Earth

Although a link has been established between chronic inflammation and neurodegenerative diseases, there have been many open questions regarding how cellular senescence, a process whereby cells that stop dividing under stress spew out a mix of inflammatory proteins, affects these pathologies. Publishing in PLOS ONE, researchers at the Buck Institute report that senescence in astrocytes, the most abundant cell type in the brain, leads to damaging “excitotoxicity” in cortical neurons that are involved in memory.

This research, led by research scientist Chandani Limbad, PhD, found that cellular senescence in astrocytes downregulates the glutamate transporters, which are vital for glutamate homeostasis in the brain. Glutamate is one of the most important neurotransmitters in the brain; an excess of it causes neurons to repeatedly fire leading to their eventual death. Memantine, an FDA-approved drug for Alzheimer’s disease, reduces glutamate toxicity in patients suffering from moderate to severe disease for up to a year, but evidence that the drug might slow pathology is weak. “This study gets to the underlying mechanisms that drive the toxicity,” said senior author and Buck professor Judith Campisi, PhD. “We have identified targets that may be of more use in drug development.”

Cellular senescence is one of the hottest topics in research on aging. Success in the Campisi lab and others around the world has given rise to companies and research projects aimed at developing either senolytics, drugs that clear senescent cells, or senomorphics, drugs that suppress the senescence-associated inflammation. Earlier work in the Campisi lab in collaboration with the Buck Institute’s Andersen lab showed that clearing senescent cells prevented Parkinson’s in a mouse model of the disease.

Campisi says that most of the research aimed at understanding the characteristics of cellular senescence involves human fibroblasts, cells in connective tissue which produce collagen and other fibers. She says this work in astrocytes should be a wake-up call to those studying Alzheimer’s disease, arguing that, “What is commonly termed non-familial Alzheimer’s disease should probably more accurately be termed age-related dementia. If you see five spontaneous Alzheimer’s patients, all of them present differently. Some have personality changes, others don’t. Memory is affected differently in each patient; some people lose motor control, others don’t. These findings highlight aging as the biggest risk factor for almost all neurodegeneration and that is where the research should be focused.”

Co-author Pierre-Yves Desprez, PhD, a scientific consultant in the Campisi lab, who also runs a lab at the California Pacific Medical Center Research Institute, says the research also has implications for those studying glioblastoma, a particularly aggressive form of brain cancer which happens in astrocytes. “Cellular senescence is a double-edged sword and the current state of senescence-associated research is messy. While senescence leads to chronic inflammation which promotes cancer and neurodegeneration, it also acts as a tumor suppressor. There are many factors secreted by senescent astrocytes, we think some of them could be exploited as a way to treat glioblastoma.”

The research, which involved unbiased RNA sequencing of transcripts expressed by senescent and non-senescent astrocytes, found changes in the expression of more than 5,000 genes whose functions are important in cancer, infectious diseases, and neurological diseases. Results are available to the research community.

Drastic ecosystem interventions like eradicating an unwanted species can sometimes backfire, but new University of Queensland-led modelling may help to avoid these ecological hiccups.

Dr Matthew Adams, from UQ's School of Earth and Environmental Sciences, said despite all good intentions, ecological interventions can have devastating consequences.

"It would be great if we could simply assume that eradicating an invasive species from a natural environment is always a good thing," Dr Adams said.

"But doing this could change the population or feeding preferences of a native predator, leading to the undesirable extinction of vulnerable species.

"A great real life example of this is in Booderee National Park on Australia's eastern shores, where the greater glider went locally extinct about a decade ago.

"Although it's unclear what exactly caused this, one possibility is that control of red foxes forced wide-ranging forest owls to switch their diet and eat more gliders.

"These are complicated ecosystems which form networks of interacting species, so we need detailed insights into how they work if we're really hoping to repair and improve them."

Dr Adams led a team of local and international researchers, who generated and analysed thousands of ecosystem population data points to build models to help environmental managers.

"These models can aid decision-makers in selecting interventions, determining whether a species' future population will be positively or negatively affected by the removal, or addition of another species," he said.

UQ Associate Professor Eve McDonald-Madden said no matter what method was used, the future of an ecological system was difficult to predict with certainty.

"No model is a crystal ball," she said.

"Having said that, to make a decision between actions we could take does not require perfection - it just requires us to know which option is better than the other.

"Some model predictions might be 'good enough' to assist managers in determining whether a drastic action is more likely to have a positive impact than no action.

"We found in small networks that the models can be right more than 70 per cent of the time, an outcome likely to be better than gut feeling or decisions that can't capture the ecosystem complexity."

The next step for the researchers is to use their models to analyse problems in real world ecosystems.

"We're currently applying our models to real world examples - from Booderee National Park, to protecting an extremely rare species in the swamps of Western Australia and guiding management of ecosystems on California's unique Channel Islands.

"More and more we're having to make drastic decisions to combat human pressures on ecosystems globally.

"Our plan is to provide the tools needed to avoid perverse outcomes from these actions, and reach the ultimate goals of saving individual species and protecting ecosystems as a whole."

