Culture

A new study suggests that differences in the expression of gene transcripts - readouts copied from DNA that help maintain and build our cells - may hold the key to understanding how mental disorders with shared genetic risk factors result in different patterns of onset, symptoms, course of illness, and treatment responses. Findings from the study, conducted by researchers at the National Institute of Mental Health (NIMH), part of the National Institutes of Health, appear in the journal Neuropsychopharmacology.

"Major mental disorders, such as schizophrenia, bipolar disorder, and major depressive disorder, share common genetic roots, but each disorder presents differently in each individual," said Francis J. McMahon, M.D., a senior author of the study and chief of the Human Genetics Branch, part of the Intramural Research Program NIMH. "We wanted to investigate why disorders present differently, despite this seeming genetic similarity."

McMahon and colleagues suspected that the brain's transcriptome may hold some clues. The human genome is made up of DNA that contains instructions for helping maintain and build our cells. These instructions must be read and then copied into so-called "transcripts" for them to be carried out. Importantly, many different transcripts can be copied from a single gene, yielding a variety of proteins and other outputs. The transcriptome is the full set of transcripts found within the body.

The researchers used postmortem tissue samples to examine the brain transcriptomes of 200 people who had been diagnosed with either schizophrenia, bipolar disorder, major depressive disorder, or who did not have a known mental illness. The researchers examined both genes and transcripts expressed in the subgenual anterior cingulate cortex, a brain site involved in mood disorders, reward, impulse control, and emotion regulation. The brain tissue samples came from the NIMH Human Brain Collection Core, curated by NIMH's Barbara Lipska, Ph.D., co-senior author of the paper.

To increase the odds of detecting rare transcripts, the researchers sequenced the transcripts at a resolution about four times greater than that used in previous studies. This technique identified 1.5 times more transcripts than earlier studies using the same method at lower resolution, confirming that this sequencing method picks up many transcripts that otherwise would have been missed.

The researchers found only modest differences in gene expression between individuals with a mental disorder and individuals without a mental disorder. However, when they focused on the transcripts, they found two to three times as many differences between individuals in the two groups. The most noticeable differences emerged when the researchers compared transcripts between two groups of individuals with a mental disorder - e.g., bipolar disorder versus schizophrenia, depression versus schizophrenia, or depression versus bipolar disorder.

"When we compared disorders in our transcript-level analyses, that is when we saw the stark differences," said Dr. McMahon. "Most transcripts that were expressed differently - produced in higher versus lower levels - turned out to be expressed in opposite directions in people with different disorders. Some transcripts were expressed in the same direction in individuals with mood disorders and the opposite direction in individuals with schizophrenia."

For example, distinct transcripts in the gene, SMARCA2, a known risk gene for autism spectrum disorder that regulates the expression of many other genes important in neuronal development, were expressed differently in brain samples from people with schizophrenia than in samples from people with bipolar disorder.

Parts of a gene's instructions may be kept in or left out during the transcription process. The researchers found that a common genetic variant that regulates this inclusion and exclusion, called splicing quantitative trait loci (sQTLs), may play a notable role in the inherited risk for each disorder.

"We found that subtle differences in gene expression across different disorders reflect more pronounced and diagnosis-specific changes at the level of transcripts," said McMahon. "A cell can express many different transcripts from the same gene, resulting in different proteins - and potentially different illness processes."

More research is needed to better understand the functions of different transcripts, the timing of alternative splicing, and the transcriptomic differences in specific brain regions and cell types. However, the current study sheds light on the importance of understanding transcript-level differences to get a full picture of why mental disorders vary in onset, progression, and symptoms.

PHILADELPHIA (February 8, 2021) - An abundance of data underscore the importance of breastfeeding and human milk for the optimal health of infants, children, mothers, and society. But while breastfeeding initiation rates have increased to more than 80% in the U.S., a disparity exists for African American mothers and infants. In this group, breastfeeding is initiated only about 69% of the time.

A new study to help identify the best strategies and practices to improve breastfeeding in the African American community leverages the opinions, knowledge, and experiences of subject matter exerts (SMEs) with national and international exposure to policies and practices influencing African American breastfeeding initiation rates. The insight from the SMEs was compared to focus group data with African American mothers who identified facilitators and barriers of breastfeeding initiation.

The comparison highlighted fundamental issues related to breastfeeding disparities, including the continued presence of stereotyping, disparities in approaches to care based on culture, and lack of access/ resources in specific communities and locations. Results of the study have been published in The Journal of Perinatal & Neonatal Nursing.

"This study reinforces the premise of the social ecological model, supporting the realization that the decision to initiate breastfeeding by African American mothers is not solely determined by the individual, but is contingent on multiple levels and factors external to the individual," says Diane Spatz, PhD, RN-BC, FAAN, Professor of Perinatal Nursing and Helen M. Shearer Term Professor of Nutrition at the University of Pennsylvania School of Nursing (Penn Nursing). "Consistent, comprehensive, and culturally relevant care practice for African American mothers by all providers that span antepartum to intrapartum to postpartum are critical."

Oakland, Calif. -- An analysis of Kaiser Permanente members in Northern California early in the COVID-19 pandemic found racial and ethnic disparities in the likelihood of testing positive for the coronavirus, but no significant disparities in mortality among those who were hospitalized.

According to the study published Feb. 8 in Annals of Internal Medicine, Latino patients were nearly 4 times as likely as white patients to become infected with the virus, while Asian and Black patients were 2 times as likely to get COVID-19 as white patients. The odds of hospitalization were also higher for Latino, Asian, and Black patients with COVID-19 than for white patients. However, the study did not find racial disparities in mortality among patients hospitalized after infection.

The authors of the study said the findings reinforce the urgent message to health systems to mitigate the spread of COVID-19 in their highest-risk communities by seeking to reduce transmission among the most vulnerable.

"We need to continue to explore the reasons why some communities have higher infection rates, which in a pandemic can be deadly," said lead author Gabriel Escobar, MD, an investigator with the Kaiser Permanente Northern California Division of Research. "It's also our responsibility as clinicians and health care leaders to improve the way we reach out to these communities."

