Culture

James McKerrow, MD, PhD, dean of the Skaggs School of Pharmacy and Pharmaceutical Sciences at University of California San Diego, has long studied neglected tropical diseases -- chronic and disabling parasitic infections that primarily affect poor and underserved communities in developing nations. They're called "neglected" because there is little financial incentive for pharmaceutical companies to develop therapies for them.

One of these neglected diseases is Chagas disease, the leading cause of heart failure in Latin America, which is spread by "kissing bugs" carrying the parasite Trypanosoma cruzi. These parasites produce an enzyme called cruzain that helps them replicate and evade the human immune system. McKerrow's research team looks for inhibitors of cruzain -- small molecules that might form the basis for new anti-parasitic medicines. One particularly effective cruzain inhibitor is called K777.

Then, in the spring of 2020, the COVID-19 pandemic began to sweep through the United States. Researchers quickly reported that SARS-CoV-2, the coronavirus that causes COVID-19, can't dock on and infect human cells unless a human enzyme called cathepsin L cleaves the virus' spike protein.

And it just so happens that cathepsin L looks and acts a lot like cruzain.

In a study published March 31, 2021 by ACS Chemical Biology, McKerrow and team show that low concentrations of K777 inhibit cathepsin L can reduce SARS-CoV-2's ability to infect four host cell lines, without harming the cells.

"Since K777 inhibits a human enzyme, not the virus itself, it's our hope that it's less likely the virus will evolve resistance against it," said McKerrow, co-senior author of the study with Thomas Meek, PhD, of Texas A&M University.

K777 wasn't equally effective in all cell lines. That's likely because not all cell lines produced the same amount of cathepsin L or the same amount of ACE2, the host cell receptor that the virus' spike protein uses to latch onto cells after it's cleaved by cathepsin L. The inhibitor was best at preventing SARS-CoV-2 infection in the cells that produced the most cathepsin L and ACE2.

The cell lines tested were derived from African green monkey kidney epithelium, human cervical epithelium and two types of human lung epithelium. While an important research tool, cell lines such as these are not necessarily representative of patients. They are easy to grow and manipulate in research laboratories because they are cancer cells, but that also means their molecular features likely differ from the average person's healthy lung or cervical cells.

"We were surprised at just how effective K777 is in blocking viral infection in the lab," McKerrow said. "Yet under usual circumstances it would be impractical and unlikely that we ourselves would be able to move the compound so quickly into clinical trials. We're fortunate that an 'entrepreneur-in-residence' program here at UC San Diego has helped bridge that gap."

Selva Therapeutics, a privately held biotechnology company, has licensed K777 from UC San Diego. In parallel with this study, the company has also found that the experimental therapeutic prevented lung damage in COVID-19 animal models and was well-tolerated by people who participated in a Phase I clinical trial to assess safety. Selva is planning a Phase IIa clinical trial in non-hospitalized COVID-19 patients for late 2021.

Many people with COVID-19 experience mild disease and can recover at home with supportive care to help relieve their symptoms. Currently, severe cases of COVID-19 may be treated with the antiviral drug remdesivir, approved by the U.S. Food and Drug Administration (FDA) for use in hospitalized patients, or a medication that has received emergency use authorization from the FDA, such as monoclonal antibodies. Worldwide, more than 124 million people have been diagnosed with COVID-19 and 2.72 million have died from the infection.

A novel mechanism has been identified that might explain why a rare mutation is associated with familial Alzheimer's disease in a new study by investigators at the University of Chicago. The paper, published on April 2 in the Journal of Experimental Medicine, characterizes a mutation located in a genetic region that was not previously thought be pathogenic, upending assumptions about what kinds of mutations can be associated with Alzheimer's Disease.

Alzheimer's, a neurodegenerative disease that currently affects more than 6 million Americans, has been characterized by the accumulation of A? peptides into plaques in the spaces between neurons in the brain. These A? peptides are generated when a larger precursor protein, APP, is cleaved into smaller fragments as APP transits through different cellular compartments.

Most mutations that have previously been associated with Alzheimer's lie either within or just next to a region of the APP gene that codes for the eventual A? peptide fragment. However, while the mutation studied by the research team is located in the APP gene, itis quite far from the area where previously characterized mutations are found. The mutation, S198P, was first found in two patients affected by Alzheimer's, and raised eyebrows due to its distance from known disease-associate mutations.

"This mutation, which is not in the region of APP that codes for the A? fragment, was so interesting because it was so far away from where all the other mutations are normally located," said senior author Sangram Sisodia, PhD, the Thomas Reynolds Sr. Family Professor of Neurosciences at UChicago, "Thus it was not clear how this mutation might be contributing to the pathology of the disease."

The investigators, led by Xulun Zhang, Ph.D., a Research Professional in the Sisodia lab, examined how S198P could affect A? peptide production by studying both cultured cells and mice. They found that the presence of the S198P mutation resulted in both cultured cells and mice having elevated levels of A? peptides. To further understand why S198P caused elevated A? levels, the authors looked at different steps of the APP-to-A? production pipeline.

Using cultured cells, the authors found that S198P causes APP to fold more quickly, allowing A? peptides to be produced from mature APP more quickly than from APP that did not contain the S198P mutation. "The rapid folding enhances the egress of APP through the cellular compartments where A? is made, allowing faster production of the A? peptide" said Sisodia. Mice harboring S198P also had more plaques causes by A? accumulation, reinforcing the likelihood that the mutation does indeed contribute to disease.

However, like with many other mutations, the presence of S198P is not a guarantee that Alzheimer's will develop. "This variant is only partially penetrant," said Sisodia, meaning that not every person with S198P will go on to develop Alzheimer's. Similar to mutations in the breast cancer genes BRCA1/2, S198P influences only the probability that an affected person will develop Alzheimer's.

"Geneticists would argue that this is not a pathogenic mutation because you can find this mutation in unaffected people, but this is a complex disease and studying these rare variants uncovers new biology," said Sisodia.

