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A study has found that disabling a gene in the myeloid cells of mice prevents them from developing obesity.

New research has found that inhibiting an immune cell gene in mice prevented them from developing obesity, even when they consumed a diet high in fat.

The studys findings, published in The Journal of Clinical Investigation, may one day help scientists develop therapies that can help people with obesity burn calories more easily.

Obesity is a major health issue, and in the United States, rates of the condition have risen over the past 40 years.

The Centers for Disease Control and Prevention (CDC) report that between 2017 and 2018, 42.4% of people in the country had obesity. Between 1999 and 2000, that figure was 30.5%.

Obesity increases the risk of heart disease, strokes, diabetes, and some types of cancer.

The CDC say that lifestyle changes, including eating a more healthful diet and getting more regular exercise, are key to reducing obesity.

One issue, however, involves obesitys effects on metabolism previous research in mice lead to the suggestion that a person with obesity burns fewer calories than a person who does not have obesity.

Better understanding how and why this might happen, and what scientists and clinicians can do about it, may help with reducing obesity.

In the present study, the researchers inhibited a gene in immune cells in mice. They did this because of an association between obesity and increased inflammation, and immune cells play a key role in controlling inflammation.

The researchers had wanted to find out what part the immune cells play in the metabolic complications of obesity. To their surprise, they found that the cells have a central role in regulating obesity and weight gain.

To study the effects of inhibiting the immune cell gene, the researchers conducted two experiments. In the first, they deleted the gene Asxl2, and in the second, they injected regular mice with nanoparticles that interfered with the function of the gene.

Once the researchers had inhibited this gene in the immune cells, they found that the mice did not develop obesity when fed a high fat diet, and that this was likely due to increased energy expenditure.

Compared with a control group of mice who had obesity but none of the gene inhibition, the mice with the inhibition burned 45% more calories, despite eating high fat diets.

For the studys principal investigator, Prof. Steven L. Teitelbaum, of the Washington University School of Medicine, in St. Louis, MO, Weve developed a proof of concept, here, that you can regulate weight gain by modulating the activity of these inflammatory cells.

It might work in a number of ways, but we believe it may be possible to control obesity and the complications of obesity by better regulating inflammation.

The team is not yet sure why inhibiting the gene in the mices immune cells resulted in them not gaining weight while on a high fat diet. The researchers suspect that the answer may involve encouraging white fat cells to burn fat rather than store it, as brown fat cells do.

While this is only preliminary research, the findings may eventually help people with obesity burn calories at a higher rate, supporting them as they make broader lifestyle changes that involve the diet and exercise.

According to Prof. Teitelbaum, A large percentage of Americans now have fatty livers, and one reason is that their fat depots cannot take up the fat they eat, so it has to go someplace else.

These mice consumed high fat diets, but they didnt get fatty livers. They dont get type 2 diabetes. It seems that limiting the inflammatory effects of their macrophages allows them to burn more fat, which keeps them leaner and healthier.

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Researchers seek answers to viruss mysteries, clues to possible treatments

Washington University School of Medicine in St. Louis is one of more than 30 genome sequencing hubs worldwide participating in a study to sequence the DNA of young, healthy adults and children who develop severe COVID-19 despite having no underlying medical problems. The researchers also will study people who never become infected despite repeated exposures to coronavirus. Knowledge gained from understanding COVID-19s extremes could lead to new therapeutic strategies for the illness.

To help unravel the mysteries of COVID-19, scientists are sequencing the DNA of young, healthy adults and children who develop severe illness despite having no underlying medical problems. The researchers are looking for genetic defects that could put certain individuals at high risk of becoming severely ill from the novel coronavirus.

The McDonnell Genome Institute at Washington University School of Medicine in St. Louis is one of more than 30 genome sequencing hubs worldwide participating in the study. Rheumatologist Megan A. Cooper, MD, PhD, an associate professor of pediatrics, is leading the research at Washington University. Called the COVID Human Genetic Effort, the international project is co-led by the National Institute of Allergy and Infectious Diseases of the National Institutes of Health (NIH), and Rockefeller University.

