Culture

Designing the best molecular building blocks for battery components is like trying to create a recipe for a new kind of cake, when you have billions of potential ingredients. The challenge involves determining which ingredients work best together — or, more simply, produce an edible (or, in the case of batteries, a safe) product. But even with state-of-the-art supercomputers, scientists cannot precisely model the chemical characteristics of every molecule that could prove to be the basis of a next-generation battery material.

Instead, researchers at the U.S. Department of Energy’s (DOE) Argonne National Laboratory have turned to the power of machine learning and artificial intelligence to dramatically accelerate the process of battery discovery.

As described in two new papers, Argonne researchers first created a highly accurate database of roughly 133,000 small organic molecules that could form the basis of battery electrolytes. To do so, they used a computationally intensive model called G4MP2. This collection of molecules, however, represented only a small subset of 166 billion larger molecules that scientists wanted to probe for electrolyte candidates.

“If we are going to use a molecule for energy storage applications, we need to know properties like its stability, and we can use this machine learning to predict properties of bigger molecules more accurately.” — Argonne chemist Rajeev Assary

Because using G4MP2 to resolve each of the 166 billion molecules would have required an impossible amount of computing time and power, the research team used a machine learning algorithm to relate the precisely known structures from the smaller data set to much more coarsely modeled structures from the larger data set.

“When it comes to determining how these molecules work, there are big tradeoffs between accuracy and the time it takes to compute a result,” said Ian Foster, Argonne Data Science and Learning division director and author of one of the papers. “We believe that machine learning represents a way to get a molecular picture that is nearly as precise at a fraction of the computational cost.”

To provide a basis for the machine learning model, Foster and his colleagues used a less computationally taxing modeling framework based on density functional theory, a quantum mechanical modeling framework used to calculate electronic structure in large systems. Density functional theory provides a good approximation of molecular properties, but is less accurate than G4MP2.

Refining the algorithm to better ascertain information about the broader class of organic molecules involved comparing the atomic positions of the molecules computed with the highly accurate G4MP2 versus those analyzed using only density functional theory. By using G4MP2 as a gold standard, the researchers could train the density functional theory model to incorporate a correction factor, improving its accuracy while keeping computational costs down.

“The machine learning algorithm gives us a way to look at the relationship between the atoms in a large molecule and their neighbors, to see how they bond and interact, and look for similarities between those molecules and others we know quite well,” said Argonne computational scientist Logan Ward, an author of one of the studies. “This will help us to make predictions about the energies of these larger molecules or the differences between the low- and high-accuracy calculations.”

“This whole project is designed to give us the biggest picture possible of battery electrolyte candidates,” added Argonne chemist Rajeev Assary, an author of both studies. “If we are going to use a molecule for energy storage applications, we need to know properties like its stability, and we can use this machine learning to predict properties of bigger molecules more accurately.”

A paper describing the formation of the G4MP2-based dataset, “Accurate quantum chemical energies for 133,000 organic molecules,” appeared in the June 27 online issue of Chemical Science.

A second paper describing the machine learning algorithm, “Machine learning prediction of accurate atomization energies of organic molecules from low-fidelity quantum chemical calculations,” appeared in the August 27 issue of MRS Communications.

Bottom Line: Deaths from choking on objects among children and teens decreased from 1968 to 2017 in this analysis that spans 50 years when efforts to prevent these deaths included a federal law, other regulations, choking hazard warning labels and public awareness campaigns. Researchers report 20,629 object-related choking deaths in children and teens (to age 17) from 1968 to 2017 based on data from the National Vital Statistics System. Deaths declined from 1.02 per 100,000 children (719 deaths) in 1968 to 0.25 per 100,000 children (184 deaths) in 2017. Although a number of laws, regulations and guidelines were adopted during that time, researchers cannot determine their effect on the decline in deaths or if other factors were involved. Additional prevention strategies should be considered to reduce the exposure of children to objects already restricted with warning labels.

To access the embargoed study: Visit our For The Media website at this link https://media.jamanetwork.com/

Authors: John D. Cramer, M.D., Wayne State University School of Medicine, Detroit, and coauthors

(doi:10.1001/jama.2019.15375)

Editor's Note: Please see the article for additional information, including other authors, author contributions and affiliations, financial disclosures, funding and support, etc.

Boston, MA -- It turns out the gut is full of surprises. And one of those surprises may have offered up a key for unlocking a new way of treating multiple sclerosis (MS). Investigators from Brigham and Women's Hospital have discovered a microRNA -- a small RNA molecule -- that increases during peak disease in a mouse model of MS and in untreated MS patients. When a synthetic version of the microRNA was orally given to the mice, it prevented disease. While several steps remain before these insights can be translated into therapy for patients, the researchers describe their results as both exciting and unexpected. Their findings are published in Cell Host & Microbe.

"We've discovered a new mechanism to regulate the microbiome and treat human disease that hadn't been known before," said senior author Howard Weiner, MD, co-director of the Ann Romney Center for Neurologic Diseases at the Brigham. "The gut microbiome is known to play an important role in MS and other diseases. Our findings, which show that a microRNA can be used to target and influence the microbiome with precision, may have applicability for MS and many other diseases, including diabetes, ALS, obesity and cancer."

