Culture

Throughout the pandemic, healthcare workers have seen more than just the lungs affected by COVID-19. Doctors have reported neurological complications including stroke, headache and seizures, but the information is limited to a number of individual reports that are not reflective of a larger population.

Researchers from Baylor College of Medicine and the University of Pittsburgh have gathered more than 80 studies, reviewed the data, and identified commonalities that are helping to paint a broader picture of how COVID-19 affects the brain.

The findings, published in Seizure: European Journal of Epilepsy, focused on electroencephalogram (EEG) abnormalities of the brain. EEG is a test used to evaluate the electrical activity in the brain. Researchers found that about one-third of patients who were given an EEG had abnormal neuroimaging localized in the frontal lobe of the brain.

"We found more than 600 patients that were affected in this way. Before, when we saw this in small groups we weren't sure if this was just a coincidence, but now we can confidently say there is a connection," said Dr. Zulfi Haneef, assistant professor of neurology/neurophysiology at Baylor.

The main reason a patient would be given an EEG is if altered mentation is noted, meaning a patient might have a slowed reaction to stimuli, followed by seizure-like events, speech issues, confusion or inability to wake up after sedation. The most common findings from the EEG were slowing or abnormal electrical discharge, mostly in the frontal lobe.

Some of the EEG alterations found in COVID-19 patients may indicate damage to the brain that might not be able to be repaired after recovering from the disease.

"As we know, the brain is an organ that cannot regenerate, so if you have any damage it will more than likely be permanent or you will not fully recover," Haneef said.

Haneef found the location of the abnormal activity interesting.

"We know that the most likely entry point for the virus is the nose, so there seems to be a connection between the part of the brain that is located directly next to that entry point," he said. "Another interesting observation was that the average age of those affected was 61, one-third were female and two-thirds were males. This suggests that brain involvement in COVID-19 could be more common in older males. More research is needed but these findings show us these are areas to focus on as we move forward."

It may not always be the virus acting directly on the brain causing the abnormal EEG readings, Haneef said. It could be the oxygen intake, heart problems related to COVID-19 or another type of side effect, which is why he says that comprehensive patient care should include more imaging of the brain or EEG testing as necessary.

"These findings tell us that we need to try EEG on a wider range of patients, as well as other types of brain imaging, such as MRI or CT scans, that will give us a closer look at the frontal lobe," Haneef said. "A lot of people think they will get the illness, get well and everything will go back to normal, but these findings tell us that there might be long-term issues, which is something we have suspected and now we are finding more evidence to back that up."

Researchers at UPF, the National Centre for Cardiovascular Research, ICREA and Ciberned have identified a physiological mechanism that maintains the regenerative capacity of muscle stem cells, and surprisingly resists the passage of time far more than expected, until geriatric age. This study presents the results of more than seven years of research and collaborations with several laboratories in Europe and the US.

Skeletal muscle regeneration depends on a muscle stem cell population (satellite cells) in a dormant or quiescent state, a situation that can be triggered by damage or stress to form new muscle fibres and expand in new stem cells.

The regenerative functions of these stem cells are known to decline with ageing. Dr. Pura Muñoz-Cánoves, the ICREA professor who leads the Cell Biology research group of the Department of Experimental and Health Sciences (DCEXS) at Pompeu Fabra University (UPF) in Barcelona, and head of the Tissue Regeneration Group of the National Centre for Cardiovascular Research (CNIC) in Madrid, and of Ciberned, and colleagues, have found in experiments with mice that all muscle stem cells, despite being quiescent, are not equal, and have identified a subgroup that maintains its regenerative capacity over time, declining only at geriatric age.

The researchers have shown that this subgroup of quiescent stem cells has a greater regenerative capacity through the activation of the FoxO signalling pathway (previously associated with longevity), which maintains the expression of a youthful gene programme throughout life; however, at geriatric age, FoxO activation in this subgroup of cells is lost, causing their loss of functionality.

According to the results presented in Nature Cell Biology, compounds that activate FoxO may have a rejuvenating effect on aged muscle stem cells, opening the way to improve the health of elderly people who are debilitated by the loss of muscle mass. It may also be useful for persons who have lost muscle mass as a result of neuromuscular diseases or effects associated with cancer or infectious or inflammatory diseases.

The body's immune system defeats diseases by sensing foreign invaders, like bacteria or viruses, and then mounting a response against them.

But just how immune cell receptors work together to sense multiple molecules and make these decisions remained a mystery. Now, researchers at the Pritzker School of Molecular Engineering (PME) at the University of Chicago have discovered a general property for understanding how these cells sense and respond to microbial signals.

By studying how molecules impact immune cells, they found that while the effect of a single molecule does not predict the effect of two molecules together, the complexity stops there. In fact, the effect of singles and pairs of molecules can be used to predict how triplets of molecules work.

