Culture

CHAMPAIGN, Ill. -- The liver has a rare superpower among body organs - the ability to regenerate, even if 70% of its mass is removed. It also keeps up its metabolic and toxin-removing work during the process of regeneration, thanks to a subset of cells that expand their workload while the rest focus on multiplication, a new study in mice found.

Furthermore, the cells of the liver communicate with each other to coordinate regeneration activity, which progresses from the center to the periphery of the missing liver lobes, researchers at the University of Illinois Urbana-Champaign said.

"It's remarkable how we still don't understand many aspects of liver regeneration," said Illinois biochemistry professor Auinash Kalsotra, who led the study published in the journal Genome Research. "After a portion is surgically removed, the rest quickly starts regenerating. Within weeks, the liver is back to its original size and mass - no more, no less."

Previous work from Kalsotra's group found that, during regeneration, mature liver cells - normally stable and slow to divide - revert to a more pliable neonatal state. This allows them to divide quickly but causes them to lose their metabolic function. Questions remained of how the liver maintained mature metabolic function while its cells reverted to an immature state, and how the cells know when to stop proliferating.

"Whether regeneration follows a surgical resection of the liver, or is due to an underlying liver disease or chronic liver injury from alcohol or toxins, the liver has to keep functioning. This study revealed a division of labor within the liver that allowed it to address the body's metabolic needs while regenerating," said Kalsotra, a member of the Carl R.. Woese Institute for Genomic Biology at Illinois.

The researchers used a technique that allowed them to individually sequence the RNA of each cell in regenerating mouse livers, revealing its activity. They studied mouse livers at various points during the regeneration process to map how regeneration progressed, as well as where metabolic function was maintained.

They identified a specific class of cells that do not proliferate, but instead ramp up their metabolic function, taking on a greater workload. These were localized near blood vessels, said graduate students Ullas Chembazhi and Sushant Bangru, the co-first authors of the paper.

Meanwhile, the regenerating cells multiplied in a coordinated manner, starting from the middle regions and progressing outward toward the liver's periphery - contrary to prevailing theories in the field that proliferation begins near the veins.

"We found it's actually the midlobular cells that are the most prolific, and that made perfect sense to us because we had just found that there are certain cells that keep and actually turn up their metabolic profiles. These metabolic cells live near the blood vessels, so it makes sense that those cells should stay put, and the interior cells are the ones that divide," Kalsotra said.

The researchers found that the regeneration and metabolic activities were coordinated through extensive cell-to-cell communication. The communication dramatically increased after part of the liver was removed, but by the time regeneration slowed and stopped, the signaling had gone back down toward base levels.

In studying the coordination between cells, they also found a possible explanation for how the regeneration process regulates itself so the liver stops growing when it reaches its original size. Mature liver cells had an abundance of receptors on their surfaces that were activated by molecules their neighboring cells released after surgery, triggering the cells to become neonatal-like and divide. During the proliferation process, however, the cells stopped expressing the receptors, allowing them to return to a mature state when division was complete.

"Normally, the cells are ready to receive these signals. But once they do and are regenerating, they don't need to keep receiving those signals because they would get into an endless run of proliferation. So they stop expressing these receptors. Once the triggers are gone and regeneration is complete, the cells start to make more of the receptors so they are ready if there's an injury again," Kalsotra said.

UNIVERSITY PARK, Pa. -- By modeling wolves in Yellowstone National Park, researchers have discovered that how a population is organized into social groups affects the spread of infectious diseases within the population. The findings may be applicable to any social species and could be useful in the protection of endangered species that suffer from disease invasion.

Like other social carnivores, wolves tend to form territorial social groups that are often aggressive toward each other and may lead to fatalities. During these encounters, infectious diseases -- like mange and canine distemper -- can spread between groups, which can further reduce the number of individuals in a group.

"Previous social group-disease models have assumed that groups do not change throughout the course of an infection, when in reality, this is unlikely to be true," said Ellen Brandell, a recently graduated doctoral student in biology, Penn State. "Individuals within groups may die, become infected and recover at different rates, and the group may split into multiple groups or multiple groups could combine into one. Our models account for these processes and provide a foundation for exploring relationships for many social species that have varying levels of social complexity."

The researchers used demographic data from two decades of Yellowstone wolf research to create models for examining the effects of sarcoptic mange and canine distemper virus on wolves that accounts for both within-group and between-group processes. The models assume that disease processes, such as transmission rates, vary among groups and within groups.

The models also allow for the incorporation of Allee effects, a phenomenon in which a group has a greater survival rate when there are more individuals in the group.

"Allee effects are especially important in social species that require assistance from others beyond reproduction to survive; for example, in animals that defend themselves from predators and hunt for prey as a group," said Peter Hudson, Willaman Professor of Biology, Penn State. "When pathogens kill individuals, this can cause the growth rate of small groups to slow, or even collapse, which, in turn can cause the greater population to decline in size."

The team's model results, which appeared March 1 in the journal Proceedings of the National Academy of Sciences, revealed that pathogens reduce population size mainly through a reduction in the number of groups since those individuals are transmitting the disease to each other to a greater extent than they are to other groups within the overall population. At the same time, Allee effects are exacerbated within infected groups, which further reduces the probability of pathogen spread outside of groups as infected groups die out quickly. As a result, uninfected groups in the population grow slightly larger.

"This occurs because the rate of aggression between groups is reduced when the presence of the pathogen decreases the number of groups, which then allows healthy surviving groups to increase in size as they suffer lower rates of aggression," said Hudson.

However, the team found that the total population size is reduced as a result of the introduction of pathogens.

"In other words," added Brandell, "when a pathogen is in a population, we might see fewer, larger groups, but the overall population size is still reduced."

Importantly, the models demonstrated that low pathogen prevalence at the population level can mask high levels of prevalence within infected groups.

"This finding emphasizes the need for representative sampling in socially structured populations as pathogen outbreaks in unsampled groups can be missed," said Brandell. "Wildlife researchers and managers should sample from many groups in a population in order to accurately depict disease prevalence. For social carnivores, this means sampling across a larger area and monitoring many groups in a population."

