Culture

HOUSTON - (Oct. 21, 2020) - How life works may come down to dumbbell-like bits of DNA.

Rice University scientists on a long quest to study the structure and function of chromosomes have found that amid the apparent chaotic state of DNA during interphase, when cells are between divisions, there are pockets of order in the configuration of certain gene-containing regions.

These structures, reported in an open-access eLife study, offer a window into how chromosomes function and promise new avenues of research for those digging into their secrets.

The work led by Rice postdoctoral fellow and lead author Ryan Cheng and principal investigator José Onuchic, co-director of the Rice-based Center for Theoretical Biological Physics (CTBP), employs sophisticated simulations and evidence from experiments to suggest several new aspects of chromosome configuration and function.

"In molecular biology and gene expression, people talk about transcription factors and inhibitors and enhancers, but it seems there is no structural information," Onuchic said. "With advances in looking at chromatin structures, it starts to become possible to know how these structures and chromatin dynamics control gene expression.

"This paper suggests, for the first time, a mechanism connecting genome structure and gene expression," he said.

The researchers lay out four results from their coarse-grained Minimal Chromatin Model (MiChroM), a technique drawn from 20 years of experience with their energy landscape theory for predicting the structure of proteins.

First, they used MiChroM to predict chromosome structural ensembles for different cell types using the associated epigenetic markers as the sole input, finding the predictions to be consistent with experimental observations.

In previous research, they used MiChroM to simulate individual chromosomes in lymphoblastoid cells. The new work implies that the principles they discovered in that work also apply generally to different human cell types, highlighting the transferability of their theoretical model.

Second, with data from experiments using 3D tracing, which helps to directly visualize the tangle of DNA in a cell's nucleus during interphase, they determined the structures of chromosomes are all different. Yet they also found distinct clusters with what appear to be common structures, genes that have flexible, dumbbell-like globular domains at the head and the tail.

Cheng said their analysis of the experimental images revealed three distinct clusters among the disorder. "We believe that one is an artifact, but in the other two, the structures are either closed, meaning the two globular domains at the head and the tail are more or less touching, or open, where the domains have come apart," he said. This same structural transition appeared in the group's simulations using MiChroM.

Third, the researchers found that genes contained in this dumbbell structure are all located within the string that links the globular ends. "The fact that we find these structures undergo an open-close transition plausibly suggests it's related to transcriptional regulation," Cheng said. "This is suggestive of a direct relationship between the structure and functional aspects of gene expression."

Finally, the section of chromosome 21 detailed via experiments and modeled at Rice showed the position of the "dumbbells" is dynamic, with "A-type" structures moving to the surface of the disordered chromosome when they are functionally active, while inactive or "B-type" structures tend to move to the interior.

What drives active chromatin to the surface requires further study, Onuchic said.

"Maybe genes that have to be expressed, for example in early development, are activated and then move to the core of the chromosome because they're not used again," he said. "But that remains to be proven. We have just started to show evidence in that regard."

"No one should be under the illusion that a program of research by five or six scientists can by itself ultimately answer all the questions about gene regulation," said co-author Peter Wolynes, co-director of the CTBP. "The same was true when we began to study protein folding. What was necessary there was to get to create new ways of thinking about the problem and make predictions that inspired experimentalists.

"In the same way, we now have to educate experimentalists in this new way of thinking about how chromosomes act," he said.

Some dreams are so vivid that they can be recalled as if they were movies, full of connections and with a beginning, middle and end. Others in contrast resemble WhatsApp GIFs, or at best a script for a video clip à la TikTok, often with powerful or meaningful images, but lacking that complex storylike structure.

These analogies regarding different kinds of dream report or dream narrative were provided by Natalia Mota, a neuroscientist affiliated with the Federal University of Rio Grande do Norte’s Brain Institute (IC-UFRN) in Brazil. Mota is one of the authors of a paper published in PLOS One on a study confirming that reports of dreams collected after rapid eye movement (REM) sleep tend to display greater complexity and connectedness than non-REM dreams.

Scientists who study sleep say it can be divided into four stages. The first two, N1 and N2, are light and typically involve short but often intense non-REM dreams. N3 is deep slow-wave sleep and is also non-REM, with few dreams or none at all. In N4, which is REM sleep, dreams tend to be longer, more expressive, and structured.

“A great deal of dream science has been produced using objective tools and human judges trained to evaluate dream reports in terms of how complex, bizarre or connected they are. We know REM dreams are longer and more like movies. Automating the process of analysis, as we did in the study, made possible the first-ever quantitative measurement of this structural difference. We developed a tool that can analyze a large amount of data at high speed and without subjective biases. Linguistic bias is absent, for example, since the tool works in any language,” said Sidarta Ribeiro, a neuroscientist affiliated with the Research, Innovation and Dissemination Center for Neuromathematics (NeuroMat), a Research, Innovation and Dissemination Center (RIDC) supported by FAPESP at the University of São Paulo (USP).

In the study, the researchers analyzed dream reports word by word using graph theory, a branch of mathematics that focuses on networks and other kinds of relationships among words or other items in a set.

“It isn’t semantic analysis. We’re not analyzing the meaning of the words. We’re dealing not with what’s said but with how it’s said,” Mota explained. “As a result, the approach permits analysis of dreams in every different kind of culture and all countries.”

The researchers used word graphs to analyze 133 dream reports supplied by 20 volunteers, who were woken up in different sleep stages but mostly during REM sleep, when dream reports are most plentiful, and during N2 (non-REM), which produces fewer dream reports.