The result, led by Asst. Prof. Nicolas Chevrier and published October 27 in the journal Cell Systems, led to a more effective cancer immunotherapy in mice and could lead to more effective vaccines for both existing and novel viruses.

Key to designing vaccines

Each of the body's innate immune cells has receptors that recognize molecules from foreign pathogens. To fight off bacteria or viruses, those cells make decisions in response to complex combinations of inputs from those molecules. Though researchers have studied singular pathways, how these pathways work together is still not well understood.

Chevrier and his collaborators set out to better understand how cells integrate multiple signals into a response. Not only would it help answer a basic fundamental question of biology, it would also help design vaccines that use adjuvants, molecules that help modulate the immune system and enhance its response.

Though just a few vaccines currently use them, adjuvants might be the key to developing new kinds of vaccines. Right now, FDA-approved adjuvants target only one or two of the cell's receptors. If researchers could find the right combination to target more, vaccines could become more effective.

Understanding how combinations work together

Chevrier and his collaborators used adjuvants to stimulate immune cells in petri dishes to figure out what happens when single molecules, pairs of molecules, and triplets of molecules are used. If the results were additive, the effects of one molecule and the effects of another molecule would, when combined, remain the same. Researchers found that wasn't the case - two molecules combined together led to different effects than each had singularly.

But they did find that the effect of single molecules and pairs of molecules could accurately predict what happened with triplets of molecules.

"It could have been infinitely complex, but it's not," Chevrier said. "We are the first to show you can predict higher-order effects across immune pathways with very simple models."

Model used to design cancer immunotherapy

To prove their theory, the researchers injected cells conditioned with certain combinations of adjuvants - creating a specific cancer immunotherapy treatment - in a mouse model with tumors. The response was potent: the tumors grew five to ten times less in treated mice versus untreated mice.

"That was very encouraging," Chevrier. "Now we need to better understand the mechanisms of why this worked so well."

The researchers also hope to search for new combinations of adjuvants that have equally strong effects and eventually mount a clinical trial in humans.

"Now that we can predict the effects of multiple adjuvants with little data and a simple model, we need to extend this knowledge to the design of vaccines against both new and old threats," Chevrier said.

To better understand how the novel coronavirus behaves and how it can be stopped, scientists have completed a three-dimensional map that reveals the location of every atom in an enzyme molecule critical to SARS-CoV-2 reproduction.

Researchers at the Department of Energy's Oak Ridge National Laboratory used neutron scattering to identify key information to improve the effectiveness of drug inhibitors designed to block the virus's replication mechanism. The research is published in the Journal of Biological Chemistry.

The SARS-CoV-2 virus, which causes the COVID-19 disease, expresses long chains of proteins composed of approximately 1,900 amino acid residues. For the virus to reproduce, those chains have to be broken down and cut into smaller strands by an enzyme called the main protease. The active protease enzyme is formed from two identical protein molecules held together by hydrogen bonds. Developing a drug that inhibits or blocks the protease activity will prevent the virus from replicating and spreading to other cells in the body.

"This new information is exactly what is needed to design inhibitors with a higher degree of specificity, ensuring the inhibitor molecules are binding very tightly to their intended targets and disabling the protease," said ORNL's Andrey Kovalevsky, corresponding author.

Neutron experiments first revealed that the site containing the amino acids where the protein chains are cut is in an electrically charged reactive state and not in a resting or neutral state, contrary to previously held beliefs. Second, they mapped the location of each hydrogen atom in the places where inhibitors would bind to the protease enzyme, as well as the electrical charges of the associated amino acids. The experiments also charted the entire network of hydrogen bonds between the protein molecules that hold the enzyme together and enable it to initiate the chemical process of cutting the protein chains.

"Half of the atoms in proteins are hydrogen. Those atoms are key players in enzymatic function and are essential to how drugs bind," Kovalevsky said. "If we don't know where those hydrogens are and how the electrical charges are distributed inside the protein, we can't design effective inhibitors for the enzyme."

The team's neutron study builds on previous research published in the journal Nature Communications, creating a complete atomic structure of the protease enzyme. The researchers have also made their data publicly available to the scientific community before both papers were published to accelerate solutions to the global pandemic.

Neutrons are ideal probes for studying biological structures because they are nondestructive and highly sensitive to light elements such as hydrogen. The neutron scattering experiments were performed at the High Flux Isotope Reactor and the Spallation Neutron Source at ORNL. The protein samples were synthesized in adjacent facilities at the Center for Structural Molecular Biology.

