Culture

Access to the Internet is essential for economic development, education, global communications, and countless other applications. For all its benefits, however, the Internet has a darker side. It has emerged as a conduit for spreading misinformation, stoking tensions, and promoting extremist ideologies. Yet there is hope.

In the latest issue of Psychological Science in the Public Interest, a team of researchers recommend ways that psychological and behavioral sciences can help decrease the negative consequences of Internet use. These recommendations emphasize helping people gain greater control over their digital environments.

"Psychological science can help to inform policy interventions in the digital world," said Anastasia Kozyreva, a researcher at the Center for Adaptive Rationality at the Max Planck Institute for Human Development in Germany and author on the paper. "It is crucial that psychological and behavioral sciences are employed to ensure users are not manipulated for financial gain and are empowered to detect and resist manipulation."

Specifically, psychological and cognitive sciences can complement interventions by other fields, such as law and ethics, which develops guidelines and regulations; education, which can provide curricula for digital information literacy; and technology, which can provide automated detection of harmful materials and help implement more ethically designed online choice architectures.

Although there is no silver bullet that could solve all the problems of the digital
world, Kozyreva and her colleagues describe three approaches to help mitigate the negative consequences. The first is to design Internet infrastructures that "nudge" people's behavior toward more positive outcomes, such as systems with default privacy-respecting settings. The second is relying more on "technocognition," which are technological solutions informed by psychological principles, such as creating obstacles to sharing offensive material online.

The final approach is improving people's cognitive and motivational competencies through "boosts," which are tactics that enhance people's agency in their digital environments and improve reasoning and resilience to manipulation. Examples of a boost include preventively inoculating users against most common manipulative practices and providing easy-to-use rules for digital literacy.

"These cognitive tools are designed to foster the civility of online discourse and protect reason and human autonomy against manipulative choice architectures, attention-grabbing techniques, and the spread of false information," said Kozyreva.

Oak Brook, IL - The January edition of SLAS Discovery features the cover article, "Cryo-EM: The Resolution Revolution and Drug Discovery" by Taiana Maia de Oliveira, Ph.D., Lotte van Beek, Ph.D., Fiona Shilliday, Ph.D., Judit E. Debreczeni, Ph.D., and Chris Phillips, Ph.D., from AstraZeneca.

Cryo-EM, a fast-growing technique in the pharmaceutical industry, enables structure determination of sought-after targets such as large multiprotein complexes and membrane proteins that eluded other structural biology methods. The intricate interactions between compounds and proteins are crucial in accelerating the drug discovery process. The cover article reviews how the structural understanding gained through Cryo-EM is influencing drug discovery projects focused on TRP channels, GPCRs, ribosomes and other high value targets.

The January issues of SLAS Discovery includes 13 articles of Original Research in addition to the cover article.

Articles of Original Research include:

In-Plate Cryopreservation of 2D and 3D Cell Models: Innovative Tools for Biomedical Research and Preclinical Drug Discovery

MALDI-TOF-Based Affinity Selection Mass Spectrometry for Automated Screening of Protein-Ligand Interactions at High-Throughput

High-Throughput Amenable MALDI-MS Detection of RNA and DNA with On-Surface Analyte Enrichment Using Fluorous Partitioning

Activity-Based Screening Assay for Mono-ADP-Ribosylhydrolases

Development of a Microscale Thermophoresis-Based Method for Screening and Characterizing Inhibitors of the Methyl-Lysine Reader Protein MRG15

Development of High-Throughput Assays for Evaluation of Hematopoietic Progenitor Kinase 1 Inhibitors

Development of a Homogeneous Time-Resolved Fluorescence Resonance Energy Transfer (TR-FRET) Assay for the Inhibition of Keap1-Nrf2 Protein-Protein Interaction

Identification of Small-Molecule Inhibitors of Neutral Ceramidase (nCDase) via Target-Based High-Throughput Screening

Optimization of a High-Throughput Cell-Based Screening Strategy to Identify Small Molecule Inhibitors of IL-23 Signaling

A New Method for Screening Natural Products to Stimulate IFN-γ Production in Jurkat Human T Lymphocytes

Validation of a High-Throughput Calcium Mobilization Assay for the Human Trace Amine-Associated Receptor 1

Development of a Testing Funnel for Identification of Small-Molecule Modulators Targeting Secretin Receptors

P-Glycoprotein-Mediated Efflux Using a Rapidly Maturing Caco2 Clone (CLEFF4) in Only 5 Days without Requiring Modified Growth Medium

A drug typically prescribed for rheumatoid arthritis may also be effective in treating a rare but potentially deadly heart complication some cancer patients experience after taking immunotherapies, according to a study published in Cancer Discovery and co-led by investigators at Vanderbilt University Medical Center (VUMC).

The researchers demonstrated that the drug abatacept reduced the severity of myocarditis in a genetic mouse model study - responses that have also been observed in three human patients who were given the same drug after corticosteroid treatments failed to reduce heart muscle inflammation. The mouse model revealed the mechanisms for how the drug works.

Javid Moslehi, MD, director of Cardio-Oncology at Vanderbilt-Ingram Cancer Center, James Allison, PhD, executive director of the Immunotherapy Platform at MD Anderson Cancer Center, Spencer Wei, PhD, a former postdoctoral fellow at MD Anderson, and Justin Balko, PharmD, PhD, associate professor of Medicine and Pathology, Microbiology, and Immunology at VUMC and Vanderbilt-Ingram conceived the research project.

"Immune checkpoint inhibitors (ICI) have revolutionized cancer treatment but are associated with immune-related side effects, such as myocarditis, which although infrequent, has up to 50% mortality," said Moslehi, associate professor of Medicine, who is a corresponding author of the study along with Allison. "We have few treatment options for the fulminant cases of ICI-myocarditis."

Immune checkpoint inhibitors are immunotherapies that target CTLA-4 or PD-1/PD-L1, which are negative regulators of T-cell immune function. When these negative regulators are inhibited, increased activation of the immune system occurs. In some patients, the immune system overreacts, resulting in myocarditis or inflammation of the heart muscle. ICI-myocarditis was initially described by Moslehi, Balko and Doug Johnson, MD, MD, MSCI, associate professor of Medicine at Vanderbilt in 2016. The trio of Moslehi, Balko and Johnson then combined forces to better understand what was effectively a new clinical syndrome.

