Publisher Health

A new study found that more than a third of those who recovered from an infection had symptoms recur days or weeks later.When the antiviral treatment Paxlovid came into wider use for Covid-19 infections earlier this year, doctors who prescribed it and patients who took it noticed that symptoms sometimes flared up again a few days after having gone away. Some people even tested negative before they experienced the rebound. But this puzzling phenomenon can occur whether you take Paxlovid or not, according to a new study.Researchers found that when patients received a placebo instead of treatment, a portion of them still experienced a rebound of their symptoms after they had initially improved.“Symptom return is common,” said Dr. Davey Smith, the chief of infectious diseases and global public health at the University of California, San Diego School of Medicine, who led the study. “It doesn’t mean that things are going south. It’s just the natural way the disease goes.” What is surprising, however, is how many people may experience a rebound, he said.To understand the natural variability in coronavirus symptoms, Dr. Smith and his team tracked 158 clinical trial participants who had tested positive for Covid from August to November 2020. Each person kept a daily diary and marked 13 different Covid symptoms as being absent, mild, moderate or severe. Among the 108 people whose symptoms had improved without antiviral treatment, and had completely disappeared for at least two consecutive days, 48 people (44 percent of those who recovered) noted that symptoms flared up again at various times during four weeks of follow-up.“The good news is that nobody who had their symptoms return needed to go to the hospital or died or even got severe symptoms,” Dr. Smith said. Eighty-five percent of those who had a rebound reported that their symptoms were mild; 15 percent had at least one moderate symptom.Read More on the Coronavirus PandemicWarnings of a ‘Tripledemic’: An expected winter rise in Covid cases appears poised to collide with a resurgent flu season and a third pathogen straining pediatric hospitals in some states.Updated Boosters for Kids: The Food and Drug Administration broadened access to updated Covid booster shots to include children as young as 5.A Decline Among Seniors: Americans over 65 remain the demographic most likely to have received the original series of Covid vaccinations. But fewer are getting booster shots, surveys indicate.Personality Changes: New research suggests that Covid’s disruption of social rituals and rites of passage have made people less extroverted, creative, agreeable and conscientious.The most common complaints during a symptom rebound were coughing, feeling fatigued and having a headache. These were all similar to symptoms people reported at the start of the study, in the active phase of their infection, Dr. Smith said.One of the limitations of the study, however, is that it looked at older strains of coronavirus in people, before vaccines became available. That makes it hard to extrapolate how frequently rebound symptoms may be an issue with the current Omicron strains, especially since most people also have some immune experience with the virus at this point in the pandemic, either because of a past infection or their vaccination. Symptoms can also change with each variant, and their severity can be very subjective, said Dr. Bruce Farber, the chief of public health and epidemiology at Northwell Health in New York. Patients noted rebound symptoms that “were remarkably mild and, quite frankly, fairly unimpressive,” he said.Why do symptoms sometimes make a comeback?The pattern of waxing and waning symptoms occurs in several respiratory diseases, including the common cold, flu and respiratory syncytial virus. “People have never really paid a lot of attention to it in the past, to be honest, as long as the patient is clinically doing better,” Dr. Farber said.Symptoms sometimes disappear and then show up again because of the body’s own immune response to infection, Dr. Farber said. While initial symptoms like a fever, cough or runny nose may be triggered by the virus itself, the body produces its own alarm signals when it senses a foreign invader. These signals come in the form of proteins that help inactivate viral RNA and tell white blood cells where to find more of the pathogen, speeding its removal from the body. At the same time, these reactions create inflammation in the body, which can give you a headache, make you feel exhausted or prolong the duration of a cough.“I call this friendly fire,” Dr. Farber said. “The immune system is very well intentioned and 100 percent needed, but it is clearly overreactive at times, and that often causes problems.”What do you need to know about rebound symptoms from Paxlovid?Concerns about rebound symptoms when taking Paxlovid — and another antiviral drug called molnupiravir — appear to have reduced people’s interest in using treatments for Covid. But the new study shows that you can have a rebound with untreated Covid as well. “I hope this can help people to be less afraid of a potential rebound,” Dr. Smith said.Paxlovid and other drugs can be lifesaving treatments for many patients with Covid, Dr. Smith said. Research has shown that they successfully reduce the risk of hospitalization and death by 88 percent in unvaccinated people. In a fact sheet for doctors prescribing Paxlovid, Pfizer noted that rebounds occurred in some patients receiving the treatment — and at similar rates among people who got a placebo.There may be several potential reasons for a Paxlovid rebound. Some doctors have speculated that in addition to the likelihood of a rebound caused by the body’s own immune system, Paxlovid taken too early may prevent the immune system from adequately preparing to fight off any remaining virus once the drug tapers off. “If you’re young and healthy, and you’ve been vaccinated and boosted, then I don’t push Paxlovid on people, for the most part,” Dr. Farber said.But experts agree that people who are sick and at high risk of developing severe Covid — including adults 65 and older, as well as those of any age with underlying health conditions like heart disease, cancer, diabetes or obesity — should seek treatment.If you do experience a rebound after treatment, there is no evidence that you need to start another course of Paxlovid. Isolate a while longer in case you are contagious to others. And try to manage symptoms with pain and fever-reducing medicines, home remedies and time, Dr. Smith said. “I recommend staying hydrated, watching ‘The Golden Girls’ and eating chicken soup.”