"This might be the quickest neutron structure of a protein ever produced. We started neutron experiments in May, and within five months, we obtained and published our results. That's something that usually takes years," said ORNL corresponding author Leighton Coates. "This work demonstrates what we can do at Oak Ridge. Everything was done here from start to finish. The proteins were expressed, purified, and crystallized, and all the data was collected and analyzed on site -- a completely vertically integrated approach."

The team will now use the newly obtained information to investigate the binding properties of drug molecule candidates to produce improved COVID-19 therapeutics.

"Not only is this the first time anyone has obtained a neutron structure of a coronavirus protein, but it's also the first time anyone has looked at this class of protease enzymes using neutrons," said ORNL's Daniel Kneller, the study's first author. "It's an outstanding example of neutron crystallography serving the community when it needs it the most."

Cucurbit downy mildew is a devastating disease for the United States cucurbit industry, which includes cucumbers, watermelon, squash, and pumpkin. The disease has caused major losses in North Carolina, which has significant cucumber and watermelon acreage. To help growers better manage this disease, a group of plant pathologists at North Carolina State University sought to better understand the biology of the pathogen that causes downy mildew.

They determined that the causal pathogen, Pseudoperonospora cubensis, has two genetically distinct host-adapted clades and also found that wild cucurbits can serve as reservoirs for this pathogen. Clade 1 isolates more frequently infect squash, pumpkin, and watermelon while clade 2 impacted cucumber and cantaloupe. They also found that evidence of recombination in clade 1 isolates but not clade 2 isolates.

"Overall, our findings have important implications for disease management because clade-specific factors such as host susceptibility and inoculum availability of each clade by region may influence pathogen outbreaks in different commercial cucurbits, timing of fungicide applications, and phenotyping for host resistance breeding efforts," explained lead author Emma Wallace.

"It was surprising to us to find two host-adapted clades with such distinct genetic differentiation and only one clade showing evidence of recombination. We were also surprised that wild cucurbits can become readily infected by one or both clades, especially since some of those wild cucurbits are widespread in the United States and some are perennial," added co-author Kimberly D'Arcangelo.

While previous research had shown evidence of two subpopulations within the pathogen, none were able to identify the main factors underlying those populations due to sampling limitations. Using a population genetics approach, Wallace and her colleagues applied a robust and standardized sampling strategy to investigate P. cubensis populations that infect wild cucurbit hosts.

"Our findings will have significant impacts on the adoption of crop-specific management practices," said corresponding author Lina Quesada. "Current disease management recommendations are provided under the assumption that P. cubensis isolates were somewhat uniform. However, this paper and related projects have revealed that the two clades can have important biological differences, such as host preference, that are relevant when thinking about how to manage disease."

Moving forward, plant pathologists will have to provide crop-specific recommendations as opposed to using the same approach for all cucurbit crops infected with downy mildew. For more information, read "Population Analyses Reveal Two Host-Adapted Clades of Pseudoperonospora cubensis, the Causal Agent of Cucurbit Downy Mildew, on Commercial and Wild Cucurbits" published in the September issue of Phytopathology.

Four in 10 people with advanced multiple sclerosis, or MS, are emotionally abused by someone responsible for caring for them, reports a study led by the University of California, Riverside.

Further, the study finds one quarter are financially exploited, one in six are neglected, one in nine are battered, and one in 12 are sexually assaulted by a caregiver.

"We knew we would find some level of abuse and neglect, but we were surprised by how prevalent it is," said Dr. Elizabeth Morrison-Banks, a health sciences clinical professor at the UC Riverside School of Medicine, who led the study. "The findings of this study represent a collective cry for help from so many families affected by multiple sclerosis across the United States."

MS is an autoimmune disease that affects more than 2.3 million people worldwide. This chronic, degenerative neurological condition periodically shutters communication between the brain and other parts of the body, resulting in symptoms that include numbness and tingling in the arms and legs, as well as blindness and paralysis.

"MS affects people in different ways," Morrison-Banks said. "Some people live with MS for many years but with milder symptoms, and they may remain completely self-sufficient and never require a caregiver. Others are less fortunate and develop neurological disability that can make them vulnerable to abuse and neglect if they are unable to move around independently, take care of their own finances, or get away from the situation when family conflict escalates. These problems are compounded if the person with MS and family lack financial resources."

Morrison-Banks explained that for families who are struggling economically, relying on a paid caregiver is often not an option, and family caregivers have to step in to fill the breach.

"Some family caregivers are also working full time, caring for children or other family members, and sometimes dealing with health issues of their own," she said. "All of these challenges can increase risk of mistreatment. I want to emphasize that the majority of family caregivers do not mistreat those they care for, even in situations that can be very challenging. Nonetheless, it is important to recognize the risk factors for mistreatment of people with disabilities, and do what we can to identify, mitigate, and prevent abuse and neglect."

