Publisher Health

An international team of researchers led by Kumamoto and Tokyo Universities (Japan) have shown that the L452R mutation of the SARS-CoV-2 spike protein, which is common to two mutant strains (Epsilon and Delta), is involved in cellular immunity evasion via the human leukocyte antigen (HLA) A24, and enhances viral infectivity. HLA-A24 is one of the most prominent HLA-class I alleles, especially in East/Southeast Asian populations, which might make them particularly vulnerable to coronavirus variants with this mutation.
The ongoing novel coronavirus (SARS-CoV-2 or COVID-19) pandemic has, as of June 2021, infected over 150 million and killed over 3.5 million people worldwide. Vaccination drives around the world are currently underway, but there are still many unknowns, including the principles of infection pathogenesis, the principles viral replication, and the relationship between immune evasion and epidemic dynamics.
Acquired immunity can be broadly classified into humoral immunity mediated by neutralizing antibodies and cellular immunity mediated by helper and killer T cells. SARS-CoV-2 “variants of concern,” such as the Alpha and Beta variants, have been studied worldwide for the possibility of humoral immunity evasion. However, cellular immunity evasion has not been reported.
In this study, the research group first used immunological experiments to demonstrate that an antigen derived from the SARS-CoV-2 spike protein is strongly recognized by HLA-A24-restricted cellular immunity, which is often found in Japanese people. They then performed a large-scale ( >750,000) sequence analysis of SARS-CoV-2 strains and found several important mutations in the spike protein region typically recognized by HLA-A24. These are the Y453F spike mutations found in strain B.1.1.298, which was prevalent in Denmark in 2020, and the L452R mutation in B.1.427/429 and B.1.617 (commonly known as the Epsilon and Delta variants respectively) that are currently spreading around the world. Further immunological experiments demonstrated that these mutations escape HLA-A24 cellular immunity. The researchers believe that this is the first time a “variant of concern” has been demonstrated to evade cellular immunity.
The Y453F and L452R mutations were located in the receptor binding domain of the SARS-CoV-2 spike protein, which are crucial for gaining entry into host cells. Researchers thus examined the effects of these mutations on the infection and replication efficiency of the virus. They found that the L452R mutation enhances its membrane fusion activity, infectivity, and viral replication.
“The L452R mutation is a hallmark of the Delta variant that is currently spreading worldwide, and in Japan, about 60% of the population have HLA-A24, which is responsible for cellular immunity. The L452R mutation not only evades the HLA-A24 cellular immunity but can also enhance the infectivity of the virus,” said the leader of immunology in the study, Dr. Chihiro Motozono.” We have been carefully investigating the immune response against emerging SARS-CoV-2 variants in real time to monitor how the mutations affect human immunity and viral infectivity.”
This research was posted in Cell Host & Microbe on 14 June 2021.
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Materials provided by Kumamoto University. Note: Content may be edited for style and length.

Newborns at risk for Type 1 diabetes because they were given antibiotics may have their gut microorganisms restored with a maternal fecal transplant, according to a Rutgers study.
The study, which involved genetic analysis of mice, appears in the journal Cell Host & Microbe.
The findings suggest that newborns at risk for Type 1 diabetes because their microbiome — the trillions of beneficial microorganisms in and on our bodies — were disturbed can have the condition reversed by transplanting fecal microbiota from their mother into their gastrointestinal tract after the antibiotic course has been completed.
Type 1 diabetes is the most common autoimmune disease in childhood.
“Our previous work has shown that exposing young animals to antibiotics perturbs the microbiome, which may change age-associated immunity and organ-specific inflammation, increasing risk of immune-mediated diseases,” said co-author Martin Blaser, director of the Center for Advanced Biotechnology and Medicine at Rutgers.
The study compared mice that were exposed to antibiotics between days 5 and 10 of life and given a transplant of maternal microbiota up to a week later, and those that were not. The researchers found that the mice given the transplant had their microbiome partially restored and their diabetes risk brought back to the baseline level.
“The mice that were exposed to antibiotics had the expression of indicator genes in their intestinal wall that were either too high or too low, but the transplant brought that back almost to the original levels and restored metabolic pathways,” said co-author Xue-Song Zhang, an assistant research professor at the Center for Advanced Biotechnology and Medicine at Rutgers. “We were able to identify groups of genes that returned to normal after the transplant as if the mice had never received the antibiotics.”
The researchers said the next step is to identify the beneficial microbes.
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Materials provided by Rutgers University. Original written by Patti Verbanas. Note: Content may be edited for style and length.

