Culture

BIRMINGHAM, Ala. - Will a reduction in tau protein in brain neurons protect against Parkinson's disease and Lewy body dementias?

A new study, published in the journal eNeuro, suggests the answer is no. If this is borne out, that result differs from Alzheimer's disease, where reducing endogenous tau levels in brain neurons is protective for multiple models of the disease -- which further suggests that the role of tau in the pathogenesis of Lewy body dementias is distinct from Alzheimer's disease.

Both Parkinson's disease dementia and Lewy body dementia are characterized by intracellular aggregates of misfolded alpha-synuclein protein in brain neurons, and the two diseases together are the second most common cause of neurodegenerative dementia after Alzheimer's.

University of Alabama at Birmingham researchers, led by Laura Volpicelli-Daley, Ph.D., associate professor of neurology, used a Parkinson's disease model she developed 11 years ago. Volpicelli-Daley applies very low concentrations of altered alpha-synuclein, which has taken on a pathologic conformation, to either in vitro or in vivo neurons. The nerve cells take up some of the fibrils. Inside the cells, the altered alpha-synuclein acts as a seed to attract the soluble alpha-synuclein that is naturally present in neurons. This transforms soluble alpha-synuclein into pathological, insoluble aggregates that impair neuron function and lead to cell death. These modified alpha-synuclein inclusions share morphology with those found in the Parkinson's disease brains after death.

This disease model -- termed templated alpha-synuclein inclusion formation -- was used to compare neurons that produce the normal amount of tau protein, against mutant neurons that lack one or both genes for tau, and thus have less or no tau protein. If endogenous tau contributes to disease progression, the heterozygous or knockout tau mutants were expected to show protection. However, the UAB researchers found no difference from the wild-type control.

In their results, the researchers first showed that there was indeed an interaction between tau and alpha-synuclein in the cells -- both proteins localized in presynaptic terminals of primary culture neurons, and in the cortex of the mouse brain, which is consistent with previous findings from preparations of human brains, and with several in vitro studies showing that the two proteins interact with each other.

However, the reduction or complete absence of tau did not prevent fibril-induced alpha-synuclein inclusion formation in primary hippocampal neurons growing in vitro. In mice, reduction or absence of tau also did not prevent fibril-induced alpha-synuclein formation in the motor control or limbic areas of the brain, including the cortex, amygdala, hippocampus and the substantia nigra pars compacta, as measured six weeks or six months after fibril injections.

Finally, while the alpha-synuclein fibrils in the mouse model caused the death of half of the wild-type neurons that produce the neurotransmitter dopamine, the dopaminergic neurons in tau-heterozygous or tau-knockout mice showed the same amount of neuron death, which meant no protection. In addition, reducing tau did not have any major impact on behavioral phenotypes of mice with fibril-induced α-synuclein inclusions.

"Here, we have shown that reduction of endogenous tau did not influence formation of templated alpha-synuclein inclusion formation or the loss of dopamine neurons," Volpicelli-Daley said. "This suggests that therapeutics directed to tau for Parkinson's disease may be more complicated than tau reduction. This is unlike Alzheimer's disease, where tau reduction has been suggested as a possible therapy."

Lake Victoria, which came under the spotlight in 2004 by the documentary "Darwin's nightmare", is not only suffering from the introduction and commercialisation of the Nile perch. A study lead researchers from the University of Liège (Belgium) has highlighted other worrying phenomena, particularly climatic ones, which have an equally important impact on the quality of the lake's waters.

Located in East Africa, just south of the Equator, Lake Victoria is the source of the Nile and is the largest tropical lake in the world. With a surface area of 68,800 km² (twice the size of Belgium), it is considered to be one of the largest water and fishery resources in East Africa, supporting more than 47 million people in the three neighbor countries (Uganda, Tanzania and Kenya).

Lake Victoria is best known to the general public following the release of the 2004 documentary Darwin's Nightmare, which focuses on the environmental and social effects of the Nile perch fishing industry. Voracious predator that can grow up to two metres long and weigh 200kg, the Nile perch is the largest freshwater fish. Its introduction into Lake Victoria in the 1950s and its population explosion in the 1960s gradually wiped out the native fish species living in the lake, causing a major ecological disaster. Today, the Nile perch population remains ubiquitous but has declined slightly due to overfishing, allowing some species to partially recover.

What is less well known - and perhaps interacting with the presence of the Nile perch - but equally damaging to the ecosystem, is the general water quality of the lake. "This declined sharply between the 1960s and the 1990s due to eutrophication, which is caused by increased inputs of nutrients (nitrogen and phosphorus) into the water bodies (rivers and lakes) as a result of increased human activities in the catchment area (intensive agriculture with fertilisers or domestic wastewater) resulting from population growth and economic development, explains Alberto Borges, FNRS Research Director at the Laboratory of Chemical Oceanography from the University of Liege. »

This eutrophication leads to a significant development of micro-algae (phytoplankton). In particular, cyanobacteria, blue-green micro-algae, can be problematic for human health as some forms are toxic. Moreover, the excess phytoplankton biomass (the organic matter from these algae) cannot generally be transformed by the rest of the food web," continues the researcher. This excess remains unused and stagnant at the bottom of the lakes, creating a phenomenon of anoxia, the absence of oxygen in the bottom waters of the lakes. This leads to the degradation of the ecosystem. »

Since the 1990s, no large-scale study of the water quality of Lake Victoria had been undertaken. It was within the framework of the LAVIGAS project - funded by the FNRS and led by Alberto Borges - that a research team was able to study the biomass and composition of phytoplankton as well as the nutrient status of the lake during three scientific missions (2018 -2019). This study shows that the phytoplankton biomass has decreased by about seven times compared to the 1990s," says the researcher, "and that the species composition has also changed in a subtle way." What seems to be good news for the environment of Lake Victoria may only be so on the surface...

