Culture

The risk of preterm infants developing necrotizing enterocolitis (NEC) is higher when they are fed formula than when they feed on breast milk. Of the many reasons why breast milk protects preterm infants from this serious condition better than formula, not all of them are well understood. In a study published in the journal Microbiome, a team of researchers at the USDA-ARS Children's Nutrition Research Center at Baylor College of Medicine and Texas Children's Hospital, and the Mead Johnson Pediatric Nutrition Institute report an association between the type of carbohydrates in formula; the products of metabolism or metabolites; and the risk of NEC in a piglet model of the human condition. The researchers suggest that further study of the metabolite profiles could provide a better understanding of the development of the disease and potentially lead to improved treatments.

"NEC is a devastating, serious disease that causes an inflammatory process that leads to intestinal damage and sometimes death. It is rare in full term babies, but it occurs more often in preterm infants. The earlier before full term the infant is born, the higher the risk of developing the disease," said corresponding author Dr. Douglas Burrin, research physiologist at the USDA-ARS Children's Nutrition Research Center and professor of pediatrics at Baylor College of Medicine. "Although this condition has been known for more than 50 years, we still don't understand exactly how it develops. In this study we worked with a premature piglet model of NEC that closely reproduces the characteristics observed in human infants."

The researchers had previously shown that the type of carbohydrate or sugar in the diet of preterm piglets affected the risk of developing NEC. Preterm infant formulas contain two main sugars, lactose and corn syrup solids. The main carbohydrates in human milk are lactose and oligosaccharides. The researchers previously showed that feeding formula containing the sugar lactose protected preterm piglets from NEC. In comparison, piglets fed formula containing corn syrup solids had a higher risk of developing the condition. In this study, the researchers took a closer look at the effect of these two different sugars on the development of NEC using a more detailed analysis than had been done in previous studies: they characterized the bacterial communities, or microbiome, of the gut, and the metabolite profiles found in the gut and the blood.

"We asked, how does the diet interact with the microbiome in the developing piglet gut, and how does that interaction shape not only the community of bacteria but also the metabolites found in the gut and blood of the piglets," Burrin said. "To identify the metabolites produced by the piglets, we partnered with Metabolon, a company that specializes in the analysis of all the main products of metabolism and their intermediates in a cell, tissue or organism. We also partnered with the Alkek Center for Metagenomics and Microbiome Research at Baylor College of Medicine to conduct the microbiome analysis in the piglets, comparing the effects the two diets have on the profiles of bacteria growing in their gut."

The researchers confirmed that formula with lactose can protect piglets from developing NEC better than formula with corn syrup solids. Fourteen percent of the piglets in the lactose-containing formula developed NEC, while 44 percent of the piglets in the corn syrup solids-containing formula presented with the condition.

"We determined that the communities of bacteria were not dramatically different between the lactose and the corn syrup solids group, but the metabolite profiles were quite different," said Burrin. "We found a clear association between the metabolite profile, the sugar in the diet and the risk of developing NEC. This suggested that the metabolite profile is perhaps an early determinant of the development of this disease, as the microbiome begins to develop."

"We think that the metabolite profiles we identified correlating with disease are going to be useful for generating and testing new hypotheses to better understand how this disease happens," said first author Lee Call, a graduate student in the Burrin lab.

The researchers' next plan is to study in more detail what these metabolites that correlate with the disease are doing to lead to the condition, for instance, what biological pathways they are triggering or how they interact with cells in the gut.

Tuesday, June 26st, Rockville, MD - Today, Insilico Medicine, Inc., a Rockville-based next-generation artificial intelligence company specializing in the application of deep learning for target identification, drug discovery and aging research announces the publication of a new research paper "Reinforced Adversarial Neural Computer for De Novo Molecular Design" in The Journal of Chemical Information and Modeling. The authors presented an original deep neural network architecture named Reinforced Adversarial Neural Computer (RANC) for the de novo design of novel small-molecule organic structures utilizing the generative adversarial network (GAN) and reinforcement learning (RL) methods.

"In this work, we introduced RANC architecture for de novo molecular design. Our engine generates more unique and diverse structures as well as clusters with the lengths close to the reference samples, keeping the distributions of key molecular descriptors as in the training sets. As a result, many of the generated structures meet the crucial criteria used in medicinal chemistry of today and are able to pass medical chemistry filters. I hope this approach will become a starting point to making perfect molecules for specific targets and multiple targets that will have a much higher chance of becoming great drugs", said Evgeny Putin, the deep learning lead at Insilico Medicine.

In silico modeling is a crucial milestone in modern drug design & development. Although computer-aided approaches in this field are well-studied, the application of deep learning methods in this research area is at the beginning facing a lot of challenges.

The comparative results have shown that RANC trained on the SMILES string representation of the molecules outperforms the other methods by several metrics relevant to drug discovery: the number of unique structures, passing medicinal chemistry filters, Muegge criteria and high quantitative estimate of drug-likeness scores. RANC is able to generate structures that match the distributions of the key chemical features/descriptors (e.g. MW, logP, TPSA) and lengths of the SMILES strings in the training dataset. Therefore, RANC can be reasonably regarded as a promising starting point to develop novel molecules with activity against different biological targets or pathways.