Hudson emphasized the importance of recognizing that population-level prevalence tends to be lower than the number of groups infected and the level of infection experienced by individuals in infected groups.

"This issue should be a central consideration when wildlife disease biologists are analyzing and interpreting prevalence and seroprevalence data," he said. "It may be especially helpful in the protection of endangered species, such as African wild dogs."

New research has found that shrimp like creatures on the South Coast of England have 70 per cent less sperm than less polluted locations elsewhere in the world. The research also discovered that individuals living in the survey area are six times less numerous per square metre than those living in cleaner waters.

This discovery, published today in Aquatic Toxicology, mirrors similar findings in other creatures, including humans. The scientist leading research at the University of Portsmouth believes pollutants might be to blame, further highlighted by this latest research.

Professor Alex Ford, Professor of Biology, University of Portsmouth, says: "We normally study the effect of chemicals on species after the water has been treated. The shrimp that we have tested are often in untreated water. The study site suffers from storm water surges, which is likely to become more common with climate change. This means that the creatures could be exposed to lots of different contaminants via sewage, historical landfills and legacy chemicals such as those in antifoulting paints. There is a direct relationship between the incidence of high rainfall events and in the levels of untreated sewage."

Professor Ford describes the shrimp as "the canary in the mine" - concerned that the plight of the shrimp is only just the tip of the iceberg in terms of fertility problems in male creatures, both great and small.

"It is thought that some male fertility problems are related to pollution," said Professor Ford. "It may not be the same pollutants, but it is all chemicals that are being released into the environment. It is not being stopped and, more importantly, the effects are not being properly monitored or understood."

Most male fertility research has historically focused on vertebrate species. Very little is known about the effects of pollution on invertebrate fertility, especially those amphipods at the bottom of the food chain.

A decade ago University of Portsmouth scientists observed little shrimp with very low sperm counts in nearby Langstone Harbour. Surprised by such a result they decided to monitor the animals over the next 10 years.

When Marina Tenório Botelho, a University of Portsmouth PHD student, couldn't continue with her lab-based research due to COVID restrictions she was given the task of data mining the decade's worth of statistics. Her routine study uncovered a worrying reality that these animals have consistently low sperm similar to those in areas that are industrially contaminated.

Professor Ford explains that other marine creatures are also suffering: "We know that pollutants are affecting male fertility levels of all species. Killer whales around our coasts are contaminated with so many pollutants that some can't reproduce. Recent studies* have also suggested that harbour porpoises contaminated with highly toxic industrial compounds, known as polychlorinated biphenyls (PCBs), have smaller testes."

Researchers at the University of Portsmouth believe this new study feeds into wider studies on male fertility. Professor Ford says: "Researchers have been looking at worldwide declines in sperm counts of humans over the past 50 years. Research* has shown that in some countries, a boy born today will have half the sperm count of his grandfather and there are fears boys are getting critically close to being infertile."

Marina Tenório Botelho's research also showed that female shrimp produce fewer numbers of eggs and appear in low densities in the same waters. It suggests that because male shrimps' capacity to fertilise females is compromised, the females in turn have fewer eggs. Scientists are concerned this could lead to a population collapse in the area, which would have a knock on effect on the rest of the food chain. Less food to go round would also eventually mean fewer birds and fish in the region.

CLEVELAND - Researchers from Cleveland Clinic's Global Center for Pathogen Research & Human Health have developed a promising new COVID-19 vaccine candidate that utilizes nanotechnology and has shown strong efficacy in preclinical disease models.

According to new findings published in mBio, the vaccine produced potent neutralizing antibodies among preclinical models and also prevented infection and disease symptoms in the face of exposure to SARS-CoV-2 (the virus that causes COVID-19). An additional reason for the vaccine candidate's early appeal is that it may be thermostable, which would make it easier to transport and store than currently authorized COVID-19 vaccines.

"Our vaccine candidate delivers antigens to trigger an immune response via nanoparticles engineered from ferritin--a protein found in almost all living organisms," said Jae Jung, PhD, director of the Global Center for Human Health & Pathogen Research and co-senior author on the study. "This protein is an attractive biomaterial for vaccine and drug delivery for many reasons, including that it does not require strict temperature control."

Added Dokyun (Leo) Kim, a graduate student in Dr. Jung's lab and co-first author on the study, "This would dramatically ease shipping and storage constraints, which are challenges we're currently experiencing in national distribution efforts. It would also be beneficial for distribution to developing countries."

Other benefits of the protein nanoparticles include minimizing cellular damage and providing stronger immunity at lower doses than traditional protein subunit vaccines against other viruses, like influenza.

The team's vaccine uses the ferritin nanoparticles to deliver tiny, weakened fragments from the region of the SARS-CoV-2 spike protein that selectively binds to the human entry point for the virus (this fragment is called the receptor-binding domain, or RBD). When the SARS-CoV-2 RBD binds with the human protein called ACE2 (angiotensin-converting enzyme 2), the virus can enter host cells and begin to replicate.

The researchers tested their vaccine candidate on a ferret model of COVID-19, which reflects the human immune response and disease development better than other preclinical models. Dr. Jung, a foremost authority in virology and virus-induced cancers, previously developed the world's first COVID-19 ferret model--a discovery that has significantly advanced research into SARS-CoV-2 infection and transmission.

In this study, the researchers administered an initial dose of the vaccine candidate followed by two booster vaccines given 14 and 28 days later. One group received the vaccines intramuscularly, while another group received them both intramuscularly and intranasally.

After the second booster, all vaccinated models produced strong neutralizing antibodies. This suggests that repeated exposure to the RBD antigen successfully prepared the immune systems to rapidly fight the virus.

A few days after the second booster (31 days after the initial vaccine dose), the researchers exposed the models to high concentrations of SARS-CoV-2. Compared to the placebo group that received adjuvant-only vaccines (adjuvants are added ingredients that help vaccines work better), those that received the RBD-nanoparticle vaccine were better protected from clinical symptoms and lung damage associated with infection. The findings suggest the vaccine candidate helped prevent infection and serious disease.

Combination intramuscular and intranasal immunization showed more potent protective immunity and faster viral clearance than intramuscular immunization alone. Both were significantly more effective than the adjuvant-only vaccine. More research will be important to uncover the mechanisms behind these differential benefits.