Paradoxically, the quantity of nutrients remained comparable to that of the 1990s. This paradox can be explained, however, because in addition to nutrients, phytoplankton (like all plants) also need light to grow. In lakes, the amount of light for phytoplankton obviously depends on the solar radiation at the surface of the lake, but also on the depth of the water on which the phytoplankton cells reside. This depth, known as the mixing layer, depends mainly on the intensity of the wind. If the wind is intense, the depth of the mixing layer is greater, and the phytoplankton cells spend less time near the surface where the light is more intense, and do not develop as well," explains Alberto Borges. Our work shows that current weather conditions are windier than in the 1990s, so the depth of the mixed layer is greater and phytoplankton growth less intense than in the 1990s." The weaker winds of the 1990s were related to the prevailing conditions of El Niño, a natural oscillation in global climate that originates from the large-scale atmospheric circulation over the Pacific Ocean and affects climate worldwide.

This rather complex story shows that the established climate regime in the Pacific Ocean (El Niño) affects the ecology of a lake in Africa, on the other side of the planet! More specifically, it shows that the growth of phytoplankton - and therefore the rest of the food chain - in large tropical lakes responds to eutrophication in a complex way and is strongly modulated by climate," says Alberto Borges. "This means that the current improvement in water quality in Lake Victoria may only be temporary, and that conditions could deteriorate again in the future if vertical mixing in the lake decreases due to reduced wind intensity (a new period of prevailing El Niño conditions) or due to continued climate warming.

Colorado State University Professor of Psychology Silvia Sara Canetto has spent many years researching patterns and meanings of suicide by culture, trying to make sense of the variability in women's and men's suicide mortality around the world. Suicide rates are generally higher in men than in women, but not everywhere - which suggests cultural influences.

Canetto and colleagues have completed a new study that provides insight into what may contribute to men's suicide vulnerability. The study tests Canetto's theory that men's suicide mortality is related to men's private-life behaviors, specifically their low engagement in family care work - not just the adversities they may encounter in aspects of their public lives, such as employment.

Theories of male suicide

Many theories have been proposed to explain male suicide, Canetto said. Most link men's suicide mortality to the stresses and the demands of their employment and their economic-provider roles. These theories typically predict that male suicide rates would be higher when their employment and economic-provider roles are under threat.

Within this perspective, the typical suicide-prevention recommendation is to strengthen men's employment/economic provider role, for example, via programs that protect or support finding employment. Studies show, however, that economic adversities, including male unemployment, do not fully explain men's suicide vulnerability.

According to Canetto, men overinvest in economic-provider work, and underinvest in family care work--a pattern that leaves them vulnerable when economic-provider work is threatened or lost.

Men's family caregiving, unemployment, and suicide

The multinational and multidisciplinary study, published in Social Psychiatry and Psychiatric Epidemiology by Canetto, Ying-Yeh Chen, ZiYi Cai, Qingsong Chang, and Paul Yip, offers evidence of a suicide-protective role for men who engage in family caregiving. In their study, family caregiving was defined as, for example, providing personal care or education for a child, and/or providing care for a dependent adult.

The researchers examined suicide, male family caregiving, and unemployment in 20 countries, including the United States, Austria, Belgium, Canada and Japan. Suicide rates were found to be lower in countries where men reported more family care work.

In countries where men reported more such care work, higher unemployment rates were not associated with higher suicide rates in men. By contrast, in countries where men reported less family care work, higher unemployment rates were associated with elevated male suicide rates. Incidentally, unemployment benefits did not reduce male suicide rates.

Taken together, the findings of this ecological study suggest that men's family care work may protect them against suicide, particularly under difficult economic circumstances, Canetto said.

"Our study took a public health perspective. It examined population-level social and economic factors that may be driving population suicide patterns, across a range of countries," Canetto said. "Its findings point to new directions for suicide prevention."

"It appears that men benefit from doing family care work in terms of suicide protection. Doing family care work would be a way for men to diversify their sources of meaning and purpose, as well as their social capital and networks" stated Canetto. Men's greater involvement in family care work would also relieve women of their disproportionate caregiving load, and give children more resources.

The study's findings suggest incorporating support for engagement in family care work in programs aimed at reducing men's suicide mortality. "This means expanding beyond dominant frameworks of men's suicide prevention with their employment-support focus," Canetto explained. "It also means going beyond treating suicide as just a mental health problem to be solved with mental health 'treatments.'"

Finally, Canetto pointed out that the study's findings are consistent with other research findings. Collectively, they suggest that "having both family care work and family economic responsibilities is more conducive to well-being, health and longevity for men and women than a gendered division of family labor."

Irvine, CA - June 18, 2021 - A new study paves the way for the development of next generation therapeutics for the prevention and treatment of Clostridioides difficile infection (CDI), the most frequent cause of healthcare-acquired gastrointestinal infections and death in developed countries.

Published today in Nature Communications, the study reveals the first 3D structure of the Clostridioides difficile toxin B (TcdB) in complex with chondroitin sulfate proteoglycan 4 (CSPG4), a human receptor. The study was co-led by senior author Rongsheng Jin, PhD, a professor in the Department of Physiology & Biophysics at the University of California, Irvine, School of Medicine, and Min Dong, PhD, an associate professor at Harvard Medical School.

"TcdB is one of two homologous C. difficile exotoxins, which are major virulence factors responsible for the spread of C. difficile infections," explained Jin. "TcdB alone is capable of causing the full-spectrum of diseases associated with CDI in humans."

Previous studies had identified CSPG4 as a potential receptor for TcdB, however the pathophysiological relevance and molecular details were unknown. Results from this new study reveal a unique binding site involving TcdB and CSPG4, and also show that CSPG4-binding residues are highly conserved across most TcdB variants known to date.

CDI has become the most common cause of antibiotic-associated diarrhea and gastroenteritis-associated death in developed countries, accounting for approximately 223,900 infections, 12,800 deaths, and $1 billion in healthcare costs in the United States in 2017. It is classified as one of the top five "urgent threats" by CDC. There is also growing global concern surrounding the emergence of rapidly spreading hypervirulent C. difficile strains, reminiscent of the current COVID pandemic.

"What these new findings tell us is that a rationally designed CSPG4-mimicking decoy could neutralize major TcdB variants, providing a unique therapeutic avenue for combating some of the hypervirulent C. difficile strains," said Jin. In contrast, researchers also revealed that the therapeutic mechanism for bezlotoxumab, the only FDA approved anti-TcdB antibody, is sensitive to escaping mutations in some bacterial strains.

