Culture

International team of scientists discover link between genes and penicillin allergy using biobanks from Estonia, UK and USA

Penicillin, a life-saving medicine, is the most common cause of drug allergy, with clinical manifestations ranging from temporary skin reactions to life-threatening systemic syndromes. Thus far, genetic factors have only been found for rare severe allergic reactions to penicillin. However, less is known about the genetics behind milder forms of penicillin hypersensitivity reactions that occur in a larger proportion of the population.

A collaborative effort by scientists from the Estonian Genome Center, University of Tartu, Statens Serum Institut, University of Oxford, Vanderbilt University Medical Center, Harvard Medical School, Broad Institute of MIT and Harvard, and 23andMe sought to identify genetic risk factors underlying penicillin-induced hypersensitivity reactions by harnessing self-reported data and the electronic health records of more than 600,000 participants of European ancestry from the UK Biobank, Estonian Biobank and Vanderbilt University Medical Center's biobank (BioVU).

The genome-wide association study (GWAS) of self-reported penicillin allergy in the different biobanks revealed a locus located in the major histocompatibility complex (MHC) I gene HLA-B. Fine-mapping of the association narrowed the signal down to the HLA-B*55:01 allele, which was further confirmed by independent replication in 23andMe's research cohort. Overall, carriers of the allele were found to have a 33% higher relative odds of penicillin allergy. The study also detected a genome-wide significant missense variant in the PTPN22 gene. This variant has been associated with several autoimmune diseases and more recently with drug-induced liver injury.

Dr Kristi Krebs, first author of the study, said: "When examining other conditions associated with the HLA-B*55:01 allele, we found a significant association with lower white blood cell counts. Further, the top hit overlapped with regions found to have regulatory function in T-cells and correlated with the expression levels of PSORS1C3, which has previously been associated with hypersensitivity reactions to several medications. These findings together raise the possibility that the variant may predispose to a T-cell-mediated process leading to a delayed penicillin reaction."

Dr João Fadista, one of the lead authors of the paper, further shared that "a genome-wide genetic correlation analysis of the self-reported penicillin allergy results revealed overlap with the autoimmune diseases rheumatoid arthritis and psoriasis. This, together with the finding in the PTPN22 gene, indicates a possible underlying autoimmune factor in the development of penicillin allergy investigated in our study."

Prof. Lili Milani, one of the lead authors of the paper, emphasized the power of biobanks, "We have leveraged data from four large-scale cohorts, including more than 100,000 cases, to provide insights into the genetic architecture associated with self-reported penicillin allergy, and provide robust evidence implicating the HLA-B*55:01 allele and autoimmune factors in this condition. Further studies are necessary to determine the precise underlying immune processes and how these change over time, as several studies have reported that a large proportion of patients labelled as allergic to penicillin develop tolerance over time."

An infection with the coronavirus SARS-CoV-2 can affect multiple organs. With this in mind, researchers of the German Center for Neurodegenerative Diseases (DZNE) and Cornell University in the US have investigated cellular factors that could be significant for an infection. To this end, they analysed the activity of 28 specific genes in a wide range of human tissues. Their findings, which provide a map of potentially disease-relevant factors across the human body, are published in the journal Cell Reports.

"SARS-CoV-2 not just infects the respiratory system, it has the potential to affect many other organs in the body. Even if the virus infects the respiratory system first, it is essential to be able to predict where it might go next. This aids to develop therapies. Our goal was thus to learn more about what makes the different organs susceptible to infection," explained Dr. Vikas Bansal, a data scientist at the DZNE's Tuebingen site. "Therefore, we looked at different tissues to see which components of the cellular machinery might be relevant for infection and also which cell types appear to be particularly susceptible." Bansal co-authored the current paper with Manvendra Singh, a Cornell presidential fellow, and with Cedric Feschotte, professor in the Department of Molecular Biology and Genetics at the Cornell University.

Searching candidates

In cooperation with his US colleagues, Bansal started by identifying 28 human genes, respectively cellular factors, that enable the virus to enter human cells or that might otherwise be important for an infection. In addition to receptors on the cell surface, these included, for example, proteins that the pathogen presumably needs in order to multiply within a cell. Importantly, the list of studied factors also contains enzymes that block the penetration of pathogens into cells - known as "restrictors factors". In summary, the 28 analysed cellular features are dubbed "SCARFs" for "SARS-CoV-2 and coronavirus associated receptors and factors".

"The virus is known to misuse the so-called ACE2 receptor, which occurs on the surface of human cells, to dock and infiltrate them. A lot of attention is therefore paid to this receptor and other factors associated with it. They are potential starting points for therapies," said Bansal. However, related corona viruses are known to use a broad range of possibilities to infect cells. According to the researcher, evidence suggests that this also applies to SARS-CoV-2. "Therefore, we have extended our analysis to cellular factors that have been found to be relevant in other corona viruses and may therefore also be important for SARS-CoV-2."

Whether this is actually the case, future experiments will have to show, explained Bansal. For such investigations, he said, the aim was to identify promising candidates. "Our study is only a snapshot, however. Research is developing rapidly. We are constantly learning new facts about this virus."

