Culture

In many neurodegenerative diseases like Parkinson's, protein aggregates form in the brain and are assumed to contribute to neuronal cell death. Yet there exists a cellular defence mechanism that counteracts these aggregates, known as amyloid fibrils, and can even dissolve fibrils already formed. This defence mechanism is based on the activity of molecular chaperones, i.e. protein folding helpers, of the heat shock protein 70 family (Hsp70). Molecular biologists from Heidelberg University and the German Cancer Research Center investigated how the Hsp70 system disaggregates amyloid fibrils of the Parkinson-specific protein α-synuclein in a test tube. The research team led by Prof. Dr Bernd Bukau expects their research results to provide new insights into how Parkinson's disease develops and what might be done to influence it. The results were published in two articles in the journal Nature.

Proteins in all cells - from bacteria to human - need to fold to their native state. The chains of amino acid building blocks assume specific three-dimensional structures that give proteins their functionality. This state of correct folding is constantly threatened by external and internal influences that can lead to incorrectly folded and hence damaged proteins. There is a risk that damaged proteins will "aggregate" or clump together into longer strands, the amyloid fibrils. This happens with α-synuclein in Parkinson's disease, for example. The fibrils, in turn, are the starting point for even larger deposits." The formation process of such fibrillar aggregates can damage cells and even lead to cell death, as is the case in neurodegenerative diseases like Parkinson's and Alzheimer's," explains Prof. Bukau, a researcher at the Center for Molecular Biology of Heidelberg University (ZMBH) and the German Cancer Research Center (DKFZ).

Prof. Bukau's research focuses on how these protein aggregates can be dissolved. In earlier work, he and his team succeeded in identifying a cellular activity that plays a vital role in dissolving fibrillar aggregates, which is based on chaperones of the Hsp70 family. Hsp70 chaperones help other proteins with folding and can even isolate and refold aggregated proteins. The latest research by Prof. Bukau and postdoc Dr Anne Wentink shows the effects the Hsp70 chaperones have on the Parkinson-specific amyloid fibrils of the α-synuclein protein. α-synuclein is a small protein that helps in the release of messengers called neurotransmitters in the brain, although its exact function remains unclear. It became known because massive deposits of this specific protein were found in Parkinson's patients and has been causally linked to the disease.

In biochemical experiments, the Heidelberg scientists were recently able to show that the human Hsp70 chaperone relies on the assistance of two specific co-chaperone partners to dissolve the amyloid fibrils of the α-synuclein protein. A precisely regulated interaction of these proteins leads to the formation of chaperone complexes on the surface of the fibrils, which then break up the aggregates. "It is the sheer local accumulation of many chaperone proteins on the surface of the α-synuclein fibrils that generates the force to break up the fibrils and detach the α-synuclein molecules," explains Dr Wentink. The close proximity between the chaperones on the restricted surface of the fibrils plays a decisive role in creating strong enough pulling forces to disrupt the fibrils.

The experiments were conducted together with colleagues from the European Molecular Biology Laboratory (EMBL) in Heidelberg, the Center for Structural Biology of Montpellier (France) and the École Polytechnique Fédérale de Lausanne (Switzerland). The project was funded by the "Top Research" programme of the Baden-Württemberg Foundation, the German Research Foundation, and the Helmholtz Association.

The second study published in Nature focuses on a previously unknown regulatory mechanism, a type of molecular switch that sets in motion the overall Hsp70 chaperone activity to dissolve the amyloid fibrils. This mechanism is based on a sequence of direct interactions between the different parts of the DNAJB1 co-chaperone and the Hsp70 chaperone. This ultimately activates Hsp70 to use ATP as an energy source, making it possible to productively bind to the fibrils and effect their disintegration. A close research collaboration of Dr Rina Rosenzweig of the Weizman Institute of Science in Rehovot (Israel) and Prof. Bukau, Dr Wentink and Dr Nadinath Nillegoda of Monash University in Melbourne (Australia) - a former Alexander von Humboldt Foundation fellow in Bernd Bukau's research group - succeeded in identifying this mechanism.

"Our latest results from the two studies give us a molecular understanding of how amyloid fibrils are dissolved. We were able to demonstrate that the chaperones work like a machine to dissolve the fibrils," adds Prof. Bukau. According to the Heidelberg researcher, this opens up new avenues for the development of agents that specifically target the chaperone-based cellular defence mechanism against amyloid formation. A better understanding of how this chaperone activity influences the course of neurodegenerative diseases will thus be of essential importance in the therapeutic exploitation of the findings described in these studies.

Boston, MA -- In the last decade, concerns have emerged around finasteride, a drug used for treating male-pattern baldness and prostate gland enlargement. Organizations such as the Post-Finasteride Syndrome Foundation have warned about suicidality and psychological adverse events in people taking the drug. But studies on the association between finasteride and suicidality have been limited. A team of researchers from Brigham and Women's Hospital has leveraged the World Health Organization's international database of individual case safety reports to add new evidence to the discussion. In JAMA Dermatology, the team reports a signal for suicidality and psychological adverse events among people taking finasteride, namely suicidal ideation among younger men taking the medication for hair loss. The team also found that reports of adverse events rose significantly after 2012.

"In this study, we find a signal, but we need further investigations to understand if there is a biological explanation," said corresponding author Quoc-Dien Trinh, MD, a urologist in the Division of Urologic Surgery at the Brigham. "Sometimes, adverse events can act like a self-fulfilling prophecy -- the more that people are aware of concerns, the more likely they may be to report them. But this isn't just a fluke. There's a clear signal here, and it challenges us to ask why that is."

David-Dan Nguyen, MPH, a research fellow at the Brigham's Center for Surgery and Public Health and current McGill University medical student, wanted to go beyond simply reporting these signals and additionally further explore this association between finasteride and suicidality and psychological adverse events.