Using genetically engineered human pluripotent stem cells, University of California San Diego School of Medicine researchers created a new type of cancer model to study in vivo how glioblastoma, the most common and aggressive form of brain cancer, develops and changes over time.

"We have developed stem cell models that are CRISPR-engineered to have tumor-associated driver mutations in glioblastoma, which harbor essentially all features of patient-derived tumors, including extrachromosomal DNA amplification," said co-senior author Frank B. Funari, PhD, professor in the Department of Pathology at UC San Diego School of Medicine and head of the Laboratory of Tumor Biology in the San Diego branch of the Ludwig Institute for Cancer Research.

"These models, or avatars as we call them, enable us to study human tumor development over long periods in vivo, which has not been feasible with patient-derived tissue samples which already harbor other genetic changes."

Reporting in the January 28, 2020 issue of Nature Communications, researchers used CRISPR editing to make precise mutations in an otherwise "normal" genome to create the genetic conditions that enable tumor development. The resulting avatars are unique in that they behave like a grade 4 glioma -- a fast-growing type of tumor that starts in the glial cells of the brain -- in their level of pathology, transcriptome signatures, engineered genetic alterations and evolution of genetic mutations, such as the emergence of extrachromosomal DNA and chromosomal rearrangements.

"The addition of single-cell RNA sequencing and computational tools enabled efficient analysis of big data to truly evaluate the surprising intra-tumor heterogeneity present in our avatars which replicates what is seen in patients samples," said co-senior author Gene W. Yeo, PhD, professor in the Department of Cellular and Molecular Medicine and the Institute for Genomic Medicine at UC San Diego and faculty member in the Sanford Consortium for Regenerative Medicine.

Existing mouse models work for testing drugs for specific mutations, but do not account for the diverse ways that tumors can develop. Human tissue samples do not allow for standardization in testing. This new avatar modeling system, said the authors, provides a platform for standardized studies on tumor biology and evolution.

"We can now test which mutations predicted by cancer genome projects are truly tumor-driving, and how they become invasive," said Yeo. "More importantly, these cancer avatars provide systematic, well-controlled opportunities for drug discovery."

Glioblastoma is highly malignant. Standard treatment is aggressive: surgery, followed by chemotherapy and radiation. Yet most tumors recur within six months. The two-year survival rate is 30 percent.

This avatar mimics the intra-tumor heterogeneity observed in people, making it a good option for detailed examination of tumor evolution and searching for therapeutic vulnerabilities based on driver genetics, said Furnari.

"Next steps include screening drugs, testing other mutations in adult and pediatric brain tumors as well as to evaluate if these approaches can model tumors in other tissues, such as the pancreas and lung," said Furnari.

Highlights

An analysis compared transplant recipients who received kidneys through national kidney paired donation and those who received kidneys from other living donors (such as relatives, friends or other paired exchange mechanisms).

Despite a higher number of risk factors for poor outcomes in the kidney paired donation group, recipients in the two groups had similar rates of organ failure and mortality over a median follow-up of 3.7 years.

Washington, DC (January 28, 2020) -- Recipients of kidney paired donation through a national program, also called kidney exchange, experience equivalent outcomes when compared with all other living donor kidney transplant recipients, according to a recent analysis. The findings, which appear in an upcoming issue of CJASN, are reassuring that a national kidney paired donation program is a safe and effective way to treat patients with incompatible living donors.

In kidney paired donation, living donor kidneys are swapped so that each recipient receives a compatible transplant. David B. Leeser, MD (East Carolina University Brody School of Medicine) and his colleagues compared the outcomes of recipients who received kidneys in this way to "control" recipients who received kidneys from other living donors (such as relatives, friends or other paired exchange mechanisms).

The analysis included 2,363 recipients who received kidneys from the National Kidney Registry, the largest program for kidney paired donation in the world, and 54,497 control recipients. Recipients in the two groups had similar rates of organ failure (5-6%) and mortality (9-10%) over a median follow-up of 3.7 years, with a maximum follow-up of 11 years.

"The study shows that patients can expect equivalent to better outcomes by using the National Kidney Registry. In the future, the transplant community may start to see living donors as a national or community resource that should be shared," said Dr. Leeser. "The result could be the ability to transplant hard to match recipients and even better matching of easy to match recipients. Since organ availability is the limiting factor in kidney transplantation nationwide, the ability to perform kidney transplants with a greater likelihood of surviving for longer periods of time is an imperative that will decrease the number of patients being placed on the waiting list for retransplant."

An accompanying editorial notes that if the early success of the National Kidney Registry is sustained, it may be the program of choice for participation. "The NKR has led the way in technology and innovation, and outcomes demonstrate success for those classically disadvantaged for living donor transplant, including black recipients and those who are highly sensitized," the authors wrote. "The current report on ten years of transplantation in a national paired donor program is encouraging, and may convince more transplant programs to 'buy in' to the National Kidney Registry."

Children aged two to three who spend more than three hours a day viewing screens such as tablets and televisions (TVs) grow up to be less physically active at age 5.5 years, compared to children who used screens for an hour or less each day, a study published in The Lancet Child and Adolescent Health journal has found.