The current standard of care for CDI involves treatments using broad spectrum antibiotics, which often lead to frequent disease recurrence. While bezlotoxumab could reduce the recurrence rate of CDI in some patients, results from this and some earlier studies indicate it has weaker potency against some TcdB variants.

"We have designed a CSPG4-mimicking decoy based on the 3D structure we observed, which could neutralize major TcdB variants and is superior to bezlotoxumab on a major TcdB variant from a hypervirulent strain (TcdB2) in our studies. As a highly conserved cellular receptor of TcdB, a CSPG4 decoy molecule would be difficult for TcdB to escape, since any mutations that disrupt toxin binding to the decoy would also disrupt binding to its native receptors," said Jin.

The team of researchers has also developed a family of recombinant protein therapeutics based on these new findings, as well as on an earlier discovery on how TcdB recognizes another human receptor Frizzled (FZD).

"We are now examining the therapeutic features of these novel antitoxin molecules, and we believe they could provide broad-spectrum protection and neutralization against most known TcdB variants, thus improving existing antibody therapeutics for CDI," said Jin, whose team has filed a patent on these neutralizing molecules.

June 18, 2021 - At least so far, the currently limited research base does not establish that cannabis has additional adverse effects on brain development or functioning in adolescents or young adults with attention-deficit/hyperactivity disorder (ADHD), concludes a review in the July/August issue of Harvard Review of Psychiatry. The journal is published in the Lippincott portfolio by Wolters Kluwer.

While ADHD is clinically defined to have impairments in cognitive functioning, cannabis use by itself is also associated with cognitive impairments: "[T]he evidence to date does not clearly support either an addictive effect or an interaction - whether protective or harmful - with cannabis use," according to the study by Philip B. Cawkwell, MD, of Stanford University School of Medicine, and colleagues. They underscore the need for further research to clarify possible effects of cannabis on brain structure, function, and behavior in young people with ADHD.

'Urgent need' for definitive studies of cannabis risk in teens with ADHD

The trends toward legalization and increased accessibility and potency of cannabis pose special concerns in young people living with ADHD. About one-fourth of teens with substance use disorder also have ADHD, while youth with ADHD are six times more likely to have drug or alcohol abuse. Some people with ADHD may even feel that cannabis improves their symptoms, studies suggest. Both groups have similar difficulties on cognitive tests, suggesting that youth with ADHD might be particularly vulnerable to effects of cannabis on cognitive function.

Dr. Cawkwell and colleagues performed a systematic review of research on the combined effects of cannabis use and ADHD in adolescence. Out of hundreds of initial "hits," the search identified just 11 studies assessing any type of neurodevelopmental outcome in adolescents or young adults with ADHD who did use cannabis compared with those who did not use cannabis.

Seven studies assessed neuroimaging findings for young ADHD patients, showing some significant differences in brain structure in cannabis users. Findings included decreased thickness in areas involved with motor and sensory function (such as the right precentral and postcentral gyri) and increased thickness in areas involved in the brain's "reward" system (such as the left nucleus accumbens). Given the limitations of the studies, the authors stress that these findings must be considered with caution and that it was impossible to determine whether or not these findings reflect causal relationships.

Functional imaging studies also reported differences in cannabis users with ADHD. Findings included differences in performance on standardized tasks and reduced density of dopamine transporters, thereby affecting the availability of dopamine, which plays a key role in the reward system.

Four studies looked at the results of neuropsychological tests or questionnaires in young people with ADHD who did and did not use cannabis. Cannabis use was associated with impaired performance on tests of sustained attention. However, the studies found no significant interaction between ADHD and cannabis use.

"Surprisingly, as cannabis use demonstrates clear and consistent adverse effects on cognition as measured by neuropsychological task performance, no study identified a significant differential impact of cannabis use on these measures for individuals with ADHD compared to non-users," Dr. Cawkwell and colleagues write. "However, this lack of interaction may just be due to the limited number of studies to date, rather than a true lack of impact," caution the study authors.

The authors note that the key limitation to this research is both the number of studies and the overall number of participants are limited. Some studies suggested differences in the effects of cannabis use at earlier ages ? a critical gap for further research. Additional factors the authors suggest need further examination include the potency of cannabis (which has roughly tripled in the past two decades, according to prior research) and the frequency of use.

Future studies may provide more definitive answers - particularly the ongoing "ABCD" study, which will provide long-term data on more than 10,000 participants followed up from age 10 to 20. Dr. Cawkwell and coauthors conclude: "[T]his important study may begin to provide answers to some of the questions that this paper has shown to be unanswered - including understanding whether cannabis does truly alter neural circuitry in youth with ADHD, how this impacts task performance, and perhaps most critically, the longer-term functional outcomes for adolescents with ADHD who also use cannabis."

Birds build nests to keep eggs and baby nestlings warm during cool weather, but also make adjustments in nest insulation in such a way the little ones can keep cool in very hot conditions. Mammals, such as rabbits or groundhogs, sleep or hibernate in underground burrows that provide stable, moderate temperatures and avoid above-ground conditions that often are far more extreme outside the burrow.

Michael Dillon, an associate professor in the University of Wyoming Department of Zoology and Physiology, was part of a research group that examined animals' ability to respond to climate change likely depends on how well they modify their habitats, such as nests and burrows.

So, how are these animals doing? Are they succeeding, struggling, or are their efforts a mixed bag in adapting their habitats to climate change?

"One of the key reasons that we wrote this paper is that we don't know the answer to this very important question!," Dillon says. "We hope the paper will encourage scientists to begin answering this question."

Dillon is a co-author of a paper, titled "Extended Phenotypes: Buffers or Amplifiers of Climate Change?," that was published June 16 in Trends in Ecology & Evolution. The journal publishes commissioned, peer-reviewed articles in all areas of ecology and evolutionary science.

The lead author of the paper is Arthur Woods, a professor of biological sciences at the University of Montana. Other contributors to the paper were from the University of Tours in Tours, France; and Stellenbosch University in Stellenbosch, South Africa.

The study investigated extended phenotypes, which are modifications that organisms -- birds, insects and mammals -- make to their habitats.