"In 2012, initial studies on adverse events associated with finasteride were published, captured the media's attention, and led to increased interest in the post-finasteride syndrome as shown by Google search trends. It made sense to compare reporting before and after 2012 to explore how increased awareness of the drug impacted adverse-event reporting," said Nguyen. "Additionally, our database allowed us to easily examine other drugs used in the treatment of male-pattern baldness and benign prostatic hyperplasia to explore pharmacologic mechanisms and mitigate confounding by indication."

The team used data from VigiBase, which collects information from 153 countries on all drug-adverse reactions and contains more than 20 million safety reports. VigiBase had 356 reports of suicidality and 2,926 reports of psychological adverse events among people taking finasteride. The researchers found a disproportionate signal for suicidal ideation, depression and anxiety among people taking finasteride for hair loss who were 45 and younger. Such signals were not detected in older patients taking the drug for enlarged prostate glands. The researchers also examined other drugs for hair loss and enlarged prostate gland treatment and found no signal.

The researchers found disproportional reporting of suicidality after 2012, coinciding with highly publicized reports in the media about concerns about the drug. They did not find a signal for all other drugs used for comparison. The team hypothesized that "stimulated reporting" may be at play -- increased awareness of concerns may have led to increased attention to and reporting of adverse events. An alternative hypothesis which may explain their findings was that finasteride's well-established side-effects may have a greater toll on younger patients with alopecia (hair loss), resulting in these patients being at higher risk of anxiety, depression and suicidal ideation.

The authors note that adverse events are likely underreported to national authorities for inclusion in VigiBase. Other limitations to the study include being unable to account for confounding variables, such as social support and higher socioeconomic status, which are associated with decreased risk of suicidality and depression. While the researchers could use the database to look for instances where individuals took finasteride and a psychiatric drug, they could not determine which drug came first. And, like all observational studies, this work could not directly address the question of causation.

"Our findings suggest that risk of suicidality and psychological adverse events should be taken into account when prescribing finasteride to younger patients with male-pattern baldness who may be more vulnerable to these effects," said Trinh. "It also suggests that further study is needed to address key gaps in our understanding of why suicidality and adverse events are associated with this drug."

Toronto, ON - Hip fractures are one of the leading causes of hospitalization among older adults and are a strong predictor of mortality. There has been a steady and substantial decline in the incidence of hip fractures in the last four decades in much of the developed world including the USA, Canada, Europe, Australia, New Zealand, Hong Kong and Taiwan. The reason for this trend is a medical mystery.

A new hypothesis by University of Toronto Professor Esme Fuller-Thomson, recently published as a letter to the editor in JAMA-Internal Medicine, proposes that the declining hip fracture rates may be a result of generational differences in lifetime exposure to lead. Recent University of Toronto MSW graduate, Amy P. Munro, co-authored the article.

"Bone mineral density is much lower in people and animals who have been exposed to lead," says Fuller Thomson, director of the Institute of Life Course and Aging and professor at the Factor-Inwentash Faculty of Social Work. "People are aware of the strong link between lead exposure and lower IQ in children, but it is not as well known that 90% of the lead in one's body is stored in bone and teeth."

The burning of leaded gasoline in automobiles between the 1920s and 1970s resulted in high levels of lead exposure throughout the Western world. After the phase out of lead in gasoline began in 1973, levels of lead in the blood of children and adults plummeted.

"When I was a child in the 1970s, blood lead levels were 15 times higher than they are today," says Fuller-Thomson, who is also cross appointed with U of T's Department of Family & Community Medicine.

"More than 99% of North American children had blood lead levels above five micrograms per deciliter 45 years ago. The levels that were 'normal' at that time would be classified as a huge public health crisis today. For comparison, during the recent Flint Michigan water crisis of 2014, 5% of the children had blood lead levels above 5 micrograms per deciliter."

Both human and animal studies suggest a link between lead exposure and lower bone mineral density. Low bone mineral density increases the risk of fracture. Studies have also shown a higher incidence of hip fractures among those living close to freeways and among those with greater exposure to traffic related pollution.

Although blood lead levels declined quickly during the late 1970s and the 1980s, the lead stored in the bone remains for many decades. Therefore, bone lead levels reflect lifetime exposure to lead pollution. Older adults born before 1925 had double the lead in their bones in comparison to those born between 1936 and 1945, and five-times the level of those born between 1965 and 1982. The authors hypothesize that each successive cohort of older adults have had less cumulative exposure to lead and that this results in a lower bone lead burden and decreased risk of fractures.

There are other plausible explanations for the improving trends in the incidence of hip fracture, including decreases during the past fifty years in the prevalence of very low body mass index, smoking and heavy drinking. However, a recent analysis of the Framingham study took into account the 'usual suspects' for hip fracture including low body mass index, smoking, drinking, early-onset menopause, older age and female sex and still found a 3.2% per year decline in hip fractures among those who have never smoked. Both men and women have shown improvements in hip fractures across time, suggesting hormone replacement therapy is unlikely to explain the observed trend.

The authors suggest that next steps to assess the validity of this hypothesis could include: comparing 1990s assessment of blood lead levels to current Medicare records of hip fractures, assessing lead levels in bones that are removed during hip replacements, and examining whether those who have particular gene variants associated with higher lead uptake are at great risk of hip fracture.

"If our hypothesis is correct and lifetime lead exposure is an important contributor to hip fracture, it is likely that we will see a continued decline in the incidence of hip fractures in the Western world for at least another four decades as each successive generation of older adults will have had less exposure to lead," says Munro.

Toronto, ON - Young adults may be less susceptible to the serious adverse health effects of COVID-19, but they have not been absolved from economic and employment downturns -- and there has been little research on how employment insecurity has affected them. New research now shows a strong association between employment insecurity and common symptoms of anxiety and depression among young adults in the U.S.

Among a sample of nearly 5,000 young American adults age 18 to 26, researchers found that since March 2020, young adults who lost their job or were part of a household that experienced employment loss were more likely than those with secure employment to experience four common symptoms of anxiety and depression. This was also true of young adults who expected an employment loss in the next four weeks.