The study, involving more than 500 children in Singapore, suggests that adhering to the World Health Organization (WHO) guidelines to limit screen time to one hour per day or less among children aged two to five years may promote healthier behaviours in later life.

Screen viewing is increasingly prevalent but excessive screen time in childhood has been linked to a range of health problems, including increased risk of obesity and reduced cognitive development.

One way that screen viewing may influence health is by replacing time that would otherwise be spent doing something else, such as physical activity and sleep. Efforts to investigate this have had mixed results, with most studies focusing on school-aged children and adolescents.

The latest study is the first to look at the effects of early-life screen use on daily activity in pre-school children.

Associate Professor Falk Mu?ller-Riemenschneider, from the Saw Swee Hock of Public Health, National University of Singapore, said; "We sought to determine whether screen viewing habits at age two to three affected how children spent their time at age five. In particular we were interested in whether screen viewing affected sleep patterns and activity levels later in childhood." [1]

Parents were asked to report how much time the children spent on average either watching or playing video games on TV, using a computer, or using a handheld device, such as mobile phone or tablet. These screen habits were recorded when the children were aged two and again at age three. An average of the two recordings were used in the analysis. At age five, the children wore an activity tracker continuously for seven days to monitor their sleep, sedentary behaviour, light physical activity, and moderate-to-vigorous physical activity.

Children in the study spent an average of 2.5 hours a day watching screens at age two to three. Television was the most commonly used device and was associated with the longest viewing time. Only a small proportion of children in the study met WHO recommendations of one hour per day or less.

The findings revealed that children who had used screens for three or more hours a day at age two to three spent an average of 40 minutes more time sitting down each day at age five than did those who had used screens for less than an hour a day at the same ages. Such higher screen use in infancy was associated with around 30 minutes less light physical activity each day, and around 10 minutes less moderate to vigorous activity each day. Similar effects were observed regardless of screen type. Higher screen time in early childhood did not appear to affect sleeping habits at age five, however.

The authors note some limitations, including that parents may be biased in their reporting of their child's screen use, and that the study did not control for other health behaviours (diet, sleep, physical activity) or environmental factors (such as time in childcare) because there was limited information about these available. The authors note that the findings were still similar when they conducted an additional analysis to see how much of an impact health behaviours had, however.

The authors advised caution when generalising from their results as the families involved in the study were not representative of the entire Singapore population.

However, they argue that the negative impact of early-life screen time on movement behaviours in later childhood highlights the importance of strategies to limit screen use during the early years.

Miss Bozhi Chen, of the Saw Swee Hock School of Public Health, National University of Singapore, said: "This analysis addresses an important research gap and strengthens existing evidence linking screen viewing time with later child health. Our findings support public health efforts to reduce screen viewing time in young children and suggest further research into the long term effects of screen viewing on movement behaviours is needed." [1]

Writing in a linked comment, Dr Dorothea Dumuid (who was not involved in the study), of the University of South Australia, cautioned that the findings do not provide evidence of a causal link between screen time and reduced physical activity, and that screen time may be a marker for other underlying causative factors not measured in this study.

She said: "In this rapidly evolving digital age, children's screen use is a key concern for parents and medical bodies. Guidelines to limit screen time have been released by many governments and WHO, however, screens offer digital and social connectedness and educational opportunities. Future research is needed to assess the influence of media content, to determine optimum durations of screen time in the context of 24 h time use, and to explore causal pathways."

Crowdsourced Research: Vulnerability, Autonomy, and Exploitation

Adrian Kwek

The use of online crowdsourcing platforms to recruit research participants has become ubiquitous in social, behavioral, and educational research. In what sense are crowd workers vulnerable as research participants, and what should ethics reviewers look out for in evaluating a crowdsourced research protocol? The article examines these questions, using the popular crowd-working platform Amazon Mechanical Turk as the key example. The author concludes that crowdsourced research participants are vulnerable to exploitation and proposes measures that ethical reviewers can take against this risk, including encouraging collective action by crowd workers themselves and ground-up crowdsourced research ethics guidelines. Adrian Kewk is senior lecturer in the Centre for University Core at the Singapore University of Social Sciences.

Oversight of Right-to-Try and Expanded Access Requests for Off-Trial Access to Investigational Drugs

Carolyn Riley Chapman, Jared Eckman, Alison S. Bateman-House

For decades, the U.S. Food and Drug Administration has provided an "expanded access" pathway that allows certain patients with life-threatening illnesses to receive an experimental drug without participating in a clinical trial. In 2018, the Right to Try Act created a second mechanism for off-trial access to investigational drugs. In contrast to the expanded access pathway, Right to Try does not require the involvement of the FDA or an institutional review board (IRB). Given that physicians, drug manufacturers, and medical institutions now have a choice whether to assist individual patients through either of the two pathways, the authors review the differences between them and propose that IRB involvement, although not required for the Right to Try pathway, may be beneficial. They discuss the benefits and burdens of IRB oversight and suggests ways that it might be improved. Carolyn Riley Chapman is a faculty affiliate of the Division of Medical Ethics in the Department of Population Health in the NYU School of Medicine at NYU Langone Health. Jared Eckman is an intern at NYU School of Medicine. Alison Bateman-House is an assistant professor in the Division of Medical Ethics at NYU School of Medicine at NYU Langone Health.

