Category Archives: Molecular Medicine

On January 20, 2020, the first case of COVID-19 emerged in the United States. More than 30 months on, the pandemic is still considered ongoing.

COVID-19, whose official name is coronavirus disease 2019, is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2 virus). The COVID-19 pandemics continuation and severity are mainly due to the viruss fast mutations and its many variants. As a type of RNA virus, SARS-CoV-2 has a very high mutation rate. This is because the RNA polymerase that replicates the viruss genes doesnt have excellent proofreading skills. However, this actually helps the virus by allowing its variants to find new hosts and escape immunity induced by vaccination or previous in

fection. As a result, during the spreading of the virus, different geographic areas have generated genetically distinct variants.

In June 2021, the World Health Organization (WHO) started using the Greek alphabet to describe variants of interest, which are SARS-CoV-2 virus strains that are considered more dangerous than earlier forms of the virus. These variants are typically considered important due to their increased transmissibility, increased virulence, or the COVID-19 vaccines reduced effectiveness against them.

Prior to the WHO rolling out these rules, researchers around the globe came up with their own lineage naming rules to facilitate their genome sequencing of the virus. As SARS-CoV-2 is a rapidly evolving virus with a high rate of lineage turnover, some Western scientists used the letter A to denote the ancestral type, which is the Wuhan original strain, and the letter B to denote a derived lineage. Many variants of interest, such as alpha, beta, delta, and omicron, belong to lineage B.

The current variants of concern, or more precisely, subvariants (i.e. subsidiary variants) of concern, are BA.4 and BA.5. As of August 13, 2022, BA.5 cases accounted for 88.8 percent of all COVID-19 cases in the United States, followed by BA.4 (5.3 percent) and the latters own newer version BA4.6 (5.1 percent). From the statistics, we can see that BA.5 is more transmissible than BA.4, but so far, scientists havent gained an understanding as to why this is the case, as both subvariants are very similar.

As BA.4 and BA.5 are derived from BA.2, theyre very similar to the latter. According to a preprint study on MedRxiv, the spike proteins of BA.4 and BA.5 are identical, and comparable to BA.2. However, each of these subvariants has its own different mutations from BA.2 in other areas of the virus.

BA.4 and BA.5 are more contagious than any other subvariants of the SARS-CoV-

2 virus. According to a Japanese study, the Re value of BA.4 and BA.5 is 1.2 times higher than that of BA.2. The Re value, also known as the Rt value, is a viruss effective reproduction number, which represents the number of people in a population that can be infected by an individual at any specific time. This number represents a viruss transmissibility. BA.4 and BA.5 are 18.3 times more infectious than BA.2, and are currently the subvariants with the fastest increasing transmission rate.

BA.2 used to be the dominant subvariant around the globe, and BA.4 and BA.5 have rapidly replaced BA.2 in many countries, including the United States, since April 2022.

Furthermore, BA.4 and BA.5 appear to have higher pathogenicity than BA.2.

In a preprinted study of animal models, some Japanese researchers infected some wild-type Syrian hamsters with 105plaque-forming units of BA.4, BA.5, or BA.2 subvariants and performed histopathological analysis. They discovered that inflammation, hemorrhage, congestion, and alveolar damage were significantly higher in the lungs of BA.4 and BA.5-infected hamsters than in BA.2-infected ones. Therefore, BA.4 and BA.5 are more pathogenic than BA.2.

So far, the symptoms of BA.4 and BA.5 appear to be mostly upper-respiratory, including sore throat, running nose, incessant cough, headache, and fatigue, which are similar to the typical Omicron symptoms.

In comparison with the other subvariants, BA.4 and BA.5 are masters at bypassing immunity from a previous infection or vaccination. So people who were formerly infected by other Omicron subvariants can also get re-infected.

As the existing COVID-19 vaccines have been developed based on the original strain. Their protection against Omicron has been significantly reduced, and their protection against BA.4 and BA.5 may be even lower.

In the preprinted Japanese study, by analyzing peripheral blood sera from some convalescents, the researchers discovered that the serum neutralizing antibody titers with BA.4 and BA.5 in those patients who had had two to three doses of COVID-19 vaccines and later had a breakthrough infection by BA.1, were significantly lower than those with BA.2. That is, the combination of full-course vaccination and breakthrough infection cannot protect people from BA.4 or BA.5 infection.

Back on June 30, 2022, the Food and Drug Administration (FDA) warned that the effectiveness of existing COVID-19 vaccines had started to wane against Omicron variants, including BA.4/5. According to the FDAs statement, post-authorization observational studies have shown that effectiveness of primary vaccination wanes over time against certain variants, including Omicron.

Is the immunity gained from a previous COVID-19 natural infection effective against BA.4/5? The answer is: it depends. Although BA.4 and BA.5 subvariants are highly immune-evasive, the immunity acquired from an Omicron infection can still be helpful in protecting people against them. However, if the infection was by a different strain, then the protection offered by the infection-induced immunity may not be great.

The following studies shed some light on this issue.

According to the latest data from the UK Health Security Agency, similar to the pandemic situation in the United States, BA.5 has become the dominant subvariant in the UK, accounting for almost 80 percent of all COVID-19 cases.

The UK Health Security Agency has been carrying out a systematic cohort study (pdf) called the SARS-CoV-2 Immunity and Reinfection EvaluatioN (SIREN).

The participants of this study are more than 44,000 National Health Service healthcare workers from 135 hospitals across the UK. These participants are under active follow-up and undergo asymptomatic SARS-CoV-2 PCR testing every 2 weeks. The cohort had a high seropositivity rate of 30 percent before the second wave hit and is now over 95 percent vaccinated.

The incidence of new infections and reinfections is evaluated in this cohort. Reinfection is defined as a new infection (i.e. PCR positive) 90 days after a prior one.

The graph shows the fortnightly trends of PCR positivity in the SIREN cohort study, and they appear to be consistent with the trends of the alpha, delta, BA.1, BA.2, and other COVID variants. Starting from mid-May 2022, due to the prevalence of BA.4/BA.5, the trend has been going upwards again.

According to the graph, there has been an increase in both primary infection and reinfection rates since May 2022. The increase in primary infection rates indicates that Omicron and its subvariants have significantly enhanced transmission rates, resulting in a large number of infections. The increase in reinfection rates indicates that people who were previously infected can still get infected right now. Therefore, the immunity from natural infection doesnt necessarily offer protection against BA.4 and BA.5. Infection-induced immunitys effectiveness in preventing BA.4/5 infection depends on the strain of the previous infection.

Another preprint study was conducted by a team of researchers from Weill Cornell Medicine-Qatar in Doha. According to the study, young and middle-aged adults who were previously infected with earlier subvariants of Omicron may have substantial protection against BA.4 and BA.5. However, for the people that were infected with a variant that appeared before Omicron, they would not have similar protection against reinfection with BA.4 or BA.5.

This preprint study used the S-gene target failure (SGTF) infections to estimate the effectiveness of previous infections with SARS-CoV-2 in preventing reinfection with Omicron BA.4/BA.5 subvariants. The SGTF status provides a proxy for BA.4/BA.5 infections.

It was discovered that infection with a pre-Omicron variant prevented reinfection by BA.4 or BA.5 with an effectiveness rate of 28.3 percent, and prevented symptomatic reinfection with an effectiveness rate of 15.1 percent. This is because first, a long time has passed since the prior infection; and second, the virus has mutated a lot since then.

