Culture

KEELE, UK, April 9, 2021 -- This study builds upon two earlier published studies (Mold et al., 2020, Journal of Alzheimer's Disease Reports) from the same group. The new data, also published in the Journal of Alzheimer's Disease Reports, demonstrate that aluminum is co-located with phosphorylated tau protein, present as tangles within neurons in the brains of early-onset or familial Alzheimer's disease (AD). "The presence of these tangles is associated with neuronal cell death, and observations of aluminum in these tangles may highlight a role for aluminum in their formation," explained lead investigator Matthew John Mold, PhD, Birchall Centre, Lennard-Jones Laboratories, Keele University, Staffordshire, UK.

The earlier research highlighted widespread co-localization of aluminum and amyloid-β in brain tissue in familial AD. The researchers used a highly-selective method of immunolabelling in the current study, combined with aluminum-specific fluorescence microscopy. Phosphorylated tau in tangles co-located with aluminum in the brain tissue of the same cohort of Colombian donors with familial AD were identified. "It is of interest and perhaps significance with respect to aluminum's role in AD that its unequivocal association with tau is not as easily recognizable as with amyloid-β. There are many more aggregates of aluminum with amyloid-β than with tau in these tissues and the latter are predominantly intracellular," remarked co-author, Professor Christopher Exley.

Per Dr. George Perry, Editor-in-Chief of Journal of Alzheimer's Disease, "Aluminum accumulation has been associated with Alzheimer's disease for nearly half a century, but it is the meticulously specific studies of Drs. Mold and Exley that are defining the exact molecular interaction of aluminum and other multivalent metals that may be critical to formation of the pathology of Alzheimer's disease."

"The new data may suggest that the association of aluminum with extracellular senile plaques precedes that with intracellular aggregates of tau. These relationships with both amyloid-β and tau may account for the high levels of aluminum observed in the brain tissue of donors with familial AD versus those without a diagnosis of neurodegenerative disease," said Dr Mold. "Tau and amyloid-beta are known to act in synergy to produce neurotoxicity in AD and our data provide new evidence for a role of aluminum in this process".

A new study using human genetics suggests researchers should prioritize clinical trials of drugs that target two proteins to manage COVID-19 in its early stages.

The findings appeared online in the journal Nature Medicine in March 2021.

Based on their analyses, the researchers are calling for prioritizing clinical trials of drugs targeting the proteins IFNAR2 and ACE2. The goal is to identify existing drugs, either FDA-approved or in clinical development for other conditions, that can be repurposed for the early management of COVID-19. Doing so, they say, will help keep people with the virus from being hospitalized.

IFNAR2 is the target for approved drugs often used by patients with relapsing forms of the central nervous system disorder multiple sclerosis. The researchers believe the most promising ACE2 therapy against COVID-19 is a drug that was developed before the pandemic began and has been evaluated in clinical trials to reduce inflammatory response in patients with severe respiratory disorders.

Dr. Juan P. Casas, a physician epidemiologist at the Veterans Affairs Boston Healthcare System, led the study. The research included collaborators from the University of Cambridge and the European Bioinformatics Institute in England, and Istituto Italiano di Tecnologia in Italy.

"When we started this project early last summer, most COVID-19 trials were being done on hospitalized patients," Casas explains. "Very few treatments were being tested to give to patients early in the natural history of the disease. However, as the availability of testing against coronavirus increased, an opportunity opened to identify and treat COVID-19 patients before they progress to more severe forms that require hospitalization.

"The problem we tried to overcome," he adds, "is how to identify if existing drugs, either approved or in clinical development for other conditions, can be repurposed for the early management of COVID-19. Most commonly used strategies for drug repurposing are based on pre-clinical studies, such as experiments in cells or animal models. However, those types of studies may have problems of reproducibility or difficulties in translating their findings to humans. That usually leads to higher rates of failure in clinical trials."

Casas and his team used genetics as the starting point to identify drugs that can be repurposed for treating COVID-19. Large-scale human genetic studies have been widely used to inform drug development programs, with some research identifying COVID-19 drug targets.

"The reason we used human genetics is as follows," says Casas, who is also a faculty member at Harvard Medical School. "Given that more than 90% of drugs target a human protein encoded by a gene, the opportunity is there to use genetic variants within those druggable genes as instruments to anticipate the effects that drugs targeting the same protein will have. In other words, genetic studies that used variants within druggable genes can be conceived as natural randomized trials."

To put things into perspective, he refers to a gene that encodes a protein called PCSK9. The protein is the target of a class of drugs called PCSK9 inhibitors, which are used to lower cholesterol and prevent cardiovascular disease. Researchers discovered that class of drugs because of studies showing that people carrying a certain variant within the PCSK9 gene tend to have high levels of cholesterol and are at greater risk for cardiovascular disease.

"That kind of genetic study was pivotal to identify the PSCK9 protein as a target for drug discovery," Casas says. "It's known that drug targets with human genetic support have a least twice the odds of success compare to the targets without human genetic support."

Building on these known benefits of human genetics for drug discovery, Casas and his team set out to identify all genes that encode proteins that served as targets for FDA-approved drugs or drugs in clinical development. They called this set of 1,263 genes the "actionable druggable genome." The genes were from two large genetic datasets that totaled more than 7,500 hospitalized COVID-19 patients and more than 1 million COVID-free controls.

