Culture

Bo Li, Kai Kou, Research Fellows of IBS Center for Soft and Living Matter, Walter Kob, Professor of University of Montpellier and Institute Universitaire de France and Steve Granick, Director of the IBS Center for Soft and Living Matter report together in the 7833 issue of the journal Nature that onset of glass transition is a highly non-trivial process involving complex non-linear responses.

As a substance that has been giving remarkable impetus to both the convenience of our daily life and the advance of modern science and technology, glasses puzzle us, however, on the basic science level. "Glasses see much incremental study but rarely a breakthrough, regardless of the endeavors from generations of scientists," commented Granick.

The reported non-monotonic dynamical length scale peaking at the onset temperature subverts the prevalent understanding that cage formation is a simple crossover between liquid and glass. "One central question in glass science is the cage formation process that gives the glassy materials their unique optical and mechanical properties," said Kob, "and we directly hit the problem by locally exciting a colloidal glass using laser beams" said Li.

The emergence of the non-monotonic length scale results from the buildup of domains with cooperative dynamics that become increasingly rigid and start to dominate the particle dynamics. "Just like the painting of Seurat, the mosaic of the dynamical grains," Kob commented with enthusiasm, "and the cage formation is directly related to the merging of them." "The beauty of science here is that we are able to see how glasses germinate from the liquids microscopically," Li said.

The simple physical picture of the enhanced cooperative dynamics for the non-monotonic response suggests the finding should be general. Kob said, "It's amazing that the physical rule behind such rich dynamics is so concise." "And our findings in a well-defined model system will help better understanding other glassy or disordered systems like polymer, granular and atomic glasses, etc." Li remarked.

In addition to the non-monotonic behavior, a scaling relation between the morphology and size of the excitation pattern is extracted based on huge amount of experimental data. "The deviation of this relation reflects the degree of a material's heterogeneity at certain condition" said Li. And Granick remarked, "This scaling law, besides its theoretical importance for physicists, will interest chemists and material scientists as well by offering them a 'ruler' that guides the design and synthesis of glass materials."

Beyond enlightening the first step of glass transition, this proof-of-concept experiment paves the way for the fundamental understanding of glasses eventually. "Using laser as a lancet, a glass sample can be precisely anatomized," said Granick. "More and more exotic yet puzzling behaviors in glasses will be assessed in this way," remarked Kob.

This work is motivated by the long-standing challenges in glass science. The sluggish and highly coupled dynamics always burry the key effect. "If only I can shrink myself, jump into the system and stir the surroundings", once Li conceived, "perhaps laser is a good choice". The femtosecond holographic laser system originally developed by Lou perfectly satisfy the needs of the local excitation. Valuable theoretical support is obtained from Kob for refining the complex experimental observations into concise physical principles. "The highly interdisciplinary environment in our center and successful international collaboration makes a once improbable brainstorm real", commented Granick.

Granick and Kob concluded: "The field of glass science, being classic but constantly challenging, is promoted by this experiments that elucidating the onset of glass transition. The conceptual importance of cage-formation for the properties of glassy materials is revealed. And the micro-rheological approach taken here opens the door to the thorough understanding of the glasses one day."

Scientists can now select individual cells from a population that grows on the surface of a laboratory dish and study their molecular contents. Developed by University of Toronto researchers, the new tool will enable a deeper study of stem cells and other rare cell types for therapy development.

The method is the first to marry cell microscopy with omics platforms to link the cells' physical parameters that are visible by eye, such as appearance, the presence of surface markers or cell-cell contacts, to their molecular makeup.

"We give the user the power to take beautiful fluorescence microscopy images to learn everything that can be learned about cells growing in situ and then connect that information with the cell's genome, transcriptome and proteome," says Aaron Wheeler, a professor of chemistry and biomedical engineering in the Donnelly Centre for Cellular and Biomolecular Research who led the work.

The platform is described in a paper out today in the journal Nature Communications.

Named DISCO, for Digital microfluidic Isolation of Single Cells for -Omics, the method allows researchers to select single cells in their local environment and analyse their contents with the DNA and protein sequencing technologies to read the cell's DNA (genome), the genes' RNA transcripts (transcriptome) and protein molecules (proteome).

