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Immune T cells are continuing to target the spike protein of SARS-CoV-2 variants of concern, although mutations are making some T cells less effective, according to new research.
Published in Nature Immunology, researchers from the University of Birmingham have shown that human T cell immunity is currently coping with mutations that have accumulated over time in COVID-19 variants.
In the study, funded by the National Institute for Health and Care Research, the research partner of the NHS, the researchers tested CD4+ T cells collected at the start of the pandemic from healthcare workers infected with COVID-19.
Some of the T-cells were still able to recognise parts of the spike protein, called epitopes, unaltered in later virus strains including the current Omicron variant. However, T cell recognition was worse against seven out of ten epitopes mutated in different variants of concern.
The researchers caution that as SARS-CoV-2 continues to mutate, T-cell recognition of additional epitopes could be lost decreasing overall protection by the immune system.
Dr Heather Long, Associate Professor in the Institute of Immunology and Immunotherapy at the University of Birmingham and lead author of the research said:
“Our paper shows that although most people have a diverse T cell response against the virus, some responses are less effective against Omicron. As further variants of concern are identified we will need to consider carefully how new viral mutations affect T-cell recognition.”
Dr Graham Taylor, Associate Professor in the Institute of Immunology and Immunotherapy at the University of Birmingham said:
“The vaccines currently in use are still vital to protect us from COVID-19. Should SARS-CoV-2 continue to mutate to evade the immune system, our findings will help researchers to develop new vaccines better suited to those variants.”
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Materials provided by University of Birmingham. Note: Content may be edited for style and length.

Changes in a single gene open the door for harmful gut bacteria to set off the inflammation that drives Crohn’s disease, according to a new study led by Weill Cornell Medicine and NewYork-Presbyterian investigators. These findings could one day help doctors better select targeted treatments for patients with this immune disorder.
This particular host gene, called AGR2, encodes part of the cell’s machinery that helps prepare new proteins properly so that they can help repel “bad” bacteria. When anything from microbes to inflammatory conditions disrupts this process, protein production gets backed up, stressing the cell. Extremes in the expression of AGR2 — when it becomes too active or just silent — are associated with such stress and the cell’s response to it, and formed the basis of the study described Nov. 15 in Cell Reports.
The investigators already suspected the cell’s stress response plays a central role in the development of Crohn’s. In addition to AGR2, many other variants linked to Crohn’s are involved in this response, according to co-senior author Dr. Randy Longman, associate professor of medicine in the Division of Gastroenterology and Hepatology and the director of the Jill Roberts Center for Inflammatory Bowel Disease at Weill Cornell Medicine and NewYork-Presbyterian/Weill Cornell Medical Center.
“What makes this study unique is that we discovered a link between one of these stress-related genetic susceptibilities and changes in the gut microbial community leading to development of this disease,” he said.
More than half a million people in the U.S. suffer from Crohn’s disease, a form of inflammatory bowel disease (IBD) in which chronic inflammation damages the lining of the gut, usually in the small intestine and the colon. A nebulous combination of factors, including genetic susceptibility and the presence of certain bacteria, can bring it on.
This study began by chance when co-senior author Dr. Steven Lipkin, vice chair for research in the Weill Department of Medicine at Weill Cornell Medicine and a medical geneticist at NewYork-Presbyterian/Weill Cornell Medical Center, genetically engineered mice to prevent expression of the AGR2 gene for a different project, and found they developed Crohn’s-like inflammation. He and his collaborators linked that inflammation to microbes known as adherent-invasive Escherichia coli (AIEC), which are among the bacteria implicated in Crohn’s.
“My lab began studying AGR2 more than 10 years ago. Now, there are more than 400 publications about the gene,” said Dr. Lipkin, who is also leader of the Cancer Genetics and Epigenetics Program at the Sandra and Edward Meyer Cancer Center at Weill Cornell Medicine. “This gene drives an important pathway relevant for IBD, cancer metastasis and other clinically relevant pathways, and is a promising precision medicine therapy target and co-theragnostic.” Theragnostics are treatment strategies that combine diagnostics and therapies.
Dr. Lipkin then approached Dr. Longman, who studies these bacteria and their role in Crohn’s disease. Together, along with a collaborative team including Dr. Kenneth Simpson at Cornell’s Ithaca campus and Dr. Balfour Sartor at UNC, they connected changes in AGR2 activity levels with increases in the group of bacteria to which AIEC belonged. Then in experiments with mice, they established that both AIEC and the errant stress response are necessary to trigger the inflammation. What’s more, their results suggested that the altered response encourages AIEC to proliferate, reinforcing the pathology.
The team went on to trace out the inflammatory pathway kicked off by this interaction. Their experiments linked it to the production of an immune signal known as IL-23, which plays a well-established role in Crohn’s.
“IL-23 is an important driver of IBD and colorectal cancer tumorigenesis and an important therapy target,” Dr. Lipkin said. “Our research has the potential to bring precision medicine to IBD and develop anti-metastasis cancer therapies to patients.”
Doctors currently have numerous ways to treat Crohn’s, including some that target specific aspects of its complex biology. However, they have little guidance on which treatment to use for a given patient. By connecting AGR2 and AIEC with IL-23, this study provides the sort of context that could help to direct these decisions, according to Dr. Longman.