The fact that S198P is located so far away from previously characterized mutations underscores that there is much to still be understood about Alzheimer's. "A lot of mutations that have been described for the past 20 years have been dismissed because they don't look like they follow the normal rules. We need to pay attention to these rare variants because they open up new areas of investigation to completely decipher this disease," said Sisodia.

Though effective treatments for Alzheimer's still remain in development, Sisodia believes his group's findings argue for a renewed focus on A? peptides. "Failures in clinical trials have led some people to think that maybe A? has nothing to do with this disease, but these results clearly support a role for A? in disease pathogenesis. I hope this revives people's notions about the importance of A? in Alzheimer's."

The identification of S198P's mechanism has led Sisodia to plan to go back to other overlooked mutations and investigate them as well. "There are all these other rare variants that were seemingly benign according to other people, but we know from clinical studies that they too drive Alzheimer's pathology and clinical phenotypes," said Sisodia. "We figured out S198P, great! Now let's move on to all these other variants!"

In a new study, researchers identify three clinical COVID-19 phenotypes, reflecting patient populations with different comorbidities, complications and clinical outcomes. The three phenotypes are described in a paper published this week in the open-access journal PLOS ONE 1st authors Elizabeth Lusczek and Nicholas Ingraham of University of Minnesota Medical School, US, and colleagues.

COVID-19 has infected more than 18 million people and led to more than 700,000 deaths around the world. Emergency department presentation varies widely, suggesting that distinct clinical phenotypes exist and, importantly, that these distinct phenotypic presentations may respond differently to treatment.

In the new study, researchers analyzed electronic health records (EHRs) from 14 hospitals in the midwestern United States and from 60 primary care clinics in the state of Minnesota. Data were available for 7,538 patients with PCR-confirmed COVID-19 between March 7 and August 25, 2020; 1,022 of these patients required hospital admission and were included in the study. Data on each patient included comorbidities, medications, lab values, clinic visits, hospital admission information, and patient demographics.

Most patients included in the study (613 patients, or 60 percent) presented with what the researchers dubbed "phenotype II." 236 patients (23.1 percent) presented with "phenotype I," or the "Adverse phenotype," which was associated with the worst clinical outcomes; these patients had the highest level of hematologic, renal and cardiac comorbidities (all p

The authors conclude that phenotype-specific medical care could improve COVID-19 outcomes, and suggest that future research is needed to determine the utility of these findings in clinical practice.

The authors add: "Patients do not suffer from COVID-19 in a uniform matter. By identifying similarly affected groups, we not only improve our understanding of the disease process, but this enables us to precisely target future interventions to the highest risk patients."

PHILADELPHIA - A team led by scientists in the Perelman School of Medicine at the University of Pennsylvania has identified nine potential new COVID-19 treatments, including three that are already approved by the Food and Drug Administration (FDA) for treating other diseases.

The team, whose findings were published in Cell Reports, screened thousands of existing drugs and drug-like molecules for their ability to inhibit the replication of the COVID-19-causing coronavirus, SARS-CoV-2. In contrast to many prior studies, the screens tested the molecules for anti-coronaviral activity in a variety of cell types, including human airway-lining cells that are similar to the ones principally affected in COVID-19.

Of the nine drugs found to reduce SARS-CoV-2 replication in respiratory cells, three already have FDA approval: the transplant-rejection drug cyclosporine, the cancer drug dacomitinib, and the antibiotic salinomycin. These could be rapidly tested in human volunteers and COVID-19 patients.

The experiments also shed light on key processes the coronavirus uses to infect different cells and found that the antiviral drug remdesivir, which has an FDA Emergency Use Authorization for treating COVID-19, does appear to work against the virus in cell-culture tests on respiratory cells, whereas hydroxychloroquine does not.

"Our discoveries here suggest new avenues for therapeutic interventions against COVID-19, and also underscore the importance of testing candidate drugs in respiratory cells," said co-senior author Sara Cherry, PhD, a professor of Pathology and Laboratory Medicine and scientific director of the High-Throughput Screening (HTS) Core at Penn Medicine.

Study collaborators included co-senior authors David Schultz, PhD, technical director of the HTS Core, and Holly Ramage, PhD, assistant professor of microbiology & immunology at Thomas Jefferson University.

Although great progress has been made in the development of vaccines and treatments for the SARS-CoV-2 coronavirus, there is still much room for improvement. In the United States, the only antiviral COVID-19 treatments that have received FDA Emergency Use Authorization -- remdesivir and several anti-SARS-CoV-2 antibody preparations -- are expensive and far from 100 percent effective.

For their screening project, Cherry and colleagues assembled a library of 3,059 compounds, including about 1,000 FDA-approved drugs and more than 2,000 drug-like molecules that have shown activity against defined biological targets. They then tested all of these for their ability to significantly inhibit SARS-CoV-2 replication in infected cells, without causing much toxicity.

Initially, they performed antiviral screens using cell types they could grow easily in the lab and infect with SARS-CoV-2, namely African Green Monkey kidney cells, and a cell line derived from human liver cells. With these screens, they identified and validated several compounds that worked in the monkey kidney cells, and 23 that worked in the human liver cells. Hydroxychloroquine, which is used as a malaria drug, and remdesivir, were effective in both cell types.

Since SARS-CoV-2 is mainly a respiratory virus and is thought to initiate infections via airway-lining cells, the researchers sought a respiratory cell type that they could infect experimentally with the virus. They eventually identified a suitable cell line, Calu-3, that is derived from human airway-lining cells. They used these respiratory-derived cells to test the antiviral compounds identified through the human liver cell screen, and found that only nine had activity in the new cells. The nine did not include hydroxychloroquine. (Remdesivir worked in the Calu-3 cells but was not included in the list because it is already in use against COVID-19.)