The rise of single-cell analyses over the past five years has enabled researchers to measure tens of thousands of molecules in each cell, transforming their ability to study tissues and organs on a granular level. But these approaches miss important information about the cells' physical features and local environment because the cells have to be placed in suspension and separated from each other prior to analysis.

"There's a revolution going on right now with single cell omics," says Wheeler, who is Canada Research Chair in Microfluidic Bioanalysis. "But I came across people who were disappointed that there weren't able to capture phenotypic information about the cell in its in situ environment."

"And I thought we might be able to come up with a way to select particular cells from that population and analyse them," he says.

DISCO is composed of a microscope fitted with a high frequency laser and a microfluidic chip for the collection of cellular material. The microscope allows the user to take detailed images of the target cell before shining the laser on it. The energy from the laser causes a tiny bubble to form and pop in the proximity of the cell, rupturing its membrane and shooting its contents up into a droplet on the microfluidic chip, from where it is retrieved for molecular sequencing.

"Our platform focuses on the metadata that you lose when you do single cell suspension, things like cell position, what were its morphological properties, who were its neighbours? Those are all the things that we can capture before we do the single cell sequencing ," says Erica Scott, a postdoctoral fellow in the lab who spearheaded the work along with two PhD students in the lab, Julian Lamanna and Harrison Edwards.

"To our knowledge, this is the only platform that can take cells in culture and do this kind of thing," she says.

In proof of principle experiments, the researchers demonstrated DISCO's ability to faithfully relate omics data to individual human and mouse brain cancer cells that were cultured side by side.

But the findings also brought into sharp focus the extent to which the contacts between cells can influence their molecular states. The expression of a whopping 5,000 mouse genes--about a fifth of the genome-- was altered in individual mouse cells that had been surrounded by human cells instead of their own kin.

The findings could have important implications for many labs that seek to gain a better understanding of healthy and diseased human tissue, such as tumours, by growing them in mice so that they can be studied in a whole-body environment. If gene expression is similarly affected in the human graft, these changes could have ramification for treatment development, said Wheeler.

Fortunately, DISCO may soon offer a window into the cells in their natural environment as the researchers are working to adapt it to the analysis of tissue slices. Their ultimate goal is to apply DISCO to the study of rare cell types, such as stem cells, whose regenerative potential is in large part regulated by their immediate environment, to help advance new therapies.

Looking for a bird's-eye view of human impact? A new study published in the journal Nature provides the most comprehensive picture yet of how human noise and light pollution affect birds throughout North America, including how these factors may interact with or mask the impacts of climate change.

Recent troubling findings suggest bird populations have declined by more than 30% in the last few decades. To develop effective strategies to reverse this trend, scientists and land managers need to understand what caused the decline.

The effects of noise and light pollution on the health of bird populations had been largely overlooked until some recent studies suggested that these stressors can harm individual species. With this new study, a continent-wide picture has emerged.

"Our study provides the most comprehensive evidence that noise and light can profoundly alter reproduction of birds, even when accounting for other aspects of human activities," said Clint Francis, a biologist at California Polytechnic State University and one of the lead study authors.

Researchers looked at a huge collection of data sets -- including those collected by citizen scientists through the NestWatch Program -- to assess how light and noise affected the reproductive success of 58,506 nests from 142 species across North America. The team considered several factors for each nest, including the time of year breeding occurred and whether at least one chick fledged from the nest.

Birds time their reproduction to coincide with peak food availability to feed their young, using daylight cues to breed about the same time each year. The researchers found that light pollution causes birds to begin nesting up to a month earlier than normal in such open environments as grasslands or wetlands and 18 days earlier in forested environments. The consequence could be a mismatch in timing -- hungry chicks may hatch before their food is readily available. If that happens, these early season nests may be less successful at fledging at least one chick, but the situation is complicated by climate change.

As the planet warms, birds' food is available earlier due to warmer weather. Birds that maintain their historical breeding times because their internal clocks are set to changes in day length may have fewer chicks survive because the food source they rely on already came and went.