Weiner, lead author Shirong Liu, MD, PhD, an instructor in the Weiner laboratory, and their colleagues investigated how the altered gut microbiome affects the course of MS. To do so, they studied the microbiome and microRNAs found in the experimental autoimmune encephalomyelitis (EAE) model of MS. Unexpectedly, they found that when they transferred fecal matter from EAE mice at peak disease, it protected the mice who received the transfer. The team found that a specific microRNA, known as miR-30d, rather than live bacteria, was responsible for preventing disease. The investigators found that miR-30d is enriched in untreated, relapsing-remitting MS patients as well.

To further investigate the effects of miR-30d, the researchers created a synthetic form of the microRNA that they could orally administer to mice. They found that giving the synthetic, oral form of the microRNA also resolved disease. The investigators next examined what components of the microbiome were changing in response to the microRNA. They found the microRNA was influencing one specific bacterial strain known as Akkermansia muciniphila, allowing it to grow and flourish in the gut. A. muciniphila has been previously reported to have anti-inflammatory properties and may help people overcome obesity.

The team also investigated the influence of the microRNA and bacterial strain on immune cells known as regulatory T cells (Tregs). They found that when the microRNA allowed the bacterial strain to expand abundantly in the gut, Tregs also increased and helped suppress MS-like symptoms in the mice.

"It's unexpected and perhaps counter-intuitive that something we find in the microbiome during peak disease could provide protection," said corresponding author Liu. "But we hypothesize that the effects we're seeing represent a protective mechanism. Most patients with relapsing-remitting MS spontaneously recover from acute attacks. What we've found here may be a part of that recovery rather than a reflection of disease progression."

The research team emphasizes that the work to date has been conducted only in preclinical models and that trials testing the safety and effectiveness of this approach in humans will be needed before the findings can be translated into therapy for patients. But the investigators remain optimistic and are currently pursuing next steps to bring their results closer to clinical impact.

"A major question in the field today is how to modulate the microbiome with specificity. We find that microRNAs may hold the answer," said Weiner.

The immune system must learn from early in life to tolerate bacteria that normally populate healthy skin, while still defending against more dangerous "bugs," but how immune cells make this distinction has long been a mystery.

In a study of young mice, UC San Francisco scientists found that an early-life window of immune tolerance available to a normally harmless bacterial species is firmly closed to another, often pathogenic species -- one that is a leading cause of drug-resistant skin infections in the U.S. and occasional source of "flesh-eating" necrosis.

These distinctive immune responses help support the mammal's symbiotic relationship with normal skin microbes while maintaining defense upon initial and subsequent exposure to potential bad actors. Further study of the biological mechanisms involved in setting up early-life immune responses to skin bacteria may lead to new strategies for fighting chronic skin infection and inflammation, the researchers say.

"It's long been clear that in infancy our developing immune systems learn to recognize our own cells and to refrain from attacking them, but it's still amazingly poorly understood how we distinguish good bugs from bad bugs," said Tiffany Scharschmidt, MD, an associate professor in the Department of Dermatology at UCSF, member of the UCSF Benioff Center for Microbiome Medicine and UCSF Bakar ImmunoX Initiative, and principal investigator for the study, which was published online November 26, 2019 in Cell Host & Microbe.

Research Addresses Mystery of Immune Tolerance

The skin is no mere wrapper; it's a full-fledged, multi-layered organ weighing several pounds that serves as a crucial physical barrier against life-threatening bacteria and other pathogens. In addition, cells of the immune system are abundant in skin and work together to recognize and attack microbes that may pose a threat.

Yet the immune system also has mechanisms in place to permit the development of a normal, healthy community of skin microbes. The skin microbiome comprises hundreds of different bacterial species and varies in composition between individuals and even between different parts of each person's skin. Many of these resident bacterial species are thought to serve helpful roles in skin health. For example, they make antibacterial molecules that serve as a chemical defense against more threatening species we might encounter -- say, on a dirty doorknob.

In an earlier study, Scharschmidt worked with Staphylococcus epidermidis, one of the most prevalent bacteria on healthy human skin. S. epidermidis is believed to be largely beneficial, but in rare situations, such as infection of implanted medical devices, it can act as a harmful pathogen.

That earlier work revealed that exposure to these healthy bacteria as a newborn led to immune tolerance: limiting skin inflammation upon subsequent encounters with this species. In contrast, delaying initial exposure to S. epidermidis until later in life resulted in a more inflammatory immune response to the same bacteria. The researchers found that this early window for tolerance was supported by a class of immune cells called regulatory T cells (Tregs), long known to play a role in maintaining tolerance to proteins from our own bodies and in preventing autoimmune diseases.

They found that Tregs were enriched in neonatal skin compared to adult skin, suggesting that the immune system could learn which bacterial species are "normal" and thus likely healthy based on which species Tregs encounter immediately after birth.

But this hypothesis presented a conundrum: If a newborn is exposed to pathogenic bacteria, would their immune systems be tricked into welcoming these dangerous invaders with open arms? "We wondered if this mechanism was an Achilles heel of the system that would also permit tolerance to pathogenic bacteria as a result of exposure during early life," Scharschmidt said -- a question that led to the new study.

Findings Could Inform Treatments for Chronic Skin Disease

Scharschmidt and her lab team now have found that early-life exposure to a multi-drug-resistant strain of Staphylococcus aureus -- the leading cause of skin infections in the U.S., a frequent aggravator of eczema, and a rare source of "flesh-eating" necrotizing fasciitis -- does not result in immune tolerance to the pathogen. The immune system is still able to respond vigorously upon later exposure to the same strain, they discovered.

