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Immunology

COVID-triggered autoimmunity may be mostly temporary – Emory Health Now

In people with severe COVID-19, the immune system goes temporarily berserk and generates a wide variety of autoantibodies: proteins that are tools for defense, but turned against the bodys own tissues.

During acute infection, COVID-19 patients immune systems resemble those of people with diseases such as lupus or rheumatoid arthritis. However, after the storm passes, the autoantibodies decay and are mostly removed from the body over time, according to a study of a small number of patients who were hospitalized and then recovered.

In apreprint posted on medRxiv, Emory immunologists provide a view of the spectrum of what COVID-generated autoantibodies react against, both during acute infection and later. Note: the results have not yet been published in a peer-reviewed journal.

The findings on COVID-19-triggered autoimmunity may have implications for both the treatment of acute infection and for long-haulers, in whom autoantibodies are suspected of contributing to persistent symptoms such as fatigue, skin rashes and joint pain.

During acute infection, testing for autoantibodies may enable identification of some patients who need early intervention to head off problems later. In addition, attenuation of autoantibody activity by giving intravenous immunoglobulin (IVIG) an approach that has been tested on a small scale may help resolve persistent symptoms, the Emory investigators suggest.

Researchers led by Ignacio Sanz, MD and Frances Eun-Hyung Lee, MD, isolated thousands of antibody-secreting cells from 7 COVID-19 patients who were in ICUs at Emory hospitals. They also looked for markers of autoimmunity in a larger group of 52 COVID-19 ICU patients.

Sanz is head of the division of rheumatology in the Department of Medicine, director of the Lowance Center for Human Immunology, and a Georgia Research Alliance Eminent Scholar. Lee is associate professor of medicine and director of Emorys Asthma/Allergy Immunology program.

The co-first authors are Matthew Woodruff, PhD, an instructor in Sanzs lab, and Richard Ramonell, MD, a fellow in pulmonary and critical care medicine at Emory University Hospital. In some of the experiments, Emory researchers collaborated with Exagen, using technology developed by the company to probe clinical autoimmune profiles.

We were trying to address the question: what is the origin of the autoantibodies? Sanz says.

That is, are they generated during the course of infection? Or were immune cells capable of making the observed autoantibodies already existing in the body, and let loose by the infection?

These possibilities are not mutually exclusive, but it appears that new generation of autoreactive clones from nave cells is a dominant mechanism in acute severe infection, he says. What we see is a broad breakdown of tolerance, at least temporarily.

The researchers characterized the antibodies the cells produced and their DNA, looking for signs of the editing processes the immune system usually applies to ensure antibodies dont react against the body itself.

The editing processes appeared to have weakened during infection. Germinal centers, the anatomical structures within lymph nodes where antibody-secreting cells mature, can collapse during intense inflammation, Sanz says. As a result, antibody-secreting cells develop in a disorganized, uncontrolled way outside highly regulated germinal centers.

In the hospitalized patients, the majority of their antibody-secreting cells produced antibodies directed against parts of the coronavirus, but some of them were also reactive against different targets in the body. The broad pattern resembled that seen in lupus, but was different in that some types of autoantibodies, such as those against DNA, were not observed. One patients immune cells were producing antibodies against glomerular basement membrane, which may contribute to lung and kidney damage.

Six months after acute infection, when some of the patients had survived and recovered, most of the indiscriminately generated antibody-secreting cells had disappeared from their blood. However, the antibodies themselves what the cells produce remain in the blood and decay gradually over time.Approaches such as IVIG could encourage recycling of lingering autoantibodies, the authors write.

Sanz says that the question of whether autoantibodies or perhaps, lingering autoreactive cells contribute to persistent symptoms needs to be tested in a larger group of COVID-19 patients. His and Lees laboratories continue to examine people with severe COVID-19 and those who recovered, as well as outpatients, including those with long haul symptoms. Their expanded study now includes an additional 150 patients, with the aim of correlating clinical features with the presence of autoantibodies.

This is something we are going to have to follow, he says. We also need to compare this to other viral infections that have been associated with autoimmunity.

The research was supported by the National Cancer Institute (SeroNet, U54CA260563), the National Institute of Allergy and Infectious Diseases (U19AI110483 Emory Autoimmunity Center of Excellence, P01AI125180, R37AI049660, R01AI121252, U01AI141993), and the National Heart Lung and Blood Institute (T32HL116271).

Additional links:

2020 Nature Immunology paper on B cell responses in severe COVID-19

Matthew Woodruffs explainer in The Conversation

Emory Health Digest article on long COVID

Emory expanding post-COVID care

Panel discussion (scroll down) on long COVID

Science Writer, Research Communicationsqeastma@emory.edu404-727-7829 Office

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COVID-triggered autoimmunity may be mostly temporary - Emory Health Now

Embryology

Studies offer insight into how the human body develops and acquires mutations throughout life – News-Medical.net

New insights into how the human body develops from one cell into trillions, and the genetic mutations that cells pick up along the way, have been generated by two studies from scientists at the Wellcome Sanger Institute, the University of Cambridge and their collaborators.