The life expectancy of women is significantly higher than that of men. However, women also suffer more often from age-related diseases and adverse drug reactions. “Our long-term goal is to make men live as long as women and also women as healthy as men in late life. But for that, we need to understand where the differences come from,” explains Yu-Xuan Lu, one of the leading authors of the study.
Rapamycin extends lifespan only in female flies
The researchers gave the anti-ageing drug rapamycin to male and female fruit flies to study the effect on the different sexes. Rapamycin is a cell growth inhibitor and immune regulator that is normally used in cancer therapy and after organ transplantations. They found that rapamycin extended the lifespan and slowed age-related intestinal pathologies in female flies but not in males.
Healthier life due to more autophagy
The researchers observed that rapamycin increased autophagy — the cell’s waste disposal process — in the female intestinal cells. Male intestinal cells, however, already seem to have a high basal autophagy activity, which cannot be further increased by rapamycin. The scientists could also see this effect of rapamycin in mice. Female mice showed increased autophagy activity after treatment with rapamycin. “Previous studies found that females had greater responses to rapamycin on lifespan extension than did males in mice, we now uncover an underlying mechanism of these differences using flies,” says Yu-Xuan Lu.
Sex-specific, personalised treatments
“Sex can be a decisive factor for the effectiveness of anti-ageing drugs. Understanding the processes that are sex-specific and determine response to therapeutics will improve the development of personalised treatments,” explains Linda Partridge, senior author of the study.
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Materials provided by Max Planck Institute for Biology of Ageing. Note: Content may be edited for style and length.

A new study have identified which blood tests are best at detecting Alzheimer’s disease during the earliest stages, and another blood test thatis optimal for detecting relevant treatment effects. These findings will speed up the development of new therapies that can slow down the disease progression.
The Swedish study lead by Professor Oskar Hanssson, Lund University, and Professor Kaj Blennow, University of Gothenburg, looked at several newly development blood tests for Alzheimer’s disease pathology and neurodegeneration in 575 individuals from the BioFINDER cohort. In 242 participants, the plasma tests were repeated for up to 6 years, along with cognitive testing and magnetic resonance imaging.
The study, published in Nature Medicine, revealed that multiple blood biomarkers, namely phospho-tau231 and Aβ42/40, were sufficient in identifying Alzheimer’s disease pathology, even in participants with no symptoms and thus, could be used as strategy to select the correct individuals for novel disease modifying trials — a task which currently requires expensive molecular imaging technique or lumbar punctures.
Yet, over the 6 years tested, it was shown that only phospho-tau217 was related to Alzheimer’s disease pathology, a decline in cognitive performance and increased brain atrophy typical of incipient Alzheimer’s. Therefore, phospho-tau217 will be an ideal marker for detection of relevant disease-modifying effects of novel interventions. The study has large implications on the use of blood test in the recently reported anti-Aβ trials.
“Distinctive blood tests may be optimal for the identification of Alzheimer’s pathology or for monitoring of disease progression and therefore have different roles in clinical trials” first author of the research study Dr. Nicholas Ashton from the University of Gothenburg explained.
“This study has shown that phospho-tau217 is uniquely placed to be an optimal test for monitoring patients in both a clinical setting and a trial setting because of its longitudinal association with Alzheimer’s development.”
An important aspect of this study was that p-tau217 was able to monitor such changes in pathology and cognition at very early stages of the disease process. This finding was replicated in an independent cohort from the USA, Wisconsin Registry for Alzheimer’s Prevention (WRAP).
“Besides improving the design of clinical trials, the novel blood tests will revolutionize the diagnoses of early stages of Alzheimer’s disease,” says Oskar Hansson. “Further, phospoho-tau217 might be used in the future to monitor the response in individual patients to disease-modifying therapies in clinical practice.
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Materials provided by University of Gothenburg. Note: Content may be edited for style and length.