Study results appear in Multiple Sclerosis and Related Disorders. According to Morrison-Banks and her colleagues, the research paper is the first published survey documenting the nature and extent of caregiver mistreatment of adults with MS in the United States. The research team collaborated with the North American Research Committee on Multiple Sclerosis to conduct a telephone survey of 206 American adults with advanced MS living across the United States.

The preliminary study found nearly 55% of respondents disclosed undergoing some form of mistreatment since they started receiving care from a family member or friend.

The researchers do not fully understand all the risk factors for mistreatment. Their anonymous telephone survey did find, however, that family members who had to be the primary caregiver every day, day in and day out, were at higher risk of mistreating the person with MS. Other risk factors included the person with MS having higher levels of cognitive impairment or fatigue, the caregiver having a mental health diagnosis, alcohol use by the caregiver or by the person with MS, and lower levels of social support within the family.

As a MS specialist at UCR Health, Morrison-Banks has worked for years with many families affected by MS.

"Being a full-time family caregiver for someone with substantial neurological disability often presents significant challenges," she said. "Many families take these challenges in stride, but others end up in situations of abuse and/or neglect."

The researchers were surprised to find no published studies documenting how many people with MS have experienced mistreatment.

"We all felt it was important to study this topic in order to help families dealing with advanced MS," Morrison-Banks said, adding the first step toward addressing the problem is to recognize that people with MS are at high risk of mistreatment.

Community service organizations such as the National Multiple Sclerosis Society, the Multiple Sclerosis Association of America, and in Riverside County a local organization called Act for MS provide support and services for families in need.

"Our study is a good reminder for all that mistreatment is occurring out there for people with MS and other disabling conditions," Morrison-Banks said. "Health care professionals should maintain a high index of suspicion. We can't assume that all people with advanced MS are living in safe situations, even if they don't bring up their concerns on their own."

The study did not include paid caregivers or trained clinicians. A study of paid caregivers is an important next step for the researchers, requiring different methods for data collection. Morrison-Banks's team would study mistreatment involving paid caregivers, including those working in nursing facilities and other institutions. Another important area for future research for the team is to study the effectiveness of interventions to detect and prevent abuse and neglect of people living with advanced multiple sclerosis.

NEW YORK, NY (Oct. 27, 2020)--Coronaviruses are adept at imitating human immune proteins that have been implicated in severe COVID-19 disease, a study from researchers at Columbia University Vagelos College of Physicians and Surgeons has found.

The study was published online ahead of print in Cell Systems.

Many plants and animals use the art of mimicry to trick their prey or predators. Viruses employ a similar strategy: Viral proteins can mimic the three-dimensional shapes of their host's proteins to trick the host into helping the virus complete its life cycle.

"Viruses use mimicry for the same reason as plants and animals--deception," says Sagi Shapira, PhD, assistant professor of systems biology at Columbia University Vagelos College of Physicians and Surgeons. "We hypothesized that identifying viral-protein look-alikes would give us clues to the way viruses--including SARS-CoV-2--cause disease."

Coronaviruses Are Masters of Mimicry

In the study, Shapira used supercomputers to search for viral mimics with a program similar to 3D facial recognition software. They scanned more than 7,000 viruses and over 4,000 hosts across Earth's ecosystems and uncovered 6 million instances of viral mimicry.

"Mimicry is a more pervasive strategy among viruses than we ever imagined," Shapira says. "It's used by all kinds of viruses, regardless of the size of the viral genome, how the virus replicates, or whether the virus infects bacteria, plants, insects or people."

But some types of viruses used mimicry more than others. Papilloma and retroviruses, not so much. Coronaviruses, on the other hand, are particularly good at it and were found to mimic over 150 proteins, including many that control blood coagulation or activate complement--a set of immune proteins that help target pathogens for destruction and increase inflammation in the body.

"We thought that by mimicking the body's immune complement and coagulation proteins, coronaviruses may drive these systems into a hyperactive state and cause the pathology we see in infected patients," Shapira says.

Human Studies Support Role of Viral Mimics in COVID

Over the course of the pandemic, it has become clear that many COVID patients have coagulation problems and some are now treated with anti-coagulants and drugs that limit complement activation.

In a separate paper published in Nature Medicine, the Columbia researchers found evidence that functional and genetic dysregulation in immune complement and coagulation proteins are associated with severe COVID-19 disease. They found that people with macular degeneration (which is associated with enhanced complement activation) were more likely to die from COVID-19, that complement and coagulation genes are more active in COVID-19 patients, and that people with certain mutations in complement and coagulation genes are more likely to be hospitalized for COVID-19.

Since that paper first appeared this spring in a preprint, other researchers have also found links between complement and COVID severity and several clinical trials of complement inhibitors have been initiated.