"Rather than being merely immature, the immune system in early life has distinctive features and capacities, including the ability to accept commensal bacteria as part of a broader self," Scharschmidt said. "In this study we demonstrated that this tolerance is not indiscriminately extended to all bacteria encountered during this early window, but rather that the immune system very early on can distinguish commensal bacteria from pathogens, and make profoundly divergent responses with important long-term consequences."

So what accounted for the difference in early-life responses to the commensal versus the pathogenic bacterium? The researchers discovered that a specific toxin made by S. aureus plays a role in preventing tolerance and maintaining the immune system's vigilance.

Postdoctoral researcher John Leech, PhD, who conducted most of the experiments and is first author of the Cell Host & Microbe study, notes that S. aureus makes a slew of toxins that can destroy host tissues or disrupt normal immune responses. But he discovered that one specific molecule, called alpha toxin, allowed the immune system to recognize S. aureus as a threat during early-life skin exposure.

"Alpha toxin is the trigger that allows the immune system to say, 'You're not one of us,'" Leech said. "The immune system recognizes this pathogenic strain as one that is dangerous, and later in life it can still mount a robust immune response against it."

The researchers found that alpha toxin prevented tolerance by triggering immune cells in skin to take biochemical steps through an "alarmin pathway," leading to secretion of a molecule called IL-1 beta. This in turn resulted in a species-specific memory response involving fewer Tregs and instead more immune cells poised to defend against S. aureus in later life.

"I am hopeful that learning how the immune system appropriately recognizes and responds to good bugs versus bad bugs will help us better understand why certain individuals are particularly susceptible to infection, or how chronic inflammatory skin disorders are apparently exacerbated by the presence of normally well-tolerated bacteria," Scharschmidt said.

"It remains to be tested," she added, "but the types of immune responses we identified in this study are not unique to skin, and so I would think the same mechanisms of tolerance or lack of tolerance may hold for other body sites."

In a joint journal statement in this issue, the editors-in-chief of six scientific journals (Science, Nature, Cell, PNAS, PLOS and The Lancet) highlight their concerns regarding the 2018 "Strengthening Transparency in Regulatory Science" rule proposed by the Environmental Protection Agency (EPA), which has recently returned to the spotlight following a hearing on evidence in policy-making. The editors-in-chief articulate their concerns on this proposed rule 18 months after first having done so in a prior joint journal statement, since which time, they have "become even more concerned," they say. In their statement, they urge careful, deliberate analysis and discussion of proposed options related to the use and protection of confidential data. "As leaders of peer-reviewed journals, we support open sharing of research data, but we also recognize the validity of scientific studies that, for confidentiality reasons, cannot indiscriminately share absolutely all data." They also express concern about how the agency plans to consider options related to existing regulations, noting that, even without retroactive application, the new standard could apply when a regulation is updated; thus, foundational science from years past - research on air quality and asthma, for example, or water quality and human health - could be deemed by the EPA to be insufficient for informing our most significant public health issues. "That would be a catastrophe," they write. The editors-in-chief call on the scientific community and general public alike to engage on this topic. "Whether submitting public comments to the EPA or communicating with lawmakers in Congress, it is important to emphasize that decision-making that affects us all must be informed by nothing less than the full suite of relevant science vetted through scientific peer review."

Men and women are continuing to increase binge drinking, regardless of parenting status, according to the latest study at Columbia University Mailman School of Public Health. Men and women with children reported consistently lower levels of binge drinking than those without children, and men without children consistently report the highest levels of binge drinking overall; yet nearly all groups increased binge drinking in the past decade. The largest increases in binge drinking were reported among women ages 30-44 without children - from 21 percent reporting binge drinking in 2006 to 42 percent in 2018. The exception was young men (ages 18-29) with children, the only group for whom binge drinking declined. The findings are published online in PLOS Medicine.

The researchers were interested in the phenomenon of "mommy drinking," and whether women who were parents were in fact showing different or increased drinking behavior. They studied trends in binge drinking and heavy drinking among 239,944 adults ages 18-55 from the National Health Interview Survey [NHIS) for the years 2006 to 2018. They then tested whether binge and heavy drinking were increasing, decreasing, or mostly unchanged among men and women according to parenting status and age. Results were based on responses to questions about past-year alcohol use. Heavy alcohol use is defined as binge drinking at least 5 times in the last 30 day. Binge drinking is measured as any occasion of having more than five drinks during the past two weeks.

Despite widespread increases in binge drinking, heavy drinking declined or remained stable for all groups with the exception of older women (ages 45-55) without children. However, for all women, the prevalence of heavy drinking in 2006 was indistinguishable from the prevalence in 2018, regardless of age group or parenting status. Similarly, alcohol abstention decreased for all groups except for young men (ages 18-29) with children, the same group that had reductions in binge drinking.

"Our study demonstrated that trends in binge and heavy drinking over time were not differentiated by parenting status for women; rather, declines and increases over time were mainly attributable to sex and age," said Katherine M. Keyes, PhD, associate professor of epidemiology, and senior author. "We observed that men and women who parent drink less than those who do not, and men who parent drink more than women who parent."

Between 2006 and 2010, excessive alcohol use led to 88,000 deaths and 2.5 million years of potential life lost among U.S. residents. Drinking is increasing among all U.S. adults, particularly among women, but regardless of parenting status. Although, on average, women still drink less than men, women ages 20-40 have evidenced the most pronounced increases in alcohol consumption, driving the national trends among adults.