By comparing the genetic profiles of the hospitalized patients and the controls, and looking at which drugs target which genes, the researchers were able to pinpoint the drugs most likely to prevent severe cases of COVID-19 that require hospitalization.

The two datasets were VA's Million Veteran Program (MVP), one of the world's largest sources for health and genetic information, and the COVID-19 Host Genetics Initiative, a consortium of more than 1,000 scientists from over 50 countries working collaboratively to share data and ideas, recruit patients, and disseminate findings.

"This study gets to the heart of why we built MVP," says Dr. Sumitra Muralidhar, director of the Million Veteran Program. "It demonstrates the potential of MVP to discover new treatments, in this case for COVID-19."

ACE2 is highly relevant to COVID-19 because the coronavirus uses that protein to enter human cells. The most promising ACE2 therapy against COVID-19 is the drug APN01, which mimics the protein. The drug works by confusing the coronavirus so it attaches to the drug instead of the ACE2 protein in the human cell. Positive evidence is emerging from small clinical trials on the effectiveness of APN01 in COVID-19 patients, especially those that are hospitalized. "Hence, if our genetic findings are correct, there's a need to test this strategy in clinical trials in COVID-19 outpatients," Casas says.

The IFNAR2 protein serves as the target for a drug family known as type-I interferons, one of which is interferon beta. That drug is approved for treating patients with a degenerative form of multiple sclerosis, a chronic disease that attacks the central nervous system and disrupts the flow of information within the brain and between the brain and the body. The researchers showed that people with a certain variant of IFNAR2 had less chance of being hospitalized due to COVID-19, compared to people without the variant.

Currently, Casas is early into planning a clinical trial to test the efficiency and safety of interferon beta in COVID-19 outpatients in VA. If his genetic findings are confirmed by a trial, he says the goal would be to prescribe the drug after people are diagnosed with COVID-19 but before their conditions require hospitalization.

Casas sees a continued need for drugs to treat people in the early phase of COVID-19, despite the ongoing worldwide vaccination campaigns.

"This is largely due to two reasons," he says. "First, it will take some time to achieve the high levels of vaccine coverage needed to create herd immunity. In addition, certain coronavirus variants are emerging that seem to lead to a reduced vaccine efficiency. We are not yet in the clear."

PHILADELPHIA - Psychosocial stress - typically resulting from difficulty coping with challenging environments - may work synergistically to put women at significantly higher risk of developing coronary heart disease, according to a study by researchers at Drexel University's Dornsife School of Public Health, recently published in the Journal of the American Heart Association.

The study specifically suggests that the effects of job strain and social strain -- the negative aspect of social relationships -- on women is a powerful one-two punch. Together they are associated with a 21% higher risk of developing coronary heart disease. Job strain occurs when a woman has inadequate power in the workplace to respond to the job's demands and expectations.

The study also found that high-stress life events, such as a spouse's death, divorce/separation or physical or verbal abuse, as well as social strain, were each independently linked with a 12% and 9% higher risk of coronary heart disease, respectively.

The Drexel study used data from a nationally representative sample of 80,825 postmenopausal women from the Women's Health Initiative Observational Study, which tracked participants from 1991 to 2015, to find better methods of preventing cancer, heart disease and osteoporosis in women. In the current follow-up study, Drexel researchers evaluated the effect of psychosocial stress from job strain, stressful life events and social strain (through a survey), and associations among these forms of stress, on coronary heart disease.

Nearly 5% of the women developed coronary heart disease during the 14-year, seven-month study. Adjusting for age, time at a job, and socioeconomic characteristics, high-stress life events were associated with a 12% increased coronary heart disease risk, and high social strain was associated with a 9% increased risk of coronary heart disease. Work strain was not independently associated with coronary heart disease.

Coronary heart disease, the leading cause of death in the United States, occurs with the heart's arteries become narrow and cannot bring sufficient oxygenated blood to the heart. The latest work builds on earlier studies linking psychosocial stress to coronary heart disease by finding out how job strain and social strain work together to compound disease risk.

"The COVID-19 pandemic has highlighted ongoing stresses for women in balancing paid work and social stressors. We know from other studies that work strain may play a role in developing CHD, but now we can better pinpoint the combined impact of stress at work and at home on these poor health outcomes," said senior author Yvonne Michael, ScD, SM, an associate professor in the Dornsife School of Public Health. "My hope is that these findings are a call for better methods of monitoring stress in the workplace and remind us of the dual-burden working women face as a result of their unpaid work as caregivers at home ."

The study's authors say that future studies should look at the effects of shift work on coronary heart disease and explore the effects of job demands according to gender.

"Our findings are a critical reminder to women, and those who care about them, that the threat of stress to human health should not go ignored," said lead author Conglong Wang, PhD, a recent Dornsife graduate who conducted the research while at Drexel. "This is particularly pertinent during the stressors caused by a pandemic."

Children may not be as infectious in spreading SARS-CoV-2 to others as previously thought, according to new University of Manitoba-led research in CMAJ (Canadian Medical Association Journal).