NEW YORK- January 28, 2020 --JDRF, the leading global organization funding type 1 diabetes (T1D) research, today announced new research that found widespread screening for islet autoantibodies reduced the occurrence of life-threatening diabetic ketoacidosis (DKA) among children with pre-symptomatic T1D.

The JDRF-funded research study known as Fr1da was published in the Journal of the American Medical Association. The project screened 90,632 children ages 2 to 5 in Bavaria, Germany, during primary care visits, revealing pre-symptomatic T1D in 280 children, or .31 percent, of the children screened. Of these 280 children, 24.9 percent developed T1D and the prevalence of DKA was less than 5 percent, which is significantly lower than in the population of unscreened children, where the prevalence of DKA is 20 percent in Germany and approximately 60 percent in the United States.

"If we identify children at high-risk of developing T1D, we can monitor their disease progression to prevent DKA, a life-threatening condition that often goes undiagnosed, as well as potentially enroll them in clinical trials aimed at halting or delaying the progression toward T1D," said Sanjoy Dutta, Ph.D., Vice President of Research at JDRF. "JDRF has proudly supported this study since it officially launched in 2015, and we congratulate Dr. Ziegler and her team for this critical work that has become a model for other initiatives around the world aimed at improving health outcomes for people with T1D."

The Fr1da study, led by Anette-Gabriele Ziegler, M.D., Ph.D., Director of the Institute of Diabetes Research at Helmholtz Zentrum München, is the first to introduce pre-school screenings for T1D in a general population. The success of the study shows that large-scale screenings are possible and that there are clear benefits to early diagnosis of T1D.

"A crucial finding of the study is that there is a 9 percent annualized risk for disease progression in children with pre-symptomatic disease," said Dr. Ziegler. "This is remarkably similar to the risk in previously studied genetically susceptible children. Its implication is that multiple antibodies can be used to identify children with pre-symptomatic T1D who could benefit from intervention in any childhood population regardless of genetic risk."

This initial research is progressing in several ways. The study will continue under the name "Fr1da-plus," adding 9 and 10-year-old children in addition to 2 to 5-year-olds. The researchers will also perform a cost-benefit analysis of the screenings, as part of the evidence to move screening to the public health sector as standard of care. Additionally, JDRF and Fr1da will use this data to inform screening protocols in the future to support JDRF's mission to accelerate cures for T1D.

This study was supported in part by a grant from JDRF. JDRF will continue to support partners in academia, industry, and government to fund groundbreaking research, and then translate this knowledge into therapies that can stop T1D from developing and to eliminate the threat of T1D for future generations.

A new research tool that mimics the behavior of diseased bone marrow provides a new strategy for understanding the bone marrow disease, Shwachman-Diamond syndrome (SDS), and hopefully, developing new treatments. With SDS, bone marrow fails to produce blood cells normally, leading to bone marrow failure and an increased risk of leukemia.

In a research paper published January 27 in Nature Biomedical Engineering, researchers describe how damaged bone marrow from SDS patients performed in the new tool, known as the organ-on-a-chip (Organ Chip). The bone marrow Organ Chip was developed in the lab of Donald Ingber, MD, PhD, at the Wyss Institute for Biologically Inspired Engineering at Harvard University and a member of the Vascular Biology Program at Boston Children’s. The chip was evaluated with SDS bone marrow samples housed in the SDS Registry at Boston Children’s Hospital.

Lack of an effective animal study model

“We need to find better ways to treat SDS to either prevent leukemia or risk-stratify patients to figure out who would benefit from earlier intervention,” says co-author Akiko Shimamura, MD, PhD, director of the Bone Marrow Failure and Myelodysplastic Syndrome Program at the Dana-Farber/Boston Children’s Cancer and Blood Disorders Center.  Shimamura also co-directs the SDS national registry maintained at Boston Children’s Hospital in collaboration with Dr. Kasiani Myers at Cincinnati Children’s.

However, progress has been slower than hoped because
of the lack of a useful animal study model that could be used to mimic the
behavior of SDS. Previous SDS animal studies produce very severe disease and animals die quickly, making it
very difficult to research the medical complications that are typically found
in SDS patients.

In the paper, Ingber, Shimamura, and colleagues describe how the bone marrow Organ Chip effectively provides a model system to develop new treatments for SDS.

“This
model can be used for biological studies and for drug screening,” says
Shimamura. “In my lab, we have identified some potential therapeutic targets
for treating SDS that we hope to test with the new bone marrow chip.”

3D Bone marrow matrix

The Ingber group developed the marrow-on-a
chip with two hollow, parallel channels divided by a semi-permeable membrane.

In the bone marrow study, the top channel was filled with blood-forming (hematopoietic) stem cells from the bone marrow of SDS patient and stromal cells, including bone marrow stem cells, derived from the bone marrow. Both are embedded in a matrix gel to mimic the three-dimensional nature of marrow tissue. The bottom chamber was lined with human endothelial cells to mimic the vasculature within bone marrow. A liquid medium that supports the growth of healthy bone marrow cells and their differentiation into many different blood cell types flows through the vascular channel. Healthy marrow was also applied to a set of organ chips to act as a healthy control group.