This work was carried out in collaboration with one of the most prominent groups in AI-enabled chemistry and quantum chemistry, lead by Prof. Alan Aspuru-Guzik. One of the co-authors of the paper is Benjamin Sanchez-Lengeling - the author of the Objective-Reinforced Generative Adversarial Networks (ORGAN), one of the first objective--reinforced molecular generators.

From a medicinal chemistry perspective, it would be very interesting to investigate how the results of modeling depend on the carefully selected reference compounds as well as the application of the model for the generation of structures with biological activity toward specific targets.

For its work in the field of artificial intelligence for drug discovery and development, Insilico Medicine received the Frost & Sullivan 2018 North American Artificial Intelligence for Aging Research and Drug Development Technology Innovation Award. The company plans to use GAN-RL systems to target age-related diseases and aging itself.

"Technology leadership in artificial intelligence for drug discovery and biomarker development, academic excellence, extensive collaborations with pharmaceutical and consumer companies, novel methods of attracting top talent, and increasing global reach have allowed Insilico Medicine to build a credible and sustainable business model in the nascent longevity biotechnology industry," noted Neelotpal Goswami. "In recognition of its pioneering research and ability to introduce novel products and solutions for age management, Frost & Sullivan is pleased to present it with the 2018 Technology Innovation Award."

Refraining from bad behavior toward a significant other during stressful life events is more important than showing positive behavior, according to a Baylor University study.

Compared with positive gestures, negative ones tend to trigger more intense and immediate responses, according to the study. And how a couple works together during trying times is associated with individual well-being as well as satisfaction with the relationship.

"When people face stressful life events, they are especially sensitive to negative behavior in their relationships, such as when a partner seems to be argumentative, overly emotional, withdrawn or fails to do something that was expected," said researcher Keith Sanford, Ph.D., professor of psychology and neuroscience in Baylor's College of Arts & Sciences.

"In contrast, they're less sensitive to positive behavior -- such as giving each other comfort," he said.

The study also found that low doses of a behavior are most important, and over time, more extreme levels have less impact.

"Because people are especially sensitive to negative relationship behavior, a moderate dose may be sufficient to produce a nearly maximum effect on increasing life stress," Sanford said. "After negative behavior reaches a certain saturation point, it appears that stress is only minimally affected by further increases in the dose of relationship problems."

The study -- "Negative Relationship Behavior Is More Important Than Positive: Correlates of Outcomes During Stressful Life Events" -- is published in Journal of Family Psychology. Sanford and co-researcher Alannah Shelby Rivers, doctoral candidate in psychology and neuroscience, surveyed couples experiencing stressful life events to measure their behavior, relationship satisfaction, personal well-being and quality of life.

The research consisted of two studies done using data from Internet samples.

In the first study, 325 couples who were married or living with a partner all reported experiences of at least one of six possible stressful events within the past month, including: losing a job, becoming a primary caregiver of an older relative, experiencing a parent's death, experiencing a child's death, not having enough resources to afford basic necessities, and experiencing bankruptcy, foreclosure or repossession of a house or car.

The second study included 154 people who were either married or living with a partner and experiencing a serious medical issue meeting one or more of these criteria: a condition requiring hospitalization or a trip to the emergency room, a serious chronic condition and a life-threatening condition. All participants reported that they had visited a medical practitioner within the past year for treatment of their conditions.

Researchers used a scale that included 18 items -- nine for negative and nine for positive behavior. Participants were asked to remember the past month, then write a few words describing different memories of interactions occurring in their relationships and indicate how often specific types of interactions occurred in their relationships.

All participants also were asked questions about how rewarding their relationships were, their general well-being (such as being active and vigorous) and their quality of life (such as health). Those in the first study also were asked about stress, their coping strategies in general and their coping style in the relationship.

The second study, examining couple's behavior during stressful medical events, showed lower levels of negative behavior than the first study dealing with other types of stressful issues.

"It is possible that couples facing stressful medical situations are less likely to blame each other," researchers wrote.

"When people face stressful life events, it's common to experience both positive and negative behavior in their relationships," Sanford said. "When the goal is to increase feelings of well-being and lessen stress, it may be more important to decrease negative behavior than to increase positive actions."

A recent study found that online responses to female presenters in TEDx and TED-Ed videos were more polarized than responses to male presenters.

In an article in top journal PLOS ONE, Brigham Young University education professors Royce Kimmons and Ross Larsen, along with three other co-authors, found that though most comments on TEDx and TED-Ed videos are neutral, women receive more of both positive and negative comments than men.

The study found that TED-Ed's animated videos -- with neither a female nor male focal point -- also receive primarily neutral responses.

"It was surprising that there was so much more polarity when you could see physical appearance," Kimmons said.

The research team saw the study as a start to understanding how online participation experiences may vary by gender.

"As online learning offerings expand, and as more and more institutions encourage academics to go online, universities need to consider how online negativity seems to disproportionately affect some academics more than others," said George Veletsianos, co-author and education professor at Royal Roads University.

Regardless of presenter gender or presentation format, researchers saw that a positive comment in a video's thread encouraged additional positive commentary and negative comments often led to additional negative commentary.

That in turn raised the question of internet comment moderation. But though Kimmons acknowledged the struggle between allowing freedom of speech while minimizing the damage from internet trolls, he advised against taking every negative comment off of a thread because, he said, deleting negativity could crush what has the potential to become a good conversation. He argued that individual media literacy would be the best moderation.

