Publisher Health

The research group working with immunologists Vigo Heissmeyer and Taku Ito-Kureha of LMU and Helmholtz Munich has revealed the essential function of m6A modifications in T cells.
The chemical modification of nucleic acids, methylation, exists not only on DNA but also on RNA. Whether this methylation is important for certain cell types and what effects it has on the interaction of cells in the body is still unclear according to current knowledge. The most abundant mRNA modification is N6-methyladenosine (also called m6A). It appears to play a crucial role in cell differentiation and to influence a number of biological processes. In m6A, a methyl group is attached to the sixth carbon atom of the nucleic base adenosine. Researchers found that a so-called writer complex is responsible for this — as in DNA. It decides which adenosine in which mRNA is modified and thus carries new information in addition to the genetic code. This information is then “read” by so-called reader proteins, which decide on the lifetime or translation of the mRNA into the encoded protein.
New success for basic research
Vigo Heissmeyer and his research team investigated how the loss of m6A affects the biology of T cells. To this end, the scientists knocked out a component of the m6A writer complex in mice — both in regulatory T cells and naive T cells. From former studies, the researchers deduced that m6A modifications are essential for T cells when they recognize an antigen. Normally, antigen recognition would lead to T cell activation, cell division and acquisition of effector functions. Regulatory T cells without m6A would lose control over the immune response. Naive cells, on the other hand, would be arrested in their differentiation and fall into a kind of coma — that was the state of research.
But the new study shows something different for naive T cells: Genetic inactivation of m6A gene regulation changes the signal transduction of T cells and increases their calcium flux, making them hyperactive and inducing cell death.
The lack of m6A regulation in T cells shows a severe inflammatory response in mice. They suffer from colitis, the chronic inflammation of the intestine. This disease is triggered by an excess of activated conventional T cells. An imbalance emerges because the regulatory T cells can no longer dampen activation of the naive ones. In the absence of m6A in T cells, a complex deregulation of the immune response occurs, naïve T cells that are activated by antigen recognition, divide initially, but also die increasingly — and can still cause the disease, presumably due to lack of suppression by regulatory T cells.
In a next step Heissmeyers Team wants to study the molecules that recognize methylation. “Our idea is to identify new key molecules of T cell activation through insights into this type of gene regulation,” Vigo Heissmeyer explains. “We can see from our study which mRNAs are modified and thus need to be precisely defined in quantity for immune responses to be error-free. If we fully understand how this regulation prevents cell death or hyperactivation, we will also know which nodes can be therapeutically manipulated.”
Story Source:
Materials provided by Ludwig-Maximilians-Universität München. Note: Content may be edited for style and length.

Prehistoric people in Europe were consuming milk thousands of years before humans evolved the genetic trait allowing us to digest the milk sugar lactose as adults, finds a new study. The research, published in Nature, mapped pre-historic patterns of milk use over the last 9,000 years, offering new insights into milk consumption and the evolution of lactose tolerance.
Until now, it was widely assumed that lactose tolerance emerged because it allowed people to consume more milk and dairy products. But this new research, led by scientists from the University of Bristol and University College London (UCL) alongside collaborators from 20 other countries, shows that famine and exposure to infectious disease best explains the evolution of our ability to consume milk and other non-fermented dairy products.
While most European adults today can drink milk without discomfort, two thirds of adults in the world today, and almost all adults 5,000 years ago, can face problems if they drink too much milk. This is because milk contains lactose, and if we don’t digest this unique sugar, it will travel to our large intestine where it can cause cramps, diarrhea, and flatulence; known as lactose intolerance. However, this new research suggests that in the UK today these effects are rare.
Professor George Davey Smith, Director of the MRC Integrative Epidemiology Unit at the University of Bristol and a co-author of the study, said: “To digest lactose we need to produce the enzyme lactase in our gut. Almost all babies produce lactase, but in the majority of people globally that production declines rapidly between weaning and adolescence. However, a genetic trait called lactase persistence has evolved multiple times over the last 10,000 years and spread in various milk-drinking populations in Europe, central and southern Asia, the Middle East and Africa. Today, around one third of adults in the world are lactase persistent.”
By mapping patterns of milk use over the last 9,000 years, probing the UK Biobank, and combining ancient DNA, radiocarbon, and archaeological data using new computer modelling techniques, the team were able to show that lactase persistence genetic trait was not common until around 1,000 BC, nearly 4,000 years after it was first detected around 4,700-4,600 BC.
“The lactase persistence genetic variant was pushed to high frequency by some sort of turbocharged natural selection. The problem is, such strong natural selection is hard to explain,” added Professor Mark Thomas, Professor of Evolutionary Genetics and study co-author from University College London.

