Culture

MEDFORD/SOMERVILLE, Mass. (October 16, 2020)-- Researchers at Tufts University have found that those distinctly funky smells from cheese are one way that fungi communicate with bacteria, and what they are saying has a lot to do with the delicious variety of flavors that cheese has to offer. The research team found that common bacteria essential to ripening cheese can sense and respond to compounds produced by fungi in the rind and released into the air, enhancing the growth of some species of bacteria over others. The composition of bacteria, yeast and fungi that make up the cheese microbiome is critical to flavor and quality of the cheese, so figuring out how that can be controlled or modified adds science to the art of cheese making.

The discovery, published in Environmental Microbiology, also provides a model for the understanding and modification of other economically and clinically important microbiomes, such as in soil or the gastrointestinal tract.

"Humans have appreciated the diverse aromas of cheeses for hundreds of years, but how these aromas impact the biology of the cheese microbiome had not been studied," said Benjamin Wolfe, professor of biology in the School of Arts and Science at Tufts University and corresponding author of the study. "Our latest findings show that cheese microbes can use these aromas to dramatically change their biology, and the findings' importance extends beyond cheese making to other fields as well."

Many microbes produce airborne chemical compounds called volatile organic compounds, or VOCs, as they interact with their environment. A widely recognized microbial VOC is geosmin, which is emitted by soil microbes and can often be smelled after a heavy rain in forests. As bacteria and fungi grow on ripening cheeses, they secrete enzymes that break down amino acids to produce acids, alcohols, aldehydes, amines, and various sulfur compounds, while other enzymes break down fatty acids to produce esters, methyl ketones, and secondary alcohols. All of those biological products contribute to the flavor and aroma of cheese and they are the reason why Camembert, Blue cheese and Limburger have their signature smells.

The Tufts researchers found that VOCs don't just contribute to the sensory experience of cheese, but also provide a way for fungi to communicate with and "feed" bacteria in the cheese microbiome. By pairing 16 different common cheese bacteria with 5 common cheese rind fungi, the researchers found that the fungi caused responses in the bacteria ranging from strong stimulation to strong inhibition. One bacteria species, Vibrio casei, responded by growing rapidly in the presence of VOCs emitted by all five of the fungi. Other bacteria, such as Psychrobacter, only grew in response to one of the fungi (Galactomyces), and two common cheese bacteria decreased significantly in number when exposed to VOCs produced by Galactomyces.

The researchers found that the VOCs altered the expression of many genes in the bacteria, including genes that affect the way they metabolize nutrients. One metabolic mechanism that was enhanced, called the glyoxylate shunt, allows the bacteria to utilize more simple compounds as "food" when more complex sources such as glucose are unavailable. In effect, they enabled the bacteria to better "eat" some of the VOCs and use them as sources for energy and growth.

"The bacteria are able to actually eat what we perceive as smells," said Casey Cosetta, post-doctoral scholar in the department of biology at Tufts University and first author of the study. "That's important because the cheese itself provides little in the way of easily metabolized sugars such as glucose. With VOCs, the fungi are really providing a useful assist to the bacteria to help them thrive."

There are direct implications of this research for cheese producers around the world. When you walk into a cheese cave there are many VOCs released into the air as the cheeses age. These VOCs may impact how neighboring cheeses develop by promoting or inhibiting the growth of specific microbes, or by changing how the bacteria produce other biological products that add to the flavor. A better understanding of this process could enable cheese producers to manipulate the VOC environment to improve the quality and variety of flavors.

The implications of the research can even extend much further. "Now that we know that airborne chemicals can control the composition of microbiomes, we can start to think about how to control the composition of other microbiomes, for example in agriculture to improve soil quality and crop production and in medicine to help manage diseases affected by the hundreds of species of bacteria in the body," said Wolfe.

(BOSTON) -- According to current estimates, the amount of data produced by humans and machines is rising at an exponential rate, with the digital universe doubling in size every two years. Very likely, the magnetic and optical data-storage systems at our disposal won't be able to archive this fast-growing volume of digital 1s and 0s anymore at some point. Plus, they cannot safely store data for more than a century without degrading.

One solution to this pending global data-storage problem could be the development of DNA - life's very own information-storage system - into a digital data storage medium. Researchers already are encoding complex information consisting of digital code into DNA's four-letter code comprised of its A, T, G, and C nucleotide bases. DNA is an ideal storage medium because, it is stable over hundreds or thousands of years, has an extraordinary information density, and its information can be efficiently read (decoded) again with advanced sequencing techniques that are continuously getting less expensive.

What lags behind is the ability to write (encode) information into DNA. The programmed synthesis of synthetic DNA sequences still is mostly performed with a decades-old chemical procedure, known as the "phosphoramidite method", that takes many steps that, although being able to be multiplexed, can only generate DNA sequences with up to around 200 nucleotides in length and makes occasional errors. It also produces environmentally toxic by-products that are not compatible with a "clean data storage technology".

Previously, George Church's team at Harvard's Wyss Institute for Biologically Inspired Engineering and Harvard Medical School (HMS) has developed the first DNA storage approach that uses a DNA-synthesizing biological enzyme known as Terminal deoxynucleotidyl Transferase (TdT), which, in principle, can synthesize much longer DNA sequences with fewer errors. Now, the researchers have applied photolithographic techniques from the computer chip industry to enzymatic DNA synthesis, and thus developed a new method to multiplex TdT's superior DNA writing ability. In their study published in Nature Communications, they demonstrated the parallel synthesis of 12 DNA strands with varying sequences on a 1.2 square millimeter array surface.

"We have championed and intensively pursued the use of DNA as a data-archiving medium accessed infrequently, yet with very high capacity and stability. Breakthroughs by us and others have enabled an exponential rise in the amount of digital data encrypted in DNA," said corresponding author Church. "This study and other advances in enzymatic DNA synthesis will push the envelope of DNA writing much further and faster than chemical approaches." Church is a Core Faculty member at the Wyss Institute and lead of its Synthetic Biology Focus Area with DNA data storage as one of its technology development areas. He also is Professor of Genetics at HMS and Professor of Health Sciences and Technology at Harvard and MIT.