“This is the first study to use graph theory to show that REM dream reports have more structural connectedness than non-REM dream reports [N2]. Analysis of the word graphs shows that more complex dreams are associated with more connectedness and less arbitrary or random graph structures. Not to depreciate the relevance of traditional methods, but these results are important because they show that computational methods can be applied to studies of dreaming,” said Joshua Martin, first author of the article. The study was part of his master’s research in psychobiology at UFRN, with supervision by Ribeiro and Mark Solms, a researcher at the University of Cape Town, South Africa, and the first to show in previous studies that dreams do not occur only during REM sleep.

“Until the start of the twenty-first century, it was taken for granted that dreams occur only during REM sleep and that it wasn’t even necessary to study dreams. REM sleep was studied and that was it,” Ribeiro said. “Now it’s agreed that we dream during both REM and non-REM sleep, but to varying degrees.”

An important point about the study is that being a cross-border collaboration it used dream reports contributed by volunteers in South Africa and analyzed in Brazil, emphasizing the universal applicability of the tool developed by the authors.

“The findings show that the tool successfully identifies the differences in dream quality and complexity between sleep stages,” Mota said. “They aren’t differences that depend on meaning. They’re differences in the way the person communicates. This is most important to avoid language bias.”

The organization and structure of dream narratives are what vary. “This leads us to questions that go beyond the meaning of words. However bizarre dreams may be, and whatever their content, what matters is how subjects organize and recount their memories,” Mota said. “We found REM dream reports to be far more complex and full of connected information.”

The word graph tool is a promising way to add to knowledge of dreams, according to the researchers. “It can be very useful for a broad analysis of dream reports worldwide, such as those in the online repository Dream Bank, which currently holds more than 20,000 reports,” Martin said.

UCLA researchers have identified a compound that can reproduce the effect of exercise in muscle cells in mice. The findings are published in the journal Cell Reports Medicine.

Normally, muscles get stronger as they are used, thanks to a series of chemical signals inside muscle cells. The newly identified compound activates those signals, which suggests that compounds like it could eventually be used to treat people with limb girdle muscular dystrophy, a form of adolescent-onset muscular dystrophy.

When muscles aren't worked regularly, they gradually atrophy. (The phenomenon is familiar to anyone who's had a cast on their leg for several weeks.) Fortunately, for people with healthy muscles, that deterioration is reversible. Muscle use stimulates chemical messengers inside the muscle cells that increase muscle mass and strength.

People with the muscle wasting disease limb girdle muscular dystrophy have a genetic defect that interferes with that chemical messenger, making their muscles unable to respond to exercise. No amount of exercise can trigger the signal to strengthen their muscles. Because the muscles never get the message, they gradually wither, and people with the disease end up in wheelchairs, almost completely paralyzed.

"It's really dramatic. When these patients lose muscle, they struggle to gain it back," said Melissa Spencer, the paper's senior author and a member of the Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research at UCLA.

The genetic defect responsible for limb girdle muscular dystrophy causes shortages of an enzyme in muscle cells called CaMK. CaMK is responsible for launching a chain of chemical signals that turns on genes to boost the cell's ability to grow and metabolize fat, which is used as an energy source.

"CaMK activates genes that promote muscle growth and fat metabolism," said Spencer, who is also a professor of neurology and the director of the neuromuscular program at the David Geffen School of Medicine at UCLA.

To find a drug that could help restore the signals related to CaMK, Spencer and her colleagues worked with Robert Damoiseaux, director of UCLA's Molecular Shared Screening Resource, to screen more than 2,000 compounds to see which ones worked in lab-grown muscle cells. So far, they have tested 14 promising candidates in mice who had a genetic defect comparable to the one that causes limb girdle muscular dystrophy in people.

The testing identified a chemical compound called AMBMP that allowed mouse muscles to work and grow the way healthy muscle cells do.

"When we put the drug into mice, we found that it activated CaMK and restored all the properties we had observed as defective in our disease model," Spencer said.

Spencer and her collaborators are planning further studies to understand how AMBMP affects CaMK and to identify similar compounds that could be more effective in humans.

UCLA neurology professor Vargehese John, associate researcher Irina Kramerova and staff research associate Jesus Campagna, co-authors of the new study, are already producing new compounds similar to AMBMP. Spencer and Kramerova will test those compounds in mice to determine the best drug candidate to advance to clinical trials.

If one of those compounds is effective in human muscles, it would be a significant step for treating people with limb girdle muscular dystrophy, as well as people whose muscles have atrophied for other reasons -- because they have been bedridden for long stretches due to an illness or injury, for example.

Are obesity, diabetes, cardiovascular illnesses and more the result of a "mismatch" between the meals we eat and the foods our bodies are prepared for?

The "mismatch hypothesis" argues that each of our bodies has evolved and adapted to digest the foods that our ancestors ate, and that human bodies will struggle and largely fail to metabolize a radically new set of foods.

"Humans evolved in a very different environment than the one we're currently living in," said Amanda Lea, a postdoctoral research fellow in the Lewis-Sigler Institute for Integrative Genomics (LSI), and the first author on a study appearing in the current issue of the journal Science Advances. "No one diet is universally bad. It's about the mismatch between your evolutionary history and what you're currently eating."

The "mismatch" idea has been around for years, but it's hard to test directly. Most experiments focus on comparing Westerners to members of hunter-gatherer societies, but that inevitably conflates any effects of diet with other genetic or lifestyle differences.

Enter the Turkana -- a subsistence-level, pastoralist population from a remote desert in northwest Kenya. In the 1980s, an extreme drought coupled with the discovery of oil nearby led to rapid transformation of the region. Large segments of the population abandoned their nomadic lifestyle, some to live in villages and others in cities. Traditional Turkana still rely on livestock -- dromedary camels, zebu cattle, fat-tailed sheep, goats, and donkeys -- for subsistence, while Turkana living in cities have switched to diets that are much higher in carbohydrates and processed foods . This is a trend that is widely observed across the world, a result of increasing globalization, even in remote communities.