The studies, published today (25 August 2021) in Nature, are the first to analyze somatic mutation in normal tissues across multiple organs within and between individuals. Researchers were able to retrace human development, including in a 78-year old individual, all the way back to the first cell division, as well as confirm that the mutation rate in the germline cells is much lower than in the other tissues of the body.

This fundamental knowledge will help to establish baselines for human development and how we acquire mutations throughout life, in both the cells of our body and the genetic code that is passed on to the next generation. Knowing what normal development and ageing looks like will in turn help to better understand the onset of disease.

In recent years, technological and experimental advances have allowed researchers to study somatic mutation in healthy tissue. This has been achieved by taking micro-biopsies of just a few hundred cells, which are then genome sequenced to an incredibly high degree of accuracy.

From the very first cell division, an individuals cells experience damage to their genome. Most of this damage is repaired by the cell, but some changes to the letters of DNA, known as somatic mutations, persist. Through cell division, these mutations are then passed on to the next generation of cells by progenitor cells. When two cells share the same mutations, this implies a shared ancestry and these markers can be used to trace development back through time.

The genetic code that is passed on via sperm and egg cells during reproduction, known as the germline, has long been thought to be protected from the mutational processes that occur in the rest of the body as we age. This helps to ensure that individuals start life with a genome that is intact, or free from the mutations acquired by the parents during their lives.

For these studies, samples of normal tissue from three adult individuals were supplied by researchers at the MRC Cancer Unit, University of Cambridge and a commercial provider. Researchers at the Wellcome Sanger Institute used laser microdissection to cut out tiny biopsies of just a few hundred cells, covering a wide range of tissues from each donor. These biopsies were then whole genome sequenced so that somatic mutations within and between individuals could be compared.

In one study, researchers created a family tree of cell lineages for each individual stretching all the way back to the fertilized egg of each person. By analyzing genomes from the different tissues they could use mutations shared by cells to trace how the tissues of the body had formed from a single cell.

This analysis revealed significant variation between individuals in which cells went on to form particular tissues. For example, the two progenitor cells created by the division of the fertilized egg cell contributed relatively equally to the body of one individual, but in another donor 93 per cent of their cells were descended from just one of the original progenitors.

Dr Tim Coorens, a first author of the studies from the Wellcome Sanger Institute, said: By examining the history of each cell, weve been able to retrace the development of a 78-year-old person all the way back to the first cell division. It was surprising to find how much variation there was in human development between individuals, and especially between tissues in the same person. Its not as straightforward as the same set of cells contributing to the heart or kidneys, say, in every person. What our study makes clear is that human embryology is not set in stone.

In the other study, scientists analyzed the genomic data to compare the mutational landscape in 29 different tissues. Researchers at Newcastle University supplied samples from a further 11 men, from which a further 162 micro-biopsies were taken to explore germline mutation in greater detail.

Such analysis is able to detect patterns of mutation, known as mutational signatures, that can be attributed to particular biological processes or substances the body is exposed to that alter the genome, such as alcohol or tobacco.

The team found ubiquitous mutational signatures across all of the tissues studied, including two that result from the normal functioning of human cells, called SBS1 and SBS5. Other signatures were specific to certain tissues, such as SBS18, which may be indicative of oxidative damage. There was substantial variability in the mutational landscape between tissues in the same individual.

Notably, the mutation rate for spermatogonia immature sperm cells derived from stem cells in the testes was found to be much lower than for other cells in the body.

Dr Raheleh Rahbari, a senior author of the studies from the Wellcome Sanger Institute, said: This study advances our understanding of the diversity of mutation rates and processes within the human body. It has long been suspected that the germline acquires fewer mutations than other cells, in order to preserve the genome that will be passed on to the next generation. Here we reveal for the first time that low germline mutation rate is not the result of selection of sperm with fewer mutations during conception or development, but is a global feature of the male germline compared to other cells. But what is not clear is how spermatogonia, which must divide to create vast numbers of sperm cells, maintain such a low mutation rate.

The studies will help to establish baselines of normal development and how we acquire mutations throughout life.

Exploring the human body via the mutations cells acquire as we age is as close as we can get to studying human biology in vivo. Our life history can be found in the history of our cells, but these studies show that this history is more complex than we might have assumed.

Dr Luiza Moore, First Study Author, Wellcome Sanger Institute

Professor Sir Mike Stratton, a senior author of the studies and Director of the Wellcome Sanger Institute, said: These studies explore the landscape of mutations that normally occur during the course of life in every cell of the human body, providing new insights into human development and important differences between cell types.

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Studies offer insight into how the human body develops and acquires mutations throughout life - News-Medical.net

Biochemistry

Long-Time Professor of Biochemistry at URI, Joel A. Dain, Dies at 89 – GoLocalProv

Tuesday, August 24, 2021

Shalom Memorial Chapel

Joel was the caring and playful father of Peter J. Dain (Deborah Blicher), of Sudbury, MA; Jonathan L. Dain (Karen Kainer), of Gainesville, FL; and Leonard E. Dain (Ivetia Paniagua), of Seattle, WA. Joel was the dear brother of Martin Dain of Sun City, FL, and was the loving and mischievous grandfather of Rebekah, Beatrice, Kristina, Max, Joshua, and Isabel. He was a resident of Kingston since 1962.