While children receiving chemotherapy routinely undergo hearing tests, adults don’t, and a new study by UC San Francisco reports for the first time that significant hearing issues often occur among adult survivors of the most common forms of cancer.
The researchers found that more than half the survivors in their study who had been treated with chemotherapy experienced significant hearing problems.
Previously, it was unknown how frequently survivors of breast, gastrointestinal, gynecologic or lung cancer suffered clinically meaningful levels of hearing loss and tinnitus (ringing in the ear).
The paper is published Wednesday, July 27, 2022 in BMJ Supportive & Palliative Care.
“While hearing loss associated with the administration of platinum drugs was reported in adults with testicular and head and neck cancer, our study is the first to demonstrate that hearing loss and tinnitus are highly prevalent problems in survivors of the four most common types of cancer,” said first author Steven W. Cheung, MD, a UCSF professor of Otolaryngology — Head and Neck Surgery.
“Another important and previously unknown finding from our study is that these high rates of hearing loss and tinnitus occur not only with platinum drugs, but with another class of chemotherapy drugs called taxanes,” he said. “Given that platinum and taxane-containing chemotherapy regimens are the ones most commonly used to treat the majority of cancers, these findings have huge implications for clinicians who treat cancer patients, as well as for cancer survivors.”
The study had 273 cancer survivors who were 61 years old on average and had completed cancer treatment about five years earlier.

An international team of researchers has developed a method for altering one class of antibiotics, using microscopic organisms that produce these compounds naturally.
The findings, published July 25 in Nature Chemistry, could lead to more efficient production of antibiotics that are effective against drug-resistant bacteria.
The team started with a microorganism that is genetically programmed to produce the antibiotic erythromycin.
Scientists from the Institute of Organic Chemistry and Chemical Biology at Germany’s Goethe University wondered if the system could be genetically altered to assemble the antibiotic with one additional fluorine atom, which can often improve pharmaceutical properties.
“We had been analyzing fatty acid synthesis for several years when we identified a part of a mouse protein that we believed could be used for directed biosynthesis of these modified antibiotics, if added to a biological system that can already make the native compound,” said Martin Grininger, professor for biomolecular chemistry at Goethe University.
Working with the lab of David Sherman at the University of Michigan, which specializes in this biological assembly system, the team used protein engineering to replace one part of the system’s native machinery with the functionally similar mouse gene.

In a presentation today at AIDS 2022, the 24th International AIDS Conference in Montreal, scientists with the National Institute of Allergy and Infectious Diseases’ (NIAID) Vaccine Research Center (VRC) and their collaborators described how their use of cutting-edge technology revealed new insights into cellular reservoirs of HIV and what those observations could mean for the next steps in HIV cure research. NIAID is part of the National Institutes of Health.
An enhanced understanding of the HIV-infected, memory CD4+ T cells that persist over decades in individuals taking antiretroviral therapy has been a long-time goal of HIV cure researchers. However, technology limitations have made it difficult to isolate or analyze these individual cells in their natural state. As a result, scientists have been unable to determine whether the cells possess distinctive attributes that HIV-cure-directed therapies may exploit.
In the presentation, Eli Boritz, M.D., Ph.D., chief of the Virus Persistence and Dynamics Section in the VRC Laboratory of Immunology, described NIAID’s long-standing collaboration with a bioengineering research group at the University of California, San Francisco. The researchers developed a custom microfluidic sorting technology termed Focused Interrogation of Cells by Nucleic Acid Detection and Sequencing (FIND-Seq). This technology defines gene expression patterns from rare cells harboring latent HIV by generating millions of single-cell reaction containers in the form of water-in-oil emulsions, in which messenger RNA capture and virus DNA detection can be performed sequentially while maintaining segregation among cells. The scientists applied the FIND-Seq technology to blood cells from six people with HIV who had begun taking ART while chronically infected and who had experienced more than one year of viral suppression. Using data produced by FIND-Seq, the scientists compared the gene expression patterns of HIV-infected memory CD4+ T cells to those of HIV-uninfected memory CD4+ T cells in the same individuals.
The researchers found clear differences between the HIV-infected CD4+ T cells and their uninfected counterparts, including gene expression patterns linked to the suppression of multiple steps in the HIV lifecycle and to cell survival and proliferation. According to the scientists, these results indicate that the HIV-infected memory CD4+ T-cell reservoir is a distinctive cell population that may be uniquely susceptible to specific targeted therapies. In this regard, the study reinforces recent interest among scientists in improving upon HIV cure strategies that are based on latency reversal by incorporating drugs that relieve blocks at multiple HIV lifecycle steps, and by combining these with agents that potentiate physiologic cell death.
ABSTRACT TITLE: Transcriptional Programs of HIV Silencing and Cell Survival in HIV-Infected Memory CD4 T Cells Under Antiretroviral Therapy.
Story Source:
Materials provided by NIH/National Institute of Allergy and Infectious Diseases. Note: Content may be edited for style and length.

