Culture

Probing the functional segments, or 'motifs', of proteins has helped scientists identify the minimal ingredients needed for them to form biological patterns.

Writing in the journal eLife, the researchers describe how they dissected the biological phenomenon of protein pattern formation into its main functional modules, and then rebuilt the process from the ground up in a completely new way.

Proteins self-organise to form patterns in living cells, which are essential for key functions such as cell division, communication and movement. A striking example is the MinDE system of the bacterium Escherichia coli (E. coli). This system produces oscillations of two protein types, MinD and MinE, between two poles of the rod-shaped bacteria, positioning the machinery for cell division to midcell. It can be reconstituted in the laboratory, allowing scientists to control and manipulate the functional elements needed for pattern formation via protein mutations.

"Because of its simplicity, the MinDE system has been invaluable in understanding the mechanisms of protein-based pattern formation," says Philipp Glock, a PhD student at the Max Planck Institute of Biochemistry in Munich, Germany, and co-lead author alongside Fridtjof Brauns and Jacob Halatek, both from the Ludwig Maximilians University of Munich. "A key question that remains is whether this structural and functional complexity can be reduced further to reveal a set of minimal ingredients for pattern formation."

To answer this, Glock and his colleagues created a minimalistic version of MinE, which plays an antagonistic role in the two-protein MinDE system, by dissecting the protein in a set of core functional motifs, guided by theoretical modelling. One motif, the short helical sequence of amino acids which MinE uses to interact with MinD, is not enough to produce patterns on its own. But adding other functional motifs of MinE one at a time enabled the scientists to fully design new minimal pattern-forming protein mutants.

The team found that at least one other functional motif is required to form patterns. This can either be a motif for membrane binding or a dimerizing motif, which binds to other molecules of the same kind. Neither of these motifs needs to be from native MinE, but can be replaced and potentially simplified further.

Mathematical modelling then allowed the authors to explain why these features are required and how they enable patterns to form. Moreover, they predicted how these patterns adapt to the cell shape in E. coli. The team says that testing these predictions is an exciting goal for future experiments.

"Our work provides a starting point for a modular and tunable experimental platform to design protein-based pattern formation from the bottom-up," says Petra Schwille, PhD, Director of the Department of Cellular and Molecular Biophysics at the Max Planck Institute of Biochemistry, and co-senior author alongside theoretical physicist Erwin Frey, from the Ludwig Maximilians University of Munich. She adds that while the patterns created by the new system are less regular than those formed by the native MinDE system, they are still sufficient for reproducing and studying basic biological processes.

The model can now be used to study which functional features, regardless of a particular protein system, need to be combined to allow for self-organisation and pattern formation in biology. "Our modular approach may also provide the necessary data for computer modelling of pattern formation in other types of bacteria, as well as more complex organisms," Schwille concludes.

The health of cells is maintained, in part, by two types of movement of their nucleoli, a team of scientists has found. This dual motion within surrounding fluid, it reports, adds to our understanding of what contributes to healthy cellular function and points to how its disruption could affect human health.

"Nucleolar malfunction can lead to disease, including cancer," explains Alexandra Zidovska, an assistant professor in New York University's Department of Physics and the senior author of the study, which appears in the journal eLife. "Thus, understanding the processes responsible for the maintenance of nucleolar shape and motion might help in the creation of new diagnostics and therapies for certain human afflictions."

Recent discoveries have shown that some cellular compartments don't have membranes, which were previously seen as necessary to hold a cell together. Researchers have since sought to understand the forces that maintain the integrity of these building blocks of life absent these membranes.

What has been observed is the nature of this behavior. Specifically, these compartments act as liquid droplets made of a material that does not mix with the fluid around them--similar to oil and water. This process, known as liquid-liquid phase separation, has now been established as one of the key cellular organizing principles.

In their study, the researchers focused on the best known example of such cellular liquid droplet: the nucleolus, which resides inside the cell nucleus and is vital to cell's protein synthesis.

"While the liquid-like nature of the nucleolus has been studied before, its relationship with the surrounding liquid is not known," explains Zidovska, who co-authored the study with Christina Caragine, an NYU doctoral student, and Shannon Haley, an undergraduate in NYU's College of Arts and Science at the time of the work and now a doctoral student at the University of California at Berkeley. "This relationship is particularly intriguing considering the surrounding liquid--the nucleoplasm--contains the entire human genome."

Yet, unclear is how the two fluids interact with each other.

To better understand this dynamic, the scientists examined the motion and fusion of human nucleoli in live human cells, while monitoring their shape, size, and smoothness of their surface. The method for studying the fusion of the nucleolar droplets was created by the team in 2018 and reported in the journal Physical Review Letters.

Their latest study showed two types of nucleolar pair movements or "dances": an unexpected correlated motion prior to their fusion and separate independent motion. Moreover, they found that the smoothness of the nucleolar interface is susceptible to both changes in gene expression and the packing state of the genome, which surrounds the nucleoli.