"It is clear from this study that the COVID-19 pandemic has had wide ranging effects on young adults," said Kyle T. Ganson, PhD, MSW, assistant professor at the University of Toronto's Factor-Inwentash Faculty of Social Work and lead author on the study. "It is imperative that public policy address the economic downturns to ensure the employment security of young adults, which may subsequently address their mental health."

The study, published online in the Journal of Adolescent Health, found that since the start of the pandemic on March 13th, nearly 60% of U.S. young adults experienced direct or household employment loss, while nearly 40% expected direct or household employment loss in the coming four weeks.

"Young adults are especially affected by employment loss since they are just starting their careers," said senior author Jason M. Nagata, MD, MSc, a specialist in adolescent and young adult medicine at the University of California, San Francisco. "Internships have been cancelled and employment offers have been rescinded during the pandemic."

The study also found that symptoms of anxiety and depression were common among the sample of young adults. In the seven days prior to the survey, 75% reported being nervous, anxious or on edge, 68% reported not being able to stop or control worrying, 67% reported having little interest or pleasure in doing things, and 64% reported feeling down, depressed, or hopeless.

"Young adults experiencing depression or anxiety should seek professional help early on," said Dr. Nagata. "During the pandemic, there are more options to access telehealth and other mental health resources virtually."

The researchers argue that social workers and mental health professionals should be screening for employment insecurity as the pandemic continues to ensure they are proving appropriate treatment and referrals to unemployment programs and resources.

"Policymakers need to consider the long-term scarring that may occur as a result of both employment losses and poor mental health," says Dr. Ganson. "We need to ensure that health insurance policies adequately cover mental health services for young adults."

A national study* of general practices in England has revealed the frequency of incidents of significant avoidable harm in primary care, and also important new details. For example, according to the research the main causes are diagnostic error (more than 60%), medication incidents (more than 25%) and delayed referrals (nearly 11%).

The study included 13 independent GPs undertaking a retrospective review of the case notes of more than 90,000 patients from 12** randomly selected general practices in three regions across England over a 12 month period.***

The research was funded by the National Institute for Health Research (NIHR) Policy Research Programme and is **** published in the BMJ Quality and Safety. It was led by Professor Tony Avery from the National Institute for Health Research Greater Manchester Patient Safety Translational Research Centre (GM PSTRC) which is a partnership between The University of Manchester Salford Royal NHS Foundation Trust in collaboration with The University of Nottingham. Researchers from Cardiff University and University of Edinburgh were also key members of the academic team.

The research is one of the largest and most comprehensive studies of avoidable harm in primary care. An instance of avoidable harm could be a problem with diagnosis, such as a delay or an incorrect diagnosis. Alternatively it could be around medication, such as a prescribing error or monitoring errors. When the results are applied to the English population as a whole, researchers expect that there are between 20,000 and 32,000 cases of significant harm to patients each year that are probably avoidable. It should be noted, however, that the population of England is more than 55 million and there are more than 300 million general practice consultations each year.

Tony Avery Professor of Primary Health Care at the University of Nottingham, said: "Avoidable harm has been identified by the World Health Organisation***** as a priority and an area of patient safety which we believe needs to be better understood before it can be improved. That's why our research is so important when considering how to reduce significant avoidable harm. We can't hope to tackle it unless we can first understand how many incidents are occurring. The COVID-19 pandemic has changed the way primary care operates making our recommendations even more relevant in a world where face to face consultations are not always possible."

The research revealed that in 80% of cases the significant harm could have been identified sooner, or prevented, if the GP had taken actions aligned with evidence-based guidelines. Researchers identified a number of factors that contributed to the harm, which include organisational, clinician and patient factors. Patient factors were most important and included old age, and complexities arising from having multiple health problems, including frailty. While there is little that primary care can do to control these patient factors, they illustrate the challenges healthcare professionals face when trying to protect patients from harm.

Andrew Carson-Stevens, Academic GP, Cardiff University and the Primary and Emergency Care Research Centre, Wales, worked on the research, and said: "Most of these cases of significant harm in general practice could be avoided by improving administrative systems that ensure healthcare professionals can: reliably make a referral to another service or clinician, review and action test results, monitor and recall patients that do not attend for important investigations, and, communicate clearly with other clinicians involved in the care of their patients."

Additional recommendations from researchers also include:

Improving the continuity of care for patients in primary care, particularly older people and those with multiple long term health conditions, frailty and complex presentations

Identifying and promoting ways in which IT can be used to address some of these improvements.

Dr Michael Devlin, Head of Professional Standards and Liaison at the MDU, said: "I am really pleased that, although there is no room for complacency, the evidence presented in this research clearly shows that GPs are doing a good job and avoidable harm incidents are rare. The conclusions are really helpful for GPs and I do hope that the recommendations will be acted on."

Professor Martin Marshall, Chair of the Royal College of GPs, said: "GPs and their teams deliver care to around one million patients every single day, and patients should be reassured by this research that in the vast majority of cases this care is safe and that errors are rare.

"GPs work exceptionally hard, in very difficult circumstances, to ensure the right clinical decisions are made. But of course they are human so occasionally errors can and do happen. It's vital that when they do, they are identified, and lessons learnt from them - ultimately, this will improve the care patients receive. The College is supportive of any resources or innovation that are designed to help minimise the risks of making avoidable errors.

"It's also important to recognise and address the root cause of why, although rare, mistakes do happen in general practice. For example, GPs are working under intense resource and workforce pressures - this was the case before the Covid-19 pandemic, and it continues to be so. We are now conducting more consultations than we were in March, alongside delivering the largest ever flu vaccination programme and preparing for a likely busy winter. It is vital that general practice receives the necessary resources and support to ensure patients continue to receive high-quality, safe care."