One of the deadliest forms of cancer is biliary tract cancer. Only one in three patients diagnosed with the disease is operable. The rest must settle for life-sustaining treatment.
The reason why this cancer is so deadly is that it is difficult to diagnose, and therefore, most patients are not diagnosed with the disease until after the cancer has had time to spread.
Nevertheless, new research from the University of Copenhagen can pave the way for early detection of biliary tract cancer and other serious cancers.
“Our study shows that biliary tract cancer causes the immune cells to change behaviour, resulting in a unique expression of microRNA molecules in the patient’s blood. These changes enable us to diagnose biliary tract cancer much earlier than with existing tests,” says Associate Professor Jesper Bøje Andersen. He is head of the group of researchers from the Biotech Research & Innovation Centre at the University of Copenhagen who are responsible for the new study.
“Sometimes tumours, including the ones you find in the biliary tract, differ considerably, and developing a comprehensive measure for these tumours can therefore be difficult. But one thing all cancers have in common is the fact that they affect the immune system,” says PhD Dan Høgdall, who is first author of the study and a doctor at the Department of Oncology at Herlev and Gentofte Hospital. He adds:
“We need to focus attention on how cancer affects the body as a whole instead of focussing solely on the cancer cells. Among other things, such a broad approach has paved the way for brand new treatments involving immunotherapy, which is targeted at the immune cells instead of the cancer cells. Adopting a broad approach can also provide us with important knowledge about early diagnostics.”
Cancer causes the immune cells to change behaviour

Published37 minutes agoSharecloseShare pageCopy linkAbout sharingImage source, Getty ImagesA man who has lived with HIV since the 1980s seems to have been cured in only the fourth such case, say doctors.He was given a bone marrow transplant to treat blood cancer leukaemia from a donor who was naturally resistant to the virus.The 66-year-old, who does not want to be identified, has stopped taking HIV medication.He said he was “beyond grateful” the virus could no longer be found in his body.The man is known as the “City of Hope” patient after the hospital where he was treated in Duarte, California.Many of his friends died from HIV in the era before antiretroviral drugs could give people a near-normal life expectancy.’I never thought I would see the day’Human immunodeficiency virus (HIV) damages the body’s immune system. This can lead to Aids (acquired immunodeficiency syndrome) and the body struggling to fight off infection.In a statement, the man said: “When I was diagnosed with HIV in 1988, like many others, I thought it was a death sentence.”I never thought I would live to see the day that I no longer have HIV.”However, he was given the therapy not for his HIV, but because he developed the blood cancer leukaemia at the age of 63.The man’s medical team decided he needed a bone marrow transplant to replace his cancerous blood cells. By coincidence, the donor was resistant to HIV.Image source, Getty ImagesThe virus gets into our body’s white blood cells by using a microscopic doorway – a protein called CCR5.However, some people, including the donor, have CCR5 mutations that bolt the door shut and keep out HIV.Cure remains ‘Holy Grail’The City of Hope patient was closely monitored after the transplant, and levels of the HIV became undetectable in his body.He has now been in remission for more than 17 months.”We were thrilled to let him know that his HIV is in remission and he no longer needs to take antiretroviral therapy that he had been on for over 30 years,” said Dr Jana Dickter, an infectious diseases doctor at City of Hope.The first time this happened was in 2011 when Timothy Ray Brown – known as the Berlin Patient – became the first person in the world to be cured of HIV.There have now been three similar cases in the past three years.The City of Hope patient is both the oldest patient to be treated in this way and the one who has lived with HIV for the longest time.However, bone marrow transplants are not going to revolutionise HIV treatment for the 38 million people in the world currently infected.Dr Dickter told me: “It’s a complex procedure with significant potential side effects. So, it’s not really a suitable option for most people living with HIV.”However, researchers are looking at ways of targeting the CCR5 doorway using gene therapy as a potential treatment.The case was reported at the Aids 2022 conference in Montreal, Canada.Commenting on the findings, Prof Sharon Lewin, president-elect of the International Aids Society, said: “A cure remains the Holy Grail of HIV research.”She said there had been a “handful of individual cure cases before” and they provided “continued hope for people living with HIV, and inspiration for the scientific community.”

