Culture

Collaborate research of the University of Jyvaskyla and the Natural Resources Institute Finland on salmonid fishes, sheds light on animal defence mechanisms and their interactions. The research demonstrates that populations with a strong physiological resistance show little behavioural avoidance and damage repair, and vice versa. The results can have important practical implications for stocking activities of endangered salmonids. The study was published in Proceedings of the Royal Society B in April 2020.

Animals can use a set of different defence mechanisms to combat infections. There are three main routes of defence that can be jointly used: behaviours that reduce exposure (such as the currently practised social distancing in humans), physiological resistance (immune system) that attacks the pathogen, and mechanisms that repair tissue damages of infection (tolerance).

"We studied populations of Atlantic salmon and sea trout from different rivers in Finland and found that those with a strong physiological resistance against an eye parasite, showed little behavioural avoidance and damage repair, and vice versa. This suggests that each defence type comes with costs for the host and that fish have to balance between these defence mechanisms" says researcher Ines Klemme from the University of Jyväskylä.

"It seems that different salmonid populations have evolved different optima of defence, likely matching the infection pressure in their own natural environment", says Klemme.

"It is important to release fish stocks to their original habitats"

The present investigation provides information of the overall level of defence and interactions between individual mechanisms. Previous studies have commonly focused on one mechanism at a time.

Repairing tissues, i.e. tolerance, does not harm the parasite itself, but avoidance and immune defence negatively affect parasite reproduction and induce counteractions that lead to the evolutionary arms races.

The results have important practical implications for artificial selection and stocking programmes.

"The results suggest that artificial selection, for example to increase immunological defences, can lead to reduction in other defence mechanisms. It is also important for aquaculture stocking programs, which are used to support threatened salmonid populations, to release fish stocks to their original populations and habitats to which they may be adapted to", says senior lecturer Anssi Karvonen from the University of Jyväskylä.

Working alongside research groups from Heidelberg, researchers from Charité - Universitätsmedizin Berlin have elucidated the novel disease processes involved in the development of pulmonary fibrosis. They were able to show that the protein known as NEDD4-2 plays a key role in lung health and that loss of this crucial regulatory molecule has a significant impact on various mechanisms involved in the development of chronic progressive lung disease. These new insights make it easier to further investigate the precise mechanisms involved in the development and progression of pulmonary fibrosis. The researchers' findings, which have been published in Nature Communications*, will enable researchers to develop new therapeutic approaches.  
 

Pulmonary fibrosis is a serious lung disease which mainly affects older people; there are virtually no effective treatments. The disease is characterized by progressive tissue changes which lead to scarring of the lung. However, its causes are largely unknown, and the cellular mechanisms involved in its development remain poorly understood. The term 'mucociliary clearance' refers to a self-cleaning mechanism which relies on ciliated cells in the lung epithelium propelling inhaled pathogens and other particles trapped in mucus out of the airways. We know that changes in the epithelium are associated with the production of excess mucus. They are also associated with the impaired clearance of this mucus and its primary structural components (known as 'mucins'). NEDD4-2 is involved in the degradation of a range of other proteins which in turn are responsible for using these processes to regulate lung epithelial function. This means NEDD4-2 is a key protein with a central role in the pathogenesis of pulmonary fibrosis.  
 

Working alongside colleagues from the German Center for Lung Research (DZL), Heidelberg University Hospital and the German Cancer Research Center, the team of researchers led by Prof. Dr. Marcus Mall (Director of Charité's Department of Pediatric Pulmonology, Immunology and Critical Medicine and Professor at the Berlin Institute of Health [BIH]) succeeded in developing a novel animal model of idiopathic pulmonary fibrosis (IPF). As NEDD4-2 is crucial for early development, the researchers only deleted the relevant encoding gene in lung epithelial cells once the animals had reached adulthood. The researchers examined the animals once they had reached a stage roughly comparable to the point at which the disease would be diagnosed in a human patient. Oxygen saturation measurements taken at that stage revealed a level of lung function impairment which is characteristic of the disease. Using tissue sections and CT imaging to examine the lungs, the researchers also found evidence of patchy scarring, a type of structural abnormality which is indicative of fibrosis. The researchers found further evidence of the significance of NEDD4-2 in the pathogenesis of IPF: lung tissue biopsy samples of patients with IPF contained significantly reduced levels of both transcripts and proteins. Using mass spectrometry, the researchers then performed what is known as 'protein profiling', an analysis of the complete set of proteins produced in the lungs. This revealed a high degree of overlap between the proteins found to be expressed differently in the lungs of patients with IPF and in the animals used in this study. "Our findings can help researchers to further investigate the pathogenesis and progression of this lung disease and develop new treatments. This model could prove useful for the preclinical testing of compounds with therapeutic potential, or to develop markers for the early detection of the disease," says Prof. Mall.
 

When studying the underlying disease mechanisms, the researchers discovered that reduced levels of NEDD4-2 in epithelial cells result in epithelial remodeling in the airways. Not only are the different cell types present in different proportions, the cells also produce increased amounts of certain mucins. When combined with changes in epithelial sodium transport and the resultant reduction in the volume of airway surface liquid, this will lead to impaired mucociliary clearance. Lack of NEDD4-2 also causes increased activity of the TGF? signaling pathway, which promotes the formation of fibrosis. Summing up the findings of the study, the study's first author, Dr. Julia Dürr, says: "This means we were able to establish that a lack of NEDD4-2 is directly linked with mucociliary clearance dysfunction and the dysregulation of the TGF? signaling pathway. According to current state of knowledge, both of these play a role in the pathogenesis of IPF."
 

Anti-fibrotic drugs have been used to treat pulmonary fibrosis for some years. While these drugs usually succeed in slowing the development of scarring, they cannot wholly replace lung transplants as a last resort treatment option. "Using our model and an already licensed anti-fibrotic agent, we were able to confirm that this type of treatment can slow disease progression but does not constitute a curative treatment." By way of explanation, Prof. Mall adds: "We hope that, by providing an improved preclinical testing model, we can help speed up the development of new therapeutic options." As a next step, the researchers plan to test predictive biomarkers which might aid in early diagnosis. They also plan to test the effectiveness of potential new drugs which could be used to treat pulmonary fibrosis.