While the group's first strategy using the TdT enzyme as an effective tool for DNA synthesis and digital data storage controlled TdT's enzyme activity with a second enzyme, they show in their new study that TdT can be controlled by the high-energy photons that UV-light is composed of. A high level of control is essential as the TdT enzyme needs to be instructed to add only one single or a short block made of one of the four A, T, G, C nucleotide bases to the growing DNA strand with high precision at each cycle of the DNA synthesis process.

Using a special codec, a computational method that encodes digital information into DNA code and decodes it again, which Church's team developed in their previous study, the researchers encoded the first two measures of the "Overworld Theme" sheet music from the 1985 Nintendo Entertainment System (NES) video game Super Mario BrothersTM within 12 synthetic DNA strands. They generated those strands on an array matrix with a surface measuring merely 1.2 square millimeters by extending short DNA "primer" sequences, which were extended in a 3x4 pattern, using their photolithographic approach.

"We applied the same photolithographic approach used by the computer chip industry to manufacture chips with electrical circuits patterned with nanometer precision to write DNA," said first author Howon Lee, Ph.D., a postdoctoral fellow in Church's group at the time of the study. "This provides enzymatic DNA synthesis with the potential of unprecedented multiplexing in the production of data-encoding DNA strands."

Photolithography, like photography, uses light to transfer images onto a substrate to induce a chemical change. The computer chip industry miniaturized this process and uses silicon instead of film as a substrate. Church's team now adapted the chip industry's capabilities in their new DNA writing approach by substituting silicon with their array matrix consisting of microfluidic cells containing the short DNA primer sequences. In order to control DNA synthesis at primers positioned in the 3x4 pattern, the team directed a beam of UV-light onto a dynamic mask (as is done in computer chip manufacturing) - which essentially is a stencil of the 3x4 pattern in which DNA synthesis is activated - and shrunk the patterned beam on the other side of the mask with optical lenses down to the size of the array matrix.

"The UV-light reflected from the mask pattern precisely hits the target area of primer elongation and frees up cobalt ions, which the TdT enzyme needs in order to function, by degrading a light-sensitive "caging" molecule that shields the ions from TdT," explained co-author Daniel Wiegand, Research Scientist at the Wyss Institute. "By the time the UV-light is turned off and the TdT enzyme deactivated again with excess caging molecules, it has added a single nucleotide base or a homopolymer block of one of the four nucleotide bases to the growing primer sequences."

This cycle can be repeated multiple times whereby in each round only one of the four nucleotide bases or a homopolymer of a specific nucleotide base is added to the array matrix. In addition, by selectively covering specific openings of the mask during each cycle, the TdT enzyme only adds that specific nucleotide base to DNA primers where it is activated by UV-light, allowing the researchers to fully program the sequence of nucleotides in each of the strands.

"Photon-directed multiplexed enzymatic DNA synthesis on this newly instrumented platform can be further developed to enable much higher automated multiplexing with improved TdT enzymes, and, eventually make DNA-based data storage significantly more effective, faster, and cheaper," said co-corresponding author Richie Kohman, Ph.D., a Lead Senior Research Scientist at the Wyss' Synthetic Biology focus area, who helped coordinate the research in Church's team at the Wyss Institute.

"This new approach to enzyme-directed synthetic DNA synthesis by the Church team is a clever piece of bioinspired engineering that combines the power of DNA replication with one of the most controllable and robust manufacturing methods developed by humanity - photolithography - to provide a solution that brings us closer to the goal of establishing DNA as a usable data storage medium," said the Wyss Institute's Founding Director Don Ingber, M.D., Ph.D., who is also the Judah Folkman Professor of Vascular Biology at Harvard Medical School and Boston Children's Hospital, and Professor of Bioengineering at the Harvard John A. Paulson School of Engineering and Applied Sciences (SEAS).

CHAMPAIGN, Ill. -- Thin tissue grafts and flexible electronics have a host of applications for wound healing, regenerative medicine and biosensing. A new device inspired by an octopus's sucker rapidly transfers delicate tissue or electronic sheets to the patient, overcoming a key barrier to clinical application, according to researchers at the University of Illinois at Urbana-Champaign and collaborators.

"For the last few decades, cell or tissue sheets have been increasingly used to treat injured or diseased tissues. A crucial aspect of tissue transplantation surgery, such as corneal tissue transplantation surgery, is surgical gripping and safe transplantation of soft tissues. However, handling these living substances remains a grand challenge because they are fragile and easily crumple when picking them up from the culture media," said study leader Hyunjoon Kong, a professor of chemical and biomolecular engineering at Illinois.

Kong's group, along with collaborators at Purdue University, the University of Illinois at Chicago, Chung-Ang University in South Korea, and the Korea Advanced Institute for Science and Technology, published their work in the journal Science Advances.

Current methods of transferring the sheets involve growing them on a temperature-sensitive soft polymer that, once transferred, shrinks and releases the thin film. However, this process takes 30-60 minutes to transfer a single sheet, requires skilled technicians and runs the risk of tearing or wrinkling, Kong said.

"During surgery, surgeons must minimize the risk of damage to soft tissues and transplant quickly, without contamination. Also, transfer of ultrathin materials without wrinkle or damage is another crucial aspect," Kong said.

Seeking a way to quickly pick up and release the thin, delicate sheets of cells or electronics without damaging them, the researchers turned to the animal kingdom for inspiration. Seeing the way an octopus or squid can pick up both wet and dry objects of all shapes with small pressure changes in their muscle-powered suction cups, rather than a sticky chemical adhesive, gave the researchers an idea.

They designed a manipulator made of a temperature-responsive layer of soft hydrogel attached to an electric heater. To pick up a thin sheet, the researchers gently heat the hydrogel to shrink it, then press it to the sheet and turn off the heat. The hydrogel expands slightly, creating suction with the soft tissue or flexible electronic film so it can be lifted and transferred. Then they gently place the thin film on the target and turn the heater back on, shrinking the hydrogel and releasing the sheet.

The entire process takes about 10 seconds. See a video at https://youtu.be/EhMySEk-lRw.

Next, the researchers hope to integrate sensors into the manipulator, to further take advantage of their soft, bio-inspired design.