Profiles of gene activity

Using information from scientific databases, the researchers analysed gene activity - also known as "expression patterns" - in around 400,000 human cells from various types of tissue. These included nasal mucosa, lungs, gut, kidneys, heart, brain and reproductive organs. Analysis was done on a single-cell level and using sophisticated bioinformatics methods. "This enabled us to investigate in which cells the SCARFs are expressed and also what percentage of cells within a given tissue express these factors," said Bansal. "Our results are certainly limited by the fact that expression patterns can change in the course of an infection and that such activity profiles do not directly reflect the abundance of proteins such as cell receptors. However, expression patterns are good indicators."

Battlegrounds and hotspots

In line with the known fact that SARS-CoV-2 attacks in particular the respiratory tract, the expression patterns identify the nasal mucosa as a "battleground". Accordingly, cells of the nasal mucosa contain both factors that facilitate infection like the ACE2 receptor as well as factors that inhibit viral entry, like IFITM3 and LY6E. "IFITM3 is a protein known to prevent other coronaviruses from crossing the cell membrane. Same might also apply to SARS-CoV-2. LY6E also acts as a defensive mechanism", said Bansal. "It thus seems that contact of the virus with the nasal mucosa leads to a tug-of-war. The question therefore is, who will emerge as the winner. Interestingly, our data suggest that the expression level of entry factors in the human nasal tissue shift with age. This could be a reason why the elderly are more susceptible to infection by SARS-CoV-2."

According to the current study, the intestine, kidneys, testes and placenta are potential hotspots, that is, these areas seem to be characterized by significant co-expression of ACE2 with TMPRSS2, an enzyme involved in viral entry in combination with ACE2. "We were also able to identify a number of cellular factors that, as alternatives to the ACE2 receptor, could contribute to SARS-CoV-2 entering the lungs, heart and central nervous system," said Bansal. "SARS-CoV-2 is by now known to be able to trigger neurological disorders. Although the virus has not yet been detected in neurons, the nervous system includes other cells such as astrocytes and pericytes that are for example involved in the regulation of the blood-brain barrier, which is the interface between the brain and the bloodstream. According to our study these cells might well be susceptible to infection. This could possibly involve a receptor called BSG. All in all, our study therefore provides a wealth of data and specific clues for future studies on the coronavirus."

Molecules are the building blocks of everyday life. Many materials are composed of them, a little like a LEGO model consists of a multitude of different bricks. But while individual LEGO bricks can be simply shifted or removed, this is not so easy in the nanoworld. Atoms and molecules behave in a completely different way to macroscopic objects and each brick requires its own "instruction manual". Scientists from Jülich and Berlin have now developed an artificial intelligence system that autonomously learns how to grip and move individual molecules using a scanning tunnelling microscope. The method, which has been published in Science Advances, is not only relevant for research but also for novel production technologies such as molecular 3D printing.

Rapid prototyping, the fast and cost-effective production of prototypes or models - better known as 3D printing - has long since established itself as an important tool for industry. "If this concept could be transferred to the nanoscale to allow individual molecules to be specifically put together or separated again just like LEGO bricks, the possibilities would be almost endless, given that there are around 1060 conceivable types of molecule," explains Dr. Christian Wagner, head of the ERC working group on molecular manipulation at Forschungszentrum Jülich.

There is one problem, however. Although the scanning tunnelling microscope is a useful tool for shifting individual molecules back and forth, a special custom "recipe" is always required in order to guide the tip of the microscope to arrange molecules spatially in a targeted manner. This recipe can neither be calculated, nor deduced by intuition - the mechanics on the nanoscale are simply too variable and complex. After all, the tip of the microscope is ultimately not a flexible gripper, but rather a rigid cone. The molecules merely adhere lightly to the microscope tip and can only be put in the right place through sophisticated movement patterns.

"To date, such targeted movement of molecules has only been possible by hand, through trial and error. But with the help of a self-learning, autonomous software control system, we have now succeeded for the first time in finding a solution for this diversity and variability on the nanoscale, and in automating this process," says a delighted Prof. Dr. Stefan Tautz, head of Jülich's Quantum Nanoscience institute.

The key to this development lies in so-called reinforcement learning, a special variant of machine learning. "We do not prescribe a solution pathway for the software agent, but rather reward success and penalize failure," explains Prof. Dr. Klaus-Robert Müller, head of the Machine Learning department at TU Berlin. The algorithm repeatedly tries to solve the task at hand and learns from its experiences. The general public first became aware of reinforcement learning a few years ago through AlphaGo Zero. This artificial intelligence system autonomously developed strategies for winning the highly complex game of Go without studying human players - and after just a few days, it was able to beat professional Go players.

"In our case, the agent was given the task of removing individual molecules from a layer in which they are held by a complex network of chemical bonds. To be precise, these were perylene molecules, such as those used in dyes and organic light-emitting diodes," explains Dr. Christian Wagner. The special challenge here is that the force required to move them must never exceed the strength of the bond with which the tip of the scanning tunnelling microscope attracts the molecule, since this bond would otherwise break. "The microscope tip therefore has to execute a special movement pattern, which we previously had to discover by hand, quite literally," Wagner adds. While the software agent initially performs completely random movement actions that break the bond between the tip of the microscope and the molecule, over time it develops rules as to which movement is the most promising for success in which situation and therefore gets better with each cycle.