A panel of investigational monoclonal antibodies (mAbs) targeting different sites of the Epstein-Barr virus (EBV) blocked infection when tested in human cells in a laboratory setting. Moreover, one of the experimental mAbs provided nearly complete protection against EBV infection and lymphoma when tested in mice. The results appear online today in the journal Immunity. Scientists from the National Institute of Allergy and Infectious Diseases (NIAID), part of the National Institutes of Health, in collaboration with researchers from Walter Reed Army Institute of Research, led the study.
EBV is one of the most common human viruses. After an EBV infection, the virus becomes dormant in the body but may reactivate in some cases. It is the primary cause of infectious mononucleosis and is associated with certain cancers, including Hodgkin lymphoma, and autoimmune diseases, such as multiple sclerosis. People with weakened immune systems, such as transplant recipients, are more likely than immunocompetent people to develop severe symptoms and complications from EBV infection. There is no licensed vaccine to protect against the virus.
The researchers developed several investigational mAbs targeting two key proteins — gH and gL — found on EBV’s surface. The two proteins are known to facilitate EBV fusion with human cells and cause infection. When tested in the laboratory setting, the investigational mAbs prevented EBV infection of human B cells and epithelial cells, which line the throat at the initial site of EBV infection. Analyzing the structure of the mAbs and their two surface proteins using X-ray crystallography and advanced microscopy, the researchers identified multiple sites of vulnerability on the virus to target. When tested in mice, one of the experimental mAbs, called mAb 769B10, provided almost complete protection against EBV infection when given. The mAb also protected all mice tested from EBV lymphoma.
The findings highlight viable EBV vaccine targets and the potential for the experimental mAbs to be used alone or in combination to prevent or treat EBV infection in immunocompromised patients most susceptible to severe EBV-related disease, according to the researchers. Additional research with mAb 769B10 is planned, the authors note.
Story Source:
Materials provided by NIH/National Institute of Allergy and Infectious Diseases. Note: Content may be edited for style and length.

Mechanics plays a fundamental role in cell biology. Cells navigate these mechanical forces to explore their environments and sense the behaviour of surrounding living cells. The physical characteristics of a cell’s environment in turn impact cell functions. Therefore, understanding how cells interact with their environment provides crucial insights into cell biology and has wider implications in medicine, including disease diagnosis and cancer therapy.
So far, researchers have developed numerous tools to study the interplay between cells and their 3D microenvironment. One of the most popular technologies is traction force microscopy (TFM). It is a leading method to determine the tractions on the substrate surface of a cell, providing important information on how cells sense, adapt and respond to the forces. However, TFM’s application is limited to providing information on the translational motion of markers on cell substrates. Information about other degrees of freedom, such as rotational motion, remains speculative due to technical constraints and limited research on the topic.
Engineering experts at the University of Hong Kong have proposed a novel technique to measure the cell traction force field and tackle the research gap. The interdisciplinary research team was led by Dr Zhiqin Chu of the Department of Electrical and Electronic Engineering and Dr Yuan Lin of the Department of Mechanical Engineering. They used single nitrogen-vacancy (NV) centres in nanodiamonds (NDs) to propose a linear polarization modulation (LPM) method which can measure both, the rotational and translational movement of markers on cell substrates.