While ferritin nanoparticles are well-characterized for their strong temperature and chemical stability, suggesting the RBD-nanoparticle vaccine may also be thermostable, future investigations will be necessary to validate. The researchers aim to confirm these findings in human clinical trials soon.

Charlottesville, VA (March 2, 2021). Researchers in the Perelman School of Medicine at the University of Pennsylvania conducted a prospective cohort study utilizing their technique of delayed near-infrared imaging with high-dose indocyanine green (called "second window ICG" or "SWIG") in the identification of brain metastases during surgery. In this study, all metastatic lesions enhanced under near-infrared light with application of SWIG. The researchers compared near-infrared SWIG images obtained at the end of tumor resection with postoperative gadolinium-enhanced MRIs, considered the gold standard for imaging. The comparison demonstrated that SWIG can be used to predict the extent of gross-total resection and, more importantly, to predict progression-free survival.

Details on the findings of this study are found in the article "Second window ICG predicts gross-total resection and progression-free survival during brain metastasis surgery," published today in the Journal of Neurosurgery (https://thejns.org/doi/10.3171/2020.8.JNS201810).

Background

The most common brain tumors are metastatic lesions, primarily those arising from cancers of the lung, breast, and colon, and from melanoma. These lesions pose increased challenges to the cancer patient, including neurological dysfunction and pain. Suggested treatments for metastatic lesions include surgery, stereotactic radiosurgery, and radiation therapy.

In the study described in this paper, the focus was on surgical removal of the metastatic lesion. Surgery can rapidly restore patients' neurological function and reduce the chance of local recurrence.

The aim of gross-total resection is complete removal of the pathological lesion. To accomplish this, the surgeon has to be able to see the tumor in its entirety and be able to remove all of it. Various preoperative and intraoperative imaging techniques have been developed over the years to aid in gross-total resection, including fluorescence-guided surgery. During this surgery, a fluorescent dye is applied to the area of resection to highlight the tumor. With the aid of a near-infrared (NIR) camera system, the surgeon can see the tumor glow, making it easier to differentiate the lesion from healthy brain tissue than using normal white light.

Indocyanine green (ICG) is a fluorescent dye used in medical diagnostics. Administered intravenously, ICG often is used to measure blood flow and organ function. ICG has a short half-life and is eliminated from the body fairly quickly. Despite the short half-life, recent studies have shown significant accumulation and a longer retention time for this dye in intracranial tumors than is found in adjacent normal brain parenchyma.

Taking advantage of the long retention of ICG in tumor tissues, the authors used what they call the second window ICG (SWIG) technique, in which a high dose of ICG is administered intravenously 24 hours before surgery. The dye leaks into the tumor, where it is retained, while over this time period normal tissues clear the dye from the rest of the body. In previous studies, the authors found this technique to be an effective way to highlight cranial tumors, including metastatic lesions, which have not proved to be easy to enhance using other fluorescent compounds.

The Present Study

In the present study, the authors' goals were to evaluate the effectiveness of using SWIG at drug concentrations of 5 mg/kg and 2.5 mg/kg (higher than the FDA-approved limit of 2 mg/kg) to identify brain metastases and predict patients' clinical outcomes.

Patients underwent surgery with SWIG between October 2014 and May 2019; clinical outcomes up to April 2020 were reviewed. Forty-seven patients (34 women and 13 men) harboring 51 metastatic lesions were included in the study analyses; 26 patients received 5-mg/kg ICG infusions and 21 received 2.5-mg/kg ICG infusions.

In the operating room, NIR imaging with SWIG was performed four times: 1) following removal of the skull bone but before opening of the dura mater ("dura view"); 2) after durotomy ("cortex view"); 3) once the gross tumor was fully exposed ("tumor view"); and 4) at the end of surgery and before closing ("final view"). The resulting NIR images were analyzed to quantify ICG fluorescence by calculating signal-to-background ratios.

All 51 metastatic lesions displayed NIR fluorescence following SWIG administration. The authors found that an ICG dose of 5 mg/kg was significantly more effective at defining tumors in the dura view than a dose of 2.5 mg/kg (92% vs. 53% of tumors, respectively). Once the dura had been removed and the cortex view reached, however, both doses of ICG were highly effective at delineating tumors (96% of tumors for the 5-mg/kg dose and 93% for the 2.5-mg/kg dose).

At tumor view, the tumor's full shape fluoresced with respect to surrounding brain tissue. At final view, after the tumor had been removed, the surgeon could assess the site of resection to see whether there was NIR fluorescence in the area of the tumor margins. Such a finding can have a direct effect on the prediction of progression-free survival.

The intensity of fluorescence varied depending on how deep the metastatic lesion was situated, with a lower intensity demonstrated in tumors located more than 10 mm deep. The intensity of fluorescence also differed according to the type of metastasis. Metastases from the lung, breast, and colon showed comparable fluorescence strength, whereas metastases from melanoma displayed a dimmer fluorescence. The authors hypothesize that this difference may be due to the quality of melanin pigment in the lesion to block light penetration.

Postoperative gadolinium-enhanced MRI is considered the gold standard for detecting residual tumors after surgery. The authors found that at final view, NIR with SWIG was as good as or better than postoperative MRI at visualizing residual lesions. In addition, the authors found that the absence of residual NIR fluorescence in the site of resection proved to be a better predictor for gross-total resection, a reduced recurrence rate, and a better progression-free survival than findings on postoperative MRI.

When asked about the article, Dr. John Y. K. Lee responded,

"ICG is an old drug, but scientists continue to find new uses for this fluorophore. The normal, intact blood-brain barrier prevents extravasation of ICG into the normal brain, and thus the enhanced permeability and retention of ICG inside brain metastasis provides the neurosurgeon with exquisite optical contrast, thus aiding the surgeon in rapid identification of the tumor. In this study, we were impressed that our technique -- second window ICG -- allows the surgeon to bring MRI-like imaging to the operating room, allowing us to predict the postoperative MRI result. Indeed, complete resection of the ICG-fluorescence was correlated with improved progression-free survival, thus allowing the surgeon to be sure that their job was performed appropriately.