"For example, by integrating pressure sensors with the manipulator, it would be possible to monitor the deformation of target objects during contact and, in turn, adjust the suction force to a level at which materials retain their structural integrity and functionality," Kong said. "By doing so, we can improve the safety and accuracy of handling these materials. In addition, we aim to examine therapeutic efficacy of cells and tissues transferred by the soft manipulator."

SAN ANTONIO, Texas, USA - American and Polish scientists, reporting Oct. 16 in the journal Science Advances, laid out a novel rationale for COVID-19 drug design - blocking a molecular "scissor" that the virus uses for virus production and to disable human proteins crucial to the immune response.

The researchers are from The University of Texas Health Science Center at San Antonio (UT Health San Antonio) and the Wroclaw University of Science and Technology. Information gleaned by the American team helped Polish chemists to develop two molecules that inhibit the cutter, an enzyme called SARS-CoV-2-PLpro.

SARS-CoV-2-PLpro promotes infection by sensing and processing both viral and human proteins, said senior author Shaun K. Olsen, PhD, associate professor of biochemistry and structural biology in the Joe R. and Teresa Lozano Long School of Medicine at UT Health San Antonio.

"This enzyme executes a double-whammy," Dr. Olsen said. "It stimulates the release of proteins that are essential for the virus to replicate, and it also inhibits molecules called cytokines and chemokines that signal the immune system to attack the infection," Dr. Olsen said.

SARS-CoV-2-PLpro cuts human proteins ubiquitin and ISG15, which help maintain protein integrity. "The enzyme acts like a molecular scissor," Dr. Olsen said. "It cleaves ubiquitin and ISG15 away from other proteins, which reverses their normal effects."

Dr. Olsen's team, which recently moved to the Long School of Medicine at UT Health San Antonio from the Medical University of South Carolina, solved the three-dimensional structures of SARS-CoV-2-PLpro and the two inhibitor molecules, which are called VIR250 and VIR251. X-ray crystallography was performed at the Argonne National Laboratory near Chicago.

"Our collaborator, Dr. Marcin Drag, and his team developed the inhibitors, which are very efficient at blocking the activity of SARS-CoV-2-PLpro, yet do not recognize other similar enzymes in human cells," Dr. Olsen said. "This is a critical point: The inhibitor is specific for this one viral enzyme and doesn't cross-react with human enzymes with a similar function."

Specificity will be a key determinant of therapeutic value down the road, he said.

The American team also compared SARS-CoV-2-PLpro against similar enzymes from coronaviruses of recent decades, SARS-CoV-1 and MERS. They learned that SARS-CoV-2-PLpro processes ubiquitin and ISG15 much differently than its SARS-1 counterpart.

"One of the key questions is whether that accounts for some of the differences we see in how those viruses affect humans, if at all," Dr. Olsen said.

By understanding similarities and differences of these enzymes in various coronaviruses, it may be possible to develop inhibitors that are effective against multiple viruses, and these inhibitors potentially could be modified when other coronavirus variants emerge in the future, he said.

NEW YORK, NY (Oct. 16)--Adults and children born with heart defects had a lower-than-expected risk of developing moderate or severe COVID-19 symptoms, finds a study of more than 7,000 patients from the congenital heart disease center at Columbia University Vagelos College of Physicians and Surgeons.

Throughout the course of the pandemic, evidence has shown that individuals with heart disease have a higher risk of life-threatening illness and complications from COVID-19. But the impact of SARS-CoV-2 infection on individuals with congenital heart defects, who are generally younger than those with adult-onset heart disease, was unknown.

About 1% (40,000) of babies born each year in the United States have one or more heart defects.

"At the beginning of the pandemic, many feared that congenital heart disease would be as big a risk factor for severe COVID-19 as adult-onset cardiovascular disease," says Matthew Lewis, MD, assistant professor of medicine at Columbia University Vagelos College of Physicians and Surgeons and co-leader of the study. "We were reassured by the low number of congenital heart patients who required hospitalization for COVID-19 and the relatively good outcomes of these patients."

Few congenital heart patients had COVID-19

Only 53 congenital heart patients (43 adults and 10 children)--less than 0.8% of patients at Columbia's congenital heart center--presented to their physician with symptoms of SARS-CoV-2 infection from March through June. (During the study period, an estimated 20% of people in the New York metropolitan area are thought to have been infected with the coronavirus.)

More than 80% (43) of these patients had mild symptoms. Of the 9 patients who developed moderate to severe symptoms, 3 died. (Another study performed at Columbia University Irving Medical Center during the same period found that roughly 22% of hospitalized patients from the general population became critically ill and about one-third of those patients died.)

In the new study, the researchers found that patients with a genetic syndrome and adults with advanced disease from their congenital heart defect were more likely to develop moderate to severe symptoms, though an individual's type of congenital heart defect did not impact symptoms severity.

Though the study sample was small, the researchers conclude that congenital heart disease alone may not be enough to increase the risk of severe COVID-19 symptoms.

Caveats

It's unlikely that people with congenital heart disease have an intrinsically lower risk of becoming severely ill from the new coronavirus, and the researchers hypothesize that the patients in this study may have adhered more strictly to social distancing guidelines compared with the general population, given the publicity about increased COVID-19 risk in patients with heart disease. The researchers caution that individuals with congenital heart disease should continue to practice strict social distancing and follow all CDC guidelines as these measures are likely contributing to the study findings.

They also note that the younger average age (34 years) of these patients and lower incidence of acquired cardiac risk factors compared with other individuals who had severe COVID-19 may explain why fewer congenital heart patients than expected had severe symptoms.

"It's possible that elderly patients with congenital heart disease might have a different risk profile than the general population," adds Brett Anderson, Florence Irving Assistant Professor of Pediatrics at Columbia University Vagelos College of Physicians and Surgeons and co-leader of the study. "We have yet to define what those risk factors are."

NEW YORK - October 16, 2020 - Results from the randomized controlled TARGET FFR trial show that while a physiology-guided percutaneous coronary intervention (PCI) optimization strategy did not achieve a significant increase in the proportion of patients with final FFR ?0.90, it reduced the proportion of patients with a residual FFR ?0.80 following PCI.