"Moms are often subject to increased scrutiny regarding their own health, and how their decisions impact the health of their children," said Sarah McKetta, MD/PhD candidate at Columbia Mailman School's Department of Epidemiology and lead author. "We found that public concern over 'mommy drinking' is not supported by the data."

"Although heavy drinking has either decreased or stabilized for most groups, binge drinking is still common and is becoming even more prevalent," said McKetta. "It's still unknown why women are increasing drinking relative to men, but we encourage physicians to screen all adults--not just select groups of men and women--for alcohol use disorders and referring them to appropriate treatment."

"Targeting subgroups or perpetuating myths that are based on normative beliefs about women's parenting roles are a distraction from the growing public health concerns of problematic alcohol use among men and women of all ages," noted Keyes.

CORVALLIS, Ore. - A new modeling approach can help researchers, policymakers and the public better understand how policy decisions will influence human migration as sea levels rise around the globe, a paper published today in Nature Climate Change suggests.

"I'm often asked 'How many people will migrate because of sea level rise?' The answer is the number depends entirely on decisions we make now," said David Wrathall, the paper's lead author and an assistant professor in Oregon State University's College of Earth, Ocean, and Atmospheric Sciences.

In the paper, a group of internationally known climate change researchers suggest that global policy decisions about greenhouse gas emissions and a range of policy decisions about where people live and work in coastal areas now will determine whether people need to migrate and where they may go.

"We've been looking at this problem the wrong way. We've been asking how many people will be vulnerable to sea level rise and assuming the same number of people will migrate," Wrathall said. "In reality, policies being made today and moving forward will exert a strong influence in shaping migration. People will move in very specific ways because of these policies."

Minimizing the negative impacts of sea level rise presents a significant societal challenge. About a billion people around the world live near the coastline and could be impacted directly or indirectly by rising sea levels as the planet warms due to climate change.

"Sea level rise is going to reorganize the human population around the globe," Wrathall said. "As the impacts of sea level rise occur, we will make decisions about how to best adapt, and those decisions will also shape migration."

The findings emerged from an interdisciplinary working group supported by the University of Maryland's National Socio-Environmental Synthesis Center.

In their paper, the researchers suggest that policymakers seeking to understand how their decisions may affect migration cannot afford to experiment on vulnerable populations in the real world with expensive and potentially dangerous policies. Instead, decision-makers can anticipate the effects of realistic policy alternatives using simulations thanks to advances in computation and modeling, Wrathall said.

A wide range of economic policies, planning decisions, infrastructure investments and adaptation measures have the potential to influence how, why and if people migrate to new places as a result of sea level changes, Wrathall said.

Armoring coastlines against surging tides and rising waters could impact whether people are able to stay in their homes or need to relocate. Tax incentives and zoning regulations that allow businesses to locate near ports, a global trend, potentially puts whole industries and labor markets at risk. Even interest rates can affect who can afford to borrow money, which could be a crucial part of people's decisions to migrate.

In addition, global decisions about the management of greenhouse gas emissions, which are responsible for the warming of the planet, could impact how quickly the planet warms and sea levels rise, Wrathall said.

"Right now, people are actually moving toward coastlines that will be more and more vulnerable as the planet warms," Wrathall said. "The only thing that will change this trend is policy. If we start changing the incentives to live, work and invest in safer places, we could make sea level rise-induced migration less expensive and disruptive down the line."

The researchers suggest that computational models should focus on global emissions policies under discussion to quantify migration impacts of sea level rise scenarios.

"All greenhouse gas emissions scenarios have a similar effect on sea level rise until about the year 2050," Wrathall said, "but then sea level rise outcomes really start to diverge. So a first step is modeling sea level rise, policy and migration in the near term."

Researchers should then simulate migration outcomes for expected adaptation policies going forward, which include defending coastlines and retreating from them.

Policy decisions also need to be modeled for their impact on the communities or regions where migrants are relocating, since those arriving will have a significant impact on their new community as well, Wrathall said.

"Future migrants will need jobs, houses and health care," he said. "Their kids will need schools. The availability of these things will affect where migrants go and their quality of life when they get there."

Modeling how those migrants make decisions will help researchers and policymakers better understand the range of realistic outcomes without having to experiment on vulnerable populations in the real world, Wrathall said. This modeling approach will provide insight on what to expect, including more realistic numbers of future migrants.

"Modeling allows us to look at all kinds of scenarios to identify the specific policies that might work to help people migrate and anticipate the policies that cause problems," Wrathall said.

A unique group of dogs helped the Inuit conquer the tough terrain of the North American Arctic, major new analysis of the remains of hundreds of animals shows.

The study shows that the Inuit brought specialised dogs with them when they migrated from Alaska and Siberia instead of adopting local dogs they would have come across during their migration. They instead maintained their own dogs, suggesting they were keen to enhance or keep the special features they had. By analysing the shape of elements from 391 dogs, the study shows that the Inuit had larger dogs with a proportionally narrower cranium to these earlier dogs. The Inuit dogs are the direct ancestors of modern Arctic sledge dogs, although their appearance has continued to change over time.

Experts had thought the Inuit used dogs to pull sledges, and this is the first study which shows they introduced a new dog population to the region to do this. These dogs then spread across the North American Arctic alongside Inuit migrants.

Dr Carly Ameen, an archaeologist from the University of Exeter who led the study, said: "Dogs have lived in North America for as long as humans, but we show here that the Inuit brought new dogs to the region which were genetically distinct and physically different from earlier dogs.

