Publisher Health

Many variants in the human genome have been linked to type 2 diabetes, but because most do not lie within genes that code for proteins, it’s unclear how they might cause disease. Now an international team, including investigators at Massachusetts General Hospital (MGH), has developed a resource to help uncover the impact of these genetic variants.
The work, which is described in Cell Reports, relies on the knolwedge that abnormalities in groups of pancreatic cells called islets, which produce and release hormones that regulate blood sugar levels, drive the development of type 2 diabetes. Unfortunately, however, it’s very difficult to obtain samples of human islets. To overcome this challenge, scientists from Spain, Belgium, Italy, Sweden, Finland, the UK, and the US banded together to obtain more than 500 human islet samples from patients with and without type 2 diabetes and to extract genomic and gene expression data from these samples. With these data, the researchers created what they named TIGER (for Translational human pancreatic Islet Genotype tissue-Expression Resource).
The research required collecting and examining an enormous amount of information, which was made possible through the use of supercomputing resources and new statistical methods.
Analyses of TIGER revealed that certain genetic variants in islets from patients with type 2 diabetes control the expression of particular genes. So far, 32 novel genes were identified that may contribute to type 2 diabetes risk.
“This resource will be very useful to identify genes that may be related with the genetic variants that we have found associated with type 2 diabetes,” says co-senior author Josep M. Mercader, PhD, a research-scientist at MGH’s Diabetes Unit and Center for Genomic Medicine. “Knowing the gene behind a given genetic association is the first step for identifying potential drug targets, or to better understand the physiology of different types of diabetes.”
TIGER’s data are publicly available and accessible to the diabetes research community through the TIGER web portal.
“We are proud that we are now able to share this wealth of data to the scientific community in an easily accessible way for all researchers in the type 2 diabetes field, without the need of computational or bioinformatic expertise,” says co-lead author Lorena Alonso, of the Barcelona Supercomputing Center, in Spain, one of the developers of the TIGER portal.
Co-lead authors include Ignasi Moran, PhD, of the Barcelona Supercomputing Center and Anthony Piron, of the Université Libre de Bruxelles. Co-senior authors include Miriam Cnop, MD PhD, of the Université Libre de Bruxelles, and David Torrents, PhD, of the Barcelona Supercomputing Center.
Other co-authors include Marta Guindo-Martínez, Sílvia Bonàs-Guarch, Goutham Atla, Irene Miguel-Escalada, Romina Royo, Montserrat Puiggròs, Xavier Garcia-Hurtado, Mara Suleiman, Lorella Marselli, Jonathan L.S. Esguerra, Jean-Valéry Turatsinze, Jason M. Torres, Vibe Nylander, Ji Chen, Lena Eliasson, Matthieu Defrance, Ramon Amela, MAGIC, Hindrik Mulder, Anna L. Gloyn, Leif Groop, Piero Marchetti, Decio L. Eizirik, and Jorge Ferrer.
This work has been supported by the European Union’s Horizon 2020 research and innovation program T2Dsystems under grant agreement No 667191.

Nearly everyone gets infected with respiratory syncytial virus (RSV) repeatedly over the course of a lifetime, starting in childhood. Most times, people fight off the virus handily and only end up with a mild cold. But some people — most often young children experiencing their first infection or older adults whose immunity has waned — develop pneumonia or bronchiolitis, serious lung infections that can lead to hospitalization and sometimes death.
Researchers at Washington University School of Medicine in St. Louis have figured out how the virus undermines the body’s defenses, a step toward understanding why the virus is capable of causing serious illness in vulnerable populations. They discovered that the virus produces a protein — called nonstructural protein 1, or NS1 — that slips inside the nucleus and alters the activity of immune genes, sabotaging the immune response.
The findings, published Oct. 12 in Cell Reports, point toward new strategies to prevent or treat RSV infection, and may even provide clues to why severe cases of RSV put people at elevated risk of developing asthma.