"We realized that we had the opportunity to study the effect of transitioning away from a traditional lifestyle, relying on almost 80% animal byproducts -- a diet extremely protein-rich and rich in fats, with very little to no carbohydrates -- to a mostly carbohydrate diet," said Julien Ayroles, an assistant professor of ecology and evolutionary biology and LSI who is the senior researcher on the new paper. "This presented an unprecedented opportunity: genetically homogenous populations whose diets stretch across a lifestyle gradient from relatively 'matched' to extremely 'mismatched' with their recent evolutionary history."

To address the question, the researchers interviewed and gathered health data from 1226 adult Turkana in 44 locations. The interviewers included Lea and Ayroles as well as the research team based at the Mpala Research Center in Kenya, led by Dino Martins. Mpala is best known as a site for world-class ecological studies, but with its research into the Turkana, it is also breaking new ground on anthropology and sociology and in genetics and genomics, using a new NSF-funded genomics lab.

"This is a very important first paper from the Turkana genomics work and the Mpala NSF Genomics and Stable Isotopes Lab," said Martins. "Doing research like this study involves a huge amount of trust and respect with our local communities and with more remote communities: how we access them, how we interact. And the reason Mpala and Turkana can be a hub for this is because we have a long-term relationship. What has happened in many parts of the world where some of this research has been done, and it's gone wrong, is when you have researchers parachuting in and out of communities. That does not make people trust you -- it just creates a lot of an anxiety and problems. But here, the communities know us. We've been there for 25 years. Our research staff are drawn from local communities."

The project originated when Ayroles visited Martins, a friend from their years at Harvard University, at the Turkana Basin Institute, where Martins was based. On a brutally hot Christmas Day, deep in the desert, miles from any known village, Ayroles had been surprised to see a group of women carrying water in jars on their heads. Martins had explained that the women were carrying water back to share with their fellow Turkana, and added that these few vessels of water would be all they would drink for a week or more.

"Julian says, 'That's not possible. Nobody can survive on that little water,'" Martins recalled. "And so his scientist's brain gets thinking, and he comes up with this project to say, 'How is it that humans can survive in this incredibly harsh environment?' And I turned it around by saying, 'Actually, I think the question is, "How is it that we've adapted to survive in other environments?" Because of course, this is the environment that we all came out of."

The project grew from there, taking shape as a study of health profiles across 10 biomarkers of Turkana living in cities, villages and rural areas. The researchers found that all 10 were excellent among Turkana still living their traditional, pastoralist lifestyle -- and among the Turkana who were leading in rural villages, making and selling charcoal or woven baskets, or raising livestock for trade.

But Turkana who had moved to cities exhibited poor cardio-metabolic health, with much higher levels of obesity, diabetes, cardiovascular illness and high blood pressure. The health metrics also showed that the longer Turkana had spent living in the city, the less healthy they tended to be, with life-long city dwellers experiencing the greatest risk of cardiovascular disease.

"We are finding more or less what we expected," said Ayroles. "Transitioning to this carbohydrate-based diet makes people sick."

"There's a cumulative effect," added Lea. "The more you experience the urban environment -- the evolutionarily mismatched environment -- the worse it's going to be for your health."

Ayroles cautioned that the research should not be interpreted as favoring a protein-based diet. "One of the most remarkable things about the Turkana is that if you and I went on the Turkana diet, we would get sick really quickly!" he said. "The key to metabolic health may be to align our diet and activity levels with that of our ancestors, but we still need to determine which components matter most."

The researchers have continued their surveys and data gathering, and they plan to expand the study to incorporate different indigenous peoples, in Pacific islands and elsewhere, who are also experiencing these shifts away from traditional lifestyles.

"We can learn so much about evolution and human health from the many traditional and subsistence-level populations around the globe," said Lea. "They are experiencing this extraordinary, rapid environmental change, and we can witness it in real time."

Two studies examining the impact of COVID-19 on neonatal intensive care units (NICUs) found the prevalence of COVID-19 in NICU infants is low, yet many hospitals at the start of the pandemic put in place strict parental visitation policies and scaled back NICU services such as lactation support and therapy.

In "Longitudinal Survey of SARS-CoV-2 Burden and Related Policies in US Neonatal Intensive Care Units," published in the American Journal of Perinatology, researchers, including Ashley Darcy-Mahoney, associate professor of nursing at the George Washington University and Pediatrix-affiliated neonatal nurse practitioner, conducted a series of cross-sectional surveys of U.S. NICUs between early March 2020 and late May 2020 during the first wave of the COVID-19 outbreak, and more recently between mid July 2020 and early August 2020. They found:

Confirmed COVID-19 disease in NICU-admitted infants was rare, with the prevalence rising from 0.03% to 0.44% across the four survey rounds.

During early rounds of the survey, hospitals provided universal screenings of expectant mothers, with a preponderance to separate mother and baby for 14 days if the mother tested positive for COVID-19, and a majority of hospitals allowing infants only expressed breastmilk. Data from the final survey round, however, suggests NICUs are using the latest evidence and following American Academy of Pediatrics and Center for Disease Control guidelines to inform these policies with rapid cycle changes.

At the beginning of the pandemic, most NICUs enacted policies that leaned toward substantial caution, limiting interactions between parents and their infants at a time when close contact is critical for neonate care.