"Nucleolus, the biggest droplet found inside the cell nucleus, serves a very important role in human aging, stress response, and general protein synthesis while existing in this special state," observes Zidovska. "Because nucleoli are surrounded by fluid that contains our genome, their movement stirs genes around them. Consequently, because the genome in the surrounding fluid and nucleoli exist in a sensitive balance, a change in one can influence the other. Disrupting this state can potentially lead to disease."

In a study published today, scientists report that the long-term success of clownfish depends more on living in a good neighbourhood than it does on good genes.

The natural home of the clownfish is the anemone, but not all anemones are equal. Study co-author Professor Geoff Jones, from the ARC Centre of Excellence for Coral Reef Studies at James Cook University (Coral CoE at JCU), says the reproductive success of the clownfish depends almost entirely on having a high-quality anemone home.

"For a clownfish, it's not 'who' you are, but 'where' you are that matters for your future reproductive success," Prof Jones said.

"In terms of their genes, clownfish are as good as they can be at finding a suitable habitat. The rest comes down to luck--of being in the right place at the right time."

"The success of big families that extend over many generations is linked to high-quality habitats, not their shared genes."

The quantitative genetic study comprises ten years of research on the coral reefs of Papua New Guinea. Family trees were established for the entire clownfish population at an island in Kimbe Bay, a well-known biodiversity hot spot. The team of scientists identified each fish individually and sampled its DNA to establish who was related to whom over five successive generations.

After constructing Kimbe Island's clownfish family tree, the researchers were able to assess the ability of the population to persist and the genetic potential to adapt to increasingly rapid environmental change. Unfortunately, the potential is almost nil.

"There are no particular genetic variants that contribute more offspring to the next generation. The quality of the host anemone contributes most to the ability of the clownfish to renew its population," Prof Jones said.

The scientists say that if high-quality anemones remain healthy, this will ensure the clownfish population can persist.

However, anemones, and coral reefs in general, are under direct threat from the impacts of climate change.

In increasingly warming waters, corals are more susceptible to bleaching. The process is the same for anemones -- their symbiotic algae leave when under stress. If they stay away long enough then the anemone starves to death, killing the fish's home at the same time.

The study is the first of its kind to evaluate the genetic capacity of a natural marine population to adapt to environmental change. This was otherwise largely the domain of evolutionary studies of species on land.

It is not surprising that intergenerational relationships in a marine population had yet to be sampled, according to co-author Dr Benoit Pujol, an evolutionary biologist from France's National Centre of Scientific Research (CNRS).

"Working out who is related to whom in the marine environment is extremely challenging," Dr Pujol said.

"Long-term genetic datasets for individuals within a marine population are incredibly rare. Until now, we just haven't had the data required to answer this question."

"But now that we have it, we find that Nemo is at the mercy of a habitat that is degrading more and more every year," added co-author Dr Serge Planes, a Director of Research at France's National Centre of Scientific Research (CNRS).

"To expect a clownfish to genetically adapt at a pace which would allow it to persist is unreasonable," he said.

"Their future depends on our ability to maintain the quality of their habitat," the authors conclude.

Miharu Nakanishi, Chief Researcher of Tokyo Metropolitan Institute of Medical Science, and her colleagues finds that psychological well-being at 52 years were prospectively associated with cognitive function at 69 years. The authors used data in women from the British 1946 birth cohort in the Medical Research Council's National Survey of Health and Development. There was a significant association between greater personal growth and lower self-acceptance at 52 years, and better cognition at 69 years.

November 26, 2019 - Tokyo, Japan -People around the world are living longer, and dementia has consequently become recognized as a public health priority in many countries. The Lancet Commission paper in 2017 collated a large body of medical research evidence that aims to address the dementia epidemic and following challenge for health and social care. It is estimated that as much as 35% of dementia cases could be prevented by targeting nine modifiable risk factors. However, relatively little is known about psychological well-being in this context.

Tokyo, Japan - Miharu Nakanishi, Chief Researcher of Tokyo Metropolitan Institute of Medical Science, and her colleagues finds that psychological well-being at 52 years were prospectively associated with cognitive function at 69 years. The authors used data in women from the British 1946 birth cohort in the Medical Research Council's National Survey of Health and Development.

Recent studies suggest that specific domains of psychological well-being, including negative affect, positive affect, and purpose in life, are related to cognitive function in older adults. Using the cohort data, the authors finds that there was a significant association between greater personal growth and lower self-acceptance at 52 years, and better cognition at 69 years. This association is adequately robust to control for childhood cognitive ability, physical activity, and other variables among nine modifiable risk factors.

The present study would add new implications to the risk reduction messages by more attention to the health promotion of middle-aged women who face midlife crises.

