structure. “The finding that certain variants of the PKP-2 gene may increase the risk of developing the disease opens new possibilities in understanding the disease mechanism leading to atopic dermatitis,” continues Katarina Tengvall. These findings will not only lead to better understanding of the disease, which may lead to better treatment strategies long term. It also opens up the possibilities of development of a genetic test for the disease.

“Our study suggests that plakophilin-2 and an intact skin barrier is important to avoid atopic dermatitis,” says senior author, Kerstin Lindblad-Toh, professor at Uppsala University and Director of SciLifeLab Uppsala. “Another gene involved in the skin barrier has recently been linked to human atopic dermatitis emphasizing the similarity between canine and human atopic dermatitis” continues Kerstin Lindblad-Toh.

Science Daily
May 28, 2013

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One gene, many mutations: Key that controls coat color in mice evolved nine times

For deer mice living in the Nebraska Sandhills, color can be the difference between life and death. When the dark-coated mice first colonized the region, they stood out starkly against the light-colored, sandy soil, making them easy prey for predators. Over the next 8,000 years, however, the mice evolved a system of camouflage, with lighter coats, changes in the stripe on their tails, and changes in body pigment that allowed them to blend into their habitat. Now Harvard researchers are using their example to answer one of the fundamental questions about evolution. Is it a process marked by large leaps — single mutations that result in dramatic changes in an organism — or is it the result of many smaller changes that accumulate over time? As described in a March 15 paper in the journal Science, a team of researchers, including former Harvard postdoctoral fellow Catherine Linnen, now an assistant professor at the University of Kentucky, and led by Hopi Hoekstra, Harvard professor of organismic and evolutionary biology and molecular and cellular biology, were able to show that the changes in mouse coat color were the result not of a single mutation but of at least nine mutations within a single gene.

“The findings demonstrate how the cumulative effect of natural selection, acting on many small genetic changes, can produce rapid and dramatic change,” said Linnen, the first author of the paper. “This helps us to understand, from a genetic perspective, the uncanny fit between so many organisms and their environments. By acting on many small changes, rather than a handful of large ones, natural selection can produce very finely honed adaptations.” Surprisingly, Hoekstra said, that honing occurred in a single gene. The role of this gene, called agouti, in camouflage was first discovered by Linnen, Hoekstra, and colleagues in 2009, and it is responsible for changes in pigmentation in the coats of many animals. Every domesticated black cat, for example, has a DNA deletion in the gene. What surprised Hoekstra and her team, however, wasn’t that the gene was involved, but that each of the nine mutations were tied to a unique change in the animal’s coats, that all the new mutations led to more camouflaging color, and that the mutations occurred in a relatively short, 8,000-year timeframe. “Essentially, it seems as though these mutations — each of which makes the mouse a little lighter and more camouflaged — have accumulated over time,” Hoekstra said. Focusing on these mutations, researchers then examined the DNA of natural populations of the mice to determine whether the mutations are actually beneficial.

“For each of the mutations associated with color change, we also find a signal that’s consistent with positive selection,” Hoekstra said. “That implies that each of the specific changes to pigmentation is beneficial. This is consistent with the story we are telling, about how these mutations are fine-tuning this trait.” While the findings offer valuable insight into the way that natural selection operates, Hoekstra said they also highlight the importance of following research questions to their ultimate end. “The question has always been whether evolution is dominated by these big leaps or smaller steps,” she said. “When we first implicated the agouti gene, we could have stopped there and concluded that evolution takes these big steps as only one major gene was involved, but that would have been wrong. When we looked more closely, within this gene, we found that even within this single locus, there are, in fact, many small steps.” Going forward, Hoekstra said, her team hopes to understand the order in which the mutations happened, which would allow it to reconstruct how the mice changed over time. “For evolutionary biologists, this is exciting because we want to learn about the past, but we only have data from the present to study it,” she said. “This ability to go back in time and reconstruct an evolutionary path is very exciting, and I think this data set is uniquely suited for this type of time travel.” Taking the time to understand not only which genes are involved but which specific mutations may be driving natural selection, Hoekstra said, can give researchers a much fuller picture of not only the molecular mechanisms by which mutations alter traits, but also the evolutionary history of an organism. “By doing this, we’ve discovered all kinds of new things,” she said. “While we often think about changes happening in the entire genome, our results suggest that even within a very basic unit — the gene — we can see evidence for evolutionary fine-tuning.”