By identifying different sets of drugs that work in different cell types, the researchers also shed light on the mechanisms SARS-CoV-2 uses to gain entry to cells. The findings suggest that in kidney and liver cells, the virus uses a mechanism that can be disrupted, for example, by hydroxychloroquine; yet the virus appears to use a different mechanism in respiratory cells, thus explaining hydroxychloroquine's lack of success in those cells -- and in COVID-19 clinical trials.

The nine antivirals active in respiratory cells did include salinomycin, a veterinary antibiotic that is also being investigated as an anticancer drug; the kinase enzyme inhibitor dacomitinib, an anticancer drug; bemcentinib, another kinase inhibitor now being tested against cancers; the antihistamine drug ebastine; and cyclosporine, an immune suppressing drug commonly used to prevent the immune rejection of transplanted organs.

The study highlights cyclosporine as particularly promising, as it appears to works against SARS-CoV-2 in respiratory and non-respiratory cells, and via two distinct mechanisms: inhibiting cell enzymes called cyclophilins, which the coronavirus hijacks to support itself, and suppressing the potentially lethal inflammation of severe COVID-19.

"There may be important benefits to the use of cyclosporine in hospitalized COVID-19 patients, and ongoing clinical trials at Penn and elsewhere are testing that hypothesis," Cherry said.

Within southeast Michigan's Middle Eastern and North African community, those who worry about deportation or believe they've been treated unfairly are likely to face more adverse conditions associated with poor health, including food insecurity and financial distress.

The MENA people who face several of these barriers are also more likely to report chronic illness and mental health issues as well as worse overall health.

That's according to a new study by the University of Michigan Rogel Cancer Center, the University of Michigan School of Public Health, and the Arab Community Center for Economic and Social Services.

"There are numerous health disparities for the MENA community that are not that different from other racial and ethnic groups where we're trying to close the gap," says Minal R. Patel, Ph.D., M.P.H., an associate professor of health behavior and health education at the U-M School of Public Health and a member of the Rogel Cancer Center. "The data show us that this is an important population where we should be focusing our efforts to address health needs."

This is the latest in a series of papers based on data from an extensive survey designed to better understand the population within one of the geographic areas the Rogel Cancer Center aims to serve. The researchers paid special attention to MENA people because metro Detroit is home to one of the United States' largest MENA communities, with about 210,000 residents hailing from Lebanon, Egypt, Syria, Iraq, Yemen and other Arab countries.

Previous state surveys had revealed significant health disparities for the MENA population, similar to what Michigan's African-American and Hispanic groups experience. However, Patel and her research team knew more specific data was needed to determine MENA people's unmet health needs as well as the impact that discrimination has on their health.

Through questionnaires distributed in community venues -- including grocery stores, mosques, and health care clinics -- to about 400 people who identified as MENA, researchers found that almost 60% of respondents felt they had experienced discrimination. Close to half did not believe the government was trying to improve life for Arab-Americans. Although fewer people worried about deportation or thought they had been treated unfairly, those who did often faced more adverse conditions associated with poor health, such as food insecurity.

More unmet health needs were also found among people who were not born in the United States (58% of the study's sample); who had lived in America for fewer years; who spoke Arabic at home; and who were from Egypt, Syria, or Yemen -- countries with unstable political environments and high poverty rates.

Public health researchers and media outlets alike have previously called attention to the physical and mental toll of immigration-related concerns on Latino immigrants. Patel says this data illustrates how the MENA people fit into that discussion.

"We were able to highlight that even though we don't share a border with a Middle Eastern country, we still have a sizeable population right next door to us that have concerns about immigration," Patel says. "This is another community where we can bring in that national conversation and think about how it is specifically impacting health."

Among risk factors that limit optimal health in the MENA population, transportation issues for health care visits, food insecurity, and financial strain were the most common, followed by unemployment and unstable housing.

Patel said she was surprised at the prevalence of food insecurity in particular given the number of grocery stores and restaurants in areas with large concentrations of the MENA population.

"When you drive through Dearborn, where much of the survey took place, it doesn't look like the makeup of your typical food desert," Patel says. "So we need to unpack that. Food insecurity is multidimensional, and the availability of food is only one component."

Overall, experiencing more risk factors for poor health, e.g., food insecurity and unemployment and unstable housing, was linked with more chronic diseases, including cancer, diabetes, high blood pressure, depression and heart conditions. In addition, mental health and general health were poorer for the people who faced multiple societal conditions that limit optimal health.

This survey was conducted in 2019, and Patel says all the issues discussed have likely worsened for the MENA community since then due to the increased stressors of the pandemic.

Washington, April 2, 2021--The Organisation for Economic Co-operation and Development (OECD) will release a new PISA report on student growth mindset on Thursday, April 8 at 5:00 a.m. ET, followed by a press conference held in collaboration with the American Educational Research Association (AERA) and the Yidan Prize Foundation at 10:30 a.m. ET.

The new report "Sky's the limit: Growth mindset, students, and schools in PISA" provides analyses on student growth mindset, a concept much discussed in the current field of psychology. Growth mindset is the belief that someone's ability and intelligence can be developed over time. PISA collected international comparable data on "growth mindset" from nearly 80 countries/economies for the first time in 2018. The report sheds lights on how educators, policy makers and researchers can further support the potential of students around the world.

Edward Ma (Yidan Prize Foundation), Carol Dweck (Stanford University), and Andreas Schleicher (OECD) will open the press conference to discuss the findings, which will be followed by Q&A with reporters, moderated by Tony Pals (AERA) on April 8, 10:30 - 11:30 a.m. ET. This event is organized as a part of the 2021 AERA Virtual Annual Meeting.

Waiting for your turn can be frustrating, especially when it comes to COVID-19 vaccinations. But prioritizing who receives the limited supply of vaccines available saves lives and reduces spread of infection, according to a study published today in the journal PNAS from the University of California, Davis.

While there is mostly universal agreement that older people should be prioritized, debates are currently underway about prioritizing a variety of other groups. Still others argue against targeting at all.