Researchers from the University of Sheffield have discovered a new insight into how a group of rare childhood brain disorders develop during pregnancy.

Findings reveal that defective immune cells in the brain contribute to the development of rare neurological diseases that cause severe physical and mental disabilities in children.

One in 7,600 children are affected and at the moment there are very limited treatment options for them.

Results could be used to help pave the way for the development of better therapies.

A new breakthrough in understanding the cause of rare childhood brain disorders has been made by researchers at the University of Sheffield.

The discovery by academics from the University's Neuroscience Institute and Bateson Centre has revealed that defective immune cells in the brain called microglia contribute to the development of leukodystrophies.

Leukodystrophies are a group of rare neurological diseases that cause severe physical and mental disabilities in children. One in 7,600 children are affected by the disorders which include symptoms that usually appear in the first year of life and get progressively worse as the child grows older.

Very few treatments are currently available for the diseases which, as with other rare disorders, can leave those affected feeling incredibly isolated.

However, the research by the University of Sheffield-led team has revealed a new insight into how the diseases often develop - a discovery that could be used to create more effective therapies.

Results from the study, published in the journal Glia, suggest that the disorders start during brain development in pregnancy.

Nearly half of our neurons die during the formation of our brain throughout pregnancy and it is the role of microglia to clear them away.

Using transparent zebrafish models to directly observe how brain cells develop, the research team found that the microglia were impaired when trying to clear away the dying neurons in the brains that went on to develop a leukodystrophy.

Animal models of leukodystrophy are rare and often don't look like the human pathology, as they lack the characteristic brain abnormalities and movement problems seen in human patients. However, researchers have created the first zebrafish model for human leukodystrophy and have shown that this model had similar physical and brain anomalies to patients.

Dr Noémie Hamilton, European Leukodystrophy Association (ELA) Research Fellow at the University of Sheffield, said: "The first and main challenge for microglia during brain development is to clear away dying neurons.

"We found that in our zebrafish model of human leukodystrophy, deficient microglia failed to digest dying neurons. Cells digest their content using their lysosomes which are an acidic cellular compartment used as a recycling factory. We showed that our zebrafish model had lysosomal defects, blocking microglia from performing normally.

"This was associated with an inflammatory response which could damage the brain and be the start of the pathology of the disease."
The study highlights that focusing on early dysfunctions during brain development and their consequences will provide a better understanding of these rare devastating diseases.

In the future, Dr Hamilton aims to test whether therapies targeting microglia in early life can alleviate the symptoms using her unique zebrafish preclinical model. She hopes that her findings can be translated into human studies to help identify new ways to treat childhood leukodystrophies.

The proteasome is a major proteolytic machine that regulates cellular proteostasis through selective degradation of ubiquitylated proteins. As the maintenance of protein homeostasis is essential to human health, malfunctions of the ubiquitin-proteasome system (UPS) causes various diseases such as cancers, inflammation, and neurodegeneration. However, we do not yet know the overall principles behind UPS.

In this study, the research team discovered a novel mode of protein degradation by the UPS under a stress condition.

"Around 2013, we discovered that proteasomes form nuclear foci in response to hyperosmotic stimuli. It was very impressive because the uniformly distributed proteasomes form foci in just a few seconds, but it took time to understand what this phenomenon means until we know liquid-liquid phase separation (LLPS). LLPS is a rapid, reversible, and wide-spread compartmentalization mechanism in cells. The proteasome foci actually exhibit liquid-like behavior and a series of experiments revealed the LLPS of proteasomes is for degradation of ubiquitylated proteins." said Yasushi Saeki, PhD, a lead author of the study.

The research results were published in Nature on February 5, 2020.

The hyperosmotic stress-induced proteasome droplets are a transient structure that disappears within a few hours after sucrose treatment. The proteasome droplets also contain ubiquitylated substrates and multiple proteasome-interacting proteins. The formation of the proteasome droplets is dependent on protein ubiquitylation and their disappearance is dependent on the activity of the proteasome, indicating that the droplets facilitate protein degradation. Acute hyperosmotic stress causes a decrease in cell volume and nucleolar stress, resulting in the failure of ribosome biosynthesis as well as accumulation of orphan ribosomal proteins as major UPS substrate in the nucleoplasm. Indeed, hyperosmotic stress induces ubiquitylation of ribosomal proteins and their degradation at the proteasome droplets. Thus, elevated levels of ubiquitylated proteins trigger the formation of the proteasome droplets.

Dr. Saeki and his colleagues further investigated how the proteasomes are recruited to this fluidic subcompartment. The research group identified RAD23B, a substrate shuttling factor of the proteasome, as a key molecule that induces LLPS of ubiquitylated clients as well as the proteasome. RAD23B has two typical ubiquitin-binding domains (UBA) and one proteasome-binding domain (UBL). The group successfully reconstituted RAD23B- and ubiquitin-containing droplets in vitro and showed that weak multivalent interactions between the RAD23B UBA domains and long polymeric ubiquitin chains drive co-phase separation. Taken together, RAD23B collects cellular ubiquitylated proteins via the UBA domains to form droplets, and then recruit the proteasomes via the UBL domain.

"This study is a good example of the interplay between ubiquitin signaling and LLPS. Given that ubiquitin mainly functions as a polymer, one of the biological meaning of the polymerization may be for LLPS. It will be greatly interesting to investigate whether other ubiquitin-binding proteins undergo phase separation." said Dr. Saeki. "Also, it has been suggested that aggregation-prone proteins convert from liquid-like droplets to solid-like assemblies. In this context, acute hyperosmotic stress may risk irreversible accumulation of protein aggregates, especially when the proteasome activity is reduced."

Research on virtual reality started in the eighties, but it is now that good quality is available to the public and it can become a mass consumer product soon. However, there is almost no scientific knowledge on the effects of virtual reality in the long run, nor any oversight over content.

An international group of researchers, with the participation of Mel Slater, director of Event Lab in the Faculty of Psychology of the University of Barcelona (UB), has published a new paper in the journal Frontiers in Virtual Reality reflecting on potential ethical problems of mass spread of virtual and augmented reality. Researchers warn about the dangers that might arise as these technologies becomes more and more realistic and urge for new research to address these scenarios.