Science Daily
April 2, 2013

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Porcupine quills reveal their prickly secrets

To pierce your skin, a porcupine quill needs only about half the force of a hypodermic needle, according to a new study. The work, which also explains why the quills are so hard to remove, could improve the design of a variety of medical instruments, from devices that poke us to those that help keep wounds shut. Porcupines are famed for their quills, which are actually large, stiff hairs that help defend the animals against natural predators. Contrary to popular notions, the large rodents can’t throw their quills at an enemy, says Jeffrey Karp, a bioengineer at Harvard Medical School in Boston. However, the quills are readily shed and can become firmly embedded in an unfortunate victim. The North American porcupine has about 30,000 quills, each one adorned with between 700 and 800 barbs along the 4 millimeters or so nearest its tip. Although those barbs help the quills remain embedded in a victim’s skin, scientists haven’t studied the details of how they do so. To better understand the function of the barbs and to determine if they might be useful for medical devices, Karp and his colleagues conducted several lab tests—with, in some cases, unexpected results.

The researchers took barbed porcupine quills and plunged them into samples of pig skin, measuring how much force it took to pierce the flesh and then how much force was required to extricate the quill. The team then performed the same tests using quills whose barbs they had sanded off. They also tested an African porcupine’s quills (which naturally have no barbs) and an 18-gauge hypodermic needle, which is approximately the same diameter as a quill from the North American porcupine. To the scientists’ surprise, barbed quills required approximately half the penetration force of the barbless quills—either those naturally barbless or those sanded clean—and only 56% of the force needed for the hypodermic needle to breach the skin. The researchers report their findings online today in the Proceedings of the National Academy of Sciences. Computer models suggest that the barbs ease the quill’s penetration by concentrating force along the edges of the barbs, similar to how the serrations on a knife blade make cutting meat easier, Karp says. Barbs render a quill about four times harder to pull out once they’re embedded, the team found. The barbs at the tip of the quill were most effective at resisting removal. In fact, the barbs located within 1 millimeter of the tip contributed about half of the pull-out resistance—possibly because the flesh more tightly surrounded the tip than it did the rest of the quill, Karp says.

The team’s findings could be used to enhance various biomedical devices or to design new ones, Karp says. For instance, he notes, rather than use wound dressings that rely on a chemical adhesive, which can trigger allergies or cause other problems, dressings could use tiny barbed needles to pierce the skin and then hold tight. Also, the staples now used to hold some surgical incisions shut—which largely rely on friction along their length to remain in the flesh—could be replaced by barbed staples that are shorter and have a smaller diameter. Even though porcupine quills cause some damage to flesh when they’re pulled out, extricating smaller, quill-inspired staples would likely cause less overall damage than pulling out the staples currently in use, Karp suggests. The team’s findings “are just one more example of how what we see in nature can help us,” says Anthony Atala, a biomedical researcher at Wake Forest Baptist Medical Center in Winston-Salem, North Carolina. Hollow versions of quill-inspired needles could help doctors better deliver drugs or chemicals through patches adhering to the skin, he notes. “Now that we know how these barbs work, we can modify them to make devices perform even better.”

ScienceNow
January 8, 2013

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How the tabby got its blotches

Domestic cats often resemble their larger, wilder counterparts—with black, striped, or tawny fur that presumably helps the big hunters blend into the landscape. For scientists, the genes involved in the evolution of cats’ color patterns have been equally well-camouflaged. But a new study appearing online today in Science reveals a mutation shared by housecats and cheetahs, which may explain how the cat got its stripes—or in this case, its blotches. The sharp, evenly spaced stripes of the tabby cat are among the most common of coat patterns. In some tabbies, however, the stripes look more like long, irregular swirls. Although fairly common in domestic cats, this pattern (called “blotched” by geneticists and cat fanciers) is unusual in the wild. In fact, cheetahs with the blotched pattern were initially thought to be a separate species—they were crowned with the name king cheetahs to distinguish them from the more common, spotted kind. To pinpoint the gene responsible for the difference, an international team of researchers scanned the genomes of feral cats that had either stripes or blotches. Their search led to an unnamed gene about which little is known except that it produces an enzyme that cuts up nearby proteins. The researchers found that every blotched tabby had mutations in both copies of this gene, whereas every striped cat had at least one copy without the mutation. They then found the distinctive mutations in the same gene among DNA samples from a pedigreed family of king cheetahs, confirming their suspicions that mutations in the gene, which they dubbed Taqpep, turned ordinary stripes into the more regal blotches.