"As well as identifying a potential treatment, this work gives us a unique opportunity to understand why this syndrome occurs, how to identify patients at risk for it, and maybe even how to prevent it from occurring in the first place" said Balko.

By recreating ICI-myocarditis in the mouse, the group showed that CTLA-4 and PD-1 are both critical in the development of myocarditis. Additionally, reversing CTLA-4 signaling via abatacept stopped disease progression and reduced deaths in the mice model. Their work provides mechanistic rationale and support for therapeutic clinical studies.

Currently, corticosteroids are the standard of care for cancer patients who develop myocarditis after treatment with immune checkpoint inhibitors. Moslehi, Joe-Elie Salem, MD, PhD, a former post-doctoral research fellow at Vanderbilt and Johnson, along with researchers from Sorbonne University in Paris, previously reported a patient case in The New England Journal of Medicine, about a 66-year-old woman with lung cancer who recovered from a severe case of immunotherapy-related myocarditis after being treated with abatacept when she did not respond to corticosteroids. The researchers stated two other cancer patients benefited from treatment with abatacept after having no response to corticosteroids.

Exposure to mutagens, or mutation-causing agents, can not only bring about changes in DNA but also appear to induce errors when genes are transcribed to make proteins, which may be an important factor in age-related diseases.

USC Leonard Davis School of Gerontology Assistant Professor Marc Vermulst and colleagues made the discovery by using state-of-the-art circle sequencing techniques to determine how frequently molecules called RNA polymerases make mistakes when they read (or "transcribe") our DNA. RNA polymerases transcribe DNA to make temporary copies of genes, which are then used to build all of the proteins required to keep us alive and healthy.

Transcription errors vastly outnumber DNA mutations

Vermulst compared our cells to a busy kitchen, teeming with hundreds of chefs that are all making dishes out of a single recipe book. Because it's so busy, they cannot take the recipe book with them when an order comes in. So instead they send the kitchen staff to the recipe book to read the recipes as carefully as possible and then bring the instructions to the chefs. Our cells work in a very similar manner. When an "order" for a protein comes in, RNA polymerases are sent to our genome (or in other words, our recipe book), to make a temporary copy of a gene. That temporary copy is then brought to the chefs, who cook the protein just like the message they received dictates. In this example, transcription errors could be an incorrect amount or ingredient that wasn't properly recorded by the person jotting down the recipe.

"The molecule doing the reading and writing is what's introducing the errors, even if the DNA itself isn't mutated," he explained.

To demonstrate that a mutagen - an agent that can cause a genetic mutation - can induce these errors, Vermulst and his team exposed yeast cells to the chemical N-Methyl-N?-nitro-N-nitrosoguanidine (MNNG), then screened for transcription errors. The cells exposed to MNNG displayed many more transcription errors than the unexposed cells, and in addition, the rate of transcription errors vastly outnumbered the rate of DNA mutations. The team confirmed similar results when the experiments were repeated in cells from the worm species C. elegans, fruit fly D. melanogaster and mice.

DNA mutations occur when the genome is inaccurately copied during cell division, leaving the newly formed cells with a mistake in their DNA. However, a few types of cells, including neurons and muscle cells, rarely divide in adults. These cells all still need to transcribe proteins, which means that harmful errors within these cells are much more likely to arise from transcription, Vermulst explained.

"There are a hundredfold more transcription errors being made for every DNA mutation that eventually arises," he said.

A possible role in several diseases

The genes that code for a protein not only instruct which amino acids to put in what order but also control the specific shape into which the finished protein folds itself. Transcription errors often cause proteins to misfold into a dysfunctional shape, which can result in clusters, or plaques, of nonfunctioning proteins that hinder healthy cell function. This raises questions of how these errors may play roles in diseases such as Alzheimer's, Parkinson's, amyotrophic lateral sclerosis (ALS) and others, Vermulst said.

In future research, Vermulst is pushing for more investigation into whether other substances known to cause DNA mutations also affect transcription, as well as if there are any substances previously thought of as safe that may be in fact inducing transcription errors.

"This is potentially a really important finding in the context of genetic toxicology: a new mechanism by which all these molecules - from exposures in our environment or from our lifestyle choices - can result in pathology," he said. "There could potentially be molecules that we're eating and drinking that are deemed safe because they don't result in any genetic changes, but do result in transcription errors, that have gone completely unnoticed because nobody had a tool to see whether or not that was happening."

He also hopes that the research will make new links between established pillars of aging research - DNA damage, mitochondrial dysfunction, oxidative species and others - and connect them in a mechanistic way to detrimental outcomes such as Alzheimer's, Parkinson's and cancer. It may also help identify sources of the symptoms in DNA repair deficiency disorder, in which patients are unable to repair damage to their genome properly and often results in accelerated aging or increased cancer risk.

While recent years have seen increased interest in the "transcriptome" - the entirety of what is transcribed from a genome - Vermulst wants to focus on the accuracy of what's being transcribed and not just the amount of each protein produced. He hopes this quality-over-quantity approach offers new insight into the fundamental processes of diseases.

"If you've done the same thing a hundred times and you don't get a solution for your problem, it might be something that you've overlooked," he said. "So we're trying to find this something else."

The current COVID-19 pandemic has caused over 1 million deaths which can be attributed to its severe progressive pulmonary compromise. The necessity to understand this disease has resulted in detailed analyses of its transmission and clinical aspects published worldwide. In this recent report, doctors in Bolivia provide, who live and work at more than 3,600m from above sea level, a high altitude specialists' perspective. At high-altitude, hypoxemia (low oxygen in the blood), the main complication in COVID-19, is every day's life experience at the High Altitude Pulmonary and Pathology Institute (HAPPI-IPPA) in La Paz, Bolivia, for 50+ years. Unlike high altitude illnesses, according to Prof. Dr. Gustavo Zubieta-Calleja, COVID-19 presents his transcendental new concept: "pneumolysis" (pneumo=lung, lysis=destruction).