"As a society we need to develop an awareness of the media we are using and how these media are influencing our personal behaviors," said Kimmons, who was encouraged to see individuals' power to sometimes shift a negative thread with a positive comment.

Kimmons said historical gender norms may play a part in the polarized comments, since the women in TEDx videos are often accomplished in fields viewed as traditionally male professions -- like STEM.

"When you have a platform where you are a powerful woman in a field that has historically been unwelcome to you, the community responds in unwelcome ways," he said.

Kimmons said the study is an important step in understanding issues of civility and harassment in online discourse, but noted that "there is a lot more work that needs to be done to help us better understand people's experiences online and help us identify instances and patterns of harassment, abuse and so forth."

In October 2015, two small minnows in the Lower Colorado River Basin -- the headwater chub and the roundtail chub -- were proposed for listing as threatened species under the Endangered Species Act of 1973. In April 2017, that proposal was withdrawn after new science identified the two small fish as members of the same species.

As technologies advance, genetic research is playing an increasingly important role in informing decisions about the conservation of threatened and endangered species. In addition to the roundtail chub, another recent example is the Mexican wolf.

The Mexican wolf is one of 43 animals listed as endangered in Arizona, where a captive breeding program for Canis lupus baileyi has been underway since the late 1970s, when the population dipped as low as seven wolves in the wild. The selective breeding of a small population brings with it specific genetic concerns: Are the genetics pure, or had the Mexican wolf, on its path to near-extinction, cross-bred with domestic dogs?

"It's a question that's been brought up since before the captive breeding population started," said Bob Fitak, a University of Arizona alumnus who wrote his dissertation on the Mexican wolf while working in Melanie Culver's conservation genetics laboratory at the UA. "Are we dealing with something that is actually a Mexican wolf, or is it something a bit different?"

Advances in genomic technology made it possible for researchers to find out. Earlier studies that examined the genetic purity of the Mexican wolf were hindered by small numbers -- fewer than 10 Mexican wolves had been analyzed, none of which came from the original three captive lineages. Fitak and his colleagues genotyped 87 Mexican wolves representing a broad spectrum of pedigrees, including all three original captive lineages, a mixture of those lineages and wolves born in the wild.

Fitak's dissertation and subsequent research led to the recent publication of "Genome-Wide Analysis of SNPs Is Consistent With No Domestic Dog Ancestry in the Endangered Mexican Wolf" in the Journal of Heredity1. Fitak, who now works for Duke University in the Department of Biology, was lead author on the paper that included Sarah Rinkevich, a UA alumna and endangered-species biologist with the U.S. Fish and Wildlife Service, and Culver, a U.S. Geological Survey geneticist at the Arizona Cooperative Fish and Wildlife Research Unit and an associate in the UA College of Agriculture and Life Sciences' School of Natural Resources and the Environment.

The study was the first to analyze the Mexican wolf utilizing genome enabling, which allows researchers to use genomic data from one species, such as domestic dogs, to study a similar species, such as Mexican wolves.

"I started in Melanie's lab about the time there was this growth in genomic technologies, so I was interested in those new concepts and new ways of applying things," Fitak said. "Wolves are pretty unique because we had a really interesting Mexican wolf population, and we had some new tools from dogs that we could use to study them in a way that hadn't been done before."

Fitak's analysis benefited from advances in genomic technologies such as SNP chips, which analyze single nucleotide polymorphisms, or SNPs. Each SNP represents a difference in a single DNA building block, making it useful as a biological marker.

Prior studies were able to analyze only about two dozen biological markers. SNP chips allowed Fitak to examine more than 172,000 SNPs across the whole genome.

The first section of Fitak's study looked at average ancestry across the genome, also known as global ancestry. The analysis showed that across the entire genome, Mexican wolves share an average of only .06 percent ancestry with domestic dogs, indicating a lack of biologically significant ancestry from domestic dogs. The Mexican wolf, which became isolated in North America prior to the domestication of dogs in Europe, shares a small amount of ancestry with the European gray wolf, while 98.9 percent of the Mexican wolf genome is specific to the subspecies.

The second section looked at local ancestry, which is ancestry at a specific chromosomal location. When individual chromosomes were analyzed, an average of 7.8 percent of the Mexican wolf genome contained fragments that could have resulted from domestic dogs.

"There are some signals of domestic dog in the Mexican wolf genome," Culver said of the 7.8 percent. "Are they just artifacts? Could that similarity be by chance because they're closely related, or could there have been some event where a domestic dog did hybridize with wolves, and if so, when was it? Was it recently or was it a long time ago, like thousands of years ago?"

To answer the questions, Fitak and his colleagues simulated what the Mexican wolf genome would look like if no hybridization took place, or if hybridization with domestic dogs occurred two generations ago, 20 generations ago or 200 generations ago. The observed Mexican wolf data matched the predictive model of no hybridization between Mexican wolves and domestic dogs.

"This study, showing no hybridization with domestic dogs found within this population, was important because it again confirms the genetic purity of the Mexican wolf," said Rinkevich, who is often involved in the listing and delisting of endangered and threatened species in her role as an endangered-species biologist. "That genetic information is important to conservation efforts."