Joel received his doctorate from Cornell University in 1956. He was a Professor of Biochemistry at URI for close to 60 years. After retiring in 2015, he continued working as an Emeritus Professor until his death. Joel was known for his influential research on the biochemical underpinnings of Tay-Sachs, diabetes, and other diseases, and for his caring and dedicated mentoring of numerous graduate students and postdocs with whom he maintained regular contact. From early on he opened his lab to female and male graduate students alike from all over the world and from diverse backgrounds. In addition to hisundergraduate and graduateteaching and research duties, he served on committees tasked with hiring University coaches, Athletic Directors, and Presidents.

Joel was an active member of various organizations that demonstrated his eclectic interests:

AAUP (American Association of University Professors)American Chemical Society (ACS) In 1995, he was elected chairman of the Rhode Island Section of the ACS.URI Athletic CouncilDemocratic Town CommitteeAmerican Philatelic Society

As a part of his professional work, Joel and Ellie took their family to live in locations as diverse as Heidelberg, Germany; Santa Rosa, California; and Tokyo, Japan, where he collaborated with scientists at local universities. He gave invited lectures at conferences and universities worldwide.

Joel and Ellie were also generous donors to numerous causes in support of human rights, scientific research, and the environment.

Sports were a very important part of Joels life. He was a runner in high school; he played junior varsity basketball at the University of Illinois; and into his 80s he was a regular at weekly pick-up basketball games at URIs Keaney Gym. He rarely missed a basketball game by his beloved URI Rams, and for almost 60 years was a fixture at Keaney Gym and then the Ryan Center. Joel was also a lifelong and ardent tennis player a love he passed on to his sons.

Joel was an avid reader and was particularly fond of suspense and detective novels. He was a regular at the Kingston Library.

Joel had a wry sense of humor which he applied to most any situation he encountered, particularly politics. He greatly enjoyed bantering with friends, family, colleagues, and acquaintances.

Joel was a lifelong stamp collector, reflecting his interest in all things international. For many years, he taught beginning stamp collecting to children through the Neighborhood Guild Community Center in South Kingstown.

Graveside services are open to the public and will be held Tuesday, August 24that 12:00 noon in New Fernwood Cemetery, 3102 Kingstown Rd., Kingston.

Due to the age and health of those attending, we ask that mourners please wear a mask and practice social distancing.

A private family gathering will be held after the service.

In lieu of flowers, contributions in Joels memory may be made to Beatrice Dain Memorial Fund in Diabetes. To make a gift, visiturifoundation.organd click theMake a Giftbutton in the upper right corner. Indicate the amount of your gift, then click select from a list of options. Scroll down to URI Programs and Initiatives and click Other Funds, then Continue. In the text box type Beatrice Dain Memorial Fundin Diabetes. Complete the form with the requiredinformationand follow the payment options.

Memorial gifts may also be made by check,payable to the URI Foundation & Alumni Engagement, and writing Beatrice Dain Memorial Fundin Diabetes in the memo line. Mail to: URI Foundation & Alumni Engagement, PO Box 1700, Kingston, RI 02881.

Contributions may also be made toMultiple Myeloma Research Foundation.

To attend the funeral service via Zoom, pleaseclick here.

Meeting ID: 849 3499 3118

Passcode: 548378

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Long-Time Professor of Biochemistry at URI, Joel A. Dain, Dies at 89 - GoLocalProv

Biochemistry

Wang Receives ASBMB Young Investigator Award | Newsroom – UNC Health and UNC School of Medicine

Greg Wang, PhD, associate professor of biochemistry and biophysics, has received the 2022 ASBMB Young Investigator Award.

Greg G. Wang, PhD, associate professor at the University of North Carolina School of Medicine and member of the UNC Lineberger Comprehensive Cancer Center, has received the 2022 ASBMB Young Investigator Award, which recognizes outstanding research contributions to biochemistry and molecular biology and contributions to the community of scientists. Wangs lab studies how chromatin modification and epigenetic modifications contribute to gene regulation and cancer development.

The ASBMB Young Investigator Award (formerly the ASBMB/ScheringPlough Research Institute Award) recognizes outstanding research contributions to biochemistry and molecular biology. The recipient must have no more than 15 years postdoctoral experience. Nominations must be originated by society members, but nominees need not be ASBMB members.

The award consists of a plaque, $5,000, and transportation and expenses to present a lecture at the ASBMB annual meeting.

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Wang Receives ASBMB Young Investigator Award | Newsroom - UNC Health and UNC School of Medicine

Biochemistry

Biochemistry offers options to help reduce huge potato losses in the US – FreshPlaza.com

Massive losses in the number one US vegetable crop, potatoes, aren't only due to pests or drought, theyre due to damage in the handling and storage of potatoes over the nine months of storage they generally undergo on their way to the supermarket as fresh potatoes or as potato chips or fries.