“RSV is a significant health burden. It leads to thousands of hospitalizations and a significant number of deaths in the U.S. every year, and there aren’t many effective therapies or any vaccines currently available for it,” said co-senior author Daisy W. Leung, PhD, an associate professor of medicine, of biochemistry & molecular biophysics, and of pathology & immunology. “NS1 is an important part of the reason RSV is capable of causing disease. Not only does the protein interfere with the immune response, it is also important for viral replication. I think the work that we describe in this paper provides a basis for targeting NS1 therapeutically or for vaccine development.”
RSV is a very common virus. Every year in the U.S., about 58,000 children under age 5 are hospitalized due to RSV infection, and 100 to 500 infected children die. Children who survive a serious case of RSV are 30% to 40% more likely than the general population to develop recurrent wheezing or asthma. The virus also kills about 14,000 older adults every year.
Before this study, RSV researchers already had NS1 on their radars as one of the weapons used by the virus to counter the body’s defenses. In 2017, Leung published a paper in Nature Microbiology identifying the precise part of the protein involved in undermining the immune response. But it wasn’t clear how the protein was doing so.
To find out, co-first author Jingjing Pei, PhD, then a postdoctoral researcher in Leung’s lab, infected cells taken from a person’s respiratory tract with RSV. Then, she used an antibody against NS1 that the Leung lab and collaborators on the study developed to track where the protein went inside the cells. She found that while the virus genome and other viral proteins stayed in the main part of the cell and produced more copies of the virus, NS1 sneaked into the nucleus.
Further experiments by co-first author Nina R. Beri, PhD, revealed what NS1 was doing in the nucleus: sabotaging the cell’s antiviral efforts by altering the expression of its immune genes. Beri, who has since graduated, conducted the experiments as a graduate student in the lab of co-senior author Jacqueline E. Payton, MD, PhD, an assistant professor of pathology & immunology.
“NS1 wasn’t just floating around the nucleus, it was interacting with the proteins that regulate gene expression,” Payton said. “The group of genes most affected were the immune-response genes whose expression gets turned on really high when a cell is infected by a virus. It was binding right at the spots on the genome that control expression — the same ones that you’d expect if it were trying to interfere with the immune response.”
By illuminating the details of how NS1 manipulates gene expression, this study provides crucial data that could aid efforts to target the protein for drug or vaccine development. It may even provide a clue to the link between RSV and asthma. The key, Payton suggested, may lie in the epigenome, the pattern of chemical units attached to DNA that influence gene expression.
“Once a cell — any cell, not just an immune cell — encounters an infection, its epigenome changes and primes it to be able to respond more quickly the next time it encounters an infection,” Payton said. “My theory is that NS1 may alter the epigenome in susceptible patients such that the next time they encounter RSV — or maybe even just dust or cat dander — they have an aberrant inflammatory response that is damaging rather than protective. That is an idea we are exploring now.”