The researchers also plan to study people who never become infected with SARS-CoV-2, the virus that causes COVID-19, despite repeated exposures. Such individuals may have genetic variations that protect against infection. For example, certain rare genetic variants are known to thwart some types of viral infections, including HIV and norovirus. Knowledge gained from understanding COVID-19s extremes unusual susceptibility and resistance could lead to new therapeutic strategies for the illness.

The first focus of our study will be patients with severe responses to SARS-CoV-2 infection severe enough to require intensive care who appear otherwise healthy and are younger than 50, said Cooper, who also leads the clinical immunology program and the Jeffrey Modell Diagnostic and Research Center for Primary Immunodeficiencies at St. Louis Childrens Hospital.

These patients dont have uncontrolled diabetes, heart disease, chronic lung disease or any other condition that we know increases the risk of severe complications from COVID-19, she said. For example, we sometimes see stories about, say, a marathon runner or a generally fit, healthy person who nevertheless got very sick from this virus, or the few healthy children who are getting very sick with COVID-19. These are the kinds of patients were interested in for this study. A small proportion of hospitalized patients will fit this category, likely less than 10%.

Cooper studies primary immunodeficiencies in children. Primary immunodeficiencies are a group of more than 450 genetic disorders of the immune system. They often are caused by mutations in single genes that affect different aspects of immunity.

With this pandemic, we can use our skills in gene hunting to search for genes that might be associated with severe COVID-19 in children and younger adults, she said. We can foresee a future ability to do a genetic sequencing test for individual patients hospitalized with SARS-CoV-2 and get an idea of whether they are likely to need more intensive care. In the meantime, we will be able to learn a great deal about how the immune system responds to this virus and what it needs to be able to respond effectively and in an appropriate manner.

These patients genetics could reveal the important immune pathways that the body needs to fight the virus. That knowledge could lead to therapies that also could help other patients who dont have a genetic susceptibility to the virus but perhaps have high-risk conditions, such as diabetes or heart disease.

Our immune systems have never seen this virus before, Cooper said. Were seeing severe COVID-19 complications play out across the world right now. It is going to take a global effort to investigate the genetic factors and the immune system factors that really control this infection.

Research related to COVID-19, including collecting and distributing of patient samples, is managed through Washington Universitys Institute of Clinical and Translational Sciences (ICTS), led by William G. Powderly, MD, who is also the Larry J. Shapiro Director of the Institute for Public Health, the J. William Campbell Professor of Medicine and co-director of the Division of Infectious Diseases.

This research is supported by funding from the St. Louis Childrens Hospital Foundation and the Jeffrey Modell Foundation.

Washington University School of Medicines 1,500 faculty physicians also are the medical staff of Barnes-Jewish and St. Louis Childrens hospitals. The School of Medicine is a leader in medical research, teaching and patient care, ranking among the top 10 medical schools in the nation by U.S. News & World Report. Through its affiliations with Barnes-Jewish and St. Louis Childrens hospitals, the School of Medicine is linked to BJC HealthCare.

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COVID-19 study looks at genetics of healthy people who develop severe illness - Washington University School of Medicine in St. Louis

Why can some people eat as much as they want, and still stay thin?

In a study published today in the journal Cell, Life Sciences Institute Director Dr. Josef Penninger and a team of international colleagues report their discovery that a gene called ALK (Anaplastic Lymphoma Kinase) plays a role in resisting weight gain.

We all know these people, who can eat whatever they want, they dont exercise, but they just dont gain weight. They make up around one per cent of the population, says senior author Penninger, professor in the Faculty of Medicines department of medical genetics and a Canada 150 research chair.

Dr. Josef Penninger

We wanted to understand why, adds Penninger. Most researchers study obesity and the genetics of obesity. We just turned it around and studied thinness, thereby starting a new field of research.

Using biobank data from Estonia, Penningers team, including researchers from Switzerland, Austria, and Australia, compared the genetic makeup and clinical profiles of 47,102 healthy thin, and normal-weight individuals aged 20-44. Among the genetic variations the team discovered in the thin group was a mutation in the ALK gene.

ALKs role in human physiology has been largely unclear. The gene is known to mutate frequently in several types of cancer, and has been identified as a driver of tumour development.