The study by Fitak, Rinkevich and Culver netted genetic data from the largest population of Mexican wolves that is now publicly available for all geneticists to use in future research. For Fitak, that might mean delving deeper into the amount of inbreeding in the Mexican wolf as the captive breeding program continues. Until then, an important question about one endangered species, the Mexican wolf, finally has been answered.

Scientists at UT Health San Antonio have edited a gene in the brain to decrease the repetitive behaviors of mice with fragile X syndrome, which is an inherited cause of autism spectrum disorders. The study is described in the July issue of Nature Biomedical Engineering.

The San Antonio researchers, who included study leader Hye Young Lee, Ph.D, and first author Bumwhee Lee, Ph.D., used nanoparticle carriers developed in California to inject a gene-editing enzyme called Cas9 into the striatum, a brain region associated with formation of habits.

Enzymes are proteins that trigger biochemical reactions. "The enzyme we used, Cas9, is like a pair of scissors," said Dr. Hye Young Lee, assistant professor in the Department of Cellular and Integrative Physiology at UT Health San Antonio. "We were able to cut the genetic blueprint, DNA, at a location that causes the exaggerated repetitive behaviors."

The researchers targeted Cas9 at a molecule called mGluR5 that is excitatory--it increases communications between neurons. The approach worked. The rodents' digging behavior slowed by 30 percent and the leaping behavior was reduced by 70 percent. In the process, the research revealed valuable information about mGluR5's function, Dr. Lee said.

Groundbreaking

The team is believed to be the first to successfully edit a causal gene for autism in the brain and diminish symptoms, the authors wrote. Significantly, the effect is permanent, Dr. Lee said.

"The approach can also be used to treat other diseases if we know the gene target," she said. This includes many neurological diseases such as epilepsy, and the brain cancer glioblastoma."

The study is also one of the first in the scientific literature to employ a safer, non-viral approach of Cas9 delivery to a brain region.

"Previous attempts by other groups used viral carriers to convey Cas9, which has potential problems because the virus can't be programmed to stop working," said Dr. Bumwhee Lee, postdoctoral fellow in Dr. Hye Young Lee's laboratory. "This can result in serious immune reactions and cell toxicity."

Philadelphia, June 26, 2018 - Poor sleep quality appears to be an important risk factor for atrial fibrillation, report scientists in the first study of its kind to demonstrate a relationship between poor sleep quality independent of sleep apnea and a higher risk of atrial fibrillation (AF). Their findings are published in HeartRhythm.

AF is an irregular, rapid heart rate that may cause symptoms such as heart palpitations, fatigue, and shortness of breath. It can substantially reduce quality of life and is associated with heightened risks of stroke, dementia, heart attack, kidney disease, and death. Obstructive sleep apnea has been established as a risk factor for AF, but the mechanism is unclear. While episodes of abnormally slow or shallow breathing (hypopnea) and apnea may cause cardiopulmonary stress, induce inflammation, and contribute to cardiovascular disease, obstructive sleep apnea also results in poor sleep. Aspects of poor sleep such as altered sleep duration, efficiency, and architecture have been linked to other cardiovascular diseases.

"While a relationship between sleep apnea and AF has previously been demonstrated, the effect of sleep itself on AF risk has remained unknown," explained lead investigator Gregory M. Marcus, MD, MAS, Electrophysiology Section, Division of Cardiology, Department of Medicine, University of California, San Francisco, CA, USA. "Strategies to enhance sleep quality are different from those that focus on relieving airway obstruction, so it is important to understand the relationship between sleep itself and AF."

Investigators drew on four different studies to determine whether poor sleep itself is a risk factor for AF. First, they used the global, internet-based Health eHeart Study and determined that individuals with more frequent nighttime awakenings while trying to sleep more often carried a diagnosis of AF. They then validated these findings by using the NIH-funded Cardiovascular Health Study, a prospective cohort study, in which they found that individuals who reported more frequent nighttime awakenings at baseline exhibited a higher risk of developing AF both before and after adjustment for potential confounders.

Within a subset of these individuals who had undergone formal sleep studies, they found that less REM sleep in particular predicted future AF. Finally, in order to see if these findings were readily translatable to patients already seen in healthcare settings and recognized by their providers as having sleeping difficulty, they drew on the California Healthcare Cost and Utilization Project (HCUP), a set of medical records databases of all California residents aged 21 or older who received care in a California ambulatory surgery unit, emergency department, or inpatient hospital unit between January 2005 and December 2009. Among several million people, the HCUP data confirmed that a diagnosis of insomnia predicted a diagnosis of AF both before and after adjustment for potential confounding effects.

These results provide more evidence that sleep quality is important to cardiovascular health and specifically to AF. Investigators determined that there was no evidence that sleep duration per se was a risk factor for AF. Instead, they consistently found sleep disruption to be an important risk factor. While the underlying mechanisms are still unknown, these findings may motivate novel ways to think about, and hence future research into, factors that influence AF risk.

This is the first study to demonstrate a relationship between worse sleep quality independent of sleep apnea and a higher risk of AF. "These data provide compelling evidence that sleep quality itself, even independent of sleep apnea, is an important determinant of AF risk," noted Dr. Marcus. "While there are several available treatments for AF, prevention of the disease would be ideal. The good news is that sleep quality can be modifiable and is something that at least to some degree is under the control of the individual. It's possible that improving sleep hygiene, such as performing regular exercise, getting to bed at a reasonable hour on a regular basis, and avoiding viewing screens before bed as well as caffeine later in the day, might help stave off AF."