Chip mimicked SDS patient cells

In the SDS experiment, after two
weeks the team observed that bone marrow on the SDS Organ Chip produced fewer
blood cells, especially mature white blood cells, compared with chips from
healthy donors.

“We found that the blood cell
production from the SDS marrow was impaired in a manner that reflected what we
see in patients,” says Shimamura.

The team also found a previously unknown abnormality in the SDS bone marrow cells on the Organ Chip. Maturing neutrophil white cells on the SDS chip did not switch on the CD13 gene as much as those on normal bone marrow. When researchers studied pathology reports of the SDS marrow from these same patients that are done as part of clinical care, they saw this abnormality was mirrored there. Over half of the SDS samples from patients had lower levels of CD13.

Shimamura’s next step is to see how
the bone marrow Organ Chip responds to potential new therapies. “We are going
to put patient marrow on the chip, and then flow candidate drugs through the
vascular chamber to see if any of the drugs improve the marrow’s ability to
produce blood cells,” she explains. “We can then remove the marrow from the
chip and study the mechanism by which the drug is working and then develop
better or more specific agents.”

In related SDS research, in late
December 2019 Daniel
Bauer, MD, PhD, an attending physician with the Dana-Farber/Boston Children’s Cancer and
Blood Disorders Center received an NIH
grant to develop CRISPR-based gene editing as a potential definitive therapy
for SDS patients. The marrow chip will be part of his experimental evaluation in
collaboration with the SDS registry.

SDS registry collaboration

This latest paper details just one of the many ways in which SDS patients and families contribute to SDS research. At just over ten years old, the SDS registry is a close collaboration between SDS patients, their families, and researchers. The goal of the registry is to hasten the pace of SDS discoveries using donated bone marrow samples from SDS patients nationwide.

Funding for this project was provided by a grant from the
National Institutes of Health.

The research was performed in collaboration with researchers at the Wyss Institute, Dana-Farber Cancer Institute, Massachusetts General Hospital, and AstraZeneca.

Learn more about one SDS family here.

Journal

Nature Biomedical Engineering

DOI

10.1038/s41551-019-0495-z

The role of primary care needs to be improved to help young stroke survivors return to work, according to a new study from Queen Mary University of London and the University of Cambridge.

Many people of working age who have a stroke want to return to work, but encounter difficulties.

In the study, published in the British Journal of General Practice (BJGP), the researchers describe a number of causes behind this. To do this, they took the results of a previous study looking at issues with returning to work after stroke at UK level to all stakeholders from a local community.

They found there was a mismatch between patient and carer needs and what is provided by primary care. This included lack of GP awareness of invisible impairments, uncertainty how primary care could help in time-limited consultations and complexity of return-to-work issues.

Primary care physicians were also not aware of relevant services they could refer patients to, such as occupational therapy support.

In addition, there was an overall lack of coordination between different stakeholders in the returning to work process. Linking with other services was considered important but challenging due to ongoing changes in service structure and the commissioning model.

A quarter of all strokes happen in working age, with a general practice of around 6,000 patients containing on average 15 stroke survivors aged between 18 and 65 years. Stroke rates are increasing in people aged under 55 while it is known that enabling people with stroke to work has positive effects on health.

Dr Anna De Simoni, lead author of the study from Queen Mary University of London's Institute of Population Health Sciences said: "Primary care is in a crucial position to support stroke survivors successfully returning to work and address inequalities in access to vocational rehabilitation support.

"Through group discussions with stakeholders from a local community, patients, carers, GPs, occupational therapists, employer representative and clinical commissioners we are able to put forward concrete proposals to address the barriers identified. "

Suggestions for improvement include a central contact in primary care for signposting to available services, a rehabilitation assessment integrated with the electronic record, and a patient-held share-care plan at discharge from stroke wards.

The Equality Act 2010 obliges employers to consider whether 'reasonable adjustments' could help stroke survivors return to work, provided there is an assessment of their impairments/disabilities.

However, the researchers found evidence of employers asking clinicians for sick notes rather than undertaking work adaptations.

Dr De Simoni added: "This is more straightforward for physical impairments. Primary care might be the only source of help for patients whose invisible impairments have not been highlighted and are exacerbated by return to employment and for self-employed or business owners."

The researchers say that more work is needed to develop the three suggestions emerged from this study into interventions, addressing potential problems together with their evaluation in terms of cost-benefit.

Georgina Hill, Research Communications Manager at the Stroke Association, said: "Stroke can strike at any age, and about a quarter of stroke survivors are of working age. This study highlights the unique challenges that stroke survivors may face in getting the support they need when returning to work. While this study looked at a small number of people in the UK, it builds on existing evidence that too often, stroke survivors and those close to them, can't get the support they need to rebuild their lives.

"Last year, our largest ever survey of people affected by stroke was published as the Lived Experience of Stroke report, which also showed that many stroke survivors experience fatigue and problems with memory and concentration which need consideration when stroke survivors return to work.