The study provides a new perspective on the measurement of multi-dimensional cell traction force field and the results have been published in the journal Nano Letters. The research, entitled ‘All-Optical Modulation of Single Defects in Nanodiamonds: Revealing Rotational and Translational Motions in Cell Traction Force Fields’, is also featured as the supplementary cover of the journal.
The research showed high-precision measurements of rotational and translational motion of the markers on the cell substrate surface. These experimental results corroborate the theoretical calculations and previous results.
Given their ultrahigh photostability, good biocompatibility, and convenient surface chemical modification, fluorescent NDs with NV centres are excellent fluorescent markers for many biological applications. The researchers found that based on the measurement results of the relationship between the fluorescence intensity and the orientation of a single NV centre to laser polarization direction, high-precision orientation measurements and background-free imaging could be achieved.

The mTOR protein plays a central role in cell growth, proliferation and survival. Its activity varies according to the availability of nutrients and some growth factors, including hormones. This protein is implicated in several diseases, including cancer, where its activity frequently increases. To better understand its regulation, a team from the University of Geneva (UNIGE), in collaboration with researchers from the Martin Luther University (MLU) of Halle-Wittenberg in Germany, and the recently inaugurated Dubochet Center for Imaging (UNIGE-UNIL-EPFL), has identified the structure of the SEA complex — an interdependent set of proteins — responsible for controlling mTOR. The discovery of this structure allows a better understanding of how cells perceive nutrient levels to regulate their growth. This work can be read in the journal Nature.
From yeast to humans, the mTOR protein (mammalian target of rapamycin) is the central controller of cell growth. This protein responds to various signals in the cell’s environment, such as nutrients and hormones, and regulates many fundamental cellular functions, such as protein and lipid synthesis, energy production by mitochondria and the organization of the cell’s structure. Disruptions in mTOR activity are the cause of several diseases, including diabetes, obesity, epilepsy and various types of cancer.
Two opposing functions in the same complex
The laboratory of Robbie Loewith, Professor in the Department of Molecular and Cellular Biology at the UNIGE Faculty of Science and director of the National Center for Competence in Research in Chemical Biology, is interested in the regulation of mTOR, and in particular in the SEA complex, which is the direct sensor of nutrients and which controls the activity of mTOR. The SEA complex is composed of eight proteins. One part of the SEA complex (SEACIT) is involved in the inhibition of mTOR activity, while the other part (SEACAT) is involved in its activation.
In the absence of nutrients, the mTOR protein is blocked by the SEACIT subcomplex and cell growth is thus prevented. In contrast, in the presence of nutrients, the SEACAT subcomplex is thought to inhibit the SEACIT subcomplex, which can no longer block the mTOR protein. The central controller can then exert its activating role in cell growth by, for example, stimulating the production of proteins and lipids. How SEACAT regulates SEACIT is still not understood.
Determining structure to understand function
To determine the interactions between the proteins of the SEA complex, and thus better understand how they work, the researchers set out to determine the structure of this complex. After biochemically separating the SEA complex from all of the other components in the cell, the scientists used the technologies of the Dubochet Center for Imaging of UNIGE, UNIL and EPFL to obtain its molecular structure by cryo-electron microscopy (cryo-EM).
”By freezing the samples very quickly at -180°C, cryo-EM allows to obtain the structure of the proteins in their original state, i.e. in their functional three-dimensional form,” explains Lucas Tafur, a researcher in the Department of Molecular and Cellular Biology and first author of the study.
SEACAT is necessary but not sufficient
The biochemical activities of the different components of the complex were then tested in the laboratory. Despite the SEACAT subcomplex being in an active form (as when in the presence of nutrients), the researchers observed that the SEACIT subcomplex is still active and capable of blocking mTOR. ”This result is very unexpected since SEACAT has long been described as the direct inhibitor of SEACIT. We therefore expected SEACIT to be inactive in the presence of active SEACAT. Our results show that SEACAT acts more as a scaffold for the recruitment of other regulatory proteins and that its presence is therefore necessary but not sufficient for the inhibition of SEACIT,” explains Robbie Loewith, the last author of the study.
Obtaining the structure of the SEA complex has allowed to highlight missing links in the mTOR regulatory cascade. ”Of course, we now need to identify the as yet unknown partners that associate with this complex. These new factors could prove to be therapeutic targets for tumors where mTOR activity is exacerbated,” concludes Lucas Tafur.