However, the use of reinforcement learning in the nanoscopic range brings with it additional challenges. The metal atoms that make up the tip of the scanning tunnelling microscope can end up shifting slightly, which alters the bond strength to the molecule each time. "Every new attempt makes the risk of a change and thus the breakage of the bond between tip and molecule greater. The software agent is therefore forced to learn particularly quickly, since its experiences can become obsolete at any time," Prof. Dr. Stefan Tautz explains. "It's a little as if the road network, traffic laws, bodywork, and rules for operating the vehicle are constantly changing while driving autonomously." The researchers have overcome this challenge by making the software learn a simple model of the environment in which the manipulation takes place in parallel with the initial cycles. The agent then simultaneously trains both in reality and in its own model, which has the effect of significantly accelerating the learning process.

"This is the first time ever that we have succeeded in bringing together artificial intelligence and nanotechnology," emphasizes Klaus-Robert Müller. "Up until now, this has only been a 'proof of principle'," Tautz adds. "However, we are confident that our work will pave the way for the robot-assisted automated construction of functional supramolecular structures, such as molecular transistors, memory cells, or qubits - with a speed, precision, and reliability far in excess of what is currently possible."

A team led by researchers at the University of Toronto and The Hospital for Sick Children has found that mothers of preterm babies have highly individual breast milk microbiomes, and that even short courses of antibiotics have prolonged effects on the diversity and abundance of microbes in their milk.

The study is the largest to date of breast milk microbiota in mothers of preterm infants, and it is the first to show that antibiotic class, timing and duration of exposure have particular effects on the most common microbes in breast milk -- many of which have the potential to influence growth and immunity to disease in newborns.

"It came as quite a shock to us that even one day of antibiotics was associated with profound changes in the microbiota of breast milk", says Deborah O'Connor, who is a professor and chair of nutritional sciences at U of T and a senior associate scientist at SickKids. "I think the take-home is that while antibiotics are often an essential treatment for mothers of preterm infants, clinicians and patients should be judicious in their use."

Most antibiotic stewardship programs in neonatal intensive care focus on limiting use in newborns themselves. The current study adds to growing evidence that these programs should include a focus on mothers as well, says O'Connor, principal investigator on the study who is also a scientist in the Joannah & Brian Lawson Centre for Child Nutrition.

The journal Cell Host and Microbe published the study today.

The researchers looked at 490 breast milk samples from 86 mothers whose infants were born preterm, during the first eight weeks after delivery. They found that the mothers' body mass index and mode of delivery influenced the breast milk microbiota, consistent with some other studies.

But the effects of antibiotics were the most pronounced, and in some cases they lasted for weeks. Many of the antibiotic-induced changes affected key microbes known to play a role in fostering disease, or in gut health and metabolic processes that promote babies' growth and development.

"Overall we saw a decrease in metabolic pathways, and increase in more pathogenic pathways in bacteria over time," says Michelle Asbury, a doctoral student in O'Connor's lab and lead author on the paper. "Of particular concern was an association between antibiotics and a member of the Proteobacteria phylum called Pseudomonas. When elevated, Proteobacteria in a preterm infant's gut can precede necrotizing enterocolitis."

About seven per cent of babies born preterm develop necrotizing enterocolitis, a frequently fatal condition in which part of the bowel dies. A class of antibiotics called cephalosporins also had a big effect on the overall diversity of breast milk microbiota.

Asbury says it is too early to know what the findings mean for preterm infant health and outcomes. She and her colleagues will dive into those questions over the next year, as they compare their findings with stool samples from the preterm infants involved in the study. This should reveal whether changes in the mothers' milk microbiomes are actually seeding the infants' guts to promote health or increase disease risk.

Meanwhile, she says it's important that mothers with preterm infants continue to take antibiotics for some cases of mastitis, blood infections and early rupture of membranes. Roughly 60 per cent of women in the current study took antibiotics -- highlighting both the vast need for these drugs and the potential for some overuse.

Sharon Unger is a co-author on the study and a professor of paediatrics at U of T, as well as a scientist and neonatologist at Sinai Health and SickKids. She says that the benefits of breast feeding far outweigh the risk that antibiotics can disrupt the breast milk microbiome, and that mothers should without question continue to provide their own milk when possible.

"But I think we can look to narrow the spectrum of antibiotics we use and to shorten the duration when possible," Unger says. She adds that advances in technology may allow for quicker diagnoses of infection and better antibiotic stewardship in the future.

As for the rapidly moving field of microbiome research, Unger says it holds great promise for preterm infants. "Clearly the microbiome is important for their metabolism, growth and immunity. But emerging evidence on the gut-brain axis and its potential to further improve neurodevelopment for these babies over the long term warps my mind."

The evidence for hormone involvement in COVID-19 infection and treatment will be evaluated and discussed by endocrine experts in a dedicated COVID-19 session at e-ECE 2020. The European Society of Endocrinology's annual meeting is going online 5-9 September 2020 and the e-ECE 2020 programme will feature cutting-edge science and the latest in clinical practice and patient care. This includes a new, dedicated COVID-19 session, where experts in the field will present, summarise and examine evidence for the role of the endocrine system and hormones in COVID-19 infection risk, disease severity and potential treatment.