Walking for exercise at a pace that induced pain or discomfort improved walking ability among people with peripheral artery disease, or PAD, according to new research published today in the Journal of the American Heart Association, an open access, peer-reviewed journal of the American Heart Association.
About 150,000 nontraumatic amputations occur annually, according to the 2021 American Heart Association policy statement: Reducing Nontraumatic Lower-Extremity Amputations by 20% by 2030: Time to Get to Our Feet. Between 8 and 10 million people in the United States have PAD. The condition disproportionately affects Black people, American Indian people and those of low socioeconomic status.
The condition occurs when the arteries that transport blood from the heart throughout the body narrow, reducing blood and oxygen flow. It usually affects the legs and feet causing symptoms while walking, such as cramping, weakness, fatigue, aching and pain or discomfort that subside within 10 minutes of rest. Previous research found that walking for exercise, particularly on a treadmill while supervised by a staff member, improves walking ability and walking distance among people with PAD. What remained unclear were the potential effects of walking at a pace that induced symptoms such as leg pain on speed, strength and balance.
This study examined the effects of home-based walking for exercise among 264 people with PAD who were participating in a randomized clinical trial, called the Low-Intensity Exercise Intervention in PAD (LITE), which included 305 people overall. From September 2015 to December 2019, participants enrolled in the LITE study at four U.S. medical centers (Northwestern University, Tulane University, University of Minnesota and University of Pittsburgh). Their average age was 69 years, 48% were women and 61% were Black adults.
Researchers randomly assigned participants to one of three groups for 12 months. The first group (38%) walked at home at a comfortable pace; the second group (41%) walked at home at a pace that induced leg symptoms; while the third group (21%) did not walk for exercise. Both walking exercise groups wore an ActiGraph, a device that monitored the intensity of their walking and the time walked.
Personalized thresholds for the ActiGraph intensity that corresponded to walking for exercise at a pace that induced leg symptoms (high intensity) and that corresponded to walking for exercise at a comfortable pace without leg symptoms (low intensity) were defined for each individual randomized to an exercise intervention. Participants randomized to exercise wore their ActiGraph device during walking exercise activity and uploaded data on exercise frequency, intensity and duration to the study website.