Findings were reported today at TCT Connect, the 32nd annual scientific symposium of the Cardiovascular Research Foundation (CRF). TCT is the world's premier educational meeting specializing in interventional cardiovascular medicine.

260 patients were successfully randomized between March 2018 and November 2019 at a single site. Following angiographically successful PCI procedures, patients were randomized (1:1) to receive either a physiology-guided incremental optimization strategy (PIOS intervention group, n=131) or blinded post-PCI coronary physiology measurements (control group, n=129). Patients undergoing successful, standard-of-care PCI for either stable angina or medically stabilized non-ST-segment-elevation myocardial infarction (NSTEMI) were eligible for randomization.

The trial's primary endpoint was defined as the proportion of patients with a final post-PCI FFR result ?0.90. The study found that the incidence of final FFR ?0.90 was 10% higher in the PIOS group than the control group but that the difference was not statistically significant (38.1% vs. 28.1%, p=0.099). However, the study's secondary endpoint, the proportion of patients with final FFR ?0.80, was significantly lower in the PIOS group (18.6% vs 29.8%, p=0.045).

Based on FFR pullback assessment of the stented vessel, a target for further optimization was present in 60 of the 131 (46%) patients randomized to PIOS, and operators considered it appropriate to perform additional post-dilatation +/- stenting in 40 of these 60 (66%) patients. Among patients who had further intervention/optimization performed, mean post-PCI FFR increased significantly from 0.76 to 0.82 (p

"When assessing the proposed optimal post-PCI FFR cutoff value of ?0.90, we found that the majority of patients with angiographically acceptable PCI results actually have a physiologically suboptimal outcome," said Damien Collison, MD, Interventional Cardiologist at the Golden Jubilee National Hospital, Glasgow, Scotland. "Up to 30% of patients may even have a final FFR result that remains below the guideline-directed threshold for performing revascularization in the first place. In our randomized controlled trial, application of an FFR-guided optimization strategy after stenting led to improvements in both FFR and CFR and significantly reduced the proportion of patients with a final post-PCI FFR ?0.80."

The TARGET FFR trial was funded by NHS National Waiting Times Centre Board endowment funds. Dr. Collison reported the following disclosures: consulting fees/honoraria from Abbott Medical and MedAlliance.

The most important components for the functioning of a biological cell are its proteins. As a result, protein production is arguably the most important process for cell growth. The faster the bacterial growth rate, the faster protein synthesis needs to take place. Because protein synthesis is the most expensive cellular process in terms of cellular resources usage, it appears reasonable to assume that the cell to increases production capacities by hosting more copies of the complicated machinery in proportion to its growth rate. This would mean that in order for growth to double, twice as many copies of all components of the translation machinery would be needed.

It has been clear since the 1960s, however, that it's not that simple. Instead, the composition of the 'cocktail' of individual components in the machinery, which itself is made from proteins and RNA, varies with the growth rate. A new, complex computer model developed in Düsseldorf shows what concentrations of the individual components are needed in order to produce different synthesis rates, explaining for the first time the reasons behind the observed variations across growth conditions.

Xiao-Pan Hu, a doctoral student in Prof. Dr. Martin Lercher's Computational Cell Biology group at the HHU, developed the model. Hu used computer modelling to encode established biochemical principles at the cellular level. The resulting model can be used to calculate the speed with which a cell can produce its components and thus predicts cell growth based on a predefined composition of its machinery.

Theoretically, each production rate can be realised using a large number of different molecule concentrations. The question is: What does nature do? Which one of the many feasible compositions do real Escherichia coli ('E. coli') bacteria use and why? Hu and his colleagues have based their work on a simple assumption reflected everywhere in nature: an organism generally has an evolutionary advantage if it needs as few resources as possible for its development. Consequently, the team searched through the many possible compositions for the one that is 'cheapest' for the cell, i.e., the one that requires the smallest possible total mass of molecules.

Comparisons with experimental data show that this assumption is correct and accurately predicts the concentrations measured in real E. coli bacteria colonies. This allowed the Düsseldorf-based research team not only to describe the data quantitatively but also to actually understand the reasons behind the data, namely that a principle found in many other areas of life also applies here.

In further analyses, the model also proved accurate for situations where the bacteria are exposed to antibiotics. In exceptional circumstances like these, the bacteria are particularly stressed and need a toolset that is arranged differently in order to grow.

The research group is currently investigating whether the findings for protein synthesis can also be applied to other cellular processes and other organisms. The models developed as part of this work should also help to design biotech procedures more efficiently. They make it possible to calculate the optimum concentrations of the individual components in the cell for the desired biological production.

Bottom Line:

Baseline levels of circulating tumor DNA (ctDNA) predicted responses to first-line, but not second-line, immune checkpoint inhibition in patients with melanoma.

Journal in Which the Study was Published:

Clinical Cancer Research, a journal of the American Association for Cancer Research

Author:

Elin Gray, PhD, an associate professor at Edith Cowan University in Australia and senior author on the study

Background:

"Immunotherapy has become an increasingly common treatment for patients with melanoma, often as the second-line treatment after disease progression on BRAF inhibitors," explained Gray. "There is a lot of interest in identifying biomarkers that reliably indicate how patients will respond to this treatment."

Circulating tumor DNA (ctDNA) is shed from tumors and can be detected in the bloodstream. ctDNA levels have been shown to correlate with responses to targeted therapies in patients with melanoma, but the potential of ctDNA to predict responses to immunotherapy remained unclear.

How the Study was Conducted:

In this study, Gray and colleagues prospectively examined the association between baseline (pre-treatment) ctDNA levels and clinical outcomes in a discovery cohort of 125 adult patients with metastatic melanoma. Thirty-two patients were treated with immune checkpoint inhibition in the first-line setting, while 27 patients received immune checkpoint inhibition in the second-line setting. The remaining 66 patients were not treated with immune checkpoint inhibition and instead received first-line treatment with targeted therapy.