Engineers work in quantifiable realism--an object exists and can be measured. Sometimes, though, the certainty of the object and how it will behave wavers. Researchers from the Automatic Control and System Dynamics Laboratory at the Technische Universität Chemnitz in Germany are starting to close the gap between reality and mathematical uncertainty.

They published an analysis of the discrepancy between mathematical proofs, algorithms, and their implementations in control systems with real, measurable outcomes. Their work appears in the July issue of IEEE/CAA Journal of Automatica Sinica (JAS), a joint publication of the IEEE and the Chinese Association of Automation.

"Control systems appear in everything from washing machines to rockets," said Pavel Osinenko, an author on the paper. "Control engineers work with objects that correspond with reality. For models of real objects, we need to develop real controllers that work in the final application. Classical mathematics are good to investigate highly abstract objects, but they overshoot on control theory."

In classical mathematic theory, Osinenko said, strength is an important factor that can miss the point of control theory. Strength, in this case, refers to the specificity of the information conveyed. Some mammals are humans, and some humans are women, and some women are mothers. In classical mathematics, it's stronger to know a variable in an equation is a human mother than simply a mammal, because more information can be inferred.

"In order for control theory to work, it requires a logical background that is way weaker," Osinenko said, noting that classical mathematics requires a logical system of several steps to ensure the most specific information to stay as strong as possible. "We need a minimalistic logical system for control theory."

The researchers analyzed a hundred-year-old theorem by mathematician Constantin Carathéodory. The theorem purports that a problem with a changeable independent variable, such as the trajectory of a thrown ball, can be solved with weak logical systems.

"It's constructive mathematics--every object that you can construct or prove to exist is computable. You can input a mathematical proof one to one in your computer," Osinenko said.

That's not the case in classical mathematics where objects are often proven by assuming they don't exist until contradictory mathematics provide evidence.

The researcher explored a variant of Caratheordory's theorem that covers several problems in practice and not just in theory. It's the link between theorems and proofs and computational certainty.

"Classical mathematics says there's a black cat in a dark room. It's definitely in there, but you can't point to its precise location," Osinenko said. "This minimal logical system is the torch with which we light up the room. The cat is right there."

The authors plan to further investigate minimal logic systems and constructive mathematics, with a focus on automated reasoning to aid in solutions for control systems.

"There's an ocean of mathematical results and theories in control theory that still wait for their constructive treatment," Osinenko said. "The next step is for us to pick one and work it out."

Myotonic dystrophy type 1 (DM1) is the most common adult-onset muscular dystrophy that affects multiple organ systems. People with this condition develop progressive muscle wasting and weakness in their lower legs, hands, neck and face. Their muscles feel stiff and tight, causing them to be slow to relax certain muscles and therefore have difficulty releasing the hand from a handshake or a doorknob. In addition, people with this condition may have fatigue, muscle pain, difficulty swallowing, cataracts, irregularities in their heartbeat and respiratory complications. In his laboratory at Baylor College of Medicine, Dr. Thomas A. Cooper is leading the way to better understand this rare but devastating condition.

"Muscle wasting in this disease, which happens over decades, is responsible for the death of 60 percent of the patients," said Cooper, who is professor of pathology and immunology, of molecular and cellular biology and of molecular physiology and biophysics at Baylor College of Medicine. "In this study we wanted to develop a novel model of the disease that would allow us to study muscle wasting in more detail."

DM1 is caused by a striking expansion of three-letter repeats (CTG) in the DMPK gene. While the unaffected population carries 5 to 37 repeats, people with the condition have 50 to 3000 repeats. The RNA transcripts containing the CTG repeat expansion accumulate in the cell nucleus. This disturbs the normal cellular processing and distribution of molecules, such as muscleblind-like (MBNL) proteins, and induces up-regulation of others, such as the CELF1 protein. These alterations result in abnormal alternative splicing, which is thought to play a central role in the development of DM1. However, how these changes triggered by the expansion of the CTG repeat lead to muscle wasting still is not completely understood.

"We think that the current animal models of DM1 do not provide researchers with a complete and practical tool to investigate the mechanisms involved in muscle loss," said Dr. Ginny Morriss, postdoctoral associate in the Cooper lab and the first author of this work. "This disease has many different components. Current animal models have some of the molecular components, but the physiological components, what's happening to the tissue, are mostly missing. We wanted to develop a mouse model of DM1 that clearly showed muscle loss and to implement a strategy that would allow us to study the pathways involved in muscle wasting."

A mouse model of reversible DM1

The researchers genetically engineered a skeletal muscle-specific mouse model of DM1 that allowed them to induce the development of the disease at will. When induced, the mice expressed 960 CUG repeats of a particular region of the human DMPK gene and the RNA transcripts containing the CUG repeat expansion accumulated inside the cell nucleus triggering the chain of events that resulted in progressive muscle wasting. When the researchers 'turned off' the expression of the 960 CUG repeats, RNA accumulation and muscle loss progressively reverted.

In this model, the researchers saw alternative splicing that was consistent with findings in previous studies that correlated it with muscle weakness. They also validated signaling pathway changes that had been previously found by others. Importantly, they saw signaling pathway changes that had not been described before. These new changes stratified with how severe muscle wasting was in the mice, showing a clear association between specific signaling pathways and muscle loss.