"Our findings have important public health and clinical implications," writes principal investigator Dr. Jared Bullard, associate professor, pediatrics/child health and medical microbiology/infectious diseases, Max Rady College of Medicine, University of Manitoba and associate medical director, Cadham Provincial Laboratory in Winnipeg, Manitoba. "If younger children are less capable of transmitting infectious virus, daycare, in-person school and cautious extracurricular activities may be safe to continue, with appropriate precautions in place, and with lower risk to child care staff, educators and support staff than initially anticipated."

Fourteen researchers from multiple disciplines at the University of Manitoba, Cadham Provincial Laboratory, Manitoba Health and Seniors Care and the Public Health Agency of Canada's National Microbiology Laboratory analyzed samples from 175 children and 130 adults in Manitoba infected with SARS-CoV-2 to see if there was a difference in infectiousness. Using cell cultures of nasopharyngeal swabs, they investigated viral loads in both groups to determine if children were more infectious.

"As an increasing number of jurisdictions consider whether in-school learning, daycares and extracurricular activities should continue or resume, a better understanding of the relative contributions of children and adolescents to SARS-CoV-2 transmission, when compared with adults, is essential," the authors write. "This is particularly important given the increased likelihood of asymptomatic infection in this group."

Tick-borne encephalitis is a disease just as nasty as it sounds. Once bitten by an infected tick, some people develop flu-like symptoms that resolve quietly but leave behind rampant neurological disease--brain swelling, memory loss, and cognitive decline. Cases are on the rise in Central Europe and Russia with some 10,000 incidents reported each year. Vaccines can provide protection, but only for a limited time. There is no cure.  

Now a new study describes antibodies capable of neutralizing the virus transmitted by tick bites. These so-called broadly neutralizing antibodies have shown promise in preventing TBE in mice and could inform the development of better vaccines for humans. Further, preliminary results suggest that the antibodies may not only prevent tick-borne encephalitis but even treat the condition, as well as the related Powassan virus emerging in the United States. 

Lead author Marianna Agudelo and colleagues in the laboratory of Rockefeller's Michel C. Nussenzweig examined nearly 800 antibodies obtained from individuals who had recovered from TBE or had been vaccinated to prevent infection. The most potent antibodies, designated VH3-48, turned out to be best suited to fend off future infections. They found that VH3-48 neutralized lab-grown varieties of the TBE virus, as well other tick-borne illnesses including the Langat, Louping ill, Omsk hemorrhagic fever, Kyasanur forest disease, and Powassan viruses. 

The researchers also showed that these powerful antibodies are not common; in fact, most of the antibodies produced by humans exposed to TBE virus are of inferior quality, with the coveted VH3-48 antibodies making only occasional appearances. Moreover, vaccinated patients in the study did not manage to develop any VH3-48 antibodies at all. "You'd expect the most prevalent antibodies to be the absolute best, but that is not what we found in TBE," Agudelo says. "This may explain how the virus tricks the immune system, misdirecting it into producing inferior antibodies." 

The discovery of VH3-48 provides hope for a more effective TBE vaccine. Current vaccines require three doses spaced over two years and only provide about five years of protection before a booster shot is required. Next-generation vaccines built around coaxing the body into producing the rare VH3-48 antibody could be more potent, require fewer booster shots, and also prove protective against a number of tick-borne viruses.  

"A vaccine like this would not just be more elegant, but also better focused," says Michel C. Nussenzweig, the Zanvil A. Cohn and Ralph M. Steinman Professor and head of the Laboratory of Molecular Immunology at Rockefeller. "Now that we have the structures of these antibodies, we know what to target in order to design more effective vaccines." 

Broadly neutralizing antibodies may also provide the first specific treatment for TBE. Nussenzweig, Agudelo, and colleagues found that mice infected with TBE recover after receiving antibody therapy, although it remains to be seen if this finding will translate to humans.

"The next step is a clinical trial with the antibodies," Nussenzweig says, "perhaps in Europe where there are many cases, to see whether we can ameliorate the symptoms of those suffering from encephalitis."

The CDC recently declared racism as a threat to public health. But when it comes to dismantling white supremacy in public health, action must be taken beyond issuing statements declaring racism a public health crisis, says Sirry Alang, associate professor of sociology and health, medicine, and society at Lehigh University. A new analysis from Alang and colleagues examines the three core functions of public health -- assessment, policy development and assurance -- and the ten recently revised essential public health services (EPHSs) to offer strategies public health can follow to dismantle white supremacy.

The article, "White Supremacy and the Core Functions of Public Health," by Alang and colleagues from the University of Minnesota School of Public Health was published in the American Journal of Public Health.

The researchers found that public health has contributed to structural racism and white supremacy, mentioning that health surveillance systems do not routinely collect data on racism, schools of public health are disproportionately white, and that research led by Black scholars is less likely to be funded than research led by their white counterparts.

"Public health research evaluates variation in the accessibility, effectiveness, and quality of health services by race. But the impact of racism and white supremacy on these outcomes are often ignored," Alang said.

To combat these challenges, the researchers suggest actions to take in response to public health's essential public health services.