Shapira says the investigation of viral protein functions and mimicry suggests that learning about underlying virus biology could be one way to gain insights into how viruses cause disease and who may be at greatest risk.

"Viruses have already figured out how to exploit their hosts," Shapira says. "By studying viruses we can not only reveal fundamental principles in biology but also how they perturb cellular homeostasis and cause pathology. The hope is that one day we may be able to use this knowledge to fight back.

"Beyond COVID-19, the information we're gathering about how individual viral proteins work--across all viruses on Earth--may one day be leveraged as building blocks in medical and agricultural interventions."

WASHINGTON--Over 80 percent of 200 COVID-19 patients in a hospital in Spain have vitamin D deficiency, according to a new study published in the Endocrine Society's Journal of Clinical Endocrinology & Metabolism.

Vitamin D is a hormone the kidneys produce that controls blood calcium concentration and impacts the immune system. Vitamin D deficiency has been linked to a variety of health concerns, although research is still underway into why the hormone impacts other systems of the body. Many studies point to the beneficial effect of vitamin D on the immune system, especially regarding protection against infections.

"One approach is to identify and treat vitamin D deficiency, especially in high-risk individuals such as the elderly, patients with comorbidities, and nursing home residents, who are the main target population for the COVID-19," said study co-author José L. Hernández, Ph.D., of the University of Cantabria in Santander, Spain. "Vitamin D treatment should be recommended in COVID-19 patients with low levels of vitamin D circulating in the blood since this approach might have beneficial effects in both the musculoskeletal and the immune system."

The researchers found 80 percent of 216 COVID-19 patients at the Hospital Universitario Marqués de Valdecilla had vitamin D deficiency, and men had lower vitamin D levels than women. COVID-19 patients with lower vitamin D levels also had raised serum levels of inflammatory markers such as ferritin and D-dimer.

A new tool for analyzing tissue damage seen on MRI brain scans can detect with more than 70 percent accuracy early signs of cognitive decline, new research shows.

The findings by imaging specialists at NYU Grossman School of Medicine center on small bright spots on scans called white matter hyperintensities. Increased numbers and size of the intense-white spots seen on the mostly gray images of the brain have long been linked to memory loss and emotional problems, especially as people age.

More spots on MRI and their occurrence in the center of the brain have also been shown to correlate with the worsening of dementia and other brain-damaging conditions, such as stroke and depression, say the study authors. The spots represent fluid-filled holes in the brain, lesions that are believed to develop from the breakdown of blood vessels that nourish nerve cells.

Current methods for grading white matter lesions rely on little more than the "trained eye," researchers say, using an imprecise three-point scale, with a score of 1 meaning minimal white spots, while grades of 2 or 3 suggest more significant disease. The new tool was developed, researchers say, in an effort to provide a uniform, objective method for calculating the spots' volume and location in the brain.

In the new study, publishing in the journal Academic Radiology online Oct. 27, the NYU Langone team randomly selected 72 MRI scans from a national database of elderly people, the Alzheimer's Disease Neuroimaging Initiative. Equal numbers were from elderly men and women, mostly white and over age 70, with normal brain function, or showing some mild cognitive decline, or suffering from severe dementia.

Using the latest MRI techniques for accurate mapping of the brain's surface, the team then used computer software to calculate the precise position and volume measurements for all observed white matter lesions. Specifically, they tabulated volumes, which are three-dimensional measurements in liters, based on each lesion's distance from both side surfaces of the brain, with normal ranges between 0 milliliters (no lesions seen) and 60 milliliters (some lesions). Volumes greater than 100 milliliters indicated severe disease. When researchers cross-checked their measurements, they found that seven out of 10 calculations correctly matched the patient's actual diagnosis.

"Amounts of white matter lesions above the normal range should serve as an early warning sign for patients and physicians," says study lead researcher Jingyun "Josh" Chen, PhD, a research assistant professor in the Department of Neurology at NYU Langone Health.

Chen cautions that the white matter brain measures alone are not sufficient to certify a finding of early dementia, but should be considered along with other factors, including a history of brain injury, memory loss, and hypertension, as clear features of cognitive decline and/or other brain and blood vessel diseases.

"Our new calculator for properly sizing white matter hyperintensities, which we call bilateral distancing, offers radiologists and other clinicians an additional standardized test for assessing these lesions in the brain, well before severe dementia or stroke damage," says study senior investigator Yulin Ge, MD, a professor in the Department of Radiology at NYU Langone.

With a standardized tracking and measuring tool, says Chen, it is now possible to monitor the growth of white matter lesions relative to that of other tau and beta-amyloid proteins also believed to be potential causes of dementia and Alzheimer's disease. The buildup of either substance could also prove or disprove one or more of the theories about what biological processes actually lead to various forms of dementia.