Other participants in the study are representatives of major companies and institutions such as BBC R&D, Digital Catapult, Dimension /Hammerhead VR, Facebook London, NESTA, Jigsaw -part of Google-, Magic Leap, Microsoft Research, and University College London.

Potential negative effects of virtual or augmented reality have not been explored

Virtual reality started more than forty years ago in a form we would recognize today: a stereo head-mounted display, head tracking, and computer graphics generated images. Despite different ups and downs in the development of the technology, a huge amount of research has been carried out across a vast range of applications in the last twenty-five years: from medicine to business, from psychotherapy to industry, from sports to travel.

However, its possible negative effects have not been explored, especially when very high quality visual and behavioral realism of virtual humans is becoming increasingly likely in the near future. Elements and even experiences in virtual or augmented reality may become indistinguishable from reality very soon. "For example, a normal computer game may be violent, but it is violence depicted through a screen, involving tiny characters. In VR you are part of the scenario, everything happening is around you, the characters are life-sized, they can look you in the eye. This is a qualitatively different type of experience compared to video games or movies," said Mel Slater, also a member of the Institute of Neurosciences of the UB (UBNeuro).

"Virtual Reality has been used almost exclusively for the good, mostly focused on psychotherapy, but - continues Mel Slater - like any technology, it can be used for good or evil. In order to prevent its use for evil we need better scientific understanding, and therefore research into its effects."

Limits between reality and virtual experiences

In order to reflect about potential dangers of virtual and augmented reality the working group set out to consider possible worst-case scenarios and possible areas of research to address these. They concentrated mainly on problems that might arise as XR becomes more and more realistic. As virtual reality becomes more real people may find it difficult to distinguish between reality and virtual reality. For example, remembering virtual events as if they had been real, and failing to distinguish over time events that really happened and those that happened in virtual reality.

Researchers also highlighted another potential problem with an ultrarealistic experience: we don't know what are the after effects and mental consequences of using virtual reality - for example in extreme violent games - and of the real-world transition from virtual reality.

"After an intense and emotional experience in virtual reality, you take the headset off, and you are suddenly in the very different real world. We are not good at rapid adjustment of behavior and emotion regulation. Re-entry to the real world, especially after repeated exposure to virtual reality, might lead to disturbances of various types: cognitive (did something happen in XR or in real life?), emotional (cause of emotions is not real, for example your avatar was insulted by a fictional virtual character), and behavioral: for example, actions accepted in XR may not be socially accepted in the real world)," explained Mel Slater.

Social isolation is other issue highlighted in the paper. "It is possible that some people may use XR to such an extent that they lose social face-to-face contact with other people so that people withdraw from society," said Mel Slater.

Some other issues they warn against were data privacy and the dangers of identity impersonation and fake news. "People (e.g., politicians) could be shown to carry out actions in virtual reality that they never did in reality. Although the same is true with just video, in virtual reality it is more powerful because it seems to happen life-sized in the same space in which you are located. It happens in front of you, not through a screen," said Slater.

A regulatory regime similar to cinema

Given these ethical challenges, researchers highlighted that there is essentially no data that can help in addressing them. So, besides the potential problems, some important research questions are outlined in the paper, such as the long-term effects of XR use, or whether XR experiences can be used to manipulate memory, or if people will continue to distinguish real from virtual events.

"It is especially important to make the creators of virtual and augmented reality applications aware of these possible dangers. However, this must be based on scientific study rather than opinion, so an urgent consideration is the funding of interdisciplinary research to address these and other issues. The most important is scientific research that could form the basis of a regulatory regime such as there is for cinema, with classifications of content by age and other conditions," said Mel Slater.

A permanent working group

After this research paper, the working group will continue with regularly meetings and discussion. "We plan to hold a one-day Workshop for Industry where we present these issues in a public forum, and form a more permanent working group from this to advise industry, government and international bodies," said Mel Salter.

Evolution is usually viewed as a slow process, with changes in traits emerging over thousands of generations only. Over the recent years, however, research has indicated that adaptation in specific traits can occur more quickly. However, very few studies outside microorganisms were able to demonstrate empirically how quickly natural selection shapes the whole genome.

A research team led by Dr. Daniel Berner at the University of Basel's Department of Environmental Sciences has now provided evidence for rapid evolution within a single generation, using threespine stickleback fish as model organism. The five-year study combined lab work, field experiments, mathematical modeling and genomic analysis.

Different habitats: lakes and rivers

In the Lake Constance area, stickleback have adapted to ecologically different habitats - lakes and rivers. To examine how quickly adaptation occurs across the genome, lake- and river-dwelling fish were crossed in the laboratory over several generations. The genomes of the two ecotypes were thus mixed, resulting in a genetically diverse experimental population.

In a second step, the researchers released thousands of these experimental fish into a natural river habitat without resident stickleback, exposing them to natural selection. After a year, the remaining fish were recaptured and examined genetically.

"The hypothesis of this experiment was that in the river habitat in which the experimental animals had to survive, genetic variants of the original river population would increase in frequency," says Berner. "However, we had no idea whether this would be measurable within a single generation."

Genomic analysis confirms hypothesis

To record potential changes in the genome, the researchers first had to identify the DNA regions most likely to be targeted by natural selection. To do so, they compared the original lake and river populations based on DNA sequence data. This revealed hundreds of regions in the genome likely important for adapting to the lake and river conditions. In precisely these regions, the experimental population's DNA sequence data from before and after the field experiment were then compared to identify changes in the frequency of genetic variants.

The result supported the hypothesis: on average, the frequency of the river variants increased by around 2.5% at the expense of the lake variants. "This difference might appear small at first glance, but is truly substantial when extrapolated over a few dozen generations," says Berner. The experiment demonstrates that evolution can occur very quickly right in front of our eyes - and not only in microorganisms. "Such rapid evolution may help some organisms to cope with the current rapid environmental changes caused by humans," Berner concludes.

ABERDEEN PROVING GROUND, Md. (April 27, 2020) - A team of Army and academic researchers are investigating how eye-pupil size changes can indicate a person's cognitive state as a means to enable teaming with autonomous agents.