As children made fewer visits to health facilities and engaged in social distancing and other COVID-19 mitigation measures, a smaller number of them also received prescription drugs, a new study suggests.
Overall, medications prescribed for children dropped by more than a quarter during the first eight months of the pandemic compared to the previous year, with the steepest declines in infection-related medicines like antibiotics and cough-and-cold drugs.
Antibiotic dispensing to children and teens plunged by nearly 56% between April and December 2020 compared with the same period in 2019. Researchers also found declines in prescriptions for chronic diseases, such as attention deficit hyperactivity disorder (ADHD) and asthma, but no change in prescriptions for antidepressants, according to the findings in Pediatrics.
“The decline in the number of children receiving antibiotics is consistent with the large decreases in infection-related pediatric visits during 2020,” said lead author Kao-Ping Chua, M.D., Ph.D., a pediatrician and researcher at University of Michigan Health C.S. Mott Children’s Hospital and the Susan B. Meister Child Health Evaluation and Research Center.
“Because antibiotics have important side effects, the dramatic decreases in antibiotic dispensing may be a welcome development,” he added. “However, declines in dispensing of chronic disease drugs could be concerning.”
Dispensing of infection-related drugs declined sharply
Researchers analyzed national prescription drug dispensing data from 92% of U.S pharmacies to assess changes in dispensing to children ages 0-19 during COVID-19.

An internal transporter that enables us to use the copper we consume in foods like shellfish and nuts to enable a host of vital body functions also has the essential role of protecting the receptor that enables us to grow new blood vessels when ours become diseased, Medical College of Georgia scientists report.
The findings published in the journal Nature Communications point toward the copper transporter ATP7A as a potential new therapeutic target in treating cardiovascular diseases like heart attack, peripheral artery disease and stroke.
“Our paper is talking about a newly discovered function of ATP7A,” says Dr. Masuko Ushio-Fukai, vascular biologist in MCG’s Vascular Biology Center. “Our paper shows that ATP7A directly binds to the receptor for vascular endothelial growth factor, called VEGFR2, to stabilize it, to regulate the receptor itself,” she says of the receptor that enables us to produce new blood vessels from our existing ones in a process called angiogenesis.
They’ve already shown that in diseases like diabetes, a major risk factor for cardiovascular disease, ATP7A expression is down, degradation of VEGFR2 is up and a healthy copper balance lost, which contributes to many of the problems these patients experience like heart attacks and impaired wound healing, says Dr. Tohru Fukai, vascular biologist and cardiologist in the VBC.
It was those findings that got the co-corresponding authors on the new paper thinking there might be a direct link between ATP7A and VEGF’s receptor.
Endothelial cells line our blood vessels, and VEGF stimulates the proliferation and movement of these cells, which lay the foundation and stimulation for restorative new blood vessels. VEGF receptors on endothelial cells are a starting point for angiogenesis, says Fukai.

In the largest study of its kind, an investigation by UC San Francisco has found no evidence that moderate coffee consumption leads to a greater risk of cardiac arrhythmia.
In fact, each additional daily cup of coffee consumed among several hundred thousand individuals was associated with a 3 percent lower risk of any arrhythmia occurring, including atrial fibrillation, premature ventricular contractions, or other common heart conditions, the researchers report. The study included a four-year follow up.
The paper is published July 19, 2021, in JAMA Internal Medicine.
“Coffee is the primary source of caffeine for most people, and it has a reputation for causing or exacerbating arrhythmias,” said senior and corresponding author Gregory Marcus, MD, professor of medicine in the Division of Cardiology at UCSF.
“But we found no evidence that caffeine consumption leads to a greater risk of arrhythmias,” said Marcus, who specializes in the treatment of arrhythmias. “Our population-based study provides reassurance that common prohibitions against caffeine to reduce arrhythmia risk are likely unwarranted.”
While some professional societies suggest avoiding caffeinated products to lower the risk for arrhythmia, this connection has not been consistently demonstrated — indeed, coffee consumption may have anti-inflammatory benefits and is associated with reduced risks of some illnesses including cancer, diabetes, and Parkinson disease.