"Thousands of years ago there was not the huge number of dog breeds as we know them today. Through analysing the DNA and morphology of the remains of hundreds of dogs we've found that the dogs used by the Inuit had distinctive skull and teeth shapes, and would have likely looked different in life to dogs already in the Arctic."

Experts also examined the DNA from 921 dogs and wolves who lived during the last 4,500 years. This analysis of the DNA, and the locations and time periods in which they were found, shows dogs from Inuit sites occupied from around 2,000 years ago were genetically different from the dogs already in the region.

Study co-lead author Tatiana Feuerborn, from the Globe Institute in Denmark and the Centre for Palaeogenetics in Sweden, said: "Archaeological evidence has shown us that before the Inuit arrived in North America dog sledging was a rarity. Our analysis of the DNA suggests dogs brought by the Inuit were distinct from the earlier dogs of the North American Arctic to fill specialist role in helping communities thrive in this hostile environment by aiding with transportation and hunting. The genetic legacy of these Inuit dogs can still be seen today in Arctic sledge dogs."

The Inuit were specialised sea mammal hunters, and were more mobile than other groups living in the Arctic, migrating huge distances across the region over 1,000 years ago, with the help of dog sledges and water craft. Today, sledge dogs whose origins can be traced back to the Inuit period continue to be an important part of Arctic communities.

1.7 million. That's how many people are infected with the human immunodeficiency virus (HIV) each year worldwide. 1.7 million people who are condemned to lifelong antiretroviral therapy (ART) or risk developing fatal AIDS . Out of the 37.9 million people living with HIV (PLWH), 22.3 million have access to ART, allowing them to have an almost normal lifespan. Unfortunately, however, the medications only go so far: they don't reach the cells where the virus lies dormant for years. Moreover, potential long-term adverse effects of these medications remain unknown.

Still, HIV research has been making steady strides to help the large number of PLWH. HIV laboratories around the globe are trying to unlock the "secrets" of the virus and find its weak spots in order to prevent or cure the infection. At the Montreal Clinical Research Institute (IRCM), scientists Éric A. Cohen and Tram NQ Pham have recently identified a way to thwart HIV infection at its very early stages. Their discovery is the subject of an article in the scientific journal Cell Reports.

The window of vulnerability: a few crucial first days

"Contrary to popular belief, HIV is not so easily transmitted," says Éric Cohen, director of the Human Retrovirology Research Unit at the IRCM and a virology professor in the Department of Microbiology, Infectious Diseases and Immunology at Université de Montréal. "We are studying the window of vulnerability of the virus, meaning the moments in the infection process when it could be weakened or attacked. We focused on the very early stages following viral invasion."

Once transmitted, HIV does not immediately spread through the body. It initially has to multiply locally, mainly in the genital tissues. It is only after this initial, local expansion that the virus spreads. This localized expansion offers a very brief window of vulnerability before the virus efficiently establishes a systemic infection.

The immune response is like an armed struggle: an enemy infiltrates and the body defends itself. Viruses are the intruders, and white blood cells are soldiers trying to hold down the fort. The white blood cells are equipped with their own "infantry units": lymphocytes, phagocytes, granulocytes and others. The phagocyte group has an even more specialized unit known as 'plasmacytoid dendritic cells' (PDCs). These small, round-shaped cells patrol the body, specializing in both pathogen detection and antiviral response orchestration. In other words, they are the whistleblowers, the ones through which the entire defence process is set into motion. When they detect a threat, they change shape and develop protuberances called dendrites. "Most importantly, they start producing large amounts of interferon, a protein that triggers a state of infection resistance in other cells," Cohen explained.

As its name implies, HIV preferentially targets the immune system: it attacks and weakens the body's own defences, and the infected person becomes susceptible to the slightest infection. As soon as it arrives, HIV gets PDCs out of the way and prevents them from sounding the alarm. "The virus doesn't seem to kill them directly, but it makes them disappear in a way that is still not understood," said Pham, the senior research associate in the Human Retrovirology Research Unit. "The loss of PDCs from both the infection site and throughout the body helps establish the infection."

A humanized mouse model to fight HIV infection

"Given what HIV does to PDCs, we wondered what would happen if we boosted PDC levels and their function both prior to and during infection," said Cohen. To test this, the scientists used a special protein known as Flt3 receptor ligand to stimulate the production of PDCs from the bone marrow of humanized mice. These rodents are engineered to have a human immune system in place of the mouse's own machinery. Consequently, in an infected humanized mouse, HIV behaves as it otherwise would in a human host.

Administration of this special protein maintained high levels of PDCs in these mice and produced some striking results: 1) the initial number of infected mice was reduced; 2) the time it took for the virus to be detectable in the blood was lengthened; and 3) the amount of virus in the blood, also known as viremia, was significantly reduced. "We observed up to a 100-fold decrease in viremia," Pham noted. "In other words, the initial infection is suppressed by maintaining a high level of PDCs."

The Implications for designing a vaccine

This seminal work also showed that the injection of the Flt3 receptor ligand not only increased PDC abundance, but also boosted their ability to detect the virus and produce interferon following its detection.

Of course, HIV infection normally goes unnoticed and by the time the viremia is detectable, it is a little too late. In this context, the discovery by Cohen and Pham is highly important in terms of prevention and a potential cure. "These new findings will be crucial in the design of an HIV vaccine, which is basically aimed at teaching the immune system to defend itself by introducing it to a weakened form of the virus," said Cohen. "We can now focus on PDCs in order to control the seeding and expansion of the virus at the early stage of infection."