A biochemistry approach that seeks to identify genetic characteristics of the wound healing process in potatoes has had success in a project led by Dylan Kosma, a biochemist in the College of Agriculture, Biotechnology & Natural Resources at the University of Nevada, Reno.

In his work, completed as part of the CollegesExperiment Stationresearch, Kosma has identified the first transcription factors known to regulate deposition of components that make up the skin that forms during the wound healing process in potatoes.

"We're working on protein transcription factors," he said. "You can think of transcription factors like the main switch in an electric panel or breaker box, with 15 circuits under control of the main switch. Finding the master switch and how it works to switch on the wound healing process in potatoes is key.

According to an article on unr.edu, One important component of potato tuber wound healing is the deposition of a corky material that makes up a large proportion of skin that covers wound sites, suberin. Suberin is a lipid polymer that is produced by all plants and is a major component of wound healing tissues in potatoes. While this wound-healing tissue can be found in nearly every plant, there is still relatively little known about its makeup and function. Even less is known about the genetic controls of wound suberin formation.

In addition to stemming the tide of losses with potatoes, Kosma hopes what they learn in this process will also be applicable to other food crops

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Biochemistry offers options to help reduce huge potato losses in the US - FreshPlaza.com

Biochemistry

FDA approval of belzutifan culminates 25-year journey at UTSW from gene discovery to a first-in-class drug – UT Southwestern

DALLAS Aug. 21, 2021 A first-in-kind kidney cancer drug developed from laboratory and translational studies conducted at UTSouthwestern Medical Center received approval from the Food and Drug Administration, providing a new treatment for patients with familial kidney cancer.

FDA approval of belzutifan culminates a 25-year journey at UTSW from gene discovery to a first-in-class drug.

Mercks belzutifan grew out of the discovery at UTSouthwestern of a protein,hypoxia-inducible factor 2-alpha(HIF-2), that is key to fuel the growth of kidney and other cancers. HIF-2 was discovered by Steven McKnight, Ph.D., Professor of Biochemistry.

This is an exciting milestone for patients with inherited forms of kidney cancer who are in need of more effective therapies, said David Russell, Ph.D., Vice Provost and Dean of Research, and Professor of Molecular Genetics, who collaborated in the early stages of the research.

The drug, once called PT2977, was developed based on a backbone discovered by UTSW researchers, with further drug development efforts conducted by a spinoff company named Peloton Therapeutics, which was launched on the UTSW campus and eventually acquired by Merck.

Drs. McKnight and Russell first identified HIF-2 in the 1990s.

HIF-2 was considered undruggable for many years until two more UTSW scientists at the time Richard Bruick, Ph.D., Professor of Biochemistry, and Kevin Gardner, Ph.D., Professor of Biophysics, who also directs a structural biology center at the City University of New York did the structural and biochemical work showing that the HIF-2 molecule contains a pocket that is potentially druggable. The two scientists then identified multiple compounds that fit into this pocket and inhibited the activity of HIF-2.

The history of belzutifans development demonstrates the value of cross-disciplinary collaborations at academic medical centers and how that can translate to new treatments for diseases, said Dr. Russell. It also underscores the value of investing in basic science discoveries at the core of advancements in medicine.

In 2011, several researchers spun off Peloton Therapeutics, and by 2019, when Merck acquired the company, at least three HIF-2 agents were under investigation.

James Brugarolas, M.D., Ph.D., Director of the UTSW Kidney Cancer Program

James Brugarolas, M.D., Ph.D., Director of the Kidney Cancer Program at UTSouthwesterns Harold C. Simmons Comprehensive Cancer Center, showed that the drug was effective against kidney cancer.

With funding from a prestigious National Cancer Institute SPORE award, they showed in a publication inNaturein 2016 that the drug was able to inhibit HIF-2in human kidney tumors transplanted into mice and stop their growth.

This and other studies led to the first clinical trial of PT2385, a precursor to PT2977, which became belzutifan. The trial, which was led by the UTSW Kidney Cancer Program, showed that the drug was well-tolerated and active.

The approval of belzutifan represents a new paradigm in the treatment of kidney cancer, said Dr. Brugarolas, Professor of Internal Medicine. By exclusively targeting HIF-2, which is essential for kidney cancers but dispensable for normal processes, belzutifan specifically disables cancer cells while sparing normal cells. Belzutifan is the best-tolerated kidney cancer drug today and one suitable for patients with familial kidney cancer. It is a testament to the prowess of designer drugs and carefully chosen targets of which it is a prime example.

1997UTSouthwestern biochemist Steven McKnight, Ph.D., and molecular geneticist David Russell, Ph.D., report the discovery of the HIF-2 gene, which they call EPAS1. The team shows that HIF-2 binds to another protein, HIF-1. The HIF-2 partner functions like a pair of tweezers to grab DNA. HIF-2 binds DNA at specific places to initiate the production of other proteins such as VEGF, which support kidney cancer growth.