Current health issues in China could be dwarfed by the future impacts of severe and frequent heatwaves caused by climate change, scientists are warning.

A study by the University of Reading, University of Edinburgh, the Met Office and several Chinese institutions, calculated that 30-day spells of deadly overnight heat, like the one that killed and hospitalised many people in north-east China in 2018, have already gone from being one-in-500-year events to one-in-60-year events since pre-industrial times.

They also found that extreme daytime heat, as well as extreme rainfall, is due to become more common in the country in future as humans continue to emit greenhouse gases into the atmosphere.

Dr Buwen Dong, co-author and climate scientist at the University of Reading and NCAS, said: "People are already suffering from more frequent extreme heat in China, and this will only get more common in future due to climate change.

"It is particularly concerning to see high night-time temperatures becoming a growing threat. This gives no respite to people struggling to cope with searing daytime heat and can lead to deadly heatstroke, particularly for vulnerable people. Better strategies for adapting and coping with rising temperatures are vital to save lives."

In two studies published by the American Meteorological Society, scientists looked at how common such hot conditions in north-east China and wet conditions in central western China have become, and will become in future, due to human-induced climate change.

They looked at almost 50 million daily temperature records captured at 2,400 weather station across China between 1961 and 2018, along with data from other sources.

The scientists also found that climate change has made rainfall more likely to occur in severe bursts in central western China. Using climate models, they calculated extreme downpours have become 1.5 times more likely since pre-industrial times, while the likelihood of persistent heavy rainfall has reduced by 47%.

Professor Elizabeth Robinson, an environmental economist at the University of Reading, who was not part of this study but addresses the vulnerability of people to climate change worldwide in the latest Lancet Countdown report, said: "The current health emergency in China is sadly causing many deaths and this report shows how climate change could also cause serious health emergencies in the region in the future.

"A hotter climate will have a severe impact on global health, with the kinds of extreme temperatures that hospitalized record numbers of people in China in 2018 likely to become more frequent in the future. Outdoor workers, older and young people, and those with pre-existing health conditions are likely to be most at risk."

Researchers at the University of Dundee have developed an unrivalled, fully automated robotic screening system which allows them to rapidly test the effect of drugs and other chemicals on human sperm.

The research team at Dundee, led by Professor Chris Barratt and Dr Paul Andrews, are working towards finding a safe and effective male contraceptive.

Results of their latest study, funded by the Bill & Melinda Gates Foundation, are published in the journal eLife.

One of the most critical functions for sperm is to move to the site of fertilisation and this paper reports the results of a systematic search for drugs that block sperm motility.

The Dundee team screened one of the world's largest collections of previously approved and clinically tested drugs, around 13,000 in total. The researchers accessed this collection, the ReFRAME collection, through a collaboration with Calibr, part of the Scripps Research Institute, as a way to fast-track development of a safe and effective male contraceptive.

The outcome of the study shows that it is possible to find effective agents that halt the sperm in its tracks and further work will be done to investigate if any of these are suitable for long term use in the male.

Chris Barratt, Professor of Reproductive Medicine in the School of Medicine, said, "This is a breakthrough in technology for the area. It allows us for the first time to assess in large numbers how compounds can affect sperm function. Surprisingly there has been no effective, reversible and widely available form of contraception developed for the male since the condom and, as such, the burden falls largely to the female.

"Finding an effective male contraceptive would be a major step in addressing that inequality."

There is an urgent need to develop new methods for male contraception, however drug discovery efforts have been hampered for a variety of reasons. Firstly, by the relatively poor understanding of human sperm biology. Secondly, by the lack of studies that convincingly link a protein target in human sperm to the key functions that sperm must carry out after leaving the male, and thirdly the absence of an efficient system to screen the effects of the myriad chemicals and known drugs that are available.

To address these deficits, the researchers at Dundee developed a miniaturised parallel testing system run by a robot that uses a fast microscope and image-processing tools that precisely track the very fast movement of human sperm, thus allowing the effects of drugs to be accurately measured.

Dr Paul Andrews, who leads the National Phenotypic Screening Centre (NPSC) in Dundee said, "The conventional way to test drugs for contraceptive activity is prohibitively time-consuming. Through the hard work of the multi-disciplinary research team in Dundee, we have managed to develop a disruptive technology platform we hope will be a game changer.

"This new system speeds up the process of drug hunting several thousand-fold. The automated system also uses a different method to examine the effects of drugs on a second critical aspect required for fertilisation, called the acrosome reaction. This dual platform now allows for major drug discovery programmes that address the critical gap in the contraceptive portfolio as well as uncover novel human sperm biology.

"By using live human sperm and examining their behaviour, or phenotype, in the presence of drugs and other chemicals, we hope to circumvent the need to second-guess which proteins are important for the cellular processes underlying sperm's fertilisation capacity."

Contraception is a critical area for research as, according to the Guttmacher Institute, there are 89 million unintended pregnancies and 48 million abortions every year, often pushing women into life choices that increase poverty and pose severe health risks. The development of a drug for the male directly addresses a critical gap in the contraceptive portfolio.