The study also found that a previous Omicron infection prevented reinfection by BA.4 or BA.5 with an effectiveness rate of 79.7 percent, and prevented symptomatic reinfection with an effectiveness rate of 76.1 percent. This is because first, the previous infection is relatively recent; and second, the viral mutations have not been large.

Therefore, regardless of previous COVID-19 infections, it is wise for us to maximize our own anti-viral immunity.

The BA.4 and BA.5 sub-lineages are the most transmissible and immune-evasive strains of the COVID-19 virus to date.What are the differences between them and the other subvariants that have given them their ability to escape immunity?

As aforementioned, BA.4 and BA.5 subvariants have identical spike sequences. In comparison with the BA.1 and BA.2 sub-lineages, they have L452R and F486V mutations and the R493Q reversion in the spike receptor binding domain (RBD), which is likely most targeted by neutralizing antibodies.

The production of neutralizing antibodies can be triggered by infection or vaccination. They can result in lifelong immunity to certain viruses. A neutralizing antibody can stop a pathogen from infecting the body by preventing the molecules on the pathogens surface from entering the human cells. As in the case of all enveloped viruses (i.e. the virus cells are inside a lipid membrane), neutralizing antibodies block the attachment of a SARS-CoV-2 virus to the cell and its entry into the cell to infect it.

Some viruses are able to evade neutralizing antibodies by having regular mutations. As a result, the antibodies can no longer recognize them. The BA.2, BA.4, and BA. 5 subvariants all carry a mutation in amino acid L452 of their spike protein. These L452 mutations facilitate their escape from some antibodies directed to certain regions of the receptor-binding domain, and such mutations have also caused several subvariants to appear.

The F486V mutations found in BA.4/5 also facilitate their escape from certain antibodies, whereas the R493Q reversion mutation restores receptor affinity (i.e. strength of the binding) and the fitness of BA.4/5. The Omicron lineage of SARS-CoV-2 continues to evolve, successively generating more subvariants that are not only more transmissible but also more evasive to antibodies.

According to Christian Althaus, a computational epidemiologist at the University of Bern, their capacity to infect people who were immune to earlier forms of COVID-19 strains has given rise to the prevalence of the BA.4 and BA.5 substrains.

The COVID-19 pandemic is entering its fourth year. People around the globe are hoping to see the light at the end of the tunnel. Then, will BA.4 and BA.5 subvariants be the last of their kind?

The answer is: no. Its almost certain that the virus will continue to mutate and persist.

According to Eric Topol, professor of molecular medicine at the Scripps Research Institute in California, We know BA.5 is not where this ends, unfortunately. We have further variants to work through for an indeterminate period of time.

Kei Sato, a virologist at the University of Tokyo, also holds the same view. He says, Nobody can say BA.4/5 is the final variant. It is highly probable that additional Omicron variants will emerge.

Already, a new variant, BA.2.75, has emerged and is spreading rapidly in India. Many medical experts believe that its another super-contagious Omicron mutant, and virologists fear that it will fuel a new wave of cases around the world.It has been given the nickname Centaurus by social media users.

So far, BA.2.75 has been detected in over 20 countries, with India being hit the hardest. According to the Indian authorities statistics, BA.2.75 is now behind two thirds of the new COVID-19 cases in India. However, it hasnt dramatically increased the countrys COVID-related hospitalization or death rate.

As the BA.2.75 subvariant is still evolving, it may develop more immune-evading mutations in the coming weeks. Some BA.2.75 sequences also have L452R mutations, which enhance the subvariants ability to re-infect people.

Link:
Will Omicron BA.5 Be the Last of the COVID Variants? - The Epoch Times

Heart failure is a common and devastating disorder for which there is no cure. Many conditions that make it difficult for the heart to pump bloodsuch as dilated cardiomyopathy and arrhythmogenic cardiomyopathycan lead to heart failure, but treatments for patients with heart failure do not take these distinct conditions into account.

Investigators from Harvard Medical School and Brigham and Womens Hospital set out to identify molecules and pathways that may contribute to heart failure, with the aim of informing more effective and personalized treatments.

Get more HMS news here

Using single nucleus RNA sequencing, or snRNAseq, to gain insight into the specific changes that occur in different cell types and cell states, the team made several surprising discoveries.

They found that while there are some shared genetic signatures, others are distinct, providing new candidate targets for therapy and predicting that personalized treatment could improve patient care. Results were published online August 4 in Science.

Our findings hold enormous potential for rethinking how we treat heart failure and point to the importance of understanding its root causes and the mutations that lead to changes that may alter how the heart functions, said co-senior author Christine Seidman, the Thomas W. Smith Professor of Medicine and professor of genetics in the Blavatnik Institute at HMS and director of the Cardiovascular Genetics Center at Brigham and Womens.

This is fundamental research, but it identifies targets that can be experimentally pursued to propel future therapeutics, she said. Our findings also point to the importance of genotyping. Not only does genotyping empower research but it can also lead to better, personalized treatment for patients.

An echocardiogram shows abnormal heart structures and functionnotably enlarged left atria and ventricle and reduced contraction in the ventriclein a patient with dilated cardiomyopathy. Video: Brigham and Womens

Seidman and Jonathan Seidman, the Henrietta B. and Frederick H. Bugher Foundation Professor of Genetics at HMS, collaborated with an international team.

To conduct their study, theSeidmans and colleagues analyzed samples from 18 control and 61 failing human hearts from patients with dilated cardiomyopathy, arrhythmogenic cardiomyopathy, or an unknown cardiomyopathy disease.

The human heart is composed of many different cell types, including cardiomyocytes (beating heart cells), fibroblasts (which help form connective tissue and contribute to scarring), and smooth muscle cells. The team used single nucleus RNA sequencing to look at the genetic readouts from individual cells and determine cellular and molecular changes in each distinct cell type.

From these data, the team identified 10 major cell types and 71 distinct transcriptional states.

They found that in the tissue from patients with dilated or arrhythmogenic cardiomyopathy, cardiomyocytes were depleted while endothelial and immune cells were increased. Overall, fibroblasts did not increase but showed altered activity.

Analyses of multiple hearts with mutations in certain disease genesincluding TTN, PKP2, and LMNAuncovered molecular and cellular differences as well as some shared responses.

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Many Paths to Failure | Harvard Medical School - Harvard Medical School

In this micrograph, a human macrophage (a type of immune cell) is shown after reduction of the gene DNMT3A. The large green structure is the cells nucleus; red indicates the presence of cytoplasmic protein. The small green dots represent mitochondrial DNA that has escaped from the nucleus into the cytoplasm, inducing an inflammatory response.

Mitochondria are organelles found within most cells, best known for generating the chemical energy required to power cellular functions. Increasingly, however, researchers are discovering how mitochondrial function and dysfunction play critical roles in numerous diseases, and even aging.

In a new study published in the August 4, 2022 online issue of Immunity, scientists at University of California San Diego School of Medicine and Salk Institute for Biological Studies report a surprising link between mitochondria, inflammation and DNMT3A and TET2, a pair of genes that normally help regulate blood cell growth, but when mutated, are associated with an increased risk of atherosclerosis.

We found that the genes DNMT3A and TET2, in addition to their normal job of altering chemical tags to regulate DNA, directly activate expression of a gene involved in mitochondrial inflammatory pathways, which hints as a new molecular target for atherosclerosis therapeutics, said Gerald Shadel, PhD, co-senior study author and director of the San Diego Nathan Shock Center of Excellence in the Basic Biology of Aging at Salk Institute. They also interact with mitochondrial inflammatory pathways, which hints at a new molecular target for atherosclerosis therapeutics.