Story Source:
Materials provided by Université de Genève. Note: Content may be edited for style and length.

People’s diet quality improved and their abdominal obesity and insulin resistance decreased in a one-year lifestyle intervention, new findings from the Finnish StopDia study show. Looking at 2,907 Finnish adults with an elevated risk for type 2 diabetes, the study is the first to examine the effects of a group-based lifestyle intervention implemented in primary health care on risk factors for type 2 diabetes. The lifestyle intervention made use of a digital app and multiple behaviour change theories. The findings were published in The Lancet Regional Health — Europe.
The StopDia approach was developed in collaboration with multiple stakeholders
In the StopDia study, roughly one hundred health care professionals, including nurses, dieticians and exercise instructors, were trained to use the empowering StopDia group counselling approach.
“The approach is a result of many years of co-creation with health care professionals involved in group counselling, so we knew the approach was well suited to practice, but it was important to have strong evidence on its effectiveness,” says Professor Pilvikki Absetz, who was responsible for the behavioural side of the interventions.
Lifestyle changes were supported by the BitHabit app where participants could choose small health-promoting habits, mark them as completed, and get feedback on their progress. The app’s lifestyle library contains more than 400 habits that are suitable for inclusion in the everyday life. The BitHabit app was developed by VTT Technical Research Centre of Finland in collaboration with the University of Eastern Finland and the Finnish Institute for Health and Welfare as part of the StopDia study.
The StopDia approach to prevent type 2 diabetes was designed and built for primary health care with a view to supporting strategic health promotion objectives. Patient and non-governmental organisations, trade unions, employers and other stakeholders were closely involved in the planning as well as in the recruitment of participants by encouraging people to take a digital type 2 diabetes risk test and to participate in the study. In one year’s time, more than 26,000 people had taken the risk test, and the study recruited adults with an elevated risk for type 2 diabetes.

Curcumin, a natural molecule related to turmeric, has been used to treat cancer patients in cancer clinical studies. While it has documented antitumor effects, challenges involving its chemistry have caused drug development to lag.
Now, a team of researchers at Kyoto University has developed a prodrug form of curcumin, TBP1901, that has shown anti-tumor effects without toxicities.
“Curcumin has long been used as a spice or food coloring, so we expect to see minimal side effects,” says lead author Masashi Kanai.
The natural polyphenol curcumin has shown promising efficacy with tumors in a number of preclinical models. Such studies have reported anecdotal evidence with cancer patients of curcumin’s effect in oral form.
However, until now the poor bioavailability and low stability of curcumin have been roadblocks to its clinical application.
Kanai’s team has found a possible detour around the problem by deductively identifying the enzyme GUSB for its key role in TBP1901 conversion to curcumin. The researchers hypothesized that this conversion would not be observed in mice with genetically impaired GUSB. They also confirmed, using a CRISPR-Cas9 screen method, that curcumin also has essential therapeutic targets.
“The high conversion rate of TBP1901 to curcumin in bone marrow warrants its clinical application for diseases growing in the marrow like multiple myeloma and leukemia,” notes Kanai.
Story Source:
Materials provided by Kyoto University. Note: Content may be edited for style and length.

Researchers at the Centre for Genomic Regulation (CRG) and Imperial College London have found a switch that regulates the activity of a gene that causes diabetes. The findings, published in Nature Cell Biology, highlights potential new vulnerabilities in the disease and could lead to the development of new therapeutic strategies.
HNF1A is a gene that provides instructions for making a protein called hepatocyte nuclear factor-1 alpha. The protein is expressed in many tissues but is particularly important for the pancreas, where it plays a role in developing beta cells. Beta cells produce the hormone insulin, which regulate blood sugar levels.
Mutations in HNF1A cause cells to create a protein that doesn’t work normally, which in turn affects the function of beta cells. This results in individuals developing a disease known as maturity-onset diabetes of the young, where symptoms such as high blood sugar can appear before individuals reach the age of 30.
Though this disease accounts for just 1% of all types of diabetes, it is high in terms of absolute numbers due to the high prevalence of diabetes amongst the worldwide population (5-10%). HNF1A is also known to play a key role in the susceptibility for the more common form of the disease, type 2 diabetes, in concert with other genetic and non-genetic factors.