"Prioritization has benefits because people differ in at least two key ways -- their risk of infection and the likelihood of serious consequences from infection," said senior author Michael Springborn, a UC Davis professor in the Department Environmental Studies and an economist focused on environmental risk, including infectious disease. "We know that front-line essential workers have less capacity to socially distance and thus an elevated risk, while seniors are more seriously impacted by infection. Accounting for this substantially increases the benefits of vaccination."

For the study, the researchers modeled COVID-19 transmission rates and the optimal allocation of an initially limited vaccine supply in the U.S. under a variety of scenarios. They found that deaths, years of life lost and infections were between 17 to 44 percent lower when vaccinations targeted vulnerable populations -- particularly seniors and essential workers -- rather than an alternative approach where everyone is equally likely to be vaccinated.

"We also found that in regions where there was a faster increase in infections, and where there is less masking and social distancing occurring, targeting was even more important in avoiding those outcomes," said lead author Jack Buckner, a Ph.D. candidate in the UC Davis Graduate Group in Ecology.

ESSENTIAL CONSIDERATIONS

Building on the standard approach in modeling analyses to account for age groups, the study is the first to include front-line essential workers as their own category. In doing so, the researchers identified that such workers should be a vaccination priority along with or shortly after seniors. Policies that target based on both age and essential worker status substantially outperformed those that consider age only.

Prioritizing essential workers versus seniors depends on the conditions. For instance, when there is a good supply of effective vaccines and the outbreak is relatively under control, targeting essential workers first to help reduce overall spread can be ideal. But if vaccine supply is limited and cases and deaths are surging, targeting seniors and the most vulnerable directly may be the better strategy.

Previous studies have assumed that a given prioritization strategy remains constant over time. This study uniquely allows for prioritization to evolve as conditions change, such as when more people in certain groups become vaccinated.

"There is a substantial value to prioritization, at least for the first few months of the vaccine rollout," Springborn said.

"Once a large proportion of the most vulnerable people or the most likely to be exposed have been vaccinated, it becomes less important who gets it," said Buckner.

STILL MUCH TO LEARN

The authors say that while the scientific community and public have learned a lot about SARS-CoV-2, the virus that causes COVID-19, there are still many uncertainties to address. This includes how well vaccines impede transmission, how much individuals will relax their protective measures as vaccinations progress, and how durable immunity will be given the rise of new variants.

The authors took a general approach that is adaptable for future disease outbreaks.

"The analytic approach put forward in this study to assess the optimal dynamic allocation of vaccines adds to the methodological toolkit with applications beyond the COVID-19 pandemic," said study author Gerardo Chowell, a professor of epidemiology and biostatistics at Georgia State University.

DEPRIVATION among society at large is 'driving' Covid-19 disparities among minority ethnic groups - predominantly South Asian and Black African or Caribbean populations - and could be considered the main cause of disproportionate infection rates, hospitalisation and deaths experienced by these populations, according to new analysis from the University of Leicester.

The study, supported by the National Institute for Health Research (NIHR) Leicester Biomedical Research Centre (BRC) comes a day after a government-commissioned review concluded race and racism have become less important factors in explaining social disparities in the UK.

Researchers at the University of Leicester used UK Biobank data of 407,830 South Asian, Black and White individuals to model a hypothetical intervention whereby 50 per cent of the general population were lifted out of material deprivation status (the 'grade' of deprivation was measured by the highly regarded Townsend score that is made up of four domains: unemployment, non-car ownership, non-home ownership and household overcrowding).

By moving the 50 per cent most deprived in the general population sample out of material deprivation, over 80 per cent of the extra, 'excess' risk of Covid-19 outcomes for South Asian and Black populations was eliminated.

Even just by moving 25 per cent of the sample out of deprivation, between 40-50 per cent of additional risk to South Asian and Black populations was alleviated.

The striking results of this large, unprecedented analysis dispute several existing studies, some of which maintain that poorer health among ethnic minority populations could be the driving factor for Covid-19 disparities.

Cameron Razieh, Lead author of the analysis and Epidemiologist at the University of Leicester specialises in ethnic minority health conditions. He explains:-

"The method of analysis we used in this study upholds that inequalities in health or health behaviours in people living with high deprivation are, in the most part, the result of the high deprivation itself.

"If we take this as truth, then we can conclude that high levels of deprivation are helping drive Covid-19 ethnic disparities. Reducing deprivation within the whole population could therefore play a pivotal role in reducing ethnic inequalities in Covid-19 outcomes observed in South Asian and Black communities."

Professor Kamlesh Khunti, joint senior author of the study who also works as Director of the UK NIHRApplied Research CollaborationsEast Midlands (ARC EM) said:-

"Material deprivation is a universal underpinning determinant of health inequalities within and between populations.

"Quantifying the extent to which material deprivation reduces risk is important but even more imperative is to now ask how we can reduce social inequality and increase social mobility.

"There is a rapidly closing window to use research evidence such as this to give those most in need a fighting chance to better manage their health."

Joint senior author Tom Yates, Professor of physical activity, sedentary behaviour and health at the University of Leicester added:-

"The data from this study calls for improved assistance to be provided to the poorest communities.

"In what we hope is the final stretch of this pandemic we must now pull together - backed by research - to ensure that for those most at risk of Covid-19 outcomes, there is still light at the end of this very long tunnel.

"History may judge harshly if we do not get this right despite the evidence elucidated."

X-Ray Experiments, Machine Learning Could Trim Years Off Battery R&D

By Glenn Roberts Jr.

An X-ray instrument at Berkeley Lab contributed to a battery study that used an innovative approach to machine learning to speed up the learning curve about a process that shortens the life of fast-charging lithium batteries.

Researchers used Berkeley Lab's Advanced Light Source, a synchrotron that produces light ranging from the infrared to X-rays for dozens of simultaneous experiments, to perform a chemical imaging technique known as scanning transmission X-ray microscopy, or STXM, at a state-of-the-art ALS beamline dubbed COSMIC.