More than 70% of adults will experience at least one traumatic experience, such as a life-threatening illness or accident, violent assault or natural disaster, in their lifetimes and nearly a third will experience four or more, according to global data.
While some people who have suffered trauma fully recover, others struggle to find lasting relief.
New CU Boulder research published this week in the journal Molecular Psychiatry sheds new light on why that may be.
Researchers found that inescapable stressors impact behavior and the brain differently than stressors that can be controlled, contributing to more generalized and enduring anxiety-like behavior. The study, conducted in mice, also implicates a specific type of brain cell, glutamate cells in the “ventral tegmental area (VTA),” as a key player underlying the impact of stressors.
“Understanding how stressful experiences shape our brain is critical in order for us to develop new treatments and therapies that can counteract these changes,” said co-senior author Michael Baratta, an assistant professor of behavioral neuroscience at CU Boulder. “This study reveals that a little-known population of cells in the brain’s reward center is critical in generating the negative consequences of exposure to stress.”
Traumatic experiences, the authors note, can lead to a broad range of negative consequences. Some people experience “associative” responses, meaning that thoughts, feelings or external reminders like people, places or things related to the original trauma can prompt anxiety and fear. For instance, a war veteran might flinch at the sound of a car backfiring or fireworks crackling.

An international team of scientists led by Mass Eye and Ear, a member of Mass General Brigham, and Boston Children’s Hospital, has discovered a new genetic mutation that may be a root cause of severe cases of childhood glaucoma, a devastating condition that runs in families and can rob children of their vision by 3 years of age.
Through advanced genome-sequencing technology, the researchers found a mutation in the thrombospondin-1 (THBS1) gene in three ethnically and geographically diverse families with childhood glaucoma histories. The researchers then confirmed their findings in a mouse model that possessed the genetic mutation and went on to develop symptoms of glaucoma driven by a previously unknown disease mechanism.
The new findings, published December 1 in the Journal of Clinical Investigation, could lead to improved screening for childhood glaucoma and earlier and more targeted treatments to prevent vision loss in children with the mutation, according to the study’s authors.
“This is a very exciting finding for families affected by childhood glaucoma,” said Janey L. Wiggs, MD, PhD, Associate Chief of Ophthalmology Clinical Research at Mass Eye and Ear and the Vice Chair for Ophthalmology Clinical Research and Paul Austin Chandler Professor of Ophthalmology at Harvard Medical School. “With this new knowledge, we can offer genetic testing to identify children in a family who may be at risk for the disease and start disease surveillance and conventional treatments earlier to preserve their vision. In the future, we would look to develop new therapies to target this genetic mutation.”
Leading cause of childhood blindness
Childhood, or congenital, glaucoma is a rare but serious disease that presents in children as early as birth and as late as 3 years of age. Despite its rarity, childhood glaucoma is responsible for 5 percent of cases of child blindness worldwide.

Long COVID patients can experience many of the same lingering negative effects on their physical, mental, and social well-being as those experienced by people who become ill with other, non-COVID illnesses, new research suggests.
The findings, to be published December 1, 2022 in the peer-reviewed JAMA Network Open, are based on a comparison of people known to have been infected with COVID-19 with individuals with similar symptoms who tested negative for COVID. The researchers found that 40% of the COVID-positive and 54% of the COVID-negative group reported moderate-to-severe residual symptoms three months after enrolling in the study.
“Many diseases, including COVID, can lead to symptoms negatively impacting one’s sense of well-being lasting months after initial infection, which is what we saw here,” said lead author Lauren Wisk, assistant professor of medicine in the division of general internal medicine and health services research at the David Geffen School of Medicine at UCLA. “Because these changes look similar for COVID- and COVID+ participants, this suggests the experience of the pandemic itself, and related stress, may be playing a role in slowing peoples’ recovery from any illness.”
The study included people both with acute COVID and without COVID (but sick with some other illness) to examine the impact of COVID on one’s well-being, also compared with the general population, Wisk noted.
“We found that, as far as well-being is concerned, COVID-positive and COVID-negative groups look more similar than different, but both still have worse well-being scores than the general population.”
The multisite study was conducted in English and Spanish under the umbrella of INSPIRE (Innovative Support for Patients with SARS-CoV-2 Infections Registry), a Centers for Disease Control and Prevention-funded project.