The German company CureVac announced on Tuesday that it was withdrawing its mRNA vaccine for Covid-19 from the approval process in Europe. The company pulled the plug after determining that it might take until June for regulators to make a ruling about the vaccine.With other mRNA vaccines from Moderna and Pfizer-BioNTech already in wide distribution, the company decided it was time to give up on its initial efforts to address the Covid-19 emergency.“The pandemic window is closing,” Franz-Werner Haas, CureVac’s chief executive, said in an interview.The company will also terminate its advance agreement with the European Commission to sell it 405 million doses of the vaccine after approval.But in the longer term, CureVac is not out of the Covid-19 vaccine business. The company is partnering with the pharmaceutical giant GSK to start a clinical trial of a new version of the vaccine that they hope will be more effective. The companies are also investigating how to combine seasonal booster shots to work against both Covid-19 and influenza.Founded 20 years ago, CureVac pioneered early research on mRNA vaccines along with the German firm BioNTech and the U.S. company Moderna. At the start of the Covid-19 pandemic, all three companies developed new vaccines against the coronavirus.While Moderna and BioNTech moved swiftly into clinical trials, CureVac was slower to find partners to support its vaccine’s development. Nevertheless, some experts saw promise in the CureVac shot, hoping that it could help address the global shortfall in Covid vaccines.The European Medicines Agency gave CureVac special priority for its application, cutting the time needed for authorization. But in June, the company made a disappointing announcement: A clinical trial found that the vaccine’s efficacy was just 48 percent. By comparison, the vaccines from BioNTech and Moderna had efficacies around 95 percent.Despite that disappointment, CureVac went ahead with its application for authorization in Europe, and submitted a final data package in September. In its updated application, CureVac asked that the vaccine be considered only for people 18 to 60 years old. In that group, the clinical trial had found a moderately higher vaccine efficacy, of 53 percent.The European regulators’ response was less than encouraging. “We were not being lined up for emergency review,” said Dr. Klaus Edvardsen, the company’s chief development officer.CureVac’s Covid-19 vaccine is now the seventh to be abandoned after entering clinical trials. Last month, Sanofi announced it was giving up on its mRNA vaccine.But CureVac’s newer version may have more success. In August, the company shared the results of an experiment on monkeys, showing that the new vaccine generated 10 times as many antibodies against the coronavirus as the original one did. CureVac will begin testing it in people in the next couple of months.Dr. Haas said the company’s strategy is now “to be fast with a second generation rather than to be very late with the first generation.”

Eating whole grain rye products instead of refined wheat alternatives can offer worthwhile health benefits. Researchers at Chalmers University of Technology, Sweden, recently published a study showing that people who ate high-fibre products made from whole grain rye lost more body fat and overall weight than those who ate corresponding products made from refined wheat.
The new results have been published in the scientific journal Clinical Nutrition. It is the largest study yet designed to evaluate the effects of particular types of grains on body weight and body fat, as well as the first study to focus specifically on rye.
The study included 242 overweight men and women between the ages of 30 and 70 who were randomly assigned carefully adjusted daily amounts of refined wheat or whole grain rye products with the same energy value. All participants also received the same general advice on healthy eating from a dietitian. The participants were examined at the start of the study, halfway through, and at twelve weeks, when the study ended.
“The results were clear – the participants who received rye products lost more weight overall, and their levels of body fat decreased compared to those who received wheat products,” says Kia Nøhr Iversen, researcher at the Division of Food and Nutrition Science at Chalmers University of Technology, and lead author of the study, which forms part of her recently presented doctoral dissertation.
Although both the rye and wheat groups lost weight during the study, those who ate rye products lost an average of one kilogram more than those who ate wheat products, with the difference attributable to fat loss.
Opening up for more individualised diets
Different people can react to the same foods in different ways, depending on, for example, the particular bacteria present in the gut, and the way they break down. At the Division of Food and Nutrition Science at Chalmers University of Technology, research is underway into how diet can be better adapted to the individual level, providing precision nutritional advice to yield greater health benefits. The new study offers unique data that can be used to further research in this area.

A researcher at the University of Missouri School of Medicine has discovered an enzyme that plays a key role in the ability of cancer cells to resist drug treatment.
Immunomodulatory drugs like thalidomide, lenalidomide and pomalidomide have improved the treatment of patients with multiple myeloma and other blood cancers. But almost all patients eventually develop resistance to these therapies.
Principal investigator Thang Van Nguyen, DVM, PhD, an assistant research professor in the Center for Precision Medicine, discovered that a protein called USP15 is highly expressed in cancer cells that become resistant to the standard immunomodulatory drugs.
“This USP15 protein protects the cancer cells from destruction by removing ubiquitin tags placed on the cells by the immunomodulatory drugs,” Nguyen said. “Those tags initiate the cell degradation process. But if those tags are removed by USP15, the cancer cells will continue to grow and multiply.”
Nguyen believes testing multiple myeloma patients for USP15 will help determine if a patient will be resistant to immunomodulatory drug therapy. That knowledge could lead to a more precise, customized treatment.