While studying the roles of DNMT3A and TET2 mutations in clonal hematopoiesis, which happens when stem cells begin making new blood cells with the same genetic mutation, co-senior study author Christopher Glass, MD, PhD, professor in the departments of Medicine and Cellular and Molecular Medicine at UC San Diego School of Medicine, and colleagues noted that abnormal inflammatory signaling related to DNMT3A and TET2 deficiency in blood cells played a major role in the inflammation response that promotes development of atherosclerosis.

Christopher Glass, MD, PhD, is professor in the departments of Medicine and Cellular and Molecular Medicine at UC San Diego School of Medicine.

But the question remained how DNMT3A and TET2 genes were involved in inflammation and atherosclerosis the buildup of fatty plaques in arteries and the primary underlying cause of cardiovascular disease. It is estimated approximately half of Americans between the ages of 45 and 84 have atherosclerosis, which is the single leading cause of death in the United States and westernized nations.

The problem was we couldnt work out how DNMT3A and TET2 were involved because the proteins they code seemingly do opposite things regarding DNA regulation, said Glass. Their antagonistic activity led us to believe there may be other mechanisms at play, which prompted us to take a different approach and contact Shadel, who had uncovered the same inflammatory pathway years earlier while examining responses to mitochondrial DNA stress.

Inside mitochondria resides a unique subset of the cells DNA that must be organized and condensed correctly to sustain normal function. Shadels team had previously investigated the effects of mitochondrial DNA stress by removing TFAM, a gene that helps ensure mitochondrial DNA is packaged correctly.

Shadel and colleagues determined that when TFAM levels are reduced, mitochondrial DNA is expelled from mitochondria into the cells interior, setting off the same molecular alarms that alert cells to a bacterial or viral invader and trigger a defensive molecular pathway that prompts an inflammatory response.

Gerald Shadel, PhD, is director of the San Diego Nathan Shock Center of Excellence in the Basic Biology of Aging at Salk Institute for Biological Studies.

Glass and Shadels labs worked together to better understand why DNMT3A and TET2 mutations led to inflammatory responses similar to those observed during mitochondrial DNA stress. The teams applied genetic engineering tools and cell imaging to examine cells from people with normal cells, those with loss of function mutations in DNMT3A or TET2 expression and those with atherosclerosis.

They discovered that experimentally reducing the expression of DNMT3A or TET2 in normal blood cells produced similar results to blood cells that had loss of function mutations and to blood cells from atherosclerosis patients. In all three cases, there was an increased inflammatory response.

They also observed that low levels of DNMT3A and TET2 expression in blood cells led to reduced TFAM expression, which in turn led to abnormal mitochondria DNA packaging, instigating inflammation due to released mitochondrial DNA.

We discovered that DNMT3A and TET2 mutations prevent their ability to bind and activate the TFAM gene, said first author Isidoro Cobo, PhD, a postdoctoral scholar in Glass lab. Missing or reducing this binding activity leads to mitochondrial DNA release and an overactive mitochondrial inflammation response. We believe this may exacerbate plaque buildup in atherosclerosis.

Shadel said the findings broaden and deepen understanding of mitochondrial function and their role in disease.

Its very exciting to see our discovery on TFAM depletion causing mitochondrial DNA stress and inflammation now have direct relevance for a disease like atherosclerosis, said Shadel. Ever since we revealed this pathway, there has been an explosion of interest in mitochondria being involved in inflammation and many reports linking mitochondrial DNA release to other clinical contexts.

Therapeutics that target inflammation signaling pathways already exist for many other diseases. Glass and Shadel believe that blocking pathways that exacerbate atherosclerosis in patients with TET2A and DNMT3A mutations could form the basis for new treatments.

Co-authors include: Tiffany N. Tanaka, Addison Lana, Calvin Yeang, Claudia Han, Johannes Schlachetki, Jean Challcombe, Bthany R. Fixen, Rick Z. Li, Hannah Fields, Randy G. Tsai and Rafael Behar, all at UC San Diego; Kailash Chandra Mangalhara, Salk; Mashito Sakai, UC San Diego and Nippon Medical School, Japan; Michael Mokry, Wilhelmina Childrens Hospital, the Netherlands; and Koen Prange and Menno Winther, University of Amsterdam, the Netherlands.

This research was supported, in part, by the Leducq Transatlantic Network Grant (16CVD01), the National Institutes of Health (P01 HL147835, 1KL2TR001444, R01 AR069876 and NS047101), the European Molecular Biology Organization (ALTF 960-2018), ZonMw (09120011910025) and the Netherlands Heart Foundation (GENIUSII and 2019B016) and Confocal Microscopy Core (NSO47101).

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Mitochondrial DNA Mutations Linked to Heart Disease Risk - University of California San Diego

The University of California, Davis, reached a major milestone attracting $1.07 billion in external research funding in the fiscal year 2021-22, up $102.9 million from the previous record set last year. In doing so, UC Davis joins an exclusive group of fewer than 20 public universities in the nation surpassing $1 billion in research funding.

The awards lend support to a wide range of research areas including advancing public health and medicine, developing new technologies in food, agriculture and the environment, empowering the underserved and enabling a more resilient society.

This new record for research award funding marks a historic moment for UC Davis, said Chancellor Gary S. May. More than ever, our university is on a mission to address some of the worlds greatest challenges, from how we feed the world to the health of all living beings. This milestone shows clearly how UC Davis research is being sought more than ever, by both the public and private sector, and across numerous fields. Im confident this kind of global impact from UC Davis will only continue to grow.

A primary contributor to this years growth came from funding within the College of Agricultural and Environmental Sciences, up by $72 million from the previous year for a total of $225 million. The School of Medicine also noticed a large increase, adding $29 million for a total of $396 million. The School of Veterinary Medicine ($89 million), College of Engineering ($79 million) and College of Biological Sciences ($68 million) rounded out the top five.

The federal government remained the largest provider of funding at $499 million, although down by $15 million from last year. The second leading source was the state of California at $210 million, up by $46 million from the previous year. Funding from industry made up the third highest source, totaling $104 million. Substantial increases also came from charities (up $26 million) and other UC programs (up $29 million).

As the funding for research grows, so does the impact that UC Davis extends around the world, said Prasant Mohapatra, vice chancellor for research at UC Davis. This years grand accomplishment of surpassing $1 billion in research funding will translate into tomorrows discoveries, insight and products that offer a brighter future for our global community.

An event to celebrate the achievement and showcase some of the exciting research discoveries and emerging technologies is planned for this fall. You can sign up to register for the event here.

The largest award, $53.4 million from the USDA Food and Nutrition Service, went to Kamaljeet Khaira, director of the University of California CalFresh Nutrition Education Program (UC CalFresh) to help reduce the chronic rate of obesity and encourage the awareness of healthy foods and increased physical activity among low-income individuals.

The goal of the GEMINI: GxExM Innovation in Intelligence for climate adaptation project is to use 3D modeling, artificial intelligence and crop genetics to develop new technologies to improve and accelerate breeding pipelines for common bean, cowpea and sorghum, which are key crops for food and income for smallholder farmers in sub-Saharan Africa. The project is co-led by Christine Diepenbrock and Brian Bailey, assistant professors in the Department of Plant Sciences, and Mason Earles, assistant professor in the Department of Biological and Agricultural Engineering, and funded by the Bill & Melinda Gates Foundation.