Professor Tony Avery concluded: "It is crucial we put this research into context and remember that for 97% of patients who present with significant health problems, there is no evidence that primary care played any part in the cause."

DALLAS - Nov. 11, 2020 - Even though repeated hits to the head are common in professional sports, the long-term effects of concussions are still poorly understood. While many believe that professional athletes who experience multiple concussions will end up with severe cognitive impairment later in life, a UT Southwestern study suggests that may not necessarily be the case.

The preliminary study, published in Cognitive and Behavioral Neurology, looked at a small cohort of retired professional football players who had a history of concussions and were diagnosed with mild cognitive impairment (MCI), a known risk factor for Alzheimer's disease. The 10 retired athletes, plus 10 nonathletes, were given a battery of cognitive tests to assess their verbal memory, learning, and language skills. The nonathletes also had MCI but no history of traumatic brain injury.

“For the most part, the athletes had a similar cognitive profile to the nonathletes,” says Nyaz Didehbani, Ph.D., assistant professor in the department of psychiatry and the study’s corresponding first author.“ But they did score lower on a couple of items, more specifically on our naming test, which has been showing up in a number of our studies. A consistent complaint from many of our athletes includes word-finding and naming difficulties.”

Name recall, or the ability to see something and name it, diminishes quite frequently with normal aging, says Munro Cullum, Ph.D., vice chair and chief of the division of psychology in the department of psychiatry and the study's senior author. "It's not that they have lost the ability, but rather have a reduced ability to quickly retrieve words when they're shown a picture."

Despite differences in their ability to name recall, the retired football players scored similarly to the nonathletes on verbal memory and learning. This is in contrast to findings from other studies in which a history of concussions in athletes has been found to also affect these areas.

"Overall, the study is suggestive that just because you've had a history of multiple concussions, it doesn't mean you will develop a neurodegenerative change or problems later in life," says Cullum.

The retired NFL players range in age from 64 to 77 and played anywhere from six to 14 years in the NFL. The nonathletes were selected from an Alzheimer's Disease Research Center database at UT Southwestern. The groups were similar in age, sex, race, and education.

One clue as to why multiple concussions appear to have a selective effect on name recall may lie within the brain itself. Imaging from other studies done by the UT Southwestern group on these athletes demonstrated an interesting phenomenon.

"We had an imaging finding of an abnormality in the white matter deep in the part of the brain where word retrieval is thought to occur," Cullum says. These studies found that changes in white matter in retired athletes with a history of concussions were linked to poorer performance in naming, though it is still unclear why only this area of the brain appears to be affected. The authors are designing experiments to learn more.

Although the degree of the cognitive impairment wasn't much worse in retired athletes with MCI, this study provides only a small picture of the issue. There is evidence from other studies that exposure to repeated concussions can lead to earlier onset of MCI and that cognitive impairment may be higher in retired athletes.

The team at UT Southwestern is working to resolve these conflicting results from other studies by following a larger cohort of retired athletes over time. They are seeking to investigate the long-term effects of concussion on the brain by assessing how cognition changes over time, the rates at which it changes, and the effects of comorbidities (the presence of other illnesses) and psychological factors in athletes with MCI and a history of head injuries.

Within the context of this study, the authors are also interested in looking at different ways to evaluate cognition to better understand the state of neurodegenerative changes in athletes and to determine if the link between concussion and MCI is direct or correlative.

"Their being professional athletes does not necessitate automatically falling into this doom-and-gloom category that the cognitive impairment will progress and worsen," says Didehbani. "Those cases are really just a subset, just like with the normal population."

Osaka, Japan - The ongoing global pandemic has created an urgent need for rapid tests that can diagnose the presence of the SARS-CoV-2 virus, the pathogen that causes COVID-19, and distinguish it from other respiratory viruses. Now, researchers from Japan have demonstrated a new system for single-virion identification of common respiratory pathogens using a machine learning algorithm trained on changes in current across silicon nanopores. This work may lead to fast and accurate screening tests for diseases like COVID-19 and influenza.

In a study published this month in ACS Sensors scientists at Osaka University have introduced a new system using silicon nanopores sensitive enough to detect even a single virus particle when coupled with a machine learning algorithm.

In this method, a silicon nitride layer just 50 nm thick suspended on a silicon wafer has tiny nanopores added, which are themselves only 300 nm in diameter. When a voltage difference is applied to the solution on either side of the wafer, ions travel through the nanopores in a process called electrophoresis.

The motion of the ions can be monitored by the current they generate, and when a viral particle enters a nanopore, it blocks some of the ions from passing through, leading to a transient dip in current. Each dip reflects the physical properties of the particle, such as volume, surface charge, and shape, so they can be used to identify the kind of virus.

The natural variation in the physical properties of virus particles had previously hindered implementation of this approach, however, using machine learning, the team built a classification algorithm trained with signals from known viruses to determine the identity of new samples. "By combining single-particle nanopore sensing with artificial intelligence, we were able to achieve highly accurate identification of multiple viral species," explains senior author Makusu Tsutsui.

The computer can discriminate the differences in electrical current waveforms that cannot be identified by human eyes, which enables highly accurate virus classification. In addition to coronavirus, the system was tested with similar pathogens - respiratory syncytial virus, adenovirus, influenza A, and influenza B.

The team believes that coronaviruses are especially well suited for this technique since their spiky outer proteins may even allow different strains to be classified separately. "This work will help with the development of a virus test kit that outperforms conventional viral inspection methods," says last author Tomoji Kawai.

Compared with other rapid viral tests like polymerase chain reaction or antibody-based screens, the new method is much faster and does not require costly reagents, which may lead to improved diagnostic tests for emerging viral particles that cause infectious diseases such as COVID-19.

Tohoku University scientists have found that human editing enzymes are likely behind a type of mutation in the COVID-19 virus that stimulates the release of pro-inflammatory molecules called cytokines by immune cells in the body. The finding, published in the journal Scientific Reports, is important for understanding how the virus is evolving.