Peer Reviewed
Experimental
Animals

Consumption of a high fat diet may be activating a response in the heart that is causing destructive growth and lead to greater risk of heart attacks, according to new research.

In a paper published in Biochemical and Biophysical Research Communications, researchers looked at the effect of feeding mice a high fat diet on oxidative stress levels on heart cells. The team from the University of Reading found that cells from the mice had twice the amount of oxidative stress, and led to heart cells being up to 1.8 times bigger due to cardiac hypertrophy which is associated with heart disease.

Named first author Dr Sunbal Naureen Bhatti, from the University of Reading said:

"Our research shows one way in which a high fat diet can cause damage to the muscle cells that make up our hearts. It appears that a switch happens at a cellular level when the mice were fed on a high fat regime which causes a normally harmless protein, Nox2, to become overactive. The precise nature of how the Nox2 protein goes onto cause oxidative damage and set off destructive hypertrophy is still being researched.

"We are really just scratching the surface of how the protein Nox2 responds to diets, but our research clearly demonstrates that high fat diets has the potential to cause significant damage to the heart."

The researchers focused on a key protein Nox2 which believed to be associated with increasing oxidative stress in the heart. The study found that the mice fed a high fat diet had twice the amount of Nox2 activity, which also led to a similar amount of reactive oxygen species (ROS), a free radical that is associated with pathological damage of the body.

To check whether Nox2 was involved in causing the cardiac stress, the team compared the results with mice bred specifically to 'knock out' Nox2, stopping the protein from activating at a cellular level. The 'knock out' mice were also fed a high fat diet, but showed little or none of the same raised levels of oxidative stress.

In addition, the team used three experimental treatments which are known to reduce Nox2-related ROS production, and found that all three showed some promise in reducing the effect of ROS in damaging the mice hearts.

The mice that were fed high fat diets received 45% of their calorie consumption from fat, 20% from protein and 35% carbohydrate.

WEST LAFAYETTE, Ind. - New technology from Purdue University innovators may help improve tissue restoration outcomes for people with breast cancer and other diseases or traumatic injuries.

Purdue researchers, along with fellowship-trained breast surgeon Carla Fisher of Indiana University School of Medicine, teamed up with Purdue startup GeniPhys to develop and perform preclinical studies on a regenerative tissue filler.

This is a first-of-a-kind, in situ scaffold-forming collagen. When applied as a filler for soft tissue defects and voids, it shows promise for accelerating and improving tissue restoration outcomes. The team's work is published in Scientific Reports.

"It would assist in maintaining the quality of life and emotional well-being of millions of breast cancer survivors each year worldwide," said Sherry Harbin, a professor in Purdue's Weldon School of Biomedical Engineering.

The innovators in Harbin's lab designed and patented the collagen polymer used for this technology. A video of the technology is available here. Harbin founded GeniPhys, a Purdue startup focused on the commercialization of the collagen polymer technology.

"Such an approach may also benefit other patient populations in need of soft tissue restoration or reconstruction, including children with congenital defects, individuals with difficult-to-heal skin ulcers, individuals suffering from traumatic injuries and cancer patients requiring resection of tumors within tissues other than breast."

A National Science Foundation SBIR Phase I award to GeniPhys supported the preclinical validation studies performed by the team, which included biomedical engineers from Purdue's Weldon School and a fellowship-trained breast surgeon from Indiana University School of Medicine. Jeannie Plantenga and Abigail Cox from Purdue's College of Veterinary Medicine also were part of the team.

The regenerative tissue filler, when applied to breast tissue voids, such as those associated with breast conserving surgery, restored breast shape and consistency and supported new breast tissue formation over time, including mammary glands, ducts and adipose tissue. The filler also helped avoid wound contraction and scar formation, which can be painful for patients and contribute to breast deformities.

This filler represents a highly purified liquid collagen protein, that when brought to physiologic conditions by mixing with a proprietary buffer, can be applied to tissue voids. The liquid collagen conforms to patient-specific void geometries and then undergoes a self-assembly reaction to form a fibrillar collagen scaffold like those that make up the body's tissues.

This scaffold has soft tissue consistency and persists, where it induces a regenerative healing response.

"This tissue filler represents the first planned medical product developed using our innovative collagen polymer technology," Harbin said. "This collagen polymer supports custom fabrication of a broad range of collagen materials for various applications including tissue restoration, therapeutic cell and drug delivery, or enhancement of tissue-implantable devices interfaces."

Europeans spend more than £700 billion (€800bn) a year on recreational visits to water bodies - but perceived poor water quality costs almost £90 billion (€100bn) in lost visits, a new study has found.

The new research - led by a European collaboration involving the University of Exeter and the University of Stirling - used data from 11,000 visits in 14 different countries to analyse the economic value of water bodies, such as rivers, lakes, waterfalls, beaches and seaside promenades.

The research team estimated that people spend an average of £35 (€40) travelling to and from these sites, with a typical family making 45 such trips each year.

The team also found that people were much less likely to visit sites if the perceived water quality fell, at a cost of well over €100 billion per year. The finding highlights the importance of maintaining and improving high bathing water quality standards.

Published in Science of the Total Environment, the team's calculations indicate that, across Europe, total expenditure relating to trips to water-based settings is in excess of £700 billion annually.

Professor Tobias Börger, of the Berlin School of Economics and Law, used data collected as part of the European Union-funded BlueHealth project, which surveyed more than 18,000 people on their use of water bodies and their health and wellbeing. He explained: "The COVID-19 crisis has taught us all how important access to natural green and blue spaces is for people's mental health and wellbeing. Our research highlights that it's also critical for the economy to maintain high standards of water quality, as the pandemic crisis begins to ease."

Following a Directive adopted by the European Commission, across the EU-member states, more than 15,000 coastal and almost 7,000 inland designated bathing water sites must now prominently display signs stating water quality over the past four years. Around 95 per cent of sites meet minimum quality standards and are considered safe for bathing, while 85 per cent are rated as having excellent water quality.

Professor Danny Campbell, from the University of Stirling, a co-author on the study, added: "While the study reveals that changes in water quality matter to people, we found that household income and educational attainment are not related to visiting water bodies. This shows that all parts of society can and do enjoy the benefits of such visits in terms of recreation, health and wellbeing."