Results:

Consistent with previous studies, patients with low baseline ctDNA levels (fewer than or equal to 20 copies per milliliter) who were treated with targeted therapy had longer progression-free survival than those with high baseline ctDNA levels (greater than 20 copies per milliliter). In patients treated with first-line immune checkpoint inhibition, those with low baseline ctDNA levels had an 80 percent longer progression-free survival than those with high ctDNA levels. Baseline ctDNA levels were associated with progression-free survival after first-line immune checkpoint inhibition even after controlling for other factors, such as sex, age, tumor stage, BRAF mutation status, and brain metastases. In contrast, there was no significant association between baseline ctDNA levels and progression-free survival in patients who received immune checkpoint inhibitors in the second-line setting.

Gray and colleagues then verified these results in a separate validation cohort of 128 patients with melanoma recruited at other institutions across Australia (the Melanoma Institute Australia and the Peter MacCallum Cancer Centre). Patients in the validation cohort were treated with immune checkpoint inhibition in either the first- or second-line setting (77 and 51 patients, respectively). Similar to results seen in the discovery cohort, baseline ctDNA levels were associated with progression-free survival in patients who received first-line immune checkpoint inhibition, but not in those who received second-line immune checkpoint inhibition. In patients treated with first-line immune checkpoint inhibition, low baseline ctDNA levels were associated with a 58 percent longer progression-free survival than those with high baseline ctDNA levels. The association was independent of sex, age, tumor stage, BRAF mutation status, and brain metastases.

In addition, the authors observed that patients with high ctDNA levels who were treated with combination immune checkpoint inhibition (anti-CTLA4 and anti-PD1) had longer progression-free survival and overall survival than those treated with a single agent (anti-PD1); however, these results were not statistically significant. Gray cautioned that these results were obtained by combining the discovery and validation cohorts and therefore require independent validation. She added that these results, if validated, highlight a potential for ctDNA to identify patients who are more likely to benefit from combination immunotherapy.

Author's Comments:

"Our results indicate that it is necessary to carefully consider context when implementing biomarkers," said Gray. "ctDNA is often heralded as a good prognostic biomarker, but we found that this is not the case for patients receiving immune checkpoint inhibitors in the second-line setting.

"We need more of these kinds of studies evaluating the accuracy of ctDNA in various disease contexts, particularly now that liquid biopsy and ctDNA are being increasingly incorporated into the clinic," she added.

Future work from Gray and colleagues will aim to understand how tumor biology and the tumor site affect the release of ctDNA. In addition, they are interested in evaluating ctDNA as a biomarker of disease progression.

Study Limitations:

Limitations of the study included small sample sizes within some subgroups and potential variability in how progressive disease was measured among different patients.

The National Institutes of Health has launched an adaptive Phase 3 clinical trial to evaluate the safety and efficacy of three immune modulator drugs in hospitalized adults with COVID-19. Some COVID-19 patients experience an immune response in which the immune system unleashes excessive amounts of proteins that trigger inflammation -- called a "cytokine storm" -- that can lead to acute respiratory distress syndrome, multiple organ failure and other life-threatening complications. The clinical trial aims to determine if modulating that immune response can reduce the need for ventilators and shorten hospital stays. The trial, known as ACTIV-1 Immune Modulators (IM), will determine if the therapeutics are able to restore balance to an overactive immune system.

Part of the Accelerating COVID-19 Therapeutic Interventions and Vaccines (ACTIV) initiative, the trial expects to enroll approximately 2,100 hospitalized adults with moderate to severe COVID-19 at medical facilities in the United States and Latin America. The National Center for Advancing Translational Sciences (NCATS), part of NIH, will coordinate and oversee the trial with funding support from the Biomedical Advanced Research and Development Authority (BARDA) of the U.S. Department of Health and Human Services Office of the Assistant Secretary for Preparedness and Response, in support of the Trump administration's Operation Warp Speed goals. BARDA's Clinical Studies Network will be responsible for operationalizing the trial through a task order awarded to contract research organization Technical Resources International, Inc.

"This is the fifth master protocol to be launched under the ACTIV partnership in an unprecedented timeframe, and focuses efforts on therapies that hold the greatest promise for treating COVID-19," said NIH Director Francis S. Collins, M.D., Ph.D. "Immune modulators provide another treatment modality in the ACTIV therapeutic toolkit to help manage the complex, multi-system conditions that can be caused by this very serious disease."

ACTIV-1 IM is a randomized, placebo-controlled trial that uses an adaptive master protocol. One of the hallmarks of master protocols is that they allow coordinated and efficient evaluation of multiple investigational agents as they become available. This enables maximum flexibility to swiftly weed out drugs that do not demonstrate effectiveness, identify those that do in a short time frame, and rapidly incorporate additional experimental agents into the trial.

The ACTIV public-private partnership selected three agents for the study from a pool of over 130 immune modulators initially reviewed based on several factors, including their relevance to COVID-19, strong evidence for use against inflammatory reaction and cytokine storm, and availability for large-scale clinical studies. The initial agents are infliximab (REMICADE), developed by Janssen Research & Development, LLC., one of the Janssen Pharmaceutical Companies of Johnson & Johnson; abatacept (ORENCIA), developed by Bristol Myers Squibb; and Cenicriviroc (CVC), an investigational late-stage agent developed by AbbVie.

All participants in the trial will receive remdesivir, which is the current standard of care treatment of hospitalized patients with COVID-19. Convalescent plasma and dexamethasone will be allowed at the discretion of the site investigator and in accordance with national guidelines. They will be randomly assigned to receive a placebo or one of the immune modulators as an add-on treatment. The trial will study the different combination treatment regimens with respect to illness severity, recovery speed, mortality and hospital resource utilization.

Enrollment is now open, and the trial is expected to last approximately six months. Results will be available shortly after the trial is completed, or possibly sooner if analysis conducted during the trial indicates that one or more of the drugs is beneficial. To ensure that the trial is being conducted in a safe and effective manner, an independent data and safety monitoring board will oversee the trial and conduct periodic reviews of the accumulating data.

The protocol team chair is William G. Powderly, M.D., director of the Institute for Clinical and Translational Sciences and co-director of the Division of Infectious Diseases at Washington University School of Medicine in St. Louis. NCATS' Clinical and Translational Science Awards (CTSA) Program and the Trial Innovation Network will play a key role in adding U.S. study sites and enrolling patients, including those from communities disproportionately affected by COVID-19.