The genetic material of coronaviruses, including the SARS-CoV-2 virus that causes COVID-19 infection, is contained in a single strand of RNA. Coronaviruses have fewer genetic mutations compared to other RNA viruses because they have a kind of RNA-proofreading machinery that protects them. Nevertheless, they still do have some mutations, and scientists would like to understand how they come about and what their effects might be.

Tohoku University immunobiologist Emi Furusawa-Nishii and colleagues investigated the genome sequences of almost 8,000 SARS-CoV-2 viruses from an international database. They specifically looked for 'point mutations', in which a nucleotide base within the virus's RNA is switched to another base.

Their analyses found that virus strains that had evolved from the original one isolated in Wuhan, China had a disproportionate number of cytosine bases that were switched to uracil, in addition to a number of other nucleotide base switches. Further analyses of the nucleotide bases preceding and following these point mutations suggested they were caused by two types of human editing deaminase enzymes, called APOBECs and ADARs.

The scientists then wanted to study the effects of the mutations on macrophages: a type of white blood cell that forms part of the body's first line of defence, or its innate immunity. They tested the production of two pro-inflammatory cytokines, called tumour necrosis factor-alpha and interleukin-6, by human macrophage cell lines. The cells were stimulated with an RNA fragment from Wuhan-type or mutated-type SARS-CoV-2 viruses. Surprisingly, they found that the uracil-rich RNA fragment in the mutated-type SARS-CoV-2 viruses increased the production of the two cytokines.

"Our findings suggest that the point mutations we detected in SARS-CoV-2 viruses were caused by RNA editing as part of the human defence reaction against the infection," says Furusawa-Nishii. "They also show that the virus's evolution is increasing innate immune responses in the host."

The scientists say further studies are needed to determine whether this increased innate immune response helps efficient virus elimination or if it leads to an aggravation of symptoms.

Osaka, Japan -- It's a fact of life that things break down. And when they do, whether it's your car, the roof, or a blocked artery, there are people who we can call to help with the repairs. A lesser known fact of life is that DNA also regularly breaks down and needs to be repaired. Researchers led by Noriyuki Sugo at Osaka University in Japan have been studying natural DNA repairmen in the developing brain. In a new study, they show that an enzyme known as Polβ prevents breaks in the DNA of specific neurons in the brain's hippocampus soon after birth.

Although Polβ was already known to prevent immature cells in the brain from dying by helping to repair DNA in neural stem cells, what it does in mature neurons was unclear. The researchers at Osaka University answered this question by creating mice in which nondividing mature neurons lacked Polβ. They found that these mice had many more breaks in their DNA, specifically in the CA1 and CA3 regions of the hippocampus—a region of the brain critical for learning and memory. The difference in the number of breaks peaked around two weeks after birth and then subsided, indicating that this phenomenon is related to brain development.

Throughout life, gene expression can be modified when certain molecules called methyl groups attach or detach themselves from DNA. During brain development, patterns of DNA methylation and demethylation can affect neurons and how they interact with each other. This in turn can affect future behavior and mental ability. However, this process appears to damage DNA. "We found that double-stranded breaks in the DNA of CA1 hippocampal neurons was related to DNA demethylation," explains Sugo. "When we prevented active demethylation, we no longer saw the increased number of double-stranded breaks, even though Polβ remained absent." On the flip side, purposefully initiating DNA demethylation resulted in more breaks in the DNA, thus confirming the relationship.

The team next focused on what happens to the mice because of all the double-stranded breaks in DNA. Analysis of the affected neurons showed that in addition to altered gene expression, the dendrites—the branch-like parts of neurons that receive input from other neurons—were thinner, shorter, and less complex than those in control mice. Along with these changes in the developing hippocampus, the mice themselves had difficulties forming certain kinds of memories.

"Although our results indicate a role for Polβ in genome maintenance during epigenetic regulation of gene expression during hippocampal development," says Sugo, "it remains unclear why genome maintenance of neurons is needed at this time. We hope to investigate whether this process is related to genome alternations observed in mental illness."

Specialized reflective panels located on top of buildings and deployed widely across a city could significantly improve network coverage, shows a KAUST modeling study.

Next-generation cellular networks (5G and beyond) will provide communication coverage to wider rural areas, while improving data exchange rates to meet rapidly rising demand. In urban areas in particular, obstacles in the form of buildings and other structures can impede wireless communication links, reducing mobile device signals and slowing data exchange.

Research has shown that reconfigurable intelligent surfaces (RISs) hold great promise as a technology for eliminating communication "blind spots" caused by blockages. RISs are specially designed surfaces comprising multiple reflective elements that can modify and redirect incoming signals, allowing for better control and performance over an entire communication network. RISs can be opaque or transparent, and they are well established in terms of their energy efficiency and effectiveness at manipulating signals. An RIS system can use both localization and beam tracking technologies to pinpoint a user's location and to follow their device--even if they are moving in a car at high speed.

"The RIS system and the way it reflects signals has been thoroughly studied in the literature, leading to various useful mathematical models," explains postdoc Mustafa Kishk, who conducted the study with his advisor Mohamed-Slim Alouini. "We used one of these well-established models for RIS behavior in our system setup. Then, using a mathematical tool called stochastic geometry, we created a large-scale system that distributes RISs at random on the faces of buildings. We then analyzed the probable coverage gains under different scenarios."

The results demonstrate that RISs can dramatically improve coverage in areas with blind spots. At a density of 300 blockages per square kilometer, the researchers found that only six RISs would be needed per kilometer to significantly enhance coverage. However, if the blockage density rises to 700 per kilometer, the system becomes inherently far more complex, and an estimated 490 RISs per kilometer would be needed.

"An interesting question still to be answered is whether there is an optimum number of RISs that can be deployed in any one area before they begin to interfere with one another," says Kishk.