"Global environmental change should be considered a disability rights issue", first author Dr Aleksandra Kosanic and her colleagues Dr Mialy Razanajatovo (also University of Konstanz), Dr Jan Petzold (Center for Earth System Research and Sustainability (CEN), University of Hamburg) and Dr Amy Dunham (Rice University, USA) argue in their recently published Letter in Science, which has since been picked up on by Forbes and Scientific American. The researchers believe that climate change and the resulting loss of ecosystem services will affect the world's disabled populations disproportionately by exacerbating inequalities and increasing marginalization. Not only may disabled communities experience limited access to knowledge, resources and services, which may prevent them from effectively responding to climate change, they write. Disabled populations may also prove more vulnerable to extreme climate events, as research on Hurricane Katrina has revealed, to the loss of ecosystem services or to infectious diseases.

A government scheme to support the mental health of people affected by terrorist attacks needs to provide a better system of immediate psychological help, according to research led by the Care Policy and Evaluation Centre at the London School of Economics and Political Science (LSE).

The study, funded through the NIHR Policy Innovation and Evaluation Research Unit, explored the effectiveness of the Department of Health and Social Care's 'Screen and Treat Programme', which was set up to identify and refer people to mental health services following terrorist attacks in Tunisia, Paris and Brussels in 2015 and 2016.

Dr Eva Cyhlarova, who carried out the research, said that: "Terrorist attacks have wide-reaching consequences. Mental health needs are common for those affected. We wanted to see how effective the Screen and Treat programme was in identifying and referring people to mental health services and to understand how the agencies involved worked together. Our evaluation showed that the programme worked well in many ways, but it was available too late."

Most of the 77 people who responded to the study questionnaire said that the attacks had a major impact on their lives, according to the findings, published in the Journal of Health Services Research & Policy.

Many people reported anxiety, depression, difficulty going out or travelling, sleep problems, panic attacks, flashbacks and hyper-vigilance. A third had reduced their working hours and a similar proportion had taken sick leave.

Of those interviewed, two-thirds sought help from their GP before being contacted by the Screen and Treat programme (which was available only about a year after the first of the terrorist attacks). Almost all thought that their GP had not been helpful in dealing with post-traumatic stress disorder (PTSD) or referring to appropriate care. Interviewees reported that they used help offered by organisations external to National Health Service (NHS), with mixed experiences.

The study found that the Screen and Treat programme was valuable but identified several areas for improvement which could inform agencies' future planning responses. One recommendation is that there is a system to provide immediate psychological help after a terrorist attack. Although people who accessed support through the programme were generally satisfied with their treatment, most people thought it should have been available sooner.

Dr Cyhlarova also interviewed people from a range of agencies who organised and delivered the programme to understand how organisations work together as part of the response.

Professionals who worked in the planning and set-up of the programme understood the delays, with one respondent saying: 'We were slow off the mark in terms of contacting people...people said they could have done with that six months earlier.' All professionals who were interviewed as part of the study felt that the delay in setting up the programme limited its effectiveness. Waiting times for treatment also varied from no delay to a few months. One person who received treatment said: 'There was a delay in getting to the right person. I could have been somewhere else by now.'

The study found that the main reasons for slow responses were funding and data-sharing issues. Several professionals felt the service should be built into the NHS and involve local services (including GPs) rather than being managed from central government.

Professor Martin Knapp, who led the research, commented: "In future, evaluations should be embedded in the response to major incidents, with the aim of reaching the entire population of potentially affected individuals. Better understanding of people's responses to this type of trauma over time in wider contexts (for example group contexts) would help identify other factors important for resilience and recovery to be incorporated in future responses."

Researchers believe that autism is caused by mutations that occur sporadically in the egg or sperm or during pregnancy. Activity-dependent neuroprotective protein (ADNP) is a dominant gene whose de novo (during pregnancy) mutations are known to cause autism-related intellectual disabilities. A new Tel Aviv University study has found that ADNP mutations continue to occur in old age and accumulate in the brains of Alzheimer's disease patients.

The study was led by Prof. Illana Gozes and conducted by her PhD students Yanina Ivashko-Pachima and Adva Hadar, in collaboration with Iris Grigg, Oxana Kapitansky and Gidon Karmon. Hadar was co-supervised by co-author Prof. David Gurwitz of TAU's Sackler Faculty of Medicine. Collaborating laboratories included those of Vlasta Korenková (BIOCEV, Czech Republic), Michael Gershovits (Weizmann Institute of Science), C. Laura Sayas (Universidad de La Laguna, Tenerife, Spain), R. Frank Kooy (University of Antwerp, Belgium) and Johannes Attems (Newcastle University, UK). It was published on October 30 in Molecular Psychiatry.

Prof. Gozes is the first incumbent of the Lily and Avraham Gildor Chair for the Investigation of Growth Factors, head of the Elton Laboratory for Molecular Neuroendocrinology at TAU's Department of Human and Molecular Genetics, Sackler Faculty of Medicine and a member of TAU's Adams Super Center for Brain Studies and the Sagol School of Neuroscience.