“This work could lead us to discover whether a USP15 inhibitor in combination with other drugs will be more effective to treat cancers,” Nguyen said. “Further studies will be required to determine the best combination to improve clinical outcomes of patients with multiple myeloma and other types of cancer.”
Nguyen’s study, “USP15 antagonizes CRL4CRBN a-mediated ubiquitylation of glutamine synthetase and neo-substrates,” was published in the journal Proceedings of the National Academy of Sciences of the United States of America.
Nguyen declares he has no conflicts of interest.
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Materials provided by University of Missouri-Columbia. Note: Content may be edited for style and length.

Mushrooms have been making headlines due to their many health advantages. Not only do they lower one’s risk of cancer and premature death, but new research led by Penn State College of Medicine also reveals that these superfoods may benefit a person’s mental health.
Penn State researchers used data on diet and mental health collected from more than 24,000 U.S. adults between 2005 and 2016. They found that people who ate mushrooms had lower odds of having depression.
According to the researchers, mushrooms contain ergothioneine, an antioxidant that may protect against cell and tissue damage in the body. Studies have shown that antioxidants help prevent several mental illnesses, such as schizophrenia, bipolar disorder and depression.
“Mushrooms are the highest dietary source of the amino acid ergothioneine — an anti-inflammatory which cannot be synthesized by humans,” said lead researcher Djibril Ba, who recently graduated from the epidemiology doctoral program at the College of Medicine. “Having high levels of this may lower the risk of oxidative stress, which could also reduce the symptoms of depression.”
White button mushrooms, which are the most commonly consumed mushroom variety in the U.S., contain potassium, which is believed to lower anxiety. In addition, certain other species of edible mushrooms, especially Hericium erinaceus, also known as Lion’s Mane, may stimulate the expression of neurotrophic factors such as nerve growth factor synthesis, which could have an impact on preventing neuropsychiatric disorders including depression.
According to the researchers, college-educated, non-Hispanic white women were more likely to eat mushrooms. The average age of surveyed participants was 45, and the majority (66%) were non-Hispanic white people. The investigators observed a significant association between mushroom consumption and lower odds of depression after accounting for socio-demographics, major risk factors, self-reported diseases, medications and other dietary factors. They said, however, that there was no clear additional benefit with relatively high mushroom intake.
“The study adds to the growing list of possible health benefits of eating mushrooms,” said Joshua Muscat, a Penn State Cancer Institute researcher and professor of public health sciences.
The team conducted a secondary analysis to see if the risk of depression could be lowered by replacing a serving of red or processed meat with a serving of mushrooms each day. However, findings show that this substitution was not associated with lower odds of depression.
Prior to this research, there have been few studies to examine the association between mushroom consumption and depression, and the majority have been clinical trials with fewer than 100 participants. The researchers said this study highlights the potential clinical and public health importance of mushroom consumption as a means of reducing depression and preventing other diseases.
The researchers noted some limitations that could be addressed in future studies. The data did not provide details on the types of mushrooms. As a result, the researchers could not determine the effects of specific types of mushrooms on depression. Food codes issued by the U.S. Department of Agriculture were used to determine mushroom intake; therefore, some entries may have been misclassified or inaccurately recorded.
John Richie and Xiang Gao from Penn State Cancer Institute; Laila Al-Shaar and Vernon Chinchilli from Penn State College of Medicine; and Robert Beelman from Penn State College of Agricultural Sciences also contributed to this research. The researchers declare no conflicts of interest or specific funding support.
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Materials provided by Penn State. Original written by Tracy Cox. Note: Content may be edited for style and length.

Eating is one of life’s greatest pleasures, and overeating is one of life’s growing problems.
In 2019, researchers from The Stuber Lab at the University of Washington School of Medicine discovered that certain cells light up in obese mice and prevent signals that indicate satiety, or feeling full. Now comes a deeper dive into what role these cells play.