"Our model can be used to anticipate the performance of any given large-scale network," adds Alouini. "We believe it will provide accurate, rapid assessments of potential real-world RIS applications. We could see RISs deployed in 6G networks, possibly in a decade."

The action of metformin, the classic drug used to treat diabetes by stabilizing blood sugar, can be blocked by a molecule from the bacteria in our intestines, a University of Gothenburg study shows.

Metformin is the primary treatment option for type 2 diabetes, but there are major variations in how individuals respond to this drug. In some people it lowers blood glucose (sugar) and delays the course of the disease, while in others its effects are less favorable.

An article published in the journal Cell Metabolism now clarifies one underlying factor that explain why metformin action can be blocked. This blocking is preceded by processes in the gut bacteria -- the intestinal microbiota -- in which the molecule imidazole propionate is produced.

The change in gut microbiota associated with type 2 diabetes has been demonstrated in previous research under the leadership of Fredrik Backhed, Professor of Molecular Medicine at Sahlgrenska Academy, University of Gothenburg.

He has also shown that the altered gut microbiota brings about a change in metabolism of the amino acid histidine. This, in turn, leads to an increase in the production of imidazole propionate, a molecule that inhibits the effects of insulin in lowering blood glucose.

The present study shows that, besides blocking the effects of insulin, imidazole propionate also reduces the efficacy of metformin in lowering blood glucose. In type 2 diabetes patients, high imidazole propionate levels proved to be associated with impaired metformin action, and vice versa.

The study also shows that imidazole propionate impairs the glucose-lowering effect of metformin in mice.

"Our study demonstrates clearly that imidazole propionate not only inhibits the effects of insulin but may also reduce the therapeutic action of the metformin," Backhed says.

"Since imidazole propionate has also been linked to inflammation in the gut, and metformin has several side effects in the form of intestinal problems, it's conceivable that imidazole propionate both blocks the treatment effect and contributes to side effects of metformin. But new studies are needed to verify this hypothesis."

How imidazole propionate obstructs the efficacy of metformin in regulating blood glucose has been thoroughly investigated through applied biochemistry and molecular biology. Ara Koh is the first author of the study.

"We found out that imidazole propionate interacts with AMPK, the same molecule as metformin. But instead of activating AMPK, imidazole propionate inhibits metformin-induced AMPK activation," she relates.

By blocking another protein, p38gamma, which is required to enable imidazole propionate to block AMPK (AMP-activated protein kinase), the researchers were able to inhibit the effects of imidazole propionate.

The research group works at the Wallenberg Laboratory for Cardiovascular and Metabolic Research at the University of Gothenburg, and the present study was conducted in collaboration with Sahlgrenska University Hospital.

"The work demonstrates the robustness of the translational research carried out at the Wallenberg Lab. There, observations of patients can be explained in molecular terms, which can give rise to new therapies," Fredrik Backhed concludes.

Naturally occurring compounds in ash leaves could be linked to susceptibility or resistance of individual trees to the fungal disease ash dieback (ADB).

Scientists at the University of Warwick and University of Exeter have identified a group of chemicals present in ash leaves which could be used as biomarkers to look for susceptibility or resistance to ADB.

Identifying resistant trees and breeding from them could help populate the UK with ADB resistant ash.

But, the same chemicals are used by trees to deter herbivorous insects, so selective breeding for ADB resistance could have the unintended consequence of leaving the UK ash population open to attack by invading pests.

Naturally occurring compounds in ash leaves could be linked to susceptibility of individual trees to the fungal disease ash dieback (ADB). But selecting trees with lower levels of these compounds and breeding for resistance could leave the UK ash tree population open to attack from invading insect pests in the future, according to scientists at the University of Warwick.

Secoiridoid glycosides are naturally occurring compounds found in plant leaves. Researchers from Warwick's School of Life Sciences and Department of Chemistry and the School of Biosciences at the University of Exeter looked at the abundance and diversity of secoiridoid glycosides in the leaves of a panel of ash trees known to be resistant and samples from trees known to be susceptible to ADB from both Denmark and the UK.

Previous research had identified five compounds in the secoiridoid glycoside family that were enriched in susceptible Danish trees, but results published today in
Nature Scientific Reports, show UK ash tree leaves produced 27 different individually identifiable chemicals in the group. In the paper entitled Diversity of secoiridoid glycosides in leaves of UK and Danish ash provide new insight for ash dieback management, researchers have identified particular secoiridoid glycoside compounds that could potentially be used as biomarkers for tolerance or susceptibly to ADB.

Lead author, Dr John Sidda, from the School of Life Sciences at Warwick, said: "Ash dieback is an enormous problem for the UK, as ash makes up 5.5% of British woodlands. It is the third most abundant tree species in the UK with numbers exceeding 100 million trees. Ash dieback could be devastating to the British landscape and it is estimated it could cost the UK economy up to £15 billion. Currently there is no treatment for the disease so it is vital we understand all the possible pathways to developing resistance.

"Our work shows that the small molecules in leaves could give a pretty reliable indication of a tree's resistance as well as new insight into possible resistance mechanisms. Work is already underway to validate our results on a much larger panel of UK trees, and to identify other compounds that contribute to ash dieback resistance."

If potential ADB tolerant ash could be identified via a rapid test, they could be selected for breeding to begin repopulating the UK countryside. However, there may be another enemy on the horizon.

The Emerald Ash Borer (EAB) beetle is an insect pest of ash which has devastated the ash tree population in North America. The pest is moving towards Europe and has already been identified in Russia and Ukraine. At the current rate of spread it will reach central Europe in 15-20 years.

Dr Sidda said: "We know that secoiridoid glycosides play a number of roles in plants, and some of these compounds act as a defence mechanism against herbivorous insect pests. In selecting trees with lower levels of these compounds in order to help protect the ash population against ADB, we may run the risk of reducing the UK's ash trees' natural defence against the EAB.