Our work reveals that ALK acts in the brain, where it regulates metabolism by integrating and controlling energy expenditure, says Michael Orthofer, the studys lead author and a postdoctoral fellow at the Institute of Molecular Biology in Vienna.

When Penningers team deleted the ALK gene in flies and mice, both were resistant to diet-induced obesity. Despite consuming the same diet and having the same activity level, mice without ALK weighed less and had less body fat.

As ALK is highly expressed in the brain, its potential role in weight gain resistance make it an attractive mark for scientists developing therapeutics for obesity.

The team will next focus on understanding how neurons that express ALK regulate the brain at a molecular level, and determining how ALK balances metabolism to promote thinness. Validating the results in additional, more diverse human population studies will also be important.

Its possible that we could reduce ALK function to see if we did stay skinny, says Penninger. ALK inhibitors are used in cancer treatments already, so we know that ALK can be targeted therapeutically.

The study was supported by the Estonian Research Council, the European Union Horizon 2020 fund, and European Regional Development Fund, the von Zastrow Foundation, and the Canada 150 Research Chairs Program.

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UBC scientist identifies a gene that controls thinness - UBC Faculty of Medicine - UBC Faculty of Medicine

INDIANAPOLIS A dime-size nanochip developed by a world-renowned researcher who recently relocated to Indianapolis could help transform the practice of medicine. It could also turn Indianapolis into a manufacturing and research hub for radically new disease and trauma treatment techniques.

It all began in August 2018, when Chandan Sen, one of the worlds leading experts in the nascent field of regenerative medicine, moved his lab from Ohio State University to the Indiana University School of Medicine. He brought along a team of about 30 researchers and $10 million in research grants, and now serves, among a myriad of other positions, as director of the newly formed Indiana Center for Regenerative Medicine and Engineering, to which IU pledged $20 million over its first five years.

IU recruited Sen away from Ohio State in part because of its desire not just to promote academic research in his field but also to help develop practical, commercial products and uses for his breakthroughs.

A scientist prefers to be in the lab and keep on making more discoveries, said Sen, 53.

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But I thought that, unless we participate in the workforce development process and the commercialization process, I dont think that the business people would be ready to do it all by themselves. Because its such a nascent field.

Its definitely new and its potential sounds like the stuff of science fiction.

Regenerative medicine, as its name hints, seeks to develop methods for replacing or reinvigorating damaged human organs, cells and tissues.

For instance, instead of giving a diabetic a lifetimes worth of insulin injections, some of his skin cells could be altered to produce insulin, curing him. Such techniques might also be used for everything from creating lab-grown replacement organs to, someday, regenerating severed limbs.

Regenerative medicine offers a form of medicine that is neither a pill nor a device, Sen said.

It is a completely new platform, where you dont necessarily depend on any given drug, but are instead modifying bodily functions.

A big, tiny breakthrough

Sen and his teams signal contribution to the field is a technique theyve dubbed tissue nanotransfection, or TNT. Put simply, it uses a nanotechnology-based chip infused with a special biological cargo that, when applied to the skin and given a brief electrical charge, can convert run-of-the-mill skin cells into other cell types. Potentially, the technique could be used for everything from regrowing blood vessels in burn-damaged tissue to creating insulin-secreting cells that could cure diabetics.

Obviously, such applications are still down the road a ways. But the technology is far enough along that some products are already making it to marketand investors, entrepreneurs and established companies are sniffing around for opportunities. According to the Alliance for Regenerative Medicine, more than 1,000 clinical trials worldwide are using regenerative medicine technologies.

Thousands of patients are already benefiting from early commercial products, and we expect that number will grow exponentially over the next few years, said Janet Lambert, the alliances CEO.

Lambert predicts that the number of approved gene therapies will double in the next one to two years. Last year, the U.S. Food and Drug Administration predicted it would be approving 10 to 20 cell and gene therapies each year by 2025.

These new techniques could do more than just revolutionize medicine. They could also upend the medical industry as we know it. And the IU School of Medicineand Indianapoliscould lead the way.

There are really only two or three places in the country that did the kind of comprehensive work that Dr. Sens group was doing, said Anantha Shekhar, executive associate dean for research at IU School of Medicine. And they were doing it from the lab all the way to the clinic, where they were already applying those technologies in patients.