"An extended phenotype can range from simply a hole in the ground occupied by an animal to leaves rolled into cavities by insects, to nests of all shapes and sizes built by birds and mammals, to termite mounds and bee colonies," Dillon says.

Extended phenotypes are important because they filter climate into local sets of conditions immediately around the organism. This is what biologists call the microclimate.

Because extended phenotypes are constructed structures, they often are modified in response to local climate variation and, potentially, in response to climate change. This process is called plasticity of the extended phenotype.

"One example might be a bird nest that is well insulated to protect eggs or young birds from cold. As climates warm, if the bird does not adjust insulation in the nest, it may, in fact, cause the young to overheat," Dillon explains.

In another prime example, termites build mounds that capture wind and solar energy to drive airflow through the colony, which stabilizes temperature, relative humidity and oxygen levels experienced by the colony.

However, the idea of microclimates is broader than constructed habitats. Microclimates typically differ substantially from nearby climates, which means that the climate in an area may provide little information about what animals experience in their microhabitats.

As an analogy, although a weather station might tell the public that the temperature in Laramie is 90 degrees Fahrenheit, simply by moving from the south to the north side of a building, one can experience microclimates that are strikingly different and often not captured by the weather data, Dillon says.

The same is true of animals of many different sizes. For example, a moose can move from an open sagebrush landscape to a shaded river corridor to cool off; a snake can move from its underground hole to a sunny rock to warm up; and a tiny insect shuttling between the top and bottom of a leaf can experience temperature differences of more than 20 degrees Fahrenheit.

"So, animals use microclimates, both by simply moving but also by building structures, such as nests, burrows, mounds and mines," Dillon says.

Across the globe, rising levels of carbon dioxide in the Earth's atmosphere are causing temperatures to rise and precipitation patterns to shift. For biologists, a key problem is to understand current effects of climate change on species, and to predict future effects, including how species' ranges may shift and what the relative risks of extinction are for different animal species' groups.

The research team favors a renewed effort to understand how extended phenotypes mediate how organisms experience climate change.

"We need a much better understanding of the basic biophysical principles by which extended phenotypes alter local conditions," says Sylvain Pincebourde, an ecologist in the Insect Biology Research Institute at the University of Tours and one of the paper's co-authors.

Another key challenge is to understand how much plasticity there is in extended phenotypes, and how much and how rapidly they can evolve.

"At this point, we pretty much have no idea," Dillon says. "Can structures that buffer temperature variability keep up with the pace of climate change?"

Just as the skeleton and muscles move the human body and hold its shape, all the cells of the body are stabilised and moved by a cellular skeleton. Unlike our skeleton, this cellular skeleton is a very dynamic structure, constantly changing and renewing itself. It consists of different types of protein filaments, which include intermediate filaments and microtubules. Now, a research team from the University of Göttingen is the first to succeed in observing a direct interaction between microtubules and intermediate filaments outside the cell, and also in quantitatively measuring this interaction. The results of the study were published in Nature Communications.

Microtubules are dynamic filaments that constantly grow and shrink again and, in this way, are responsible for many important processes in cells. The research team observed that intermediate filaments stabilise microtubules: when intermediate filaments are added to microtubules, shrinkage is suppressed and thus the lifespan of the microtubules is extended. To investigate whether this is actually due to direct interactions between the two filaments, a single microtubule was positioned crossed with a single intermediate filament.

Dr Laura Schaedel, who shares first authorship of the publication with Charlotta Lorenz (PhD student at the Institute for X-ray Physics at the University of Göttingen), explains: "The intermediate filament was 'pulled' over the microtubule like a bow over a violin string." Lorenz adds, "This allows the two filaments to bind to each other. However, this bond is broken again shortly afterwards due to the pulling. The process of 'tearing apart' provides information about the strength of the bond." Professor Stefan Klumpp from the Institute for the Dynamics of Complex Systems at Göttingen University, who led the project together with Professor Sarah Köster from the Institute for X-ray Physics, says, "In addition, we used models and simulations to show that the direct interaction leads to stabilisation." The stabilisation of dynamic microtubules can be an important issue for biological cells, for example to regulate their local stability. "The interactions that we observed are important because they enable better understanding of cellular processes," says Köster.

These results are in turn relevant for understanding many other processes, such as those involved in diseased cells. The new method to take direct measurements of the actual interaction of two different biopolymers can also be applied to other protein filaments, as well as to non-biological fibres.

The body is well protected against invading pathogens by barriers such as the skin. But if you injure yourself and break your skin, pathogens can easily enter your body through the wound and cause severe infections. If this occurs, the innate immune system takes over the first rapid defense with an effective arsenal of cellular weapons infiltrating the wounded tissue in large numbers. As one of the first cell types on the spot, neutrophil granulocytes are recruited within few hours from the bloodstream to the infection site to eliminate potential microbial invaders.

Swarming against infections

"Neutrophils are very efficient in hunting and killing bacteria," says Tim Lämmermann. The group leader at the MPI of Immunobiology and Epigenetics in Freiburg studies this important cell type. Neutrophils are highly abundant cells that make up about 50-70% of white blood cells in the human body. It is estimated that 100 billion neutrophils are produced from stem cells in the bone marrow in an adult every day. "These cells patrol almost all corners of our body, and they are very efficient in sensing anything potentially harmful in our body. Once individual neutrophils detect damaged cells or invading microbes in the tissue, they start secreting attractive signals that act through cell-surface receptors on neighboring neutrophils to recruit more and more cells." By using this intercellular communication, neutrophils can act together as a cell collective and coordinate effectively their clearance for pathogens as a swarm.

A fine line between host protection and tissue destruction

However, this form of beneficial inflammation can also overshoot and lead to massive tissue damage. If the intensity or the duration of the response becomes dysregulated, the same mechanisms that serve to eliminate invading pathogens can also cause collateral damage to healthy tissues. For example, the substances that neutrophils release to kill invading pathogens also erode the meshwork of proteins and sugars, which provides structural support to tissues. "In this study, we started with the question what stops the swarming response to avoid uncontrolled neutrophil accumulation and prevent excessive inflammation, which can contribute to degenerative diseases such as cancer, diabetes, and autoimmune diseases," says Tim Lämmermann. In former studies, he and his team already discovered the molecular mechanisms initiating the collective-like swarming behavior. However, the processes that bring this response to an end have remained unknown.