While research from other health systems has also found racial disparities related to COVID-19, this analysis was the first to follow a cohort of patients from virus testing through the complete course of the disease, the authors said.

"COVID-19 has dramatically altered the patterns of health care delivery across the world making it more difficult than ever to trace patients' experiences and outcomes," said coauthor Vincent Liu, MD, MS, a research scientist with the Northern California Division of Research and critical care specialist with The Permanente Medical Group. "Kaiser Permanente's comprehensive health data from testing to medical care and hospitalization allow us to carefully assess the impact of racial and ethnic differences at each stage."

The study examined a total of 3.5 million Kaiser Permanente members in Northern California, 2.6% of whom, or 91,212 people, received a COVID-19 test between Feb. 1 and May 31, 2020. Of the total, 4%, or 3,686, tested positive.

The study confirmed other research linking specific comorbidities with increased mortality from COVID-19, and that nonwhite patients were more likely to have chronic health conditions. However, the authors noted that there are complex reasons why that might be. "Many factors may contribute to comorbidity and intrinsic risk, including the totality of ways in which societies foster racial discrimination, through mutually reinforcing inequitable systems (structural racism)," they wrote.

Unadjusted hospital mortality rates were highest among white patients (17%), followed by Black patients (12.7%), Asian patients (10.5%), and Hispanic patients (9.7%). After adjusting for age, severity of illness, and comorbidities, racial and ethnic differences were no longer significantly different.

Neighborhood and age as risk factors

Along with following the outcomes for those who tested positive, the analysis also looked at the role of geographic location, finding infections clustered in areas with higher proportions of nonwhite members, regardless of their health risks for COVID-19.

The researchers found race was a major factor in likelihood of infection, but contributed in a minor way to hospitalization, admission, and death. For those adverse outcomes, age was the major predictor.

The findings bring an important message to health care leaders, said coauthor Stephen Parodi, MD, associate executive director of The Permanente Medical Group and national infectious disease leader at Kaiser Permanente. "Health care systems are in a position to take action in their communities in response to these inequities," Dr. Parodi said. "Specifically, we must continue to pursue initiatives such as community education, contact tracing, and public health partnerships. We are deepening community connections to address social determinants in response to an unprecedented health threat that is taking an unequal toll."

Clinicians also have a role in reducing inequities, and Kaiser Permanente has taken steps to support clinicians in doing so, said coauthor Yi-Fen "Irene" Chen, MD, associate executive director of The Permanente Medical Group. "The pandemic has moved many medical visits to telehealth, which has many benefits, but we must remain aware of the digital divide that could make this technology harder to access in some traditionally underrepresented communities," Dr. Chen said. "Addressing such issues is part of Kaiser Permanente's longstanding commitment to health equity."

Dr. Chen noted the importance of addressing equity in vaccination. "Now that COVID-19 vaccines are available, physicians and health care providers must employ culturally tailored messaging for communities that experience health disparities, to make sure they are optimally informed and protected," she said.

It's well understood that a difficult childhood can increase the likelihood of mental illness, but according to new research from the University of South Australia, a happy and secure childhood does not always protect a child from developing a mental illness later in life.

Conducted in partnership with the University of Canberra, the finding is part of a study published in Current Psychology, which examined how early childhood experiences relate to different developmental pathways, and how these might be associated with poor mental health.

Given that both positive and negative childhood experiences were found to manifest as anxiety or other mental health disorders into adulthood, researchers believe that it's our ability to adapt - or rather not adapt - to unexpected scenarios that might be influencing mental health.

In Australia, almost 50 per cent of the population will experience mental illness at some point in their lives, with an estimated 314,000 children aged 4-11 (almost 14 per cent) experiencing a mental disorder.

The national recurrent expenditure on mental health-related services is estimated at $9.9 billion or about $400 per person.

While the study reaffirmed that people who had adverse and unpredictable early life experiences had elevated symptoms of poor mental health (including depression and paranoia), it also found that children who grew up in stable and supportive environments were also at risk of experiencing symptoms of anxiety in adulthood.

Lead researcher, and PhD candidate, UniSA's Bianca Kahl, says the study highlights the indiscriminate nature of mental illness and reveals key insights about potential risk factors for all children.

"As the prevalence of mental health conditions expands, it's imperative that we also extend our knowledge of this very complex and varied condition," Kahl says.

"This research shows that mental health conditions are not solely determined by early life events, and that a child who is raised in a happy home, could still grow up to have a mental health disorder.

"There's certainly some missing factors in understanding how our childhood environment and early life experiences might translate into mental health outcomes in adulthood.

"We suspect that it's our expectations about our environments and our ability to adapt to scenarios when our expectations are not being met, that may be influencing our experiences of distress.

"If, as children, we learn how to adapt to change, and we learn how to cope when things do not go our way, we may be in a better position to respond to stress and other risk factors for poor mental health.

"Testing this hypothesis is the focus of the next research study."

Global greenhouse gas emissions over the last century have made southern China a hotspot for bat-borne coronaviruses, by driving growth of forest habitat favoured by bats.

A new study published today in the journal Science of the Total Environment provides the first evidence of a mechanism by which climate change could have played a direct role in the emergence of SARS-CoV-2, the virus that caused the COVID-19 pandemic.

The study has revealed large-scale changes in the type of vegetation in the southern Chinese Yunnan province, and adjacent regions in Myanmar and Laos, over the last century. Climatic changes including increases in temperature, sunlight, and atmospheric carbon dioxide - which affect the growth of plants and trees - have changed natural habitats from tropical shrubland to tropical savannah and deciduous woodland. This created a suitable environment for many bat species that predominantly live in forests.

The number of coronaviruses in an area is closely linked to the number of different bat species present. The study found that an additional 40 bat species have moved into the southern Chinese Yunnan province in the past century, harbouring around 100 more types of bat-borne coronavirus. This 'global hotspot' is the region where genetic data suggests SARS-CoV-2 may have arisen.