Chen says the team plans to broaden and test their measuring tool on an additional 1,495 brain scans to include a more diverse group from the same database.

Physicians can access the tool, which is available without cost online at github.com/jingyunc/wmhs.

A new paper in Behavioral Ecology, published by Oxford University Press, finds that wild vampire bats that are sick spend less time near others from their community, which slows how quickly a disease will spread. The research team had previously seen this behavior in the lab, and used a field experiment to confirm it in the wild.

As a pathogen spreads across a population, changes in social behavior can alter how the disease spreads. Transmission rates can increase when parasites change host behavior or decrease when healthy individuals avoid sick ones. In certain social insects, sick ones might self-isolate voluntarily or be excluded by their colony mates. A simpler mechanism causing reduced transmission is that infected animals often show sickness behavior, which includes increased lethargy and sleep, and reduced movement and sociality. This sickness-induced social distancing does not require cooperation from others and is probably common across species.

Researchers here conducted a field experiment to investigate how sickness behavior affects relationships over time using a dynamic social network created from high-resolution proximity data. After capturing 31 adult female vampire bats from a roost inside a hollow tree at Lamanai, Belize, researchers simulated "sick" bats by injecting a random half of bats with the immune-challenging substance, lipopolysaccharide, while the control group received saline injections.

Over the next three days, the researchers glued proximity sensors to the bats, released them back into their hollow tree, and tracked changes over time in the associations among all 16 "sick" bats and 15 control bats under natural conditions.

Compared to control bats, "sick" bats associated with fewer groupmates, spent less time with others, and were less socially connected to healthy groupmates when considering both direct and indirect connections. During the six hours of the treatment period, a 'sick' bat associated on average with four fewer associates than a control bat. A control bat had, on average, a 49% chance of associating with each control bat, but only a 35% chance of associating with each "sick" bat. During the treatment period, "sick" bats spent 25 fewer minutes associating per partner. These differences declined after the treatment period and when the bats were sleeping or foraging outside the roost.

"The sensors gave us an amazing new window into how the social behavior of these bats changed from hour to hour and even minute to minute during the course of the day and night, even while they are hidden in the darkness of a hollow tree," said the study's lead author, Simon Ripperger. "We've gone from collecting data every day to every few seconds."

Cerebrospinal fluid as liquid biopsy for the precise characterization and policing of medulloblastoma

Results from a proof-of-concept study led by Joan Seoane show the promise of
cerebrospinal fluid as liquid biopsy for the more precise characterization and real time tracking of medulloblastoma.

Circulating tumor DNA from cerebrospinal fluid reveals genomic alterations during disease evolution -even prior to surgery- to more precisely guide treatment decision making.

Cerebrospinal fluid as liquid biopsy against medulloblastoma translates in less invasive sampling, better identification and characterization of disease relapse.

Building on previous research 1 - 3 led by Joan Seoane, Director of Translational Research at the Vall d'Hebron Institute of Oncology (VHIO) and ICREA Research Professor, latest findings from a proof-of-concept study published in Nature Communications, show that the analysis of cerebrospinal fluid (CSF) circulating tumor DNA (ctDNA), allows for the more precise characterization, molecular diagnosis (including subtyping and risk stratification), and real time tracking of medulloblastoma (MB) - the most prevalent malignant brain tumor in childhood.

Carried out in multidisciplinary collaboration across the Vall d'Hebron Barcelona Hospital Campus, results also evidence that this novel and less invasive approach can also provide precious insights into minimal residual disease, tumor evolution, and identify disease at relapse.

While the genomic characterization of medulloblastoma promises a more precise molecular diagnosis, accessing tumor tissue -due to the very nature of its location- is complex and can suppose high-risk surgical procedures and stereotactic biopsies, neither of which can guarantee access to a truly representative part of the tumor. The classification of this tumor type is also particularly challenging due to its ever changing intra-tumor heterogeneity which demands an in-depth and serial analysis of the evolving genomic landscapes in response to treatment or during disease recurrence. Establishing the molecular make-up of medulloblastoma is particularly critical since this tumor type is the most common of all paediatric brain cancers.

"Results from this present study represent a potentially practice-changing approach in more precisely steering the surgical and clinical management of these young patients. By evidencing the promise of cerebrospinal fluid as liquid biopsy for the personalized treatment of this extremely aggressive disease, our findings could ultimately spur the development of more effective and tailored therapeutic strategies. As importantly, they could also reduce excessive treatment to prevent long-term secondary effects," observes corresponding author Joan Seoane, who also leads VHIO's Gene Expression and Cancer Group.