The future Army battlespace will require humans and AI agents to team effectively to accomplish mission-critical goals. Although AI agents can fill gaps in human performance, they are rigid and lack the flexibility inherent to human behavior, which could interfere with teaming.

"Humans' brains are amazing, adaptable systems that automatically apply the right cognitive processes to complete a task and initiates each process at the right time," said Dr. Russell Cohen Hoffing, a scientist at the U.S. Army Combat Capabilities Development Command's Army Research Laboratory. "However, our brain's resources are limited. Being able to predict a Soldier's mental status before resources are maxed out is an opportunity for an autonomous agent to deploy capabilities to aid the Soldier. To make progress on enabling this technology, we wanted to better understand how physiological signals, such as pupil size changes, are related to performance and cognitive states."

A joint effort between researchers from the Army and the Institute of Collaborative Biotechnologies at the University of California, Santa Barbara, the Cognitive Resilience and Sleep History, or CRASH, project seeks to understand how variations in state (as measured by physiological sensors) influence subsequent performance. PLOS ONE published the team's research on a subset of the data set, "Dissociable mappings of tonic and phasic pupillary features onto cognitive processes involved in mental arithmetic".

In this research, the team sought to understand the cognitive processes that affect pupil size changes--and the reliability of these relationships--as a foundation to estimate how human cognitive processes and performance can vary in real-world, cognitively challenging tasks, Cohen Hoffing said. The pupil is a unique data source, as it is the only internal organ of the body that brain networks directly modulate and is visible to the outside world.

"The potential of this research is exciting because eye tracking technologies are becoming universal in both commercial and military contexts," Cohen Hoffing said. "Inherent to eye tracking algorithms, pupil size is estimated but rarely used for analytics. Our research program aims to generate knowledge products that enhance usability of this type of data to have greater insight into cognitive processes such as attention and decision making."

The researchers collected repeated measurements from participants on eight separate occasions over four months. The data provided insights into the consistency of the pupil response and relationships to behavior both within and between individuals--with a unique glimpse into cognitive processes over time rather than in single-session studies, Cohen Hoffing said.

The findings of the study demonstrated that researchers can use pupil features to index both static and rapid-time varying aspects of cognition to understand how cognitive processes influence performance. Results indicated that at the trial-level, the time that each participant took to answer a mental arithmetic question correlated with the time to maximum pupil dilation and the size of the pupil. The relationship between performance and rapid pupil features indicated that a latent pupil response correlated with the process of reaching an answer, while pupil response increases correlated with the amount of attention applied to provide an answer. In contrast, average pupil size correlated with variability in how fast participants completed questions--suggesting that average pupil size indicates a readiness to perform the mental arithmetic task.

Results of the study confirm and extend previous research, showing that cognition reliably influences the pupil on at least two time-courses: a rapid, transient influence and a longer-lasting, sustained influence.

"These findings allow us to further understand in which cases pupil data may be useful for human and agent teaming," said Dr. Steven Thurman, Army scientist and senior author on the manuscript. "For example, it may be the case that pupil size is most reliable in complex, real-world contexts only when averaging data over the course of several seconds or minutes. Such a case would enable the ability to track longer timescale changes in mental states, like vigilance, workload or fatigue, but potentially limit its use for tracking moment-to-moment decisions. It is important to employ longitudinal studies like this to understand the utility of pupil data on these varying timescales."

Future studies will examine how to apply this research in real-world contexts, such as using virtual reality to test whether pupil size features can be exploited in dynamic contexts. This will be a steppingstone to test the efficacy of adaptive autonomous agents that use pupil size as an effective measure of hidden human states.

For example, do they resuscitate patients even though the prospects of recovery are slim and the risk to the healthcare team high? How should healthcare workers respond?

This is one of the topics covered in the COVID-19 Special Issue of the Wits Journal of Clinical Medicine. The journal, published by Wits University Press under open access conditions, presents the first clinical data on COVID-19 published in South Africa.

The special issue covers a range of aspects of the pandemic, from the clinical, through ethical, to the social dynamics of its impact.

Highlights include:

Diagnosis of COVID-19: Considerations, controversies and challenges in South Africa
Social dimensions of COVID-19 in South Africa: A neglected element of the treatment plan
Clinical ethical challenges in the COVID-19 crisis in South Africa
Potential impact of SARS-CoV-2 infection in HIV-positive patients in South Africa
COVID-19: The concept of herd immunity - is it a strategy for South Africa?

Editor-in-chief of the Wits Journal of Clinical Medicine Professor Pravin Manga says it is important for health professionals and the public to have access to scientific information:

"Social media is awash with all sorts of quackery regarding prevention and treatment remedies for COVID-19 and it is during these times that we need to be rational and be guided by science rather than by emotion."

Manga is Professor of Internal Medicine, School of Clinical Medicine, in the Faculty of Health Sciences at Wits.

In addition to being a public resource, more than 10 articles in this issue aim to guide healthcare workers. These articles address the ethical aspects related to the pandemic.

For example, which patients should healthcare workers admit to already-filled intensive care units and who decides this? Associate Professor Kevin Behrens, Director and Head of the Steve Biko Centre for Bioethics discusses such ethical conundrums in his review.

Professor Laurel Baldwin-Ragaven in the Department of Family Medicine and Primary Care presents a sobering overview of how some of South Africa's vast social disparities may manifest during COVID-19, and outlines our clinical and social responsibilities.

Professor Charles Feldman in the Division of Pulmonology, Department of Internal Medicine at Wits interrogates the aggravating issue of South Africa's additional burdens of HIV and tuberculosis and the risk of COVID-19 infection in HIV-positive patients.

Professor Ismail S. Kalla in Pulmonology in Internal Medicine and Professor Abdullah Laher in Emergency Medicine in the School of Clinical Medicine explore whether herd immunity offers possibilities as a strategy for fighting COVID-19 in South Africa.

This special issue includes a guide to worldwide Medical Resources on COVID-19, as well as a handy poster-style patient guide for healthcare workers.

COLUMBUS, Ohio - Lactating mothers who use e-cigarettes or nicotine replacement therapies may be putting their breastfed babies at risk for skull defects, a new study in animals suggests.