"Climate change over the last century has made the habitat in the southern Chinese Yunnan province suitable for more bat species," said Dr Robert Beyer, a researcher in the University of Cambridge's Department of Zoology and first author of the study, who has recently taken up a European research fellowship at the Potsdam Institute for Climate Impact Research, Germany.

He added: "Understanding how the global distribution of bat species has shifted as a result of climate change may be an important step in reconstructing the origin of the COVID-19 outbreak."

To get their results, the researchers created a map of the world's vegetation as it was a century ago, using records of temperature, precipitation, and cloud cover. Then they used information on the vegetation requirements of the world's bat species to work out the global distribution of each species in the early 1900s. Comparing this to current distributions allowed them to see how bat 'species richness', the number of different species, has changed across the globe over the last century due to climate change.

"As climate change altered habitats, species left some areas and moved into others - taking their viruses with them. This not only altered the regions where viruses are present, but most likely allowed for new interactions between animals and viruses, causing more harmful viruses to be transmitted or evolve," said Beyer.

The world's bat population carries around 3,000 different types of coronavirus, with each bat species harbouring an average of 2.7 coronaviruses - most without showing symptoms. An increase in the number of bat species in a particular region, driven by climate change, may increase the likelihood that a coronavirus harmful to humans is present, transmitted, or evolves there.

Most coronaviruses carried by bats cannot jump into humans. But several coronaviruses known to infect humans are very likely to have originated in bats, including three that can cause human fatalities: Middle East Respiratory Syndrome (MERS) CoV, and Severe Acute Respiratory Syndrome (SARS) CoV-1 and CoV-2.

The region identified by the study as a hotspot for a climate-driven increase in bat species richness is also home to pangolins, which are suggested to have acted as intermediate hosts to SARS-CoV-2. The virus is likely to have jumped from bats to these animals, which were then sold at a wildlife market in Wuhan - where the initial human outbreak occurred.

The researchers echo calls from previous studies that urge policy-makers to acknowledge the role of climate change in outbreaks of viral diseases, and to address climate change as part of COVID-19 economic recovery programmes.

"The COVID-19 pandemic has caused tremendous social and economic damage. Governments must seize the opportunity to reduce health risks from infectious diseases by taking decisive action to mitigate climate change," said Professor Andrea Manica in the University of Cambridge's Department of Zoology, who was involved in the study.

"The fact that climate change can accelerate the transmission of wildlife pathogens to humans should be an urgent wake-up call to reduce global emissions," added Professor Camilo Mora at the University of Hawai'i at Manoa, who initiated the project.

The researchers emphasised the need to limit the expansion of urban areas, farmland, and hunting grounds into natural habitat to reduce contact between humans and disease-carrying animals.

The study showed that over the last century, climate change has also driven increases in the number of bat species in regions around Central Africa, and scattered patches in Central and South America.

Neanderthals' gut microbiota already included some beneficial micro-organisms that are also found in our own intestine. An international research group led by the University of Bologna achieved this result by extracting and analysing ancient DNA from 50,000-year-old faecal sediments sampled at the archaeological site of El Salt, near Alicante (Spain).

Published in Communication Biology, their paper puts forward the hypothesis of the existence of ancestral components of human microbiota that have been living in the human gastrointestinal tract since before the separation between the Homo Sapiens and Neanderthals that occurred more than 700,000 years ago.

"These results allow us to understand which components of the human gut microbiota are essential for our health, as they are integral elements of our biology also from an evolutionary point of view" explains Marco Candela, the professor of the Department of Pharmacy and Biotechnology of the University of Bologna, who coordinated the study. "Nowadays there is a progressive reduction of our microbiota diversity due to the context of our modern life: this research group's findings could guide us in devising diet- and lifestyle-tailored solutions to counteract this phenomenon".

THE ISSUES OF THE "MODERN" MICROBIOTA

The gut microbiota is the collection of trillions of symbiont micro-organisms that populate our gastrointestinal tract. It represents an essential component of our biology and carries out important functions in our bodies, such as regulating our metabolism and immune system and protecting us from pathogenic micro-organisms.

Recent studies have shown how some features of modernity - such as the consumption of processed food, drug use, life in hyper-sanitized environments - lead to a critical reduction of biodiversity in the gut microbiota. This depletion is mainly due to the loss of a set of microorganisms referred to as "old friends".

"The process of depletion of the gut microbiota in modern western urban populations could represent a significant wake-up call," says Simone Rampelli, who is a researcher at the University of Bologna and first author of the study. "This depletion process would become particularly alarming if it involved the loss of those microbiota components that are crucial to our physiology".

Indeed, there are some alarming signs. For example, in the West, we are witnessing a dramatic increase in cases of chronic inflammatory diseases, such as inflammatory bowel disease, metabolic syndrome, type 2 diabetes and colorectal cancer.

HOW THE "ANCIENT" MICROBIOTA CAN HELP

How can we identify the components of the gut microbiota that are more important for our health? And how can we protect them with targeted solutions? This was the starting point behind the idea of identifying the ancestral traits of our microbiota - i.e. the core of the human gut microbiota, which has remained consistent throughout our evolutionary history. Technology nowadays allows to successfully rise to this challenge thanks to a new scientific field, paleomicrobiology, which studies ancient microorganisms from archaeological remains through DNA sequencing.

The research group analysed ancient DNA samples collected in El Salt (Spain), a site where many Neanderthals lived. To be more precise, they analysed the ancient DNA extracted from 50,000 years old sedimentary faeces (the oldest sample of faecal material available to date). In this way, they managed to piece together the composition of the micro-organisms populating the intestine of Neanderthals. By comparing the composition of the Neanderthals' microbiota to ours, many similarities aroused.

"Through the analysis of ancient DNA, we were able to isolate a core of microorganisms shared with modern Homo sapiens", explains Silvia Turroni, researcher at the University of Bologna and first author of the study. "This finding allows us to state that these ancient micro-organisms populated the intestine of our species before the separation between Sapiens and Neanderthals, which occurred about 700,000 years ago".