Neutrophil swarming is still a relatively novel topic in the inflammation and infection research fields, and the underlying mechanisms are just beginning to be investigated. The newest study by the lab of Tim Lämmermann now reveals how neutrophils self-limit their swarming activity in bacteria-infected tissues and thus balance search versus destroy phases for efficient pathogen elimination.

By using specialized microscopy for the real-time visualization of immune cell dynamics in living mouse tissues, the researchers demonstrate that swarming neutrophils become insensitive to their own secreted signals that initiated the swarm in the first place. "We identified a molecular break in neutrophils that stops their movement, once they sense high concentrations of accumulating swarm attractants in large neutrophil clusters" says Tim Lämmermann. "This was surprising as the prevailing view suggested that external signals released from the tissue environment are critical for stopping neutrophil activity in the resolution phase of an inflammation," comments Wolfgang Kastenmüller, collaborating scientist of the Max Planck Research Group Systems Immunology at the University of Würzburg.

An internal start-stop system for optimal bacterial clearance

In light of the discovered start-stop system in neutrophils, the researchers re-evaluated current views on how neutrophils navigate in tissues to eliminate bacteria efficiently. In experiments with neutrophils lacking the stop mechanism, the team observed immune cells excessively swarming and scanning large areas of bacteria-infected tissue, which contrasted the behavior of cells with functioning start-stop system. However, this amplified swarming and scanning did not make these cells better pathogen-killers. "Strikingly, we made the opposite finding. It is not beneficial when neutrophils move around too fast and run around like crazy. Instead, it appears more advantageous for them to stop and enjoy together a nice meal of bacteria - this is more efficient to contain bacterial growth in tissues," explains Tim Lämmermann.

With these results, the team paves the way for a better understanding of neutrophil biology, which is essential for immune host defense against bacteria and could inform therapeutic approaches in the future. Moreover, the swarming behavior and underlying mechanisms could also inform other categories of collective behavior and self-organization in cells and insects.

The ability to insert desirable genes into animal or human cells is the basis of modern life science research and of widespread biomedical applications. The methods used to date for this purpose are mostly non-specific, making it difficult for scientists to control which cell will or will not take up a gene. For this gene transfer, the target genes are often packaged into "viral vectors." These are viruses in which part of the genetic material has been replaced by the target genes. When researchers add these viral vectors to cells, the vectors introduce the genes into the cells. This is the principle behind some of the current SARS-CoV-2 vaccines such as those from AstraZeneca or Johnson&Johnson. However, it is difficult - even impossible - to control into which cells the target genes enter, since the viral vectors tend to dock non-specifically onto all cells of a certain cell type. A team of researchers from the Cluster of Excellence CIBSS - Centre for Integrative Biological Signalling Studies at the University of Freiburg, led by Dr. Maximilian Hörner, Prof. Dr. Wolfgang Schamel and Prof. Dr. Wilfried Weber, has developed a new technology that enables them to introduce target genes in a controlled manner and thereby control processes in individual selected cells. The researchers have published their work in the current issue of Science Advances.

Alteration to a viral vector

In their new method, the Freiburg researchers introduce the genetic information with an optical remote control. As a result, only cells that are illuminated with red light take up the desired genes. To do this, the scientists modified a type of viral vector known as an AAV vector, which is already in clinical use. "We took away the viral vector's ability to dock with cells," Hörner explains, "which is an essential step before the genetic material can be introduced."

To enable this control by light, the researchers have taken a red light photoreceptor system from the plant Arabidopsis thaliana (thale cress). This system consists of two proteins, PhyB and PIF, which bind to each other as soon as PhyB is illuminated with red light. The Freiburg team placed the protein PIF on the surface of the viral vector and modified the other protein PhyB so that it could bind to human cells. Once this modified vector, called OptoAAV, is in a cell culture along with the cell-binding protein, the protein binds to all cells. "If a selected cell is now illuminated with red light, the modified vector can bind to this cell and introduce the target genes into the illuminated cell," Hörner explains.

A key aspect of biological signal research

This new approach allows the researchers to introduce target genes into the desired cells within a tissue culture. The scientists also succeeded in illuminating the tissue culture successively at different locations, thus enabling the targeted introduction of different genes into different cells within a culture. With this technique, it is now possible to control desired processes in individual cells. This is essential for understanding how a single cell communicates with cells in its environment, for example, to control the development or regeneration of an organ. "As these viral vectors become more widely used in the therapeutic field," Weber says, "we think this new technology has the potential to make such biomedical applications more precise."

Cluster of Excellence CIBSS - Centre for Integrative Biological Signalling Studies

Researchers in the Cluster of Excellence CIBSS - Centre for Integrative Biological Signalling Studies at the University of Freiburg are investigating the fundamental communication processes that determine multicellular life in humans, animals and plants. In this way, they aim to gain a higher-level, integrative understanding of biological signaling processes in order to develop tailored molecular tools using methods from synthetic and chemical biology to precisely control signaling processes. In this way, the researchers seek to develop strategies for the treatment of cancer using immunotherapies or for resource-conserving crops production, among other things. Maximilian Hörner and Wolfgang Schamel are group leader in the Cluster of Excellence, Wilfried Weber is a member of the speaker team.

Tsukuba, Japan - Sometimes a dead log isn't just a dead log. This one in Japan turned out to be the habitat of a species previously unknown to science.

In a new study published in the journal Nematology, a University of Tsukuba-led research team has described a new species of nematode found inside bark beetles that emerged from a dead log of a fir tree.

Nematodes, also known as roundworms, are a diverse phylum (category) of unsegmented worm-like animals that live in a wide variety of habitats and have diverse life habits. Many nematodes, including this previously unknown species, are either parasitic or live inside a host organism for the duration of a particular life stage.