"We discovered that the birds that advanced the timing of their reproduction in response to increased light pollution actually have better reproductive success," Francis said. "A likely interpretation of this response is that light pollution actually allows these birds to 'catch up' to the shift towards earlier availability of food due to climate change."

These findings suggest two conclusions about how birds respond to climate change. First, at least temporarily, birds in areas impacted by light pollution may track climate change better than those in in natural habitats that are darker. Second, when scientists thought birds were adjusting their reproductive timing to climate change, birds actually may have been responding instead to the light cues because many studies were done in areas exposed to some light pollution.

When considering noise pollution, results showed that birds living in forested environments tend to be more sensitive to noise than birds in open environments.

Researchers delved into greater detail for 27 species looking for physical traits that could explain the variations in species' responses to light and noise. A bird's ability to see in low light and the pitch of its call were related to species' responses to light and noise pollution, respectively.

The more light a bird's eye is capable of taking in, the more that species moved its breeding time earlier in the year in response to light pollution and the more that species experienced improved nest success as a result of light pollution. Noise pollution delayed nesting for birds' whose songs are at a lower frequency and thus more difficult to hear through low-frequency human noise. Mating decisions are made based on the male's song, and in some cases, females need to hear the male's song to become physically ready to breed.

These trait and environment-specific results have strong implications for managing wildlands.

"We show convincingly across a lot of species that noise and light pollution are having strong effects on wild populations," Francis said. "If there's a proposed development and land managers are worried about a bird that they have no information on, they can use this study to see whether the development is likely to affect the bird. Is it a forest bird? If so, it is likely that it is more sensitive to light and noise."

The study is the first step toward a larger goal of developing a sensitivity index for all North American birds. The index would allow managers and conservationists to cross-reference multiple physical traits for a species to assess how factors such as light and noise pollution would affect it and each species.

EMBARGOED FOR RELEASE UNTIL 11 A.M. ET, WEDNESDAY, NOV. 11, 2020

PITTSBURGH, Nov. 11, 2020 - Researchers from the Pittsburgh Center for Pain Research at the University of Pittsburgh School of Medicine announced today in the journal Neuron that they've uncovered additional complexities behind mechanical allodynia--the sensation of pain from innocuous stimuli, such as light touch.

Different types of injury that cause mechanical allodynia activate distinct spinal circuits that process the information from the skin to the brain, scientists discovered. The finding may explain why pain medications don't alleviate an adverse sensation in all patients. It also suggests that new treatment strategies for pain management need to consider ways in which pain signals are processed in the spinal cord.

"Even though the pain outcome is the same, the neural circuits that conduct the signal are different depending on the kind of injury you have--say, arthritis or nerve trauma," said senior author Rebecca Seal, Ph.D., associate professor in Pitt's Department of Neurobiology. "And if you have different neural pathways depending on the type of injury, that might explain why therapies sometimes don't work."

For patients who experience mechanical allodynia, even the most mundane actions can hurt: Putting on clothes or even tossing in bed can be excruciatingly painful. The condition currently has no cure.

While recent studies identified the critical role of skin receptors for the perception of pain after a light touch, little was known about the way information is transferred from the nerve endings in the skin to the central nervous system where the pain sensation forms.

"People typically think of mechanical allodynia as a condition that is uniform in terms of its underlying neural circuitry in the central nervous system," said Seal. "We now show that is not the case."

Pitt researchers used several pain models to determine if calretinin-expressing (CR) neurons located in the outermost layer of the dorsal horn--one of the three gray columns of the spinal cord--are important to convey mechanical allodynia.

Experiments in mice showed that these neurons are critical for transmitting pain signals induced by inflammatory injuries but not by nerve injury.

Conversely, another subset of neurons of the spinal cord--this time PKC-gamma neurons, which lay adjacent to CR neurons at the border between the second and third layer of the dorsal horn--were responsible for animals feeling neuropathic-induced pain but not pain of inflammatory origin.

Lastly, researchers found that Cholecystokinin (CCK) neurons located deeper within the layers of the dorsal horn are important for both types of injuries.