"We discovered thousands of mutations in aging human brains, especially in the individual Alzheimer's brains," explains Prof. Gozes. "We were surprised to find a significant overlap in Alzheimer's genes undergoing mutations with genes that impact autism, intellectual disability and mechanisms associated with the cell skeleton/transport system health. Importantly, the cell skeleton/transport system includes the protein Tau, one of the major proteins affected in Alzheimer's disease, which form the toxic neurofibrillary tangles."

The protein ADNP was first discovered in Prof. Gozes's laboratory at TAU 20 years ago. Postmortem studies have indicated that it undergoes mutations in the aging Alzheimer's brain.

"Brain changes associated with Alzheimer's disease may begin 20 or more years before any symptoms appear," adds Prof. Gozes. "As neuronal damage increases, the brain can no longer compensate for the changes, and individuals show cognitive decline. Currently, the diagnosis of Alzheimer's occurs when the brain damage of individual patients is already widespread, so that current drugs can at most offer symptomatic relief. But they provide no cure."

In their new study, Prof. Gozes and her group propose a paradigm-shifting concept in the understanding of Alzheimer's disease. According to the research, accumulating mosaic somatic mutations -- uninherited genetic alterations passed on during cell division -- promote brain pathology. This could provide an avenue toward developing new diagnostic measures and therapies.

Through a complete sequencing of protein encoding DNA (a technique called RNA-sequencing) and further bioinformatics analysis, the team identified thousands of mutations in the aging Alzheimer's brain. Further sophisticated cell cultures and live cell imaging technologies allowed for the identification of protective molecules that could serve as potential drug candidates.

"We found in cell cultures that the ADNP-derived snippet, the drug candidate NAP, inhibited mutated-ADNP toxicity and enhanced the healthy function of Tau, a key brain protein involved in Alzheimer's disease and other brain diseases," says Prof. Gozes. "We hope that new diagnostics and treatment modes will be developed based on our discoveries."

The study was partially supported by the Israel Science Foundation, AMN Foundation, ERA-NET Neuron, Alicia Koplowitz Foundation, Spanish Friends of Tel Aviv University, Anne and Alex Cohen, Canadian Friends of Tel Aviv University, and Drs. Ronith and Armand Stemmer, French Friends of Tel Aviv University. Additional support included UK, Czech, Spanish and EU grants to the international collaborators.

The use of ADNP and related mutations for Alzheimer's diagnosis and for ADNP-related peptide/peptide mimetics AD/ASD treatment is under patent protection (I. Gozes, A. Hadar, Y. Ivashko-Pachima). Prof. Gozes also serves as the chief scientific officer of Coronis Neurosciences, a company developing NAP (CP201) for the treatment of ADNP syndrome, the autism spectrum disorder.

New York, November 19, 2019 - Oligomerix, Inc., a privately held company pioneering the development of tau oligomer inhibitors for Alzheimer's disease (AD) and related neurodegenerative disorders, and the Feinstein Institutes for Medical Research announced today the publication of preclinical data demonstrating that an oral small molecule drug inhibits the formation of neurotoxic tau oligomers in an animal model of tau aggregation most relevant to AD. The study showed that the compound blocked tau self-association, which is the earliest step in the toxic tau aggregation cascade, and inhibited the downstream events that lead to tau fibril formation.

Tau aggregation and the aggregated protein's evolution into neurofibrillary tangles in the brain of affected individuals is one of the hallmarks of AD. Abnormal tau pathology is also associated with several other neurodegenerative diseases.

In a paper published November 19, 2019 online in the Journal of Alzheimer's Disease titled "In Vivo Validation of a Small Molecule Inhibitor of Tau Self-Association in htau Mice" researchers reported that the compound inhibited hippocampal self-associated tau in the htau mouse model of tauopathy which expresses the six CNS isoforms of the human tau protein. The drug also reduced the amount of insoluble tau aggregates and phosphorylated insoluble aggregates in a linear, dose-dependent fashion in relation to brain compound levels. Immunocytochemical analysis demonstrated that the compound decreased the accumulation of misfolded tau associated with tau aggregates.

The tau oligomer inhibitor was administered in feed at three different doses, and was well tolerated by the treated mice, with no adverse events or behavioral abnormalities observed.

"This study validates Oligomerix's approach for inhibiting tau aggregation and shows that targeting tau oligomer formation at the beginning of the aggregation cascade can inhibit the entire downstream aggregation pathway," commented James Moe, Ph.D., MBA, President and CEO of Oligomerix, and an author of the publication.

"There is an urgent need for new approaches to the treatment of Alzheimer's disease, and this study describes promising results with a novel compound," said Peter Davies, Ph.D., director of the Litwin-Zucker Center for Alzheimer's Disease & Memory Disorders at the Feinstein Institutes and author on the paper. "A drug that could slow or prevent the development of Alzheimer's disease pathology could be a huge step forward."

Dr. Moe said, "Our next steps will include studies to assess whether this lead compound might be beneficial in an inherited form of tauopathy, and whether it can ameliorate behavioral defects." The company is conducting preventive and therapeutic studies in the JNPL3 mouse model of tauopathy that expresses the human tau 4R0N isoform with the mutation P301L associated with frontotemporal dementia.