"Medulloblastoma is highly a complex, heterogenous tumor type that evolves over time. Currently, acquiring further samples to monitor and track changes in the tumor to more precisely match the most effective therapy in real time represents a major challenge. By liquid biopsy of cerebrospinal fluid, we aim to respond to the critical need of rendering the molecular characterization and monitoring of this disease more precise," adds Laura Escudero, first author of the study and a Post-Doctoral Fellow of Joan's group at VHIO.

Hydrocephalus is an abnormal accumulation of cerebrospinal fluid and is very common in paediatric patients whose tumors are growing in the area of the posterior fossa, including medulloblastoma. In these cases, cerebrospinal fluid drainage must be performed prior to surgery to reduce increased intracranial pressure (ICP). Since the fluid is routinely collected for cytologic evaluation, this facilitates easy access to samples for research in the laboratory.

This latest research -supported through funding received from the Spanish Association against Cancer (AECC) and the Fero Foundation- demonstrates that the evaluation of cerebrospinal fluid can not only identify genomic alterations during tumor progression even before surgery, but also detect disease recurrence and track cancer progression to better inform treatment decision making in real time. Data derived from the liquid biopsy is therefore fundamental in disease prognosis as well as gauging tumor aggressiveness. This information is crucial for both the surgeon and the oncologist when balancing the risks and benefits of each intervention and therapeutic strategy.

The study investigators also show that CSF ctDNA facilitates the subgrouping and risk stratification of patients suffering from medulloblastoma, which provides valuable insights for the diagnosis and prognosis of disease towards more effectively matching therapies to the unique specificities of each individual patient. Specifically, certain genetic mutations are critical in treatment selection, such as mutations in the PTCH1 gene which encodes a protein called patched-1. In this case, inhibitors of the Hedgehog signaling pathway could be a more effective treatment option.

"Our research represents an important forward step towards better characterizing medulloblastoma, providing an earlier and more accurate molecular diagnosis, more closely monitoring our patients, and providing crucial data on minimal residual disease tumor evolution and disease at relapse. Larger cohort studies are now warranted to bring cerebrospinal fluid as liquid biopsy closer to the clinic and deliver on the promise of precision medicine for the treatment of this disease," concludes Joan Seoane.

A National Institutes of Health study of 5,000 women has found that approximately 1 in 4 experienced high levels of depressive symptoms at some point in the three years after giving birth. The rest of the women experienced low levels of depression throughout the three-year span. The study was conducted by researchers at NIH's Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD). It appears in the journal Pediatrics.

The American Academy of Pediatrics recommends that pediatricians screen mothers for postpartum depression at well-child visits at one, two, four and six months after childbirth. Researchers identified four trajectories of postpartum depressive symptoms and the factors that may increase a woman's risk for elevated symptoms. The findings suggest that extending screening for postpartum depressive symptoms for at least two years after childbirth may be beneficial, the authors write.

"Our study indicates that six months may not be long enough to gauge depressive symptoms," said Diane Putnick, Ph.D., the primary author and a staff scientist in the NICHD Epidemiology Branch. "These long-term data are key to improving our understanding of mom's mental health, which we know is critical to her child's well-being and development."

The researchers analyzed data from the Upstate KIDS study, which included babies born between 2008 and 2010 from 57 counties in New York State. The study followed 5,000 women for three years after their children were born.

Researchers assessed women's symptoms through a brief, five-item depression screening questionnaire, but the study did not clinically diagnose depression in the women. Women with underlying conditions, such as mood disorders and/or gestational diabetes, were more likely to have higher levels of depressive symptoms that persisted throughout the study period.

The researchers noted that the study participants were primarily white, non-Hispanic women. Future studies should include a more diverse, broad population to provide more inclusive data on postpartum depression, Dr. Putnick said.

Scientists from the iMolecule group at Skoltech Center for Computational and Data-Intensive Science and Engineering (CDISE) developed BiteNet, a machine learning (ML) algorithm that helps find drug binding sites, i.e. potential drug targets, in proteins. BiteNet can analyze 1,000 protein structures in 1.5 minutes and find optimal spots for drug molecules to attach. The research was published in the Communications Biology journal.

Proteins, the molecules that control most biological processes, are typically the common targets for drugs. To produce a therapeutic effect, drugs should attach to proteins at specific sites called binding sites. The protein's ability to bind to a drug is determined by the site's amino acid sequence and spatial structure. Binding sites are real "hot spots" in pharmacology. The more binding sites are known, the more opportunities there are for creating more effective and safer drugs.