Assessment

Under assessment, public health professionals are tasked with assessing and monitoring population health status, factors that influence health, and community needs and assets. Additionally, they are to investigate, diagnose and address health problems and hazards affecting the population.

The researchers suggest public health professionals consider tracking and reporting respondents' exposures to and experiences of police brutality and other indicators of structural racism and white supremacy, as well as investigate the complex mechanisms through which white supremacy shapes health outcomes.

Policy Development

Under policy development, tasks include communicating effectively to inform and educate people about improving health, strengthening communities and partnerships to improve health, creating and implementing policies that affect health, and utilizing legal and regulatory actions designed to improve and protect health.

The researchers encourage public health professionals to take action by educating public and policymakers on indicators of white supremacy and how it affects health, ensure equitable allocation of resources, and develop and enforce regulations and policies to dismantle practices that maintain structural racism and white supremacy.

Assurance

Under assurance, the essential public health services include ensuring an effective system that enables equitable access to services and care, building a diverse and skilled workforce, and improving and innovating public health functions.

The researchers recommend public health professionals acknowledge racist systems and advocate for antiracist policies, set clear expectations for education on equity, focus on antiracist methodologies and ensure the infrastructure for teaching, research and practice is grounded in critical race theory so that the implications of historical and contemporary manifestations of white supremacy are addressed.

"Public health can do better by ensuring that assessment includes data collection, monitoring and reporting of racism pertinent to the health of Black, Indigenous and people of color. Policy development must center the experiences of people most impacted by white supremacy. Assurance requires us to analyze the impact of white supremacy on training curricula, research funding and resources, racial composition of the healthcare workforce, and on health outcomes," wrote the researchers.

Moving forward, Alang says public health institutions have to develop and enforce regulations and policies to dismantle practices that maintain structural racism and white supremacy.

"Public health cannot address racial inequities in health outcomes without addressing white supremacy in the field itself--the discipline, profession and practice of public health, and public health schools," Alang explained. "The newly revised ten essential public health services now highlight equity, but to live up to our goal of equity, they must also tackle structural racism and its roots: white supremacy."

Scientists at the Victor Chang Cardiac Research Institute in Sydney have discovered a critical new gene that it is hoped could help human hearts repair damaged heart muscle after a heart attack.

Researchers have identified a genetic switch in zebrafish that turns on cells allowing them to divide and multiply after a heart attack, resulting in the complete regeneration and healing of damaged heart muscle in these fish.

It's already known that zebrafish can heal their own hearts, but how they performed this incredible feat remained unknown, until now. In research recently published in the prestigious journal, Science, the team at the Institute drilled down into a critical gene known as Klf1 that previously had only been identified in red blood cells. For the first time they discovered it plays a vital role in healing damaged hearts.

Dr Kazu Kikuchi, who led this world first research, said he was astonished by the findings.

"Our research has identified a secret switch that allows heart muscle cells to divide and multiply after the heart is injured. It kicks in when needed and turns off when the heart is fully healed. In humans where damaged and scarred heart muscle cannot replace itself, this could be a game-changer," Dr Kikuchi explains.

"With these tiny little fish sharing over 70% of human genes, this really has the potential to save many, many lives and lead to new drug developments."

The gene works by making remaining uninjured heart muscle cells more immature and changing their metabolic wiring. This allows them to divide and make new cells.

When the gene was removed, the zebrafish heart lost its ability to repair itself after an injury such as a heart attack, which pinpointed it as a crucial self-healing tool.

Professor Bob Graham, Head of the Institute's Molecular Cardiology and Biophysics Division, says they hope to utilise this world-first discovery, made in collaboration with the Garvan Institute of Medical Research, to transform the treatment of heart attack patients and other heart diseases.

"The team has been able to find this vitally important protein that swings into action after an event like a heart attack and supercharges the cells to heal damaged heart muscle. It's an incredible discovery," says Prof Graham.

"The gene may also act as a switch in human hearts. We are now hoping further research into its function may provide us with a clue to turn on regeneration in human hearts, to improve their ability to pump blood around the body."

Importantly, the team also found that the Klf1 gene played no role in the early development of the heart and that its regenerative properties were only switched on after a heart injury.

Professor Graham added: "This is clear evidence that the regeneration you get after a heart injury is not the same as what happens during the development of the heart but involves an entirely different pathway; an issue that has been debated for years."

Animals are remarkably diverse in their sleep and activity patterns due to foraging strategies, social behavior and their desire to avoid predators. With more than 3,000 types of cichlids, these freshwater fish may just be one of the most diverse species in the world. Lake Malawi alone, which stretches 350 miles through eastern Africa, is home to more than 500 cichlid species. They evolved from a few species that likely entered the lake about 3 million years ago and now display very different behaviors and inhabit well-defined niches throughout the lake.

So how is it possible that so many different species can coexist in this large tropical lake? Many factors have been considered including the multitude of ecological resources available, predation, and the ability of cichlid species to evolve highly specific courtship and feeding behavior. Despite the dramatic difference between day and nightlife, the way fish exploit different times of day has not been studied systematically.