Understanding how the HNF1A gene is switched on or off in beta cells could have important implications for understanding why defects in this gene lead to diabetes, or how it could be harnessed to correct the underlying problem. Using a combination of mouse and human models, researchers have now focused on an enigmatic part of the genome near HNF1A that has a unique function that has not been described before. This DNA regulatory element works like as rheostat; if the HNF1A gene transcribes too much it dials it down, if the gene is slacking it dials it back up.
“We coined this a stabilizer, in contrast to other DNA regulatory elements such as enhancers, promoters and silencers, and call this particular element HASTER, for HNF1A stabilizer,” explains Jorge Ferrer, Senior Researcher at the CRG and Group Leader at CIBERDEM.

Inside cells, molecular droplets form defined compartments for chemical reactions. Not only sticky interactions between molecules, but also dynamic reactions can form such droplets, as it was found by researchers from the Max Planck Institute for Dynamics and Self-Organization (MPI-DS) and the University of Oxford. They revealed a new regulatory mechanism by which life controls and organizes itself.
Traditionally, cellular organelles defined by a membrane have been considered the functional units of a cell. In recent years, it was shown that also molecular droplets formed inside the cell provide a micro-environment for important reactions. Such droplets are not enclosed by a membrane, and arise from phase separation. Hence, they form dynamically and can be regulated according to the needs of the cell.
Nonequilibrium drives can induce droplet formation
In the department of Living Matter Physics, managing director Ramin Golestanian and coworkers aim to reveal the organizational principles of living matter. “The formation of droplets in cells so far was ascribed to attractive, sticky interactions between molecules — similar to how droplets form in non-living, equilibrium systems, such as droplets of oil in a vinaigrette,” explains Jaime Agudo-Canalejo, group leader at the MPI-DS. “We now found that the nonequilibrium drive provided by enzymatic reactions can cause the formation of enzyme-rich droplets, even without any stickiness. Instead, the enzymes are pushed against each other by the chemical fluxes they create” he continues.
The researchers explored this novel mechanism by formulating a model in which the effect of a multicomponent enzymatic reaction on the micro-environment is described. They also considered the underlying feedback mechanism due to which the induced phase separation can in turn affect the initial enzymatic reaction. “When the enzymatic activity gets too intense, phase separation occurs and acts to reduce it, providing a new form of autoregulation,” says Matthew Cotton, first author of the study. This complex interplay of molecular interactions can provide a dynamic environment for cellular processes. Hence, the model adds another piece to the complex puzzle of how life is able to organize itself.
Story Source:
Materials provided by Max Planck Institute for Dynamics and Self-Organization. Note: Content may be edited for style and length.

We tend to eat, drink, and move less when we’re feeling under the weather. And we’re not alone — most animals reduce those same three behaviors when they’re fighting an infection.
Now, a new study pinpoints the cluster of neurons that control these responses, referred to as sickness behaviors. By provoking immune responses in mice, researchers demonstrated that a specific population of cells in the brainstem potently induce three telltale sickness behaviors. In addition, inhibiting these neurons blunts each of these behavioral elements of the sickness response. The findings, published in Nature, directly link inflammation to neural pathways regulating behavior, offering insight into how the immune system interacts with the brain.
“We are still in the early days of trying to understand the brain’s role in infection,” says Jeffrey M. Friedman, Marilyn M. Simpson Professor at The Rockefeller University. “But with these results, we now have a unique opportunity to ask: What does your brain look like when you’re sick?”
Sickness behaviors have been shown to play an important role in an animal’s recovery from an infection. Prior studies have bolstered that theory by demonstrating that animals forced to eat when they’re sick showed a significantly increased mortality. “These behavioral changes during infection are really important for survival,” says lead author Anoj Ilanges, a former graduate student in Friedman’s lab, now a group leader at the HHMI Janelia Research Campus
But it has never been clear how the brain coordinates that near-universal urge to refuse meals and curl up under the covers with the onset of infection. So Friedman and Ilanges set out to map the brain regions behind sickness behaviors in mice.