2003The laboratories of Richard Bruick, Ph.D., and Kevin Gardner, Ph.D., uncover aspects of the atomic blueprint of HIF-2. They show how HIF-2 docks with HIF-1 to assemble into a functional HIF-2 complex. They identify a cavity within the HIF-2 protein, hypothesizing that it may offer a foothold for a drug. Working with UTSouthwesterns High-Throughput Screening laboratory, Drs. Bruick and Gardner develop a test to identify chemicals among 200,000 drug-like molecules that bind to the HIF-2 cavity, preventing HIF-2 binding to HIF-1. By interfering with HIF-2 binding to HIF-1, these compounds block HIF-2 action. The most promising chemicals undergo a refinement process by medicinal chemists at UTSouthwestern.

2010Peloton Therapeutics is founded by UTSW researchers to develop the HIF-2 blocking chemicals into drugs. Peloton scientists create libraries of related compounds, ultimately identifying PT2385 and PT2977 to test in humans. A related drug, PT2399, is identified for laboratory work.

2016Dr. James Brugarolas validates HIF-2 as a target in kidney cancer. In experiments incorporating more than 250 mice transplanted with human kidney tumors, researchers show that PT2399 blocks HIF-2 while not affecting related proteins, is active against 50% of human kidney tumors, and has more activity and is better tolerated than sunitinib (the most commonly used drug for renal cancer treatment at the time).

2018Dr. Kevin Courtney reports the results of a phase 1 clinical trial testing PT2385 in humans. The trial represents the first-in-human study of a first-in-class inhibitor of HIF-2. The trial, which involves 51 patients, shows that PT2385 is safe, well tolerated, and active against kidney cancer in humans. More than 50% of patients see their cancer regress or stabilize.

2019U.S. drug manufacturer Merck acquires Peloton Therapeutics for $1.05 billion, with an additional $1.15 billion contingent on sales and regulatory milestones.

2020Through studies of tumor biopsy samples from patients who participated in the Phase 1 clinical trial, Drs. Courtney, Brugarolas, and Ivan Pedrosa report the identification of drug resistance mutations in patients, establishing HIF-2 as the first-known core dependency of kidney cancer.

Dr. Brugarolas holds The Sherry Wigley Crow Cancer Research Endowed Chair in Honor of Robert Lewis Kirby, M.D. Dr. McKnight holds the Distinguished Chair in Basic Biomedical Research. Dr. Pedrosa holds the Jack Reynolds, M.D., Chair in Radiology. Dr. Russell holds the Eugene McDermott Distinguished Chair in Molecular Genetics. Disclosures: UTSouthwestern and some of its researchers will receive financial compensation, through prior agreements with Peloton, based on belzutifans FDA approval.

About UTSouthwestern Medical Center

UTSouthwestern, one of the nations premier academic medical centers, integrates pioneering biomedical research with exceptional clinical care and education. The institutions faculty has received six Nobel Prizes, and includes 25 members of the National Academy of Sciences, 16 members of the National Academy of Medicine, and 13 Howard Hughes Medical Institute Investigators. The full-time faculty of more than 2,800 is responsible for groundbreaking medical advances and is committed to translating science-driven research quickly to new clinical treatments. UTSouthwestern physicians provide care in about 80 specialties to more than 117,000 hospitalized patients, more than 360,000 emergency room cases, and oversee nearly 3 million outpatient visits a year.

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FDA approval of belzutifan culminates 25-year journey at UTSW from gene discovery to a first-in-class drug - UT Southwestern

Biochemistry

New study examines ‘Achilles heel’ of cancer tumours, paving the way for new treatment strategies – UBC Faculty of Medicine

Researchers at UBCs faculty of medicine and BC Cancer Research Institute have uncovered a weakness in a key enzyme that solid tumour cancer cells rely on to adapt and survive when oxygen levels are low.

The findings, published today in Science Advances, will help researchers develop new treatment strategies to limit the progression of solid cancer tumours, which represent the majority of tumour types that arise in the body.

Solid tumours rely on blood supply to deliver oxygen and nutrients to help them grow. As the tumours advance, these blood vessels are unable to provide oxygen and nutrients to every part of the tumour, which results in areas of low oxygen. Over time, this low-oxygen environment leads to a buildup of acid inside the tumour cells.

To overcome this stress, the cells adapt by unleashing enzymes that neutralize the acidic conditions of their environment, allowing the cells to not only survive, but ultimately become a more aggressive form of tumour capable of spreading to other organs. One of these enzymes is called Carbonic Anhydrase IX (CAIX).

Cancer cells depend on the CAIX enzyme to survive, which ultimately makes it their Achilles heel. By inhibiting its activity, we can effectively stop the cells from growing, explains the studys senior author Dr. Shoukat Dedhar, professor in UBC faculty of medicines department of biochemistry and molecular biology and distinguished scientist at BC Cancer.

Dr. Dedhar and colleagues previously identified a unique compound, known as SLC-0111currently being evaluated in Phase 1 clinical trialsas a powerful inhibitor of the CAIX enzyme. While pre-clinical models of breast, pancreatic and brain cancers have demonstrated the effectiveness of this compound in suppressing tumour growth and spread, other cellular properties diminish its effectiveness.