The log from the trunk of a fallen Veitch's fir tree (Abies veitchii) was collected from the experimental forest of the Sugadaira Montane Research Center of the University of Tsukuba, Nagano, in June 2018. This log was found to be infected with bark beetles, including the species Cryphalus piceae. These beetles were dissected and their microbial contents cultured to allow the nematodes they contained to propagate. Nematodes were also isolated from the bark of the log. Although several other nematode species were identified, their cultures did not propagate, so only the new species was examined in detail for this study.

Principal investigator of the biodiversity project Professor Yousuke Degawa describes the novel nematode: "Members of the genus Cryptaphelenchus commonly lack a functional rectum and anus, which is a typical characteristic of predator/entemoparasitic species. This suggests that this mycophagous genus has retained this ancestral character. The female of the newly described species can be identified based on its long and slender tail, and the male has a cuticular extension surrounding its tail. We named the species Cryptaphelenchus abietis, for the name of the tree from which it was isolated."

Molecular genetic sequencing clarified the phylogenetic position of this new species in relation to other nematode species. It was clearly a member of the genus Cryptaphelenchus, a group of nematodes that usually feed on fungi when they are not inside their associated insect hosts.

As Senior Researcher Natsumi Kanzaki, the study's first author, explains, "Most similar nematodes have been found to be quite difficult to culture. Because of how easily Cryptaphelenchus abietis can be cultivated in a laboratory setting, this new species may be particularly useful for future studies of the physiological and ecological evolution of nematodes in relation to their genomic characters."

Thousands of years ago, archaic humans such as Neanderthals and Denisovans went extinct. But before that, they interbred with the ancestors of present-day humans, who still to this day carry genetic mutations from the extinct species.

Over 40 percent of the Neanderthal genome is thought to have survived in different present-day humans of non-African descent, but spread out so that any individual genome is only composed of up to two percent Neanderthal material. Some human populations also carry genetic material from Denisovans - a mysterious group of archaic humans that may have lived in Eastern Eurasia and Oceania thousands of years ago.

The introduction of beneficial genetic material into our gene pool, a process known as adaptive introgression, often happened because it was advantageous to humans after they expanded across the globe. To name a few examples, scientists believe some of the mutations affected skin development and metabolism. But many mutations are yet still undiscovered.

Now, researchers from GLOBE Institute at the University of Copenhagen have developed a new method using deep learning techniques to search the human genome for undiscovered mutations.

"We developed a deep learning method called 'genomatnn' that jointly models introgression, which is the transfer of genetic information between species, and natural selection. The model was developed in order to identify regions in the human genome where this introgression could have happened," says Associate Professor Fernando Racimo, GLOBE Institute, corresponding author of the new study.

"Our method is highly accurate and outcompetes previous approaches in power. We applied it to various human genomic datasets and found several candidate beneficial gene variants that were introduced into the human gene pool," he says.

The new method is based on a so-called convolutional neural network (CNN), which is a type of deep learning framework commonly used in image and video recognition.

Using hundreds of thousands of simulations, the researchers at the University of Copenhagen trained the CNN to identify patterns in images of the genome that would be produced by adaptive introgression with archaic humans.

Besides confirming already suggested genetic mutations from adaptive introgression, the researchers also discovered possible mutations that were not known to be introgressed.

"We recovered previously identified candidates for adaptive introgression in modern humans, as well as several candidates which have not previously been described," says postdoc Graham Gower, first author of the new study.

Some of the previously undescribed mutations are involved in core pathways in human metabolism and immunity.

"In European genomes, we found two strong candidates for adaptive introgression from Neanderthals in regions of the genome that affect phenotypes related to blood, including blood cell counts. In Melanesian genomes, we found candidate variants introgressed from Denisovans that potentially affected a wide range of traits, such as blood-related diseases, tumor suppression, skin development, metabolism, and various neurological diseases. It's not clear how such traits are affected in present-day carriers of the archaic variants, e.g. neutrally, positively or negatively, although historically the introgressed genetic material is assumed to have had a positive effect on those individuals carrying them," he explains.

The next stage for the research team is to adapt the method to more complex demographic and selection scenarios to understand the overall fate of Neanderthal genetic material. Graham Gower points out that the team aims to follow up on the function of the candidate variants in the genome that they found in this study.

Looking forward, it remains a challenge to search the human genome for genetic material from as yet unsampled populations, so-called ghost populations. However, the researchers are hopeful that they can further train the neural network to recognize mutations from these unsampled populations.

"Future work could also involve developing a CNN that can detect adaptive introgression from a ghost population, for cases in which genomic data from the source is unavailable," says Graham Gower.

"Boomers" and "millennials" who go to church are more likely to trust their neighbours and donate to charity, according to a new study.

Religious beliefs and participation help close the gaps in civic participation between millennials and their elders, researchers have found.

Experts have measured the social "capital" religion gives people of all ages. They found those in their 20s and 30s were less likely to join groups and associations, and less likely to be religious, but being involved with the church gave them more "religious capital" than older people who also attended services.

The study shows boomers often have more social capital than millennials and are more likely to be religious. Religious millennials may be more likely to encounter and interact with boomers, and this could "boost" the value of their religious capital. Religious boomers, in contrast, are likely to encounter others of the same age with similar social lives, so their church-based interactions have less of a social benefit.

The research, by Stuart Fox from Brunel University, Ekaterina Kolpinskaya, from the University of Exeter, Jennifer Hampton and Esther Muddiman, from the Wales Institute of Social and Economic Research and Data (WISERD) based at Cardiff University and Ceryn Evans from Swansea University, is published in The Sociological Review.

Researchers used data from the UK's Household Longitudinal Study (UKHLS). The sample included information about all those born between 1946 and 1958, and those born after 1982. They measured religious participation through self-reported frequency of attendance at religious services.

Researchers found participating in religion gave boomers and millennials more social trust, despite how often they attended church. Those who participated at least once a year were more likely to trust their neighbours - by around four to five percentage points.

Millennials who said their religious belief made "some" difference to their daily life were around four percentage points more likely to donate to charity than those who said it didn't make difference, while those who said it made ""much" difference are seven percentage points more likely.

Boomers who attended religious services at least once a week were the most likely to donate to charity, and around eight percentage points more likely than those of a similar age who didn't attend church. The same is true for millennials, although the difference between those who participate weekly and who do not participate at all is 12 points.