"The CTSA Program's nimbleness and innovation in conducting clinical trials--along with the network's extensive capacity and broad geographical reach--have positioned it to rapidly implement this important trial," said NCATS Director Christopher P. Austin, M.D. "The innovative trial design will allow efficient evaluation of three different potential COVID-19 treatments concurrently, delivering new possible treatments for patients more quickly and valuable insights into the science of clinical translation."

Animal cooperation typically involves sharing crucial resources -- and the rules of sharing get complicated, especially when males are involved.

Natural selection theory dictates that males generally compete with each other for food and mates. Thus male cooperation in the animal world is an enigma, especially among unrelated animals.

In a new paper published in Scientific Reports, biologists from the Wildlife Institute of India and the University of Minnesota demonstrated the hows and whys of cooperation among male lions. By studying one of the rarest lion populations in the world -- the Asian lions that live as a single population in the Gir Forest of India -- researchers found that cooperation among lions does not necessarily indicate that they are related.

"In a 2017 study, we detailed the behavioural nuances of why male lions cooperate: to better protect their territories and have more access to mating opportunities than males who live alone," said study lead author Stotra Chakrabarti, a postdoctoral research associate in the Department of Fisheries, Wildlife, and Conservation Biology at the University of Minnesota. "However, a lack of genetic data from the population at this stage had prevented us from determining if such cooperation extended to relatives only, or whether non-kin were included as well."

Subsequent monitoring of individual lions and collection of tissue, hair and blood samples from known individuals set the stage to find out whether the cooperating males were related or they came together by chance.

"Genetic analyses of the Gir lions were tricky because they have undergone two population bottlenecks that have rendered discerning kin versus non-kin quite challenging," said Vishnupriya Kolipakam, co-author and faculty at the Wildlife Institute of India..

By synthesizing long-term behavioural and genetic records of known mothers, offspring and siblings, researchers were able to develop a baseline panel against which male coalition partners were compared to understand the level of relatedness between them.

By observing 23 male lions belonging to 10 coalitions, Chakrabarti and co-authors could identify that males who lived in large coalitions (such as trios and quartets) were typically brothers and cousins, but more than 70 percent of pairs consisted of unrelated males.

In large coalitions, sharing is costlier because resources are divided between many lions, and often low-ranking partners are excluded from opportunities to breed. Such coalitions are only possible between related animals.

"Forgoing mating opportunities is generally a severe evolutionary cost, unless in doing so you help related individuals," said Joseph Bump, co-author and associate professor at the University of Minnesota. "As a consequence, this evidence supports a conclusion that large male lion coalitions are feasible only when all partners are brothers and/or cousins."

Large coalitions fared the best as a group, but the fitness of individual lions -- measured by the number of potential offspring sired -- was higher in pairs. Such high fitness for individual male lions in pairs allowed even unrelated individuals to team up, because pairs always fared better than single males in terms of territory and mate acquisition.

"The results of our study show that male coalitions prosper better than loners in established lion societies and this can have crucial implications for their conservation, especially when establishing new populations through reintroductions," said YV Jhala, principal investigator of the Gir lion project and the Dean of the Wildlife Institute of India.

Though large coalitions fared better as a group, they are rare in the Gir system because so few sets of sibling lions grow to maturity. An analysis of 20 years of lion demography data indicates only 12%-13% of the observed lion coalitions in Gir are made of three or four males.

"This calculation of demography and the availability of kin to support cooperation is often missing from studies on animal societies, but it is of fundamental value that enhances our understanding of how optimality in group formation is constrained in the real world," Jhala said.

The study revealed new details about the behavior of male lions. For example, in a rare observation, researchers determined one of the study's coalitions could be a father-son duo because they were related and had an age difference of about five years.

"Such an observation was only possible because we could combine field observations with genetic data, and it shows that there could be multiple pathways for coalition formation in lions," said Kolipakam.

Researchers also observed that related male partners were no more likely to support each other during fights with rivals than unrelated partners.

"This shows that kin support is not the only reason why males cooperate with each other, but kin support makes the cooperation even more beneficial," Bump said.

The study indicates that underlying mechanisms facilitating cooperation in lions can be multifaceted.

"We have quantified the ultimate reasons why unrelated males team up, but it would be worthwhile to investigate other aspects of male cooperation, including how their bonds are forged in the first place, how they find compatible partners, what breaks the ice between them when they first meet and how they decide who will lead and who will follow." Chakrabarti said.

Washington, DC - October 16, 2020 - In the absence of approved, effective treatments for COVID-19, some hospitals have been treating patients with severe COVID symptoms with blood plasma from recovering patients. The blood of recovered patients contains antibodies that act against the coronavirus. While plasma hasn't yet shown a benefit in randomized trials, some small retrospective studies suggest it may reduce illness severity and reduce hospitalization time.

This week in mBio, an open-access journal of the American Society for Microbiology, researchers report that antibody levels in the blood of COVID-19 patients drop rapidly during the weeks after their bodies have cleared the virus and symptoms have subsided. If convalescent plasma is ultimately shown to have a clear benefit, the authors concluded, then it needs to be collected during a specific window of time after recovery. However, recovering patients can't donate blood until at least 14 days after symptoms have subsided, to give the body time to clear viral particles.

"We don't want to transfuse the virus, just transfuse the antibodies," said Andrés Finzi, Ph.D., at the University of Montreal, in Canada. "But at the same time, our work shows that the capacity of the plasma to neutralize viral particles is going down during those first weeks."

The spike protein of SARS-CoV-2 plays a crucial role in helping the virus grab and invade host cells. Antibodies produced by the body's immune system bind to a part of this protein and block the capacity of this "key" to engage with the host's cellular "lock", said Finzi, preventing the viral particle from infecting a cell host.

Previous studies suggest that antibodies against the SARS-CoV-2 spike protein peak 2 or 3 weeks after the onset of symptoms. Findings from an earlier cross-sectional study by Finzi's group, involving more than 100 patients, suggested that the ability of plasma to neutralize the virus decreased significantly between 3 and 6 weeks after symptom onset.