SAFEGUARDING THE MICROBIOTA

These ancestral components of the human gut microbiota include many well-known bacteria (among which Blautia, Dorea, Roseburia, Ruminococcus and Faecalibacterium) that are fundamental to our health. Indeed, by producing short-chain fatty acids from dietary fibre, these bacteria regulate our metabolic and immune balance. There is also the Bifidobacterium: a microorganism playing a key role in regulating our immune defences, especially in early childhood. Finally, in the Neanderthal gut microbiota, researchers identified some of those "old friends". This confirms the researchers' hypotheses about the ancestral nature of these components and their recent depletion in the human gut microbiota due to our modern life context.

"In the current modernization scenario, in which there is a progressive reduction of microbiota diversity, this information could guide integrated diet- and lifestyle-tailored strategies to safeguard the micro-organisms that are fundamental to our health", concludes Candela. "To this end, promoting lifestyles that are sustainable for our gut microbiota is of the utmost importance, as it will help maintain the configurations that are compatible with our biology".

(Boston)--A new study recommends healthy children with symptoms of sleep disordered breathing, such as snoring or temporary cessation of breathing, should consider undergoing a sleep study (polysomnography) and should discuss the potential benefits of this with their pediatrician or otolaryngologist to possibly manage the child's symptoms medically and before surgery.

Sleep disordered breathing is common in children and ranges from mild snoring to severe sleep apnea. Doing a sleep study provides more information on the severity of the condition. Often doctors suggest adenotonsillectomy (removal of both the adenoids and tonsils) to improve the condition. There are conflicting guidelines on the potential benefit of sleep studies.

To determine the prevalence and characteristics of children with normal elective sleep studies for obstructive sleep disordered breathing, researchers performed a retrospective study on patients aged two to 18 who underwent diagnostic polysomnography for sleep disordered breathing between 2012 and 2018.

"We found that many children (44.7 percent) who would theoretically proceed to surgery without a preoperative sleep study if the guidelines were strictly followed, had normal sleep studies, potentially calling into question the need for surgery," explained corresponding author Michael Cohen, MD, assistant professor of otolaryngology-head & neck surgery at Boston University School of Medicine (BUSM).

They also found Caucasian children, children older than four years old, children without respiratory symptoms other than snoring and children with smaller tonsils, were more likely to have normal sleep studies.

According to coauthor Jessica Levi, MD, associate professor of otolaryngology and pediatrics at BUSM, this research demonstrates that obtaining sleep studies can affect management decisions on whether to proceed with an adenotonsillectomy, or medically manage the child's symptoms. "The potential delays in care and cost associated with obtaining polysomnography should be weighed against parental concerns and the possibility that the outcome could change management. These factors should be discussed with the family of each patient with a goal of shared decision-making," adds Levi, who is also director of pediatric otolaryngology at Boston Medical Center.

These findings appear online in the journal Annals of Otology, Rhinology & Laryngology.

Gene expression is a highly regulated process, which involves several steps. These include transcription of DNA instructions into RNA, removal of non-coding segments from the RNA message, and its subsequent translation into proteins. All these steps involve specific molecular machineries responsible for conducting each process with high accuracy. The Galej group, based at EMBL Grenoble, studies the structure and function of the RNA-protein complexes that are involved in the regulation of gene expression.

During transcription, genetic information contained in the DNA is used to create a precursor messenger RNA (pre-mRNA) thanks to the action of an enzyme, RNA Polymerase II. To maintain only the necessary coding segments required to produce a protein, short fragments of the pre-mRNA are kept and others are removed . This process is known as pre-mRNA splicing and is catalysed by a large and dynamic RNA-protein complex, the spliceosome. This is a key focus of study for the Galej group, for which they have recently received an ERC grant.

More than 100 proteins and five small nuclear RNAs (snRNAs) are involved in building the spliceosome complex and orchestrating pre-mRNA splicing. Before the snRNAs can be incorporated into the spliceosome, they need to undergo an endonucleolytic processing step (in other words, a process where an enzyme has to cut the RNA, also called 3'-end processing), which is catalysed by the Integrator complex. Discovered fifteen years ago, Integrator remained largely uncharacterised structurally, which triggered the Galej group's interest.

Unveiling the structure of key components and their interaction network

Until recently, the Integrator complex was thought to be involved mainly in the 3'-end processing of snRNAs, but studies in the past four years have begun to suggest that this might not be its major function. "We - and the scientific community - originally thought that the Integrator complex was specialised in cutting only one specific type of RNA, snRNA, but recently researchers started to realise that it is actually doing a lot more and influences thousands of RNAs from different classes. More and more evidence suggests that Integrator is one of the key players in global transcription regulation in higher eukaryotes," explains group leader Wojtek Galej.

Recent investigation has revealed that the Integrator complex is broadly involved in the transcription attenuation process, meaning that it can make sure some genes are not expressed. Playing such an essential role in the regulation of gene expression gives even more reason to have a closer look at its molecular structure.

To study the large and dynamic 14-subunit Integrator complex, the Galej group had to combine biochemistry, cell biology, and cryo-electron microscopy (cryo-EM) imaging to determine its architecture. "A very talented PhD student in the group, Moritz Pfleiderer, used cell biology and mass spectrometry methods to first dissect this big complex into smaller modules, which are easier to handle. It was a classic divide and conquer approach," says Galej. "Then Moritz obtained the structure of Integrator's catalytic core using single-particle cryo-EM". For data collection and structure determination of these subcomplexes, the group had access to cryo-EM platforms at EMBL Heidelberg and the local CM01 beamline at the ESRF, which is run with the involvement of EMBL scientists.

Cryo-EM data allowed the scientists to establish the structure and the specific arrangement of the proteins comprising Integrator's catalytic core - the part of the complex responsible for cutting the RNA during the primary transcription process. This discovery provides insights into the interfaces between these proteins, the mechanisms involved, and how they come together inside the cell.