A school- and family-based intervention, called the CHIRPY DRAGON program, may be an effective intervention for preventing obesity in children in urban China, according to a study published November 26 in the open-access journal PLOS Medicine by Bai Li of the University of Bristol, Peymane Adab of the University of Birmingham , and Wei Jia Liu of the Guangzhou Centre of Disease Control and Prevention, and colleagues.

In low- and middle-income countries where childhood obesity is increasing rapidly, there is a lack of rigorous development and evaluation of prevention interventions. Previous childhood obesity prevention trials conducted in China have not provided robust, high-quality evidence of effective interventions. Without effective prevention programs, China is estimated to have 50 million overweight/obese children by 2030. In the new study, the researchers developed CHIRPY DRAGON (CHInese pRimary school children PhYsical activity and DietaRy behAviour chanGes InterventiON), with the goal of preventing obesity in urban, primary school-aged children in China. Participants in the randomized controlled trial included 1,461 six-year-old children from 40 primary schools in Guangzhou, China.

One group of schools received a package of activities designed to increase healthy eating and physical activity (i.e., the CHIRPY DRAGON program) over 12 months and the other group of schools continued with their usual activities. Children, particularly girls and those who were overweight or obese at baseline, in the group of schools receiving the program had a lower body-mass index at the end of the 12-month period, compared with children in the schools not receiving the program. In the intervention group, significant beneficial effects were also observed for the consumption of fruits and vegetables, sugar-sweetened beverages and unhealthy snacks, in addition to sedentary behavior and physical activity. The program was also good value for money (£1,760 per quality-adjusted life-years). It is not yet determined whether this intervention program can be successfully transferred to other contexts, but it may be effective in other locations that share similar characteristics to urban China.

A new actor in the immune system of plants has been identified. KAUST scientists have identified the protein MAP4K4 is needed to mount proper defenses against environmental pathogens.

The discovery helps explain the tight control of immune signaling in plants and reveals targets in a molecular pathway that could be manipulated by crop breeders. "Our findings are directly applicable to make plants more resistant to pathogens," says study author, Heribert Hirt, Professor of Plant Science at KAUST's Desert Agriculture Initiative.

MAP4K4 (short for mitogen-activated protein kinase kinase kinase kinase 4) is a well-established player in human immunity and inflammation, but its role in plant disease resistance was unknown. Hirt and his collaborators stumbled on it during a large screen for proteins involved in signal transduction in the weedy thale cress Arabidopsis. By studying mutant plants that lack a working copy of MAP4K4, Hirt's team then drilled down into the core functions of this protein.

First, they showed that MAP4K4 was essential for proper immune responses to flg22, a peptide derived from a bacterial protein found within the filamentous flagellum of disease-causing microbes. Working with colleagues in France, the KAUST researchers--led by Hirt and postdoctoral fellow, Yunhe Jiang--then detailed how.

They demonstrated that MAP4K4 directly adds chemical tags (in the form of phosphate groups) at several sites of another protein, BIK1. This helps stabilize BIK1 and promotes the production of highly toxic molecules that play a central role in pathogen resistance, explains Jiang. The researchers also showed that MAP4K4 tags a repressor of BIK1 with phosphate decorations. This chemical adornment disables the negative regulator to further promote BIK1 activation.

So far, Hirt and his lab group in the Biological and Environmental Science and Engineering Division of KAUST have only described this function of MAP4K4 in Arabidopsis immunity. They reported the findings on 2 September 2019 in Reports.

"The next step is to test our findings also in crops by generating knock-out mutants," Hirt says. "This is quite feasible now by using CRISPR-Cas9 gene-editing technology that is established in tomato, rice and other species of agricultural importance."

The researchers also plan to examine the roles of other regulatory proteins within the MAP4K family, of which at least 10 exist in plants. Intriguingly, Jiang showed that one family member, MAP4K3, seems to act synergistically with MAP4K4 to control BIK1 stabilization and pathogen-induced immune responses.

Closely related MAP4K proteins may thus share overlapping functions but also have distinct features that collectively contribute to the fidelity of immune signaling in plants. A better knowledge of these signaling mechanisms could help agribusinesses keep plant pathogens at bay.

In every weather situation, plants need to be robust and flexible at the same time. These structural properties come from its cell wall: It's responsible to keep the plant in shape, to compensate its osmotic pressure and to protect it against pathogens e.g. bacteria, viruses or fungal attacks. The cell walls of plants are largely built from polymers and - the polysaccharide - cellulose. As a linking agent, polysaccharides have the important task to connect long-chain polymers and to build a molecular network of tiny strands, called fibrils. Those contribute to the tensile strenght of the plant.
One of the sugar building blocks is the branched-chain monosaccharid Apiose, derived from the latin word „Apium", a plant genus, to which celeriac and parsley are part of.

„Apiose is preoccupying the Plant Biochemical Research for more than a hundred years, since its function in plants has not yet been fully understood. Besides, the mechanism, which is responsible for the production of Apiose in nature, was still not known", tells Bernd Nidetzky, CSO of the Austrian Centre of Industrial Biotechnology (acib) and Director of the Institute of Biotechnology and Bioprocestechnology at the Technical University of Graz, Austria.