Lake Malawi's cichlids are presumed to be active during the daytime, most likely to avoid predation, although this has never been investigated scientifically. By examining alterations in the circadian timing of activity and the duration of rest-wake cycles, researchers from Florida Atlantic University in collaboration with the University of Massachusetts Amherst, are the first to identify a single nocturnal species of a Malawi cichlid - the Tropheops sp. "red cheek."

The study, published in the Journal of Experimental Biology, reveals that nocturnal behavior in the red cheek, a member of a highly speciose and ecologically diverse lineage, was maintained when fish were provided shelter, but not under constant darkness, suggesting it results from acute response to light rather than an endogenous circadian rhythm. In addition, researchers discovered that nocturnality is associated with increased eye size after correcting for evolutionary history, suggesting a link between visual processing and nighttime activity.

Lake Malawi cichlids in the study exhibited substantial and continuous variation in activity levels and patterns, and closely related species differed markedly in activity. Findings suggest that circadian regulation of activity may provide a mechanism for niche exploitation in African cichlids. Researchers also identified diversity of locomotor behavior, and together, these results provide a system for investigating the molecular and neural basis underlying variation in nocturnal activity.

To examine the effects of ecological niche and evolutionary history on the regulation of locomotor activity and rest, researchers measured locomotor activity across the circadian cycle in 11 Lake Malawi cichlid species. The species were selected for diversity in habitat, behavior and lineage representation and included the near-shore rock-dwelling clade of Malawi cichlids (mbuna) as well as representative species from another major lineage within the lake. Prior to this study, the circadian regulation of activity and rest within a lineage that inhabits a shared environment was unknown.

"Given that Malawi cichlids exhibit an impressive magnitude of diversity in an array of anatomical and behavioral traits, we predicted that they may also exhibit high magnitudes and continuous variation in rest-activity patterns. We think these differences also extend to sleep and foraging behavior, providing a system to investigate how complex traits that are critical for survival evolve," said Alex Keene, Ph.D., lead author and a professor of biological sciences in FAU's Charles E. Schmidt College of Science, on the John D. MacArthur Campus at Jupiter. "Our finding that the timing and duration of rest and activity varies dramatically, and continuously, between populations of Lake Malawi cichlids raise the possibility that these differences play a critical role in the rapid speciation of this system."

Expressive language sampling (ELS) is a useful tool for measuring communication development in youth with Down syndrome, a new multi-site study has found.

The study, co-led by Angela Thurman and Leonard Abbeduto from the UC Davis MIND Institute and the Department of Psychiatry and Behavioral Sciences, focused on language as an outcome measure to detect meaningful changes in communication skills of individuals with Down syndrome. It successfully tested and validated ELS as a reliable set of procedures for collecting, measuring and analyzing the spoken language of participants interacting in a naturalistic setting.

Down syndrome and language delays

Down syndrome is the leading genetic cause of intellectual disability. Approximately one in every 700 babies in the United States is born with Down syndrome. Individuals with Down syndrome frequently have speech and language delays that might severely affect their independence and successful community inclusion.

"Interventions leading to improvements in language would have great impacts on the quality of life of individuals with Down syndrome," said Abbeduto, director of the UC Davis MIND Institute, professor of psychiatry and behavioral sciences and senior author of the study. "To develop and evaluate such interventions, we need a validated measurement tool and ELS provides that."

The ELS procedure

During the ELS procedure, researchers collect samples of participants' speech during two types of natural interactions: conversation and narration.

In conversation, trained examiners engage participants on a variety of topics in a sequenced and standardized manner. They start the conversation with a subject the participants find interesting then introduce a topic from predetermined age-appropriate lists. In their interactions, they follow a script to minimize their participation and maximize the participants' contribution. On average, the conversation lasts around 12 minutes.

In narration, the participants independently construct and tell the story in a wordless picture book. This process usually takes 10 to 15 minutes.

The researchers analyze the collected conversation and narration samples. In a previous ELS application involving participants with fragile X syndrome, the researchers derived five language outcome measures: talkativeness, lexical diversity (vocabulary), syntax, dysfluency (utterance planning) and unintelligibility (speech articulation).

Validity and reliability of the ELS measures in Down syndrome studies

For this study, four university testing sites recruited 107 participants with Down syndrome (55 males, 52 females). Participants were between the ages of 6 and 23 (mean age of 15.13 years) and with IQ levels under 70 (mean IQ of 48.73).

The participants came for a first visit to complete the ELS procedures and to take assessment tests of their IQ, autism symptom severity and other measures. Four weeks later, they revisited for a retest of the ELS procedures. This retest was to assess practice effects over repeated administrations and to check the reliability of ELS measures.

The study found that the ELS measures were generally valid and reliable across ages and IQ levels. It showed that the vocabulary, syntax and speech intelligibility variables demonstrated strong validity as outcome measures. Also, the ELS procedures were feasible for the majority of participants who successfully completed the tasks. Youth who were under 12, had phrase-level speech or less, and had a 4-year-old developmental level or lower found it more difficult to complete.

"Spoken language is the primary way we interact with the people around us, making language a frequent target of treatment. However, we have not had tools sensitive and accurate enough to confidently measure change in language treatment studies," said Thurman, associate professor of psychiatry and first author on the study. "The data from this study provide a critical first step indicating these procedures can be used to effectively measure language for people with Down syndrome."