View the video on the research: https://www.youtube.com/watch?v=fBaQMSF1QVo

Initially, all physicians worldwide assumed that the lung affliction in COVID-19 (evidenced by CAT scans and caused by SARS-CoV-2) was the same as in older strains SARS-CoV. However, as fatality rates increased in Intensive Care Units, it became evident that this pathology was entirely new.

The SARS-CoV-2 virus enters the body through inhalation of the viral load, and travels through the bronchi to the surface of the alveoli respiratory sacs where pneumocytes (alveolar lung cells), and their capillaries are located. The pneumocytes allow the diffusion of oxygen molecules to the capillaries where red blood cells capture and transport them to all tissues. They also allow the passage of carbon dioxide molecules (a waste product of respiration) to be exhaled.

SARS-CoV-2 penetrates pneumocytes through the ACE2 receptors and starts self-replication of its RNA within. Pneumocytes are eventually destroyed liberating all replicated SARS-CoV-2 RNA that further infect other adjacent pneumocytes. The paper authored by Prof. Dr. Gustavo Zubieta-Calleja, suggests that multiple diseases may arise from SARS-CoV-2 entering the capillaries.

The coronavirus intrusion gradually reduces the lung's gas exchange area. This results in alveoli inflammation and a superimposed alteration of lung function similar to High Altitude Pulmonary Edema (HAPE). Both in COVID-19 and HAPE, sea level patients cannot take in enough oxygen as if they were rapidly placed on the summit of Mt. Everest, without time for adaptation. Nevertheless, HAPE is entirely reversible as its mechanism is different, and there is no destruction of alveoli.

The extreme hypoxemia experienced in COVID-19 patients leads physicians to use ventilators (a mechanical way of pumping air into the lungs) to improve oxygenation. However, using high pressures on partially destroyed and fragile lungs can result in the worst outcomes. Whereas non-invasive ventilation results in better outcomes.

If patients survive the acute pneumolysis with critically low oxygen levels in COVID-19, recovery results in irreversible fibrosis (scars) in the lungs. This damaged tissue is no longer useful for gas exchange, so compensation can be commonly achieved by increasing the number of red blood cells (hemoglobin oxygen transporters). This poly-erythrocythemia) is a compensation mechanism found in high-altitude residents who suffer chronic lung diseases or other oxygen transport disorders, commonly known as "Chronic Mountain Sickness".

In COVID-19, sea level hemoglobin can also become insufficient. The authors postulate that a fundamental treatment strategy to increase the transport of oxygen could be erythropoietin. This hormone naturally increases red blood cell production and protects the heart, brain, and vessels from hypoxia's hazards.

Prompt administration of oxygen is important as it can reduce the formation of HAPE-type edema and cardiopulmonary overwork. The use of anti-inflammatory medication, being tops Aspirin for its analgesic, anti-inflammatory, anti-fever, and anti-coagulation effects, are also proposed. Timely use of antibiotics (to protect from super-infection), adequate oral rehydration, antitussives (promoting a resting lung) and other anti-coagulation drugs should also be considered on each individual case.

To allow people to return to work, Dr. Zubieta-Calleja proposes the use of space type earth suits with electric ventilator open circuit adequately filtered air, reducing contagion risk. The CoV-2 is a natural biological cleansing mechanism attacking more severely those with decreased immunity, inflammatory processes, or overlapping diseases. "The individual ultimate survival tool under COVID-19 presence..." as he explains: "is a strong immune system".

The existence of GPS-like brain cells, which can store maps of the places we've been, like our kitchen or holiday destination, was already widely known, but this discovery shows there is also a type of brain cell sensitive to the distance and direction of objects that can store their locations on these maps.

The research, led by Dr Steven Poulter and Dr Colin Lever from Durham University, and co-directed by Dr Thomas Wills from the University of Central London (UCL), found that Vector Trace cells can track how far we have travelled and remember where things are, which are added to our memory map of the places we have been.

Dr Steven Poulter said: "The discovery of Vector Trace cells is particularly important as the area of the brain they are found in is one of the first to be attacked by brain disorders such as Alzheimer's disease, which could explain why a common symptom and key early 'warning sign' is the losing or misplacement of objects."

Dr Lever added: "It looks like Vector Trace cells connect to creative brain networks which help us to plan our actions and imagine complex scenarios in our mind's eye. Vector trace cells acting together likely allow us to recreate the spatial relationships between ourselves and objects, and between the objects in a scene, even when those objects are not directly visible to us."

Brain cells that make up the biological equivalent of a satellite-navigation system were first discovered > by Professors John O'Keefe, Edvard Moser, May-Britt Moser. Their discovery shed light on one of neurosciences great mysteries - how we know where we are in space - and won them the 2014 Nobel Prize in Medicine.

Speaking about the discovery, Professor John O'Keefe said: "I'm very impressed. Not only have they discovered a new type of brain cell, the Vector Trace cell, but their analysis of its properties is exhaustive and compelling. This discovery sheds considerable light on this important but enigmatic structure of the brain, supporting the idea that it is indeed the memory system we have always believed it to be."

Professor Lord Robert Winston added: "This fascinating work on Vector Trace cells uncovers further levels of our memory, so often lost with brain damage and ageing. This discovery gives a possible insight into certain kinds of dementia which are now of massive importance.

He added: "The idea that loss or change of such cells might be an early biomarker of disease could lead to earlier diagnosis and more effective therapies for one of the most intractable medical conditions."

Chestnut Hill, Mass. (12/21/2020) - When confronted with comparisons to high status friends and colleagues, consumers prefer to make a "status pivot" into another area where they can shine brighter than their successful peers, according to new research into how consumers respond to status competition, which appears in the Journal of Consumer Research.

With a status pivot, consumers "change the game" when they buy and display products to showcase their accomplishments in other areas where they fare better, referred to as "alternative domains," than if they try to hold firm and buy products in the domain where their peers prevail, said Boston College Associate Professor of Marketing Nailya Ordabayeva, a co-author of the new paper.