Cigarette smoking has already been linked to increased risk for these abnormalities in previous research. This study tested the effects of nicotine alone on head and face development.

Researchers added nicotine to the drinking water of adult female mice that were nursing litters of newborn pups. The nicotine exposure was the equivalent of about one-half to a full pack of cigarettes per day.

Scientists found in 15-day-old pups that the skull joints across the top of their heads were narrowed, putting them on a path to fuse earlier than normal. Because mouse pups at this age don't drink water, breast milk was the only possible source of their nicotine exposure.

In human babies, this skull abnormality not only changes the shape of the head but can require neurosurgery to make room for the brain to grow.

The study builds upon previous work by the Ohio State University researchers that showed in mice that nicotine exposure during pregnancy altered offspring's craniofacial growth and development.

"We knew based on previous data in pregnancy that we'd see some changes, but we were a bit taken aback to find there were discernible differences when the nicotine exposure was occurring only during lactation," said James Cray, associate professor of anatomy in Ohio State's College of Medicine and senior author of the study.

"Our data suggest that nicotine alone can alter development of the head and face. That means mothers who vape are likely exposing their unborn children or infants to an amount of nicotine and its metabolites that can disturb growth in the same way cigarettes can."

The research was scheduled to be presented at the April 2020 American Association for Anatomy meeting held as part of the Experimental Biology conference, which was canceled because of the COVID-19 pandemic. In lieu of that presentation, the abstract was published in The FASEB Journal.

The disorder seen in these studies is called craniosynostosis, which results from the premature closure of joints, or sutures, that connect sections of the skull and remain flexible early in life as the brain continues to grow. One or more of the sutures can be affected.

"Where there is supposed to be a growth site to allow for expansion of the brain, the joints are locked together. The brain can't push those skull sections apart, so it grows in other directions," Cray explained.

The Centers for Disease Control and Prevention estimates that 1 in every 2,500 babies is born with craniosynostosis. A definitive cause is unknown, but the disorder has been linked in studies to genetic mutations and mothers' use of certain medications.

Craniosynostosis can alter the shape of the head and impair the development of the eyes and vital organs and, if not repaired in surgery, may lead to developmental delays. Symptoms include altered head shape, projectile vomiting, poor feeding, high-pitched crying and sleepiness caused by increased pressure on the brain. Children with the disorder who don't need surgery live normal lives with uncorrected abnormalities.

Based on previous work, Cray and colleagues targeted the nicotine dose in this study at 100 micrograms per milliliter, expecting mice to drink 3 to 5 milliliters of water per day. The researchers confirmed the mouse moms' level of exposure by measuring chemicals that are metabolites of nicotine in their blood.

When the pups were 15 days old, which roughly equates to age 1-2 years in humans, the scientists used micro-CT scanning to measure their heads. They found abnormalities in development of the pups' coronal sutures, joints that span the top of the head from ear to ear.

Cray is continuing this work, next planning to vaporize nicotine in mouse studies to mimic the effects of e-cigarettes on head and face development in offspring. His lab is also studying nicotine's effects on bone cells, looking for potential mechanisms to explain the damage. Early results suggest nicotine increases cell division and also puts so much stress on cells in the skull that they prematurely discard components that contribute to their normal function.

"The broader implication of this work, simply put, is that nicotine cannot be viewed as a relatively safe chemical that acts only on addiction," Cray said. "We know a lot as a scientific community about cigarettes. But we don't know as much about the components in cigarettes. The need to better understand the effects of nicotine alone is our specific aim."

Plant breeding has considerably increased agricultural yields in recent decades and thus made a major contribution to combating global hunger and poverty. At the same time, however, the intensification of farming has had negative environmental effects. Increases in food production will continue to be crucial for the future because the world population and demand continue to grow. A recent study by the University of Göttingen shows that new plant breeding technologies - such as genetic engineering and gene editing - can help to increase food production whilst being more environmentally friendly. The results have been published in the journal Applied Economic Perspectives and Policy.

For the study, the agricultural economist Professor Matin Qaim from the University of Göttingen evaluated 50 years' worth of research from around the world. Since the 1960s, there has been a "Green Revolution": high-yielding varieties of wheat, rice and maize have been developed and widely cultivated, especially in Asia and Latin America. As a result, crop yields tripled, which not only increased farmers' incomes, but also improved ordinary consumers' access to food. However, the high yields were accompanied by intensive use of chemical fertilizers and pesticides. In addition, developments concentrated on a small number of cereal species, which led to a reduction in agricultural diversity.

"Cereals are cheap sources of calories, which explains why hunger has been significantly reduced in recent decades," explains Qaim. "Unfortunately, the Green Revolution was less successful in combating widespread micronutrient deficiency. This requires a more balanced diet and more diversity in agricultural production with more beans, vegetables, fruit and other locally adapted species."

New molecular breeding technologies can help modify plants to produce higher yields. In addition, plants can be bred to require less fertilizer and pesticides because they make better use of soil nutrients and are more resistant to disease, pests and extreme weather conditions. The new technologies can also speed up the breeding of new traits, enabling faster adaptation to climate change. "Even though new methods like CRISPR were only invented a few years ago, they have already been used successfully in many different crops. The methods are relatively simple and inexpensive, so even small laboratories can use them to improve local species. This is an important step towards greater diversity," says Qaim.

Genetically modified organisms (GMO) have been grown for about 25 years but remain controversial, especially in Europe. Although these varieties are classified as safe in scientific studies, there is still widespread public concern about possible health and environmental risks. To a large extent, these concerns are related to the fact that GMOs contain genes introduced from other species. "The low public acceptance has led to high regulatory hurdles that are not scientifically justified and seriously slow down the development of the technology," explains Qaim. Gene-editing methods are different because they usually do not transfer foreign genes. In principle, the targeted changes in the plant's DNA could occur naturally. "The problem is that the regulatory authorities in Europe treat plants developed using gene editing in the same way as genetically modified plants where foreign genes are introduced. This fuels public fears and prevents the further development and use of the technology in agriculture. Unfortunately, the European attitude has far-reaching implications for many poor countries, especially in Africa, where new agricultural technologies are particularly important for small farms," says Qaim. "We urgently need a different and more evidence-based public discourse about new breeding technologies, because they can make an important contribution to sustainable agriculture and food security."