This research project aims to integrate molecular and cellular physiology measurements on single neurons in order to identify how disease-causing genetic mutations alter neuron behaviors. Gerald Quon, an assistant professor in the Department of Molecular and Cellular Biology and the Genome Center, is leading the project that is funded by the National Institutes of Health (NIH).

The goal of the alternative COVID-19 antigen production project is to explore the viability of a range of biomanufacturing technologies to produce antigens using six different systems: two plants, and cultured mammalian, bacterial, yeast and filamentous fungal cells. The two-year project is led by Karen McDonald, a professor in the Department of Chemical Engineering, and funded by the National Institute of Standards and Technologies (NIST) through the Bioindustrial Manufacturing and Design Ecosystem (BioMADE),

The psychedelics research project led by David Olson, an associate professor in the departments of Chemistry and Biochemistry and Molecular Medicine, plans to screen hundreds of compounds to discover new, nonhallucinogenic treatments for substance use disorders. Funded by the National Institute on Drug Abuse, part of the National Institutes of Health, the study will help us understand the basic mechanisms by which these compounds impact addiction and may help development of more effective and better tolerated treatments.

The two projects from UC Davis Continuing and Professional Education Human Services are focused on supporting the delivery of training and workforce development services for public child welfare agencies and community-based organizations providing intensive services to vulnerable children, youth and families throughout California. Funded by the California Department of Social Services, the programs include instruction and development of new courses and training programs to meet evolving needs of the states child- and family-serving agencies. The projects are led by program directors Alison Book and Nancy Hafer.

The Blackstone Charitable Foundation project supports the creation of entrepreneurs and innovators under the name "Blackstone LaunchPad with a focus on entrepreneurial skill-building so students can succeed in any career they choose. The UC Davis Blackstone LaunchPad makes progress towards specific milestones of increasing cumulative UC Davis student participation each year to support their skills in moving from ideas to growth to ultimately positive impact through a variety of on- and off-campus activities. The project is led by Andrew Hargadon, a professor and Soderquist Chair in Entrepreneurship in the Graduate School of Management (administered by the Mike and Renee Child Institute for Innovation and Entrepreneurship) and sponsored by Hanumantha Unnava, dean of the school.

The project titled Examining how teacher-student interactions within mathematics and literacy instructional contexts relate to the developmental and academic outcomes of early elementary students with autism proposes to bridge the gap between autism research and general education practices. The project is led by Nicole Sparapani, an associate professor in the School of Education and the MIND Institute, along with co-principal investigators Professor Peter Mundy and Nancy Tseng, lecturer in the UC Davis School of Education. Funded by the Institute of Education Sciences, the team will explore how general education teachers can use inclusive math and literacy instructional practices to support learners with autism in their kindergarten to third grade general education classrooms in large, diverse public school districts in Northern California.

The goal of this project from the School of Law is to provide legal services without charge to indigent persons, particularly client groups that have traditionally lacked significant legal representation including migrants, survivors of domestic violence and individuals whose civil rights have been violated. It is led by Gabriel Chin, professor of law and director of Clinical Legal Education, and funded by the State Bar of California.

This research project will examine hospital-to-home transitions for older adult couples who are managing heart failure. The ultimate goal is to develop interventions to support better symptom response and management during these transitions. The project is led by Julie T. Bidwell, an assistant professor in the Family Caregiving Institute at the Betty Irene Moore School of Nursing, and supported by the National Institutes of Health and National Institute of Nursing Research.

This project aims to improve breast cancer, heart health and Alzheimers disease care for women. The Krueger v. Wyeth Settlement Funds award will enable UC Davis Health researchers to study health disparities and advance projects focused on women of color and those in underserved communities. These women are traditionally underrepresented in research and have unique disease risks. As program director, Angela Haczku, a professor of medicine and associate dean of research at the School of Medicine, is assisting principal investigators Professor Luis Carvajal-Carmona, Professor Diana Miglioretti, Professor Amparo Villablanca and Professor Rachel Whitmer, School of Medicine leading the work in the four major projects of this collaborative research award.

Through a project funded by the National Science Foundation titled Impacts of rapid landscape change and biodiversity on virus host specificity, the researchers plan to investigate emerging and re-emerging viruses in transitional ecosystems where landscape change is most likely to influence disease transmission from wildlife to humans. The project is led by Christine Johnson, professor of epidemiology and ecosystem health in the UC Davis School of Veterinary Medicine and Assistant Researcher Tierra Smiley Evans (EpiCenter for Disease Dynamics, One Health Institute), Professor Lark Coffey (Department of Pathology, Microbiology and Immunology, UC Davis School of Veterinary Medicine), Rebekah Kading (Colorado State University), Mike Boots (UC Berkeley), and Ohnmar Aung and Pyae Phyo Aung (Nature Conservation Society - Myanmar).

Interdisciplinary research conducted by Organized Research Units, Special Research Programs, and IMPACT Centerswithin the Office of Research continued to attract significant funding at $113 million, up 19% from last year.** These joint efforts often focus on addressing complex, large-scale challenges that require expertise from many perspectives. Notable examples include:

The UC Davis Energy and Efficiency Institute, as a sub-awardee from Lawrence Berkeley Laboratory, will establish the California Flexible Load Research and Deployment Hub to conduct electricity sector applied research and development and technology demonstration and deployment projects. The goal of the project is to reduce dependence on fossil generation, firm up renewable resources to help California achieve its renewable generation and decarbonization goals. The principal investigator at UC Davis is Professor John Kissock, Department of Mechanical and Aerospace Engineering. The project is funded by the California Energy Commission.

The goal ofthis projectis to identify treatments and develop therapeutics to stop Alzheimers disease from causing irreversible damage to the brain.John H Morrison, professor in the Department of Neurology and director of the California National Primate Research Center, and his team are developing nonhuman primate models of Alzheimers disease that could explain the biochemical and cellular basis of neurodegeneration associated with the disease, and provide new therapeutic targets.This project was funded through theNational Institute on Aging(NIA).

This cooperative effort between the National Park Service and the Air Quality Research Center(AQRC)at UC Davis will analyze data and develop new methods and approaches to enhance the quality and scope of monitoringparticulate matter andvisibility in national parks, wilderness areas, wildlife refuges and other protected areas designated by Congress. The project is an enhancement to the Interagency Monitoring of Protected Visual Environments (IMPROVE) network,which is operated by the AQRC at UC Davis,and is led by AnnM.Dillner, associate director of analytical research, with funding from theU.S. National Park Service and support from the U.S. Environmental Protection Agency.

Note: Reports are based on the principal investigators home school or college. Where funds are awarded up-front to cover several years, the money is counted in the first year the award was received. Incrementally funded awards are counted as authorized in each year.

*Project funding allocated in fiscal year 2019, but active in fiscal year 2022.

