Culture

When listening to a song or watching a dance, humans tend to follow the rhythm of the music. This is because one fundamental aspect of music is its rhythm, the way we synchronize with the temporal regularities of a melody or a dance. A recent study explores how our brain fuses with musical rhythm and the extent to which humans share this ability with other animals.

Alexandre Celma-Miralles and Juan Manuel Toro, an ICREA research professor with the Department of Information and Communication Technologies (DTIC), and members of the Comparative Cognition and Language (LCC) research group at the Center for Brain and Cognition (CBC) at UPF, explain this peculiarity in an article published this November in the journal Brain and Cognition.

"This study explores the relationship between the rhythmic structure of music and the spatial dimension of sound. We study how the brain interacts with sounds that are spatially separate to build up a metrical structure", explain Celma-Miralles and Toro, the authors of the study.

So, they compared the neural responses of professional musicians with those of untrained listeners while both groups listened to a waltz. In one of the study experiments, the participants had to pay attention to sounds defined by their spatial position (the sounds were separated in space). In another experiment the participants had to pay attention to a visual distraction. Data for the study were obtained from the frequencies of EEG recordings of each subject.

Rhythm and beat are enhanced by experience

The researchers found that regardless of the participant's musical training, the brains of all listeners synchronized with the rhythm. The results also showed that musicians' neuronal responses were much stronger and more resistant to distractions than those of non-musicians. That is, the study revealed that training facilitates rhythmic synchronization.

As the researchers state, "the most relevant point of this study is that it demonstrates that our brains are prepared to follow rhythm, regardless of whether we listen to a song or watch a dance". This reinforces the idea that the neuronal processing of rhythm and beat is facilitated by previous experience with rhythmic events during long periods of formal musical training.

Researchers from the national psychiatric project iPSYCH have found that autism and ADHD share changes in the same genes. The new knowledge relates directly to the biological causes of the two child psychiatric disorders.

In Denmark, approximately one per cent of schoolchildren have autism and two to three per cent are diagnosed with ADHD. Autism and ADHD are different developmental disorders, but they can have certain common symptoms. For example, children with autism can demonstrate violent or aggressive behaviour, be impulsive, and have problems in school and with social relations - and these same symptoms can be shared by children with ADHD.

Researchers from iPSYCH, Denmark's largest research project in the field of psychiatry, have now discovered that the similarities between the two diagnoses can be linked to changes in the same genes. The new study is the largest study to date of rare mutations in the genome of people with ADHD and autism.

"The very fact that mutations are found to the same extent and in the same genes in children with autism and in children with ADHD, points towards the same biological mechanisms being involved," says Anders Børglum, who is professor at Aarhus University, principal investigator at iPSYCH and one of the leading researchers behind the study. The study was carried out in collaboration with the Broad Institute and Harvard.

First time a gene is linked to ADHD and autism

The results have just been published in the international journal Nature Neuroscience.

"This is the first time that the genome has been mapped so comprehensively for both ADHD and autism, and the discovery that children with ADHD have the same amount of deleterious gene mutations in their DNA as children with autism is both striking and quite surprising," says Anders Børglum.

The findings point directly towards which biological causal mechanisms are shared by ADHD and autism.

"In the study, the gene that is most frequently affected by mutations in people with ADHD or autism is the so-called MAP1A gene. The gene is involved in the formation of the physical structure of nerve cells - their inner 'skeleton', so to speak - and is important for the development of the brain," explains Anders Børglum.

This is the first time that this gene has been linked to the development of ADHD and autism, and the mutations found by the researchers give a significantly increased risk of developing autism and/or ADHD.

"We discovered an increased burden of mutations that destroy or severely affect the MAP1A gene in those with ADHD and autism, while very few of the control subjects had such changes in the gene," explains Anders Børglum.

This means that the risk of ADHD and autism increases by more than 15 times for people who carry such a mutation. The researchers have analysed the genes of approximately 8,000 people with autism and/or ADHD, and 5,000 people without either of the two disorders, all from Denmark. The study also incorporated additional data from approx. 45,000 international control subjects who did not have any psychiatric disorders.

"The study shows that many more genes for ADHD and autism can be identified directly by studying more people in a similar way with extensive DNA sequencing, thereby providing a more complete picture of the biological causal mechanisms and possible approaches to medical treatment," explains the researcher.

As part of the project, Anders Børglum and his colleagues have had access to samples from the Danish National Biobank at the Statens Serum Institut and to data from the Danish Psychiatric Central Research Register. People born in Denmark between 1981 and 2005 were matched with diagnoses of autism, ADHD and mental retardation.