"However, our results indicate that there may be higher concentrations of secoiridoid glycosides in UK ash compared to Danish ash, so UK trees might be better protected against future herbivore threats such as EAB. There is also much more structural diversity of secoiridoid glycosides in the UK and Danish trees than we first thought.

"Researching and understanding these chemical compounds further will help us plan for protecting the UK ash population over the next few decades."

Professor Murray Grant, Elizabeth Creak Chair in Food Security at the University of Warwick and report co-author said: "These results are exciting as they reveal an unexpected diversity in this class of chemical compounds between ADB susceptible and tolerant UK trees, and also between Danish and UK ash. These may act as a potential reservoir of protective compounds that contribute to tree health.

"Our ongoing research is focussed on better understanding the biology of these compounds. We are grateful to funding from UKRI that allows us to expand this study to identify other chemical markers that discriminate tolerant and susceptible trees with the goal of developing a screen for ADB tolerant ash."

Researchers from HEC Montreal and York University published a new paper in the Journal of Marketing that examines how people who attain "prestigious" posts in high-profile organizations can manage their professional brands to promote career mobility.

The study, forthcoming in the Journal of Marketing, is titled "Working It: Managing Professional Brands in Prestigious Posts" and is authored by Marie-Agnès Parmentier and Eileen Fischer.

Job insecurity is pervasive. There are no guarantees of continued employment, even for those who are extremely successful in their field. This research addresses two primary questions: (1) for individuals managing their professional brands, what tensions are triggered while working in a prestigious post? and (2) what practices are conducive to mitigating these tensions and enhancing professional brand equity in a way that promotes career mobility?

The research team analyzed interviews with creative directors who have had one or more prestigious posts at top high fashion heritage brands, including Balenciaga, Chanel, Dior, Gucci, and Saint Laurent Paris. This context is well suited to the research questions given the frequent turnover among creative directors, which has been characterized by the media as akin to a game of musical chairs.

The analysis highlights that working a prestigious post in contexts such as heritage fashion triggers two types of tensions for an individual managing his/her professional brand: resource-related and identity-related. Resource-related tensions arise because prestigious posts both contribute resources and deplete resources critical to an individual's professional brand. Identity-related tensions arise because prestigious posts tend both to enhance a person's professional brand's identity and dilute that identity.

The researchers identified several practices that can mitigate these tensions. One practice that is largely internally oriented consists of "transporting teams" to support the professional brand. This means continuously surrounding oneself with trusted individuals who can help the professional brand perform effectively in a manner that is consistent over time and across organizational settings. A second practice that is both internally and externally oriented is "out-conforming to commercial logics." This means working to exceed expectations related to the commercial logics that are valorized along with artistic logics in fields such as heritage fashion. A third mitigating practice is "selectively neglecting local normative expectations." Of course, professional brands will be contractually obliged to perform in specific ways that reflect the institutionalized expectations of the organizations for which they are working. However, there are likely to be more tacit expectations of which they are aware, but which they choose to neglect in order to protect or promote their professional brand. A final mitigating practice involves "materializing the professional brand in the broader market." This means creating and publicly circulating digital or material artefacts that instantiate the individual's professional brand, but that are not sponsored by the organization that employs the individual.

Unlike prior studies on person branding, this research considers the perspective of professionals who hold prestigious jobs in organizations embedded in highly institutionalized fields. It highlights that external stakeholders' evaluations of an individual's professional brand influence who might offer that individual the next post or provide the resources to establish his/her own enterprise. Parmentier elaborates that "The unique focus of this study leads to surfacing hitherto neglected factors that may fuel, if not disloyalty to an employer, at least some efforts to limit the extent to which the professional brand allows his/her identity to become conflated with that of the organization."

Fischer adds, "The paper sends a clear message to individuals trying to manage their professional brands while holding prestigious posts: strive to strike a balance between benefiting from the affiliation while at the same time maintaining your professional independence." The paper also calls on organizations who employ professionals in prestigious posts to approach the relationship in a way that works to the mutual benefit of the employer and the employee. Organizations may wish to regard their relationships with key personnel who hold prestigious posts as akin to a co-branding alliance where both parties to the alliance benefit from it, even if the alliance is not permanent.

Philadelphia, November 11, 2020 - Sleep is crucial for consolidating our memories, and sleep deprivation has long been known to interfere with learning and memory. Now a new study shows that getting only half a night's sleep - as many medical workers and military personnel often do - hijacks the brain's ability to unlearn fear-related memories. That might put people at greater risk of conditions such as anxiety or posttraumatic stress disorder.

The study appears in Biological Psychiatry: Cognitive Neuroscience and Neuroimaging, published by Elsevier.

"This study provides us with new insights into how sleep deprivation affects brain function to disrupt fear extinction," said Cameron Carter, MD, Editor of Biological Psychiatry: Cognitive Neuroscience and Neuroimaging.

The researchers, led by Anne Germain, PhD, at the University of Pittsburgh and Edward Pace-Schott, PhD, at Harvard Medical School and Massachusetts General Hospital, studied 150 healthy adults in the sleep laboratory. One third of subjects got normal sleep, one third were sleep restricted, so they slept only the first half the night, and one third were sleep deprived, so they got no sleep at all. In the morning, all the subjects underwent fear conditioning.

"Our team used a three-phase experimental model for the acquisition and overcoming of fearful memories while their brains were scanned using functional magnetic resonance imaging," said Dr. Pace-Schott. In the conditioning paradigm, subjects were presented with three colors, two of which were paired with a mild electric shock. Following this fear conditioning, the subjects underwent fear extinction, in which one of the colors was presented without any shocks to learn that it was now "safe." That evening, subjects were tested for their reactivity to the three colors, a measure of their fear extinction recall, or how well they had "unlearned" the threat.