The findings fit well with a growing body of work looking at people's experiences of inland and coastal waters and health across Europe. Co-author of the study, Dr Mathew White at the University of Exeter, said: "Blue spaces benefit people in a variety of ways. They encourage physical activity, they help de-stress and relax people, and they are important places for spending quality time with family and friends, all things which help people's mental and physical health. This research finds that good water quality is key in encouraging people to take up these benefits."

The team hopes their study will help planners and regulators justify the costs of building and maintaining the infrastructure needed to keep bathing water quality high.

DALLAS, March 1, 2021 — Studies representing nearly 2 million adults worldwide show that eating about five daily servings of fruits and vegetables, in which 2 are fruits and 3 are vegetables, is likely the optimal amount for a longer life, according to new research published today in the American Heart Association’s flagship journal Circulation.

Diets rich in fruits and vegetables help reduce risk for numerous chronic health conditions that are leading causes of death, including cardiovascular disease and cancer. Yet, only about one in 10 adults eat enough fruits or vegetables, according to the U.S. Centers for Disease Control and Prevention.

“While groups like the American Heart Association recommend four to five servings each of fruits and vegetables daily, consumers likely get inconsistent messages about what defines optimal daily intake of fruits and vegetables such as the recommended amount, and which foods to include and avoid,” said lead study author Dong D. Wang, M.D., Sc.D., an epidemiologist, nutritionist and a member of the medical faculty at Harvard Medical School and Brigham and Women’s Hospital in Boston.

Wang and colleagues analyzed data from the Nurses’ Health Study and the Health Professionals Follow-Up Study, two studies including more than 100,000 adults who were followed for up to 30 years. Both datasets included detailed dietary information repeatedly collected every two to four years. For this analysis, researchers also pooled data on fruit and vegetable intake and death from 26 studies that included about 1.9 million participants from 29 countries and territories in North and South America, Europe, Asia, Africa and Australia.

Analysis of all studies, with a composite of more than 2 million participants, revealed:

Intake of about five servings of fruits and vegetables daily was associated with the lowest risk of death. Eating more than five servings was not associated with additional benefit. 
Eating about two servings daily of fruits and three servings daily of vegetables was associated with the greatest longevity.
Compared to those who consumed two servings of fruit and vegetables per day, participants who consumed five servings a day of fruits and vegetable had a 13% lower risk of death from all causes; a 12% lower risk of death from cardiovascular disease, including heart disease and stroke; a 10% lower risk of death from cancer; and a 35% lower risk of death from respiratory disease, such as chronic obstructive pulmonary disease (COPD).
Not all foods that one might consider to be fruits and vegetables offered the same benefits. For example: Starchy vegetables, such as peas and corn, fruit juices and potatoes were not associated with reduced risk of death from all causes or specific chronic diseases.
On the other hand, green leafy vegetables, including spinach, lettuce and kale, and fruit and vegetables rich in beta carotene and vitamin C, such as citrus fruits, berries and carrots, showed benefits.

“Our analysis in the two cohorts of U.S. men and women yielded results similar to those from 26 cohorts around the world, which supports the biological plausibility of our findings and suggests these findings can be applied to broader populations,” Wang said.

Wang said this study identifies an optimal intake level of fruits and vegetables and supports the evidence-based, succinct public health message of ‘5-a-day,’ meaning people should ideally consume five servings of fruit and vegetable each day. “This amount likely offers the most benefit in terms of prevention of major chronic disease and is a relatively achievable intake for the general public,” he said. “We also found that not all fruits and vegetables offer the same degree of benefit, even though current dietary recommendations generally treat all types of fruits and vegetables, including starchy vegetables, fruit juices and potatoes, the same.”

A limitation of the research is that it is observational, showing an association between fruit and vegetable consumption and risk of death; it does not confer a direct cause-and-effect relationship.

“The American Heart Association recommends filling at least half your plate with fruits and vegetables at each meal,” said Anne Thorndike, M.D., M.P.H., chair of the American Heart Association’s nutrition committee and an associate professor of medicine at Harvard Medical School in Boston. “This research provides strong evidence for the lifelong benefits of eating fruits and vegetables and suggests a goal amount to consume daily for ideal health. Fruits and vegetables are naturally packaged sources of nutrients that can be included in most meals and snacks, and they are essential for keeping our hearts and bodies healthy.” 

Diversity, equity and inclusion (DEI) leaders in academic medicine are subject to increasing expectations with limited resources and there is an urgent need for psychiatry departments to commit to fully supporting their efforts, according to an article now available in the American Journal of Psychiatry written by top DEI leaders in academic psychiatry from across the country.

The authors, representing prominent public and private institutions, include Ayana Jordan, M.D., Ph.D., Yale University, and current APA ECP Trustee-at-Large; Ruth S. Shim, M.D., M.P.H. University of California, Davis; Carolyn I. Rodriguez, M.D., Ph.D., Stanford University; Eraka Bath, M.D., University of California, Los Angeles; Jean-Marie Alves-Bradford, M.D., Columbia University; Lisa Eyler, Ph.D., University of California, San Diego; Nhi-Ha Trinh, M.D., Harvard University; Helena Hansen, M.D., Ph.D., New York University; and Christina Mangurian, M.D., M.A.S., University of California, San Francisco.

Dr. Jordan and colleagues describe, from their collective experiences, the growing expectations of people in DEI positions, in part resulting from the recent focus on racial justice and need to address structural racism. "DEI leaders are being summoned for one-on-one and programmatic consultation, anti-racist curriculum development, anti-bias training, and skill acquisition," they write. "However, many of these institutions do not provide the appropriate resources or support necessary to institute an effective response for cultural change....This lack of scaffolding leads to an exacerbation of the 'minority tax,' thereby placing more duress on the very same people adversely affected by structural racism." Notably, almost half of these DEI leaders have not received salary or compensation for the roles.