The global COVID-19 pandemic has massively affected how we all live and work and has become the major focus of medical research, as the scientific and medical communities strive to understand it better, develop effective treatments and create a vaccine. This has led to a huge volume of studies being pushed out to the public domain, including some that have not been subject the usual rigorous, scrutiny of peer review. This has resulted in conflicting messages in the media and has contributed to mistrust of experts.

Although initially thought to be a respiratory, influenza-like condition, several studies have now implicated that the severity of COVID-19 infection is increased in people with cardiovascular disease, diabetes and obesity. This raises the possibility that the consequences of viral infection are being affected by the endocrine system. Additionally, severe illness is more common in men, further suggesting that sex, possibly male and female sex hormones, are affecting coronavirus infection. More recently the glucocorticoid, dexamethasone, has shown promise as a treatment in severely ill patients with COVID-19. All of these findings indicate a key role for the endocrine system in mediating infection, disease severity and as a possible therapeutic target.

In the dedicated COVID-19 session at 16:45 CET on 8 September, three experts will review the evidence for the endocrine system's role in SARS-C0V-2 infection, and discuss how to mitigate these risks, with a view to better managing future cases and saving more lives.

* Daniel Drucker will discuss, 'Endocrine targets related to COVID infection'

* Julia Prado will discuss, 'Managing the cytokine storm'

* Matteo Rottoli will discuss, 'How strong is obesity as a risk factor for COVID-19 patients?'

These sessions aim to critically evaluate the role of the endocrine system and endocrinology in the COVID-19 pandemic, with expert debate and hopes of identifying new protective strategies and treatment options, to reduce the disease severity and risk of death in the future.

CATONSVILLE, MD, September 3, 2020 - Social media has forever changed our society and how people do business. A 2013 report by J.D. Power found nearly two-thirds of customers have used a company's social media site to connect with customer service. New research in the INFORMS journal Information Systems Research finds businesses that use Twitter as a social care channel are seeing a 19% increase in customer satisfaction.

The study, "The Voice of the Customer: Managing Customer Care on Twitter," looks at data from Twitter service accounts for the four big telecommunications firms in the United States. The two that rise to the top among online customer care are AT&T and Verizon compared to Sprint and T-Mobile.

"It's clear more customers than ever use social media to seek help from businesses. We strive to determine an optimal strategy to manage digital customer care such as Twitter," said Vijay Mookerjee of the University of Texas at Dallas.

Mookerjee alongside Reza Mousavi and Monica Johar of the University of North Carolina at Charlotte conducted the study. They found that responding to customer queries on social media has profound impacts on customer sentiment as well as the appearance of service quality.

"The top two firms, AT&T and Verizon, do better in terms of the effectiveness of care support over Sprint and T-Mobile," continued Mookerjee, a professor of information systems at UT Dallas. "Good digital care consists not merely of responding to tweets, but effort-intensive activity in which customer tweets need to be carefully examined and adequately addressed."

Customers also expect better quality of care from firms that charge more money for similar cellular plans.

"This type of quality care may require designing some sort of ticket generation system that would detect the tweets that require follow up. Then put in place a good customer service team that would be able to resolve the issues. Simply sending out automated tweets is not sufficient for achieving good quality care," said Mookerjee.

Meanwhile, an event that is perceived positive by customers would lower their expectations of care quality. But the researchers say an event that is perceived as negative by the customer, such as a price hike, would increase customers' expectations of care quality. One way around negative events is tailoring response efforts in anticipation of potentially influential events, such as marketing campaigns, a new product release or even a data security breach.

BINGHAMTON, NY -- Although researchers have known for decades that depression runs in families, new research from Binghamton University, State University of New York, suggests that children suffering from social anxiety may be at particular risk for depression in the future.

"We already know from previous research that children with social anxiety symptoms are at high risk of developing depression, as are offspring of depressed mothers," said Holly Kobezak, co-author of the new paper and lab manager at the Mood Disorders Institute at Binghamton University. "Our findings take what is already known one step further by suggesting that the combination of these risk factors may be even more insidious than the presence of either risk factor alone."

The researchers invited approximately 250 eight- to 14-year-old children whose mothers either did or did not have a history of major depressive disorder (MDD) into their lab to complete questionnaires measuring social anxiety and depression symptoms. Symptoms were reassessed at six-month intervals over a period of two years in order to capture changes in symptom levels over time as children progressed further into adolescence, which is a critical time period for the development of depression.

Their results showed that high levels of social anxiety predicted increases in depression symptoms over time, but only among children of mothers with a history of MDD.

"This provides preliminary evidence that risk for the development of depression among children with social anxiety may be particularly high among children who are already at risk for depression based on a maternal history of the disorder," Kobezak said.

According to Kobezak, these findings allow the researchers to pinpoint a subgroup of children who may be at particularly high risk for developing depression on the basis of two established risk factors that have rarely, if ever, been evaluated in combination.

"This information is useful because it can help us more precisely identify children at need of early intervention and may lay the groundwork for research that works to identify mechanisms of risk that can be targeted in clinical interventions for this group of children," she said.

The researchers hope that their findings will encourage others to explore the specific ways in which social anxiety symptoms and exposure to maternal depression may work together to increase risk of depression in children over time.