Results from the largest prospective study of its kind indicate that in the initial days and weeks after experiencing trauma, individuals facing potentially threatening situations who had less activity in their hippocampus — a brain structure critical for forming memories of situations that are dangerous and that are safe — developed more severe posttraumatic stress disorder (PTSD) symptoms.
This association between reduced hippocampal activity and risk of PTSD was particularly strong in individuals who had greater involuntary defensive reactions to being startled.
This research, published in the JNeurosci, suggests that individuals with greater defensive reactions to potentially threatening events might have a harder time learning whether an event is dangerous or safe. They also are more likely to experience severe forms of PTSD, which include symptoms such as always being on guard for danger, self-destructive behavior like drinking too much or driving too fast, trouble sleeping and concentrating, irritability, angry outbursts, and nightmares.
“These findings are important both to identify specific brain responses associated with vulnerability to develop PTSD, and to identify potential treatments focused on memory processes for these individuals to prevent or treat PTSD,” said senior author Vishnu Murty, PhD, assistant professor of psychology and neuroscience at Temple University.
This research is part of the national Advancing Understanding of RecOvery afteR traumA (AURORA) Study, a multi-institution project funded by the National Institutes of Health, non-profit funding organizations such as One Mind, and partnerships with leading tech companies. The organizing principal investigator is Samuel McLean, MD, MPH, professor of psychiatry and emergency medicine at the University of North Carolina School of Medicine and director of the UNC Institute for Trauma Recovery.
AURORA allows researchers to leverage data from patient participants who enter emergency departments at hospitals across the country after experiencing trauma, such as car accidents or other serious incidents. The ultimate goal of AURORA is to spur on the development and testing of preventive and treatment interventions for individuals who have experienced traumatic events.
AURORA scientists have known that only a subset of trauma survivors develop PTSD, and that PTSD is associated with increased sensitivity to threats and decreased ability to engage neural structures retrieving emotional memories. Yet how these two processes interact to increase risk for developing PTSD is not clear. To better understand these processes, Murty and colleagues characterized brain and behavioral responses from individuals two weeks following trauma.
Using brain-imaging techniques coupled with laboratory and survey-based tests for trauma, researchers found that the individuals with less activity in their hippocampus and greatest defensive responses to startling events following trauma had the most severe symptoms.
“In these individuals, greater defensive reactions to threats may bias them against learning information about what is happening so that they can discern what is safe and what is dangerous,” said Büşra Tanriverdi, the lead researcher on the study and graduate student at Temple. “These findings highlight an important PTSD biomarker focused on how people form and retrieve memories after trauma.”
“These latest findings add to our list of AURORA discoveries that are helping us understand the differences between individuals who go on to develop posttraumatic stress disorder and those who do not,” said McLean, an author on the paper. “Studies focusing on the early aftermath of trauma are critical because we need a better understanding of how PTSD develops so we can prevent PTSD and best treat PTSD.”
“Since initiating our financial support of the AURORA Study in 2016, we remain steadfast in our commitment to helping AURORA investigators make important discoveries and to bridge the gaps that exist in mental health research funding and patient support,” said Brandon Staglin, president of One Mind.

Nanoscientists and theoretical physicists at UNSW Medicine & Health’s EMBL Australia Node in Single Molecule Science joined forces to demystify the complicated mechanisms governing how quickly two matching strands of DNA can fully come together — or hybridise — to form double stranded DNA. Their findings are published in the journal Nucleic Acids Research.
A theory was proposed some 50 years ago hypothesising that how quickly DNA strands hybridise is determined by the initial contact that leads to further binding of the string of matching bases on the DNA strands — called nucleating interactions. Until now, this theory had never been proven due to the many complexities around DNA biology.
“There are an enormous number of pathways through which two fully dissociated strands can bind to each other. DNA stands don’t come together into a fully hybridised duplex in an instant. At some point, only two or three base pairs will spontaneously join. This is what a nucleating event is,” said Associate Professor Lawrence Lee who led the team of researchers from UNSW Medicine & Health, UNSW Science, and Imperial College London.
“We built a simple mathematic model, which only has two parameters, and asked: if we only knew how many nucleating interactions there were, and how stable they were, can we predict hybridisation rates? And we found that the answer was yes,” he said.
To test this model quantitatively, the research team translated the original hypothesis into a mathematical formula that they could use to measure against their experimental observations with synthetic DNA.
A/Prof Lee explains that simplicity was pivotal to the predictive power of their model.
“If a mathematical model contains too many different parameters, it is no longer useful for making predictions. The key difference to previous attempts to understand DNA hybridisation rates was that our model had few parameters and was tested against DNA sequences that should not form secondary structures,” he said.
DNA secondary structures form when the strands fold onto themselves, which can potentially obscured nucleation and binding sites.
“The theory is, if this initial small interaction is stable enough, it will go from there to a very fast zippering up of the DNA strands. If the limiting step is nucleating, then it follows that if you have more nucleating states, then the DNA should hybridise faster,” said A/Prof Lee.
This discovery has the potential to improve our understanding of biological systems. The ability to predict or control the rate of DNA hybridisation, could also help to refine or expand the utility of nanotechnologies. With this new understanding, researchers can adjust the number and stability of nucleation interactions and, in turn, control the rate of DNA binding. This can be achieved in many ways, including by altering the reaction temperature, DNA sequence, and ionic strength of the solution.
“We can generate high resolution images using DNA paint — fluorescent strands of DNA used as tags for microscopy — because we are measuring the binding and unbinding of DNA to individual molecules. But, it can take a long time to acquire data. If we could rationally design sequences for DNA paint, so that it can bind more rapidly, then we could reduce the acquisition time for super-resolution imaging,” said A/Prof Lee.
Story Source:
Materials provided by University of New South Wales. Note: Content may be edited for style and length.