The new study aligns closely with a study published at the end of August by Darcy-Mahoney and her co-authors in the Journal of Perinatology. In "Impact of restrictions on parental presence in neonatal intensive care units related to coronavirus disease 2019," the researchers surveyed 277 facilities globally in April 2020. They found:

NICU policies allowing 24/7 parental presence decreased (from 83% before COVID-19 to 53% during COVID-19). The researchers also saw a decrease in NICUs allowing full parental participation in rounds (71-32%).

Of the 277 NICUs surveyed, 120 (43%) reported reductions in therapy services, lactation medicine, and/or social work support.

NICUs with single-family room designs best preserved 24/7 parental presence after the emergence of COVID-19 (64% of NICUs surveyed) when compared to a hybrid design (57%) or open bay design (45%).

CHAPEL HILL, NC - A study published in Cell Reports shows how next generation genetic sequencing can track mutations in the SARS-CoV-2 virus, which can in effect help with transmission tracing, diagnostic testing accuracy and vaccine effectiveness.

"Once you have the virus' genetic sequence with next generation sequencing (NGS), then you can start asking more questions," said Dirk Dittmer, PhD, professor of microbiology and immunology at the UNC School of Medicine, and senior author of the study. "Where have we seen this exact sequence before? Did it come from a different state or country? When did this patient travel there and who else may have it?"

Dittmer says this type of virus monitoring is also important in diagnostic testing. Much of the testing developed to diagnose COVID-19 looks for one portion of the gene sequence that causes the novel coronavirus. If that sequence mutates, the test is no longer accurate and results will be affected. Dittmer says that within their study, his team did find variations in the virus' genetic sequence, but fortunately none of the variations were located in the portion of the virus targeted in common diagnostic testing.

"We are concerned about future mutations though," Dittmer said. "It is inherent in a virus' nature to mutate. Changes in other areas of the genetic sequence can not only disrupt testing, but hinder the effectiveness of vaccines."

That's why Dittmer's lab has been collaborating with multiple other labs at UNC-Chapel Hill to stay up to date on what, if any changes should be made to testing protocols and possible vaccine development. Dittmer's lab receives positive SARS-CoV-2 samples from the lab of Melissa Miller, PhD, director of UNC Medical Center Microbiology and Molecular Microbiology Laboratories, where UNC's COVID-19 diagnostic testing was developed and put in place March 16.

"Because we are only looking at one gene sequence for the virus, we have told the FDA that we will continually monitor for changes in this gene sequence so that we can be assured that our test is still reliable," said Miller, a co-author of the study. "NGS will help us do that."

Dittmer's recent study is the largest to focus on suburban and rural communities. Researchers were able to reconstruct the mutational landscape of cases seen at the UNC Medical Center in Chapel Hill, NC, a tertiary clinical care center. From March 30 through May 8, 175 samples from confirmed COVID-19-positive patients were analyzed.

Out of the samples tested, 57% carried the spike D614G variant noted in similar studies. The presence of this variant is associated with a higher genome copy number and its prevalence has expanded throughout the pandemic. The genetic variations found in these samples also support the hypotheses that the majority of cases in North Carolina originated from people traveling within the U.S. rather than internationally.

With a grant from the N.C. Policy Collaboratory based at UNC-Chapel Hill, Dittmer's lab will continue using NGS to track the SARS-CoV-2 virus through the remainder of 2020. The goal is to enroll every patient at UNC Hospitals with flu or respiratory symptoms for COVID-19 diagnostic testing. These samples will be sequenced and compiled to form a comprehensive profile of any virus that these patients carry, information that will continue to help a community of researchers in their fight against SARS-CoV-2 and potentially novel coronaviruses.

New radio images from the Atacama Large Millimeter/submillimeter Array (ALMA) show for the first time the direct effect of volcanic activity on the atmosphere of Jupiter's moon Io.

Io is the most volcanically active moon in our solar system. It hosts more than 400 active volcanoes, spewing out sulfur gases that give Io its yellow-white-orange-red colors when they freeze out on its surface.

Although it is extremely thin - about a billion times thinner than Earth's atmosphere - Io has an atmosphere that can teach us about Io's volcanic activity and provide us a window into the exotic moon's interior and what is happening below its colorful crust.

Previous research has shown that Io's atmosphere is dominated by sulfur dioxide gas, ultimately sourced from volcanic activity. "However, it is not known which process drives the dynamics in Io's atmosphere," said Imke de Pater of the University of California, Berkeley. "Is it volcanic activity, or gas that has sublimated (transitioned from solid to gaseous state) from the icy surface when Io is in sunlight?"

To distinguish between the different processes that give rise to Io's atmosphere, a team of astronomers used ALMA to make snapshots of the moon when it passed in and out of Jupiter's shadow (they call this an "eclipse").

"When Io passes into Jupiter's shadow, and is out of direct sunlight, it is too cold for sulfur dioxide gas, and it condenses onto Io's surface. During that time we can only see volcanically-sourced sulfur dioxide. We can therefore see exactly how much of the atmosphere is impacted by volcanic activity," explained Statia Luszcz-Cook from Columbia University, New York.

Thanks to ALMA's exquisite resolution and sensitivity, the astronomers could, for the first time, clearly see the plumes of sulfur dioxide (SO2) and sulfur monoxide (SO) rise up from the volcanoes. Based on the snapshots, they calculated that active volcanoes directly produce 30-50 percent of Io's atmosphere.

The ALMA images also showed a third gas coming out of volcanoes: potassium chloride (KCl). "We see KCl in volcanic regions where we do not see SO2 or SO," said Luszcz-Cook. "This is strong evidence that the magma reservoirs are different under different volcanoes."