Two pediatric brain cancers that are challenging to treat if they recur, medulloblastoma and ependymoma, are the target of a clinical trial using a new type of therapy. A multi-institutional, international team led by researchers at Baylor College of Medicine, Texas Children's Hospital and the Hospital for Sick Children (SickKids) has developed a novel approach that delivers appropriately-targeted chimeric antigen receptor (CAR) T cell therapy directly into the cerebrospinal fluid that surrounds the tumor.

The researchers report in the journal Nature Medicine that this approach was effective in treating these cancers in mouse models of human disease. The findings support further clinical studies to evaluate this strategy to treat pediatric brain cancers, the most common cause of cancer death in childhood. Indeed, a first-in-child clinical trial currently is recruiting patients at Texas Children's Hospital and Baylor College of Medicine to test the safety and anti-tumor efficacy of this approach (Clinicaltrials.gov identifier: NCT02442297).

"Recurrences of medulloblastoma and ependymoma can be disseminated throughout the lining of the brain and spinal cord, which are bathed in cerebrospinal fluid. This location offers the opportunity to deliver therapies into the cerebrospinal fluid compartment and could provide a better chance for the therapy to reach and eliminate the tumor than administering it through the blood stream," said co-corresponding author Dr. Nabil Ahmed, associate professor of pediatrics and immunology, section of hematology-oncology at Baylor and Texas Children's Hospital.

"The vast majority of children with recurrent metastatic medulloblastoma or ependymoma currently have a deadly prognosis, so it is very exciting to think we have identified a novel approach to treat this underserved patient population," said co-corresponding author Dr. Michael Taylor, neurosurgeon, senior scientist in the Developmental and Stem Cell Biology program, Garron Family Chair in Cancer Research at SickKids, and professor in the Departments of Surgery and Laboratory Medicine and Pathobiology at the University of Toronto.

This project was led by Dr. Laura Donovan, post-doctoral fellow in the Developmental and Stem Cell Biology program at SickKids, who performed in-depth molecular studies of the target profile of recurrent medulloblastoma and ependymoma. These studied guided the design of CAR T cells engineered by Ahmed and colleagues at Baylor's Center for Cell and Gene Therapy and Texas Children's Hospital to target the most appropriate cancer molecules.

CAR T cells are a form of immunotherapy involving engineering of T cells, a type of immune cell that fights cancer. The researchers genetically engineered CAR T cells to recognize specific molecules on the surface of the tumor cells. When these CAR T cells encounter the tumor, they can fight it more effectively. CAR T cells have been impressively effective for patients with certain types of leukemia and are FDA-approved for this disease.

In mouse model studies, CAR T cells were administered into the cerebrospinal fluid around the tumor or into the blood stream of mice harboring multiple patient-derived medulloblastoma and ependymoma tumors. The tumor size and animal survival were studied for about 200 days.

The results showed that administering tumor-specific CAR T cells into the cerebrospinal fluid was more effective than administering them via the blood.

"As opposed to delivery through the blood, cerebrospinal fluid delivery overcomes the blood-brain barrier and also offers the advantage of minimizing exposure of other tissues of the body to the CAR T cells and, consequently, potential side effects," Donovan said.

In some of their experiments, the researchers combined CAR T cells with an approved cancer medication called azacytidine. The results showed that combining immunotherapy with azacytidine was significantly more effective than either treatment alone.

"This work was possible thanks to the concerted collaboration of our Pediatric Cancer Dream Team supported by Stand Up To Cancer® (SU2C) St. Baldrick's Foundation Translational Research Grant, which brought together scientists studying tumor genomics and tumor immunotherapy around the world to enable the design of more effective therapies for children with incurable and hard to treat cancers," Ahmed said.

Biomedical engineers at Duke University have used deep brain stimulation based on light to treat motor dysfunction in an animal model of Parkinson's disease. Succeeding where earlier attempts have failed, the method promises to provide new insights into why deep brain stimulation works and ways in which it can be improved on a patient-by-patient basis.

The results appear online on April 20 in The Journal of Neuroscience.

"If you think of the area of the brain being treated in deep brain stimulation as a plate of spaghetti, with the meatballs representing nerve cell bodies and the spaghetti representing nerve cell axons, there's a longstanding debate about whether the treatment is affecting the spaghetti, the meatballs or some combination of the two," said Warren Grill, the Edmund T. Pratt, Jr. School Distinguished Professor of Biomedical Engineering at Duke.

"But it's an impossible question to answer using traditional methods because electrical deep brain stimulation affects them both as well as the peppers, onions and everything else in the dish. Our new light-based method, however, is capable of targeting just a single ingredient, so we can now begin teasing out the individual effects of activating different neural elements."

In Grill's metaphor, the meatballs are the neurons that make up the subthalamic nucleus, a small component of the basal ganglia control system that is believed to perform action selection. While its exact function remains unknown, research suggests that it holds muscular responses in check. The spaghetti in the bowl represents long nerve fibers called the hyperdirect pathway that extend into the region from neurons in the cerebral cortex, the thin outer layer of neurons responsible for most of the brain's information processing. And the peppers, onions and other ingredients are the various types of support cells found throughout the brain.

As Grill suggests, teasing out the role all of these various types of cells plays in mediating the effects of deep brain stimulation is nearly impossible using traditional methods. Individual types of cells cannot be singled out by electrical stimulation, and the electric pulses blind researchers' sensors for a crucial millisecond directly after firing.

In 2006, a team of researchers attempted to use optogenetics to skirt these issues. Optogenetics is a method of genetically modifying specific cells to express light-sensitive ion channels, allowing researchers to control their activity with flashes of light. The researchers embedded these light-sensitive ion channels into the subthalamic nucleus "meatballs" in rats and flashed pulses of light at the same rate used in deep brain stimulation. The treatment, however, failed to alleviate any of the rats' physical symptoms, leading the researchers to conclude that stimulating the subthalamic nucleus on its own is an inadequate treatment approach.

But the study never sat quite right in Grill's mind.