In the new longitudinal study, Finzi and his colleagues analyzed blood samples collected at one-month intervals from 31 individuals recovering from COVID-19. They measured levels of immunoglobulins that act against the coronavirus S protein and tested the ability of the antibodies to neutralize the virus.

The researchers observed variation on the level of individual patients but identified a consistent overall signal: The levels of Immunoglobulins G, A, and M that target the binding site decreased between 6 and 10 weeks after symptoms began. During the same time period, the ability of the antibodies to neutralize the virus similarly fell.

Finzi's group has continued to study blood samples from the patients. Understanding how the levels of antibodies change over time, he said, is critical not only for optimizing the use of convalescent plasma but also for understanding vaccine efficacy and whether or not previously infected people are at risk of re-infection.

"How long do antibodies protect you?" he asked.

Finzi's other research focuses on the immune response to human immunodeficiency virus, or HIV, which differs dramatically from SARS-CoV-2.

"Essential services" is a phrase that has become commonplace in the era of COVID-19. In a new commentary piece, scholars from Lehigh University and Ohio State University argue that LGBTQ+ college and university campus resource centers are essential to the health, well-being and academic achievement of LGBTQ+ students. These centers, they write, are uniquely positioned to meet the needs of these students during COVID-19 and, as such, must continue to receive support and funding.

"Why LGBTQ+ Campus Resource Centers are Essential" has been published by Psychology of Sexual Orientation and Gender Diversity, a publication of the American Psychological Association and is authored by Chelsea Gilbert, PhD student in Educational Studies at Ohio State University; Nicole L. Johnson, a faculty member in Counseling Psychology at Lehigh University; Claire Siepser, Master of Education student in Counseling Psychology at Lehigh University; and, Ann E. Fink, a faculty member in the Department of Biological Sciences at Lehigh University.

"LGBTQ+ populations are particularly vulnerable to certain stressors and risks at play during the COVID-19 pandemic, particularly if they also belong to other marginalized social groups," says Fink. "LGBTQ+ Campus Centers are essential resources for LGBTQ+ students and require adequate funding and institutional support."

Lesbian, Gay, Bisexual, Transgender, Queer (LGBTQ) and other marginalized genders and sexualities (+) face well-documented health disparities, according to information distributed by the Centers for Disease Control and Prevention. These disparities have been exacerbated by the pandemic. The authors specifically cite research which finds significantly higher risk for COVID-19 among the houseless and the fact that LGBTQ+ youth have higher rates of houselessness than the general population. In addition, they write that "The current administration's reversal of non-discrimination protections for LGBTQ+ individuals within healthcare settings has likely exacerbated these concerns around negative experiences...For those who do access care for COVID-19-related symptoms, a lack of LGBTQ+-competent providers may increase their vulnerability within healthcare settings..."

College students often experience marginalization and discrimination, according to a 2014 study that found that more than 25% of Lesgian, Gay and Bisexual college students either witnessed or experienced some of form of harassment which correlated with increased reports of anxiety and depression.

"College students' experiences shifted dramatically as a result of COVID-19, often to the detriment of their health and well-being. For example, many LGBTQ+ students returned to unsafe and/or unsupportive homes when they were unable to remain on-campus; the abrupt and unexpected shift into these harmful and traumatic environments has exacerbated the need for additional support services..." they write.

"These are challenging times within higher education, and tough budgetary decisions are being made daily," says Gilbert, who for five years served as the Director of the Pride Center for Sexual Orientation & Gender Diversity at Lehigh. "It is my hope that decision-makers for these budgets might read our piece and consider the ways that LGBTQ+ student services provide invaluable resources to campus communities in light of COVID-19."

According to the Campus LGBTQ Centers Directory, there are over 275 LGBTQ+ campus resource centers in the U.S. Research demonstrates that the presence of these centers is correlated with lower levels of discrimination, less distress and increased self-acceptance akong LGBTQ+ students. The core functions of these campus resource centers fall into three categories, the authors write: counseling, support and student sense of belonging; education and training; and, advocacy for LGBTQ+ students.

"It is my hope that the individuals who are in charge of making challenging decisions about what is considered essential during times of crisis will read this piece and see the true need for LGBTQ+ student services, especially in the midst of a pandemic," says Johnson.

Adds Siepser: "It is difficult to assess the depth and longevity of the psychological impact of this crisis and thus it is important to continue to support the LGBTQ+ students who are being disproportionately affected by COVID-19."

The authors call on administrators, faculty and students to undertake efforts to ensure that "institutional leaders and decision-makers understand the gravity of LGBTQ+ student needs under COVID-19 and then act to meet those needs."

"Students, faculty, and staff who may not have direct control over these decisions, can use their voices to advocate for such important decisions," says Johnson "This article includes a section dedicated to suggestions for action that we hope inspires many to do just that. Take action!"

A new Alzheimer's study found that impaired blood flow in the brain is correlated with the buildup of tau tangles, a hallmark indicator of cognitive decline.

The work, published this week in the Journal of Neuroscience, suggests that treatments targeting vascular health in the brain -- as well as amyloid plaques and tau tangles -- may be more effective in preserving memory and cognitive function than single-target therapies.

"This study confirms that we should carefully consider vascular health and associated risk factors -- like high blood pressure, smoking and physical inactivity -- in the course of Alzheimer's prevention," said Judy Pa, an associate professor of neurology at the Keck School of Medicine of USC's Mark and Mary Stevens Neuroimaging and Informatics Institute (INI) and the study's senior author.

Researchers wanted to understand how restricted blood flow in the brain relates to the buildup of tau proteins characteristic of Alzheimer's disease. To do so, the team examined MRI and PET images, as well as cerebrospinal fluid, among two groups: cognitively normal individuals and those at various stages of dementia, including mild cognitive impairment and Alzheimer's disease.

Pa and her colleagues found that those with a strong overlap between vascular dysfunction and tau pathology in key Alzheimer's brain regions had the worst cognitive symptoms.

"This connection was most pronounced among those in more advanced stages of the disease, suggesting that the pathway corresponds to cognitive decline over time," Pa said.