Researchers also employed "in situ" X-ray diffraction at another synchrotron - SLAC's Stanford Synchrotron Radiation Lightsource - which attempted to recreate the conditions present in a battery, and additionally provided a many-particle battery model. All three forms of data were combined in a format to help the machine-learning algorithms learn the physics at work in the battery.

While typical machine-learning algorithms seek out images that either do or don't match a training set of images, in this study the researchers applied a deeper set of data from experiments and other sources to enable more refined results. It represents the first time this brand of "scientific machine learning" was applied to battery cycling, researchers noted. The study was published recently in Nature Materials.

The study benefited from an ability at the COSMIC beamline to single out the chemical states of about 100 individual particles, which was enabled by COSMIC's high-speed, high-resolution imaging capabilities. Young-Sang Yu, a research scientist at the ALS who participated in the study, noted that each selected particle was imaged at about 50 different energy steps during the cycling process, for a total of 5,000 images.

The data from ALS experiments and other experiments were combined with data from fast-charging mathematical models, and with information about the chemistry and physics of fast charging, and then incorporated into the machine-learning algorithms.

"Rather than having the computer directly figure out the model by simply feeding it data, as we did in the two previous studies, we taught the computer how to choose or learn the right equations, and thus the right physics," said Stanford postdoctoral researcher Stephen Dongmin Kang, a study co-author.

Patrick Herring, senior research scientist for Toyota Research Institute, which supported the work through its Accelerated Materials Design and Discovery program, said, "By understanding the fundamental reactions that occur within the battery, we can extend its life, enable faster charging, and ultimately design better battery materials."

Read SLAC's release, "In a leap for battery research, machine learning gets scientific smarts."

To Speed Discovery, Infrared Microscopy Goes 'Off the Grid'

By Lori Tamura

Question: What do a roundworm, a Sharpie pen, and high-vacuum grease have in common? Answer: They've all been analyzed in recent proof-of-principle microscopy experiments at Berkeley Lab's Advanced Light Source (ALS).

In the journal Communications Biology , researchers from Caltech, UC Berkeley, and the Berkeley Synchrotron Infrared Structural Biology Imaging Program (BSISB) reported a more efficient way to collect "high-dimensional" infrared images - where each pixel contains rich physical and chemical information. With the new method, scans that would've taken up to 10 hours to complete can now be done in under an hour, potentially broadening the scope of biological spectromicroscopy to time-sensitive experiments.

"We realized that sampling our model organism - the small roundworm C. elegans - as it changes over time was challenging for software rather than hardware reasons," said Elizabeth Holman, a graduate student in chemistry at Caltech and co-first author of the paper. "For example, image sampling was limited to uniform-grid raster scans with rectangular boundaries and fixed distances between sample points."

The new technique, implemented at the ALS with co-first author Yuan-Sheng Fang, a graduate student in physics at UC Berkeley, uses a grid-less, adaptive approach that autonomously increases sampling in areas displaying greater physical or chemical contrast. In the proof-of-concept infrared microscopy experiments, the researchers examined two samples.

The first was a two-component system in which both components (permanent-marker ink and high-vacuum grease) were well characterized. Details of the sample were very difficult to see clearly with the naked eye, so it was a good test of how the software would perform with minimal guidance from a human experimenter. The second sample was a live, larval-stage C. elegans, a biological model system studied by thousands of researchers.

In both cases, autonomous adaptive data acquisition (AADA) methods clearly outperformed nonadaptive methods. In the second example, increased sampling density corresponded with known C. elegans anatomical features, and the head region was mapped in 45 minutes versus about 4.9 hours using commercially available software.

"Outside of our specific published work, the results suggest that integrating AADA into existing scanning-based satellite, drone, and/or microscope techniques can facilitate research in fields ranging from hyperspectral remote sensing to ocean and space exploration," said Holman.

Actor in a Supporting Role: Substrate Effects on 2D Layers

By Lori Tamura

Atomically thin layers are of great technological interest because of potentially useful electronic properties that emerge as the layer thickness approaches the 2D limit. Such materials tend to form weak bonds outside the layer and are thus generally assumed to be unaffected by substrates that provide physical support.

To make further progress, however, scientists must rigorously test this assumption, not only to better understand single-layer physics, but also because the existence of substrate effects raises the possibility of tuning layer properties by tweaking the substrate.

As reported in the journal Physical Review Letters, a team led by Tai-Chang Chiang of the University of Illinois at Urbana-Champaign and his postdoctoral associate, Meng-Kai Lin, used Berkeley Lab's Advanced Light Source (ALS) to probe changes in the electronic properties of a 2D semiconductor, titanium telluride, as the thickness of a substrate, platinum telluride, was increased. Single-layer titanium telluride is highly sensitive to what lies underneath, making it particularly useful as a test case for investigating substrate coupling effects.

The results showed that as the substrate thickness increased, a dramatic and systematic variation occurred in the single-layer titanium telluride. An electronic phenomenon known as a charge density wave -- a coupled charge and lattice distortion characteristic of single-layer titanium telluride -- was suppressed.

"The experimental findings, combined with first-principles theoretical simulations, led to a detailed explanation of the results in terms of the basic quantum mechanical interactions between the single layer and the tunable substrate," said Lin.

Given that the interfacial bonding remained weak, the researchers concluded that the observed changes were correlated with the substrate's transformation from a semiconductor to a semimetal as it increased in thickness.

"This systematic study illustrates the crucial role that substrate interactions play in the physics of ultrathin films," said Lin. "The scientific understanding derived from our work also provides a framework for designing and engineering ultrathin films for useful and enhanced properties."

Parkinson's disease (PD) is well known as a debilitating disease that gradually worsens over time. Although the disease's progression has been largely tied to the loss of motor functions, non-motor symptoms, including the loss of cognitive abilities, often emerge early in the disease.

Much less understood is the role that specific neural circuits play in these distinct motor and non-motor functions.

A new study led by neurobiologists at the University of California San Diego and their colleagues found that specific, identifiable neural pathways are charged with particular functions during stages of the disease. Their findings, published recently in Nature Neuroscience, can help form the basis for improving therapeutic strategies for precise symptoms of Parkinson's at various levels of disease progression.