In this study, the research team, which included Dr. Shawn Chafe, a research associate in Dr. Dedhars lab, together with Dr. Franco Vizeacoumar and colleagues from the University of Saskatchewan, set out to examine these cellular properties and identify other weaknesses of the CAIX enzyme using a powerful tool known as a genome-wide synthetic lethal screen. This tool looks at the genetics of a cancer cell and systematically deletes one gene at a time to determine if a cancer cell can be killed by eliminating the CAIX enzyme together with another specific gene.

According to Dr. Dedhar, the results of their examination were surprising and point to an unexpected role of proteins and processes that control a form of cell death called ferroptosis. This form of cell death happens when iron builds up and weakens the tumours metabolism and cell membranes.

We now know that the CAIX enzyme blocks cancer cells from dying as a result of ferroptosis, says Dr. Dedhar. Combining inhibitors of CAIX, including SLC-0111, with compounds known to bring about ferroptosis results in catastrophic cell death and debilitates tumor growth.

There is currently a large international effort underway to identify drugs that can induce ferroptosis. This study is a major step forward in this quest.

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New study examines 'Achilles heel' of cancer tumours, paving the way for new treatment strategies - UBC Faculty of Medicine

Biochemistry

Eight receive excellence awards as academic year opens – uwec.edu

University of Wisconsin-Eau Claire Chancellor James Schmidt honored eight faculty and staff members for their excellence during the Blugold Breakfast and academic year opening meeting on Aug. 24.

Recipients of UW-Eau Claire's 2021 excellence awards are, from left, Rob Mattison, Signe Matson, Dr. Jeanette Olsen, Kris Presler, Dr. Sanchita Hati, Dr. Rose-Marie Avin, Dr. Pam Forman and Dr. Heather Ann Moody.

The chancellor recognized the following 2021 award winners:

Each award recipient received a university medallion and $1,500. All of the UW-Eau Claire Foundation excellence awards for faculty and staff are funded by Markquart Motors and Markquart Toyota of Eau Claire. The award honoring the 2021 UW System Board of Regents Excellence in Teaching Award nominee is funded by the Arnold and Lois Domer Foundation of Eau Claire.

Dr. Rose-Marie Avin, professor of economics and director of the Womens, Gender and Sexuality Studies program, received the Excellence in Equity, Diversity and Inclusion Award.

Avin has demonstrated a sincere commitment to equity, diversity and inclusion during her 34 years at UW-Eau Claire through outstanding service and teaching, according to her nomination materials.

Dr. Avins entire lifes work has been dedicated to EDI, nominators say. Her advocacy on behalf of EDI is global and transnational.

Through her courses and immersion programs, Avin taught students to advocate for gender, racial and economic justice in the U.S. and other nations such as Nicaragua, Spain, Vietnam, India, Brazil and Argentina.

Avin has included UW-Eau Claire students in her work to fight racism, sexism, homophobia and xenophobia in the world.

You have showed me that the world is so many shades of gray, a student wrote in a letter to the WGSS program. I cannot express in words how appreciative of this I am. It is impossible.

Dr. Pam Forman, professor and chair of the sociology department and a faculty member in the Office of Research and Sponsored Programs.

Students select the Excellence in Advising Award, and Blugolds say Forman, who has been at UW-Eau Claire for 17 years, always takes time for them, even when she is running in multiple directions.

The sociology students who Forman advises describe her as unmatched in empathy, passion for application of sociology in real-world contexts and commitment to students.

Forman promotes an inclusive campus by updating sociology students about current events and extending her expertise to all.

As a department chair, Dr. Forman is exceptional, nomination documents state. As an advisor, Dr. Forman consistently goes above and beyond. As an ally to all students, Dr. Forman is unmatched.

Dr. Sanchita Hati, professor of chemistry and biochemistry, received the Excellence in Scholarship Award.

Hati, who has been at UW-Eau Claire for 15 years, is a productive researcher who has an exemplary publication record with undergraduate students, according to nomination materials. Her students have presented at least one poster at the national meeting of the American Chemical Society every year since 2014.

She has moved research into the teaching laboratory and, in some classes, all students in her upper-level biochemistry courses have become authors on a peer-reviewed publication, according to the nomination materials. Her peers in science recognize her as an outstanding scholar.

Hati currently manages three distinct projects: exploring protein dynamics to design the next generation of antibiotics, developing a noninvasive tool for cancer diagnostics in collaboration with Mayo Clinic and investigating the role of oxidative stress on the severity of COVID-19 infections.

Beyond direct contributions to science, Dr. Hati is also an outstanding role model who encourages students to become independent, lifelong learners, according to nomination materials. She has directly mentored 50 undergraduates in her research group, and about half of these students have entered Ph.D. programs, including many at prestigious universities like Dartmouth and Northwestern.

Rob Mattison, senior information systems and technology services videographer in Learning and Technology Services, received the University Staff Excellence in Service Award.

Mattison, who has been at UW-Eau Claire for nine years, shows respect to all members of the university community and has a genuine goal to brighten the day of people he encounters, according to nomination materials.