That finding is particularly important because it suggests the pathway could be a useful biological marker for measuring Alzheimer's progression in patients. The effect was also most pronounced in amyloid-positive individuals, pointing to a relationship between cerebrovascular, tau and amyloid pathologies.

The research team included a group of experts from the INI and across the Keck School of Medicine's departments of neurology, radiology and physiology and neuroscience. Future steps include evaluating how the synergy between these pathologies relates to cognitive decline over time.

"We're now starting to fully appreciate the role of vascular dysfunction in Alzheimer's disease," said Arthur W. Toga, a coauthor of the study and director of the INI. "Controlling risk factors like smoking and high blood pressure are accessible lifestyle modifications that offer hope for those at risk."

PISCATAWAY, NJ - When governments create a minimum price for alcoholic beverages, deaths and hospitalizations related to alcohol use significantly decrease, according to results from a new report in the Journal of Studies on Alcohol and Drugs.

Called "minimum unit pricing," such policies "would result in a substantial and lasting reduction in the harms caused by alcohol in society," says lead researcher Adam Sherk, Ph.D., of the Canadian Institute for Substance Use Research at the University of Victoria in British Columbia, Canada.

"As we continue to weather the COVID-19 pandemic and hear concerns about overwhelming our health care systems, this study shows that a minimum unit price for alcohol would help to free up valuable resources by decreasing alcohol's burden on our health care systems," says Sherk.

Minimum unit pricing strategies set a "floor price" for alcohol sales. Specifically, a standard drink -- defined by pure alcohol content [in Canada and the United States, about the amount of ethanol in a 5% bottle of beer] -- cannot be sold below a predetermined value. Such policies help prevent the sale of cheap drinks with high alcohol content. They tend to have their largest effect on inexpensive spirits and the smallest effect on wine.

Similar pricing strategies have already been implemented with initial success in places such as Scotland, Wales and some provinces in Canada. In their study, Sherk and his colleagues sought to determine the potential effect of minimum unit pricing in Québec, a province that has yet to institute such a policy.

For their research, the investigators used a new, open-access model -- the International Model of Alcohol Harms and Policies (InterMAHP) -- which can be used to estimate alcohol harms in a country or state as well as the potential health impact of alcohol policies designed to limit such harms.

Using this model, Sherk and his colleagues input per capita alcohol use data from the Canadian Institute for Substance Use Research. Further, data about hospitalizations and deaths were obtained from government statistics, as was information about sales of wine, spirits and liqueurs (which are partially controlled by the government in Canada). Information about beer sales was obtained from the market research company Nielsen.

In Québec in 2014, the year analyzed, there were an estimated 2,850 deaths and 24,694 hospitalizations attributable to alcohol use, the researchers found. These included deaths from cancer, cardiovascular conditions, and injuries. The leading causes of hospitalizations from alcohol use were unintentional injuries, psychiatric conditions, cancer, digestive conditions, and communicable disease.

The researchers' modeling determined that, if the province had previously instituted a minimum unit pricing policy of CAD$1.50 per standard drink (about USD$1.12), 169 deaths would have been prevented, a reduction of 5.9 percent. Having instituted a minimum unit price of CAD$1.75 per drink (about USD$1.31) would have prevented 327 deaths, a decrease of 11.5 percent.

Further, a minimum unit pricing policy of CAD$1.50 per drink would have resulted in 2,063 fewer hospitalizations that year (an 8.4 percent decrease). A price of CAD$1.75 would have reduced hospitalizations by 4,014, or 16.3 percent.

But what impact would this pricing have on any purported health benefits of alcohol? Although their data did show that alcohol use was related to decreased hospitalizations for cardiovascular conditions and diabetes, the modeling demonstrated that minimum unit pricing would have prevented even more hospitalizations.

"This report adds to the growing body of evidence that minimum unit pricing policies are an effective way for governments to reduce alcohol-related hospital visits and save lives," says Sherk. "National and jurisdictional governments, including Québec, should consider following the lead of countries like Scotland and implementing these policies."

(To learn more about The International Model of Alcohol Harms and Policies [InterMAHP], visit http://www.intermahp.cisur.ca.)

The increased adherence of women to Coronavirus policies may be one of the reasons for the lower vulnerability and mortality that they experienced, compared to men, in the early phase of the epidemic. "Policy makers who promote a new normality made of reduced mobility, face masks and other behavioral changes," says Vincenzo Galasso, one of the authors of a new study on gender differences in the reaction to COVID-19, "should, therefore, design a gender-differentiated communication if they want to increase the compliance of men."

Two of the authors of the research, which appeared on PNAS (Proceedings of the National Academy of Sciences) are scholars of Bocconi University, Vincenzo Galasso and Paola Profeta, affiliated to Bocconi's COVID Crisis Lab.

The authors observe substantial gender differences in both attitudes and behaviors through a two-wave survey (March and April 2020), with 21,649 respondents in Australia, Austria, France, Germany, Italy, New Zealand, the UK and the US, which is part of the international project REPEAT (REpresentations, PErceptions and ATtitudes on the COVID-19).

Women around the world are more inclined than men to consider COVID-19 a very serious health problem (59% against 48.7% in March and 39.6% against 33% in April), they are more inclined to agree with public policies that fight the pandemic, such as mobility restrictions and social distancing (54,1 against 47,7 in an index that goes from 1 to 100 in March and 42,6 against 37,4 in April) and are clearly more inclined to follow the rules concerning COVID-19 (88,1% against 83,2% in March and 77,6% against 71,8% in April).

The share of individuals complying with the rules drops over time, particularly in Germany, from 85.8% of women and 81.5% of men in March to 70.5% of women and 63.7% of men in April, but the large gender gap persists.

"The biggest differences between men and women relate to behaviors that serve to protect others above all, such as coughing in the elbow, unlike those that can protect both themselves and others," says Profeta.
Gender differences persist even after the study controlled a large number of sociodemographic characteristics and psychological factors.

However, such differences are smaller among married couples, who live together and share their views with each other, and among individuals most directly exposed to the pandemic. They decrease over time if men and women are exposed to the same flow of information about the pandemic.