On the one hand, when faced with a peer who displays the trappings of financial success and professional achievements, a consumer could entrench and purchase goods and services in the same area as the peer in an effort to reflect equal levels of success. Instead, the new research shows, individuals prefer to make a status pivot and excel in alternative domains - such as personal relationships, social life, parenting, physical and mental health, and fitness.

The findings hold implications for marketers of premium and luxury brands who are trying to understand what kind of products consumers embrace to compete with others, and what kinds of products can help relieve consumers' stress about "upward comparison," according to Ordabayeva.

"We examined how people choose among different product options and consumption strategies to cope with such status threats and how effective these strategies are in alleviating the stress of upward comparisons," said Ordabayeva. "We show that comparison to more successful peers strengthens consumers' belief that success in one life domain, such as financial well-being, must come at the cost of failure in other life domains, such as personal life, which ultimately boosts consumers' preference to display success in these alternative domains where they believe their successful peers may be failing."

The researchers examined consumption choices in a variety of settings: runners at the Boston Marathon, golfers in Switzerland, residents and visitors to glamorous Monaco, users of a social media platform, working parents, as well as hundreds of survey takers online. They looked for the ways in which consumers choose their status coping strategies - staying within domain, or pivoting to another area, an alternative domain.

In a number of the team's studies, the researchers examined consumers' choices in the form of which bumper sticker they would display on their car. When being compared to financially more successful peers, Boston Marathon runners, survey takers online, and owners of inexpensive cars at an elite Swiss golf club showed interest in displaying car bumper stickers that showcased their accomplishments in alternative domains such as family, spirituality, and volunteering.

In addition, being compared to successful peers led consumers to display pictures and messages about family, parenthood, and friendships, rather than professional accomplishments, on their coffee mugs and smartphone covers, according to Ordabayeva and co-authors Dafna Goor, of London Business School, and Anat Keinan, of Boston University.

"We found that pivoting to alternative domains is so appealing and effective because experiencing a status threat motivates consumers to focus on trade-offs and downsides associated with achieving high status," said Ordabayeva. "Importantly, we find that status pivoting is particularly prevalent when consumers do not believe they can attain a similar level of success in the domain of the threat as their successful peer."

Ordabayeva said the researchers were surprised to see how much more appealing status pivoting is for a broad range of consumer groups when compared to choosing to pursue status restoration within the same domain as a successful peer. Unlike previous studies that focused on within-domain status restoration, the project offered study participants an alternative strategy to consider.

"The fact that simply giving people more options to cope with status threats can so dramatically shift their preferences away from within-domain restoration and toward status pivoting was surprising to us, and it highlighted that we have still much to learn about tactics that can increase consumers' resilience against status threats in the marketplace," Ordabayeva said.

She said the findings point to the need for further study of status pivoting, including how particular demographic groups embrace the strategy and whether or not seeking high status recognition in another aspect of life motivates consumers to put more time and effort into alternate domains like parenting, or personal relationships.

LA JOLLA--The COVID-19 pandemic has highlighted how our small genetic differences can have a tremendous effect on how our bodies respond to disease.

"The difference is within us," says Vivek Chandra, Ph.D., an instructor at La Jolla Institute for Immunology (LJI). "We can get infected by the same bacteria or viruses, but the ways our diseases progress can be very different."

Genetic variations are important, but there's more to the puzzle. To truly understand how genes affect health, researchers need to track down the switches (also called "enhancers") that control when and where a gene is expressed in the body.

Now researchers at La Jolla Institute for Immunology (LJI) have created 3D maps of how enhancer sequences and genes interact in several types of immune cells. Their new study in Nature Genetics opens the door to understanding individual risk for diseases from asthma to cancer.

"Nobody has done this mapping, either technically or analytically, to this precision in immune cells," says LJI Associate Professor Pandurangan Vijayanand M.D., Ph.D., co-senior author of the new study.

"Going forward, we can apply this framework to understand cell types involved in many different diseases," says study co-senior author Ferhat Ay, Ph.D., the Institute Leadership assistant professor of computational biology at LJI and an assistant adjunct professor at the UC San Diego School of Medicine.

The work, published Dec. 21, 2020, is part of LJI's DICE Cis-Regulatory Interactome Project.

DNA's Hidden Players

Many of us are taught that a cell has machinery that hums along the genetic code, "reading" genes and making proteins. But there are two key genetic players with hidden roles in this process.

First are "promoters." These are the DNA sequences that sit in the genetic code in front of genes. For a gene to be noticed, it needs to have a promoter. In 2018, the Vijayanand Laboratory published a seminal Cell study that revealed the impact of genetic variants in a set of human immune cells. This work gave Vijayanand's team a window into which genetic variants are important in which immune cells.

For the new study, Chandra and LJI Bioinformatics Postdoctoral Fellow Sourya Bhattacharyya, Ph.D., worked together to map the target genes for important DNA sequences called "enhancers." An enhancer serves as a specific switch to turn a gene on in a cell-specific manner.

"People have found a lot of these switches, but it hasn't been easy to know which switch is connected to which gene," Vijayanand says.

The researchers compare the situation to moving into a new house where you don't know which light switch controls which light--but on a much bigger scale. There could be a million switches, and the lights they control could be a mile away.

"We really want to figure out the wiring," says Ay.

Building a 3D Genetic Map

The scientists used a genome-wide mapping technique to finally see the wiring between the lights and switches. They knew that no matter how far away an enhancer was in the DNA code, it would need to find a way to be physically near the promoter it controls. The team's new 3D maps showed how enhancers on one part of a DNA strand actually loop around to meet promoters.

To their surprise, the researchers linked genes to enhancers very far away in the DNA sequences. Thinking at a molecular scale, for some of the genes, the enhancers appear miles away. "To date, fewer than a handful examples of such ultra-long distance connections have been discovered and validated" says Dr. Chandra, who performed genome editing experiments (CRISPR) that validated some of the discoveries in the paper.