The study, published April 8 in Journal of Neurodevelopmental Disorders, is available online. The researchers provided online manuals to help other investigators with the administration, training and assessment of fidelity of ELS procedures.

Cyberbullying already accounts for one in four cases of bullying and, according to the latest UNICEF report issued on the occasion of 'Safer Internet Day', it affects at least two students per class in Spanish schools.

In this regard, the Laboratory of Studies on Coexistence and Violence Prevention at the University of Cordoba, under the direction of professors Rosario Ortega-Ruiz and Eva M. Romera, has just published a study examining family communication and its impact on cyber-gossip and the excessive use of social media-two of the main factors with the greatest influence on cyber-bullying. Their results point in the same direction: an atmosphere of trust in the family is an antidote to this type of behaviour, reducing the risk of schoolchildren engaging inproblematic use of the Internet and excessive involvement in cyber-gossip.

The study, completed by professors Eva Romera, Rosario Ortega-Ruiz and young researchers Antonio Camacho and Daniel Falla, stresses the impact of what in the scientific literature is called "filial disclosure", a term referring to the relationship of trust between children, adolescents and young people and their parents.

"Dialogue between parents and their children, when it allows them to speak spontaneously, revealing their own ideas, feelings and interests, has very positive effects. An affectionate, warm and convivial intra-family climate encourages children to express themselves naturally and reveal their emotions, worries, ideasand problems. A parental bond of this nature provides security and favours an ability to face many of the challenges that cyber behaviour entails", the researchers stress.

They are not referring to a control mechanism exercised by parents, and far less a "heavy-handed" disciplinary approach, but rather cultivating a climate of trust and security. "According to our results," says Prof. Eva Romera, "the communicational mechanism of filial disclosure tends to shield schoolchildren from the risks that lead them to become involved in phenomena like cyberbullying, excessive use of the Internet and cyber-gossip, fostered by social situations that can be problematic and, in some cases, precipitate the emergence of other cyber behaviour problems."

The study, which was carried out with a large sample of Andalusian primary school students from urban, rural, public and state-subsidized schools, was published in Comunicar, the Spanish journal with the greatest international impact in the field, and its results also reveal that the age factor is very important.

In this regard, early adolescence (ages 12-13) is a critical evolutionary period. On the one hand, schoolchildren are at greater risk, and on the other, it is a period in which there is the most pronouncedcorrelation between the variables studied. "Parents should always pay attention to the quality of their communication with their sons and daughters, but in these years they should know that there is a lot at stake, in order to steer them away from cyberbullying and to prevent, through their dialogue and trust, specific episodes of cyberbullying and problematic use of the Internet from seriously affecting them", stresses Professor Eva Romera.

The study, whose results could inform the designs of virtual harassment prevention programs, underscores the importance of family climates and that, rather than excessive control, communication, trust and dialogue are often the keys to effective child-raising.

In all adult vertebrates, neural stem cells can be recruited to produce new neurons in the brain. However, little is known about these so-called "activation" processes.

Scientists at the Institut Pasteur, CNRS, and Tel Aviv University working in collaboration with the École Polytechnique and INRAE have successfully performed 3D visualization and spatial and temporal distribution analysis of neural stem cell activation in the adult brain of a zebrafish vertebrate model.

Their findings demonstrate for the first time that activation events for these cells are coordinated in time and space. In particular, these results may help improve our understanding of regulation processes triggered during brain tumor formation. These findings are published in the April 5, 2021 issue of the journal Cell Stem Cell.

Stem cells, which are found in many adult organs in vertebrates including humans, are capable of proliferating and differentiating to generate new functional cells. For instance, stem cells in the brain (neural stem cells) produce new neurons in adulthood. Most of the time, neural stem cells are in a dormant state known as "quiescence". In order to produce neurons, they must therefore first activate and then divide. This activation stage is crucial: it is a prerequisite for stem cell recruitment and is also critical to their survival (cells that activate excessively become exhausted quickly) and to the position and type of neurons formed.

Within their niche, neural stem cells activate and return to a dormant state in random order and asynchronously, suggesting that these events may be coordinated at cell population level. Scientists in the Zebrafish Neurogenetics Unit at the Institut Pasteur chose zebrafish to test this hypothesis, since zebrafish adult brains contain large quantities of neural stem cells, otherwise similar to mammalian stem cells. Through intravital (non-invasive) two-photon imaging of adult fish, they were able to film stem cells in their niche for several weeks and study the activation pattern of each cell in relation to neighboring cells in real time. Spatial statistical analysis and modeling performed both in real time and in long-term computational simulations demonstrated the existence of inhibitory interactions generated by activated cells, delaying the activation of other adjacent stem cells by several days. By administering a pharmacological molecule in vivo, the scientists also identified the molecular pathway involved, which is known as the Notch signaling pathway. Finally, they demonstrated that these interactions enabled steady neuronal production in time and space.