"It was not surprising to any of us that most DEI leaders were women of color," said Mangurian. "But what was surprising is that so many of us did not receive the support we deserved. Our work suggests that leadership in psychiatry -- and across all of academic medicine -- should re-examine their current investments so they can provide sufficient financial and administrative support to these extraordinary DEI leaders. This will not only help ensure these women of color thrive and stay within academia, but will help move us closer to our shared goal of creating a more diverse, equitable, and inclusive environment."

In an accompanying commentary, Altha Stewart, M.D., APA past-president, notes that recent personal accounts by Black academics suggest the lack of leadership support on racism issues "is a major factor in departure from academic medicine by Black physicians (including psychiatrists)." Dr. Stewart discusses the historical underpinnings of structural racism in academic medicine and emphasizes the need for senior leaders to recognize and address the unintentional but well-institutionalized barriers in their systems and to work to create more balanced, equitable, and welcoming environments. "To retain BIPOC faculty, institutional leadership must believe, validate, and act on faculty's experiences of racism," writes Dr. Stewart.

Jordan and colleagues offer a series of recommendations in the areas of financial, administration and structural practices to effectively support DEI leadership, including:

Structural

Strategically elevate the title of the DEI leader to vice or associate chair in the department, to clearly state the importance of the role.

Include that person in the departmental cabinet, executive committee, and/or other leadership team.

Administrative

The roles and responsibilities of the DEI position should be clear when the job description is first presented to potential candidates, with responsibilities commensurate with financial effort provided.

As with all leaders, term limits are recommended for this role with evaluation at 5 years and a 10-year maximum term.

Financial

DEI efforts should receive financial support, including salary reflective of effort and expectations; discretionary funds to implement policies; and support staff.

"Real change will require that no one be exempt in demonstrating the organization's commitment to diversity and inclusion by creating the welcoming environments that will support institutionalization of this new culture," Jordan and colleagues conclude.

PHILADELPHIA-- Hospital emergency departments (EDs) not only care for patients with overdose and other complications from opioid use, but they also serve as vital touch points to engage patients into longer-term treatment. After an overdose, patients are at risk for repeat overdose and death. Pennsylvania is unique in establishing a voluntary incentive program to improve the rate at which patients with opioid use disorder receive follow-up treatment after emergency department care. Evaluations of the program show that financial incentives are effective in producing rapid treatment innovations for opioid use disorder.

In a study, researchers at the Perelman School of Medicine at the University of Pennsylvania found that Pennsylvania's financial incentive policy encouraged hospitals to enact rapid system and practice changes to support treatment for opioid use disorder for patients visiting the ED. The study, which was recently published in Psychiatric Services, evaluates the efficacy of the Opioid Hospital Quality Improvement Program (O-HQIP), which Pennsylvania pioneered in 2019. The program seeks to increase the rate of follow-up treatment for Medicaid patients within seven days of an ED encounter for opioid-related illness by offering financial compensation to hospitals who participated in the program.

"Policy makers have recognized that strengthening the linkage from the ED to treatment is an opportunity to combat the opioid epidemic," said senior author Zachary Meisel, MD, MPH, MSHP, an associate professor of Emergency Medicine and director of the Center for Emergency Care Policy and Research at Penn. "Offering financial incentives provides momentum for efforts to improve treatment access for opioid use disorder."

The program identified four distinct treatment pathways: initiation of buprenorphine treatment during the ED encounter; warm handoff to outpatient treatment; referral to treatment for pregnant patients; and inpatient initiation of methadone or buprenorphine treatment. An initial incentive for participation was paid to hospitals in 2019 and was contingent on participation in all four pathways, with lesser payments for partial participation. In future years, hospital can earn additional incentives for improvements in performance.

To evaluate the degree of the program's success, researchers conducted 20 semistructured interviews with leaders from a diverse sample of hospitals and health systems across Pennsylvania. Study interviews revealed that the incentives oriented institutional priorities toward expanding opioid treatment access. Hospitals were often on the cusp of change and responded to this nudge to prioritize opioid treatment access. However, the study also revealed that most hospitals--specifically, smaller or independent hospitals with lower volumes of patients with opioid use disorder--were unable to justify investing in these resources internally. Some hospitals noted resources as a barrier to participation, despite the incentive payments.

Finally, while initiating buprenorphine in the ED is proven to improve patients' health outcomes and retention in treatment, many hospitals found implementing a pathway for buprenorphine difficult and time-consuming, and all partially participating hospitals chose to forgo this pathway.

"Future work is needed to determine the effectiveness in improving patient outcomes not only for the this initiative in Pennsylvania, but also for emerging treatment methods and payment innovations in the care of patients with opioid use disorder," said Jeanmarie Perrone, MD, Director of the Division of Medical Toxicology and Addiction Medicine Initiatives, and a professor of Emergency Medicine at Penn. "Specifically, given that evidence supports improved treatment retention after ED initiation of buprenorphine rather than referral for initiation, incentives are needed that overcome the multifaceted barriers for this key treatment modality."

Oak Brook, IL - The March edition of SLAS Discovery features the cover article, "Therapeutic and Vaccine Options for COVID-19: Status After 6 Months of the Disease Outbreak" by Christian Ogaugwu (Federal University Oye-Ekiti, Ekiti State, Nigeria ), Dawid Maciorowski, Subba Rao Durvasula, Ph.D., Ravi Durvasula, M.D., and Adinarayana Kunamneni, Ph.D. (Loyola University Medical Center, Maywood, IL, USA).

This cover article focuses on the therapeutic and vaccine options available against the novel coronavirus, roughly six months after the outbreak; because the COVID-19-related death toll worldwide had reached 500,000 in six months (and ballooned to over 2,000,000 at the time of publishing) the importance of options to temper the disease cannot be overemphasized. The article highlights the available treatment alternatives for mild and serious active cases of COVID-19 infections and explores the vaccine options that should aid to confer immunity to vaccinated individuals. In addition to providing information on available options to tackle COVID-19, this article summarizes global efforts towards bringing an end to this pandemic. The authors have concluded a combinatorial therapy is to be designed with both immunizations, as well as small compounds. Other articles in this issue discuss repurposed therapies used for treatment of COVID-19 cases, as well as promising vaccines at different stages of clinical trials.

The March issue of SLAS Discovery includes nine articles of original research in addition to the cover article.