The team began by exposing mice to LPS, a piece of bacterial cell wall that activates the immune system and potently induces sickness behavior. Shortly after an injection of LPS, there was a spike in activity in a brainstem region known as the dorsal vagal complex, among a population of neurons expressing the neuropeptide ADCYAP1. To confirm that they had found the right brain cells, the researchers then activated those neurons in healthy mice and they found that the animals ate, drank, and moved around less. In contrast, when the ADCYAP1 neurons were deactivated , the effect of LPS on these behaviors was significantly reduced.
“We didn’t know if the same or different neurons regulated each of these behaviors,” Friedman says, “We found it surprising that a single neuronal population appears to regulate each of these components of the sickness response.”
The authors were not, however, altogether surprised that this brainstem region was involved in mediating sickness behaviors. The dorsal vagal complex is one of a precious few physiological crossroads of the central nervous system, where an absence of the blood brain barrier enables circulating factors in the blood to pass information directly to the brain. “This region has emerged as a kind of alert center for the brain, conveying information about aversive or noxious substances that, more often than not, reduce food intake,” Friedman says.
In the coming months, Friedman’s team at Rockefeller intends to incorporate these findings into their overall goal of understanding the physiological signals and neural circuitry that regulate feeding behavior. They are specifically interested in understanding why even mice engineered to eat voraciously will nonetheless stop eating when exposed to bacterial infections.
Meanwhile, Ilanges plans to investigate what role other brain regions play in response to infections, expanding our knowledge of the brain’s role during this critical process. “We looked at one region of the brain, but there are many others that become activated with the immune response,” he says. “This opens the door to asking what the brain is doing, holistically, during infection.”
Story Source:
Materials provided by Rockefeller University. Note: Content may be edited for style and length.

Immunotherapy, a biotherapy that boosts the ability of the immune system to recognize and attack mutant tumor cells, has transformed the treatment landscape for patients battling cancer, which emerges from the progressive accumulation of DNA mutations. However, many patients do not respond to immunotherapy. For instance, among highly-mutated colorectal and endometrial cancers, research has shown that only half will show a response to immunotherapy.
A new study by Yale School of Medicine researchers published Oct. 27 in the journal Cancer Discovery, a journal of the American Association for Cancer Research, has identified a possible explanation for why this happens. In an analysis of a phase 2 trial investigating the immunotherapy drug pembrolizumab in 24 patients with endometrial cancer, the Yale team identifies a specific mechanism of faulty DNA repair in tumors as a key factor in determining patient outcomes.
“We wanted to understand why some patients respond better than others to immunotherapy,” said co-corresponding author Ryan Chow, an M.D./Ph.D. candidate working in Yale’s Department of Genetics and the Systems Biology Institute.
For the study, the Yale team focused on the failure of a process known as “mismatch repair.” When cells divide, errors often arise in their DNA. Through mismatch repair, a special group of proteins recognizes and corrects errors in the DNA. A breakdown in this editing process occurs in many different types of cancer, however, leading to high mutation levels.
The research team — led by Chow, Dr. Eric Song, an ophthalmology resident and former M.D./Ph.D. student at Yale, and Dr. Alessandro Santin, a professor of obstetrics, gynecology, and reproductive sciences — zeroed in on the fact that mismatch repair deficiency can result from two distinct mechanisms. In one, mutations occur in the DNA repair machinery itself, leading to the production of defective repair proteins; in the second, production of the DNA repair machinery is halted entirely. In both cases, the tumors accumulate very high levels of mutations that would be expected to make them good candidates for immunotherapy.
“An analogy would be a dysfunctional toy factory,” Chow said. “Maybe the factory makes broken toys that don’t work, or the factory has no personnel and stops producing toys altogether. Either way, kids won’t be happy.”
However, the researchers found that tumors with defective DNA repair proteins had significantly better responses to immunotherapy than those in which the production of DNA repair proteins had been silenced. These differences could ultimately be traced to changes in the immune response that was mounted against each of the two classes of tumors, they said.
“When it comes to immunotherapy, it seems that the journey — in this case, the underlying cause of mismatch repair deficiency — may be just as important as the destination,” Chow said.
Added Song: “The innovative use of clinical trial data can guide our understanding of how immunotherapy manipulates the immune system and ultimately improve how we treat patients.”
Santin is part of the Yale Cancer Center and Song is a resident at Smilow Cancer Hospital.
Story Source:
Materials provided by Yale University. Original written by Bill Hathaway. Note: Content may be edited for style and length.