"This is the first real-time and long-term imaging of an entire neural stem cell population in the brain of an adult vertebrate. These findings demonstrate for the first time that neural stem cell activation events in the vertebrate brain are coordinated in time and space within the niche," commented Laure Bally-Cuif, CNRS scientist, lead author of the study, and Head of the Zebrafish Neurogenetics Unit1 at the Institut Pasteur. Unexpectedly, this study has also demonstrated that the stem cells themselves are involved in this coordination. Therefore, this research has prompted the emergence of a new concept whereby stem cell populations self-organize as a dynamic system enabling spatiotemporal coordination of the behavior of each individual cell.

Such regulation may occur in tumor masses containing cancerous stem cells, in which stem cells in various states of quiescence or activation have been observed. It is also likely that such regulation takes place in the stem cell populations of other adult organs where stem cells are found in compact niches, such as epithelia.

Link a to a video showing stem cells covering one of the cerebral hemispheres of an adult fish. The stem cells were monitored for 23 days to analyze their positions, activation events, and differentiation. The fish were anesthetized and filmed using a two-photon microscope every 3 days. The dots show the center of each cell and the arrows show dividing stem cells : https://www.youtube.com/watch?v=bPZsMz5tsGM

Researchers from Tokyo Medical and Dental University (TMDU) demonstrate an mRNA delivery system that effectively produces BDNF protein in rat brain to protect neurons from ischemia

Tokyo - A lack of oxygen to brain tissue--known as ischemia--leads to the death of neurons, which results in stroke. Despite considerable research, there are currently no treatments that successfully prevent neuronal death. Now, Tokyo Medical and Dental University (TMDU) researchers have reported a way of delivering mRNA to produce a therapeutic protein that protects neurons. Their findings, demonstrated in rats, are published in Biomaterials.

Brain-derived neurotrophic factor (BDNF) is a protein that enhances the survival and function of neurons. However, the BDNF molecule is too large to cross the brain's protective barrier and is rapidly removed from the central nervous system, making it difficult for BDNF to make its mark as a treatment.

The researchers therefore devised a way of producing BDNF where it is needed most.

They designed a delivery system containing BDNF messenger RNA (mRNA), which is the information molecule needed to make BDNF. When the mRNA gets inside a cell, it can be used as a blueprint to make the protein.

Their system--known as an mRNA nanomicelle--is a tiny ball-like parcel of mRNA surrounded by polymer strands. The polymer protects the mRNA from molecules that might break it down and helps to disguise it from the immune system.

"As well as protecting the mRNA by providing containment, the polymer allows the release of the cargo to be controlled," study first author Yuta Fukushima explains. "By selecting polymers with particular properties, we can ensure the mRNA is released when and where it is needed."

The effectiveness of the mRNA therapy was tested on rats that had experienced brain ischemia. The nanomicelles were found to increase the survival of hippocampal neurons. In particular, the nanomicelles showed better effects when administered 2 days after the ischemia than when given immediately. This indicates that the nanomicelles extend the opportunity for providing effective treatment.

In addition, long-term therapeutic benefits were observed 20 days after ischemia when the mRNA nanomicelle was administered on both days 2 and 5. Treated rats showed better spatial memory than untreated rats in a maze experiment.

"We are very encouraged by the performance of our system," says study corresponding author Keiji Itaka. "Our experiments not only demonstrated that the mRNA nanomicelle could prevent neuron death, but also that the potential treatment window could be extended. We expect these findings to have a significant impact on the development of practical clinical treatments."

A Curtin University study has found the introduced European honeybee could lead to native bee population decline or extinction when colonies compete for the same nectar and pollen sources in urban gardens and areas of bush.

Published in the 'Biological Journal of the Linnean Society', the research found competition between the native bees and the introduced European honeybee could be particularly intense in residential gardens dominated by non-native flowers, and occurred when the bees shared the same flower preferences.

Under these conditions, it would appear that European honeybees, being very abundant, and effective foragers, with the ability to exploit a wide range of flowers, can outcompete native bees for nectar and pollen resources.

Lead author, Forrest Foundation Scholar Miss Kit Prendergast, from Curtin's School of Molecular and Life Sciences said the research was conducted over two years in urban gardens and areas of native vegetation on the Swan Coastal Plain at Perth, Western Australia and revealed a complex relationship between native and introduced bees.

"Not all native bee species were impacted, but when native bees preferred many of the same flower species as honeybees or were of larger body size, meaning they needed more food, this was when honeybees had a negative impact on native bees," Miss Prendergast said.

"This occurs due to resource competition, where honeybees were more successful at exploiting food resources from flowers, leaving not enough nectar and pollen to support native bee populations.

Unlike native bees, honeybees occur in colonies of tens of thousands of individuals, and are better at telling other colony members where flower patches are. This communication is done by using a combination of movement and vibrations known as the "waggle dance" and using scent.

"Competition from honeybees was particularly fierce in residential gardens where there are lower proportions of the native wildflowers that our native bees have co-evolved to forage on," Miss Prendergast said.

"This impact of competition with a super-abundant, domesticated and feral introduced bee, when combined with pressures from habitat loss as a result of increasing urbanisation and agriculture, especially livestock agriculture, places some native bee species at risk of becoming endangered or even extinct."

Miss Prendergast said planting more flowering plants, particularly those preferred by vulnerable species of native bees, could help prevent them from declining in number. Controlling the density of honeybees would also be critical in reducing the pressure on vulnerable native bees.