"We are also currently conducting IND-enabling studies for this compound, and plan to initiate human clinical trials in 2021," added Dr. Moe.

AD is a growing public health crisis, with no effective treatments or cures. According to the World Health Organization, more than 150 million people globally could suffer from dementia by 2050. To date, the majority of clinical studies for AD have focused on targeting amyloid beta deposition in the brain, the other major pathological hallmark of AD.

Research has shown tau load and distribution directly correlate with disease progression in AD, and as a result, interest has begun to turn to tau as a potential therapeutic target. However, there are few programs in clinical development, and those that are currently in the clinic are focused on intervening after tau proteins have misfolded and oligomers have formed, in contrast to Oligomerix's approach of targeting the first step in this process.

"Research best progresses through teamwork and collaboration," said Kevin J. Tracey, M.D., president and CEO of the Feinstein Institutes. "Drs. Davies and Moe and their research teams are providing crucial leadership by their efforts to combat Alzheimer's disease."

Oligomerix has developed a proprietary platform for drug discovery and biomarker development for central nervous system disorders which targets tau self-association. The platform has enabled Oligomerix to develop orally active, small molecule therapeutic candidates with good blood brain barrier penetration. In parallel, the company is developing a novel and translatable tau fragment-specific biomarker with potential to help guide clinical development by serving as a surrogate marker for tau oligomer levels in the brain.

People who play games - such as cards and board games - are more likely to stay mentally sharp in later life, a study suggests.

Those who regularly played non-digital games scored better on memory and thinking tests in their 70s, the research found.

The study also found that a behaviour change in later life could still make a difference.

People who increased game playing during their 70s were more likely to maintain certain thinking skills as they grew older.

Psychologists at the University of Edinburgh tested more than 1000 people aged 70 for memory, problem solving, thinking speed and general thinking ability.

The participants then repeated the same thinking tests every three years until aged 79.

The group were also asked how often they played games like cards, chess, bingo or crosswords - at ages 70 and 76.

Researchers used statistical models to analyse the relationship between a person's level of game playing and their thinking skills.

The team took into account the results of an intelligence test that the participants sat when they were 11 years old.

They also considered lifestyle factors, such as education, socio-economic status and activity levels.

People who increased game playing in later years were found to have experienced less decline in thinking skills in their seventies - particularly in memory function and thinking speed.

Researchers say the findings help to better understand what kinds of lifestyles and behaviours might be associated with better outcomes for cognitive health in later life.

The study may also help people make decisions about how best to protect their thinking skills as they age.

Dr Drew Altschul, of the University of Edinburgh's School of Philosophy, Psychology and Language Sciences, said: "These latest findings add to evidence that being more engaged in activities during the life course might be associated with better thinking skills in later life. For those in their 70s or beyond, another message seems to be that playing non-digital games may be a positive behaviour in terms of reducing cognitive decline."

Professor Ian Deary, Director of the University of Edinburgh's Centre for Cognitive Ageing and Cognitive Epidemiology (CCACE), said: "We and others are narrowing down the sorts of activities that might help to keep people sharp in older age. In our Lothian sample, it's not just general intellectual and social activity, it seems; it is something in this group of games that has this small but detectable association with better cognitive ageing. It'd be good to find out if some of these games are more potent than others. We also point out that several other things are related to better cognitive ageing, such as being physically fit and not smoking."

Caroline Abrahams, Charity Director at Age UK, said: "Even though some people's thinking skills can decline as we get older, this research is further evidence that it doesn't have to be inevitable. The connection between playing board games and other non-digital games later in life and sharper thinking and memory skills adds to what we know about steps we can take to protect our cognitive health, including not drinking excess alcohol, being active and eating a healthy diet."

The participants were part of the Lothian Birth Cohort 1936 study, a group of individuals who were born in 1936 and took part in the Scottish Mental Survey of 1947.

Since 1999, researchers have been working with the Lothian Birth Cohorts to chart how a person's thinking power changes over their lifetime. The follow-up times in the Cohorts are among the longest in the world.

Researchers from VIB-UGent Center for Medical Biotechnology, University of Iowa (USA) and other collaborators, developed a novel approach to better understand a basic defense mechanism of our immune system. Central is ISG15, a small protein with a role in the immune system. With the newly developed method, scientists can now identify and study proteins tagged with ISG15, allowing them to unravel its many functions in fighting disease, potentially leading to novel antimicrobial drugs. The work appears in Nature Communications.

Tagging proteins

Proteins are molecules expressed by our cells to carry out all types of biological functions. To keep control of the expressed proteins, cells can attach a chemical 'tag' onto a protein to modify its activity. One of the most well-known protein modifications is a small protein, called ubiquitin. First discovered as a label to tag a protein for degradation, ubiquitin is now known to have various functions.