A study published Oct. 7 in the journal Neuron reports on the function of glutamatergic neurons in mice. These cells are located in the lateral hypothalamic area of the brain, a hub that regulates motivated behaviors, including feeding.
The researchers found that these neurons communicate to two different brain regions: the lateral habenula, a key brain region in the pathophysiology of depression, and the ventral tegmental area, best known for the major role it plays in motivation, reward and addiction.
“We found these cells are not a monolithic group, and that different flavors of these cells do different things,” said Stuber, a joint UW professor of anesthesiology and pain medicine and pharmacology. He works at the UW Center for the Neurobiology of Addiction, Pain, and Emotion, and was the paper’s senior author. Mark Rossi, acting instructor of anesthesiology and pain medicine, is the lead author.
The study is another step in understanding the brain circuits involved in eating disorders.
The Stuber Lab studies the function of major cell groups in the brain’s reward circuit, and characterizes their role in addiction and mental illness — in hopes of finding treatments. One question is whether these cells can be targeted by drugs without harming other parts of the brain.
Their recent study systematically analyzed the lateral hypothalamic glutamate neurons. Researchers found that, when mice are being fed, the neurons in the lateral habenula are more responsive than those in the ventral tegmental area, suggesting that these neurons may play a greater role in guiding feeding.
Researchers also looked at the influence of the hormones leptin and ghrelin on how we eat. Both leptin and ghrelin are thought to regulate behavior through their influence on the mesolimbic dopamine system, a key component of the reward pathway in the brain. But little has been known about how these hormones influence neurons in the lateral hypothalamic area of the brain. The investigators found that leptin blunts the activity of neurons that project to the lateral habenula and increases the activity of neurons that project to the ventral tegmental area. But ghrelin does the opposite.
This study indicated that brain circuits that control feeding at least partially overlap with brain circuitry involved in drug addiction.
The study adds to the growing body of research on the role of the brain in obesity, which the World Health Organization calls a global epidemic. New data from the Centers for Disease Control and Prevention showed 16 states now have obesity rates of 35% or higher. That’s an increase of four states — Delaware, Iowa, Ohio and Texas — in just a year.

Intermittent fasting can produce clinically significant weight loss as well as improve metabolic health in individuals with obesity, according to a new study review led by University of Illinois Chicago researchers.
“We noted that intermittent fasting is not better than regular dieting; both produce the same amount of weight loss and similar changes in blood pressure, cholesterol and inflammation,” said Krista Varady, professor of nutrition at the UIC College of Applied Health Sciences and author of “Cardiometabolic Benefits of Intermittent Fasting.”
According to the analysis published in the Annual Review of Nutrition, all forms of fasting reviewed produced mild to moderate weight loss, 1%-8% from baseline weight, which represents results that are similar to that of more traditional, calorie-restrictive diets. Intermittent fasting regimens may also benefit health by decreasing blood pressure and insulin resistance, and in some cases, cholesterol and triglyceride levels are also lowered. Other health benefits, such as improved appetite regulation and positive changes in the gut microbiome, have also been demonstrated.
The review looked at over 25 research studies involving three types of intermittent fasting: Alternate day fasting, which typically involves a feast day alternated with a fast day where 500 calories are consumed in one meal. 5:2 diet, a modified version of alternate day fasting that involves five feast days and two fast days per week. Time-restricted eating, which confines eating to a specified number of hours per day, usually four to 10 hours, with no calorie restrictions during the eating period.Various studies of time-restricted eating show participants with obesity losing an average of 3% of their body weight, regardless of the time of the eating window.
Studies showed alternate day fasting resulted in weight loss of 3%-8% of body weight over three to eight weeks, with results peaking at 12 weeks. Individuals on alternate day fasting typically do not overeat or binge on feast days, which results in mild to moderate weight loss, according to the review.