Io is volcanically active due to a process called tidal heating. Io orbits Jupiter in an orbit that is not quite circular and, like our Moon always faces the same side of Earth, so does the same side of Io always face Jupiter. The gravitational pull of Jupiter's other moons Europa and Ganymede causes tremendous amounts of internal friction and heat, giving rise to volcanoes such as Loki Patera, which spans more than 200 kilometers (124 miles) across. "By studying Io's atmosphere and volcanic activity we learn more about not only the volcanoes themselves, but also the tidal heating process and Io's interior," added Luszcz-Cook.

A big unknown remains the temperature in Io's lower atmosphere. In future research, the astronomers hope to measure this with ALMA. "To measure the temperature of Io's atmosphere, we need to obtain a higher resolution in our observations, which requires that we observe the moon for a longer period of time. We can only do this when Io is in sunlight since it does not spend much time in eclipse," said de Pater. "During such an observation, Io will rotate by tens of degrees. We will need to apply software that helps us make un-smeared images. We have done this previously with radio images of Jupiter made with ALMA (https://public.nrao.edu/news/image-release-alma-shows-whats-inside-jupiters-storms/) and the Very Large Array (VLA) (https://public.nrao.edu/news/vla-jupiter-atmosphere/)."

Welcome to shopping during the coronavirus pandemic: customers clad in masks, slathered with sanitizer and surrounded by signage urging them to avoid close contact. Despite guidelines plastered on the walls and floors of grocery and retail stores encouraging customers to maintain six-feet of physical distance, many do not. A new study by researchers at the University of Houston Conrad N. Hilton College of Hotel and Restaurant Management identifies two key messaging components -- negativity and anthropomorphism, or attributing human characteristics to nonhuman objects -- could improve the persuasiveness of those appeals and trigger compliance.

Adjusting the messaging to stress the negative health outcomes associated with not following physical distancing guidelines, including the possibility of severe sickness or death, could more effectively persuade consumers to comply, according to the study co-authored by UH associate professor Priyanko Guchait and published in The Service Industries Journal. The study found that adding intimidating human attributes to the otherwise invisible coronavirus, such as a scary red face with long sharp teeth and tentacles, significantly strengthens that message.

"We don't know how the coronavirus looks because we can't see it, so how can people be afraid of it? Giving it human characteristics and making it look scary strengthens the effect when combined with the negative messaging," said Guchait.

The researchers applied the regulatory focus theory, a persuasion theory in the field of psychology which focuses on framing the information either negatively or positively. Based on a hypothetical supermarket scenario, survey respondents were presented with different physical distancing messages that either used preventive or promotive language - some included a "Mr. Deadly COVID-19" scary face.

The preventive messaging emphasized potential costs and negative outcomes: If you don't maintain physical distance, you could get infected and endanger your life. In contrast, promotive messaging highlighted potential benefits and positive outcomes: Maintaining physical distance protects you from infection and secures your life.

"Preventive language was significantly more effective in this study because people are persuaded by loss language, especially in high-risk, health-related situations. It's the same thing with traffic accidents where people follow the rules because they know they could die. They experience fear and that's why they follow traffic rules," said Guchait, who collaborated on the research with visiting scholar The Khoa Do and Chen-Ya Wang from National Tsing Hua University in Taiwan.

Despite a consistent rise in coronavirus cases and deaths, many customers underestimate the importance of complying with physical distancing. A survey of grocery and food workers conducted by the United Food and Commercial Workers International Union at the beginning of the pandemic last spring, found that up to 85% of customers at grocery and retail stores did not practice physical distancing. Other surveys have revealed that people consistently underrate the risk of getting infected themselves or transmitting the virus to others.

The researchers hope the service industry will adapt and change how they frame and present physical distancing appeals, particularly small retail and grocery businesses which lack the resources to fully implement expensive health and safety interventions.

"This is more about playing with the human mind, which we know is more impactful than actual devices such as partitions or physical barriers," said Guchait. "We encourage stores to add the picture of a scary coronavirus along with preventive messaging because it could save them money but, more importantly, it could save lives."

Cucurbit downy mildew is a devastating disease affecting economically important crops such as cucumber, cantaloupe, squash, pumpkins, and watermelon. Previously effective fungicide have been failing in the United States and Europe, making accurate and early diagnosis critical for timely disease management.

As the disease is rapid, infectious, and hard-to-diagnose, a team of plant pathologists with North Carolina State University and Michigan State University put together a clear and summarized guide to cucurbit downy mildew for beginners and experts. Accorded to Andres Salcedo, "We realized the necessity to compile relevant and concise information about the causal agent of cucurbit downy mildew and developed a guide of multiple alternatives for its diagnosis and handling."

As cucurbit downy mildew is caused by Pseudoperonospora cubensis, an obligate pathogen that cannot be cultured using standard microbiological methods, this guide provides well-documented written and graphic material to help with diagnosis based on symptoms and the presence of the pathogen in the plant. The guide also covers diagnosis methods based on DNA testing and microscopy as well as methodologies for isolation, damage evaluation, multiplication, and storage under laboratory conditions.

The ability to quickly identify cucurbit downy mildew is crucial for cost-effective chemical or cultural control strategies. To help those who are trying to assess the efficacy of new disease management products, this guide also provides protocols for pathogen handling and evaluation. Parts of the guide are also being used to develop extension training videos to further inform a broader audience about cucurbit downy mildew.

To see the guide for yourself, read "Diagnostic Guide for Cucurbit Downy Mildew" published in Plant Health Progress.

JACKSONVILLE, Fla. -- Mayo Clinic researchers, along with national and global collaborators, have developed a potential test for Machado-Joseph disease, or spinocerebellar ataxia type 3 (SCA3) ? a disease that has no cure. They also have clarified the role of a gene target associated with the disease.