**Interdisciplinary totals reported by principal investigators administrative unit

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UC Davis Sets a New Record, Surpasses $1 Billion in Research Funding - University of California, Davis

Yale University, New Haven, CT, USA

Gita A. Pathak&Renato Polimanti

Institute for Molecular Medicine Finland (FIMM), Univerisity of Helsinki, Helsinki, Finland

Juha Karjalainen,Mark Daly,Andrea Ganna&Mark J. Daly

Broad Institute of MIT and Harvard, Cambridge, MA, USA

Christine Stevens,Mark Daly,Andrea Ganna,Masahiro Kanai,Rachel G. Liao,Amy Trankiem,Mary K. Balaconis,Huy Nguyen,Matthew Solomonson,Kumar Veerapen,Samuli Ripatti,Lindo Nkambul,Mark J. Daly,Sam Bryant&Vijay G. Sankaran

Massachusetts General Hospital, Broad Institute of MIT and Harvard, Cambridge, MA, USA

Benjamin M. Neale

Analytic and Translational Genetics Unit, Massachusetts General Hospital, Boston, MA, USA

Mark Daly,Andrea Ganna,Konrad J. Karczewski,Alicia R. Martin,Elizabeth G. Atkinson,Masahiro Kanai,Kristin Tsuo,Nikolas Baya,Patrick Turley,Rahul Gupta,Raymond K. Walters,Duncan S. Palmer,Gopal Sarma,Matthew Solomonson,Nathan Cheng,Wenhan Lu,Claire Churchhouse,Jacqueline I. Goldstein,Daniel King,Wei Zhou,Cotton Seed,Mark J. Daly,Benjamin M. Neale,Hilary Finucane,F. Kyle Satterstrom&Sam Bryant

Icahn School of Medicine at Mount Sinai, New York, NY, USA

Shea J. Andrews,Laura G. Sloofman,Stuart C. Sealfon,Clive Hoggart&Slayton J. Underwood

Institute for Molecular Medicine Finland (FIMM), University of Helsinki, Helsinki, Finland

Mattia Cordioli,Matti Pirinen,Kati Donner,Katja Kivinen,Aarno Palotie&Mari Kaunisto

Icahn School of Medicine at Mount Sinai, Genetics and Genomic Sciences, York City, NY, USA

Nadia Harerimana

Centre for Bioinformatics and Data Analysis, Medical University of Bialystok, Bialystok, Poland

Karolina Chwialkowska

University of Michigan, Ann Arbor, MI, USA

Brooke Wolford

Ancestry, Lehi, UT, USA

Genevieve Roberts,Danny Park,Catherine A. Ball,Marie Coignet,Shannon McCurdy,Spencer Knight,Raghavendran Partha,Brooke Rhead,Miao Zhang,Nathan Berkowitz,Michael Gaddis,Keith Noto,Luong Ruiz,Milos Pavlovic,Eurie L. Hong,Kristin Rand,Ahna Girshick,Harendra Guturu&Asher Haug Baltzell

Institute for Molecular Medicine Finland (FIMM), Helsinki, Finland

Mari E. K. Niemi&Sara Pigazzini

University of Liege, GIGA-Institute, Lige, Belgium

Souad Rahmouni,Michel Georges&Yasmine Belhaj

CHC Mont-Lgia, Lige, Belgium

Julien Guntz&Sabine Claassen

5BHUL (Lige Biobank), CHU of Lige, Lige, Belgium

Yves Beguin&Stphanie Gofflot

Institute for Molecular Medicine Finland, University of Helsinki, Helsinki, Finland

Mattia Cordioli

Analytic & Translational Genetics Unit, Massachusetts General Hospital, Boston, MA, USA

Lindokuhle Nkambule,Lindokuhle Nkambul,Lindokuhle Nkambule&Lindo Nkambul

Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA, USA

Lindokuhle Nkambule

Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA

Lindokuhle Nkambule,Konrad J. Karczewski,Alicia R. Martin,Elizabeth G. Atkinson,Masahiro Kanai,Kristin Tsuo,Nikolas Baya,Patrick Turley,Rahul Gupta,Raymond K. Walters,Duncan S. Palmer,Gopal Sarma,Matthew Solomonson,Nathan Cheng,Wenhan Lu,Claire Churchhouse,Jacqueline I. Goldstein,Daniel King,Wei Zhou,Cotton Seed,Benjamin M. Neale,Hilary Finucane,F. Kyle Satterstrom,Sam Bryant&Caroline Cusick

CHU of Liege, Lige, Belgium

Michel Moutschen,Benoit Misset,Gilles Darcis,Julien Guiot,Samira Azarzar,Olivier Malaise,Pascale Huynen,Christelle Meuris,Marie Thys,Jessica Jacques,Philippe Lonard,Frederic Frippiat,Jean-Baptiste Giot,Anne-Sophie Sauvage,Christian Von Frenckell&Bernard Lambermont

University of Liege, Lige, Belgium

Michel Moutschen,Benoit Misset,Gilles Darcis,Julien Guiot&Samira Azarzar

Department of Human Genetics, McGill University, Montreal, Quebec, Canada

Tomoko Nakanishi

Lady Davis Institute, Jewish General Hospital, McGill University, Montreal, Quebec, Canada

Tomoko Nakanishi,David R. Morrison,J. Brent Richards,Guillaume Butler-Laporte,Vincenzo Forgetta,Biswarup Ghosh,Laetitia Laurent,Danielle Henry,Tala Abdullah,Olumide Adeleye,Noor Mamlouk,Nofar Kimchi,Zaman Afrasiabi,Nardin Rezk,Branka Vulesevic,Meriem Bouab,Charlotte Guzman,Louis Petitjean,Chris Tselios,Xiaoqing Xue,Jonathan Afilalo&Darin Adra

Kyoto-McGill International Collaborative School in Genomic Medicine, Graduate School of Medicine, Kyoto University, Kyoto, Japan

Tomoko Nakanishi

Research Fellow, Japan Society for the Promotion of Science, Tokyo, Japan

Tomoko Nakanishi

McGill Genome Centre and Department of Human Genetics, McGill University, Montreal, Quebec, Canada

Vincent Mooser,Rui Li,Alexandre Belisle,Pierre Lepage,Jiannis Ragoussis,Daniel Auld&G. Mark Lathrop

Department of Human Genetics, Epidemiology, Biostatistics and Occupational Health, McGill University, Montreal, Quebec, Canada

J. Brent Richards

Department of Twin Research, Kings College London, London, UK

J. Brent Richards

Department of Epidemiology, Biostatistics and Occupational Health, McGill University, Montral, Qubec, Canada

Guillaume Butler-Laporte

Department of Emergency Medicine, McGill University, Montreal, Quebec, Canada

Marc Afilalo

Emergency Department, Jewish General Hospital, McGill University, Montreal, Quebec, Canada

Marc Afilalo

McGill AIDS Centre, Department of Microbiology and Immunology, Lady Davis Institute for Medical Research, Jewish General Hospital, McGill University, Montreal, Quebec, Canada

Maureen Oliveira

McGill Centre for Viral Diseases, Lady Davis Institute, Department of Infectious Disease, Jewish General Hospital, Montreal, Quebec, Canada

Bluma Brenner

Research Centre of the Centre Hospitalier de lUniversit de Montral, Montreal, Canada

Nathalie Brassard

Department of Medicine, Research Centre of the Centre Hospitalier de lUniversit de Montral, Montreal, Canada

Madeleine Durand

Department of Medicine, Universit de Montral, Montreal, Canada

Madeleine Durand,Michal Chass&Daniel E. Kaufmann

Department of Medicine and Human Genetics, McGill University, Montreal, Quebec, Canada

Erwin Schurr

Department of Intensive Care, Research Centre of the Centre Hospitalier de lUniversit de Montral, Montreal, Quebec, Canada

Michal Chass

Division of Infectious Diseases, Research Centre of the Centre Hospitalier de lUniversit de Montral, Montreal, Quebec, Canada

Daniel E. Kaufmann

MRC Human Genetics Unit, Institute of Genetics and Cancer, University of Edinburgh, Western General Hospital, Edinburgh, UK

Caroline Hayward,Anne Richmond&J. Kenneth Baillie

Center for Applied Genomics, Childrens Hospital of Philadelphia, Philadelphia, PA, USA