"An important point is that our findings provide insight into the circumstances that may put children at heightened risk of depression, but equally important is research that will help us understand why this may be true," said Kobezak. "With that said, we hope future research will investigate additional variables that can explain the impact of the transactional relationship between social anxiety and maternal MDD on depression. For example, future research could focus on disruptions in social functioning and interpersonal relations resulting from these experiences and whether this might be why these children are at such elevated risk. If so, this could be specifically targeted by interventions."

NASA-NOAA's Suomi NPP satellite provided a nighttime look at Hurricane Nana just after it began making landfall in Belize.

At 11 p.m. EDT on Sept. 2, Nana strengthened to a Category 1 hurricane on the Saffir-Simpson hurricane wind scale. It had maximum sustained winds near 75 mph (120 kph). At the time, it was just 60 miles (95 km) southeast of Belize City, Belize. At 2 a.m. EDT on Sept. 3, Hurricane Nana made landfall on the coast of Belize between Dangriga and Placencia with maximum sustained winds near 75 mph (120 kph). By 5 a.m. EDT, the storm had weakened to a tropical storm as it continued to move inland.

NASA's Night-Time View of Nana's Landfall

The Visible Infrared Imaging Radiometer Suite (VIIRS) instrument aboard NASA-NOAA's Suomi NPP satellite passed the Caribbean Sea overnight on Sept. 3 at 3:25 a.m. EDT (0725 UTC) and captured a nighttime image of Hurricane Nana just after making landfall in southern Belize.  Bands of thunderstorms wrapped around the storm's center and extended into the Caribbean Sea. At NASA's Goddard Space Flight Center in Greenbelt, Md., the imagery was created using the NASA Worldview application.

Warnings and Watches on Sept. 3

NOAA's National Hurricane Center (NHC) noted on Sept. 3 that a Tropical Storm Warning is in effect for the Caribbean Sea coast of Guatemala, Isla Roatan and the Bay Islands of Honduras.  A Tropical Storm Watch is in effect for the northern coast of Honduras from Punta Patuca westward to the Guatemala border.

Tropical Storm Nana's Status on Sept. 3

At 8 a.m. EDT (1200 UTC) on Sept. 3, the center of Tropical Storm Nana was located near latitude 16.6 north, longitude 89.7 west. Nana is moving toward the west-southwest near 15 mph (24 kph), and this general motion is expected to continue through today with some decrease in forward speed.  Maximum sustained winds have decreased to near 60 mph (95 kph) with higher gusts. The estimated minimum central pressure is 1000 millibars.

Nana's Fated Forecast

On the forecast track, Nana will continue to move inland over Guatemala and extreme southeastern Mexico today and tonight. Rapid weakening is forecast today and tonight, and Nana will likely become a remnant low-pressure area on Friday, Sept. 4.

University of Calgary scientists have discovered how to capture "live" images of immune cells inside the lungs. The group at the Snyder Institute for Chronic Diseases at the Cumming School of Medicine is the first in the world to find a way to record, in real time, how the immune system battles bacteria impacting the alveoli, or air sacs, in the lungs of mice. The discovery has already provided new insights about the immune systems' cleaners, called alveolar macrophages. Once thought to be stationary, the scientists observed the macrophages at work, crawling over, between and around the alveolar spaces in search of bacteria and viruses.

"It makes sense that macrophages would move around, but we could only hypothesise this because we couldn't see them in action. Now we can," says Dr. Paul Kubes, PhD, principal investigator. "There are many more alveoli in the lungs than macrophages, and these tiny cleaners are very efficient at servicing every air sac."

The researchers say the job the macrophages do is quite simple. Think of a hotel, where there are more rooms than cleaning staff. The staff use hallways to clean and keep things in order. Inside the lungs, there is a corridor that provides a space between the alveoli. The macrophages use this space to move around to destroy any foreign particles including bacteria and viruses impacting the air sacs.

The scientists needed to conquer three major obstacles in order to capture live images of this immune cell at work. The team needed to develop a way to capture an image from air to liquid to air again, they needed to stabilize the lungs long enough to get a clear picture, and they needed to find a way to identify and mark the macrophages.

"This work is a culmination of years of research by scientists around the world. We pulled everything together, combining and refining many imaging techniques," says Arpan Neupane, PhD candidate and first author on the study. "Even six years ago, this would not have been possible."

The ability to see macrophages at work has revealed something else: the scientists watched as the powerful cleaners became paralyzed and stopped doing their important job.

"We know when someone is battling a serious infection, especially a respiratory virus like flu or COVID-19, they often develop a secondary infection which can lead to death," says Kubes. "With this new imaging technique, we were able to see what's happening with the macrophages during this process."

It turns out, at a certain point during the battle against infections, the efficient cleaners become paralyzed making it easier for new infections to take root and flourish.

"The next step in our research is to find out why this is happening so that we can develop targeted therapies to kick start the macrophages into action again," says Kubes.

What would you do if you knew how long you had until Alzheimer's disease set in? Don't despair. New research from the University of California, Berkeley, suggests one defense against this virulent form of dementia -- for which no treatment currently exists -- is deep, restorative sleep, and plenty of it.

UC Berkeley neuroscientists Matthew Walker and Joseph Winer have found a way to estimate, with some degree of accuracy, a time frame for when Alzheimer's is most likely to strike in a person's lifetime.