So it was very attractive to think of starting with a bang bringing a comprehensive group here and creating a new center.

Ambitious goals

Instead of merely treating chronic conditions, regenerative medicine could end them, once and for all.

For instance, consider a car with an oil leak. The traditional medical approach might be to live with the chronic condition by pouring in a fresh quart of oil every few days. The regenerative medicine approach would fix the leak. Its good for the car, good for the cars owner but not necessarily good for the guy who was selling all those quarts of oil.

Which is why these new techniques, if they catch on, could cause turmoil in the medical industry.

Because regenerative medicine has the potential to durably treat the underlying cause of disease, rather than merely ameliorating the symptoms, this technology has the potential of being extremely disruptive to the current practice of medicine, Lambert said.

This has the potential to be hugely disruptive, Sen added, because so much of medicine today relies on huge industrial infrastructures to manage, not cure, chronic diseases and disabilities.

If such disruption comes to pass, the leaders of 16 Tech, a 50-acre innovation district northwest of downtown that aspires to house dozens of medical-related startups and established firms, would love to be its epicenter.

The Center for Regenerative Medicine will be one of the tenants of 16 Techs first building, a $30 million, 120,000-square-foot research and office building scheduled to open in June.

Regenerative medicine is probably one of the next major waves of medical innovation in the world, 16 Tech CEO Bob Coy said. To have him here doing this work gives Indianapolis and Indiana an opportunity to develop an industrial cluster in regenerative medicine.

Coy believes the most momentous early step on that road was the recent establishment by Sen of masters and doctoral programs in regenerative medicine at the IU School of Medicine. Its the first degree of its type in the country, earning IU and Indianapolis the enviable status of first mover.

I think, for example, of [Pittsburghs] Carnegie Mellon University, which, back in the late 1960s, created the first college of computer science in the country, Coy said. And now you know Carnegie Mellons reputation in computer science.

What isnt in place yet is a state or city program to promote development of a regenerative medicine hub.

We need to start doing that, Coy said. That means putting a lot of the infrastructure in place to support startups that are based on this technology, as well as recruiting companies that want to collaborate with Dr. Sen.

In spite of the lack of a coherent recruitment program, Coys phone has started to ring, thanks largely to Sens presence.

There have been a few meetings Ive had with people who already have relationships with him, who, when they come to town, have reached out to meet and talk about what were doing at 16 Tech, he said.

Fueling entrepreneurship

One of the first 16 Tech startups with designs on the regenerative medicine niche is Sexton Biotechnologies.

The company was groomed by Cook Regentec, a division of Bloomington-based Cook Group charged with incubating and accelerating technologies for regenerative medicine and the related field of cell gene therapy.

Any products that show promise are either folded into the company, turned into their own divisions or, as in Sextons case, spun off as an independent entity with Cook retaining a financial stake.

Its a measure of the newness of this field that Sextons 17 employees arent working on new medicines, but rather marketing basic tools needed to conduct research. The companys offerings include a vial for storing cell and gene products in liquid nitrogen, and a cell culture growth medium.

Theres a ready market for such tailor-made gear, because, for years, researchers in the regenerative medicine field had to make do with jury-rigged equipment.

What most of those companies did was repurpose things like tools from the blood banking industry, or tools from bio pharma, said Sean Werner, Sextons president.

So thats why a lot of newer companies are starting to build tools explicitly for the industry, as opposed to everybody just having to cobble together stuff that was already out there.

Werner said investors recognize the momentous opportunity in regenerative medicine and are flocking to the field.

Its not something you have to explain, he said. Companies and VC groups are trying to get a piece of it.

What has investors and medical researchers charged up is the almost unlimited range of potential applications, from healing burns to, perhaps someday, regenerating limbs.

I think it would be a huge revolution if were able to, for example, regenerate insulin-secreting cells in children who have become juvenile diabetics or have for whatever reason lost their pancreas, Shekhar said. Those are the kinds of things that will start to change the way we see certain diseases.

Lambert predicted that, as the science advances, so will the business case.