The researchers used a mix of approaches to shed more light on the anatomical and functional importance of a center of brain circuitry known as the basal ganglia, located deep in the cranium. Specifically, the researchers, working in mice, investigated circuit pathways tied to specific neurons in the external globus pallidus, or GPe, and their role in different Parkinson's disease-related behaviors. The GPe is known for its strong output and influence on several downstream brain regions.

The investigations included a multi-pronged approach using electrophysiology, viral tracing and behavioral experiments. The researchers identified two populations of GPe neurons and their distinctive pathways tied to different behavioral symptoms.

"Our work demonstrates that the distinct neural circuitries in the basal ganglia are differentially involved in the motor and non-motor symptoms of Parkinsonian-like behaviors that occur at different stages of the disease," said Lim, an associate professor in the Neurobiology Section of the Division of Biological Sciences at UC San Diego. "This suggests that evaluation of the detailed circuit mechanisms is needed to fully understand the changes in brain during the progression of PD, and could provide better therapeutic strategies for the treatment of PD."

Lim said the most surprising finding from the research was the fact that dopaminergic neurons, those that are gradually lost during Parkinson's disease progression, could be linked so specifically to changes in different brain areas.

"Selective manipulation of specific changes can rescue one type of symptom--without affecting other symptoms--of Parkinson's Disease," said Lim.

With the new framework in hand, Lim and his colleagues are now looking deeper at the circuit pathways and how they are tied to different disease symptom stages, in particular with an emphasis on delaying the progression of the disease.

"Our findings provide a novel framework for understanding the circuit basis of varying behavioral symptoms of the Parkinsonian state, which could provide better strategies for the treatment of PD," the researchers write in the paper.

Researchers at the University of California, San Francisco, have discovered that aggressive, triple-negative breast cancers (TNBCs) can evade treatment by reorganizing and softening the collagen matrix that surrounds the cancer cells. The study, which will be published April 2 in the Journal of Experimental Medicine (JEM), shows that the softer matrix activates a signaling pathway that promotes the cancer cells’ survival, and suggests that targeting this pathway could enhance the effectiveness of chemo- and radiotherapy in TNBC patients.

TNBC is an aggressive type of breast cancer with worse survival rates than other forms of the disease. Because TNBC cells lack the HER2 signaling receptor and the estrogen and progesterone hormone receptors, they cannot be eliminated by drugs that specifically target these proteins. Instead, TNBC patients are normally treated with a combination of surgery and chemotherapy/radiation, but these treatments are often unable to completely eliminate the tumor, leading to local recurrence and metastasis to other tissues.

“Currently, there are no reliable methods to identify patients that are likely to respond well and those that are likely to be resistant to treatment,” says Valerie M. Weaver, a professor and Director of the Center for Bioengineering and Tissue Regeneration in the Department of Surgery at UCSF. “There is an urgent need for a deeper understanding of the biological basis for therapeutic response in TNBC that will inform treatment decisions and the development of effective strategies to overcome therapy resistance.”

One factor that could influence the response to therapy is the meshwork of collagen and other proteins that surrounds the cancer cells within tumors. This extracellular matrix can activate various signaling pathways within cells that determine whether or not cells die when they are exposed to stress.

Weaver and colleagues, including Catherine C. Park, professor and Chair of the Department of Radiation Oncology at UCSF, and graduate student Allison P. Drain, analyzed the extracellular matrix in tumor samples taken from TNBC patients. In untreated TNBC, collagen proteins were aligned into long, linear fibers, creating a matrix that is much stiffer than normal, healthy breast tissue. But in TNBC treated with chemotherapy, the collagen fibers in the remaining tumor were reorganized to form a much softer matrix.

“This raised the intriguing possibility that the softened, remodeled extracellular matrix might be causally linked to the pathogenesis of the treatment-resistant, residual tumor tissue,” Weaver says.

The researchers found that tumors grown in the lab or in mice were more resistant to both radiation and the chemotherapy agent paclitaxel when they were surrounded by a softer extracellular matrix. Cancer cells grown in a stiff environment activate a signaling protein called JNK that makes the cells more likely to die in response to stress. In contrast, cancer cells surrounded by a softer matrix activate a protein called NF-kB that counteracts JNK and promotes cell survival. Accordingly, treating mice with a drug that inhibits NF-kB improved their therapeutic response, significantly slowing tumor growth when combined with radiotherapy.

Weaver and colleagues found that TNBC patients whose tumors had high levels of NF-kB activity showed higher rates of treatment resistance. NF-kB activity was also elevated in remodeled, softened tumors that remained after treatment.

“Therapies designed to modulate stiffness-dependent NF-κB or JNK activity might therefore improve the treatment response of TNBCs and enhance the long-term survival of these patients,” Weaver says. “However, further efforts will be needed to clarify the nature of the mechanisms that mediate treatment resistance and develop effective, selective, and safe therapeutics.”

Bottom Line: Among patients at high risk of melanoma, those who received routine skin cancer screening and education about skin self-exams were significantly more likely to be diagnosed with thinner and earlier stage melanomas.

Journal in Which the Study was Published: Cancer Epidemiology, Biomarkers & Prevention, a journal of the American Association for Cancer Research

Author: Michael Sargen, MD, a dermatologist and clinical fellow in the Division of Cancer Epidemiology and Genetics at the National Cancer Institute (NCI), part of the National Institutes of Health (NIH)

Background: "Whole-body screening for melanoma is currently routine for individuals at high risk for melanoma. These individuals include members of melanoma-prone families, categorized as having at least two relatives who have had melanoma, and those with inherited pathogenic gene variants that increase melanoma risk," said Sargen. "However, the benefit of screening in melanoma-prone families has not been previously quantified."