"Now that we know more about how spinal circuitry of pain is organized, we can use gene therapy to shut it off," said Seal. Her lab currently is working on developing ways to target neurons in the spinal cord using viral gene therapy and chemogenetics in patients experiencing mechanical allodynia.

"A lot of work has been done to understand how sensory neurons transmit pain signals, but we didn't know much about what happens in the spinal cord," she added. "Cracking that black box open in this unique way feels particularly exciting."

In a manuscript published in the same issue of Neuron and co-authored by Seal, Graziana Gatto, Ph.D., and Martyn Goulding, Ph.D., both of The Salk Institute for Biological Sciences in California, use similar experimental approaches to describe the wiring of the motor behavioral responses to acute pain and touch sensation in the spinal cord.

Carbon dioxide fuels photosynthesis, the process by which plants generate their food in the form of carbohydrates. The atmosphere's carbon dioxide levels are rapidly increasing, but there is uncertainty about whether plants can turn these extra resources into higher yields while retaining nutritional quality.

A team from the University of Illinois and Monash University studied how the root crop cassava, which feeds over 1 billion people, will adapt to the amount of carbon dioxide expected by the second half of this century. They grew the crop in an outdoor research facility called SoyFACE that artificially boosts carbon dioxide to understand how increasing levels will impact crops in the coming decades.

This study is the result of a partnership between two international research projects that are supported by the Bill & Melinda Gates Foundation. Cassava Source-Sink is focused on improving the yield of cassava; Realizing Increased Photosynthetic Efficiency (RIPE) is improving photosynthesis to boost crop yields with support from the Gates Foundation, Foundation for Food and Agriculture Research, and U.K. Foreign, Commonwealth & Development Office.

In the Journal of Experimental Botany, they reported significant yield increases ranging from 22 to 39 percent in seven out of eight varieties of cassava. Each cultivar selected for the study is 'farmer preferred' in Africa, where cassava makes up a quarter or more of diets in several countries. Counter to past studies on other crops, they found no decrease in protein quality nor nitrogen content in the leaves, which are consumed by humans and livestock in addition to the starchy tubers.

"We wanted to know how cassava copes with elevated carbon dioxide," said RIPE Deputy Director Donald Ort, Robert Emerson Professor of Crop Sciences and Plant Biology at Illinois' Carl R. Woese Institute for Genomic Biology. "Sometimes, plants cannot make use of extra carbohydrates, which then triggers the plant to down-regulate photosynthesis. We found cassava could maintain photosynthetic efficiency and nutritional quality."

To take in carbon dioxide, plants open tiny pores in their leaves (called stomata) that allow water to exit through transpiration. This study found that when carbon dioxide levels increase from 400 to 600 ppm, cassava leaves could conserve 58 percent more water on average by optimizing stomatal conductance, which is the rate that carbon enters compared to water exiting the leaf.

"Cassava's natural ability to produce high yields with little water is part of what makes this crop a staple in drought-prone regions across sub-Saharan Africa," said co-author Amanda De Souza, a postdoctoral researcher for the RIPE project at Illinois. "It is not surprising to see this trait magnified in C3 crops, but it is encouraging since we predict water scarcity to be a major barrier to food security."

While the team did not find much difference in how well the eight varieties photosynthesized, they discovered differences in their growth and development due to how the plants distributed carbohydrates to their roots, stems, and leaves--which is called partitioning. Cassava plant breeders try to maximize the resources allocated to the roots, referred to as the 'sink' where the plant stores carbon.

"We can capitalize on these differences in partitioning to develop cassava varieties that sink more carbon into their roots to boost yields," said Ursula Ruiz Vera, a postdoctoral researcher for both projects, who led the study at Illinois. "We aim to enhance the natural resilience and productivity of this crop that is uniquely situated to help smallholder farmers withstand pressures from our changing climate."

Researchers can now more accurately and precisely target specific proteins in yeast, mammalian cells and mice to study how knocking down specific protein traits can influence physical manifestation in a cell or organism.

The Japan-based team published their results on November 11th in Nature Communications.