The results, recently published in Molecular Cell alongside the structural analysis, highlight that this complex is composed of a network of multiple subunits interacting with one another. However, several subunits have been identified as stable modules, most tightly associated with each other. "If you try to break down this complex, it will be divided into three or four different pieces, which quite likely constitute its building blocks inside the cell," says Galej.

Leads for future investigation

With this new structure, the Galej group has come up with some new ideas about how RNA could be recognised by the Integrator complex. These are important insights, as they suggest how the substrate might be delivered to the enzyme's active site, where the reaction happens. Interestingly, Integrator has some similarities with other cellular machineries involved in the 3'-end processing of the messenger RNAs that encode proteins. However, the inner arrangement of the Integrator proteins is quite unique compared with the other 3'-end processing complexes, and some proteins are twisted in their positions. This peculiar architecture could have played an important role in the specialisation of this complex, which evolved to fulfil different functions.

Although the study provides the first insights into the architecture of Integrator's catalytic core, more investigations are needed to characterise additional parts of the complex and their involvement in gene expression. Ongoing studies in the Galej group should provide such insights, as well as unravelling the molecular basis of some of the genetic disorders associated with mutations in the components of the Integrator complex, which can result in neurodevelopmental disorders. These studies could facilitate drug design to target these mutations in the future.

The early prognosis of high-risk older adults for amnestic mild cognitive impairment (aMCI), using noninvasive and sensitive neuromarkers, is key for early prevention of Alzheimer's disease. A recent study, published in the Journal of Alzheimer's Disease, by researchers at the University of Kentucky establishes what they believe is a new way to predict the risk years before a clinical diagnosis. Their work shows that direct measures of brain signatures during mental activity are more sensitive and accurate predictors of memory decline than current standard behavioral testing.

"Many studies have measured electrophysiological rhythms during resting and sleep to predict Alzheimer's risk. This study demonstrates that better predictions of a person's cognitive risk can be made when the brain is challenged with a task. Additionally, we learned that out of thousands of possible brain oscillation measures, left-frontal brainwaves during so-called working memory tasks are good predictors for dementia risk," explained lead investigator Yang Jiang, associate professor of behavioral sciences and an affiliated faculty member at the Sanders-Brown Center on Aging.

When looking for a specific car in a large parking lot, older persons increasingly make more mistakes and take more time than young people due to brain and cognitive aging. Jiang says it has already been reported that brain waves associated with that type of daily memory task differ in cognitively normal older people and those of patients with memory loss and dementia. For this new study, researchers followed healthy older adults for 10 years. They reported that a specific pattern of frontal brainwaves during an everyday memory task predicts a person's risk of cognitive impairment roughly five years before clinical diagnosis. This pattern was not observed in older people who remained cognitively normal over the next 10 years.

Jiang says predicting and preventing cognitive decline is very important to allow preventive measures, such as life-style changes, and for researchers to help achieve a greater quality of life for the rapidly growing aging population. "Compared to current methods using neuroimaging as biomarkers, this method of measuring can be easily set up in clinics, is non-invasive, fast and affordable. Also, reliably predicting the risk of cognitive decline in an individual is new. Our older participants will soon be able to have better version of brainwave tests here at UK."

The clinical and translation work of this study was a team science effort with multiple investigators from UK's Sanders-Brown Center on Aging serving as coauthors including Erin Abner, Richard Kryscio, Greg Jicha, Fred Schmitt, Charles Smith, and collaborators from the Oak Ridge National Laboratory, University of Tennessee, and the Institute of Psychology, Beijing China.

This project was brought to SBCoA by scientists at the Oak Ridge National Laboratory co-author Nancy Munro to David Wekstein and Drs. William Markesbery and Charles Smith nearly 15 years ago with funding from the Department of Energy. The research team received funding from NIH in recent years to expand this work in large-scale and diverse populations. Jiang says their longitudinal study underscores the importance of having a successful Alzheimer's research center at UK.

Linda Van Eldik, director of the Sanders-Brown Center on Aging, said, "This further emphasizes the long-standing national and international reputation of UK's Sanders-Brown Center on Aging and the high quality of our investigators and the research they do."

USC researchers have developed a new method to counter emergent mutations of the coronavirus and hasten vaccine development to stop the pathogen responsible for killing thousands of people and ruining the economy.

Using artificial intelligence (AI), the research team at the USC Viterbi School of Engineering developed a method to speed the analysis of vaccines and zero in on the best potential preventive medical therapy.

The method is easily adaptable to analyze potential mutations of the virus, ensuring the best possible vaccines are quickly identified -- solutions that give humans a big advantage over the evolving contagion. Their machine-learning model can accomplish vaccine design cycles that once took months or years in a matter of seconds and minutes, the study says.

"This AI framework, applied to the specifics of this virus, can provide vaccine candidates within seconds and move them to clinical trials quickly to achieve preventive medical therapies without compromising safety," said Paul Bogdan, associate professor of electrical and computer engineering at USC Viterbi and corresponding author of the study. "Moreover, this can be adapted to help us stay ahead of the coronavirus as it mutates around the world."

The findings appear today in Nature Research's Scientific Reports

When applied to SARS-CoV-2 -- the virus that causes COVID-19 -- the computer model quickly eliminated 95% of the compounds that could've possibly treated the pathogen and pinpointed the best options, the study says.

The AI-assisted method predicted 26 potential vaccines that would work against the coronavirus. From those, the scientists identified the best 11 from which to construct a multi-epitope vaccine, which can attack the spike proteins that the coronavirus uses to bind and penetrate a host cell. Vaccines target the region -- or epitope -- of the contagion to disrupt the spike protein, neutralizing the ability of the virus to replicate.

Moreover, the engineers can construct a new multi-epitope vaccine for a new virus in less than a minute and validate its quality within an hour. By contrast, current processes to control the virus require growing the pathogen in the lab, deactivating it and injecting the virus that caused a disease. The process is time-consuming and takes more than one year; meanwhile, the disease spreads.