One enzyme, four steps

acib and TU Graz together with the Universities Pavia (Italy) and Barcelona (Spain) discovered, how Apiose is produced by a single enzyme called UAXS(UDP-apiose/UDP-xylose Synthase). For the first time, the scientists were able to decode the entire mechanism of this enzyme. These groundbreaking discoveries were published in the prestigious journal Nature Catalysis. „Isolated from the cress Arabidopsis thaliana, the catalyst possesses special properties: Whereas most biosynthetic processes for the manufacturing of complex molecules need several reaction steps, the UAXS-enzyme selectively catalyzes four reaction steps", Nidetzky reveals. By doing so, the enzyme is able to break down organic carbon compounds as well as to establish new molecular compounds. This results in the change from an six ring sugar molecule (Hexose) to a structural converted five ring sugar (Pentose). By creating new organic carbon compounds, the enzyme is responsible for giving plants their strenght properties.

The elucidation of the encymatic mechanism of Adipose was able due to the interdisciplinary collaboration from the research areas enyzmology and biocatalysis, structural biology and molecular modelling.

New insights in the capabilities and uses of enzymes

The unusual and highly complex reaction sequence of Apiose biosynthesis enables the enymologists new, fascination insights into the molecular evolution of higher plants and gives information about how certain enzymes are able to coordinate multi step processes, leading to a final product. Nidetzky: „By understanding the biogenesis of the carbohydrate Apiose in plants grants us the basis for future industrial applications, for instance the production of valuable sugar molecules for possible products e.g. fine chemicals or novel biopharmaceuticals."

When listening to a song or watching a dance, humans tend to follow the rhythm of the music. This is because one fundamental aspect of music is its rhythm, the way we synchronize with the temporal regularities of a melody or a dance. A recent study explores how our brain fuses with musical rhythm and the extent to which humans share this ability with other animals.

Alexandre Celma-Miralles and Juan Manuel Toro, an ICREA research professor with the Department of Information and Communication Technologies (DTIC), and members of the Comparative Cognition and Language (LCC) research group at the Center for Brain and Cognition (CBC) at UPF, explain this peculiarity in an article published this November in the journal Brain and Cognition.

"This study explores the relationship between the rhythmic structure of music and the spatial dimension of sound. We study how the brain interacts with sounds that are spatially separate to build up a metrical structure", explain Celma-Miralles and Toro, the authors of the study.

So, they compared the neural responses of professional musicians with those of untrained listeners while both groups listened to a waltz. In one of the study experiments, the participants had to pay attention to sounds defined by their spatial position (the sounds were separated in space). In another experiment the participants had to pay attention to a visual distraction. Data for the study were obtained from the frequencies of EEG recordings of each subject.

Rhythm and beat are enhanced by experience

The researchers found that regardless of the participant's musical training, the brains of all listeners synchronized with the rhythm. The results also showed that musicians' neuronal responses were much stronger and more resistant to distractions than those of non-musicians. That is, the study revealed that training facilitates rhythmic synchronization.

As the researchers state, "the most relevant point of this study is that it demonstrates that our brains are prepared to follow rhythm, regardless of whether we listen to a song or watch a dance". This reinforces the idea that the neuronal processing of rhythm and beat is facilitated by previous experience with rhythmic events during long periods of formal musical training.

Researchers from the national psychiatric project iPSYCH have found that autism and ADHD share changes in the same genes. The new knowledge relates directly to the biological causes of the two child psychiatric disorders.

In Denmark, approximately one per cent of schoolchildren have autism and two to three per cent are diagnosed with ADHD. Autism and ADHD are different developmental disorders, but they can have certain common symptoms. For example, children with autism can demonstrate violent or aggressive behaviour, be impulsive, and have problems in school and with social relations - and these same symptoms can be shared by children with ADHD.

Researchers from iPSYCH, Denmark's largest research project in the field of psychiatry, have now discovered that the similarities between the two diagnoses can be linked to changes in the same genes. The new study is the largest study to date of rare mutations in the genome of people with ADHD and autism.

"The very fact that mutations are found to the same extent and in the same genes in children with autism and in children with ADHD, points towards the same biological mechanisms being involved," says Anders Børglum, who is professor at Aarhus University, principal investigator at iPSYCH and one of the leading researchers behind the study. The study was carried out in collaboration with the Broad Institute and Harvard.

First time a gene is linked to ADHD and autism

The results have just been published in the international journal Nature Neuroscience.

"This is the first time that the genome has been mapped so comprehensively for both ADHD and autism, and the discovery that children with ADHD have the same amount of deleterious gene mutations in their DNA as children with autism is both striking and quite surprising," says Anders Børglum.

The findings point directly towards which biological causal mechanisms are shared by ADHD and autism.

"In the study, the gene that is most frequently affected by mutations in people with ADHD or autism is the so-called MAP1A gene. The gene is involved in the formation of the physical structure of nerve cells - their inner 'skeleton', so to speak - and is important for the development of the brain," explains Anders Børglum.

This is the first time that this gene has been linked to the development of ADHD and autism, and the mutations found by the researchers give a significantly increased risk of developing autism and/or ADHD.

"We discovered an increased burden of mutations that destroy or severely affect the MAP1A gene in those with ADHD and autism, while very few of the control subjects had such changes in the gene," explains Anders Børglum.