Further scrutiny of the cheetah skin made it clear that Taqpep didn’t control the actual colors, because levels of the gene didn’t change between dark and light areas. However, another gene, Edn3, was active at the base of the black hairs. Wondering if the two genes worked in tandem to produce stripes, the researchers studied housecat embryos at several stages of development. They found that the tabby pattern appears only after the hairs begin to grow at 7 weeks of gestation. Meanwhile, levels of Taqpep increase throughout gestation. The researchers propose that very early in development, Taqpep establishes a pattern of stripes or spots, which is then implemented by varying levels of Edn3 as the embryo grows. The role of Taqpep in setting the pattern early on also explains why the number of stripes or spots doesn’t change as the cat ages (unlike in nonmammalian spotted animals such as salamanders and some fish).

“We knew the gene was out there, but we didn’t know what it did. It’s exciting to use the power of genetics to unravel these pathways,” says co-author of the study Stephen O’Brien, a geneticist who was then at the National Laboratory for Cancer Research in Frederick, Maryland, but now heads the Theodosius Dobzhansky Center for Genome Informatics in St. Petersburg, Russia. The possibility that Taqpep might be involved in pigment was totally off anyone’s radar,” says geneticist Sheila Schmutz of the University of Saskatchewan in Saskatoon, Canada. “Scientists who study color patterns now have a totally new gene with a well-defined function to work with.” O’Brien and his collaborators Gregory Barsh and Christopher Kaelin of the HudsonAlpha Institute for Biotechnology in Huntsville, Alabama, wonder why cats have frequently spawned this plethora of color variation and why the blotch-producing Taqpep mutation didn’t simply disappear after one or two generations in the wild. O’Brien is not convinced that protective coloration is the only survival advantage conferred by pigment-related genes like Taqpep. “Big predatory cats hunt their prey; camouflage may be helpful but isn’t essential to survival,” he notes. O’Brien predicts that color-producing genes will prove to play some other vital role—perhaps in resistance to disease. Taqpep, he says, belongs to a family of genes that are involved in immunity and produce receptors that are often co-opted by viruses seeking entry into a cell. A mutation in this gene may have helped some cats survive infection, he says. Geneticist Elaine Ostrander of the National Human Genome Research Institute in Bethesda, Maryland, says that although many papers report a gene or two linked to a particular color, this work ties together several steps in a pattern-producing pathway. “It’s an exciting missing piece of the puzzle,” she says.

ScienceNow
October 30, 2012

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Skin hair skims heat off elephants

Body hair in mammals is typically thought to have evolved to keep us warm in colder prehistoric times, but a new study suggests that it may do the opposite, at least in elephants. Epidermal hair may have evolved to help the animals keep cool in the hot regions they live in, according to new research published Oct 10 in the open access journal PLOS ONE by Conor Myhrvold and colleagues at Princeton University. Though the idea that low surface densities of hair can help dissipate heat is a popular concept in engineering, the biological and evolutionary significance of sparse skin hair is not well known. The authors studied the effects of skin hair densities in Asian and African elephants on thermoregulation in these animals, and concluded that elephant skin hair significantly enhances their capacity to keep cool under different scenarios like higher daytime temperatures or less windy days. Their research suggests that the dense body hair of furry animals helps with insulation, but as skin hair grows sparser, a tipping point is reached where, for animals such as elephants, skin hair begins to help release heat from the body rather than retain it.

According to the authors, elephants have the greatest need for such heat loss to maintain a constant body temperature, since they are large terrestrial mammals that live in hot climates. Their results are the first to suggest that animal hairs could play a role in heat dissipation that could be beneficial to certain animals, like elephants. Elie Bou-Zeid, corresponding author on the study, says “Sparse hair increases heat dissipation from the skin of elephants and help the largest terrestrial mammal meet its thermoregulation needs.”

Science Daily
October 30, 2012

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Using ultrasound waves, researchers boost skin’s permeability to drugs

Using ultrasound waves, MIT engineers have found a way to enhance the permeability of skin to drugs, making transdermal drug delivery more efficient. This technology could pave the way for noninvasive drug delivery or needle-free vaccinations, according to the researchers. “This could be used for topical drugs such as steroids — cortisol, for example — systemic drugs and proteins such as insulin, as well as antigens for vaccination, among many other things,” says Carl Schoellhammer, an MIT graduate student in chemical engineering and one of the lead authors of a recent paper on the new system. Ultrasound — sound waves with frequencies greater than the upper limit of human hearing — can increase skin permeability by lightly wearing away the top layer of the skin, an effect that is transient and pain-free. In a paper appearing in the Journal of Controlled Release, the research team found that applying two separate beams of ultrasound waves — one of low frequency and one of high frequency — can uniformly boost permeability across a region of skin more rapidly than using a single beam of ultrasound waves.