"We validated the upregulation of the activity of protein AMPK-alpha, which had been shown previously by another group in another model. AMPK-alpha regulates the way the muscles metabolize and function," Morriss said. "One of the new changes we discovered in our model was the dramatic reduction of signaling activity mediated by PDGFR-beta, which is involved in energy metabolism pathways."

In addition, Cooper, Morriss and their colleagues found a connection with the human condition. They analyzed human tissue samples from patients and unaffected individuals and found in the patients the same signaling pathway changes they had found in their mouse model.

"The field has been focusing on alternative splicing. But, one of the things our findings tell us is that, although many of the characteristics of the disease result from alternative splicing defects, in addition there are other mechanisms at play and therefore other potential targets to treat this disease. There is more going on here than just alternative splicing," said Cooper, who also is the S. Donald Greenberg and R. Clarence and Irene H. Fulbright Professor and a member of the Dan L Duncan Comprehensive Cancer Center at Baylor.

"Now we have a mouse model in which we can test mechanisms involved in the disease. Because we made our model reversible, we can use it to test hypotheses about how the repeats cause the characteristics of the disease. We can systematically test each one of those hypothesis independently in our model blocking each signaling event specifically and determining how much that affects the disease. We can in this way determine how much each of the disease components, signaling pathways and alternative splicing, contribute to the disease," Cooper said.

HAMILTON, ON, June 25, 2018 - Clusters of stars across the vast reaches of time and space of the entire universe were all created the same way, researchers at McMaster University have determined.

Researchers Corey Howard, Ralph Pudritz and William Harris, authors of a paper published June 25 in the journal Nature Astronomy, used highly-sophisticated computer simulations to re-create what happens inside gigantic clouds of concentrated gases known to give rise to clusters of stars that are bound together by gravity.

Pudritz and Harris, both professors of Physics and Astronomy at McMaster, were Howard's PhD thesis supervisors and guided his research. Howard recently completed post-doctoral research at the university.

The state-of-the-art simulations follow a cloud of interstellar gas 500 light years in diameter, projecting 5 million years' worth of evolution wrought by turbulence, gravity and feedback from intense radiation pressure produced by massive stars within forming clusters.

The research shows how those forces create dense filaments that funnel gas into what ultimately become super-bright clusters of stars that can merge with other clusters to form vast globular clusters.

"Most stars in galaxies form as members of star clusters within dense molecular clouds, so one of the most basic questions in astronomy is how do clusters that range from hundreds to millions of stars form under a wide variety of conditions," Pudritz says. "Our simulations were carefully designed to determine whether or not this a universal process."

The authors programmed data for such variables as gas pressure, space turbulence and radiation force into their simulation and let it run using resources that included SciNet, Canada's largest supercomputer centre.

After a month, the program turned out star clusters identical to those known to exist, showing that the researchers had managed to reverse-engineer the formation of star clusters, taking a major step towards understanding their formation, which has long been a subject of debate among astrophysicists.

"Our work shows that, given a large enough collection of gas, a massive star cluster is the natural outcome," Howard says. "Since massive star clusters trace the conditions of the galaxies in which they form, we may also be able use this knowledge to reverse-engineer the conditions in the distant universe."

Many had previously argued that clusters of different sizes and ages had formed differently, the authors said, but the new research shows they all form the same way.

The simulations show that the outcome depends on the initial reservoir of gas, that will, after turbulence, gravity and feedback have done their work, create clusters of stars of various sizes over the course of a few million years.

"This is the first convincing route to modelling the formation of star clusters," Harris says. "It applies across all mass scales - little clusters and big ones - and it should work at any particular time in the universe's history, in any particular galaxy."

Such simulations would have been unthinkable even 10 years ago, the authors say. The success of this project, they say, suggests that similar research on other complex problems, such as the formation of entire galaxies down to the births of specific individual stars, could soon be within reach.

Immune cells commonly blamed in Alzheimer's and other neurodegenerative diseases are actually precision cleaning machines protecting the central nervous system, new research from the University of Virginia School of Medicine shows.

The discovery adds nuance and complexity to our understanding of immune cells known as microglia. By appreciating the role of these cells in full, scientists are better positioned to develop new treatments and tailor medicine to individual patients' needs.

"What we're finding now is that at very acute time points, whether it's in disease or whether it's injury, the microglia are doing a lot," said researcher Geoffrey Norris, PhD. "It's important to know the role and function of these cells, especially going forward for human therapy."

Understanding Microglia

Norris and colleagues in UVA's Department of Neuroscience and its Center for Brain Immunology and Glia (BIG) developed a new model that lets them study microglia in the context of acute injury. Researchers already knew that the cells play a critical role in brain development, but their role in adulthood was much murkier, with many scientists arguing their activity was harmful. UVA's research reveals that injury to the central nervous system activates the microglia, and the cells respond with remarkable precision. "It seems that microglia are very responsive to the job at hand," Norris said. "So rather than being good or bad, what we're basically seeing is that they're doing what they need to do."

He compared the cells to a construction crew knocking down a damaged building. "If you have a crumbling building after a house fire, you usually take the building away, right? You load it up on dump trucks and take it away," he said. "That's what the microglia are doing with this debris."