"We have found that the sleep you're having right now is almost like a crystal ball telling you when and how fast Alzheimer's pathology will develop in your brain," said Walker, a UC Berkeley professor of psychology and neuroscience and senior author of the paper published today, Sept. 3, in the journal Current Biology.

"The silver lining here is that there's something we can do about it," he added. "The brain washes itself during deep sleep, and so there may be the chance to turn back the clock by getting more sleep earlier in life."

Walker and fellow researchers matched the overnight sleep quality of 32 healthy older adults against the buildup in their brains of the toxic plaque known as beta-amyloid, a key player in the onset and progression of Alzheimer's, which destroys memory pathways and other brain functions and afflicts more than 40 million people worldwide.

Their findings show that the study participants who started out experiencing more fragmented sleep and less non-rapid eye movement (non-REM) slow-wave sleep were most likely to show an increase in beta-amyloid over the course of the study.

Although all participants remained healthy throughout the study period, the trajectory of their beta-amyloid growth correlated with baseline sleep quality. The researchers were able to forecast the increase in beta-amyloid plaques, which are thought to mark the beginning of Alzheimer's.

"Rather than waiting for someone to develop dementia many years down the road, we are able to assess how sleep quality predicts changes in beta-amyloid plaques across multiple timepoints. In doing so, we can measure how quickly this toxic protein accumulates in the brain over time, which can indicate the beginning of Alzheimer's disease," said Winer, the study's lead author and a Ph.D. student in Walker's Center for Human Sleep Science at UC Berkeley.

In addition to predicting the time it is likely to take for the onset of Alzheimer's, the results reinforce the link between poor sleep and the disease, which is particularly critical in the face of a tsunami of aging baby boomers on the horizon.

While previous studies have found that sleep cleanses the brain of beta-amyloid deposits, these new findings identify deep non-REM slow-wave sleep as the target of intervention against cognitive decline.

And though genetic testing can predict one's inherent susceptibility to Alzheimer's, and blood tests offer a diagnostic tool, neither offers the potential for a lifestyle therapeutic intervention that sleep does, the researchers point out.

"If deep, restorative sleep can slow down this disease, we should be making it a major priority," Winer said. "And if physicians know about this connection, they can ask their older patients about their sleep quality and suggest sleep as a prevention strategy."

The 32 healthy participants in their 60s, 70s and 80s who are enrolled in the sleep study are part of the Berkeley Aging Cohort Study headed by UC Berkeley public health professor William Jagust, also a co-author on this latest study. The study of healthy aging was launched in 2005 with a grant from the National Institutes of Health.

For the experiment, each participant spent an eight-hour night of sleep in Walker's lab while undergoing polysomnography, a battery of tests that record brain waves, heart rate, blood-oxygen levels and other physiological measures of sleep quality.

Over the course of the multi-year study, the researchers periodically tracked the growth rate of the beta-amyloid protein in the participants' brains using positron emission tomography, or PET scans, and compared the individuals' beta-amyloid levels to their sleep profiles.

Researchers focused on the brain activity present during deep slow-wave sleep. They also assessed the study participants' sleep efficiency, which is defined as actual time spent asleep, as opposed to lying sleepless in bed.

The results supported their hypothesis that sleep quality is a biomarker and predictor of disease down the road.

"We know there's a connection between people's sleep quality and what's going on in the brain, in terms of Alzheimer's disease. But what hasn't been tested before is whether your sleep right now predicts what's going to happen to you years later," Winer said. "And that's the question we had."

And they got their answer: "Measuring sleep effectively helps us travel into the future and estimate where your amyloid buildup will be," Walker said.

As for next steps, Walker and Winer are looking at how they can take the study participants who are at high risk of contracting Alzheimer's and implement methods that might boost the quality of their sleep.

"Our hope is that if we intervene, then in three or four years the buildup is no longer where we thought it would be because we improved their sleep," Winer said.

"Indeed, if we can bend the arrow of Alzheimer's risk downward by improving sleep, it would be a significant and hopeful advance," Walker concluded.

ITHACA, N.Y. - New research from Cornell University developed potential roadmaps for how the coronavirus infects organs and identifies what molecular factors could help facilitate or restrict infection.

"The data suggest that it's not just a respiratory disease," said lead author Cedric Feschotte, molecular biology professor. "It's much broader than that and has the potential to affect many other organs. Our analyses suggest that there is a wide range of cellular vulnerabilities."

The study maps the expression of 28 human genes dubbed "SCARFs" - SARS-Cov-2 and Coronavirus-Associated Receptors and Factors. By looking at the single-cell RNA expression of these genes, they can predict which tissues and cell types are most vulnerable to coronavirus infection - in both adults and embryos.

The team analyzed the RNA expression of healthy human tissues to develop a comprehensive profile of the molecular factors that both facilitate and restrict SARS-CoV2 infection.

Without the immune system's ability to respond quickly, Feschotte said, naturally occurring restriction factors already present in the tissues represent the body's main line of defense against SARS-CoV-2.

Mapping the different entry points for the virus also is essential for trying to predict where the virus will go after it enters the body. Moreover, by pinpointing the molecular routes of infection, other researchers can use those areas as targets for developing drugs to overcome the infection.

The study indicates alternate entry paths for how the virus could enter the lungs, central nervous system and heart. Their research also supports emerging clinical data that shows SARS-CoV-2 also infects the intestines, kidney and placenta. They noted that specific groups of cells within the prostate and testes are likely to be permissive for SARS-CoV-2 and may help explain male-specific vulnerabilities.