USC method could help counter COVID-19 mutations

The method is especially useful during this stage of the pandemic as the coronavirus begins to mutate in populations around the world. Some scientists are concerned that the mutations may minimize the effectiveness of vaccines by Pfizer and Moderna, which are now being distributed. Recent variants of the virus that have emerged in the United Kingdom, South Africa and Brazil seem to spread more easily, which scientists say will rapidly lead to many more cases, deaths and hospitalizations.

But Bogdan said that if SARS-CoV-2 becomes uncontrollable by current vaccines, or if new vaccines are needed to deal with other emerging viruses, then USC's AI-assisted method can be used to design other preventive mechanisms quickly.

For example, the study explains that the USC scientists used only one B-cell epitope and one T-cell epitope, whereas applying a bigger dataset and more possible combinations can develop a more comprehensive and quicker vaccine design tool. The study estimates the method can perform accurate predictions with over 700,000 different proteins in the dataset.

"The proposed vaccine design framework can tackle the three most frequently observed mutations and be extended to deal with other potentially unknown mutations," Bogdan said.

The raw data for the research comes from a giant bioinformatics database called the Immune Epitope Database (IEDB) in which scientists around the world have been compiling data about the coronavirus, among other diseases. IEDB contains over 600,000 known epitopes from some 3,600 different species, along with the Virus Pathogen Resource, a complementary repository of information about pathogenic viruses. The genome and spike protein sequence of SARS-CoV-2 comes from the National Center for Biotechnical Information.

COVID-19 has led to 87 million cases and more than 1.88 million deaths worldwide, including more than 400,000 fatalities in the United States. It has devastated the social, financial and political fabric of many countries.

The study authors are Bogdan, Zikun Yang and Shahin Nazarian of the Ming Hsieh Department of Electrical and Computer Engineering at USC Viterbi.

Support for the study comes from the National Science Foundation (NSF) under the Career Award (CPS/CNS-1453860) and NSF grants (CCF-1837131, MCB-1936775 and CNS-1932620); a U.S. Army Research Office grant (W911NF-17-1-0076); a Defense Advanced Research Projects Agency (DARPA) Young Faculty Award and Director Award grant (N66001-17-1-4044), and a Northrop Grumman grant.

The group led by Dr. Enrique J. Calderón - "Clinical Epidemiology and Vascular Risk" at the Institute of Biomedicine of Seville - IBiS/University Hospitals Virgen del Rocío and Macarena/CSIC/University of Seville, also a member of CIBERESP, participated in a project with researchers from CIBER-BBN, in which they developed systems to detect Pneumocystis jirovecii, an atypical fungus responsible for very severe pneumonia in immunosuppressed patients. The results have been published in the journals Nanomaterials and Journal of Fungi, and are the fruit of collaboration with the CIBER-BBN groups led by Dr. Laura Lechuga, Dr. Ramon Eritja and Dr. Ramón Martínez Máñez.

Currently, the detection of the fungus in patients, who may be asymptomatic carriers until they develop pneumonia, uses the PCR technique, which takes several hours and requires adequate facilities and qualified personnel. However, the application of nanotechnology now makes it possible to develop more sensitive and efficient biosensors to detect specific sequences corresponding to pathogens responsible for infectious diseases in a shorter time and without the need for major infrastructure.

In this case, a specific sequence that corresponds to the gene belonging to the ribosomal subunit (mtLSU rRNA) of the fungus P. jirovecii has been detected using fork-shaped capture probes. These specific probes, "are more efficient and capable of recognising a specific genomic sequence of the fungus and forming very stable triplex structures that can be detected in different biosensor platforms," as Dr. Avignon, a CIBER-BBN researcher at the IQAC-CSIC, points out.

Using an optical biosensor based on SPR technology, Dr. Laura Lechuga's team at ICN2 was able to detect, in real time and without the use of markers, P. jirovecii in bronchoalveolar lavages and nasopharyngeal aspirates with a limit detection at the nM level and all in a matter of minutes.

Likewise, the group headed by Dr. Ramón Martínez-Máñez, scientific director of CIBER-BBN and principal investigator of the IQMA-IDM group at the Universitat Politècnica de València, used the strategy of molecular gates composed of an anodic albumin matrix to develop a sensor capable of efficiently detecting real samples of P. jirovecii without prior amplification steps in just one hour.

"These advances in the diagnosis of PcP have great potential for the development of highly sensitive point-of-care devices using samples taken straight from patients and are applicable in a wide variety of settings," says Dr. Enrique J. Calderón, internist at the Virgen del Rocío University Hospital in Seville and senior lecturer in the Department of Medicine.

The researchers also emphasise that these techniques are very selective and can discriminate patients with other respiratory pathologies derived from other microorganisms, thus enabling a more reliable diagnosis of infectious diseases.

The spinal column consists of 24 vertebrae that provide axial support to the torso and protection to the spinal cord that runs through its central cavity. The vertebrae are connected by means of intervertebral discs. These discs are highly hydrated, flexible and highly mechanically resistant. They allow the column its flexibility and act as shock absorbers during daily activities such as walking, running and in impact situations, such as jumping.

These unique features are made possible by the discs' tissue composition and structure. At its centre, there is a gel-like substance called nucleus pulposus (NP). This is surrounded by a fibrocartilage, the annulus fibrosus (AF), that laterally confines NP and enables high fluid pressure within, thus stabilizing the disc mechanically, like an inflated tyre. Upwards and downwards of the NP, are thin layers of cartilage (cartilage endplates, CEP), which separate the NP and the inner part of the AF of the vertebral bone (Fig 1). These layers of cartilage regulate the exchange of water and important biomolecules between the vertebrae and the NP, thus contributing to both the mechanics and the functional biological regulation of the disc.

A recent study published in the journal Bioinformatics presents a model to study the intervertebral disc resorting to experimental knowledge, and for the first time, network modelling solutions in systems biology, to mimic the cellular behaviour of NP cells exposed to a 3D multifactorial biochemical environment. This research has been carried out by members of the BCN MedTech Research Unit, a centre attached to the UPF Department of Information and Communication Technologies (DTIC), with Laura Baumgartner, a UPF PhD student as first author of the article, under the guidance of Jérôme Noailly, co-author of the study.