The University of Dundee is uniquely positioned to do this work. It combines the internationally recognised expertise in male fertility research in the School of Medicine with world-class robotic high-throughput imaging facilities at the National Phenotypic Screening Centre and the deep knowledge of drug design, synthesis and safety testing present in the Drug Discovery Unit, both within the School of Life Sciences.

New insight on how information relating to sound and movement is processed in the brain has been published today in the open-access journal eLife.

The study in mice suggests that both sound and movement are processed simultaneously in part of the brain called the inferior colliculus (IC), a region that is best known for sound processing only. The findings also show how the brain may prevent movement-related sounds from interfering with the animals' hearing as they travel.

Nearly all cells in the nervous system that carry hearing-related information converge in the IC during sound processing. This helps the brain to accurately determine the timing and location of sounds, which is essential for animal survival. For this reason, the properties of IC cells during sound processing have been well studied, but little is known about how IC cells function while animals move around.

"Animals must be able to distinguish any noise they make from any external sounds they move away from," says lead author Yoonsun Yang, a researcher at the Center for Neuroscience Imaging Research (CNIR) within the Institute for Basic Science, Suwon, Korea. "Previously it was thought that this occurs mainly at the cortex level in the brain, after much of the auditory processing has been done. But evidence that the activity of auditory neurons below the cortex also changes during different motor activities led us to ask if IC cells function differently during movement."

To learn more, Yang and her colleagues recorded the activity of cells in the IC in mice walking on a treadmill. They found that activity in the IC was either enhanced or reduced during the animals' movement and even moments before any movement began. This suggests that the brain region actively processes movement-related information alongside external sound.

They repeated this experiment in deaf mice as they walked on a treadmill and found that movement also enhanced or reduced activity in the IC cells in the absence of hearing. This helped the scientists rule out the possibility that the sound of the animals' movement was causing changes in IC cell activity.

The team next played sounds to the healthy mice as they walked, and found that responses in the IC were reduced during movement. "While the activity changes caused by movement may allow IC cells to monitor walking, the suppression of the response to external sounds may help prevent the animals' own sounds from drowning out other noises, including those that might signal a threat," explains senior author Gunsoo Kim, PhD, who leads the Auditory Processing Laboratory at CNIR.

"These results reveal a crucial role for the IC in processing both sound and movement-related information, rather than just sound," Kim concludes. "This integration means that mice and potentially other animals can respond to external sounds more rapidly and accurately, and adjust their behaviours to promote survival."

Experts in population mapping at the University of Southampton have identified cities and provinces within mainland China, and cities and countries worldwide, which are at high-risk from the spread of the 2019 Novel Coronavirus (2019-nCoV).

A report by the University's WorldPop team has found Bangkok (Thailand) is currently the city most at risk from a global spread of the virus - based on the number of air travellers predicted to arrive there from the worst affected cities in mainland China. Hong Kong (China) is second on the list, followed by Taipei (Taiwan, the Republic of China). Sydney (12), New York (16) and London (19) are among 30 other major international cities ranked in the research.

The most 'at-risk' countries or regions worldwide are Thailand (1), Japan (2) and Hong Kong (3). USA is placed 6th on the list, Australia 10th and the UK 17th.

Within mainland China, the cities of Beijing, Guangzhou, Shanghai and Chongqing are all identified as high-risk by the researchers, along with the Chinese provinces of Guangdong, Zhejiang, Sichuan and Henan.

Full data can be found in the report on the WorldPop website at: https://www.worldpop.org/events/china.

Andrew Tatem, Director of WorldPop and professor within Geography and Environmental Science at the University of Southampton, says: "It's vital that we understand patterns of population movement, both within China and globally, in order to assess how this new virus might spread - domestically and internationally. By mapping these trends and identifying high-risk areas, we can help inform public health interventions, such as screenings and healthcare preparedness."

The team at WorldPop used anonymised mobile phone and IP address data (2013-15)1, along with international air travel data (2018)2 to understand typical patterns of movement of people within China, and worldwide, during the annual 40-day Lunar New Year celebrations (including the seven day public holiday from 24 to 30 January).

From this, they identified 18 Chinese cities (including Wuhan) at high-risk from the new coronavirus and established the volume of air passengers likely to be travelling from these cities to global destinations (over a three month period). The team was then able to rank the top 30 most at-risk countries and cities around the world.

The researchers acknowledge that their analysis is based on 'non-outbreak' travel patterns, but highlight that a high proportion of people travelled with symptoms at an early stage of the outbreak, before restrictions were put in place. In fact, travel cordons are likely to have only coincided with the latter stages of peak population numbers leaving Wuhan for the holiday period. According to Wuhan authorities it is likely more than five million people had already left the city.

Lead report author Dr Shengjie Lai of the University of Southampton comments: "The spread of the new coronavirus is a fast moving situation and we are closely monitoring the epidemic in order to provide further up-to-date analysis on the likely spread, including the effectiveness of the transport lockdown in Chinese cities and transmission by people returning from the Lunar New Year holiday, which has been extended to 2 February."

WorldPop at the University of Southampton conducted this research in collaboration with the University of Toronto, St Michael's Hospital Toronto, disease surveillance organisation Bluedot in Toronto and the China Centre for Disease Control and Prevention.