While early programs focused primarily on rare genetic diseases and blood cancers, were already seeing the field expand into more common age-related neurological disorders, such as Parkinsons and Alzheimers, she said.

I expect this trend to continue in the coming years, greatly increasing the number of patients poised to benefit from these therapies.

Werner said regenerative medicine also is seeking advancements in manufacturing technologies that will lower the cost of product development.

It all adds up to a huge opportunity the state is well-positioned to seize, Werner believes.

Indiana is a perfect place for this kind of thing to really ramp up, he said. Theres no reason we cant lead the field.

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IU team pursuing breathtaking advancements in regenerative medicine - The Republic

The complement system is part of the bodys immune system to fight pathogens and remove cell debris. Its role in two autoimmune diseases and a mental disorder is a surprise.

The complement system is part of the bodys immune system to fight pathogens and remove cell debris. Its role in two autoimmune diseases and a mental disorder is a surprise.Variants in a gene of the human immune system cause men and women to have different vulnerabilities to the autoimmune diseases lupus and Sjgrens syndrome, according to findings published today in the journal Nature. This extends recent work that showed the gene variants could increase risk for schizophrenia.

The gene variants are a member of the complement system, a cascade of proteins that help antibodies and phagocytic cells remove damaged cells of a persons own body, as well as an infection defense that promotes inflammation and attacks pathogens. Normally the complement system keeps a person healthy in the face of pathogens; it also helps cart away the debris of damaged human cells before the body can mount an autoimmune attack. Now complement gene variants apparently play a contributing role in the diseases systemic lupus erythematosus, Sjgrens syndrome and schizophrenia.

It had been known that all three illnesses had common genetic associations with a section of the human chromosome called the major histocompatibility complex, or MHC. This region on chromosome 6 includes many genes that regulate the immune system. However, making an association with a specific gene or with the mutational variants of a specific gene that are called alleles has been difficult, partly because the MHC on human chromosome 6 spans three million base-pairs of DNA.

The Nature paper is a collaboration of 22 authors at 10 institutions in the United States and one in England, along with many members of a schizophrenia working group. Robert Kimberly, M.D., professor of medicine at the University of Alabama at Birmingham and director of the UAB Center for Clinical and Translational Science, is a co-author of the research, which was led by corresponding author Steven McCarroll, Ph.D., assistant professor of genetics at Harvard Medical School.

The identified alleles are complement component 4A and 4B, known as C4A and C4B.

The research showed that different combinations of C4A and C4B copy numbers generate a sevenfold variation in risk for lupus and 16-fold variation in risk for Sjgrens syndrome among people with common C4 genotypes. Paradoxically, the same C4 alleles that previously were shown to increase risk for schizophrenia had a different impact for lupus and Sjgrens syndrome they greatly reduced risk in those diseases. In all three illnesses, the C4 alleles acted more strongly in men than in women.

For the complement proteins that are encoded by the genes for C4 and for complement component 3, or C3, both C4 protein and its effector C3 protein were present at greater levels in men than in women in cerebrospinal fluid and blood plasma among adults ages 20-50. Intriguingly, that is the age range when the three diseases differentially affect men and women for unknown reasons. Lupus and Sjgrens syndrome affect women of childbearing age nine times more than they do men of similar age. In contrast, in schizophrenia, women exhibit less severe symptoms, more frequent remission of symptoms, lower relapse rates and lower overall incidence than men, who are affected more frequently and more severely.

Both men and women have an age-dependent elevation of C4 and C3 protein levels in blood plasma. In men, this occurs early in adulthood, ages 20-30. In women, the elevation is closer to menopause, ages 40-50. Thus, differences in complement protein levels in men and women occur mostly during the reproductive years, ages 20-50.

The researchers say sex differences in complement protein levels may help explain the larger effects of C4 alleles in men, the greater risk of women for lupus and Sjgrens, and the greater vulnerability of men for schizophrenia.

Robert Kimberly, M.D.The ages of pronounced sex differences in complement levels correspond to the ages when men and women differ in disease incidence. In schizophrenia cases, men outnumber women in early adulthood; but that disparity of onset lessens after age 40. In lupus, female cases greatly outnumber male cases during childbearing years; but that difference is much less for disease onset after age 50 or during childhood. In Sjgrens syndrome, women are more vulnerable than are men before age 50.