How the Study was Conducted: To better understand if screening and education among melanoma-prone families could result in earlier melanoma detection, Sargen and colleagues evaluated data from the NCI Familial Melanoma Study, which was initiated in 1976 to investigate inherited and environmental risk factors for the disease. "At enrollment and subsequent in-person visits to the NIH, study participants received whole-body screening for melanoma, total body photographs with closeups of potentially problematic moles, education about the appearance of melanoma, and strategies for protecting their skin from ultraviolet (UV) damage," Sargen explained. Participants in the study were also counseled to follow up with their local dermatologist annually for whole-body screening exams.

To evaluate the success of the study, Sargen and colleagues compared differences in melanoma thickness and tumor stage between participants diagnosed with melanoma before and after enrollment (the pre-study cohort and the prospective cohort, respectively). "Tumor thickness, or how deep the tumor grows beneath the surface of the skin, is associated with an increased risk of death from melanoma," said Sargen. The researchers also compared tumor thickness trends between participants in their study and cases in the general population by using data from Surveillance, Epidemiology, and End Results (SEER) registries.

Results: There was a total of 293 melanoma cases in the NCI Familial Melanoma Study, with 246 cases in the pre-study cohort, and 47 cases in the prospective cohort. Participants enrolled in the study from 1976 through 2014. There was a total of 79,530 cases analyzed in the SEER registries between 1973 to 2016. Because all of the participants in the NCI Familial Melanoma Study were white, analyses of SEER data were also restricted to white patients. Information on melanoma thickness was missing for 24 percent of melanoma cases in the NCI Familial Melanoma Study and 8.7 percent of melanoma cases found in the SEER registry; the researchers imputed the missing data.

Sargen and colleagues evaluated if the interventions in the NCI Familial Melanoma Study impacted melanoma thickness and tumor stage at diagnosis by comparing these features between the prospective and pre-study cohorts. After adjusting for gender and age, the researchers found that cases in the prospective cohort had significantly thinner melanomas compared with cases in the pre-study cohort (0.6mm versus 1.1mm, respectively). Further, cases in the prospective cohort were significantly more likely to be diagnosed at the early T1 stage compared with cases in the pre-study cohort (83 percent versus 40 percent, respectively).

Next, the researchers evaluated whether changes in melanoma thickness over time among cases in the NCI Familial Melanoma Study differed from trends observed in the general population. "Melanoma thickness at diagnosis in the United States has been decreasing since 1973, when we started tracking such data," Sargen explained. When the researchers compared the observed tumor thickness among members of melanoma-prone families with the expected tumor thickness based on the U.S. general population with respect to age, calendar period, and gender, they found that the melanomas diagnosed after enrollment in the NCI Familial Melanoma study were thinner than the predictions based on the U.S. general population.

Author's Comments: "This suggests that the downward trend in melanoma thickness observed in the general population does not fully explain the reductions in thickness seen in melanoma-prone families, and that long-term surveillance may assist in the earlier diagnosis of melanoma in high-risk populations," Sargen said.

"Our results suggest that the screening and education provided in the NCI Familial Melanoma Study may improve early detection of melanoma in melanoma-prone families," he added.

Study Limitations: Limitations of this study include the relatively small sample size of melanoma cases in the NCI Familial Melanoma Study and the imputation of missing melanoma thickness data.

"Additionally, since this was a prospective cohort study, we were not able to distinguish the independent effect of each intervention," Sargen said. "Randomized control studies are needed to understand the impact of each aspect of the intervention, such as whole-body screening, melanoma education, or strategies for skin protection."

Researchers from University of Queensland, University of Melbourne, and Universidad Finis Terrae published a new paper in the Journal of Marketing that studies consumer resistance to a nationwide plastic bag ban implemented in Chile in 2019.

The study, forthcoming in the Journal of Marketing, is titled "How Do I Carry All This Now?': Understanding Consumer Resistance to Sustainability Interventions" and is authored by Claudia Gonzalez-Arcos, Alison M. Joubert, Daiane Scaraboto, Rodrigo Guesalaga, and Jörgen Sandberg.

As environmental crisis challenges accelerate, governments are searching for solutions to reduce the negative impacts of economic activity. One popular measure has been to ban disposable plastic bags. Bans on plastic bags may seem like an easy way to reduce plastic pollution, but are often met with strong pushback by consumers, retailers, and other members of society.

The researchers studied consumer resistance to a nationwide plastic bag ban implemented in Chile in February 2019 with the goal of answering the following questions: What causes consumer resistance to sustainability interventions such as bans on plastic bags? And how can consumer resistance be reduced to make such interventions more effective? They conducted interviews, observed consumers, and collected documents, news articles, and social media posts related to the Chilean ban, starting in 2013 when an initial ban in coastal areas was announced until four months after the implementation of the ban in the entire country in 2019.

Gonzalez-Arcos says, "We discovered that consumers refuse to accept or support a sustainability intervention because the individual behaviors being targeted--in this case using disposable plastic bags for shopping--are not separate from, but embedded in, social practices." Social practices are activities, materials, and meanings that are similarly understood and shared by a group of people. Eating, cooking, shopping, driving, and reading are examples of social practices shared by large groups. These practices determine people's way of life and, to a large extent, who they are. From this perspective, a behavior such as using a plastic bag to carry groceries is simply a performance of the socially shared, habituated practice of shopping.

An intervention like banning plastic bags triggers change in the social practice of shopping because plastic bags are one of the materials that constitute this practice. Plastic bags are used in many shopping activities (bagging groceries, carrying them home) and meanings (convenience, speed). To change the social practice of shopping after a plastic bag ban, consumers need to navigate three processes: (1) sensemaking, which means understanding and developing new meanings for the changing shopping practice; (2) accommodating, which means developing new competencies for using and handling the new materials used to shop; and (3) stabilizing, which means performing the changed practice often and efficiently. Consumers do not find these processes easy: engaging in them disrupts routines, lifestyles, and even consumers' perceptions of themselves.