As part of this project, the team also developed an open-access, user-friendly web interface where anyone can look up the single-cell RNA expressions of SCARFs. This will facilitate easy access to data that will help scientists around the world.

New Orleans, LA - A team of LSU Health New Orleans radiologists investigated the usefulness of chest x-rays in COVID-19 and found they could aid in a rapid diagnosis of the disease, especially in areas with limited testing capacity or delayed test results. Their findings are published in Radiology: Cardiothoracic Imaging, available here.
"In mid to late March of this year, when COVID-19 cases were spiking in New Orleans, we recognized an unusual pattern on chest x-rays that seemed to correlate with COVID positivity," notes David Smith, MD, Associate Professor of Clinical Radiology at LSU Health New Orleans School of Medicine.
The radiologists conducted a retrospective study of nearly 400 persons under investigation (PUI) for COVID-19 in New Orleans. They reviewed the patients' chest X-rays along with concurrent reverse-transcription polymerase chain reaction (RT-PCR) virus tests. Using well-documented COVID-19 imaging patterns, two experienced radiologists categorized each chest x-ray as characteristic, nonspecific, or negative in appearance for COVID-19.
The radiologists found a characteristic chest x-ray appearance is highly specific (96.6%) and has a high positive predictive value of 83.8% for SARS-CoV-2 infection in the setting of pandemic.

"The presence of patchy and/or confluent, band-like ground glass opacity or consolidation in a peripheral and mid-to-lower lung zone distribution on a chest radiograph is highly suggestive of SARS-CoV-2 infection and should be used in conjunction with clinical judgment to make a diagnosis," says Bradley Spieler MD, Associate Professor of Diagnostic Radiology and Vice Chairman of Research in the Department of Radiology at LSU Health New Orleans School of Medicine.

"The chest radiograph, while low in sensitivity, can indicate COVID-19 in patients whose radiographs exhibit characteristic COVID-19 findings, when used in concert with clinical factors," adds John-Paul Grenier, MD, an LSU Health New Orleans Radiology Resident. "While not a substitute for RT-PCR virus tests or Chest CT, radiographs could provide a rapid, cost-effective diagnosis of COVID-19 in a subset of infected patients during the COVID-19 pandemic. The utility of this technique is described in the context of known disadvantages of RT-PCR, considered the gold standard in COVID-19 diagnosis, and Chest CT, which is currently not recommended for COVID-19 diagnosis. "

"This discovery is useful to aid in diagnosis in the setting of pandemic spread of COVID-19, especially when adequate testing is lacking," says Dr. Smith.

"We believe this work has great potential to aid all health care providers in the fight against COVID-19," concludes Dr. Spieler.

Catherine Batte, MS, from the Department of Physics and Astronomy at Louisiana State University, also collaborated on the study.

"The COVID-19 pandemic has been especially tough on the people of New Orleans," declares Dr. Grenier. "We hope that the insights we've gained from studying this disease in our community can be used to help other communities across the globe."

Little is known about what determines strategy implementation around quality improvement (QI) in small and medium-sized primary care practices. New research led by George Mason University's College of Health and Human Services found that independent, physician-owned practices, adopted more QI strategies than hospital-owned practices and community clinics.

Dr. Tulay Soylu, currently assistant professor of instruction at Temple University, led the study published in the Journal of General Internal Medicine in collaboration with George Mason faculty for her dissertation in Mason's Health Services Research PhD Program. The study was a component of a larger practice-level intervention, Heart of Virginia Healthcare, which provided technical assistance to primary care practices in Virginia to improve cardiovascular care. An observational study design surveyed 175 small and medium-sized primary care practices in Virginia to examine how practice characteristics (such as location, size, ownership, and whether they were part of accountable care organizations) and practice readiness to change affected quality improvement (QI) efforts.

The study found that independent, physician-owned practices adopted more changes than hospital-owned practices and community clinics. "The independent practices focused more on patient care coordination (such as developing a care plan and managing medication) rather than organizational improvement strategies (such as optimizing teams or workflow,)" explains Soylu. Community clinics appear to need additional time to implement QI activities, as they face greater financial challenges and often serve sicker patients.

"Adopting evidence-based QI strategies should be part of transforming primary care so practice can track population health, enhance patient experiences and outcomes, reduce costs, and improve provider experience," explains Soylu. "A strong foundation of primary care is essential for the US healthcare system and the COVID-19 pandemic has underscore this need," explains Soylu.

This study provides empirical evidence to primary care practices and policymakers, which highlights the importance of the strategy implementation variation by practice characteristics. QI authorities should consider these characteristics before designing a QI intervention.

If naked mole-rats were human, they would be prescribed hearing aids. With six mutations in genes associated with hearing, naked mole-rats can barely hear the constant squeaking they use to communicate with one another. This hearing loss, which is strange for such social, vocal animals, is an adaptive, beneficial trait, according to new findings published in the journal Current Biology.

Naked mole-rats are East African hairless mammals that are bald and wrinkly with buck teeth. They live in underground colonies and their social structure resembles that of bees -- there are soldiers, workers and a queen. A lot of cooperation is required for a mole-rat colony to function. Naked mole-rats need to decide where to dig, how to defend the colony, and how to convey the location of food sources, and much of this is accomplished by vocal communication.