Dr Fox said: "While lower levels of religious capital are contributing to lower levels of social capital among millennials, religious activity is also a more effective source of social capital for millennials than their elders.

"We found millennials are less likely to join groups or associations than boomers, regardless of their religious participation, so have less social capital."

Researchers found the effect of religion on membership of community associations is limited, apart from older Baptists and Methodists, who were around eight per cent and four per cent respectively more likely to join community associations than their peers who are involved in other religions, or none.

Millennials who said religious beliefs made a big difference to their daily lives were significantly more likely to join community associations - by around 13 points. The research shows millennials who participated in religious services at least once a year - or once a month, or once a week - is around 10 points more likely to join a community association than one who does not. For boomers the same difference is 3 points.

Dr Kolpinskaya said: "We found religious participation increases associational membership for both generations regardless of its intensity: what matters is the difference between boomers or millennials who participate in religious activity at all, and boomers or millennials who do not."

An international survey by the University of Münster's Cluster of Excellence "Religion and Politics" provides the first empirical evidence of an identity-related political cleavage of European societies that has resulted in the emergence of two entrenched camps of substantial size. "We see two distinct groups with opposing positions, which we call 'Defenders' and 'Explorers'", says psychologist Mitja Back, spokesperson of the interdisciplinary research team that conducted the most comprehensive survey of identity conflicts in Europe to date. "Who belongs to our country, who threatens whom, who is disadvantaged? Across all such questions of identity, the initial analyses of the survey reveal a new line of conflict between the two groups, which have almost diametrically opposite opinions. In debates over identity, these opinions have hardened into seemingly irreconcilable conflicts. The study could open up new avenues to tackle these conflicts".

The two camps together account for a significant proportion of citizens in all countries: more than one-third in Germany (Fig. 3.1) and almost three-quarters in Poland (Fig. 3.4). In liberal democratic states like Germany, the proportion of 'Defenders' is 20% and that of 'Explorers', 14%. In France and Sweden, 14% and 29% 'Defenders', and 11% and 15% 'Explorers', respectively, were observed. In a semi-authoritarian country like Poland, where according to the researchers the government provides populist support to the 'Defenders' opinions, the proportion of both groups combined is 72%. "This shows how much the conflict can escalate in a country: the polarized positions can grow to form the majority", says Mitja Back. "The degree to which a population becomes polarized and how far feelings of threat and narrow ideas of identity also entail feelings of disadvantage and mistrust therefore vary depending on the political system. This suggests that identity conflicts are open to political influence".

Who are 'Explorers' and 'Defenders'?

5,011 respondents in Germany, France, Poland and Sweden took part in the survey, which the Cluster of Excellence conducted with "Kantar Deutschland" at the end of 2020. Its authors are the sociologists Detlef Pollack and Olaf Müller, the psychologists Mitja Back and Gerald Echterhoff, and the political scientist Bernd Schlipphak. Their Working Report, "Of Defenders and Explorers: An identity conflict over belonging and threat" (http://go.wwu.de/izpgb), provides initial results. Drawing on the detailed results on more than 20 questions examined, they used cluster analyses to form groups comprising people with very similar attitudes and displaying strong differences one from the other. This yielded the patterns of 'Explorers' and 'Defenders' across all questions.

In all countries, the 'Defender' group largely endorse a narrow definition of who belongs to their country, with only those belonging who were born in the country, have ancestors of the ethno-national majority, and/or belong to the dominant religion. They therefore defend traditional criteria such as ethnic and religious homogeneity. At the same time, 'Defenders' feel rather threatened by foreigners such as Muslims and refugees, and consider themselves rather disadvantaged. They are also more dissatisfied with democracy and more distrustful of political institutions.

The 'Explorer' group, on the other hand, reject a narrow definition of belonging based on ethno-religious criteria. Its members do not feel threatened by foreigners, but instead see immigration and growing diversity as an opportunity, and they also advocate a society with many notions of life oriented towards equality. They see themselves as being well represented by the political system, are more satisfied with democracy, and are more likely to trust political institutions. In semi-authoritarian Poland, however, where the government provides populist support to 'Defenders' positions on ethno-religious homogeneity and protection against foreigners, the 'Explorers' also feel disadvantaged and are dissatisfied with democracy and government.

The two groups also differ strongly in cultural, religious, psychological and social terms (Figs. 3.6 and 3.7), with 'Defenders' in all countries being far more attached to home and religious than 'Explorers'. The former also have a stronger preference for social hierarchies and trust other people less, while the reverse is true of the latter. 'Explorers' also tend to be quite young, highly educated, more likely to live in a city, and less likely to be affected by socio-economic hardship. Except in Poland, 'Defenders' are more likely than 'Explorers' to be found among the elderly and the low educated. They tend to live in rural areas and, again with the exception of Poland, consider themselves to have a lower social status.

Political effects and recommendations

The cultural conflict also has strong political effects: 'Defenders' favour populist parties and believe much more in the concept of a "strong leader"; they are also prone to conspiracy theories and advocate elements of direct democracy. 'Explorers' hold diametrically opposed views. For example, 26% of 'Defenders' in Germany and 57% in Poland are likely to vote for a populist party (Fig. 6.6), while 'Explorers' tend not to.

According to the researchers, this can represent fundamentally different concepts of politics: 'Defenders' favour concepts more in line with anti-pluralist ideas that claim that political regulations should express a single popular will; 'Explorers', in contrast, share attitudes more compatible with pluralist ideas that claim that politics is a process of negotiation and compromise between different interests. Mitja Back: "A person's positioning in the conflict as 'Explorer' or 'Defender' can have a strong impact on the form of democracy desired. Cultural conflicts over identity have therefore become very entrenched politically, and now structure the population's social and political views to a significant extent".

By linking their results to other insights from current research, the authors see the polarized positions as being rooted in fundamental and rather stable psychological needs of varying strength, such as security and stability ('Defenders'), or openness and change ('Explorers'). According to the report, this implies that societies are always composed of a mixture of 'Explorers' and 'Defenders'. In contrast to more material conflicts, the identity conflict is therefore more difficult to negotiate, and especially so when ideas of identity are framed in religious or fundamentalist terms. Identity conflict is also exacerbated by the effects of globalization, such as migration, increasingly supranational instead of national policies, and crises such as the financial crisis and the Covid 19 pandemic. "This makes questions of identity - who belongs to the country, or who triggers feelings of threat - all the more urgent".