In addition to changed social practices such as shopping, consumers face other challenges that prompt them to resist plastic bag bans. Plastic bags and other sustainability interventions often fail to acknowledge that individual actions are part of broader social practices and aim for individual behavioral change rather than change to the social practice itself. Consequently, consumers face three major challenges: (1) battles about who is responsible for making practices more sustainable; (2) unsettling emotions brought about by the changing practice; and (3) changes to other linked practices that dismantle their ways of life. Once these reasons for consumer resistance are known, they provide greater clarity around why consumers will push back against sustainability interventions.

"Consumer resistance interferes with social practice change, which significantly undermines the effectiveness of the sustainability intervention. Our findings show policy makers and other agents involved in sustainability interventions that changing social practices--not individual behaviors--should be their primary goal," explains Joubert. The study presents a framework for designing and managing practice-based sustainability interventions that considers the role of consumer resistance.

To plan and design a practice-based intervention, the researchers recommend the following steps:

Identify the practice being targeted (e.g., shopping), and how it is likely to be disrupted (e.g., material will be eliminated--plastic bags).

Distribute responsibility for change among those involved in the practice (e.g., consumers, retailers, bag manufacturers, government).

Determine potential emotions that may manifest (positive to leverage and negative to placate).

Identify links between the targeted practice and other social practices (e.g., the plastic bags used in shopping are also used for garbage and waste management).

Next, to monitor and adjust practice-based interventions if consumer resistance emerges, these three main strategies are recommended:

Refocus sensemaking if consumers are experiencing tension and lacking focus.

Encourage accommodation if consumers are avoiding risks and restricting their experimentation during the change process.

Accelerate stabilization if consumers are grappling with discomfort and do not seem to be able to settle with a new version of the social practice.

In May 2020, a team led by thoracic surgeon Konrad Hoetzenecker of the Department of Surgery of MedUni Vienna and Vienna General Hospital performed a lung transplant on a 44-year-old patient who had been seriously ill with Covid-19, making her the first patient in Europe to receive a lung transplant for this indication. The Vienna lung transplantation programme now plays a leading role in an international consortium comprising experts from the USA, Europe and Asia. Based on the expertise from Vienna, approximately 40 transplants have now been carried out on Covid-19 patients throughout the world. In a study published in the leading journal "The Lancet Respiratory Medicine", the consortium has now proposed the first general selection criteria for lung transplantation in Covid-19 patients.

"We have collated the first experiences in the world of performing lung transplants on Covid-19 patients. It is clear that such a complex intervention should only be considered for patients who, by virtue of their age and good general health, have a good chance of recovery with new lungs," explains Konrad Hoetzenecker, Head of the lung transplantation programme at MedUni Vienna and Vienna General Hospital. The Vienna team performs around 100 lung transplants a year, making it one of the largest programmes in the world, alongside Toronto, Cleveland and Hanover.

Medical guidelines for the world

The following factors were established as criteria for potential transplantation: exhaustion of all conservative treatment options, no recovery of the Covid-19-damaged lungs despite at least four weeks of ventilation/ECMO, evidence of advanced and irreversible lung damage in several consecutive CT scans, age below 65 and no relevant comorbidities. In addition to this, candidates for a lung transplant must be in good physical condition and have a good chance of complete physical rehabilitation following the transplant. "These guidelines can be applied worldwide for making a sound selection of patients who are suitable for a lung transplant following a Covid-19 infection."

The surgical team at MedUni Vienna and Vienna General Hospital has meanwhile carried out twelve lung transplantations on Covid-19 patients, demonstrating that even the most seriously ill patients, who would otherwise die, can survive with a lung transplant.

Patient No. 1

In March 2020, patient number one suffered total pulmonary failure as a result of Covid-19, so that artificial ventilation was no longer possible. She could only be kept alive by the circulation pump. At the time of the transplant, the PCR test showed that virus particles were still present but were no longer infectious. The MedUni Vienna/Vienna General Hospital thoracic surgeons and surgical team managed to replace the patient's completely destroyed lungs with new donor lungs.

The interfacial decomposition products forming the so-called solid-electrolyte interphase (SEI) during the first charging/discharging significantly determine the electrochemical performances of lithium (Li) batteries. To date, the dynamic evolutions, chemical compositions, stabilities and the influencing factors of the SEI films have been captured tremendous attentions.

It's noted that, in contrast to the SEI film formation at the surface of electrodes, a kind of SEI shells usually conformally forms at the outmost layer of the on-site deposited Li once the freshly deposited Li contacts with the electrolyte, which could directly influence Li nucleation, growth behaviors and electrochemical properties at the electrode/electrolyte interface.

Furthermore, the chemical/morphological instabilities of the on-site formed SEI shell pose challenges for the in-situ characterizations. Directly capturing the dynamic evolution of the SEI shells is crucial to interprete their impacts on the anode/elelctrolyte interface and battery performances.

The electrochemical atomic force microscopy (EC-AFM) enables the real-time characterization of the morphology change, mechanical modulus and potential/current distribution at the electrode/electrolyte interface under working conditions, providing an important in-situ analysis method with high spatial resolution for exploring the dynamic evolution of the on-site formed SEI shell on the deposited Li.

Recently, Prof. Li-Jun Wan and Prof. Rui Wen et al. provide the straightforward visualized evidence of SEI shells evolution during Li deposition/stripping to reveal anode degradation via in-situ EC-AFM.

During Li deposition, the quasi-spherical Li particles nucleate and grow on a Cu electrode. Subsequently, the collapse of the SEI shells is distinctly captured with the continuous Li stripping. As the cycling progresses, new Li deposits are prone to renucleating on the deposit-free sites with higher electrochemical activity. The fresh SEI shells form on freshly-deposited Li while the original SEI shells retain their collapsed morphology at the same position. Severe SEI regeneration/collapse along with electrolyte depletion and interfacial impedance increasing take one of the responsiblities for the degradation of anodes.

This work reveals the interfacial evolution at nanoscale, provides deep insights into the fundamental comprehension of SEI properties and further guides improvement strategies of the interface design in Li batteries.