Despite decades of research, Alzheimer’s disease remains a debilitating and eventually fatal dementia with no effective treatment options. More than 95 percent of Alzheimer’s disease cases have no known origin. Now, scientists from the Salk Institute have found that neurons from people with Alzheimer’s disease show deterioration and undergo a late-life stress process called senescence. These neurons have a loss of functional activity, impaired metabolism, and increased brain inflammation.
The researchers also discovered that targeting the deteriorating neurons with therapeutics could be an effective strategy for preventing or treating Alzheimer’s disease. The findings were published online in Cell Stem Cell on December 1, 2022.
“Our study clearly demonstrates that these non-replicating cells are going through the deterioration process of senescence and that it is directly related to neuroinflammation and Alzheimer’s disease,” says co-corresponding author and Professor Rusty Gage, president of the Salk Institute and holder of the Vi and John Adler Chair for Research on Age-Related Neurodegenerative Disease.
As cells age, they can undergo cellular senescence, which contributes to tissue dysfunction and age-related disorders. Senescence is also thought to play a role in cellular stress, molecular damage, and cancer initiation. However, scientists previously believed that senescence primarily occurred in dividing cells, not in neurons. Little was known about the senescence-like state of aging human neurons.
In this study, Gage and his team took skin samples from people with Alzheimer’s disease and converted those cells directly into neurons in the lab. They tested these neurons to see if they undergo senescence and examined the mechanisms involved in the process. They also explored senescence markers and gene expression of post-mortem brains from 20 people with Alzheimer’s disease and matched healthy controls. This allowed the team to confirm that their results from the lab held true in actual human brain tissue.
The Gage team found that senescent neurons are a source of the late-life brain inflammation observed in Alzheimer’s disease. As the neurons deteriorate, they release inflammatory factors that trigger a cascade of brain inflammation and cause other brain cells to run haywire. Additionally, the gene KRAS, which is commonly involved in cancer, could activate the senescent response.

Researchers have long been working on how to treat obesity, a serious condition that can lead to hypertension, diabetes, chronic inflammation, and cardiovascular diseases. Studies have also revealed a strong correlation of obesity and cancer — recent data show that smoking, drinking alcohol, and obesity are the biggest contributors to cancer worldwide.
The development of fat cells, which are produced from a tiny fibroblast-like progenitor, not only activates the fat cells’ specific genes but also grows them by storing more lipids (adipocytes and adipose tissue). In fact, lipid storage is the defining function of a fat cell. But the storage of too much lipid can make fat cells unhealthy and lead to obesity.
Challenges in targeting fat cells
The ability to target fat cells and safely uncouple unhealthy fat formation from healthy fat metabolism would be the answer to many peoples’ prayers. A major challenge in obesity treatment is that fat tissue, which is not continuous in the body but is found piece by piece in “depots,” has been difficult to target in a depot-specific manner, pinpointed at the exact location.
There are two main kinds of fat: visceral fat, internal tissues that surround the stomach, liver, and intestines, and subcutaneous fat, found under the skin anywhere in the body. Visceral fat produces potbellies; subcutaneous fat can create chin jowls, arm fat, etc. To date, there has been no way to specifically treat visceral adipose tissue. And current treatments for subcutaneous fat like liposuction are invasive and destructive.
New studies use cationic nanonmaterials to target fat
Two new studies from researchers at Columbia Engineering and Columbia University Irving Medical Center (CUIMC) may have the answer to targeting fat cells depot-specifically and healthily. The papers demonstrate a new method to treat obesity by using cationic nanomaterials that can target specific areas of fat and inhibit the unhealthy storage of enlarged fat cells. The materials remodel fat rather than destroying it, as, for example, liposuction does. The first paper, published today by Nature Nanotechnology, focuses on visceral adiposity, or belly fat. The second paper, published online November 28 by Biomaterials, focuses on fat underneath the skin as well as chronic inflammation associated with obesity.

A new theory suggests irritable bowel syndrome (IBS), the most common gastrointestinal disorder, may be caused by gravity.
Brennan Spiegel, MD, MSHS, director of Health Services Research at Cedars-Sinai and author of the hypothesis, explains that IBS — and many other conditions — could result from the body’s inability to manage gravity.
“As long as there’s been life on Earth, from the earliest organisms to Homo sapiens, gravity has relentlessly shaped everything on the planet,” said Spiegel, who is also a professor of Medicine. “Our bodies are affected by gravity from the moment we’re born to the day we die. It’s a force so fundamental that we rarely note its constant influence on our health.”
The hypothesis, published in the American Journal of Gastroenterology, describes how the intestines, spine, heart, nerves and brain evolved to manage gravity.
“Our body systems are constantly pulled downward,” Spiegel noted. “If these systems cannot manage the drag of gravity, then it can cause issues like pain, cramping, lightheadedness, sweating, rapid heartbeat and back issues — all symptoms seen with IBS. It can even contribute to bacterial overgrowth in the gut, a problem also linked to IBS.”
The underlying mechanism of IBS has been puzzling researchers since it was first described over a century ago. While the disorder affects up to 10% of the world’s population, experts still aren’t sure exactly how or why it develops.