The inherited disease is linked to a mutation in the ATXN3 gene. This mutation, which affects the central nervous system, appears between the ages of 40 and 70, and is characterized by an unsteady gait, loss of muscle control, and decline of motor and sensory nerves. Symptoms may resemble those of Parkinson's disease or multiple sclerosis. The researchers present their findings in Science Translational Medicine.

In the retrospective study, the researchers set out to find a molecular target to help assess potential treatments for SCA3 and the group of neurodegenerative diseases in which it's categorized. Guiding the researchers in this effort was previous work at Mayo Clinic on Lou Gehrig's disease ? also known as amyotrophic lateral sclerosis ? as well as frontotemporal dementia with mutations in the C9orf72 gene.

SCA3 is defined by the characteristic accumulation of a mutant protein: polyQ ataxin-3. Researchers think this protein bunches up inside the cell and causes toxicity by interfering with cell actions in a number of ways. While there is no treatment for SCA3, the goal is to reduce protein accumulation.

"We were able to develop an immunoassay, or test, that can quantify the amount of mutant protein in human biofluids, such as cerebrospinal fluid and blood of patients with SCA3," says Mercedes Prudencio, Ph.D., first author of the study. "We can use the test to determine the effectiveness of new therapies aimed at decreasing the amount of mutant protein." Dr. Prudencio is an assistant professor of neuroscience, Mayo Clinic College of Medicine and Science.

"There is an unmet patient need for biomarkers for SCA3 that can tell us whether therapies targeting polyQ ATXN3 proteins are working," says Leonard Petrucelli, Ph.D., one of the senior authors on the paper. "If therapies can be more targeted toward decreasing the mutant protein, rather than the normal protein, this would have great implications for the field." Dr. Petrucelli is the Ralph B. and Ruth K. Abrams Professor of Neuroscience.

The researchers also clarified that a genetic alteration, called a single nucleotide polymorphism, previously identified and linked to SCA3, was strongly associated with the mutant ATXN3 gene among the study samples.

"While the mutant protein levels may serve as a marker to evaluate whether certain SCA3 therapies are working, the genetic alteration that is strongly associated with that mutant protein offers a new opportunity to develop therapies that specifically target it," says Dr. Prudencio. The results of the study pave the way for accelerated clinical trials involving SCA3 therapies.

Historically, SCA3 was more common in people from the Azores and Portugal. However, cases of the disorder have been found in people across Europe, Asia and the Americas. The study cohort included patient samples from around the globe, including Japan, Mexico, the Netherlands, Norway, Portugal, Sweden, and the U.S. The findings were validated through a collection of SCA3 samples from European countries over the course of many years by Ataxia Centre, which is affiliated with University College London.

"This was truly an international effort in team science," says Zbigniew Wszolek, M.D., a senior author on the paper. "SCA3 is a rare and complex disorder, and the collaboration on this work goes a long way in ultimately being able to help patients and their families who are suffering." Dr. Wszolek is a professor of neurology, Mayo Clinic College of Medicine and Science, and the Haworth Family Professor in Neurodegenerative Diseases.

Mayo Clinic researchers plan to follow patients with SCA3 through the Mayo Clinic Ataxia Program as a next step in furthering studies around this neurodegenerative disorder.

This research was funded by the National Institutes of Health; National Institute of Neurological Disorders and Stroke; Mayo Clinic; and the Donald G. and Jodi P. Heeringa family. University College London Queen Square Institute of Neurology was part of the research collaboration, with Professor Paola Giunti, M.D., a corresponding senior author on this paper. See the published paper for a full list of authors, funding sources and competing interests.

Approximately 30% of breast cancer patients who receive chemotherapy treatment gain weight, though it is unclear why this phenomenon occurs in some women but not in others. Beyond weight gain, chemotherapy is also known to increase the risk of high blood pressure and glucose intolerance, a prediabetes condition. Although this is a familiar phenomenon, the mechanisms underlying these processes have not yet been identified. A new study, just published in the journal BMC Medicine, suggests that gut bacteria are partially responsible for metabolic changes that lead to weight gain following chemotherapy treatment.

The research was initiated by Dr. Ayelet Shai, Director of Oncology at the Galilee Medical Center, who led the study with Prof. Omry Koren, an expert in gastrointestinal bacteria at the Azrieli Faculty of Medicine of Bar-Ilan University.

Dr. Shai says that symptoms she has witnessed as an oncologist led her to initiate the study: "In my clinical work with women recovering from breast and gynecological tumors, I have seen many of them gain weight following treatment and experience difficulty returning to their original weight. When I read in medical literature about the link between the microbiome and obesity in people without cancer, I thought it would be interesting to see if the microbiome of patients is one of the causes of obesity and other metabolic changes," she says.

The study conducted by Dr. Shai and Prof. Koren involved 33 women who were about to begin chemotherapy for breast cancer and gynecological cancer. The women were weighed once before the treatment, and once again approximately five weeks after treatment began. Prior to treatment, a stool sample was used to genetically characterize the microbiome of each of the women. Nine of the women were found to have gained weight to a degree that was defined as significant (3% or more). The microbiome of these women exhibited a smaller diversity of gut bacteria and different bacterial strains compared to that of the women who did not experience weight gain.

The study showed that the composition of intestinal bacteria may predict which women will gain weight as a result of chemotherapy. In addition when the gut microbiota of women who gained weight were transferred to germ-free mice, they developed glucose intolerance and signs of chronic inflammatory condition were detected in their blood. These findings suggest that bacteria are partially responsible for metabolic changes that lead to weight gain following chemotherapy treatment.