The research doesn't rule out the possibility that the microglia could be too aggressive in their debris removal, or perhaps something could go wrong during removal and contribute to disease. To continue the house analogy, maybe the demolition crew is knocking down a slightly damaged kitchen rather than simply repairing it. "Whether the microglia activity is detrimental or not is really just starting to be teased out," Norris said.

Fast Acting, Deep Cleaning

UVA's new model allowed the researchers to observe as the cells swallowed up damaged material while leaving healthy cells untouched - strikes surgical in their precision. "If you look just a couple of microns away, their neighboring microglia are basically unresponsive," Norris said. "So it's a very contained area of activation, which was very interesting to us."

The researchers also noted how quickly the cells were changing and how quickly they cleared debris. Scientists working on treatments for neurological diseases may need to factor that in. Depending on the progression of a disease such as Alzheimer's or Parkinson's, "it might be that the microglia have already done a lot of work and you would need another approach," Norris said.

'A New Generation of Therapeutic Agents'

Jonathan Kipnis, PhD, chairman of UVA's Department of Neuroscience and director of the BIG Center, predicted the new understanding of microglia will have important ramifications.

"Microglia were the neglected cells of the brain for decades," Kipnis said. "The tide is changing, and we now realize how interesting and unique the biology of these cells is. This work shows the physiological response of microglia after CNS [central nervous system] injury, which is very different from their role in neurodevelopment or in chronic pathologies, such as Alzheimer's disease. Understanding microglia biology in physiology and pathology will bring us closer to development of a new generation of therapeutic agents for neurological disorders."

A plaster which sticks to the inside of your mouth is revolutionising the treatment of painful recurring ulcers.

Scientists from the University of Sheffield's School of Clinical Dentistry, working in close collaboration with Dermtreat A/S from Copenhagen, have developed a unique patch using special polymers which are able to stick to moist surfaces.

The patch successfully administers steroids directly to oral ulcers or lesions whilst also creating a protective barrier around the affected area, accelerating the healing process.

The novel plaster is a breakthrough therapy for the treatment of mucosal conditions such as oral lichen planus (OLP) and recurrent aphthous stomatitis (RAS), which are diseases that cause painful lesions and affect 1-2 per cent of the population.

Until now, ulcers and lesions inside the mouth have been treated using either creams or mouthwashes, which are used in the whole mouth rather than targeting the specific area, making them less effective. However, the biodegradable Rivelin® patch, has a long adhesion time and a high flexibility which conforms to the surface inside the mouth.

Dr Craig Murdoch, Reader in Oral Bioscience School of Clinical Dentistry and lead author of the research, said: "Chronic inflammatory conditions such as OLP and RAS, which cause erosive and painful oral lesions, have a considerable impact on quality of life.

"Current treatments consist of using steroids in the form of mouthwashes, creams or ointments, but these are often ineffective due to inadequate drug contact times with the lesion.

"The patch acts like a plaster inside your mouth, which means it is very effective at directly targeting the specific area as well as forming a protective barrier.

"Patients who have trialled the patch found it to be very comfortable to wear and they were really pleased with the length of adhesion which makes it particularly effective and efficient."

Jens Hansen, Chief Executive Officer at Dermtreat A/S, added: "Collaboration with the University of Sheffield has undoubtedly accelerated the translation of our intellectual property towards clinical use. Our company are very confident that we will soon gain regulatory approval for the first adhesive drug delivery technology to address pressing clinical needs in oral medicine.

"We look forward to continuing this collaboration, which will be increasingly directed at finding new clinical applications for muco-adhesive patches."

Dermtreat A/S was recently awarded $17.7 million from the venture capital firm Sofinnova. The funding will take the patches into phase two clinical trials, which will run at several sites in both the US and the UK - including at the Charles Clifford Dental Hospital in Sheffield. In addition, Dermtreat are funding further research at the Dental School to develop the next generation of patches that contain other useful drugs.

In a quiet courtroom, an attorney steps up to a lectern to deliver a closing argument. The defendant in the case is charged with murder, having stabbed a woman to death in front of her infant child.

"He beat her in the face," the attorney says, pounding a fist on the lectern, voice rising. After killing the victim, the defendant "ran from the apartment, and left behind one-year-old Kendall, alone with his mother's body."

The case and closing argument were real. The attorney was acting. In total, six attorneys with trial experience - three men and three women - performed identical reenactments of the closing argument for a psychology study at Arizona State University. The study shows gender bias skews the way people perceive an attorney's effectiveness when expressing anger.

According to the study "Closing with Emotion: The Differential Impact of Male versus Female Attorneys Expressing Anger in Court," published June 25 in the journal Law and Human Behavior, male and female test viewers found the angry male attorneys to be commanding, powerful, competent and hirable. They found angry female attorneys to be shrill, hysterical, grating and ineffective.

"A good attorney is expected to show traditionally male characteristics in court - anger, aggression, power. But what's happening is that men benefit from this, while we are penalizing women for showing these same characteristics," said Jessica Salerno, an ASU psychology professor and lead researcher on the study. "We watch so many courtroom dramas where lawyers are expressing emotion, and there are fireworks in the courtroom. People expect attorneys to express themselves this way. This expectation sets men up well for success, but for women it backfires."

Past studies have established that showing emotion in various situations hurts women while at the same time benefits men. However, these past studies are set in situations where emotion is unexpected, such as a business meeting.