When ultrasound waves travel through a fluid, they create tiny bubbles that move chaotically. Once the bubbles reach a certain size, they become unstable and implode. Surrounding fluid rushes into the empty space, generating high-speed “microjets” of fluid that create microscopic abrasions on the skin. In this case, the fluid could be water or a liquid containing the drug to be delivered. In recent years, researchers working to enhance transdermal drug delivery have focused on low-frequency ultrasound, because the high-frequency waves don’t have enough energy to make the bubbles pop. However, those systems usually produce abrasions in scattered, random spots across the treated area. In the new study, the MIT team found that combining high and low frequencies offers better results. The high-frequency ultrasound waves generate additional bubbles, which are popped by the low-frequency waves. The high-frequency ultrasound waves also limit the lateral movement of the bubbles, keeping them contained in the desired treatment area and creating more uniform abrasion, Schoellhammer says. “It’s a very innovative way to improve the technology, increasing the amount of drug that can be delivered through the skin and expanding the types of drugs that could be delivered this way,” says Samir Mitragotri, a professor of chemical engineering at the University of California at Santa Barbara, who was not part of the research team.

The researchers tested their new approach using pig skin and found that it boosted permeability much more than a single-frequency system. First, they delivered the ultrasound waves, then applied either glucose or inulin (a carbohydrate) to the treated skin. Glucose was absorbed 10 times better, and inulin four times better. “We think we can increase the enhancement of delivery even more by tweaking a few other things,” Schoellhammer says. Such a system could be used to deliver any type of drug that is currently given by capsule, potentially increasing the dosage that can be administered. It could also be used to deliver drugs for skin conditions such as acne or psoriasis, or to enhance the activity of transdermal patches already in use, such as nicotine patches. Ultrasound transdermal drug delivery could also offer a noninvasive way for diabetics to control their blood sugar levels, through short- or long-term delivery of insulin, the researchers say. Following ultrasound treatment, improved permeability can last up to 24 hours, allowing for delivery of insulin or other drugs over an extended period of time. Such devices also hold potential for administering vaccines, according to the researchers. It has already been shown that injections into the skin can induce the type of immune response necessary for immunization, so vaccination by skin patch could be a needle-free, pain-free way to deliver vaccines. This would be especially beneficial in developing countries, since the training required to administer such patches would be less intensive than that needed to give injections. The Blankschtein and Langer groups are now pursuing this line of research.

Science Daily
October 2, 2012

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Protective role of skin microbiota described

A research team at the National Institutes of Health has found that bacteria that normally live in the skin may help protect the body from infection. As the largest organ of the body, the skin represents a major site of interaction with microbes in the environment. Although immune cells in the skin protect against harmful organisms, until now, it has not been known if the millions of naturally occurring commensal bacteria in the skin — collectively known as the skin microbiota — also have a beneficial role. Using mouse models, the NIH team observed that commensals contribute to protective immunity by interacting with the immune cells in the skin. Their findings appear online on July 26 in Science. The investigators colonized germ-free mice (mice bred with no naturally occurring microbes in the gut or skin) with the human skin commensal Staphylococcus epidermidis. The team observed that colonizing the mice with this one species of good bacteria enabled an immune cell in the mouse skin to produce a cell-signaling molecule needed to protect against harmful microbes. The researchers subsequently infected both colonized and non-colonized germ-free mice with a parasite. Mice that were not colonized with the bacteria did not mount an effective immune response to the parasite; mice that were colonized did.

In separate experiments, the team sought to determine if the presence or absence of commensals in the gut played a role in skin immunity. They observed that adding or eliminating beneficial bacteria in the gut did not affect the immune response at the skin. These findings indicate that microbiota found in different tissues — skin, gut, lung — have unique roles at each site and that maintaining good health requires the presence of several different sets of commensal communities. This study provides new insights into the protective role of skin commensals and demonstrates that skin health relies on the interaction of commensals and immune cells. Further research is needed, say the authors, to determine whether skin disorders such as eczema and psoriasis may be caused or exacerbated by an imbalance of skin commensals and potentially harmful microbes that influence the skin and its immune cells.