A group led by a researcher affiliated with the University of São Paulo's São Carlos Chemistry Institute (IQSC-USP) in Brazil has developed a novel palladium compound that acts against ovarian tumor cells without affecting healthy tissues. Palladium is a silvery white metal belonging to the same group as platinum.

The molecule acts more selectively and powerfully in vitro than cisplatin, a platinum-based chemotherapy medication that is used to treat several types of cancer (such as testicular, bladder and head and neck cancer). This new compound also has the advantage of being effective against ovarian tumors that are resistant to cisplatin.

An article describing the study and signed by researchers from Brazil, the United Kingdom and Italy has been published in Dalton Transactions and is featured on the cover of the journal. The research was supported by São Paulo Research Foundation - FAPESP.

"Cisplatin is a highly effective chemo drug for this kind of tumor, which is typically very aggressive and needs to be combated rapidly. However, it can have severe side effects, especially on the kidneys, nervous system and hearing. This is because the molecule isn't very selective, so it also affects healthy cells," said Victor Marcelo Deflon, a professor at IQSC-USP and principal investigator for the project.

The study was conducted during the PhD research of Carolina Gonçalves Oliveira, currently a professor at the Federal University of Uberlândia's Chemistry Institute (IQ-UFU).

More stable

As the researchers explained, palladium compounds are quickly metabolized in humans, hindering their penetration into tumor cells and preventing them from reaching their molecular target. Therefore, to make their use in cancer treatment feasible, it was necessary to develop molecules capable of forming more stable palladium species.

The group produced several platinum- and palladium-based complexes. After testing the various combinations, the scientists identified two that contained compounds called thiosemicarbazones, a class of ligands that promote stabilization. The chemical structures of the compounds were characterized by X-ray diffraction, a technique in which X-rays directed toward a sample produce a diffraction pattern that is used to analyze the material's structure.

Some thiosemicarbazones are known to act on topoisomerases, enzymes that are present in tumors and participate in DNA replication, making them a potential target for chemotherapy drugs.

Cisplatin acts directly on DNA, changing its structure in ways that prevent tumor cells from copying it. "They're different targets, but both cisplatin and these palladium compounds inhibit tumor cell division," Deflon explained.

Effect on the cell nucleus

Complex 1, named as such by the researchers because they considered it the most promising combination of palladium and thiosemicarbazone, acts directly on topoisomerase. Tests performed by the group using cultured tumor cells showed that 70% of the complex crossed the tumor cell membrane within 24 hours. Most of it was deposited in the cytoskeleton, a network of interlinking protein filaments present in the cytoplasm of all cells. A small proportion (approximately 3%) entered the nucleus. An even smaller proportion of platinum manages to reach the nucleus from the platinum-containing compounds currently in use.

The action of Complex 1 was twice as potent against tumor cells normally resistant to cisplatin. Moreover, it did not affect healthy cells. This selectivity should make it less toxic and avoid the side effects of current treatments.

Complex 2 is more selective than cisplatin, but its action is more effective only against a variety of tumor cells that are also sensitive to cisplatin, suggesting that its action mechanism may be the same as that of cisplatin. More experiments will have to be performed to refute this hypothesis. Furthermore, only 18% of the complex is able to cross the tumor cell membrane.

The researchers are now working on a project to develop even more effective versions of Complex 1. The idea is to obtain a molecule that can be tested in animal models with a better chance of success. Only after successful tests in these models will it be possible to begin clinical trials.

Researchers from Aalto University, the University of São Paulo and the University of British Columbia have found a way to make a new kind of fibre from a combination of chitin nanoparticles, extracted from residual blue crab shells and alginate, a compound found in seaweed. This new bio-based material is sturdy and has antimicrobial properties.

The team studied how differences in the concentration of each component, the size of the nanoparticles, and other variables affect the mechanical properties and spinnability of the final thread. With this information, the researchers were able to produce strong, flexible threads continuously.

Professor Orlando Rojas from the Biobased Colloids and Materials (BiCMat) team at Aalto University, says that the researchers wanted to make a fibre that combined the properties of chitin - known for its antimicrobial properties - and seaweed alginate, which forms strong gels, 'The designed material, took advantage of the strong interaction between the components, which are oppositely charged. We found that when a solution of alginate contacts a suspension of chitin nanofibers, the alginate wraps around the chitin nanoparticles, forming fibrils that align in parallel as the thread is drawn upward'.

Alginate dissolves readily in water. Brown algae have alginic acid in its cell walls, which can be converted to sodium alginate. The blue crab shells were ground and purified; then the material was partially deacetylated using simple procedures.

The research team sees great potential for the material to be used for such things as threads for surgical procedures and webs for internal tissue engineering. Other uses include pads and web-like meshes for applications on the skin, for wound healing, skin conditioning and burn treatments. 'It's a well-known fact that that chitin nanoparticles are antimicrobial and bioactive, for example, they have shown to help hair growth' Rojas adds.

Rojas says that for further development, the research team is looking into scaleability after demonstrating that the threads can be formed continuously, 'This can be eventually made scalable by using simultaneous microfiber dry-drawing from the respective suspensions'.