"We have shown for the first time that the pre-treatment microbiome of patients that gained weight following chemotherapy is different than the microbiome of patients that did not gain weight, and that fecal transplantation from patients that gained weight results in glucose intolerance, adverse lipid changes and inflammatory changes in germ-free mice," says Prof. Koren. These results suggest that the intestinal microbiome is mediating metabolic changes in women treated by chemotherapy. Moreover, the pre-chemotherapy composition of the intestinal microbiome can predict which patients will gain weight following treatment.

Dr. Shai and Prof. Koren are currently in the midst of a follow-up study which aims to examine the results in a larger patient population and to examine the microbiome of women at the end of chemotherapy in order to understand the effect of the treatment on bacterial composition. The researchers also plan to study the effect of chemotherapy on obesity in germ-free mice following fecal transplantation.

If the results obtained in the initial study are repeated, it will be possible to consider a stool test for women before starting treatment, so that the patient knows if she is at risk of gaining weight. As October marks Breast Cancer Awareness Month, Dr. Shai says, "We hope that in the future we will be able to identify those women who are at risk for weight gain through a simple examination and perhaps even suggest ways to prevent this phenomenon."

Non-pharmaceutical interventions such as voluntary shelter-in-place, quarantines, and other steps taken to control the SARS-CoV-2 virus can reduce the peak number of infections, daily infection rates, cumulative infections, and overall deaths, a new study published in the journal PLOS ONE has found.

"High compliance with voluntary quarantine - where the entire household stays home if there is a person with symptoms or risk of exposure in the household - has a significant impact on reducing the spread," said Pinar Keskinocak, the William W. George Chair and professor in the H. Milton Stewart School of Industrial and Systems Engineering (ISyE) and director of the Center for Health and Humanitarian Systems at the Georgia Institute of Technology. "Shelter-in-place (SIP) puts the brakes on the spread for some time, but if people go back to 'business as usual' after SIP, the significant impact is lost, so it needs to be followed up by voluntary quarantine and other physical distancing measures."

Utilizing data from the state of Georgia, the study determined that a combination of non-pharmaceutical interventions, with various levels of compliance that change over time, could in some instances cut cumulative infections in half and reduce the peak number of infections to about a third of what could have been seen, "flattening the peak" to avoid overwhelming a state's healthcare system.

The study compared actual statistics to revised models of what could have happened in the state during the past seven and a half months without the physical distancing. As Covid-19 cases increase toward what may be a new peak this fall, the study could help public health officials evaluate the benefits of potential intervention strategies, for example, in the debate around K-12 school closure.

The study modeled the number of Covid-19 infections and resulting severe outcomes, and the need for hospital capacity under social distancing, particularly, school closures, shelter-in-place, and voluntary quarantine.

"As one would expect, there is variation across the state in the observed data, which depends in large part on people's behaviors," said Nicoleta Serban, who is the Joseph C. Mello chair and professor in ISyE. "For example, mobility increased faster in some counties compared to others, which is likely to be correlated with increased physical and social interactions, and therefore faster spread of the coronavirus."

The team, including Georgia Tech ISyE Ph.D. students Buse Eylul Oruc and Arden Baxter, developed and used an agent-based simulation model to project the infection spread. "This is a sophisticated mathematical model which mimics what might happen in practice - under different scenarios - by capturing the progression of the disease in an individual, as well as the interactions between people in the household, in peer groups such as schools or workplaces, or in community groups such as grocery stores," Oruc said.

The model utilizes parameters specific to Covid-19 and data from Georgia on population interactions and demographics. The study covered a period starting February 18, evaluating different social distancing scenarios, including baselines in which no intervention would have taken place or the only intervention would have been K-12 school closure, comparing them to combinations of shelter-in-place and voluntary quarantine with different timelines and compliance levels.

Outcomes were compared at the state and community level for the number and percentage of cumulative and daily new symptomatic and asymptomatic infections, hospitalizations, and deaths; Covid-19-related demand for hospital beds, ICU beds, and ventilators.

The number of hospitalizations in Georgia turned out to be fewer than models last spring had forecast, but "models accurately predicted which hospital regions of the state that would have the largest gaps between number of people with severe outcomes and available care capacity - and therefore face potential shortages of ICU beds, hospital beds, and ventilators," Baxter said.

The results suggest that shelter-in place followed by voluntary quarantine reduced peak infections to less than a third of what we would have seen if no intervention had taken place and to less than a half if only schools had been closed. The models predicted correctly that the interventions would delay the peak from April to sometime between late July to mid-September, reducing the daily strain on health care systems.

According to the study, increasing shelter-in-place duration from four to five weeks yielded between 2% to 9% and 3% to 11% decrease in cumulative infection and deaths, respectively. Regardless of the shelter-in-place duration, increasing voluntary quarantine compliance decreased daily new infections and cumulative infections by about 50%. The cumulative number of deaths ranged from 6,660 to 19,430 under different scenarios.

As infection rates rise in the United States during late October, the study could help public health officials select the best techniques for addressing the viral threat. Georgia's total population is approximately 10.5 million, and Covid-19 related deaths have exceeded 7,600.

"The study further highlighted and quantified the impact of how compliance with public health measures impact infectious disease spread," Keskinocak said. "The takeaway message is that each of us have the power to control our health by making the right choices."

"As individuals and as a nation, we often expect technological or medical fixes or cures to health problems, whereas many of these problems, whether they are at the individual level or the public health level, are caused by or exacerbated by our choices and behaviors," Keskinocak said. "For many of them, we don't need a new fancy device, drug, or technology to make things better. As individuals, or households, or communities, we have the power and the responsibility to impact and improve our own health, and the public health, by making healthy choices."

University of Minnesota Medical School physician researchers studied hydroxychloroquine as a treatment to prevent COVID-19 for those with high-risk for exposure to the virus - health care workers.