Science Daily
August 7, 2012

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Patients’ skin cells turned into heart muscle cells to repair their damaged hearts

For the first time scientists have succeeded in taking skin cells from heart failure patients and reprogramming them to transform into healthy, new heart muscle cells that are capable of integrating with existing heart tissue. The research, which is published online May 22 in the European Heart Journal, opens up the prospect of treating heart failure patients with their own, human-induced pluripotent stem cells (hiPSCs) to repair their damaged hearts. As the reprogrammed cells would be derived from the patients themselves, this could avoid the problem of the patients’ immune systems rejecting the cells as “foreign.” However, the researchers warn that there are a number of obstacles to overcome before it would be possible to use hiPSCs in humans in this way, and it could take at least five to ten years before clinical trials could start. Recent advances in stem cell biology and tissue engineering have enabled researchers to consider ways of restoring and repairing damaged heart muscle with new cells, but a major problem has been the lack of good sources of human heart muscle cells and the problem of rejection by the immune system. Recent studies have shown that it is possible to derive hiPSCs from young and healthy people and that these are capable of transforming into heart cells. However, it has not been shown that hiPSCs could be obtained from elderly and diseased patients. In addition, until now researchers have not been able to show that heart cells created from hiPSCs could integrate with existing heart tissue.

Professor Lior Gepstein, Professor of Medicine (Cardiology) and Physiology at the Sohnis Research Laboratory for Cardiac Electrophysiology and Regenerative Medicine, Technion-Israel Institute of Technology and Rambam Medical Center in Haifa, Israel, who led the research, said: “What is new and exciting about our research is that we have shown that it’s possible to take skin cells from an elderly patient with advanced heart failure and end up with his own beating cells in a laboratory dish that are healthy and young — the equivalent to the stage of his heart cells when he was just born.” Ms Limor Zwi-Dantsis, who is a PhD student in the Sohnis Research Laboratory, Prof Gepstein and their colleagues took skin cells from two male heart failure patients (aged 51 and 61) and reprogrammed them by delivering three genes or “transcription factors” (Sox2, Klf4 and Oct4), followed by a small molecule called valproic acid, to the cell nucleus. Crucially, this reprogramming cocktail did not include a transcription factor called c-Myc, which has been used for creating stem cells but which is a known cancer-causing gene. “One of the obstacles to using hiPSCs clinically in humans is the potential for the cells to develop out of control and become tumours,” explained Prof Gepstein. “This potential risk may stem from several reasons, including the oncogenic factor c-Myc, and the random integration into the cell’s DNA of the virus that is used to carry the transcription factors — a process known as insertional oncogenesis.”

The researchers also used an alternative strategy that involved a virus that delivered reprogramming information to the cell nucleus but which was capable of being removed afterwards so as to avoid insertional oncogenesis. The resulting hiPSCs were able to differentiate to become heart muscle cells (cardiomyocytes) just as effectively as hiPSCs that had been developed from healthy, young volunteers who acted as controls for this study. Then the researchers were able to make the cardiomyocytes develop into heart muscle tissue, which they cultured together with pre-existing cardiac tissue. Within 24-48 hours the tissues were beating together. “The tissue was behaving like a tiny microscopic cardiac tissue composed of approximately 1000 cells in each beating area,” said Prof Gepstein. Finally, the new tissue was transplanted into healthy rat hearts and the researchers found that the grafted tissue started to establish connections with the cells in the host tissue. “In this study we have shown for the first time that it’s possible to establish hiPSCs from heart failure patients — who represent the target patient population for future cell therapy strategies using these cells — and coax them to differentiate into heart muscle cells that can integrate with host cardiac tissue,” said Prof Gepstein. “We hope that hiPSCs derived cardiomyocytes will not be rejected following transplantation into the same patients from which they were derived. Whether this will be the case or not is the focus of active investigation. One of the obstacles in dealing with this issue is that, at this stage, we can only transplant human cells into animal models and so we have to treat the animals with immunosuppressive drugs so the cells won’t be rejected.”