Joseph T. Glessner,Hakon Hakonarson&Xiao Chang

Department of Pediatrics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA

Joseph T. Glessner&Hakon Hakonarson

Vanderbilt University Medical Center, Nashville, TN, USA

Douglas M. Shaw,Jennifer Below,Hannah Polikowski,Petty E. Lauren,Hung-Hsin Chen,Zhu Wanying,Lea Davis&V. Eric Kerchberger

Centre for Genomic and Experimental Medicine, Institute of Genetics and Cancer, University of Edinburgh, Western General Hospital, Edinburgh, UK

Archie Campbell,David J. Porteous&Chloe Fawns-Ritchie

Usher Institute, University of Edinburgh, Nine, Edinburgh Bioquarter, Edinburgh, UK

Archie Campbell

University of Texas Health, Houston, TX, USA

Marcela Morris&Joseph B. McCormick

Department of Psychology, University of Edinburgh, Edinburgh, UK

Chloe Fawns-Ritchie&Chloe Fawns-Ritchie

University of North Carolina at Chapel Hill, Chapel Hill, NC, USA

Kari North

Center for Applied Genomics, The Childrens Hospital of Philadelphia, Philadelphia, PA, USA

Xiao Chang,Joseph R. Glessner&Hakon Hakonarson

Division of Human Genetics, Department of Pediatrics, The Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA

Joseph R. Glessner

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A first update on mapping the human genetic architecture of COVID-19 - Nature.com

Often when researching the molecular and biological changes that happen in space, models such as rodents, worms, and yeast are used to study the effects and consequences of long-duration space flight as a way to understand how microgravity impacts humans in space. However, OHIOs Nate Szewczyk, Ph.D., and several other researchers from around the world have published a paper that proposes a program for the European Space Agency that could potentially revolutionize space medicine by routinely collecting astronauts biological samples from astronauts for use with cutting-edge technologies to understand the effects on their genes, mRNA, proteins, and metabolites (commonly referred to as omics technologies).

The paper, titled Routine omics collection is a golden opportunity for European human research in space and analog environments, published in the journal Patterns, details how omics profiling is primed to transform space medicine and improve occupational healthcare for astronauts. The papers authors anticipate that omics profiling will improve astronauts health and mitigate spaceflight risks, which could increase mission success on more ambitious endeavors such as voyages to Mars. The group of researchers go on to highlight in the paper the collaborative steps that should be taken to design a standardized data resource that can be used for years to come as data and science evolves.

Weve been lobbying for a routine omics collection program to become part of the standard measure for astronauts in the European Space Agency, Szewczyk said. By recovering and analyzing this data, we have the opportunity to further investigate the best practices in personalized medicine for the individuals sent into space.

A twin study was done by NASA where the organization did molecular profiling of one individual which showed it is possible to use large data approaches to understand astronaut health. In the NASA study, they measured how fit the astronaut was before flight, in flight, and after flight to gather their health information and how it may fluctuate in space. After being able to analyze and see the utility of this big data set, NASA decided to make it a standard approach going forward.

We took advantage of NASA making this standard practice because we feel it is something other space agencies need to address to ensure they are finding the best approach to their astronauts health while in space, Szewczyk added.

One of Szewczyks colleagues, Brian Clark, Ph.D., who directs the Ohio Musculoskeletal and Neurological Institute (OMNI) at OHIO noted it is an exciting time for the field of astrobiology. For decades we have known that space flight poses substantial risks to human health and that the physiological effects of prolonged space flight vary tremendously from one person to the other. If you look at ten people that spend six-months on the International Space Station, you will see dramatically different responses between people in things like the amount of muscle and bone loss that they experience. Some experience a staggering amount of loss while others fare considerably better. The advent of omics technologies is clearly our best bet to understand what drives this variability and truly advance personalized space medicine. The knowledge to be gained from these kinds of studies extends far beyond the confines of outer space and has implications for traditional medicine, such as understanding the impact of prolonged disuse that occurs following injury, reconstructive surgery, and illness. It is great to see this call to action and we are extremely proud of Nates stature and influence in the space medicine field.

The team who coauthored the paper is comprised of scientists, including Szewczyk, whose work focuses on space omics. They are tasked with looking at how NASA made the decision to take an omics approach to understanding the molecular and biological impact of astronauts in space and if this measure is something that the European Space Agency should follow along with as well.

Besides identifying whether this practice is beneficial to other space agencies, which data types to collect, which sampling methods to use, and at which time points, they are also looking at what can be measured by multi-omics approaches, such as astronauts genomes and what genes are being expressed, what metabolites are present, are there any changes in proteins, and more.

Thanks to innovations in science, instead of measuring models and translating that data to humans, we are now able to measure people and look at an individuals genome and predict if their genome is at risk for cancer or diabetes, or if a specific drug may or may not work on them based on their genome, Szewczyk said. This is an opportunity to take the same modern molecular medicine approaches and use it on astronauts to identify potential health risks. It is more meaningful than using models and a real opportunity for all space agencies to know and say that the astronauts theyre sending into space are and will be safe.

Along with providing insight to how routine omics collection can improve astronauts health, the team of researchers also appraise ethical and legal considerations pertinent to omics data derived from European astronauts and spaceflight participants, with the goal of creating a policy landscape where data can be as open as possible to maximize scientific potential but as closed as necessary to protect the data subjects.

Szewczyk is an Osteopathic Heritage Foundation Ralph S. Licklider, D.O. Endowed Professor in Molecular Medicine and Principal Investigator of the Ohio Musculoskeletal and Neurological Institute in the Heritage College of Osteopathic Medicine. He has previously flown worms into space, analyzing what changed in them in space and comparing the gene expressions in space with rodents and astronauts, looking for commonalities in change like proteins that allows muscles to function and proteins that allow cells to produce energy. He is currently following up findings from these past flights on two new investigations scheduled to fly to the International Space Station in the coming years.

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OMNI scientist Szewczyk collaborates on proposal that could revolutionize space medicine, improve astronaut health - Ohio University

The Summer Scholars Program in Genome Sciences & Medicine, a collaboration between the Duke Program in Precision Medicine, the Duke Center for Genomic and Computational Biology (GCB), andNorth Carolina Central University (NCCU), concluded the 10-week program last week in Durham, North Carolina.

This summer, eight scholars from across the country were paired with a faculty research mentor to learn laboratory skills, designing a research project, and effectively presenting future research.

This summer program has provided me with the skills I need for the rest of my research career, said Paola J. Maldonado, a rising sophomore from the University of Puerto Rico. Working in research is what I want to do, and this experience really solidified that for me. Maldonado was mentored by Jen-Tsan Ashley Chi, PhD, associate professor of molecular genetics and microbiology and assistant professor of medicine in the division of rheumatology and immunology.

Brielle-Anne Michel, a rising junior at Wake Forest University studying biochemistry and molecular biology, was mentored by HiroakiMatsunami, PhD, professor of molecular genetics and microbiology and neurobiology at Duke. The most exciting part of this program was getting to work with the scientific technologies Ive learned about in undergrad classes but havent seen firsthand, she said. I had mentorsshow me the steps to take, and I was able to do several trials completely by my myself, which was exciting.

Students experienced 10 weeks of everything from working in labs, weekly seminars with Duke professors and graduate student mentors, and tips on networking. Among the many skills obtained, they learned more about how to form research abstracts, posters, writing personal statements and CVs, and presenting their research effectively.