In-silico modelling to study intervertebral disc degeneration

Intervertebral disc degeneration is defined by a progressive loss of water and structure, and consequently of functionality. It differs from the natural ageing of the disc by the early onset of its symptoms, which has serious effects on the workforce. It is a major risk factor for chronic lower back pain, which can in turn cause disability.

The progressive degradation of the disc consists of accumulations of microscopic lesions, most likely caused by a (prolonged) alteration of the activity of local cells, which are essential to preserve tissue integrity. The factors leading to the change in this cell activity are not fully known and seem to be caused by interactions of multiple mechanical and biochemical stimuli, which limits in vivo or in vitro exploration. This lack of knowledge means that treatments for debilitating lower back pain are not able to solve the root problem, and so focus mainly on pain control with highly variable and short-term effectiveness.

In-silico modelling is particularly attractive because it allows integrating the influence of different stimuli on cells of the nucleus pulposus exposed to a 3D multifactorial environment. It also offers the chance to test a large number of possible scenarios of degeneration that might explain the great variability of clinical cases, which would be impossible by performing experiments.

As Laura Baumgartner explains in greater detail, "The in-silico modelling used in this study was the agent-based model, simulating a volume of 1mm³ with 4000 cells of the nucleus pulposus as agents. Cellular activity in the nucleus pulposus was estimated through the expression of messenger RNA of various components of the tissue that may be affected in the event of intervertebral degeneration: central proteoglycan proteins that form aggrecan aggregates and type I, II and III collagen, and two proteases that degrade the tissue, the enzyme stromelysin-1 (MMP-3) and ADAMTS, with a particular affinity for aggrecans". The values were obtained for inflamed and non-inflamed cells. In addition, cell viability was estimated by means of different biochemical profiles. The regulation of this cellular activity will determine the evolution of the composition of the disc tissues and their ability to maintain their integrity, retain water and fully undertake their role.

This advanced modelling, the first results of which have been validated, offers for the first time the possibility of predicting risk factors such as metabolic problems that can affect the nutrition of the intervertebral disc cells, deregulation problems of the inflammatory system that can lead to its over-activity, or morphological or mechanical risk factors, among others.

The study spawns a new horizon in the exploration of the intervertebral disc and its translation to better managing a large number of back pain problems. This potential will be explored in great depth in the new European project Disc4All (H2020-MSCA-ITN-ETN-2020 GA: 955.735), coordinated by Jérôme Noailly, which began in late 2020 and in which 15 theses are to be conducted focusing on the integrated description of disc degeneration mechanisms and on the exploitation of these descriptions to stratify patients with the ultimate goal of finding new therapeutic targets.

Advancing the knowledge of intervertebral disc regeneration

A later work published in January this year by the same authors in the International Journal of Molecular Sciences with international participants, presents an extensive review of previous work on the pathophysiology and advanced strategies of intervertebral disc regeneration. It provides an integrating analysis of the current knowledge of the multiscale function and the regulation of the intervertebral disc in health and disease, the potential regenerative strategies, and in-silico models that might provide support for the development of advanced therapies.

What is common between a technology for storing energy in a solar cell and that for water purification? They both rely on the use of porous materials, or more specifically, "nanoporous" materials that can trap gas molecules within narrow spaces on their surface, called "pores", which are only nanometers (one-billionth of a meter) in size! In chemistry parlance, the phenomenon is known as "adsorption" and has played an important role in the synthesis of porous materials of different compositions, pore sizes, and even pore geometries.

Traditionally, activated carbon (AC, or a porous form of carbon) has been a popular adsorbent for practical applications owing to its higher capacity of adsorption than that of other porous materials. Lately, however, porous boron nitride (p-BN) has emerged as a promising alternative because of its impressive performance, as highlighted by a recent study claiming that p-BN can adsorb a relatively large amount of carbon dioxide at room temperature.

Now, a group of scientists from Okayama University and Nagasaki University, Japan, has put this claim to the test in their latest study, where they examined the adsorbing characteristics of p-BN in detail. "A BN unit and two carbon atoms (i.e., CC) both have the same number of electrons and similar structures, but their interaction with gas molecules are different due to the atomically heterogeneous nature of BN. Despite this, there has been very little research on BN materials. In our study, we wanted to see if BN has specific adsorption properties that cannot be observed in carbon materials," explains Dr. Takahiro Ohkubo from Okayama University, who led this study published in the journal RSC Advances.

To begin with, the scientists synthesized p-BN samples at high temperature conditions under presence of nitrogen and investigated their structure using X-ray diffraction, infrared (IR) spectra analysis, and high-resolution electron microscopy. The samples only differed from one another with respect to the temperatures at which they were synthesized. While X-ray diffraction data and IR revealed an "amorphous" phase (lacking well-defined structure) BN comprising "hexagonal phase" BN (h-BN) microcrystals for all samples, the one treated at 1673 K (1400°C), called p-BN-1673, showed the most ordered structure. After examining it under the electron microscope, the scientists found that this sample was composed of stacked layers of curved sheets with nanometer-size pores formed in between.

The scientists next looked at thermogravimetric curves of the samples to estimate their stability against oxidation and discovered that it was directly linked to the synthesis temperature, with higher temperatures entailing higher stability. Moreover, some additional species of carbon and oxygen were introduced into the h-BN crystal framework especially in p-BN-1473, giving rise to chemically active sites for nitrogen adsorption. While these species ordinarily reduce oxidation stability, the crystallinity of h-BN helped preserve it up to 973 K under normal conditions--a property not present in carbon-based adsorbents!

Finally, upon comparing the gas adsorption ability of p-BN and AC with nitrogen and argon as adsorbates, scientists observed that p-BN pores adsorbed nitrogen more strongly than argon and in relatively much larger amount (~ 150%-200%) than did AC. They attributed this observation to an additional physical interaction between nitrogen and p-BN pores that was absent for argon, and the creation of adsorption sites in p-BN by the impregnated carbon and oxygen species.