Much research has to be conducted before these results could be translated into treatment for heart failure patients in the clinic. “There are several obstacles to clinical translation,” said Prof Gepstein. “These include: scaling up to derive a clinically relevant number of cells; developing transplantation strategies that will increase cell graft survival, maturation, integration and regenerative potential; developing safe procedures to eliminate the risks for causing cancer or problems with the heart’s normal rhythm; further tests in animals; and large industry funding since it is likely to be a very expensive endeavour. I assume it will take at least five to ten years to clinical trials if one can overcome these problems.” Prof Gepstein and his colleagues will be carrying out further research into some of these areas, including evaluating using hiPSCs in cell therapy and tissue engineering strategies for repairing damaged hearts in various animal models, investigating inherited cardiac disorders, and drug development and testing.

Science Daily
June 12, 2012

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Light-induced delivery of nitric oxide eradicates drug-resistant bacteria

Researchers at UC Santa Cruz have developed a novel approach for eradicating drug-resistant bacteria from wounds and skin infections, using light to trigger the controlled release of nitric oxide. The UCSC team developed a photoactive compound that releases nitric oxide when exposed to light, and loaded it into a porous, biocompatible material that could be applied as a sprayable powder. In laboratory tests, the light-triggered nitric oxide treatment eradicated a highly drug-resistant strain of Acinetobacter baumannii, a type of gram-negative bacteria that causes hard-to-treat and potentially lethal infections throughout the world, including serious infections in soldiers wounded in Iraq and Afghanistan. The team led by Pradip Mascharak, professor of chemistry and biochemistry at UC Santa Cruz, and graduate student Brandon Heilman published their results in the Journal of the American Chemical Society (JACS). The paper is currently available online and will be featured on the cover of a future print issue of the journal.

Nitric oxide has potent antimicrobial effects and is known to play a role in the immune system and promote wound healing. Gaseous nitric oxide has been used to treat infected wounds, but handling the toxic and reactive gas poses many challenges. So researchers have begun exploring a variety of other methods for delivering nitric oxide as an antibiotic treatment. Because nitric oxide attacks a large number of targets in microorganisms, including DNA, proteins, and lipids, many scientists expect bacteria will not easily develop resistance to it. Mascharak’s lab developed a photoactive manganese nitrosyl, a compound that rapidly releases nitric oxide when exposed to light. As a carrier for this compound, the researchers used a porous silicate material known as MCM-41, which traps the photoactive compound inside its pores. They also tested a related aluminosilicate material (Al-MCM-41), which holds the photoactive compound even more tightly. Tests showed that after the light-triggered release of nitric oxide, the byproduct of the reaction remains trapped inside the powdery, biocompatible material. “It only delivers nitric oxide. The rest remains trapped in the material, which can be washed out of the wound,” Mascharak said. “We think it could be used as a sprayable powder for treating battlefield wounds.”

Acinetobacter baumannii has earned the nickname “Iraqibacter” because it has caused so many serious infections in soldiers wounded in Iraq. Some strains of the bacteria are resistant to virtually all antibiotics. Mascharak’s lab tested their compound against a strain, isolated from a soldier injured in Afghanistan, that showed resistance to nine of 11 antibiotics tested. To test the photoactive compound, the researchers developed a laboratory model of skin and soft-tissue infections. A standard antibacterial assay involves growing bacteria on the surface of an agar plate (a petri dish with a layer of firm, gelatin-like growth medium). In an infection, however, bacteria are not only on the surface but also deeper within the skin or soft tissues. “We realized that there wasn’t a good model for in vitro testing of antibiotics against soft-tissue infections,” Heilman said. To more closely mimic the conditions in an infected wound, Heilman mixed bacteria into a warm solution of “soft brine agar” and poured that onto agar plates to solidify. The bacteria then grew throughout a 1.1-millimeter-thick layer of soft agar, allowing growth and colonization to occur in a manner similar to that seen in skin and soft-tissue infections.

Heilman then applied the aluminosilicate powder, with and without the photoactive manganese nitrosyl compound, to a defined area of the plates before shining visible light on them. The released nitric oxide effectively cleared the bacteria from the treated areas of the plates, showing that the nitric oxide easily penetrated through the agar layer. The amount of light used to activate the compound (100 milliWatts per square centimeter) is a typical light flux on a sunny day, Mascharak said. The ability to control the release of nitric oxide using light is a significant advantage for clinical applications, he added. Tests showed that illumination of the material causes a steady release of nitric oxide, which can be stopped and started repeatedly by turning the light off and on. In the field, this could be accomplished by covering and uncovering the treated area.

Science Daily
June 12, 2012

Original web page at Science Daily