Of course, the enhancer sequences are also made up of DNA letters. The new study shows that variations in the enhancer sequences can actually disable the "switch"--or impair the "wiring"--leading to problems in turning on the right gene in the right cell type. With their new maps, researchers can predict whether DNA sequence changes in these switches will increase disease risk in a person.

As with everything in genetics, even the promoters are more complex than scientists had realized. The new work shows that some "turned off" promoter sequences--previously thought to do nothing--are actually switching on genes far away in the DNA sequence. "They might be connected to other genes that you would never expect," says Ay.

This discovery means that researchers may need to change how they think of gene regulation. When researchers uncover a genetic variant linked to a disease, they usually go looking for the nearby gene. Now, they'll need to use different tools to hunt for potential target genes scattered through the genome.

"People working on all kinds of diseases are completely rethinking how they find variants and the genes they associate with," says Ferhat.

The LJI team will be helping though. Their findings in immune cells will be openly available online through the DICE (Database of Immune Cell Expression, Expression of quantitative trait loci and Epigenomics) database.

The new study also shows how this same approach can be used on other cell types. "The next steps are endless," says Vijayanand.

Animal toxins are research targets owing to their therapeutic and biotechnological potential. Researchers at the Federal University of the ABC (UFABC), Federal University of São Paulo (UNIFESP) and Federal University of Ceará (UFC) in Brazil have discovered that VmCT1, an antimicrobial peptide isolated from the venom of the scorpion Vaejovis mexicanus, and its analogs kill Trypanosoma cruzi, the parasite that causes Chagas disease. Previous research has demonstrated VmCT1's potential against Gram-positive and Gram-negative bacteria, as well as tumor cells and other protozoans.

"VmCT1 contains 13 amino acid residues and displayed good selectivity and high potency against all three developmental phases of the protozoan Trypanosoma cruzi, the etiological agent of Chagas disease," said Vani Xavier de Oliveira Junior, a professor at UFABC's Center for Natural and Human Sciences and principal investigator for the study.

An article on the study is published in Parasitology, a journal owned by Cambridge University Press, and highlighted in the Cambridge Core Blog's Paper of the Month column. The study was supported by FAPESP.

"Not all species of scorpion are dangerous to humans," Oliveira said. "Venom from the genus Vaejovis affects only insects. On the other hand, it has potential therapeutic value because it contains several effective antimicrobial peptides, whose main role is defending the host."

Chagas is considered a neglected disease by the World Health Organization (WHO). It is endemic in several countries, affecting some 8 million people worldwide and killing around 10,000 per year.

"Treatment is currently available only in the form of two drugs that have severe side-effects and work only in the acute phase, when the patient may have few or no symptoms of the disease," Oliveira said. "This is why the search for novel medications is so important. Antimicrobial peptides are especially promising."

The researchers assessed the trypanocidal effect of VmCT1 and synthesized novel analogs with arginine substitutions in key positions to boost their biological action. Arginine is a positively charged amino acid and helps disrupt the parasite's membrane.

The results showed that the natural peptide was effective against all three phases of the parasite's development, while one of the analogs displayed both enhanced biological activity and better selectivity.

"In addition, we discovered that changes to physicochemical parameters influenced activity in the biological model, demonstrating that this kind of peptide reengineering can deliver more effective analogs than the native peptide," Oliveira said.

The selectivity of antimicrobial peptides to the pathogen relates to their cationicity, a trait that influences peptide-membrane interaction. According to the authors, the analogs with the positively charged amino acid arginine are more likely to interact with phospholipids in the membranes of microorganisms, promoting destabilization, disruption and/or permeabilization of the membranes.

"VmCT1 comprises a small peptide sequence, which helps obtain chemically altered molecules quickly and facilitates modulation between its biological activity and toxicity in human cells," said Cibele Nicolaski Pedron, a researcher at UFABC and first author of the article.

The trypanocidal activity was due to the formation of pores, evidenced by electron scanning microscopy. The damage done to the membranes by the peptides was significant, causing the death of parasites at levels not toxic to host cells.

"Our results demonstrate that VmCT1 and its arginine-substituted analogs are promising antiparasitic molecules that offer new prospects for the treatment of Chagas disease," said Alice Martins, a researcher at UFC and a co-author of the article.

The technological products developed in the study were registered with the National Industrial Property Institute (INPI), Brazil's patent and trademark office.

DALLAS - Dec. 21, 2020 - A UT Southwestern research team has catalogued gene activity in the skeletal muscle of mice, comparing healthy animals to those carrying a genetic mutation that causes Duchenne muscular dystrophy (DMD) in humans. The findings, published online recently in PNAS, could lead to new treatments for this devastating degenerative disease and insights into factors that affect muscle development.

Understanding the activity of genes can shed light on pathologies that affect different tissues in the body. However, says Rhonda Bassel-Duby, Ph.D., a professor of molecular biology at UTSW, studying skeletal muscle has been a challenge because of a key difference from other tissue types; rather than containing a single nucleus that controls the activity of the genes, a skeletal muscle fiber can contain hundreds of nuclei. And it was unknown which genes were activated in all these nuclei, making it unclear how gene expression differs between healthy skeletal muscle tissue and tissue affected by DMD.

To answer these questions, Eric Olson, Ph.D., chairman and professor of molecular biology at UTSW, Bassel-Duby, and their colleagues isolated tissue from the tibialis anterior, a muscle in mice similar to one in humans that runs down the shin. They took these samples from both healthy animals and from a mouse model of DMD that they generated using gene-editing technology to introduce a mutation that commonly causes DMD in people. The researchers then isolated muscle tissue from both sets of animals, In muscle fibers from both groups, the scientists identified 14 types of nuclei based on similar gene profiles. These nuclei appear to perform different jobs based on their predominant gene activity, such as maintaining mature muscle, liaising with neurons or tendons, or regenerating new muscle fibers. The researchers also identified nuclei of other types of cells, such as smooth muscle cells, endothelial cells, cells that produce fat or connective tissue, and immune cells known as macrophages.