Over 40% of online petitions started by residents of central Russia get results. In the Far East, this is the case with only 2% of online petitions, while in the regions of the North Caucasus it is even less. Russian experts, Nadezhda Radina https://www.hse.ru/en/org/persons/62303992 (HSE University) and Daria Krupnaya, studied the willingness of authorities and businesses to respond to citizens' digital activism based on data from the Change.org platform.

Results Versus Inaction
Traditionally, a petition is a collective appeal, usually to authorities or organizations. An electronic petition is an appeal published online, and they are conducted mostly on specialized sites. The most well-known ones in Russia are:

Roi.ru (Russian Public Initiative)
Change.org
OnlinePetition
democrator.ru

Change.org is active in 196 countries and 14 languages. Officials have the right to ignore petitions posted on the site (petition results on the site are not legally binding, insofar as the platform does not collect enough information about the signers). However, a large public response puts pressure on officials and businesses to take action.

'Nearly every hour, a petition on Change.org achieves victory,' the site says. Of the 22,452 Russian-language petitions created on the site from 2012 to 2017 that the researchers analyzed, 4% (918) received the status of 'fulfilled' (as indicated by the petition's creator after the collection of signatures).

Topics and Issues
The issues of petitions provide insight into the concerns of a given region. About half (44%) of the 22.4 thousand filed petitions in Russia concern social issues, and the second largest portion (18%) concern political issues.

Breakdown of Russian petition issues by category (%):
Society - 44%
Politics - 18%
Culture - 11%
Animals - 9%
Environment-- 6%
Education - 4%
Sports - 3,8%
Medicine - 3%
Economy - 0,7%
Religion - 0,5%
The North-West Federal District is primarily distinguished by its concern for social issues - 51% of petitions started in this region fell into this category. Russia's most politically active residents can be found in central Russia: 43.8% of petitions from the Central Federal District concern the resignation of officials, changing decisions, amending laws, fighting corruption, and so on. Political issues also dominate petitions created in Siberian (34%) and North Caucasian (23%) districts.

Emulating the Centre
'With the exception of the strong political bent of petitions started in the Central Federal District, there were no significant differences found between regions of Russia in terms of the kinds of demands being made -- people are concerned about similar problems everywhere,' the study authors note.

With a share of 42%, the Central Federal District had the highest number of petitions that were successful in Russia, while the Far Eastern and the North Caucasian districts had the lowest -- 2% and 1%, respectively.

Federal District Ratings
by percent share of successful petitions in Russia (%)
1. Central - 42%
2. North-West - 14%
3. Privolzhsky - 13%
4. Southern - 12%
5. Siberian - 9%
6. Ural - 7%
7. Far Eastern - 2%
8. North Caucasus - 1%
Petitions concerning society, culture, politics, and animal welfare enjoy the highest success rates. The Central Federal District's success rate can be explained by the population's civic activity in urban areas, the greater responsiveness of the petition addressees, more advanced infrastructure (for example, the quality and accessibility of the Internet), and users' involvement with technology that facilitates active participation.

Examples of successful petitions from the site Change.org
(number of signatures)
'Social Insurance Fund, stop the torture: give me my wheelchair. It's the law.' (209,701)
'Help!!! The authorities have lifted the ban on shooting the Baikal seals!!!' (374,326)
'Provide cancer patients with life-saving medicine! We have the right to life!' (428,105)
'Stop discrimination on the basis of appearance and age at PJSC Aeroflot' (50 223)
'We demand compensation for the victims of the St. Petersburg metro terrorist attack on 03.04.2017' (157 649)
'Novgorod officials must provide housing to WWII veterans, as required by law.' (191 740)
Regional Values
The response of government bodies and businesses to petitions from non-state platforms provides an indication of the quality of a given region's management. Successful petitions point to a willingness to enter into dialogue with civil society, and the issues of the petitions provide insight into the values of a given region.

By grouping the successful petitions by issue category, the researchers divided the federal districts into three clusters:

So long as they contribute to the animal rights protections, governmental bodies and businesses are safe to ignore other demands of the population. In the Far Eastern Federal District, 95% of successful petitions were in defense of animal rights.
Governmental bodies and businesses respond only to crucial problems. The Ural, North Caucasian and Siberian federal districts rank highest in social issue victories. According Ronald Inglehart's system of value classification, rational survival values are predominantly shared here, with a certain tendency toward post-materialistic values.
In response to population demands, governmental bodies and businesses are partly willing to address a wide range of current issues. In the Central, Volga, South and North-West federal districts -- mostly urban areas with city populations of a million people or more -- there is a predominance of post-materialist values (rational values of self-expression). In these regions, petitions on social issues (48.3%), political issues (17%), as well as on cultural issues (12.7%), education (11.3%) and sports (4.5%) were successful.

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."