Rob routinely goes above and beyond his job duties to assist faculty in creating engaging video content for courses, according to nomination materials. This was especially true in 2020 as Rob worked long days preparing courses and content for virtual learning. Many of the courses offered on this campus are made better through Robs efforts.

Mattison is a consummate professional, according to nomination materials, who strives for high-quality work while maintaining a casual, friendly, funny and enthusiastic demeanor. He cares about the well-being of students and considers his co-workers to be family.

Rob is an example of what excellence means at UWEC, according to nomination materials. He puts more effort into his job than anyone could ask while living his dream and is supportive of everyone and their dreams.

Signe Matson, lead academic advisor in the Advising, Retention and Career Center, received the Academic and Professional Staff Excellence in Service Award.

Matson, who has been at UW-Eau Claire for 21 years, has been the lead advisor in the arts and humanities cluster since the formation of the Advising, Retention and Career Center in 2016. Students have appreciated Matsons support over the years.

Signe is a very kind and caring advisor! one nominator states. She has provided a lot of helpful information and guidance as I consider a degree at UWEC while taking courses as a special student. Going back to school as a nontraditional student is a bit intimidating, but Signe has been full of encouragement and helped break down the steps in a clear and understandable manner.

Matson has helped with training and mentoring new staff members, and is a steady and reliable team member who has a wealth of institutional knowledge, according to nomination materials. Matson is considered a hard-working, compassionate and student-first person who is a great resource inside and outside ARCC.

Signes knowledge of campus resources, advising experience, calm professional demeanor and positive attitude make collaborating with her in this work a delight, according to nomination papers. I trust Signe to serve our students while holding true to the mission of the university.

Dr. Heather Ann Moody, associate professor of American Indian studies, received the Faculty Excellence in Service Award.

Moody, who has been at UW-Eau Claire for 14 years, is a true example of a servant leader with a passion for undergraduate education and mentorship, commitment to EDI and extensive service beyond campus, according to nomination materials. In 2019, Moody received an Outstanding Women of Color in Education Award from the UW System.

Dr. Moodys professional service to the greater Eau Claire community and to the state of Wisconsin reflects the values of this university and embodies the spirit of the Excellence in Service Award, according to nomination materials.

Moody has been instrumental in leading important EDI initiatives at UW-Eau Claire. She is a co-chair of the EDI Strategic Plan Committee that will guide the institution for the next five years and also co-chairs the Center for Racial and Restorative Justice Implementation Committee.

Dr. Moody is a model faculty member in her dedication and willingness to provide service to both our university and surrounding communities, according to nomination materials. She exemplifies what service means and does so with great knowledge, care and enthusiasm. Dr. Moody goes above and beyond in her service to support the growth of knowledge and understanding on the UWEC campus related to the Native American people within Wisconsin.

Dr. Jeanette Olsen, assistant professor and director of assessment and evaluation in the College of Nursing and Health Sciences, received the Excellence in Teaching Award.

Olsen, who has been at UW-Eau Claire for five years, was praised in nomination materials for her dedication to students and her ability to provide multiple methods of learning to accommodate every type of student. Students say Olsen takes a genuine interest in the lives of those in her classroom.

She always has time to answer questions and is willing to take the time to make sure you understand it, student nominators say. If you don't, she will find a different way to teach it. Even though she has students for just one semester, she knows and remembers everyone's name. She makes you feel important. She makes every question feel valid and is excited to help foster a growth of knowledge.

Olsen is extremely knowledgeable and approachable, always has a smile on her face and she truly cared about us as her students and wanted us to do well and succeed as nurses.

Dr. Olsen greatly encouraged me and my classmates in the nursing program to achieve our fullest potential, a student says. She remains an inspiration to me and is someone I hope to emulate in my nursing career.

Kris Presler, a professor of mathematics, was UW-Eau Claires nominee for the UW System Board of Regents Excellence in Teaching Award.

Presler, who has been at UW-Eau Claire for 18 years, helps his students realize that mistakes are just opportunities for learning that should be embraced and not feared, according to nomination materials.

Presler is described as a true professional who is full of humility and grace, valuing the people he serves each day. He works to bring humor into his courses to produce a more engaged classroom environment where laughter leads to a greater approachability, approachability to questions and questions to understanding.

Students praise Presler for his professional mentorship and advising in technical upper-level courses.

Actuaries often excel at math but struggle to clearly communicate their ideas and analysis with others, nominators say. Kris actuarial science curriculum was mathematically challenging and prepared students for exams, but also placed a heavy emphasis on creating well-rounded, articulate actuaries.

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Eight receive excellence awards as academic year opens - uwec.edu

Anatomy

The anatomy of a breakup: Olivia Rodrigo’s ‘Sour’ // The – Observer Online

On May 21, Olivia Rodrigo, formerly known as the drivers license girl, released her long awaited debut album, Sour. On it, she is moody, self-centered and petty with no filters. In a culture in which were all projecting more mature and put-together versions of ourselves she wanted it to be like, messy. Sour is the beautifully imperfect portrait of an insecure teenage girl who went through the worst thing imaginable: a breakup.