When the researchers compared populations of these 14 different nuclei between the healthy and DMD mice, they found marked differences. For example, compared with the healthy animals, those with DMD had significantly fewer mature muscle nuclei. Instead, they had significantly more macrophages, reflecting the inflammation present in DMD muscles, as well as a category of regenerative cells not present in healthy tissue at all. Nuclei involved in interfacing with nerve cells and tendons had the most differences in gene expression between the two groups, suggesting that they're the most affected by DMD of all the nuclei types.

In addition, almost all the muscle nuclei isolated from the DMD animals had increased gene activity in the ubiquitin pathway, which tags proteins for degradation, as well as higher activation of genes that function in apoptosis, or cell death - reflecting the degradation of muscle that characterizes DMD.

Bassel-Duby notes that the study has a couple of key limitations: For example, the technology used did not reveal where the muscle nuclei were located within the muscle tissue, which could lend valuable clues on how nuclei might communicate with each other and affect gene activity. It's also still unknown if mending the genetic mutation that causes DMD might return gene activation to normal. She and her colleagues plan to investigate both these questions in future studies.

By developing a better understanding of how muscle fibers operate in both healthy and diseased tissue, she adds, researchers could eventually learn to manipulate gene activity to optimum levels. As a more immediate goal, identifying differences present in DMD patients could lead to new targets for treatment.

"Identifying specific gene activities in these nuclei could give us new ideas for treatments that have been previously overlooked," Bassel-Duby says. "Ultimately, we could eventually find ways to prevent these patients' muscles from degenerating and improve their quality of life."

"Our study provides new insights into the molecular underpinnings of Duchenne muscular dystrophy at an unprecedented level of resolution and highlights a collection of genes and signaling pathways with central roles in this disease," adds Olson. "This work opens the door to new approaches for ameliorating the severe pathological consequences of this disease through either pharmacological or genetic interventions."

A new study by Columbia University Mailman School of Public Health researchers poses a hypothetical question: What if air quality improvements in New York City during the spring 2020 COVID-19 shutdown were sustained for five years without the economic and health costs of the pandemic? They estimate cumulative benefits of clean air during this period would amount to thousands of avoided cases of illness and death in children and adults, as well as associated economic benefits between $32 to $77 billion. The study's findings are published in the journal Environmental Research.

The researchers leveraged the unintended "natural experiment" of cleaner air in New York City during the COVID-19 shutdown to simulate the potential future health and economic benefits from sustained air quality improvements of a similar magnitude. They do not frame this study as an estimate of the benefits of the pandemic. Rather they offer this hypothetical clean air scenario as an aspirational goal for policies to reduce emissions, largely from fossil fuel combustion.

Exploratory analyses found that neighborhoods with higher percentages of low-income residents or higher percentages of Black or Latinx residents tended to have proportionally higher benefits from reduced PM2.5 concentrations when compared to neighborhoods with lower levels of poverty or Black or Latinx populations. However, this does not mean that the disparity in health outcomes across neighborhoods would be eliminated under this scenario because underlying risk factors would still remain. The researchers also caution that limited air quality monitors and available data during the shutdown period constrained their ability to assess the impact of improved air quality on health disparities across neighborhoods.

Air quality improvements during the New York City spring shutdown were the result of an estimated 60-percent decline in automobile traffic, as well as declines in air traffic, construction, restaurant operation, and electricity generation.

"Air quality improvements from the shutdown happened as the result of a tragic situation. However, our hypothetical clean air scenario could be achieved through air pollution and climate mitigation policies, including those that support low carbon modes of transportation and reduce emissions in other sectors," says study first author Frederica Perera, DrPH, PhD, director of translational research at the Columbia Center for Children's Environmental Health and professor of environmental health sciences at Columbia Mailman School.

The researchers estimated a citywide 23-percent reduction in fine particulate matter (PM2.5 ) concentrations during the COVID-19 shutdown period (March 15-May 15, 2020) compared to the average level for those months in 2015-2018 (the business-as-usual period) using air quality monitoring data from the New York State Department of Environmental Conservation. Based on 2020 data, they extrapolated ambient levels of PM2.5 for a five-year period. They then used BenMAP, a publicly available computer tool supported by the U.S. Environmental Protection Agency, to estimate the number of avoided air pollution-related illnesses and deaths and quantify their economic value using methods the researchers developed in earlier research. Specifically, they estimate potential avoided cases of infant and adult mortality, adverse birth outcomes, autism spectrum disorder, and childhood asthma.

Feel like you're suffering from face blindness? Research shows masks change the way we process faces

TORONTO, Dec. 21, 2020 - Ever want to walk over to say hello to someone but you're not sure the person behind the mask is in fact someone you know? Researchers at York University in Toronto and Ben-Gurion University in Israel say you're not alone. A new study, led by researchers in the Faculty of Health and VISTA (Vision Science to Applications) program at York, finds that our ability to recognize faces is severely impaired by masks, and this decreased face perception is impacting our social interactions with others.

"Face masks are an essential tool in our efforts to minimize COVID-19 transmission, and those masks are here for the foreseeable future. Therefore, it is important to understand how masks affect our most important perceptual ability, that is face perception," says Professor Erez Freud, of the Department of Psychology at York University's Faculty of Health. "We found not only that face masks reduce our ability to recognize faces, but also that they change the way we process faces. Face perception typically relies on holistic processing, that is the processing of the face as whole. However, for masked faces, this form of perception is not as efficient, and observers process different face features separately."

Freud and his co-authors recruited 496 adults to complete a common face recognition task online in which they viewed unfamiliar faces and then tried to recognize them under different conditions. The sample included 253 females and 243 males.

Using an adapted version of the Cambridge Face Memory Test ? the most validated measure of face perception abilities in humans ? they evaluated face processing abilities for masked and unmasked faces. Participants in the study were randomly assigned to one of two groups.

The researchers found that masks interfere with what is considered as normal, holistic processing of faces. This decrease in performance moves a substantial number of participants into the lower performance range often found in people with a congenital deficit in face perception (known as "face blindness" or prosopagnosia).