Skoltech CDISE assistant professor Petr Popov and PhD student Igor Kozlovskii developed a new computational approach for spatio-temporal detection of binding sites in proteins by applying deep learning algorithms and computer vision to protein structures treated as 3D images. With this new technology, one can detect even elusive sites: for instance, scientists managed to detect binding sites concealed in experimental atomic structures or formed by several protein molecules for the ion channel, G protein-coupled receptor, and the epithelial growth factor, one of the most important drug targets.

Petr Popov, the study lead and assistant professor at Skoltech, comments: "The human genome consists of nearly 20,000 proteins, and very few among them get associated with a pharmacological target. Our approach allows searching the protein for binding sites for drug-like compounds, thus expanding the array of possible pharmacological targets. Besides, initial structure-based drug discovery strongly depends on the choice of the protein's atomic structure. Working on a structure with the binding site barred for the drug or missing altogether can fail. Our method enables analyzing a large number of structures in a protein and finding the most suitable one for a specific stage."

According to Igor Kozlovskii, the first author of the paper, BiteNet outperforms its counterparts both in speed and accuracy: "BiteNet is based on the computer vision, we treat protein structures as images, and binding sites as objects to detect on this images. It takes about 0.1 seconds to analyze one spatial structure and 1.5 minutes to evaluate 1,000 protein structures of about 2,000 atoms."

Okazaki, Japan - It is common that neurons transmit information to another group of neurons by increasing or decreasing their activity, i.e. "firing rate changes". In addition to firing rate changes, synchronized activity of a certain group of neurons, i.e. "correlated activity", has been suggested to play an important role in conveying information. This study revealed that, in the basal ganglia, information for the movement control is conveyed primarily by firing rate changes and correlated activity play only minor role in healthy conditions (Figure).

The research team consists of Dr. Woranan Wongmassang, Professor Atsushi Nambu, and their colleagues recorded neuronal activity of multiple neurons simultaneously in the basal ganglia while monkeys performed a motor task that required their arm movements. They found that most neurons located in the arm regions of the basal ganglia showed firing rate changes in relation to arm movements. On the other hand, the percentage of neurons that showed correlated activity during the task was very small.

Professor Nambu claims, "Unlike in healthy conditions, a large proportion of neurons in the basal ganglia show strong synchronized activity in Parkinson's disease. So, it is possible that symptoms could be improved by decreasing abnormally increased correlated activity in the basal ganglia. The findings provide important clues to develop effective treatment for Parkinson's disease."

Blue mussels in the Baltic Sea are getting smaller with time but bigger in numbers, according to a new study from Stockholm University. Analyzing data from the last 24 years, the main reason for this appears to be changes in food quality. The type of phytoplankton that is available for blue mussels to eat can in turn be linked to our changing climate.

Blue mussels in the Baltic Sea are already small in their nature - the length of the mussels is about the length of a nail to the mere eye. In this study, the researchers discovered that blue mussels are now weighing around half of what they used to weigh in the 90's, despite the mean length difference just being a few millimeters. But on the other hand there are now more mussels that are really tiny, sometimes as many as 1000 in one square meter compared to about 500 per square meter before.

Mussels compose the largest biomass of animals without a backbone in the Baltic, providing food to eider ducks and fish, for example. But because they are getting 'smaller' it means less food for the species feeding on them. It is also estimated that all blue mussels in the Baltic, together filter the entire waters of Baltic sea every year - and this is essential for cleaning the water from particles and helping to combat eutrophication - one of the Baltics biggest threats. Since the mussel size is affected it might therefore have effects on filtration rates, although this was not tested in this particular study:

"Even though an increase in the number of mussels to some extent may compensate for the smaller size, it is likely that important functions like filtration of the water has been reduced, which could lead to more turbid water" says Agnes Karlsson, Assistant Professor at Department of Ecology, Environment and Plant Sciences (DEEP) at Stockholm University.

The reason for the mussels getting smaller is likely altered mix of phytoplankton, now with greater quantities of cyanobacteria and particles from land. Warmer waters favour cyanobacteria, in turn causing increased summer blooms. Yet, the study found no direct role of increasing temperature for the decrease in mussel size. This means that indirect effects of climate change might be more important for mussels. The study is based on continuously monitored and collected samples of both mussels and phytoplankton from 1993 to 2016:

"We want to call attention to the benefits of long-term monitoring. If not for monitoring, we wouldn't have known that this key species for the Baltic is on a slippery slope", says Agnes Karlsson, Assistant Professor at Department of Ecology, Environment and Plant Sciences (DEEP) at Stockholm University.

The study highlights the importance of keeping an eagle eye perspective when considering how environmental changes affect key-organism in the long-run:

"There is often multiple and interacting factors responsible for changes in an organisms' condition or population and all of this likely affects the entire ecosystem functioning" says Camilla Liénart, postdoc at Department of Ecology, Environment and Plant Sciences (DEEP) at Stockholm University.