The labs of Francis Impens at the VIB-UGent Center for Medical Biotechnology and Lilliana Radoshevich (University of Iowa, USA) investigated an ubiquitin-like modification called ISG15. Like ubiquitin, ISG15 can be attached to target proteins. However, the molecular function of ISG15 is elusive, since the identity of the modified proteins and their exact sites of modification are still unknown.

Prof. Impens (VIB-UGent): "ISG15 and ubiquitin share the same amino acid sequence at their end, exactly where these modifiers are attached to target proteins. As a result, the peptides derived from the proteins modified by ISG15 display the same tag as peptides derived from proteins modified by ubiquitin. So, we took advantage of the technology developed to identify ubiquitin modification sites for the identification of ISG15 modification sites."

Finding ISG15

Unlike ubiquitin, ISG15 is absent under normal conditions. ISG15 is only expressed upon stresses such as a viral or bacterial infection. Thus, they had to complement their approach with an infection model. Prof. Radoshevich infected mice with Listeria and the livers of these animals were analyzed for ISG15 by Prof. Impens with the tools developed to study ubiquitin modification sites.

Fabien Thery, from the Impens lab and co-first author of the study, explains: "As infection model we chose the bug Listeria monocytogenes. Leading to the 'old French cheese disease', Listeria is a food-born bacterial pathogen hiding from the immune system inside host cells."

Yifeng Zhang, co-first author from the Radoshevich lab, elaborates: "The liver is a very interesting organ: it is a central player in the metabolism, but it also acts as a blood filter to sense and remove any potential threats such as viruses and bacteria."

Together, both labs report for the first time the discovery of nearly thousand ISG15 sites on more than four hundred protein targets during bacterial infection.

Prof. Radoshevich: "We found that ISG15 targets numerous enzymes involved in metabolic processes, but also that it targets key regulators of autophagy, a process in response to a lack of nutrients inside a cell. It leads to the destruction of cellular components to generate new sources of energy and promote cell survival. Alternatively, autophagy can be used as an antibacterial strategy. Our finding that ISG15 modulates this process is most exciting."

This work revealed a new link between ISG15, cellular metabolism, and autophagy. The authors have already started to use their approach to investigate ISG15 targets during infection with other pathogens such as Influenza virus or Coxsackie virus. Together, these studies may reveal antimicrobial pathways of our immune system that can be exploited to design new drugs.

Research from a leading international expert on the health of the Great Lakes suggests that the growing intensity and scale of pollution from plastics poses serious risks to human health and will continue to have profound consequences on the ecosystem.

In an article published this month in the Journal of Waste Resources and Recycling, Gail Krantzberg, a professor in the Booth School of Engineering Practice and Technology at McMaster University, argues that while plastic waste in the oceans has generated widespread global attention, few realize the problem is also getting much worse closer to home.

"We are increasingly detecting microplastics in the waters and fish and wildlife in the Great Lakes," she says. "A fish with a gut full of plastics cannot be a healthy fish and can, in fact, starve to death. We know this problem is increasing in severity."

Microplastics, which are typically less than 5 mm in size, are found in textiles, medicines and personal care products such as facial scrubs, toothpastes and cleansers.

Significant concentrations of microplastics have found their way into the Great Lakes and surrounding watersheds for several reasons which include dense urban populations which produce more plastic litter, increasingly severe storms which overwhelm municipal water treatment facilities sending runoff into the ecosystem and the failure of recycling efforts.

Much of what we believe we are recycling actually ends up in the landfill and flies away into our streams, rivers and lakes, explains Krantzberg.

Some studies have found that plastic debris can travel up to 100 km in the atmosphere, possibly further, and accumulates in large quantities along shorelines, beaches, and in open freshwater and marine environments.

"It is hard to conceive of recapturing all the plastics that are now in the lakes, but we can make a difference by eliminating many unnecessary plastics from use such as plastic straws, cutlery, bags and other disposable waste," she says.

By some estimates, the overall economic impact of plastics to marine ecosystems is expected to reach $13-billion US per year.

New guidelines for scientists who use computational modelling to analyse behavioural data have been published today in the open-access journal eLife.

The goal of computational modelling in the behavioural sciences is to use precise mathematical models to make better sense of data concerning behaviours. These data often come in the form of choices, but can also include reaction times, eye movements and other behaviours that are easy to observe, and even neural data. The mathematical models consist of equations that link the variables behind the data, such as stimuli and past experiences, to behaviour in the immediate future. In this way, computational models provide a kind of hypothesis about how behaviour is generated.

"Using computers to simulate and study behaviour has revolutionised psychology and neuroscience research," explains co-author Robert Wilson, Assistant Professor in Cognition/Neural Systems and Director of the Neuroscience of Reinforcement Learning Lab at the University of Arizona, US. "Fitting computational models to experimental data allows us to achieve a number of objectives, which can include probing the algorithms underlying behaviour and better understanding the effects of drugs, illnesses and interventions."