The Summer Scholars program gave me my first opportunity to do hands-on research, said Sydney Vander, a pre-med chemistry major at Xavier University of Louisiana. Thanks to this program, I was able to develop important skills, such as, critical thinking, problem solving, and effective communication. Vander aspires to be a physician and shared how the Summer Scholars program helped her realize that she can incorporate research into her future career path. One day she hopes to perform clinical research while also providing care for patients.

The Summer Scholars Program in Genome Sciences & Medicine is supported by an R25 grant by the National Human Genome Research Institute at NIH and is designed for full-time first- and second-year underrepresented in STEMstudents at any college or university.

A special thanks to 2022 faculty mentors, Ashley Chi, PhD; Ornit Chiba-Falek, PhD; Lindsey Constantini, PhD (NCCU); Charlie Gersbach, PhD; Paul Magwene, PhD; Alex Marshall, PhD (NCCU); Hiro Matsunami, PhD; and Anne West, MD, PhD

Learn more about the Summer Scholars Program in Genome Sciences & Medicine

View all photos from the Summer Scholars Poster Session on July 29, 2022

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Summer Scholars leave Duke with a once-in-a-lifetime research experience - Duke University

An 11-year-old boy sat in a Belgrade hospital with a cough and fever. Doctors said he might have been exposed to tuberculosis, but he was more worried about something else they said. One of the patients there was feared to be positive for smallpox. It was 1972, and Yugoslavia was experiencing Europes last major outbreak of the dreaded disease.

That boy was Janko Nikolich-ugich, MD, PhD, who was never sure if he ever had tuberculosis he was still treated for it or if the other patient really did have smallpox. But living through an epidemic in his younger years sparked an interest in infectious diseases for Dr. Nikolich-ugich, an internationally recognized immunologist and gerontologist at the University of Arizona Health Sciences.

Infections have really shaped our civilization more than anything else, said Dr. Nikolich, head of the UArizona College of Medicine Tucsons Department of Immunobiology and co-director of the Arizona Center on Aging. Our relationship with microbes is still one of the most critical relationships we have in this world in many ways.

Dr. Nikolichs decision to pursue a career in health care was influenced by more than his childhood illness his father, grandfather and grandmother all happened to be doctors. He followed in their footsteps, receiving a medical degree and doctorate in immunology from Belgrade University. When he fulfilled his compulsory military service from 1986 to 1987, he spent most of his time providing medical treatment to the troops and their families.

As Dr. Nikolich returned to a civilian career, he decided to emigrate to the United States, where opportunities to pursue serious research were plentiful. He started as an assistant professor at the Sloan-Kettering Institute for Cancer Research and in the Division of Molecular Medicine at the Cornell University School of Medicine and worked his way up to a senior scientist role in the Vaccine and Gene Therapy Institute at the Oregon Health and Science University.

In 2008, he joined the University of Arizona Health Sciences, where he continues to make discoveries and advances in the areas of immunity and infection in older adults. His research focuses on persistent viruses including cytomegalovirus, a herpesvirus that can lay dormant in the cells of a persons body before reactivating later in life.

That process of awakening or reactivating of the viruses can have a higher impact on us, or a lower impact on us, depending on our age and our condition, said Dr. Nikolich.

A significant part of his career has been spent examining outbreaks of different viruses. He has studied different annual influenza outbreaks and the mosquito-borne Chikungunya virus and West Nile virus. The latter caused the largest recognized epidemic of neuroinvasive arthropod-borne viral illness in the Western Hemisphere in 2002. Around the same time, his laboratory geared up to study Severe Acute Respiratory Syndrome, or SARS, a viral respiratory disease caused by a coronavirus. While he did not end up working with that particular coronavirus, the preparation was useful when SARS-CoV-2 came around.

Science forces you into doing new things all the time, he said. Biology will always have surprises for you. The more you have read about things in the past, without even knowing it will be helpful, that recall becomes really critical.

Dr. Nikolichs decades of research into the immune system, infections and aging made him uniquely prepared to take on major challenges when the COVID-19 pandemic began.

Science forces you into doing new things all the time. Biology will always have surprises for you.Janko Nikolich-ugich, MD, PhD

As the mysterious SARS-CoV-2 virus was spreading in early 2020, he collaborated with Deepta Bhattacharya, PhD, professor in the Department of Immunobiology and BIO5 Institute member, to create one of the most accurate antibody tests in the world. Accuracy is of the utmost importance when dealing with such a widespread virus.

We needed something that would be a lot more than 99% accurate, said Dr. Nikolich, who also is a member of the BIO5 Institute.

The test is so accurate because it recognizes antibodies made in response to two independent parts of the viruss spike protein. It will only return a positive result if there are antibody signals for both components. Having an extremely accurate antibody test gave the team more concrete evidence of past infections and provided more insight into how long antibody immunity might last. They were among the first to publish research about long-term immunity to COVID-19.

Dr. Nikolich was in Serbia with his parents when the coronavirus began to march across Europe in March 2020. He doubts if he wore a mask on the plane home, as no one knew how the virus was being spread. Less than a year later, he again boarded a plane double-masked this time to visit his 97-year-old father, who had been diagnosed with COVID-19.

He fought the virus OK. He spiked pretty impressive antibody titers, he said. He never really developed full respiratory distress, but his body could not cope with it. He just stopped eating.

In late 2020, COVID-19 claimed the life of Zarko Nikolic, MD.

I was there to direct his care and make sure he was comfortable, Dr. Nikolich said. And that was a blessing.

His mother, Mirjana Nikolic, passed away almost two years later. Consequences of a prior COVID-19 infection were likely a contributing factor. Dr. Nikolich said his passion for fighting COVID-19 was there before his parents passed away, but he shares the pain millions of people have felt from losing a loved one during the pandemic.

My laboratory studies the decline of immunity in older adults. When a virus like this strikes, we have to do some research and try to understand it. One piece of data people might not realize is people over the age of 80 were dying of COVID-19 at a clip 270 times higher than people between 18-39, he said. Thats not 270% more, thats 270-fold. That means for every one person age 18-39 who died, more than 270 people over the age of 80 were dying, and that is a staggering number.

Today, Dr. Nikolich continues to unravel the mysteries of the human immune response to COVID-19. Part of his research is happening through the National Institutes of Healths Researching COVID to Enhance Recovery (RECOVER) initiative, which is studying long COVID. Dr. Nikolich is leading the Arizona Post-SARS-CoV-2 Cohort Consortium (AZP3C), a six-institution statewide partnership supported by the RECOVER Clinical Science Core at New York University Langone Health.

To study the long-term effects of COVID-19, the AZP3C team will recruit individuals who have experienced or are in the acute phase of COVID-19, including adults from vulnerable, older and underserved populations and representing diverse races and ethnicities.

Looking beyond COVID-19, Dr. Nikolich is uniting a team of experts to come up with solutions for the next pandemic as director of the Aegis Consortium, a UArizona Health Sciences initiative.

The Aegis Consortiums focus is on prediction and preparedness, the acute and long-term aftereffects of pandemics on individuals and societies, and the use of built and natural environments in pandemic control. The three-pronged approach is designed to identify mechanisms and strategies to stave off new pandemics.

We know a lot about the coronavirus and COVID-19, but there is still more to learn, Dr. Nikolich said. Unfortunately, we also know this will not be the last pandemic we see. The Aegis Consortium is uniting experts in research, technology and innovation to develop solutions that protect the world from future pandemics.