Brain imaging recorded during the tasks showed activation in brain areas associated with emotional regulation, such as the prefrontal cortex, in people who got normal sleep. But the brain activity looked very different in people with restricted sleep, said Dr. Pace-Schott. "We found that among the three groups, those who had only gotten half a night's sleep showed the most activity in brain regions associated with fear and the least activity in areas associated with control of emotion."

Surprisingly, people who got no sleep lacked the brain activation in fear-related areas during fear conditioning and extinction. During the extinction recall 12 hours later, their brain activity looked more similar to those with normal sleep, suggesting that a limited night of sleep may be worse than none at all.

The researchers hypothesize that sleeping only half the night results in a loss of rapid eye movement (REM) sleep, which has been shown to be important for memory consolidation and usually happens toward the end of a normal sleep period.

Dr. Carter said the study used "noninvasive brain imaging to give us a novel window into how sleep deprivation disrupts the normal fear extinction mechanisms and potentially increases vulnerability to posttraumatic stress symptoms."

"Medical workers and soldiers often have curtailed or interrupted sleep rather than missing an entire night's sleep," Dr. Pace-Schott said. "Our findings suggest that such partially sleep-deprived individuals might be especially vulnerable to fear-related conditions such as posttraumatic stress disorder."

High doses of vitamin C under study for treating COVID-19 may benefit some populations, but investigators exploring its potential in aging say key factors in effectiveness include levels of the natural transporter needed to get the vitamin inside cells.

Age, race, gender, as well as expression levels and genetic variations of those vitamin C transporters that make them less efficient, all may be factors in the effectiveness of vitamin C therapy against COVID-19 and other maladies, investigators at the Medical College of Georgia Center for Healthy Aging report in a commentary in the journal Aging and Disease.

The investigators recommend that those factors be considered in the design and execution of clinical trials, and when trial results are analyzed, for COVID-19 as well as other conditions, says Dr. Sadanand Fulzele, aging researcher and the article's corresponding author.

The novel nature and lack of immunity against the coronavirus has prompted a worldwide pursuit of effective treatments for COVID-19, they write. That includes repurposing drugs with known safety profiles, including Vitamin C, an established immune system booster and antioxidant, which made it a logical choice to explore in COVID-19. Both strategies are needed in response to infection with the novel coronavirus to ensure a strong immune response to stop the virus from replicating in the body, and to avoid the over-the-top, destructive immune response the virus itself can generate if it does.

There are at least 30 clinical trials underway in which vitamin C, alone or in combination with other treatments, is being evaluated against COVID-19, some with doses up to 10 times the recommended 65 to 90 milligrams daily of vitamin C.

Factors like whether or not vitamin C can get inside the cell, likely are an issue in the effectiveness the therapies ultimately show, says Dr. Carlos M. Isales, co-director of the MCG Center for Healthy Aging and chief of the MCG Division of Endocrinology, Diabetes and Metabolism.

In fact, without adequate transporters on a cell's surface to get the water-soluble vitamin past the lipid layer of cell membranes, particularly large doses may enable the vitamin to cluster around the outside of cells where it actually starts producing oxidants, like damaging reactive oxygen species, rather than helping eliminate them, says Isales, a study coauthor.

"We think it's important to look at transporter expression," Fulzele says.

They suspect low transporter expression is a factor in the mixed results from vitamin C's use in a variety of other conditions. Clinical trials in osteoarthritis, for example, an autoimmune disease where a misdirected immune system is attacking the joints, has gotten mixed results, Fulzele says. However its usage in other viral-induced problems, like potentially deadly sepsis, has shown benefit in reducing organ failure and improving lung function in acute respiratory distress syndrome, which is also a major cause of sickness and death with COVID-19.

At the time their Aging and Disease paper was published, there were not yet published studies of the efficacies of high-dose, intravenous vitamin studies underway for COVID-19.

Fulzele, who works on vitamin C in aging, and others have shown that some conditions, like osteoarthritis and even normal aging, are associated with significant downregulation of at least one subtype of vitamin C transporter.

In fact, part of the paradox and concern with COVID-19 is that those most at risk mostly have both lower levels of vitamin C before they get sick and fewer transporters to enable the vitamin to be of benefit if they get more, Fulzele says.

Many of those most at risk from COVID-19, including individuals who are older, Black, male and with chronic medical conditions like osteoarthritis, hypertension and diabetes, tend to have lower levels of vitamin C, another reason vitamin C therapy would be considered a reasonable treatment, Isales says. The investigators also note that patients may develop a vitamin C deficiency over the course of their COVID-19 illness since, during an active infection, vitamin C is consumed at a more rapid rate. Insufficient levels can augment the damage done by an overzealous immune response.

While not routinely done, transporter expression can be measured today using PCR technology, a method also used for novel coronavirus as well as influenza testing. While increasing transporter expression is not yet doable in humans, one of Fulzele's many research goals is to find a drug or other method to directly increase expression, which should improve the health of older individuals as well as those with other medical conditions that compromise those levels.

He notes that reduced transporter levels that occur naturally with age are a factor in the reduced immune function that also typically accompanies aging. That means that even when a 60-year-old and 20-year-old both have a healthy diet in which they consume similar, sufficient amounts of vitamin C, the vitamin is not as effective at boosting the older individual's immune response. Reduced immune function in older individuals is known to put them at increased risk for problems like cancer and COVID-19.

Low vitamin C levels also have been correlated with higher mortality in older individuals from causes like cardiovascular disease. High oxidative stress, a major factor in conditions like cardiovascular disease as well as aging and now COVID-19, also is associated with significantly reduced expression of the vitamin C transporter.

Isales and Fulzele doubt that taking a lot of vitamin C is a good preventive strategy against COVID-19, except in those individuals with a known deficiency.

Vitamin C is an essential vitamin, which means people have to consume it in their food or supplements. Foods naturally high in vitamin C include oranges, potatoes, tomatoes, broccoli and Brussels sprouts. The vitamin's diverse roles in the body also include formation of blood vessels, collagen and cartilage.