A study led by D. Ross Camidge, MD, PhD, director of thoracic oncology at the University of Colorado School of Medicine and CU Cancer Center member, has helped to define MET amplification as a rare but potentially actionable driver for non-small cell lung cancer (NSCLC).
Camidge says many of the major developments in the treatment of non-small cell lung cancer have come from defining molecularly specific subsets of the disease for which researchers have been able to develop targeted treatments. Until now, all of these subsets have been based on either genetic mutations or gene rearrangements (where two separate genes fuse to create an oncogene).
“What we’ve started to realize is that non-small cell lung cancer isn’t just one disease,” Camidge says. “Over the last 15 or so years, we’ve started to pull apart separate diseases within that umbrella. Now, there are at least eight different molecularly specific subtypes with an FDA-approved therapy.”
Gene amplification as cancer driver
The new paper, titled “Crizotinib in Patients With MET-Amplified NSCLC,” and published in the June issue of the Journal of Thoracic Oncology, introduces a third means of defining NSCLC subsets that can be targeted with a specific drug. Rather than a mutation or a gene rearrangement, this third category represents oncogene activation through gene amplification. Gene amplification occurs when there is an increase in the usual number of copies of a particular gene, but the process can be difficult to identify.
“Unlike gene mutations or gene rearrangements — which are either there or not — gene amplification is a continuous variable,” Camidge says. “How many extra copies do you need for it to make a difference? Is it an increase in just that one gene because it’s so important to the cancer, or is it being dragged along for the ride by an increase in lots of other genes in the same part of the chromosome? Where do you put the cut point to say this level matters and this level does not? That’s why identifying gene amplification as a definable driver of NSCLC has been challenging.”
For this study, Camidge and the other investigators in the Pfizer-sponsored study focused specifically on MET amplification. MET is a gene that encodes a protein normally involved in cell growth. Although it is normally well-controlled, it can become dysregulated and drive some cancers’ behavior. This can sometimes occur as a result of genetic mutations or gene rearrangement, but it can also occur through gene amplification.

When it comes to craft beer, the flavor doesn’t have to be all in the hops. As a panel of amateur beer tasters at Washington State University recently demonstrated, malted barley, the number one ingredient in beer besides water, can have a range of desirable flavors too.
Researchers recruited a panel of about 100 craft beer drinkers to taste some so-called SMaSH beers — those brewed with a single barley malt and single hop. All the beers contained the same hop variety, called Tahoma, but each had a malt from a different barley genotype, or genetic makeup. Trained tasters can distinguish these easily, but even the untrained panel could taste the difference among five different barley varieties — and definitely favored some more than others.
“We found that the untrained panelists could differentiate among the barley breeding lines in the beer,” said Evan Craine, a WSU doctoral student and first author on the study in the Journal of Food Science. “They did a good job of selecting attributes that revealed distinctive profiles for each of the beers.”
The panel generally preferred the four barley breeding lines developed at WSU over the control, known as Copeland, a high-quality malting barley widely grown in Washington state. The panelists were able to easily identify the flavor profiles of the beers, such as one with a “fruity and sweet aromatic” flavor and another with a “citrus” profile made with a barley called Palmer, a variety recently released by WSU for commercial use.
While the untrained panel could distinguish flavors from brewed beers, they were not as adept at tasting the differences among “hot steep” samples which are made by combining hot water and ground barley malt before filtering. This creates a sweet liquid — similar to that made by brewers before yeast is added to create alcohol.
The researchers had hoped amateur beer tasters could distinguish flavor differences in the hot steep as it would shorten the testing process for new barley varieties. Corresponding author Kevin Murphy was not ready to give up on the method.