The pre-exposure prophylaxis trial results, which were published in Clinical Infectious Diseases, determined that taking 400mg of hydroxychloroquine once or twice weekly did not prevent the development of COVID-19 in health care workers better than the placebo.

"This randomized placebo-controlled trial launched on April 6, with the objective of evaluating whether or not hydroxychloroquine taken once or twice weekly in health care workers at high risk for COVID-19 exposure could prevent COVID-19 infection," said principal investigator Radha Rajasingham, MD, an infectious diseases physician and researcher at the U of M Medical School.

The double-blind trial enrolled 1,483 health care workers and first responders from across the U.S. and Canada. Participants were randomly assigned to receive once-weekly hydroxychloroquine, twice-weekly hydroxychloroquine or placebo. Participants were followed for a minimum of four weeks and up to twelve weeks to evaluate who developed COVID-19.

Overall, 7.9% assigned the placebo developed COVID-19, while 5.9% assigned hydroxychloroquine developed COVID-19. Those results were not statistically significant, meaning there was not a meaningful difference between hydroxychloroquine and the placebo. Side effects were reported in 21% of participants assigned the placebo; 31% in the once-weekly hydroxychloroquine group and 36% in the twice-weekly hydroxychloroquine group. The most common side effects were nausea, upset stomach and diarrhea. There was no increased risk of serious side effects or cardiac complications from taking hydroxychloroquine compared to the placebo.

Non-Cancerous Tissue from Nephrectomy Specimens: A Window into Kidney Pathology

Kidney pathology from non-cancerous portions of the kidney from patients undergoing nephrectomy can offer insight into the spectrum of kidney histopathological findings in humans. Researchers reviewed pathology reports from 1,347 patients who underwent nephrectomy between 1999-2018, examining the association between the degree of scarring in the glomerulus, tubules/interstitium, and vessels, with kidney function at the time of kidney removal. They also looked at the relationship between age and kidney function among each category of scarring. The researchers found that more scarring in the glomerulus, tubules/interstitium, and the vessels was associated with worse kidney function. They also found that though older individuals were more likely to have more scarring in the glomerulus and tubules/interstitium, and that taking into account age did not change these findings.

CLEVELAND--Brain cell dysfunction in low oxygen is, surprisingly, caused by the very same responder system that is intended to be protective, according to a new published study by a team of researchers at the Case Western Reserve University School of Medicine.

"These powerful protein responders initially protect brain cells from low oxygen as expected, but we find that their prolonged activity leads to unintended collateral damage that ultimately impairs brain cell function," said the study's principal investigator Paul Tesar, a professor in the Department of Genetics and Genome Sciences at the Case Western Reserve School of Medicine and the Dr. Donald and Ruth Weber Goodman Professor of Innovative Therapeutics.

Defining the mechanism of brain-cell damage in low oxygen conditions provides an opportunity to develop effective therapies, including a class of drugs studied in their research that could inform future clinical approaches for many neurological diseases caused by low oxygen. The work also clarifies how the response to low oxygen causes disease in other tissues outside the brain.

Their research was published online Oct. 21 in the journal Cell Stem Cell.

The body's response to low oxygen

With the dawn of an oxygenated atmosphere, a burst of multicellular life was possible, as oxygen could be used to produce the energy needed to support complex life functions. Given the requirement of oxygen for life, nearly all organisms evolved a mechanism to rapidly respond to low oxygen--a condition called hypoxia. The Noble Prize in Physiology or Medicine was awarded in 2019 for discoveries of how cells in our body sense low oxygen levels and respond to stay alive.

At the core of this ancient response are proteins called hypoxia-inducible factors (HIFs), which instruct the cell to minimize oxygen consumption and maximize their access to oxygen. In this way, HIFs can be thought of as valiant heroes attempting to protect and resuscitate cells in the immediate response to low oxygen.

Prolonged hypoxia causes dysfunction in many tissues. In particular, stem cells in the brain are impaired by hypoxia in many diseases, including stroke, cerebral palsy related to premature birth, respiratory distress syndromes, multiple sclerosis and vascular dementia. Even the significant neurological damage caused by COVID-19 is attributed to hypoxia.

Until now, the precise causes of cell malfunction due to low oxygen were unknown.

The dark side of the hypoxia response

In this study, researchers developed a new approach to closely study how the hypoxia responder proteins function. By comparing how they work in brain-stem cells with other tissues, such as heart and skin, the scientists confirmed that the hypoxia responder proteins perform a beneficial function to promote cell survival in low oxygen in all tissues. However, these same hypoxia responder proteins had a previously unappreciated dark side, as they also switched on other cellular processes outside of the core beneficial response.

The team then demonstrated that this additional--and previously unknown--response is what impaired brain-stem cell function. This suggests that, while hypoxia responder proteins evolved to promote cell survival in all tissues of the body in low-oxygen conditions, their powerful effects can also have unintended consequences to disrupt cell function.

New opportunities for treating hypoxia damage

The authors tested thousands of drugs to try to restore brain-stem cell function to overcome the damaging effects of the hypoxia responder proteins. They discovered a group of drugs that specifically overcome the damage-inducing response, while leaving the beneficial response intact.

"One of the exciting avenues that stems from this work is identifying drugs that specifically target the damaging side of the hypoxia response while sparing the beneficial side," said first author Kevin Allan, a graduate student in Case Western's Medical Scientist Training Program. "This offers a new perspective on combating tissue damage due to hypoxia."

"Whether the damaging side of the hypoxia response is solely an unintended pathological effect or potentially a previously undiscovered normal process that goes awry in disease remains unknown," Tesar said. "Our work opens the door to a new way of thinking about how cells respond to low oxygen in health and disease."