"Conditional gene knockout and small interfering RNA (siRNA), which is used to silence proteins without knocking them out completely, has been employed in many studies," said Masato T. Kanemaki, professor at the National Institute of Genetics in the Research Organization of Information and Systems (ROIS). "However, these technologies are not ideal for studying highly dynamic processes, such as cell cycle, differentiation, or neural activity, because of the slow rate of depletion of the protein of interest."

Kanemaki and his team had previously developed an approach called the AID system, which uses a small protein tag, known as a degron, fused to proteins to induce degradation. To initiate the degradation process, the researchers administered auxin, a plant hormone that helps regulate plant growth. In previous conditional gene knockout and siRNA studies, according to Kanemaki, it typically takes two or three days for a target protein to deplete. The AID system allows for a general, more efficient approach by which the target protein can be depleted in less than a few hours.

"The original AID system has two major drawbacks: leaky degradation and the requirement for a high dose of auxin," Kanemaki said. "These negative features make it difficult to control precisely the expression level of a protein of interest in living cells and apply this method to mice."

The ability to knockout genes in mice is a critical step in genetic research and therapeutics. According to Kanemaki, an approach may work well in cultured cells, but it must work in a whole model system, such as a mouse. The "leaky degradation" of the AID system meant that a targeted protein would only degraded weakly without auxin, but the level of auxin required to induce full degradation appeared to have long-term negative effects on cell growth.

"In this paper, we describe the AID2 system, which overcomes all the drawbacks of the original AID system," Kanemaki said, noting that they did not detect leaky degradation with the system, the degradation was quicker, and the required dose of auxin was much lower.

To establish the AID2 system, the researchers employed what is known as a "bump-and-hole" strategy to create an empty space in a mutant version of a plant protein (called TIR1) that recognizes and induces the degradation of degron-fused proteins. An auxin analog can bind directly to the TIR1 mutant and initiate the degradation process. Since the approach is very efficient, less auxin analog is needed. The researchers found that depletion could be induced at a concentration about 670 times lower than in the original system.

"With the AID 2 system, it is possible to rapidly deplete a protein of interest in cultured cells and mice," Kanemaki said. "Next, we plan to use the system to find something new in chromosome biology, and to apply the AID2 system to other model organisms."

A large international consortium led by scientists at Uppsala University and the Broad Institute of MIT and Harvard has sequenced the genome of 130 mammals and analysed the data together with 110 existing genomes to allow scientist to identify which are the important positions in the DNA. This new information can help both research on disease mutations in humans and how best to preserve endangered species. The study is published in Nature.

When scientists and medical doctors want to understand which mutations give rise to diseases such as cancer, heart disease or schizophrenia, they compare the genomes from many patients and matched control individuals. They often find tens to hundreds of regions that predispose to disease. These regions typically do not overlap genes, but lie outside genes, and each region may contain hundreds of mutations among which it is hard to pinpoint the one predisposing to disease.

During evolution, the majority of positions in the DNA mutate randomly many times. If a position has not changed in 100 million years (since the first mammal), that specific position is very likely to have an important function in the genome. With the help of this concept, evolutionary constraint, it is much easier to find the regulatory elements that govern when, where and how much of a protein is made from a gene.

"The comparison of the genomes from the 240 mammals will help geneticists to identify the mutations that lead to human diseases," says Professor Kerstin Lindblad-Toh of Uppsala University, SciLifeLab and the Broad Institute of MIT and Harvard.

In addition to understanding the human genome, all these genomes together, sampled broadly across mammals, can be used to study how specific species adapt to different environments. For example, some otters have a thick, water-resistant coat, and some mice, but not all, have adapted to hibernation. These animal traits can help us understand human traits such as metabolic diseases.

With climate change and more animal habitats being affected by human activities, it is becoming more and more important to defend endangered species. Traditionally, scientists study many individuals in different populations of a species to understand the genetic diversity that exist in it. This is important for understanding how to protect specific species. In this study, animals on the IUCN (International Union for Conservation of Nature) red list of endangered species had less variation in their genome, which is consistent with their endangered status.