The album opener, brutal, was an unexpected punch to the gut. The beginning of Sour sees her screaming accusations at life with self-deprecating lyrics detailing just how much of a lie the golden teenage years are. With pop punk instrumentation and a vocal performance Alex Turner would be proud of, we stand at the peak of her angst. This is the starting point of Sour

Listening to track 2, traitor, hurts. She is at her most vulnerable, betrayed and left alone to deal with the shipwreck of her breakup. Dont you dare forget about the way you betrayed me, she sings. By the time drivers license comes around, she has exhausted the indignation and is left deeply sad, haunted by red lights and stop signs that remind her of her lover. This song launched Rodrigo into what is possibly the fastest rise to superstardom the world has ever seen, spending eight weeks at the top of the Billboard Hot 100 and leading to not one, but two SNL features. Her polished vocal performance, the sharp imagery and the legendary bridge birthed one of the best heartbreak ballads to hit the charts in years.

1 step forward, 3 steps back sees Rodrigo relay a stream of consciousness as she melancholically recounts her self-destructive relationship with both her lover and herself. With unembellished vocals and no energy for pretense, she is all cried out at this point. And yet, as we all know, the journey to healing is not a straight line.

Track 6, deja vu, sees Rodrigo revert to petty obsession, as she picks apart her lovers new relationship, proclaiming its a cheap copy of what she had with him. She snarkily profiles his girlfriend choice, another actress / I hate to think that I was just your type, and mocks the girl too, she thinks its special / but its all reused. Sensibly enough, the next track, the snarky chart-topper good 4 u, sees her at her most bitter.

On this track, she becomes unhinged. Screw that, screw you / You will never have to hurt the way you know that I do probably takes the prize of most immature moment on the album, but its that same immaturity that makes this song so endearing and relatable. At this point, skeptics have to concede that there is no facade to Olivia Rodrigo, because this song makes her sound like a self-involved brat.

After wrapping up the pity party, she shrinks to the size of an ant on enough for you. The acoustic instrumentals reflect how little she thinks of herself, as she confesses she wouldve done anything to get her lover to stay. The next song, happier, is a sign that Rodrigo is starting to move on, as she bitterly accepts the breakup, singing I hope youre happy, but not like how you were with me. She fights with the bitterness, though. She realizes shes being petty by picking the new girl and the new relationship apart, but as the human being that she is, she keeps doing it anyway. On jealousy, jealousy, Rodrigo borrows the psychologist glasses from her dad and matter-of-factly recounts her woes, struggling between Instagram envy and self-love, between being petty and generous, featuring lines like Im happy for them, but then again Im not.

Then finally, FINALLY, she moves on. On favorite crime, she retells the story of her broken relationship with sadness. This song sees Rodrigo personify Taylor Swift on folklore, as she describes herself as a willing accomplice in her lovers crimes, with the closing line, Well, I hope I was your favorite crime. Theres a magic in the songs simplicity that almost makes it feel like a grandiose epic; with the haunting final harmonies, she exorcizes the pain out of her story, and turns the page. This is where Sourshouldve ended but it didnt.

For the last track, hope ur ok, it is evident where she was trying to go: This was the full-circle moment, when she finally broke free of her post-breakup tunnel vision and spread her wings in kindness and gratitude again. However, based on the albums subject matter, it seems unnecessary, and it will rest besides Dua Lipas Boys Will Be Boys as part of the underwhelming final album tracks that tried to be deep but felt inauthentic.

Except for this final track, Rodrigos effort feels cohesive, honest and meaningful. Sour is a solid album that deserves every last bit of the praise and attention it is getting. Watch out for this one; we just got a Sour taste of the next main pop girl.

Album: Sour by Olivia Rodrigo

Label: Geffen Records

Favorite Song: brutal

If you like: drivers license

Shamrocks: 4.5/5 shamrocks

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The anatomy of a breakup: Olivia Rodrigo's 'Sour' // The - Observer Online

Anatomy

‘Anatomy Of Time’: first trailer for Venice Horizons title (exclusive) – Screen International

Screen can unveil the first trailer for Jakrawal Nilthamrongs Anatomy Of Time, which is set to premiere in the Horizons strand of this years Venice Film Festival (September 1-11).

Thailands Jakrawal won a Tiger award at International Film Festival Rotterdam in 2015 with his debut narrative feature Vanishing Point. He makes his Venice debut with his second film, a drama spanning 50 years of a womans life from her carefree 20s in 1960s rural Thailand to present-day Bangkok as the wife of a disgraced army general.

The film is backed by Thailands Diversion and Mit Out Sound Films, Frances Damned Films, Netherlands Sluizer Film and Singapores MGO Films. Jakrawal is a producer of 2018 Horizons prize-winner Manta Ray, directed by Phuttiphong Aroonpheng, the DoP on Vanishing Point and Anatomy Of Time.

Diversion is handling internationalsales.

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'Anatomy Of Time': first trailer for Venice Horizons title (exclusive) - Screen International