The structural integrity of the brain’s white matter as measured with an advanced MRI technique is lower in cognitively normal people who carry a genetic mutation associated with Alzheimer’s disease than it is in non-carriers, according to a study in Radiology. Researchers said the findings show the promise of widely available imaging techniques in helping to understand early structural changes in the brain before symptoms of dementia become apparent.
People who carry the autosomal dominant Alzheimer disease (ADAD) mutation have a higher risk of Alzheimer’s disease, a type of dementia that affects about one in nine people in the United States. The mutation is linked to a buildup of abnormal protein called amyloid-beta in the brain that affects both the gray matter and the signal-carrying white matter.
“It’s thought that the amyloid deposition in the gray matter could disrupt its function, and as a result the white matter won’t function correctly or could even atrophy,” said study lead author Jeffrey W. Prescott, M.D., Ph.D., neuroradiologist at the MetroHealth Medical Center in Cleveland.
An earlier study by Dr. Prescott and colleagues on patients with sporadic Alzheimer’s disease, which comprises 99% of cases, found that white matter structural connectivity, as measured with an MRI technique called diffusion tensor imaging (DTI), degraded significantly as patients developed more amyloid burden.
“The current work extends these results by showing that similar findings are detectable in asymptomatic at-risk patients,” said Jeffrey R. Petrella, M.D., professor of radiology at Duke University and senior author on both studies.
In the new study, Dr. Prescott and colleagues used data from the Dominantly Inherited Alzheimer Network (DIAN) to compare ADAD mutation carriers with non-carriers to see if there were changes in structural connectivity that could be related to the mutation.

When it comes to cancer detection, size matters. Traditional diagnostic imaging cannot detect tumors smaller than a certain size, causing missed opportunities for early detection and treatment. Circulating tumor exosomes are especially small cancer biomarkers and easy to miss. These nanovesicles are composed of molecules that reflect the parental cells. But, because they are tiny (~30-150nm in diameter) and complex, the precise detection of exosome-carried biomarkers with molecular specificity is elusive.
Until now, reports Wei-Chuan Shih, professor of electrical and computer engineering at the University of Houston Cullen College of Engineering, in IEEE Sensors journal.
“This work demonstrates, for the first time, that the strong synergy of arrayed radiative coupling and substrate undercut can enable high-performance biosensing in the visible light spectrum where high-quality, low-cost silicon detectors are readily available for point-of-care application,” said Shih. “The result is a remarkable sensitivity improvement, with a refractive index sensitivity increase from 207 nm/RIU to 578 nm/RIU.”
Technically speaking, Shih has restored the electric field around nanodisks, providing accessibility to an otherwise buried enhanced electric field. Nanodisks are antibody-functionalized artificial nanostructures which help capture exosomes with molecular specificity.
“We report radiatively coupled arrayed gold nanodisks on invisible substrate (AGNIS) as a label-free (no need for fluorescent labels), cost-effective, and high-performance platform for molecularly specific exosome biosensing. The AGNIS substrate has been fabricated by wafer-scale nanosphere lithography without the need for costly lithography,” said Shih.
This allows fast screening of the surface proteins of exosomes for diagnostics and biomarker discovery. As an example, Shih has shown that multiple surface antigens (CD9, CD63 & CD81) were more plentiful in cancer-derived exosomes than those from normal cells.
Current exosome profiling relies primarily on DNA sequencing technology, fluorescent techniques such as flow cytometry, or enzyme-linked immunosorbent assay (ELISA), which involves sophisticated sample preparation procedures and requires labeling and amplification, all processes that are labor-intensive and costly. Shih’s goal is to amplify the signal by developing the label-free technique.
“By decorating the gold nanodisks surface with different antibodies (e.g., CD9, CD63, and CD81), label-free exosome profiling has shown increased expression of all three surface proteins in cancer-derived exosomes,” said Shih. “The sensitivity for detecting exosomes is within 112-600 (exosomes/?L), which would be sufficient in many clinical applications.”
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Materials provided by University of Houston. Original written by Laurie Fickman. Note: Content may be edited for style and length.