With these results, the Dr. Ohkubo and team are confident about the emergence of p-BN as a next-generation adsorbent material. "Given its superior oxidation stability and nature of adsorption, we are looking forward to the applications of porous BN as a novel adsorbent and catalyst support material, especially in cases where the use of carbon adsorbents is not feasible," comments Dr. Ohkubo.

Looks like carbon is about to go out of fashion on yet another front!

Treating severe COVID-19 patients with the anticancer drug bevacizumab may reduce mortality and speed up recovery, according to a small clinical study in Italy and China that was led by researchers at Karolinska Institutet in Sweden between February and April 2020. On average, blood oxygen levels, body temperature and inflammatory markers significantly improved in patients treated with a single dose of bevacizumab in addition to standard care. The research is published in Nature Communications.

"To reduce COVID-19 mortality, we aim to develop an effective therapeutic paradigm for treating patients with severe COVID-19," says corresponding author Yihai Cao, professor of vascular biology at the Department of Microbiology, Tumor and Cell Biology at Karolinska Institutet. "Our findings suggest that bevacizumab plus standard care is highly beneficial for patients with severe COVID-19 and should be considered as a potential first-line therapeutic regimen for this group."

Bevacizumab is a medication that has been used to treat various types of cancer since 2004. It works by slowing the formation of new blood vessels by inhibiting a growth factor known as VEGF. Many patients with severe COVID-19 have elevated levels of VEGF as well as symptoms associated with this marker, including excess fluid and disorganized blood vessels in the lungs. Against this background, the researchers designed a clinical trial to investigate the effect of combining bevacizumab with standard care for treating patients with severe COVID-19.

Twenty-six patients were recruited from two hospitals in China and Italy between mid-February and early April in 2020. The patients had confirmed COVID-19 and symptoms such as difficulty breathing, low blood oxygen levels and pneumonia. They were retrospectively matched with 26 patients of similar characteristics who received standard care at the same hospitals in roughly the same time period and thus served as the control group.

The recruits received standard care plus a single low dose of about 7.5 mg/kg bevacizumab, which markedly improved blood oxygen levels within 24 hours compared to the control group. By the end of the 28-day follow-up period, 92 percent of the bevacizumab-treated patients no longer needed the same level of oxygen support as before the trial began, compared with an improvement rate of 62 percent for the controls.

None of the bevacizumab-treated patients died and 17 (65 percent) improved so much that they were able to leave the hospital within the follow-up period. In the control group, three died and only 46 percent were discharged within 28 days. Bevacizumab also shortened the duration of oxygen-support to a median of nine days compared with 20 for the standard care group.

Other interesting findings include reduction in fever, an increase in white blood cells and a sharp decrease of c-reactive protein (CRP) levels, an inflammatory marker. No severe safety concerns were detected.

"Many patients with severe COVID-19 require significant oxygen support during long hospital stays, which pose global challenges to medical supplies," Yihai Cao says. "Our study shows that bevacizumab could help reduce the need for oxygen support and reduce days in hospital, thus improving the outcome for the individual patient while easing pressure on medical resources."

The limitations of the study include the non-randomized nature of the trial, the short-term follow-up and the small size of the cohort.

The next step will be to design randomized and placebo-controlled trials by recruiting a large number of patients, allowing further assessment of the potential benefits of bevacizumab both in and of itself and in combination with other therapies such as antivirals and anti-inflammatory drugs.

A research team led by Prof. HE Shunping from the Institute of Hydrobiology (IHB) of the Chinese Academy of Sciences has discovered through genome sequencing that the non-teleost ray-finned fishes--bichir, paddlefish, bowfin and alligator gar--exhibit mosaic genomic features of lobe- and ray-finned fishes. The study was published in Cell.

The water-to-land transition during the Devonian is one of the most prominent events in vertebrate evolution. During this transition, various organs underwent adaptive changes, particularly those related to locomotion and respiration systems.

Rich fossil evidence suggests that many traits and functions related to this terrestrial evolution were present long before the ancestor of lobe- and ray-finned fishes appeared. Therefore, investigation of the genomes of extant species from early divergent lineages of ray-finned fishes may illuminate the genetic regulatory processes underlying trait evolution during the terrestrial transition.

The researchers produced a chromosome level assembly of the bichir (Polypterus senegalus), and draft genome assemblies for the American paddlefish (Polyodon spathula), the bowfin (Amia calva) and the alligator gar (Atractosteus spatula), which are representative species for each lineage of non-teleost ray-finned fishes.

The appearance of derived supporting appendicular structures was involved in the evolution of terrestrial locomotion, one of the major transitions in vertebrate evolution. Through comparative genomic analyses, the researchers found that early divergent lineages of ray-finned fishes exhibit many mosaic genomic features of lobe- and ray-finned fishes, particularly relating to regulatory elements for limb development.

The researchers then characterized olfactory receptor (OR) genes. Olfaction is important for vertebrate survival. Vertebrate genomes contain numerous OR genes, predominantly expressed in the olfactory epithelium of the nasal cavity. They found that non-teleost actinopterygians have mosaic OR features with a mixture of both types of OR genes, in accordance with the air-breathing characteristics of some species in these lineages.

To understand the evolution of lungs and their relationship to the swim bladders of fish, the researchers sequenced transcriptomes from 355 samples representing 10 tissues of eight vertebrate species. They confirmed that the lung and swim bladder are homologous organs, and discovered that functional lung-related genes are present in early ray-finned fishes.

In order to test the hypothesis that dominance of the conus arteriosus was an ancestral characteristic of the vertebrate cardiac outflow tract, the researchers functionally validated the essential role of a highly conserved element for cardiovascular development from a jawed vertebrate. The results implied that the ancestors of jawed vertebrates already had the potential gene networks for a cardio-respiratory system that could support air breathing.

The findings of this study are of great importance to understanding the water-to-land transition during vertebrate evolution since they clarify the genetic basis for limb development and for the respiratory system.