"The face inversion effect is a well-known phenomenon that shows a reduced ability to identify inverted faces compared to upright faces," says Freud. "During our experiment, we found that this well-known inversion effect is reduced for masked faces, suggesting that those faces are processed in a more analytical manner, by specific features rather than the greater whole. This finding can explain why it is so difficult for us to perceive masked faces. If we can't create a holistic representation of a masked face, then our face recognition ability is more likely to fail."

We use face recognition in every aspect of our social interaction; we find clues for the identity, gender, emotion, and intentions of people around us, say researchers. However, in the era of face masks, faces do not look the same. This change is what researchers say may impact our ability to interact with people around us and interpret social interaction.

These changes in performance could have significant effects on activities of daily living as well as other situations involving personal interactions, such as education. Given that mask wearing has rapidly become an important norm in countries around the globe, future research should explore the social and psychological implications of wearing masks on human behaviour, the researchers say.

The study, published in Scientific Reports today was led by Freud in collaboration with Professor Shayna Rosenbaum, both of the Department of Psychology and the Centre for Vision Research at York University, and Andreja Stajduhar, an undergraduate student in the Department of Psychology, and was co-authored by Professors Tzvi Ganel and Galia Avidan in the Department of Psychology at Israel's Ben-Gurion University.

Berkeley -- Imagine typing on a computer without a keyboard, playing a video game without a controller or driving a car without a wheel.

That's one of the goals of a new device developed by engineers at the University of California, Berkeley, that can recognize hand gestures based on electrical signals detected in the forearm. The system, which couples wearable biosensors with artificial intelligence (AI), could one day be used to control prosthetics or to interact with almost any type of electronic device.

"Prosthetics are one important application of this technology, but besides that, it also offers a very intuitive way of communicating with computers." said Ali Moin, who helped design the device as a doctoral student in UC Berkeley's Department of Electrical Engineering and Computer Sciences. "Reading hand gestures is one way of improving human-computer interaction. And, while there are other ways of doing that, by, for instance, using cameras and computer vision, this is a good solution that also maintains an individual's privacy."

Moin is co-first author of a new paper describing the device, which appeared online Dec. 21 in the journal Nature Electronics.

To create the hand gesture recognition system, the team collaborated with Ana Arias, a professor of electrical engineering at UC Berkeley, to design a flexible armband that can read the electrical signals at 64 different points on the forearm. The electrical signals are then fed into an electrical chip, which is programmed with an AI algorithm capable of associating these signal patterns in the forearm with specific hand gestures.

The team succeeded in teaching the algorithm to recognize 21 individual hand gestures, including a thumbs-up, a fist, a flat hand, holding up individual fingers and counting numbers.

"When you want your hand muscles to contract, your brain sends electrical signals through neurons in your neck and shoulders to muscle fibers in your arms and hands," Moin said. "Essentially, what the electrodes in the cuff are sensing is this electrical field. It's not that precise, in the sense that we can't pinpoint which exact fibers were triggered, but with the high density of electrodes, it can still learn to recognize certain patterns."

Like other AI software, the algorithm has to first "learn" how electrical signals in the arm correspond with individual hand gestures. To do this, each user has to wear the cuff while making the hand gestures one by one.

However, the new device uses a type of advanced AI called a hyperdimensional computing algorithm, which is capable of updating itself with new information.

For instance, if the electrical signals associated with a specific hand gesture change because a user's arm gets sweaty, or they raise their arm above their head, the algorithm can incorporate this new information into its model.

"In gesture recognition, your signals are going to change over time, and that can affect the performance of your model," Moin said. "We were able to greatly improve the classification accuracy by updating the model on the device."

Another advantage of the new device is that all of the computing occurs locally on the chip: No personal data are transmitted to a nearby computer or device. Not only does this speed up the computing time, but it also ensures that personal biological data remain private.

"When Amazon or Apple creates their algorithms, they run a bunch of software in the cloud that creates the model, and then the model gets downloaded onto your device," said Jan Rabaey, the Donald O. Pedersen Distinguished Professor of Electrical Engineering at UC Berkeley and senior author of the paper. "The problem is that then you're stuck with that particular model. In our approach, we implemented a process where the learning is done on the device itself. And it is extremely quick: You only have to do it one time, and it starts doing the job. But if you do it more times, it can get better. So, it is continuously learning, which is how humans do it."

While the device is not ready to be a commercial product yet, Rabaey said that it could likely get there with a few tweaks.

"Most of these technologies already exist elsewhere, but what's unique about this device is that it integrates the biosensing, signal processing and interpretation, and artificial intelligence into one system that is relatively small and flexible and has a low power budget," Rabaey said.

So you want to look trimmer, be smarter, and successful next year? You strive to exercise and call your friends more, and spend less?

You are not alone. New Year's resolutions are as ubiquitous as they are difficult to keep. Does it even make sense to set such lofty goals for the new year, hoping anew each January first that this time really is the charm?

Any motivational researcher would have "ambivalent feelings" about New Year's resolutions, says Richard Ryan, an international expert on motivational research and professor emeritus of psychology at the University of Rochester. "The evidence shows that most of the time people aren't successful at them."

But don't throw in the towel quite yet. Ryan, who is also a clinical psychologist, says that any occasion that gives us an opportunity to reflect on our lives is ultimately a good thing. It doesn't have to be on New Year's. "Whenever that happens, if it's really a reflective change--something that you put your heart behind--that can be good for people."

And he has another tip: what proves most satisfying, and may also be what's most needed as the COVID-19 pandemic rages on, are goals that involve giving to others.

"Think of how you can help," says Ryan. "There's a lot of distress out there: If we can set goals that aim to help others, those kinds of goals will, in turn, also add to our own well-being."

His advice is grounded in decades of research. Together with Edward Deci (also a University of Rochester professor emeritus of psychology) Ryan is the cofounder of self-determination theory (SDT), a broad framework for the study of human motivation and personality. Developed by the duo over nearly 40 years, the theory has become one of the most widely accepted frameworks of human motivation in contemporary behavioral science. Its starting point is the idea that all humans have the natural--or intrinsic--tendency to behave in effective and healthful ways.