Articles of Original Research include:

CETSA MS Profiling for a Comparative Assessment of FDA-Approved Antivirals Repurposed for COVID-19 Therapy Identifies Trip13 as a Remdesivir Off-Target

A Scalable Approach Reveals Functional Responses of iPSC Cardiomyocyte 3D Spheroids

Assessment of Drug Proarrhythmic Potential in Electrically Paced Human Induced Pluripotent Stem Cell-Derived Ventricular Cardiomyocytes Using Multielectrode Array

Major Improvements in Robustness and Efficiency during the Screening of Novel Enzyme Effectors by the 3-Point Kinetics Assay

Optimization of a Colorimetric Assay to Determine Lactate Dehydrogenase B Activity Using Design of Experiments

AlphaScreen Identifies MSUT2 Inhibitors for Tauopathy-Targeting Therapeutic Discovery

Leveraging Automation toward Development of a High-Throughput Gene Expression Profiling Platform

Quantitative Automated Assays in Living Cells to Screen for Inhibitors of Hemichannel Function

A "Target Class" Screen to Identify Activators of Two-Pore Domain Potassium (K2P) Channels

Development of a Cell-Based Assay for Identifying KCa3.1 Inhibitors Using Intestinal Epithelial Cell Lines

Characterizations of the Urate Transporter, GLUT9, and Its Potent Inhibitors by Patch-Clamp Technique

Other articles include:

Therapeutic and Vaccine Options for COVID-19: Status after Six Months of the Disease Outbreak

Saporin, a Polynucleotide-Adenosine Nucleosidase, May Be an Efficacious Therapeutic Agent for SARS-CoV-2 Infection

COMPARE Analysis: A Bioinformatic Approach to Accelerate Drug Repurposing against COVID-19 and Other Emerging Epidemics

Parallel All-Optical Assay to Study Use-Dependent Functioning of Voltage-Gated Ion Channels in a Miniaturized Format

With eight months to go before the UN Climate Change Conference (COP26), an international survey experiment has found evidence of "overwhelming" support across seven major countries for governments to "do more" to protect the environment.

The survey directly asks the public about policies they want to see backed by governments at COP26, when the UK and Italy will gather world leaders in Glasgow from 1 November to commit to urgent global climate action.

Researchers at the University of Cambridge worked with polling agency YouGov on a message-testing experiment involving 14,627 adults, with samples of around 2,000 each in Brazil, China, India, Indonesia, Poland, the UK and the US. Polling took place from 8th to 31st December 2020.

Participants were randomly assigned to read either one of four "treatment" texts about climate change - drafted to reflect current UN messaging, public health, social norms and patriotism - or a neutral text, unrelated to climate and used to test "baseline" support.

The participants were then asked if they agreed or disagreed with the statement that "all national governments should do more to protect the environment."

Baseline figures showed extremely high levels of support for government-led action. In six of these countries, at least nine out of ten participants agreed that governments should do more for the environment. In the US, the figure was three out of four (79%).

Compared to the baseline, exposure to one of the climate change texts led to a small but significant rise of about one or two percentage points on average. The figures ranged in the UK from 89-93%; as against 96-98% in Brazil, 91-95% in China, 92-97% in India, 99-100% in Indonesia, 91-94% in Poland and 76-79% in the USA.

Across all the responses, a majority (55%) of those who voted for former President Donald Trump in the November 2020 presidential elections agreed, although this figure was well below the 95% figure for those who voted for President Joe Biden. In the UK, 87% of Conservative supporters agreed, as compared to 97% of Labour supporters.

The issue may have even bridged the Brexit divide, with 96% of Remain voters and 86% of Leave voters in agreement on the need for more action.

Dr Lee de-Wit, a political psychologist at the University of Cambridge, said that the clearest evidence that a message had had an impact was in China, "where pollution is a daily reality for many". Support for more action rose from 91% to 95% among those that read about public health benefits of tackling climate change - a text that focused on air pollution.

"We live in a time of polarisation, and environmental issues have long embodied the political divisions in society. However, this may be changing. We can see an overwhelming consensus emerging for greater government-led action to protect the environment in major nations," de-Wit said.

"As we approach COP26, politicians the world over should take confidence from these findings. Voters across party lines want to see more government action. The time is now."

The survey also asked which policies governments should support at COP26. In each of these seven countries, baseline figures showed that at least 50% supported four policies.

The most popular on average was action "to protect and preserve" wildlife, marine life and plants; followed by a policy "to plant more trees to absorb the gases that cause climate change"; then spending more on developing clean technologies; then reducing "the production over thirty years of the gases that cause climate change."

Participants were also asked if they thought that businesses should be made "to pay for the damage they do when their activities contribute to climate change". In every country except China, baseline figures showed this to be a more popular policy than giving businesses a "fair timetable to stop activities that contribute to climate change." Across the seven countries, on average, 58% supported making businesses pay and 48% supported the timetable option.

In the United Kingdom, baseline figures for the most popular policies were protecting wildlife (84%), planting trees (81%) and spending more on clean technology (75%). Some 70% thought businesses should pay for environmental damage, while 67% supported reducing the production of greenhouse gases over 30 years. Baseline support for giving businesses a fair timetable to adapt stood at 55%. Only 5% believed that governments are "doing all they should".

In the United States, baseline figures were 70% for protecting wildlife, 67% for planting trees, and 60% for spending more on clean technology. Some 54% thought businesses should pay for environmental damage, while 51% supported reducing the production of greenhouse gases over 30 years. Baseline support for giving businesses a fair timetable to adapt stood at 42%. Only 10% believed that governments are "doing all they should".

Across the seven countries, for participants who had been exposed to one of the climate change texts, support for these policies rose by around 1% on average, which was not a significant change. However, support for tree-planting did rise significantly from a baseline of 73% to 76% for those exposed to the UN's current messaging, and to 75% for those who read a text on the public health benefits of tackling climate change.

De-Wit said that in the run up to COP26: "We face huge challenges protecting the environment, but global public opinion may no longer be chief among them."

Dr Sander van der Linden, Director of Cambridge's Social Decision-Making Lab, also involved in the research, added: "These survey results make it clear that irrespective of age, gender and nationality, citizens around the world want governments to do more to protect the environment."