"Native bees are an integral and important part of any ecosystem, including in the Southwest Australian biodiversity hotspot in which our research was conducted," Miss Prendergast said.

"European honeybees have been introduced around the world and pose an added threat to many native bee species already at risk of declining numbers or even extinction due to increasing urbanisation."

Researchers at GMI - Gregor Mendel Institute of Molecular Plant Biology of the Austrian Academy of Sciences - uncover an ingenious mechanism by which Arabidopsis safeguards the integrity of its genome. The paper is published in the journal Nature Cell Biology.

Is it possible for one single gene product to silence undesirable genetic elements? Can such a strong effect be seen in the regulation of Transposable Elements (TEs), or genome parasites? If yes, how does this gene product singlehandedly keep transposons in check? New research from Frédéric Berger's group at GMI provides answers to these questions and dissects a mechanism of gene silencing that has long remained shrouded in mystery.

Genome parasites

Although jumping transposons promote genomic variation at an evolutionary scale, their effects on an individual organism are massively deleterious. If left unregulated, they could give rise to genome instability and various diseases. In the model plant Arabidopsis, loss of function of one single gene product identified 30 years ago, Decreased DNA Methylation I (DDM1), was shown to result in vast and uncontrollable transposition events. DDM1 is a chromatin remodeler that helps keep DNA tightly packed to silence TEs, but the underlying mechanism how DDM1 silences TE was still unknown.

Trapped before they jump!

The team around GMI group leader Frédéric Berger, with co-first authors Akihisa Osakabe and Bhagyshree Jamge, describe the molecular mechanism of action of DDM1. They show that DDM1 targets TEs by binding H2A.W, a variant of the histone H2A, one of the building blocks that coat DNA to form the condensed and tightly packed heterochromatin. The team demonstrates that the deposition of H2A.W by DDM1 on DNA regions rich with TEs is not only necessary, but also sufficient to remodel the chromatin and silence the TEs. Importantly, the team shows that this mechanism dominates by far other known TE silencing mechanisms in Arabidopsis and that the effect of DDM1 is specific for jumping genes with intact transposing potential, i.e., potentially mobile TEs. "Transposons integrate the genome and thus share chromatin with the host. They can be viewed as enemies hiding in houses. What makes these houses distinct from those hosting protein coding genes? - The material used to build these houses is different: it enshrines transposons such that they can't go out and multiply," says Frédéric Berger. The silencing mechanism described does not affect fragments of jumping genes that have lost their ability to transpose independently, neither does it affect protein coding genes. Frédéric Berger does not hesitate to describe the mechanism with some humor: "Basically, the strategy is: enshrine your enemy in building blocks made of special material and send him to hell!".

Sent to hell packaged by DHL

The association with hell comes from "Hells", the name of the human ortholog of Arabidopsis DDM1. The researchers propose a new class of chromatin remodelers, grouping DDM1 and Hells together with their mouse ortholog Lsh, that they term "DHL". The DHL chromatin remodelers show conserved binding sites for the histone variants. In addition, all three remodelers have been associated with genomic instability and disease in their respective organisms, in case mutations lead to their loss of function.

DHL remodelers control transposons dynamics

DDM1 is the key factor in "camouflaging" TEs away from the transcriptional machinery by utilizing special "building blocks" that prevent their recognition. Asked about the broader impact of this novel mechanism, Frédéric Berger states: "DDM1 orthologs in mammals deposit the H2A.W ortholog variant macroH2A, which has been implicated in various human syndromes and cancers. Better insight into the mechanism of action of this class of histone binding proteins will advance our understanding of genome dynamics with impacts on medicine and evolution".

Engineering silencing mechanisms in yeast

Frédéric Berger, who has received funding from the "1000 Ideen" grant for high-risk research from the Austrian Science Fund (FWF), is already investigating emergent properties of these histone variants and chromatin remodelers and engineering novel silencing pathways in yeast based on the Arabidopsis H2A.W and DDM1.

Novel PF74-like small molecules targeting the HIV-1 capsid protein: Balance of potency and metabolic stability
https://doi.org/10.1016/j.apsb.2020.07.016

Of all known small molecules targeting human immunodeficiency virus (HIV) capsid protein (CA), PF74 represents by far the best characterized chemotype, due to its ability to confer antiviral phenotypes in both early and late phases of viral replication. However, the prohibitively low metabolic stability renders PF74 a poor antiviral lead. The authors report on their medicinal chemistry efforts toward identifying novel and metabolically stable small molecules targeting the PF74 binding site. Specifically, they replaced the inter-domain-interacting, electron-rich indole ring of PF74 with less electron-rich isosteres, including imidazolidine-2,4-dione, pyrimidine-2,4-dione, and benzamide, and identified four potent antiviral compounds (10, 19, 20 and 26) with markedly improved metabolic stability. Compared to PF74, analog 20 exhibited similar submicromolar potency, and much longer (51-fold) half-life in human liver microsomes (HLMs). Molecular docking corroborated that 20 binds to the PF74 binding site, and revealed distinct binding interactions conferred by the benzamide moiety. Collectively, the authors data support compound 20 as a promising antiviral lead.