According to Ryan, who is also a professor at the Institute for Positive Psychology and Education at Australian Catholic University, acts of willingly helping others satisfy all three of the basic psychological needs identified in SDT research: the needs for autonomy, competence, and relatedness. Autonomy in this context means that you can engage in activities in which you feel true volition and find personal value. Competence means feeling effective and having a sense of accomplishment. Finally, relatedness means working with and feeling connected to others.

"If you want to make a New Year's resolution that really makes you happy, think about the ways in which you can contribute to the world," says Ryan. "All three of these basic needs are fulfilled. The research shows it's not just good for the world but also really good for you."

Q&A: Why New Year's resolutions (often) don't work

What's the problem with most New Year's resolutions?

The saddest part is that most people don't succeed at their January 1 resolutions. But that is because most of these midnight resolutions look more like pressure coming from the outside--an attempt to look better, relieve guilt, or meet the standards of others. Losing weight, for example, is one of the most common New Year's goals and one that people tend to do poorly at. Part of the reason for that is where it's coming from: it's often coming from internal or external pressure--as opposed to a goal that's something that you might intrinsically value such as having more health or vitality. If the goal is one that is not "authentic" and not really coming from your own values or interests, the energy for it fades fast.

Are any resolutions particularly toxic?

There are many goals that even when achieved will not bring people more happiness. A goal of making more money, for example, may get a person working harder, but may actually leave them less connected to others, or feeling less autonomy on a day-to-day basis. It could make the person less happy. Goals that work are ones where we can find real satisfaction in achieving them.

It's intuitive that giving to others is satisfying. But how does that work on a psychological level?

We found that when people are focused on giving to others they experience deeper satisfactions than when their goals are more self-oriented. For example, experiments show that doing something benevolent for others, even when you will never meet the beneficiary, increases your positive mood and energy. Most recently, we published a study [in the Journal of Personality and Social Psychology] about what we call people's "integrative span." We discovered that your happiness increases as your focus of concern and care gets wider. If your main concerns and cares are narrow and selfish--just about "me and the people very close to me," versus about "my family and my community," versus about "the larger world and everything in it"-- the less happy you are prone to be. A broader scope of caring and concern for others, in contrast, predicts a higher well-being.

How do we make any resolution more likely to stick?

Beyond the focus of your goals, there are some key elements to success at any resolution you might make. First, make sure your goal is one you truly embrace--that you are fully behind and care about. An achievable goal is also one that is not abstract, like "improve my health" but concrete--such as "increase my daily step count" or "drink sparkling water rather than sugared soda at lunch." These latter goals are clear and achievable in a way that a vague global resolution can never be. Once having a clear aim, the next step is making a realistic plan on how and when it will be implemented.

Just as important, research shows that the more you can make achieving your resolution fun and "intrinsically motivated" the more you'll persist. For example, a plan to increase your step count might include a walk each day with a good friend--which will both achieve your step goal and satisfy relatedness needs. By finding an activity that both gets you to your goal and that you actually enjoy--or at least don't find aversive--you'll be more likely to carry on.

Finally, successful resolutions are usually built upon optimal challenges. Setting the bar too high will feel discouraging and lead to disengagement. Keep in mind that with almost any long-term goal the best strategy is to set small incremental goals--not "I'm going to climb Everest" but rather "I'm going to take these first few steps toward base camp."

Any special advice for 2021?

The past year has been tough; you can make the new one kinder. Any new goals you set that involve changing habits or lifestyles will inevitably involve some setbacks, lapses, and failures. So when failures happen, remember to be a compassionate self-coach. Forget the harsh judgments and instead take interest in what you can learn from the setback and where you got stuck. And then restart with that much more wisdom in hand.

How do I find the goal I ultimately most care about?

For most of us, if we give ourselves occasional moments of reflection-taking the time to really think about what's going well in our lives and what really matters-we can usually identify some things we could change. Often that means listening to that little nagging feeling about the things that we know would improve our lives. It means allowing ourselves to tune into that inner signal in an open, non-defensive way and to consider the possibilities and the choices that you really have. In truth, there are always ways to make life better, but the road upward need not be a painful one--if you are going in the right direction.

(AURORA, Colo.) December 21, 2020 - As the pandemic was starting to take hold, researchers from the Center for Health, Work & Environment (CHWE) at the Colorado School of Public Health (ColoradoSPH) performed a study to better understand the impact of COVID-19 on the well-being of workers in Colorado. The team evaluated changes to employees' work and home life resulting from COVID-19 and individual perceptions of workplace safety and health climates. These climates reflect employee perceptions of how committed their employer is to their safety and health. They are commonly used as an indicator of organizational safety and health cultures.

This study, published in the Journal of Occupational and Environmental Medicine, examined whether safety and health climates were related to employee well-being during the COVID-19 pandemic in a sample of small businesses. CHWE has become an expert in the field of small business safety and health research based on its Small + Safe + Well (SSWell) study, a four-year, Total Worker Health® intervention. The research group distributed a COVID-specific employee survey to the existing employer group of SSWell organizations and received responses from 491 employees from 30 small businesses across Colorado.

"When the pandemic hit last spring, we knew that work changed significantly. We wanted to understand how the small businesses in our SSWell study were responding to the pandemic and how this was related to their employees' health," said Dr. Natalie Schwatka, one of the lead researchers and assistant professor at the ColoradoSPH.

"We learned that when employees perceived strong health and safety climates, they also reported better well-being," says Dr. Carol Brown, lead researcher and deputy director of CHWE. Employee perceptions of safety and health climates were significantly, positively related to their self-reported well-being during the first wave of COVID-19, even when there were changes to childcare, the ability to work, and limited social contacts.

"Safety and health climates may influence employee well-being even when other disruptions occur, suggesting that during emergencies, small businesses with strong climates may be better prepared to maintain employee well-being," according to Dr. Schwatka.

The team hopes the results of the survey will encourage organizations to approach emergency preparedness as a health and safety issue. "Businesses cannot always predict when an emergency is going to happen, but they can create a working environment that supports their employees' health, safety, and well-being" says Dr. Schwatka. "In doing so, they have laid a foundation for how to successfully respond to an emergency."