This means that the risk of ADHD and autism increases by more than 15 times for people who carry such a mutation. The researchers have analysed the genes of approximately 8,000 people with autism and/or ADHD, and 5,000 people without either of the two disorders, all from Denmark. The study also incorporated additional data from approx. 45,000 international control subjects who did not have any psychiatric disorders.

"The study shows that many more genes for ADHD and autism can be identified directly by studying more people in a similar way with extensive DNA sequencing, thereby providing a more complete picture of the biological causal mechanisms and possible approaches to medical treatment," explains the researcher.

As part of the project, Anders Børglum and his colleagues have had access to samples from the Danish National Biobank at the Statens Serum Institut and to data from the Danish Psychiatric Central Research Register. People born in Denmark between 1981 and 2005 were matched with diagnoses of autism, ADHD and mental retardation.

Over 40% of online petitions started by residents of central Russia get results. In the Far East, this is the case with only 2% of online petitions, while in the regions of the North Caucasus it is even less. Russian experts, Nadezhda Radina https://www.hse.ru/en/org/persons/62303992 (HSE University) and Daria Krupnaya, studied the willingness of authorities and businesses to respond to citizens' digital activism based on data from the Change.org platform.

Results Versus Inaction
Traditionally, a petition is a collective appeal, usually to authorities or organizations. An electronic petition is an appeal published online, and they are conducted mostly on specialized sites. The most well-known ones in Russia are:

Roi.ru (Russian Public Initiative)
Change.org
OnlinePetition
democrator.ru

Change.org is active in 196 countries and 14 languages. Officials have the right to ignore petitions posted on the site (petition results on the site are not legally binding, insofar as the platform does not collect enough information about the signers). However, a large public response puts pressure on officials and businesses to take action.

'Nearly every hour, a petition on Change.org achieves victory,' the site says. Of the 22,452 Russian-language petitions created on the site from 2012 to 2017 that the researchers analyzed, 4% (918) received the status of 'fulfilled' (as indicated by the petition's creator after the collection of signatures).

Topics and Issues
The issues of petitions provide insight into the concerns of a given region. About half (44%) of the 22.4 thousand filed petitions in Russia concern social issues, and the second largest portion (18%) concern political issues.

Breakdown of Russian petition issues by category (%):
Society - 44%
Politics - 18%
Culture - 11%
Animals - 9%
Environment-- 6%
Education - 4%
Sports - 3,8%
Medicine - 3%
Economy - 0,7%
Religion - 0,5%
The North-West Federal District is primarily distinguished by its concern for social issues - 51% of petitions started in this region fell into this category. Russia's most politically active residents can be found in central Russia: 43.8% of petitions from the Central Federal District concern the resignation of officials, changing decisions, amending laws, fighting corruption, and so on. Political issues also dominate petitions created in Siberian (34%) and North Caucasian (23%) districts.

Emulating the Centre
'With the exception of the strong political bent of petitions started in the Central Federal District, there were no significant differences found between regions of Russia in terms of the kinds of demands being made -- people are concerned about similar problems everywhere,' the study authors note.

With a share of 42%, the Central Federal District had the highest number of petitions that were successful in Russia, while the Far Eastern and the North Caucasian districts had the lowest -- 2% and 1%, respectively.

Federal District Ratings
by percent share of successful petitions in Russia (%)
1. Central - 42%
2. North-West - 14%
3. Privolzhsky - 13%
4. Southern - 12%
5. Siberian - 9%
6. Ural - 7%
7. Far Eastern - 2%
8. North Caucasus - 1%
Petitions concerning society, culture, politics, and animal welfare enjoy the highest success rates. The Central Federal District's success rate can be explained by the population's civic activity in urban areas, the greater responsiveness of the petition addressees, more advanced infrastructure (for example, the quality and accessibility of the Internet), and users' involvement with technology that facilitates active participation.

Examples of successful petitions from the site Change.org
(number of signatures)
'Social Insurance Fund, stop the torture: give me my wheelchair. It's the law.' (209,701)
'Help!!! The authorities have lifted the ban on shooting the Baikal seals!!!' (374,326)
'Provide cancer patients with life-saving medicine! We have the right to life!' (428,105)
'Stop discrimination on the basis of appearance and age at PJSC Aeroflot' (50 223)
'We demand compensation for the victims of the St. Petersburg metro terrorist attack on 03.04.2017' (157 649)
'Novgorod officials must provide housing to WWII veterans, as required by law.' (191 740)
Regional Values
The response of government bodies and businesses to petitions from non-state platforms provides an indication of the quality of a given region's management. Successful petitions point to a willingness to enter into dialogue with civil society, and the issues of the petitions provide insight into the values of a given region.

By grouping the successful petitions by issue category, the researchers divided the federal districts into three clusters:

So long as they contribute to the animal rights protections, governmental bodies and businesses are safe to ignore other demands of the population. In the Far Eastern Federal District, 95% of successful petitions were in defense of animal rights.
Governmental bodies and businesses respond only to crucial problems. The Ural, North Caucasian and Siberian federal districts rank highest in social issue victories. According Ronald Inglehart's system of value classification, rational survival values are predominantly shared here, with a certain tendency toward post-materialistic values.
In response to population demands, governmental bodies and businesses are partly willing to address a wide range of current issues. In the Central, Volga, South and North-West federal districts -- mostly urban areas with city populations of a million people or more -- there is a predominance of post-materialist values (rational values of self-expression). In these regions, petitions on social issues (48.3%), political issues (17%), as well as on cultural issues (12.7%), education (11.3%) and sports (4.5%) were successful.