"Naked mole-rats are constantly chirping and squeaking," said Thomas Park, professor of biological sciences and neuroscience at the University of Illinois Chicago and one of the lead authors on the paper.

Park has been studying naked mole-rats for decades and has described some of their odd traits, such as their ability to thrive under conditions of low oxygen underground and their high tolerance for pain.

"We were curious about their hearing since they are so vocal, but research had suggested that their hearing is actually quite bad," Park said.

Park and colleagues tested the hearing of mole-rats using technology similar to that used for testing human hearing. They performed an auditory brain stem response test, during which electrodes placed on the scalp pick up signals indicative of sound being processed in the brain. The researchers found the signals were weak, confirming naked mole-rats have poor hearing. In fact, "their hearing is so bad that they would be candidates for hearing aids if they were people," Park said.

Once the hearing loss was confirmed, Park and colleagues turned to the mole-rats' genetics and found six mutations in genes associated with hearing loss in humans.

"The fact that there were so many of these mutations strongly suggests that these mutations were selected for because they are adaptive in some way," Park explained.

The researchers also found the naked mole-rats lacked cochlear amplification, a process by which specialized cells in the inner ear help amplify sound signals before those signals are sent to the brain. Cochlear amplification is aided by cells called outer hair cells, which are located in the inner ear. Without proper functioning of these cells, sounds are severely dampened.

"If the naked mole-rats didn't have these mutations, the constant noise they produce could actually kill the hair cells responsible for hearing," Park said.

Hair cells receive auditory vibrations and send signals to the brain where they are interpreted as sound. Really loud sounds actually kill hair cells, which, unlike other types of cells, can't regenerate. Park said this is why hearing loss in most mammals is progressive.

"Because the naked mole-rats lack functional cochlear amplification, the sounds they hear don't ever get up to a level where they are lethal to hair cells, and so the naked mole-rats can withstand this constant cacophony without going totally deaf," Park said. "They are the only mammals we know of that lack cochlear amplification."

The new findings suggest that mole rats may be a good animal model to investigate hearing loss in humans.

GAINESVILLE, Fla. --- Some male butterflies go to extreme lengths to ensure their paternity - sealing their mate's genitalia with a waxy "chastity belt" to prevent future liaisons. But female butterflies can fight back by evolving larger or more complex organs that are tougher to plug. Males, in turn, counterattack by fastening on even more fantastic structures with winglike projections, slippery scales or pointy hooks.

It's a battle that pits male and female reproductive interests against one another, with the losing sex evolving adaptations to thwart the winner's strategies.

Could this sexual one-upmanship ultimately result in new species? It's a longstanding hypothesis and one that would help explain how butterflies became so diverse. But it has proven difficult to test.

Ana Paula dos Santos de Carvalho, a doctoral student in the Kawahara Lab at the Florida Museum of Natural History, tackled the question in a study of mating plugs in brush-footed butterflies. She traced the trait's evolution and analyzed the rate at which new species appeared across the Acraeini tribe, a group of about 300 species. Unexpectedly, lineages with and without mating plugs evolved at the same rate, suggesting other factors such as habitat may be responsible for driving the insects' diversity.

"I was expecting to see an association between plugs and new species appearing faster, but my work suggested there was no link at all," Carvalho said. "Other studies had proposed a connection between sexual conflict and diversity, so these results came as a surprise."

Found in about 1% of butterfly species, external mating plugs, also known as sphragis, can resemble a scab or a blob of petroleum jelly in some species while others take astonishingly architectural forms.

But they all serve the same purpose: enforcing female monogamy. Because a female butterfly fertilizes the majority of her eggs with sperm from her last partner, males have a vested interest in blocking rivals. Females, however, stand to benefit by mating with more than one male. Another partner may provide higher-quality sperm, and multiple mating events can increase the genetic diversity of offspring. Plus, females get a health boost from the nutrients included in males' sperm packets.

To help guarantee their own successors, males in plug-producing species omit the courtship behavior that often precedes mating in other butterflies. Instead, "males pursue the females, grab them midair and drag them to the ground," Carvalho said. After depositing their sperm, males excrete a pre-molded mating plug, which hardens on the female's abdomen.

Plugs may indirectly constrain males as well. Making a mating plug is an expensive investment of time and resources, potentially limiting how many females a male can inseminate, she said.

Whether females can remove the plug requires further study, but in her fieldwork and museum specimen analysis, Carvalho noted the structures were often partially broken or missing in species with smaller, more delicate plugs. In species with large, complex plugs, she usually found the structures intact and rarely encountered a female without one - a sign that males may be "winning."

But Carvalho's study revealed some female victories as well. In the evolutionary family tree she constructed for Acraeini butterflies, she found evidence that mating plugs originated once across the tribe and were subsequently lost in some species, suggesting a successful female counteroffensive. Wide variations in the shape and size of female genitalia also hint at attempts to render mating plugs ineffective.

"Butterflies and moths continue to surprise us," said study co-author Akito Kawahara, curator at the Florida Museum's McGuire Center for Lepidoptera and Biodiversity. "This study suggests we still have a lot to learn about what drives insect diversity and the role sexual conflict plays in evolution."