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Understanding Infectious Diseases to Improve Health | UArizona Health Sciences - University of Arizona

WASHINGTON: During a recent study researchers have discovered how mitochondrial function, and dysfunction, play critical roles in numerous diseases, and even ageing.

In a new study published in the online issue of Immunity, scientists at the University of California San Diego School of Medicine and Salk Institute for Biological Studies report a surprising link between mitochondria, inflammation and DNMT3A and TET2, a pair of genes that normally help regulate blood cell growth, but when mutated, are associated with an increased risk of atherosclerosis.

We found that the genes DNMT3A and TET2, in addition to their normal job of altering chemical tags to regulate DNA, directly activate expression of a gene involved in mitochondrial inflammatory pathways, which hints as a new molecular target for atherosclerosis therapeutics, said Gerald Shadel, PhD, co-senior study author and director of the San Diego Nathan Shock Center of Excellence in the Basic Biology of Aging at Salk Institute. They also interact with mitochondrial inflammatory pathways, which hints at a new molecular target for atherosclerosis therapeutics.

While studying the roles of DNMT3A and TET2 mutations in clonal hematopoiesis, which happens when stem cells begin making new blood cells with the same genetic mutation, co-senior study author Christopher Glass, MD, PhD, professor in the departments of Medicine and Cellular and Molecular Medicine at UC San Diego School of Medicine, and colleagues noted that abnormal inflammatory signaling related to DNMT3A and TET2 deficiency in blood cells played a major role in the inflammation response that promotes development of atherosclerosis.

But the question remained how DNMT3A and TET2 genes were involved in inflammation and atherosclerosis the buildup of fatty plaques in arteries and the primary underlying cause of cardiovascular disease. It is estimated approximately half of Americans between the ages of 45 and 84 have atherosclerosis, which is the single leading cause of death in the United States and westernized nations.

The problem was we couldnt work out how DNMT3A and TET2 were involved because the proteins they code seemingly do opposite things regarding DNA regulation, said Glass. Their antagonistic activity led us to believe there may be other mechanisms at play, which prompted us to take a different approach and contact Shadel, who had uncovered the same inflammatory pathway years earlier while examining responses to mitochondrial DNA stress.

What they found

Inside mitochondria resides a unique subset of the cells DNA that must be organized and condensed correctly to sustain normal function. Shadels team had previously investigated the effects of mitochondrial DNA stress by removing TFAM, a gene that helps ensure mitochondrial DNA is packaged correctly.

Shadel and colleagues determined that when TFAM levels are reduced, mitochondrial DNA is expelled from mitochondria into the cells interior, setting off the same molecular alarms that alert cells to a bacterial or viral invader and trigger a defensive molecular pathway that prompts an inflammatory response.

Glass and Shadels labs worked together to better understand why DNMT3A and TET2 mutations led to inflammatory responses similar to those observed during mitochondrial DNA stress. The teams applied genetic engineering tools and cell imaging to examine cells from people with normal cells, those with loss of function mutations in DNMT3A or TET2 expression and those with atherosclerosis.

They discovered that experimentally reducing the expression of DNMT3A or TET2 in normal blood cells produced similar results to blood cells that had loss of function mutations and to blood cells from atherosclerosis patients. In all three cases, there was an increased inflammatory response.

They also observed that low levels of DNMT3A and TET2 expression in blood cells led to reduced TFAM expression, which in turn led to abnormal mitochondria DNA packaging, instigating inflammation due to released mitochondrial DNA.

We discovered that DNMT3A and TET2 mutations prevent their ability to bind and activate the TFAM gene, said first author Isidoro Cobo, PhD, a postdoctoral scholar in Glass lab. Missing or reducing this binding activity leads to mitochondrial DNA release and an overactive mitochondrial inflammation response. We believe this may exacerbate plaque buildup in atherosclerosis.

Shadel said the findings broaden and deepen understanding of mitochondrial function and their role in disease.

Its very exciting to see our discovery on TFAM depletion causing mitochondrial DNA stress and inflammation now have direct relevance for a disease like atherosclerosis, said Shadel. Ever since we revealed this pathway, there has been an explosion of interest in mitochondria being involved in inflammation and many reports linking mitochondrial DNA release to other clinical contexts.

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Mitochondrial DNA mutations associated with heart disease risk - DTNEXT

Tributes are pouring in at news of the death of John Bienenstock, known internationally as a visionary physician, scientist, academic and a leader at McMaster University. He died July 25 at age 85.

The professor of pathology officially retired in 1998, but he remained active in his research and as director of the McMaster Brain Body Institute at St. Josephs Healthcare Hamilton until his death.

During his tenure at McMaster, he became renowned worldwide as a pioneer in mucosal immunology introducing the concept of a common mucosal immune system. He also advanced the knowledge of neuroimmunology and in understanding how the brain and nervous system collaborate. He published more than 500 peer-reviewed articles and authored, edited or co-edited 10 books including a standard textbook on mucosal immunology and allergy.

He was chair of the Department of Pathology from 1978 to 1989, and dean and vice-president of the Faculty of Health Sciences at McMaster from 1989 to 1997. He was known for establishing a substantial research infrastructure at the Faculty.

His accomplishments were recognized. He became a Fellow of the Royal Society of Canada in 1992; a McMaster Distinguished University Professor in 1999; a member of the Order of Canada in 2002 and was inducted into the Canadian Medical Hall of Fame in 2011. He became a member of the Faculty of Health Sciences Community of Distinction in 2014. He also received an honorary MD from Goteborg, Sweden.

He was born in Budapest, Hungary in 1936, obtained his medical degree at Kings College London and Westminster Hospital Medical School, U.K. in 1960, and did a postdoctoral term at Harvard University before joining McMaster Universitys medical school start-up in 1968. The first class began in 1969.

Bienenstock was also a mentor and friend to many graduate students and fellow researchers, supervising more than 60 post doctoral fellows and 10 doctoral students.

He leaves his family: his wife Dody; their children, the late Jimson (Johanna), Adam (Jill), and Robin; their grandchildren, Bella, Elsa, Sam, Leo, Sebastiano and Oliva and his sister Tsultrim Zangmo (Veronica).

Typical of the tributes, is this one from Dr. Kevin Smith, former CEO of St. Josephs Healthcare and current President & CEO, University Health Network John was the single most important mentor in my career and unquestionably the most creative person a true renaissance man I have ever had the privilege of working with. He took great joy in the success of others and made hard work fun. He became a dear and beloved friend who I will forever treasure and miss.

Dr. John Bienenstock has had an immense impact on the Faculty since he started here 54 years ago. He was a visionary as a scientist, as an administrator and as an academic, inspiring generations of scientists and clinicians to think outside of the box. He was a friend and mentor to so many of us, and his legacy of innovation will continue, Paul OByrne, Distinguished University Professor, Medicine, and Dean and Vice-President, Faculty of Health Sciences, McMaster University.

John Bienenstock was a remarkably creative individual, a revolutionary thinker and a pioneer in the study of mucosal Immunology. Johns impact on our community has been deep and far-reaching. As holder of the John Bienenstock Chair in Molecular Medicine, I am continually inspired by Johns legacy of scientific excellence and impact, Jonathan Bramson, Professor, Medicine and Vice-Dean, Research, Faculty of Health Sciences, McMaster University

The Canadian Medical Hall of Fames 2011 tribute to John Bienenstock is here. https://www.youtube.com/watch?v=yyXxiBw8qlQ

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Distinguished health researcher, hospital executive John Bienenstock remembered - The Bay Observer - Providing a Fresh Perspective for Hamilton and...