The researchers therefore urge politicians to refrain from taking one of the two sides. Neither in liberal democracies nor in authoritarian countries has this led to movement in entrenched conflicts, as at least one group always feels excluded. Rather, it is important to take the underlying psychological needs on both sides seriously, and to understand them as social resources, while tracing the sometimes widely divergent demands of both groups back to their functional core. "In this way, it is possible to filter out which positions are not acceptable to each group, and which are open to negotiation. Only by doing so can we find a basis for compromise that currently seems impossible, as well as space for dialogue without one side devaluing the other". (vvm/sca)

RUDN University doctors found alterations in serum amino acid profile in children with attention deficit hyperactivity disorder (ADHD). The findings will help to understand the mechanism of the disorder and develop new treatment strategies. The study is published in the journal Biomedical Reports.

Attention deficit hyperactivity disorder (ADHD) is a neurodevelopmental disorder that manifests itself in childhood. Children with ADHD find it difficult to concentrate and manage their impulsivity. It is known that ADHD is also manifested at the neurochemical level -- for example, the work of dopamine and norepinephrine is disrupted. However, there is still no definitive data on how the responsible for brain function amino acids profile changes in ADHD. Although drugs consisting of amino acids are often used for the treatment of ADHD. Scientists of the RUDN University detected the alterations of the amino acid profile in blood serum in children with ADHD.

"Amino acids serve a significant role in brain development and functioning. In particular, certain amino acids or their precursors are well-established to be involved in neuronal signaling as neurotransmitters. Correspondingly, disruption of amino acid metabolism results in significant neurological disorders, particularly in children. Therefore, unraveling the potential underlying mechanisms implicated in ADHD pathogenesis is essential for improving our understanding of the disorder and further development of management strategies", Anatoly Skalny, DSc, Head of RUDN Department of medical elements studies

102 children aged 7 to 14 years were involved in the study. 71 of them were diagnosed with ADHD, the rest of the participants were neurotypical (without diagnosed disorders). The level of amino acids in the blood serum was measured using liquid chromatography. Then scientists compared the data obtained in children with ADHD and neurotypical children using statistical methods.

It turned out that the serum amino acid profile in children with ADHD differs from neurotypical children. Histidine, glutamine, and proline levels were found to be 29%, 10%, and 20% lower, respectively. Aspartic acid and glutamate were found to be 7% higher, and hydroxyproline-42% higher. Accordingly, the ratio of glutamine to glutamate in children with ADHD is 28% lower than normal, and the ratio of proline to hydroxyproline is 29% lower. The first ratio is one of the indicators of the transmission of nerve impulses, and the second can be a marker of disorders of collagen metabolism and connective tissue. Related diseases are sometimes considered to be associated with ADHD.

&laquoThe observed alterations in Pro/Hypro and Gln/Glu levels and ratios are likely associated with the coexisting connective tissue pathology and alterations in glutamatergic neurotransmission in ADHD, respectively. However, further in vivo and in vitro studies are required in order to investigate the detailed mechanisms linking amino acid metabolism with ADHD", Anatoly Skalny, DSc, Head of RUDN Department of medical elements studies

Testicular cancer is the most common cancer among men under 40 in Europe and the USA. National statistics from the Cancer League indicate 471 new cases and 12 deaths in Switzerland. In general, the prospects for successful treatment of testicular cancer are good over time and, especially with early diagnosis, even further improved. Even if metastases are already present, testicular cancer can be successfully treated with appropriate therapy in the majority of cases.

New classification enables even more targeted treatment

The primary treatment for testicular cancer is the removal of the affected testicle. However, the disease is often only discovered at a stage where metastases are already present and then, after the primary surgical procedure, follow-up drug or radiological treatment is necessary. The new data have been used to make a more detailed classification of metastatic disease stages, making it possible to plan and carry out therapy in an even more targeted manner. Prof. Dr. med. Jörg Beyer, co-initiator of the study project and first author of one of the two publications of the «IGCCCG Update Consortium» estimates: "In many cases, we may be able to administer medication a little more selectively. At the same time, we have an increased certainty that we will not miss any case with an aggressive progression. And with the new classification, the benefits for the patient are twofold: a reduced treatment burden with respect to chemotherapy and increased certainty in terms of outcome."

International research consortium conducts extensive study

Previous treatment guidelines were based on data from 1975 to 1990 involving a total of 5862 patients. The new study compared these results with more recent data from 1990 to 2013 and a larger number of patients. The International Germ-Cell Cancer Collaborative Group Update research consortium (IGCCCG Update Consortium) examined data from 30 medical centers in 17 countries (Australia, Europe, Russia and America). The study included documentation of 12 149 patients with metastatic testicular cancer. Particular attention was paid to potential criteria that could help refine classification.

And another piece of good news: better prognosis for testicular cancer patients

Compared with the original data, the new study results revealed that the prognosis has improved significantly in all cases. In the "good prognosis" classification, 5-year survival increased from 86% to a new 95%. And in the "intermediate prognosis" group, this value increased from 72% to 88%. The improvement was most impressive in the group with widely metastasized disease and the poorest prognosis: 5-year survival increased from 48% to 67%. Prof. Dr. med. Daniel Aebersold, Chairman of the Board of UCI University Cancer Center Inselspital, adds: "The study impressively demonstrates the progress made in cancer therapy. In just well over twenty years, it has been possible to significantly improve the prospects of a long-term tumor-free life after a testicular cancer diagnosis."

Prospects

The next step will be to incorporate the consortium's findings into treatment guidelines and reduce the burden of cancer therapy. In addition, new approaches to the treatment of metastatic testicular cancer need to be considered, such as those currently being investigated in a SAKK study which aim to combine radio- and chemotherapy. It can be assumed that optimized therapies for testicular cancer will lead to a further improved prognosis with reduced treatment intensity in the coming years.