Salerno and her team, which included Hannah J. Phalen, ASU doctoral candidate, Rosa Reyes, ASU graduate student, and Nicholas J. Schweitzer, an associate professor in ASU's School of Behavioral and Social Sciences, wanted to arrange a situation where emotion was expected.

In this instance, an attorney delivering a closing argument in a gruesome murder case. So, the research team gathered nearly 700 participants to watch videos of the actors delivering the closing argument. Participants shared their impressions of the attorneys, and whether or not they would hire them.

"We asked the participants how angry they thought the actors were," Salerno said. "Participants felt the men and women were similarly angry. But unfortunately, we did replicate the results found in other studies. The angry men were found to be more effective, and viewers wanted to hire them. This backfired for women. People thought the angry women were less effective, and they wanted to hire them less."

Additionally, women and men felt the same way, which Salerno said shows that this bias is operating at an implicit level.

"We all grow up in the same culture," she said. "We are exposed to the same gender stereotypes. In the long term, this means that female attorneys may not be able to demonstrate the conviction and power people expect from men. This has unfortunate long-term implications for their careers and effectiveness with juries."

A novel concept for a biosensor of the metabolite known as lactate, combines an electron transporting polymer with lactate oxidase, which is the enzyme that specifically catalyzes the oxidation of lactate. Lactate is associated with critical medical conditions so its detection is important for healthcare.

Biosensor performance hinges on electron transfer between sensing electrode and enzyme: this increases when there is a decrease in the distance between enzyme active sites and the electrode surface. Redox enzymes have emerged as optimal components for biosensors because their ability to realize electron transfer complements their specificity in target binding and catalytic activity.

Typical efforts to achieve good electrical communication involve convoluted electrode modifications and additional mediators, which are redox active molecules that shuttle electrons between electrode and enzyme. Therefore, biosensors to date have been limited in terms of their target metabolites and environments. This has hampered their use for applications across diverse fields such as biotechnology, agriculture, and biomedicine. Instead, their main use has been restricted to in vitro electrochemical biosensors for glucose monitoring in diabetes patients.

To fill this gap, Sahika Inal from KAUST and collaborators from Imperial College London and the University of Cambridge, UK, have developed a biosensor that can be adapted in a micron-scale transistor configuration to detect any metabolite of interest.

At the heart of the proof-of-concept device, the researchers have conjugated lactate oxidase with a so-called organic electrochemical transistor polymer. This electron transporting polymer simultaneously acts as an efficient switch and a powerful signal amplifier: it can accept electrons from the enzymatic reaction and undergo multiple reduction reactions through several redox active sites.

This polymer also bears hydrophilic side chains that facilitate intramolecular interactions with lactate oxidase, which brings the enzyme close to the transducing material. This promotes electrical communication and, consequently, enhances the polymer sensitivity toward lactate. These polymer-enzyme interactions also avoid modifying the electrode surface and use of a mediator, "which simplifies device fabrication," explains Inal. She adds that, unlike previous biosensors, the device does not require a reference electrode, which provides design flexibility.

"Our biggest challenge was identifying the right material for this sensor," says Inal. After this first hurdle, her team encountered issues when interpreting the biosensor response. "This device surprised us with its high efficiency," she says.

Inal's team at KAUST is currently working on a design that will detect metabolites in different environments. "An obvious application for this system is a lab-on-a-chip lactate sensor," she adds. Such a sensor would be especially useful in wearable lactate monitoring devices. Moreover, this new system also opens new options for how enzymes can be exploited to generate and store energy.

Our faces can reveal a lot about us, and now scientists are revealing a lot about faces. PLOS Genetics announces a special collection of papers to highlight recent advances in our understanding of how faces form, curated by Seth Weinberg of the University of Pittsburgh, and colleagues. The collection, entitled "Craniofacial genetics: where have we been and where are we going," publishes June 22 and features research on the development of the face and skull, facial birth defects and normal facial variation.

Research into the genetics that shape the face has made tremendous advances in recent years. Along with the mouse, the zebrafish has emerged as a powerful model for studying facial development. Many of the cellular processes that form the human face are highly similar in zebrafish, which have the added benefits of transparent embryos that can be examined under the microscope and multiple genetic tools for exploring genetic factors that control facial development.

Scientists have also identified numerous genes that contribute to facial malformations and syndromes through the use of rapid, high-throughput genomic technologies. These technologies have pinpointed mutations that cause both rare and common conditions such as cleft lip and palate disorders, in diverse populations. Scientists are beginning to see a growing list of genes in which genetic variants contribute to multiple diseases, and now must untangle the mechanisms that result in these individual malformations.

The study of facial variation has revealed that the multitude of human faces holds more variety than the faces of other animals, or other human body parts. By understanding the genetics underlying small differences in faces, scientists may one day be able to predict a person's face from the genome. This technology would enable us to construct faces from DNA collected at crime scenes, from the bones of our ancient ancestors or from an unborn child. All of these applications have considerable ethical and societal implications.

Major breakthroughs are occurring in the field of craniofacial genetics, and the curators of the special collection expect that this research will continue to accelerate. PLOS Genetics seeks to feature these breakthroughs through the publication of this collection and to advance the understanding of the genetics of facial formation so that these discoveries will ultimately benefit the public.