"Neurons being stimulated with optogenetics don't generally respond very quickly, and it seemed to me that the researchers were flashing their lights faster than the neurons could keep up with," said Grill. "The data bore this out, as the neurons appeared to be responding randomly rather than in sync with the flashes. And previous research that we conducted showed that random patterns of deep brain stimulation are not effective at relieving symptoms."

It took more than a decade for Grill to be able to test his theory, but two recent developments allowed him to follow his hunch. Researchers developed a faster form of optogenetics called Chronos that could keep up with the speeds traditionally used in deep brain stimulation. And Chunxiu Yu, a research scientist with expertise in optogenetics, joined Grill's laboratory. Also contributing to the work in Grill's laboratory were Isaac Cassar, a biomedical engineering doctoral student, and Jaydeep Sambangi, a biomedical engineering undergraduate.

In the new paper, Yu embedded the Chronos optogenetics machinery into the subthalamic nucleus neurons of rats that have been given Parkinson's disease-like conditions in one-half of their brains. This model helps researchers determine when a treatment is successful because the resulting physical movement symptoms only occur on one side of the rat's body. They then delivered deep brain stimulation using light flashes at the standard 130 flashes per second.

As Grill first suspected nearly 15 years ago, the technique worked, and the rats' physical symptoms were substantially alleviated.

According to Grill, their result has several important implications. One is that researchers need to consider the kinetic properties of how rapidly optogenetic approaches can act when designing their experiments and pay close attention to performance in their studies. Another insight was the way that other neurons outside of the subthalamic nucleus responded to the treatment. While there was not a large difference in their average activity levels, there was a dramatic shift in the pattern in which those neurons fired, which offers clues as to how deep brain stimulation works.

But perhaps the most important result is simply that the technique worked at all. Besides offering a much clearer look at neural activity by removing electrical artifacts, the ability to deliver deep brain stimulation to precise subsets of neurons should allow researchers to begin probing exactly which parts of the brain need to be stimulated and how therapies might be tailored to treat different motor control symptoms on a case-by-case basis.

As their next experiment in this line of research, Grill and his colleagues plan to recreate this same study but in the hyperdirect pathway -- the spaghetti instead of the meatballs -- to see what its individual contribution to relieving symptoms might be.

"This is very important because somewhere in that big bowl of spaghetti are some elements that are responsible for treating symptoms and some elements that generate side effects," said Grill. "And if we can figure out which is which, we can design electrode stimulation geometries and patterns to target the elements that suppress symptoms while leaving the others alone."

In the most detailed study to date of epidemic spread, an international team of researchers has modeled measles dynamics based on over 40 years of data collected in England and Wales. The models--which span the prevaccination period, introduction of measles vaccination, and local elimination by vaccination in the 1990s--reveal that, before the introduction of a vaccine, measles could persist in both large population centers and by spread among sets of smaller towns. The study also provides critical data on the importance of spatial modeling for the long-term control of global epidemics and could help inform the long-term public health response to the current COVID-19 pandemic.

A paper describing the study appears April 27, 2020 in the journal Nature Ecology & Evolution.

"During the last 20 years there have been tremendous inroads towards eradicating measles--one of the major killers of children globally--as annual deaths have been driven down from more than a million to less than 200,000," said Ottar N. Bjørnstad, Distinguished Professor of Entomology and Biology at Penn State and one of the leaders of the research team. "However, previous efforts to eradicate smallpox and polio highlight the complexity of moving from local control to global eradication. Our study provides critical data on how long-term control efforts will need both general and detailed spatial models to finally stop this deadly disease."

Prior to the introduction of a vaccine, the number of measles cases in England and Wales would undergo, periodic--often biennial--epidemics. This pattern, driven by herd immunity, is common among a number of diseases and in other locales. The researchers sought to locate the reservoirs where the virus persists in the dips between epidemics, which are the sources for reintroduction of the virus into the general populace in the next major epidemic. This persistence question is central to understanding the dynamics of measles and other viral diseases and for coordinating public health interventions.

The research team combined spatial modeling with the detailed historical data of measles cases in England and Wales to address these questions. The uniquely detailed dataset includes weekly measles reports from almost a thousand locations across England and Wales beginning in 1944 and continuing until the disease was all but locally eliminated by vaccination in the 1990s.

"Previous work stressed the importance of large centers as sources of infection," said Bryan T. Grenfell, the Kathryn Briger and Sarah Fenton Professor of Ecology and Evolutionary Biology and of Public Affairs at Princeton University and another leader of the research team. "However, our new modeling shows that local spread among smaller towns can also contribute to persistence of the virus."

The researchers' new model quantifies the relative influence of different sources of infection, including major cities, spread among smaller towns, and unidentifiable outside sources. Following the introduction of vaccination, the source of reintroduction shifted from a combination of large centers and local spread to mainly unidentifiable sources, possibly outside of England and Wales.

"Having access to this unique dataset allowed us to test these news models of measles dynamics with unprecedented rigor," said Max S. Y. Lau, assistant professor in the Rollins School of Public Health at Emory University and first author of the paper. "Going forward, we can apply what we learn from this test case to understand disease spread beyond measles."

"Measles has always been the 'model organism' of epidemic dynamics--like C. elegans or the fruitfly are for evolution--and, along with influenza, a paradigm for understanding herd immunity," said Grenfell. "So, as COVID-19 approaches endemicity, these new models can help us understand and prepare for modeling its spatial spread, as well as understand the impact that the eventual development of a vaccine might have on its dynamics."

Beyond the COVID-19 pandemic, the models also could help scientists understand how diseases survive and spread at a time when a portion of the public is opposed to vaccines, said co-author C. Jessica E. Metcalf, assistant professor of ecology and evolutionary biology and public affairs. "Understanding the drivers of persistence is also of growing importance in a context of growing vaccine hesitancy, which further complicates dynamics and amplifies the challenges of control," she said.

The researchers added that wide perspective should be taken when applying the results to other diseases.

"Our model and previous experience highlights the complexity of globally eradicating a virus," said Bjørnstad. "Smallpox was eradicated by 1977 through a massive global effort of mass-vaccination of all children, followed by targeted efforts in regional hotspots and finally local quarantining and ring vaccination to squash the scourge. Polio, in contrast, while also targeted through vaccination for more than 50 years keeps escaping 'the final blow' as it successfully shifts and diffuses across regional pockets of susceptible individuals to evade eradication."