"We hope that our extensive data set, which is available to all scientists in the world, will be used for understanding disease genetics and the protection of biodiversity," says Lindblad-Toh.

In 2030, one in three people in Europe will be over the age of 65, and all of these people will want to enjoy their old age and lead an active lifestyle. To be able to do so, however, it is crucial that people maintain their physical and mental health.

Wanted: simple and inexpensive prevention

Published last year, the VITAL study in the US indicated that vitamin D and omega-3 fatty acids did not lower the risk of developing new cancer or major cardiovascular diseases in men and women aged between 50 and 60. Now, the largest European study on old age, DO-HEALTH, has investigated the effects of these supplements on aging. The EU-funded project is led by Heike A. Bischoff-Ferrari, professor of geriatric medicine and aging research at the University of Zurich, head of clinic at the UniversityHospital Zurich and senior physician at the university clinic for geriatrics at the Waid and Triemli hospitals in Zurich.

The first findings of the three-year clinical trial published by the international team of researchers has found no effects on lower extremity function, memory or bone fracture incidence. However, the study's findings suggest that, compared to the control group, some subgroups experienced increased benefits of vitamin D and omega-3 supplementation when it comes to lowering infection rates and systolic blood pressure.

Largest randomized double-blind study on old age

For their study, the researchers recruited 2,157 relatively healthy men and women aged 70 or older who lived at home and had no significant pre-existing conditions. About half of the participants came from Switzerland, followed by Austria, Germany, France and Portugal.

They were randomized into eight groups and received none, one, two or all three of the following interventions: supplementation of omega-3 fatty acids (1 gram/day), supplementation of vitamin D (2,000 IU/day) and/or a simple home-exercise program. Neither the trial centers nor the participants knew which group they were in. The control groups were given placebos and carried out control exercises focused on joint flexibility.

In each of the study's three years, the seven European trial centers conducted comprehensive full-day visits to observe participants' health and functions, while also carrying out extensive surveys over the phone every three months. The researchers examined, for example, bone and muscle density, blood pressure, memory functions, walking speed as well as important biomarkers. Moreover, they recorded events such as new diseases, infections, falls, visits to the doctor and hospital stays.

Significant positive effects for some subgroups only

"Our findings suggest that supplementation of vitamin D and omega-3s in adults aged 70 or older who lead an active lifestyle and have no pre-existing conditions does not provide any benefits when it comes to bone health, memory and muscle function. However, we believe there is an effect on infections, such as Covid-19," says Bischoff-Ferrari.

Omega-3s reduced the risk of infections by 11% in total, in particular for upper respiratory (10%) and urinary tract infections (62%), while vitamin D lowered systolic blood pressure in men by 2.5 mmHg and the risk of infections in younger participants (70 to 74-year-old) by 16%.

"Given the high safety and low costs of these supplements as well as the high mortality associated with infections in older adults, these findings are very relevant for the health of the general population," says Bischoff-Ferrari. The gender-specific effects of vitamin D on lowering systolic blood pressure also warrant additional research.

Placing findings in the right context

The researchers attribute the lack of effect on bone health, muscle function and memory to the relatively good health of the study's participants, most of whom took regular exercise. Moreover, about half of the participants were so-called healthy agers, with no pre-existing conditions or vitamin D insufficiency. In addition to the supplementation prescribed by the study, they were also allowed to take 800 IUs of vitamin D daily. "The results therefore do not contradict the Federal Office of Public Health's current recommendation on vitamin D supplementation and fall prevention for older people, nor the proven preventive effects of exercise programs," says Bischoff-Ferrari.

Unique database for research on old age

The study team is now expecting the results on the DO-HEALTH interventions when it comes to cancer prevention, cholesterol levels, cardiovascular diseases, falls, frailty and health costs. "Then we'll be able to fully assess the role of supplementation in preventive geriatrics," says Bischoff-Ferrari. Going forward, the comprehensive database and biobank set up for the DO-HEALTH study is also expected to help assess the aging process and health risks for each person early on and individually, with the aim of personalized prevention. "Ultimately, the goal of DO-HEALTH is to enable more people to age in a healthy and active way," says Bischoff-Ferrari.

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.