There are four key uses of computational modelling across the scientific literature, according to Wilson and his co-author Anne Collins, Principal Investigator at the Computational Cognitive Neuroscience (CCN) Lab, part of the Department of Psychology and the Helen Wills Neuroscience Institute at the University of California, Berkeley, US. Each of these practices has their own strengths and weaknesses and can be mishandled in a number of ways, potentially leading to incorrect and misleading conclusions and highlighting the need for them to be carried out responsibly.

To address this need, Wilson and Collins offer their 10 simple rules, designed for both beginners and seasoned researchers, to ensure that computational modelling is used with care and yields meaningful insights on what a model is saying about the mind.

Their rules encompass a number of principles that include: designing effective experiments with computational modelling in mind; generating, simulating, comparing and validating models; extracting variables from models to compare with physiological data; reporting on the analyses; and, finally, advice on the next steps once the reporting is completed.

While these guidelines cover the simplest modelling techniques that can be used by beginners, they are also applicable more generally. Likewise, for clarity, the authors decided to focus on a single narrow domain - reinforcement learning models applied to choice data - as the same techniques used in this domain can be applied more widely to other observable behaviours.

"Our work highlights how to avoid common pitfalls and misinterpretations that can arise with computational modelling," Collins explains. "We learned many of these lessons the hard way, by actually making these mistakes for ourselves over a combined 20-plus years in the field.

"By following these guidelines, we hope other scientists will avoid some of the errors that slowed down our own research," she adds. "We would also hope to start seeing improvements in the quality of computational modelling in the behavioural sciences."

RIVERSIDE, Calif. -- Bacteria, fungi, and viruses can enter our gut through the food we eat. Fortunately, the epithelial cells that line our intestines serve as a robust barrier to prevent these microorganisms from invading the rest of our bodies.

A research team led by a biomedical scientist at the University of California, Riverside, has found that simulated microgravity, such as that encountered in spaceflight, disrupts the functioning of the epithelial barrier even after removal from the microgravity environment.

"Our findings have implications for our understanding of the effects of space travel on intestinal function of astronauts in space, as well as their capability to withstand the effects of agents that compromise intestinal epithelial barrier function following their return to Earth," said Declan McCole, a professor of biomedical sciences at the UC Riverside School of Medicine, who led the study published today in Scientific Reports.

The microgravity environment encountered in space has profound effects on human physiology, leading to clinical symptoms and illnesses including gastroenteritis; previous studies have shown microgravity weakens the human immune system. Microgravity has also been shown to increase the intestinal disease-causing ability of food-borne bacteria such as salmonella.

"Our study shows for the first time that a microgravity environment makes epithelial cells less able to resist the effects of an agent that weakens the barrier properties of these cells," McCole said. "Importantly, we observed that this defect was retained up to 14 days after removal from the microgravity environment."

The permeability-inducing agent McCole's team chose to investigate was acetaldehyde, an alcohol metabolite. McCole explained alcohol compromises barrier function and increases gastrointestinal permeability in normal subjects and in patients with alcoholic liver disease.

The barrier function of the intestinal epithelium, he added, is critical for maintaining a healthy intestine; when disrupted, it can lead to increased permeability or leakiness. This, in turn, can greatly increase the risk of infections and chronic inflammatory conditions such as inflammatory bowel disease, celiac disease, Type 1 diabetes, and liver disease.

McCole's team used a rotating wall vessel -- a bioreactor that maintains cells in a controlled rotation environment that simulates near weightlessness -- to examine the impact of simulated microgravity on cultured intestinal epithelial cells.

Following culture for 18 days in the vessel, the team discovered intestinal epithelial cells showed delayed formation of "tight junctions," which are junctions that connect individual epithelial cells and are necessary for maintaining impermeability. The rotating wall vessel also produces an altered pattern of tight junction assembly that is retained up to 14 days after the intestinal epithelial cells were removed from the vessel.

"Our study is the first to investigate if functional changes to epithelial cell barrier properties are sustained over time following removal from a simulated microgravity environment," McCole said. "Our work can inform long-term space travel and colonization where exposure to a food-borne pathogen may result in a more severe pathology than on Earth."

New University of Arizona-led research has revealed the structure and function of one of bacteria's latest strategies in the fight against viruses: a fleet of highly organized enzymes that provide a rapid immune response capable of quickly shredding the harmful DNA of viral invaders.

"This is part of what's often referred to as the world's oldest war," said Nancy Horton, associate professor of molecular and cellular biology who leads the laboratory that conducted the research published last month in Structure. "This war takes place everywhere - from the oceans to the soil to our own guts."

Enzymes are proteins within living cells that speed up chemical reactions. Some enzymes can assume multiple shapes, each with a different function, and toggle between them. In this case, a specific enzyme - SgrAI - has a shape that slowly cuts invasive DNA. However, when many such enzymes link up and wrap around a length of DNA, they create a filament that increases DNA-cleaving ability by 200 times.

"SgrAI enzymes contain two metal atoms, and they have to put them right next to the place where the DNA is going to get cleaved," Horton said. "The structure of the enzyme in the non-filament form holds one of the two metal atoms in the wrong spot. In the filament structure, we see a change in the enzyme shape that pushes that atom into place."