Scientists from the department of Anatomy and Embryology at the Faculty of Medicine of the University of Tsukuba created a computer model to simulate the development of complex structures based on the Delta-Notch signaling pathway. This work may lead to a more comprehensive picture of the process that results in the formation of organs and other physiological systems.
The development of a tiny embryo consisting of undifferentiated cells into a healthy fetus with spatially defined organs depends on the complex interplay between genetic instructions and signaling molecules. For example, “Notch” genes are found in almost all animals and insects, and encode for receptor proteins that extend through a cell’s membrane. This allows external signaling molecules to coordinate the cell’s development by turning specific genes on or off at just the right time and location. However, there is still much we do not understand about the details of this mechanism.
Now, to better understand the role of signaling systems in organ development and cell differentiation, a team of scientists at the University of Tsukuba created a computer simulation that models the Delta-Notch signaling pathway in biliary cell differentiation. The differentiation of epithelial cells that are essential for the development of liver’s bile ducts are special in that they receive signals in the form of Delta ligands from portal vein cells to ensure they are in the proper location. “A Delta ligand released by a portal vein cell can bind to a Notch receptor to regulate gene expression in the epithelial cell,” first author Masaharu Yoshihara explains.
The scientists used a set of coupled differential equations to show how the concentrations of each change over time on a 20 × 20 two-dimensional matrix mimicking the planar cross-section of the liver. The diffusion of Delta molecules led to concentration differences based on the location, ensuring that epithelial differentiation occurred at only the correct places, which the authors called “fine-grained differentiation.” However, even with a portal vein cell from the liver sending out Delta molecules, certain conditions resulted in no cell differentiation, showing that proper development is dependent on the rates of production of Delta ligands and Notch receptors. “This project demonstrates the ability of computer models to simulate the formation of spatial structure using complex feedback signaling pathways,” senior author Professor Satoru Takahashi says. Future models may incorporate other signaling molecules, as well as cell migration.
The work is published in the BMC Research Notes as “Mathematical analysis of the effect of portal vein cells on biliary epithelial cell differentiation through the Delta-Notch signaling pathway.”
Funding: This work was supported by the Japan Society for the Promotion of Science through Grants-in-Aid for Scientific Research (Grant Number 19H00966), KAKENHI Grant-in-Aid for Early-Career Scientists (Grant Number 20K15775), and Ph.D. Program in Humanics (Doctoral Program for World-leading Innovative and Smart Education).
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More than 700 imaging satellites are orbiting the earth, and every day they beam vast oceans of information — including data that reflects climate change, health and poverty — to databases on the ground. There’s just one problem: While the geospatial data could help researchers and policymakers address critical challenges, only those with considerable wealth and expertise can access it.
Now, a team based at the University of California, Berkeley, has devised a machine learning system to tap the problem-solving potential of satellite imaging, using low-cost, easy-to-use technology that could bring access and analytical power to researchers and governments worldwide. The study, “A generalizable and accessible approach to machine learning with global satellite imagery,” was published today (Tuesday, July 20) in the journal Nature Communications.
“Satellite images contain an incredible amount of data about the world, but the trick is how to translate the data into usable insights without having a human comb through every single image,” said co-author Esther Rolf, a final-year Ph.D. student in computer science. “We designed our system for accessibility, so that one person should be able to run it on a laptop, without specialized training, to address their local problems.”
“We’re entering a regime in which our actions are having truly global impact,” said co-author Solomon Hsiang, director of the Global Policy Lab at the Goldman School of Public Policy. “Things are moving faster than they’ve ever moved in the past. We’re changing resource allocations faster than ever. We’re transforming the planet. That requires a more responsive management system that is able to see these things happen, so that we can respond in a timely, effective way.”
The project was a collaboration between the Global Policy Lab, which Hsiang directs, and Benjamin Recht’s research team in the department of Electrical Engineering and Computer Sciences. Other co-authors are Berkeley Ph.D. graduates Tamma Carleton, now at University of California, Santa Barbara; Jonathan Proctor, now at Harvard’s Center for the Environment and Data Science Initiative; Ian Bolliger, now at the Rhodium Group; and Vaishaal Shankar, now at Amazon; and Berkeley Ph.D. student Miyabi Ishihara.
All of them were at Berkeley when the project began. Their collaboration has been remarkable for bringing together disciplines that often look at the world in different ways and speak different languages: computer science, environmental and climate science, statistics, economics and public policy.

While researchers have known for years that immunoglobulin A (IgA) is important for gut health, it has remained unclear exactly what role it plays in preventing infection and disease. But now, researchers from Japan have found that eliminating IgA disrupts the balance of the intestinal ecosystem, making it susceptible to disease.
In a study published online in May in Gut, researchers from Tokyo Medical and Dental University (TMDU) have revealed that IgA deficiency results in substantial inflammation of the ileum, a specific part of the small intestine.
IgA is present in large quantities in the small intestine, where it helps protect the body against microorganisms that could potentially cross the lining of the gut to cause disease. People who do not produce IgA are more likely to develop inflammatory bowel disease, allergies, or autoimmune disease, or to get repeated infections. However, attempts to explore the connection between IgA and disease in the laboratory have been hampered by contradictory results, with some studies suggesting that IgA is not important for gut health, and others concluding it is crucial.
“We sought to resolve this apparent discrepancy by generating a definitive mouse model of IgA deficiency,” says senior author of the study Takahiro Adachi. “To do this, we used a cutting-edge gene engineering technology called CRISPR/Cas9 to delete the gene encoding IgA.”
The researchers then analyzed the IgA-deficient mice in detail to determine the effect on gut health, inflammation, and the gut microbiota (the microorganisms that live in our digestive tract).
“The results were striking,” explains Adachi. “We found that the IgA-deficient mice had spontaneous inflammation in the ileal portion of the small intestine, with enhanced immune cell activation and the production of pro-inflammatory cytokines.” In addition, the gut microbiota in these mice was unbalanced, especially in the ileum.
“Our findings suggest that IgA plays a protective role in the intestine by maintaining a healthy balance of microorganisms in the gut and preventing pathologic inflammation,” says Adachi.
Given that IgA deficiency is a known risk factor for inflammatory bowel disease such as Crohn’s disease and ulcerative colitis, this new mouse model could be helpful for investigating these inflammatory conditions in the future. According to Takashi Nagaishi, lead author of the paper, the specific inflammation observed in the ileum of these mice, instead of the colon, makes this especially promising as a model of Crohn’s disease in humans.
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Materials provided by Tokyo Medical and Dental University. Note: Content may be edited for style and length.