The researchers say the differing effect of C4 alleles in schizophrenia versus lupus and Sjgrens syndrome will be important to consider in any therapeutic effort to engage the complement system. They also said, Why and how biology has come to create this sexual dimorphism in the complement system in humans presents interesting questions for immune and evolutionary biology.

Co-authors with McCarroll and Kimberly for the paper, Complement genes contribute sex-biased vulnerability in diverse illnesses, are Nolan Kamitaki, Aswin Sekar, Heather de Rivera, Katherine Tooley and Christine Seidman, Harvard Medical School, Massachusetts; Robert Handsaker and Christopher Whelan, Broad Institute of Massachusetts Institute of Technology; David Morris, Philip Tombleson and Timothy Vyse, Kings College London, London, United Kingdom; Kimberly Taylor and Lindsey Criswell, University of California-San Francisco School of Medicine; Loes Olde Loohuis and Roel Ophoff, University of California-Los Angeles; Michael Boehnke, University of Michigan; Kenneth Kaufman and John Harley, Cincinnati Childrens Hospital Medical Center, Ohio; Carl Langefeld, Wake Forest School of Medicine, North Carolina; Michele Pato and Carlos Pato, State University of New York, Downstate Medical Center; and Robert Graham, Genentech Inc., South San Francisco, California.

Support came from National Institutes of Health grants HG006855, MH112491, MH105641 and MH105653; and from the Stanley Center for Psychiatric Research.

At UAB, Kimberly holds the Howard L. Holley Research Chair in Rheumatology.

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Complement genes add to sex-based vulnerability in lupus and schizophrenia - UAB News

In patients with coronavirus disease 2019 (COVID-19), higher sputum cell expression of angiotensin converting enzyme 2 (ACE2) and transmembrane protease serine 2 (TMPRSS2) was observed in certain patients with asthma while lower expression was found in patients who used inhaled corticosteroids (ICS), according to study results published in the American Journal of Respiratory and Critical Care Medicine.

COVID-19, caused by severe acute respiratory syndrome-coronavirus 2 (SARS-CoV-2), may be more severe in patients with chronic lung disease, including patients with asthma, and it appears that demographic or biological factors influence susceptibility to the infection or severity of disease. Because ACE2 and TMPRSS2 mediate viral infection of host cells, researchers reasoned that differences in ACE2 or TMPRSS2 gene expression in sputum cells in patients with asthma may identify subgroups at risk for COVID-19 morbidity.

By analyzing gene expression for ACE2 and TMPRSS2 as well as intercellular adhesion molecule 1 (ICAM-1) in sputum cells from 330 participants and 79 healthy control individuals, researchers found that gene expression of ACE2 was lower than TMPRSS2, and that expression levels of both genes were similar in patients with asthma and healthy individuals. In patients with asthma, however, men, African Americans, and people with diabetes had higher expression of ACE2 and TMPRSS2. In patients with asthma, ICAM-1 expression increased and there were fewer consistent differences related to sex, race, and ICS use. Use of ICS was associated with lower expression of ACE2 and TMPRSS2, while treatment with triamcinolone acetonide did not decrease expression of either gene or ICAM-1.

Higher expression of ACE2 and TMPRSS2 in males, African Americans, and patients with diabetes mellitus provides rationale for monitoring these asthma subgroups for poor COVID-19 outcomes, the study authors wrote. The lower expression of ACE2 and TMPRSS2 with ICS use warrants prospective study of ICS use as a predictor of decreased susceptibility to SARS-CoV-2 infection and decreased COVID-19 morbidity.

Reference

Peters MC, Sajuthi S, Deford P, et al; for the National Heart, Lung, and Blood Institute Severe Asthma Research Program-3 Investigators. COVID-19 related genes in sputum cells in asthma: Relationship to demographic features and corticosteroids [published online April 29, 2020]. Am J Respir Crit Care Med. doi:10.1164/rccm.202003-0821OC

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COVID-19-Related Genes Have Higher Expression in Certain Patients With Asthma - Pulmonology Advisor