The findings can be viewed here.

Rutgers scientists for the first time have pinpointed the sizes of microplastics from a highly urbanized estuarine and coastal system with numerous sources of fresh water, including the Hudson River and Raritan River.

Their study of tiny pieces of plastic in the Hudson-Raritan Estuary in New Jersey and New York indicates that stormwater could be an important source of the plastic pollution that plagues oceans, bays, rivers and other waters and threatens aquatic and other life.

"Stormwater, an understudied pathway for microplastics to enter waterways, had similar or higher concentrations of plastics compared with effluent from wastewater sewage treatment plants," said senior author Nicole Fahrenfeld, an associate professor in the Department of Civil and Environmental Engineering in the School of Engineering at Rutgers University-New Brunswick. "More research is needed to increase understanding of the full impact of microplastics on ecosystems."

In the early 1900s, General Bakelite began manufacturing Bakelite, the first synthetic plastic on Earth, in Perth Amboy, New Jersey. Today, plastics are used in myriad products worldwide and are widespread in marine and other environments, posing risks to wildlife and aquatic life.

Possible sources of microplastics - often fragments of larger pieces of plastic - include municipal, industrial and stormwater outfalls.

The Rutgers team collected water samples during a relatively dry period in July 2018 and after a heavy rainfall in April 2019. They also collected samples of wastewater entering treatment plants, wastewater discharges and stormwater.

The highest levels of microplastics, ranging from two-hundredths of an inch to less than a tenth of an inch long, were observed during summer low-flow conditions at the mouth of the Raritan River, according to the study in the journal Chemosphere. Higher concentrations of smaller microplastics collected from Raritan Bay and the Atlantic Ocean off New Jersey likely came from the Hudson River, according to Fahrenfeld.

"The smaller microplastics likely spent more time in the turbulent Hudson River, leading to increased aging and breakdown of plastics," she said.

Polyethylene, which is widely used in high-density polyethylene bottles, trash bags and other items, was the most commonly observed polymer, or plastic, in the Raritan River and Hudson-Raritan Estuary.

A 2017 Rutgers-led study found high levels of microplastics in the Raritan and Passaic rivers. Scientists later identified more than 300 organic chemical compounds that appeared to be associated with microplastic particles in the two rivers.

March 1, 2021 - A new paper published online in the Annals of the American Thoracic Society discusses how smoking may affect risk for COVID-19 and the types of research that are needed to better understand the link between smoking and COVID-19 risk.

In "Smoking and COVID-19: The Real Deal," Enid Neptune, MD, and Michelle N. Eakin, PhD, of the Division of Pulmonary and Critical Care Medicine, Johns Hopkins University, discuss research to date on this topic and propose areas of research that can help clarify this relationship.

Studies have shown that current smokers with COVID-19 have twice the risk of dying in the hospital as nonsmokers. However, the data on whether tobacco use increases the risk of SARS-CoV-2 infection is mixed.

"The relationship between smoking and COVID-19 is complex, and much of the research to date has been inconclusive or contradictory," said Dr. Neptune. "To resolve this issue, rigorous study design is needed. This research should accurately confirm smoking exposure, with readouts that distinguish infection from sickness and provide an objective assessment of confounding factors."

Dr. Neptune adds that a significant amount of research has focused on whether smoking has an effect on lung ACE2, a protein that provides an entry point for SARS-CoV-2 (the virus that causes COVID-19) to attach itself to cells inside the airways and airspace of the lungs. "The use of ACE2 expression as a quantifiable index of SARS-CoV-2 infectivity and morbidity is highly problematic," she said. "A strenuous exploration of how and whether tobacco smoke and nicotine affect SARS-CoV-2 infectivity or viral load (amount of virus) is needed to provide context to the ACE2 expression data."

According to Drs. Neptune and Eakin, the following topics should also be addressed in future research:

Airway/Airspace Injury (Direct Toxic Effects). It will be especially important to describe the effects of tobacco smoke on nasal tissue (epithelium), as the nose is the primary entry point for SARS-CoV-2 and little research has been done on smoke's effects on this part of the anatomy. The researchers believe advanced preclinical and in vitro ("in the laboratory") models of smoking plus SARS-CoV-2 infection will provide the most reliable answers to this question.

Inflammation Profile That Supports Viral Pathogenesis. Another important research question is whether smoking compromises the body's inflammatory response to viruses or contributes to an inability to regulate these responses. Researchers have previously shown that smoking affects the body's ability to respond to many respiratory viruses; we need to know more about whether this holds true for SARS-CoV-2.

Disturbances in RAS Signaling. Renin Angiotensin Signaling (RAS) proteins control intracellular signaling pathways that impact lung health. There is some evidence that disruption of conventional RAS signaling protects against lung injury from cigarette smoking in chronic obstructive pulmonary disease (COPD), which is associated with improved COPD outcomes, but we do not know whether this also holds true for COVID-19.

Measurements of the activity of RAS processing enzymes and the proteins produced by this activity in smoking and non-smoking COVID patients would provide some guidance for pilot therapeutic studies.

Nicotine Signaling and SARS-CoV-2 Infection. Some research has shown that nicotine exposure and nicotine signaling (within the brain) may reduce SARS-CoV-2 infection and illness. The effects of nicotine should be studied, in addition to studying smoking, since nicotine-delivering e-cigarettes are now so widely used. This research should be done very cautiously, because nicotine dependence has major public health consequences.

"There are several other areas of smoking-COVID research that might be explored, beyond those discussed in our paper," Dr. Neptune said. These include:

Whether the stress of life during the pandemic has led to increased use of tobacco for self-medication;

If hospitalization for COVID-19 helps smokers quit;

Whether altered taste and smell due to COVID-19 reduce the desire to smoke.

Dr. Neptune concludes, "Our paper shows that the impact of tobacco exposure on the development of COVID-19 is challenging to address with clinical studies, and needs rigorous validation with cell and animal studies. Taken together, the multiple published studies on smoking and COVID have not yet resolved the issue. Our intention in publishing this paper is to identify the interpretative challenges of the overall dataset and recommend ways forward."