A new study finds that earlier high school start times can have significant adverse consequences for students, including increased rates of tardiness and absenteeism.

"The American Academy of Pediatrics recommends that high schools begin class after 8:30 a.m., but we know that most schools start much earlier," says Melinda Morrill, an associate professor of economics at North Carolina State University and corresponding author of a paper on the work. "We were able to look at five high schools that moved start times from 8:05 a.m. to 7:25 a.m. in order to examine the effect that the change had on students."

The researchers looked at data on seven cohorts of students, with graduation years ranging from 2013 to 2019. Specifically, researchers looked at data from the freshman, sophomore and junior years of each cohort. The change in start times was implemented in the 2012-13 school year. As an additional control group, the researchers also looked at data from 14 other high schools in the same school district that had already adopted a 7:25 a.m. start time.

"There's a growing body of research that suggests earlier start times can hurt test scores," Morrill says. "We looked at that, but the numbers weren't statistically significant one way or the other."

"However, the move to the earlier start times caused a small increase in the number of students who did not advance to 12th grade on time," says John Westall, a Ph.D. candidate at NC State and co-author of the paper. "Specifically, the move from 8:05 to 7:25 was associated with students being 8% more likely not to advance to 12th grade on schedule."

"We also wanted to look beyond testing to see if there were effects on other measures of academic engagement," Morrill says. "And we found a significant increase in both absences and tardiness."

"The change to an earlier start time led to an increase of about one additional absence per year and just over three additional tardy arrivals per year for students," Westall says. "So students were definitely missing more school."

"Looking at all 19 of the schools, we found that historically, the five schools that started at 8:05 had significantly lower rates of absenteeism and tardiness than the 14 schools that started at 7:25," Morrill says. "But once those five schools moved their start time to 7:25, those advantages disappeared.

"The take-home message here is that we need to look at more than just test scores if we want to understand all of the ways that early start times can affect high school students," Morrill says. "We know that school districts have to consider a wide range of issues, such as transportation logistics, student safety, extracurricular activities and school finances. But the more we look, the more the findings suggest that there are significant consequences of early start times for students."

University of Texas at Dallas researchers have developed a promising method for remotely stimulating activity in deep brain regions, advancing understanding of how molecules act in the brain and paving the way for better cancer treatments and therapies for other diseases.

The approach is based on the powerful combination of gold nanoparticles and lasers, which also plays a critical role in another UT Dallas research project aimed at developing a rapid diagnostic test for influenza and, possibly, the COVID-19 virus.

Gold for Neuromodulation

Light is an important tool to modulate biological systems, but absorption and scattering in biological tissues significantly limit its penetration. The system developed by researchers in the Erik Jonsson School of Engineering and Computer Science and the School of Behavioral and Brain Sciences packages molecules inside microscopic gold-coated capsules, or nanovesicles, that can be very sensitive to near-infrared light.

The system could solve challenges in treating diseases, such as ensuring that medication is delivered to difficult-to-reach tumors in deep brain regions while reducing damage to healthy tissue. Using that example, the nanovesicles and their cargo are injected into the brain tissue. External near-infrared lasers that penetrate the tissue cause the capsules to open and release the drug. The researchers describe the approach and results of tests in an animal model in an article published online in the chemistry journal Angewandte Chemie.

"Our system converts light to a mechanical wave that shakes the vesicle open," said Dr. Zhenpeng Qin, assistant professor of mechanical engineering at UT Dallas and corresponding author of the study.

Other researchers have used near-infrared light to trigger drug-carrying nanoparticles, such as phospholipid liposomes, which release their cargo when heated by the laser, but Qin's approach with gold-coated nanovesicles uses about 40 times less laser energy.

In tests in animal models, Qin and his colleagues found that the near-infrared light penetrated 4 millimeters in the brain, which was enough to reach most targeted brain regions. Qin said he anticipates the laser penetrates far enough to reach targets deep in the rodent brain that will help answer important questions in neuromodulation.

"We want to improve the tests' sensitivity so that doctors can make the judgment call right in front of the patient, to be able to say either you have it or you don't have it."

While the nanovesicle system must undergo more development and testing before it could be used in clinical care, Qin said the approach eventually could be applied to neurological disorders or other cancers. Dr. Hejian Xiong, research associate in Qin's lab and co-author of the journal article, received a new postdoctoral fellowship from the Phospholipid Research Center in Germany to study the use of gold-coated nanovesicles and ultra-short near-infrared lasers to target and relieve pain in patients after surgery. The project aims to provide an adjustable pain management system that could reduce the need for opioids.

Infectious Disease Testing

In a separate research project, Qin recently received a $293,000 grant from the Congressionally Directed Medical Research Programs to develop a rapid, accurate and less expensive test for infectious diseases, including influenza, that could be conducted in doctors' offices. The testing principle could also be applied to diagnose COVID-19.

While many doctors conduct rapid flu tests on site, the tests can miss influenza in 30% to 50% of cases, according to the Centers for Disease Control and Prevention. Samples must be sent to a lab for an accurate diagnosis, which can take days.

"We want to improve the tests' sensitivity so that doctors can make the judgment call right in front of the patient, to be able to say either you have it or you don't have it," Qin said.

In the testing method, gold nanoparticles are attached to antibody molecules that can recognize and bind with protein molecules found on the surfaces of viruses. Researchers apply short laser pulses to activate the nanoparticles to generate nanoscale bubbles, or nanobubbles. The accumulation of the nanobubbles signals the presence of a virus.

"By using optics to detect and count the nanobubbles, we can sensitively and quickly detect the presence of specific respiratory viruses," Qin said.

One of the advantages of the approach is that it would not require extensive sample preparation, Qin said. The method could help doctors diagnose viruses much faster and reduce health care costs by eliminating the need for expensive lab visits. The approach could be used to detect a single virus or multiple viruses.

Ultimately, researchers envision the test being broadly used in hospitals and clinics that do not have labs; however, the diagnostic method will need to be tested further before it can be made widely available.

Qin's group is not working with the live coronavirus, only with viral genes, proteins and antibodies. Qin has previously obtained such patient samples for his research on respiratory syncytial virus and influenza.