A rapid immune response is important because bacteria-attacking viruses, called bacteriophage, attach outside the bacterial cell before injecting it with their own genetic material. Once inside, the bacteriophage hijack the bacteria's replication machinery to make copies of itself. Eventually, the newly synthesized viruses burst from the captured cell to infect other bacteria.

"This is really basic research," Horton said. "But you have to know how things work before you can fix them. And there are a lot of other medically important enzymes that use this mechanism. When they don't work, they have been implicated in cancer, autoimmune diseases, diabetes and more - it's that fundamental to cell biology."

The findings are part of Horton's larger research interest into the existence of filament-forming enzymes.

Finding Filaments

Filaments were first discovered about 50 years ago before being lost to science by the very methods meant to reveal a cell's inner workings.

In the 1960s, researchers used microscopes that bounced electrons off their subjects to render detail smaller than visible wavelengths of light. But then x-ray crystallography - the technique that led to the discovery of the structure of DNA - came along and gave researchers the ability to achieve even higher resolution images. X-ray crystallography overtook labs in the ensuing decades, and filaments went undetected because they don't form detectable crystalline structures.

Filaments were forgotten to science until around 2010, when a handful of labs around the world, including Horton's, began investigating cellular structures again using newer, higher resolution electron microscopes.

"When my lab first published a paper on the existence of filaments (in 2010), I was met with a lot of resistance," Horton said. "Around the time I was discovering this, I noticed some other labs had also discovered it. After going back through the scientific literature, I realized we knew about this decades ago, but we forgot about it. That's why I call it a renaissance - it's a rediscovery. But then we didn't know why and how filaments formed. So the recent work we've done is to look at why filaments form, what advantages they provide and what their purpose is."

This month, Horton published a compendium in Nature Reviews Molecular and Cellular Biology of the independent filament discoveries where she identifies them as the same phenomenon.

She is now a leader in the burgeoning field of enzyme filamentation. She is using National Science Foundation grants totaling more than $2.3 million to study the structure and mechanism of filament formation by SgrAI and phosphofructokinase, a human metabolic enzyme known as PFK, to learn about the benefots of filament formation to the regulation of enzyme activity.

Across the globe, caring for loved ones is what matters most.

But, for decades this has not been the focus of many social psychology studies. An international team of researchers led by evolutionary and social psychologists from Arizona State University surveyed over 7,000 people from 27 different countries about what motivates them, and the findings go against 40 years of research. The study will be published on December 3 in Perspectives on Psychological Science.

"People consistently rated kin care and mate retention as the most important motivations in their lives, and we found this over and over, in all 27 countries that participated," said Ahra Ko, an ASU psychology graduate student and first author on the paper. "The findings replicated in regions with collectivistic cultures, such as Korea and China, and in regions with individualistic cultures like Europe and the US."

The study included people from diverse countries - ranging from Australia and Bulgaria to Thailand and Uganda - that covered all continents except Antarctica. The ASU team sent a survey about fundamental motivations to scientists in each of the participating countries. Then, the researchers in each country translated the questions into the native language and made edits so that all the questions were culturally appropriate.

For the past 40 years, evolutionary psychological research has focused on how people find romantic or sexual partners and how this desire affects other behaviors, like consumer decisions. But study participants consistently rated this motivation - called mate seeking - as the least important factor in their lives.

Evolutionary psychologists define kin care as caring for and supporting family members, and mate retention as maintaining long-term committed romantic or sexual relationships. These two motivations were the most important even in groups of people thought to prioritize finding new romantic and sexual partnerships, like young adults and people not in committed relationships.

"The focus on mate seeking in evolutionary psychology is understandable, given the importance of reproduction. Another reason for the overemphasis on initial attraction is that college students have historically been the majority of participants," said Cari Pick, an ASU psychology graduate student and second author on the paper. "College students do appear to be relatively more interested in finding sexual and romantic partners than other groups of people."

In all 27 countries, singles prioritized finding new partners more than people in committed relationships, and men ranked mate seeking higher than women. But, the differences between these groups were small because of the overall priority given to kin care.

"Studying attraction is easy and sexy, but people's everyday interests are actually more focused on something more wholesome - family values," said Douglas Kenrick, President's Professor of Psychology at ASU and senior author on the study. "Everybody cares about their family and loved ones the most, which, surprisingly, hasn't been as carefully studied as a motivator of human behavior."

The motivations of mate seeking and kin care were also related to psychological well-being, but in opposite ways. People who ranked mate seeking as the most important were less satisfied with their lives and were more likely to be depressed or anxious. People who ranked kin care and long-term relationships as the most important rated their lives as more satisfying.

"People might think they will be happy with numerous sexual partners, but really they are happiest taking care of the people they already have," Kenrick said.

The research team is currently working on collecting information about the relationships among fundamental motivations and well-being around the world.