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Experts at Indiana University School of Medicine have helped identify that a common protein found in neurodegenerative diseases forms amyloid filaments in an age-dependent manner without a connection to disease.
Many age-dependent neurodegenerative diseases, like Alzheimer’s and Parkinson’s, are characterized by amyloid abundance, or plaque. In a new paper published in Nature, researchers from the MRC Laboratory of Molecular Biology in Cambridge, England, United Kingdom and colleagues around the world, including several IU School of Medicine experts, used electron cryo-microscopy structure determination to discover that lysosomal type II transmembrane protein, TMEM106B, also forms amyloid filaments in human brains but, uniquely, it forms in an age-dependent manner and might not be connected to a type of disease.
“Until now, the presence of abundant intraneuronal amyloid filaments in human tissues has always been associated with disease,” said Bernardino Ghetti, MD, a distinguished professor and professor of pathology and laboratory medicine at IU School of Medicine. “While TMEM106B has been associated with frontotemporal dementias and other diseases, the evidence for a causal relationship between TMEM106B aggregation and disease now remains unclear.”
Researchers studied 22 individuals with abundant amyloid deposits, including sporadic and inherited Alzheimer’s, as well as the frontal cortex of three neurologically normal individuals. They also studied three TMEM106B folds, with no clear relationships between folds and diseases. The TMEM106B filaments discovered in the brains of older, but not younger, neurologically normal individuals suggests that these proteins form in an age-dependent manner and that there was no clear relationship between protein folds and neurodegenerative diseases. Previously, TMEM106B has been identified as a risk factor for frontotemporal lobar degeneration, but this research opens the dialogue as the protein may no longer be associated with the cause of a disease.
“This insight encourages us to further assess the role of filament formation, like TMEM106B, in relation to human aging and other pathologies, as well as if they’re found outside the nervous system,” Ghetti said.
The study was supported by National Institutes of Health grants. Other study authors from IU School of Medicine include Holly Garringer, PhD, Grace Hallinan, PhD, Kathy Newell, MD and Ruben Vidal, PhD. Previously, this research group also explored the pathological differences in inherited versus sporadic Alzheimer’s disease.
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Numerous studies have shown that spirituality can help improve quality of life for people with chronic diseases like cancer. According to a literature review published today in JACC Heart Failure, spirituality can also have a positive impact on quality of life for heart failure patients. It further concludes spirituality should be considered a potential target for palliative care interventions to improve patient-centered and clinical outcomes in these individuals.
“Patients who have heart failure experience a poorer quality of life compared to their peers, with high levels of depression, anxiety and spiritual distress,” said Rachel S. Tobin, MD, resident in Internal Medicine at Duke University Hospital, and lead author of the study. “Contributing to diminished quality of life is the fact that heart failure, unlike many other chronic diseases, is very unpredictable and can lead to hopelessness, isolation and altered self-image.”
The American College of Cardiology and other major cardiovascular societies recommend palliative care for heart failure patients. Spirituality is a core domain of palliative care, with the goal of identifying and addressing spiritual concerns and providing patients with appropriate spiritual and religious resources. However, limited research has been conducted on spirituality’s impact on patients with heart failure, and there are no known tools designed to measure it.
According to the researchers, spirituality is hard to define, but they reference several definitions that describe spirituality as how individuals find meaning and purpose in life, which can be separate from religious beliefs.
For instance, the Institute of Medicine defines spirituality as “the needs and expectations which humans have to find meaning, purpose and value in their life. Such needs can be specifically religious, but even people who have no religious faith or are not members of an organized religion have belief systems that give their lives meaning and purpose.”
Researchers conducted a review of 47 articles in order to explore the current knowledge of spirituality in heart failure patients; describe associations between spirituality and quality of life, as well as patient outcomes; and propose clinical applications and future directions for spirituality in this population. There were approximately 10 varying instruments used to measure spirituality, some simple, others complex. Key data examined include: In the Palliative Care in Heart Failure (PAL-HF) trial, spiritual well-being improved in patients randomized to a palliative care intervention compared to usual care as evaluated by FACIT-Sp. ?The FICA spiritual history tool was also used to gather information on spirituality. Patients randomized to palliative care had increased quality of life as measured by Kansas City Cardiomyopathy Questionnaire (KCCQ) and Functional Assessment of Chronic Illness Therapy-Palliative Care (FACIT-Pal). They were also found to have lower levels of anxiety and depression. Another study found that after a 12-week mail-based psychosocial intervention, patients completing the intervention had higher quality of life as measured by KCCQ, as well as less depression and searching for meaning. Out of the 33 patients included, 85.7% felt that the intervention was worthwhile. In a pilot study, spiritual counseling was associated with improved quality of life, although there was no control group to determine if the effect was significant.”The literature suggests not only can spirituality improve quality of life for the patient, it can help support caregivers and potentially help heart failure patients from needing to be readmitted to the hospital,” Tobin said. “What we have suggested and are now doing is developing a spirituality screening tool, similar to ones used to screen for depression. This can be used to identify heart failure patients in palliative care who are at risk for spiritual distress. However, this is just a start. More research needs to be done.”
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Materials provided by American College of Cardiology. Note: Content may be edited for style and length.

Black patients with cancer experienced significantly worse outcomes after COVID-19 diagnosis than non-Hispanic white cancer patients in a study published March 28 in JAMA Network Open. Investigators of the COVID-19 and Cancer Consortium, which includes more than 125 cancer centers and other organizations, studied the electronic health records of 3,506 patients for the analysis, including data of 1,068 Black patients and 2,438 non-Hispanic white patients.
“We saw worse COVID-19 illness at presentation, higher rates of hospitalization, higher rates of intensive care unit admission, higher rates of mechanical ventilation and worse death rates in Black patients compared to non-Hispanic white patients, even after making the two groups comparable in terms of type, status and treatment of cancer by statistical analysis methods,” said senior and corresponding author Dimpy Shah, MD, PhD, assistant professor of population health sciences at The University of Texas Health Science Center at San Antonio (UT Health San Antonio). Dr. Shah leads the cancer and infectious diseases epidemiology research program at the Mays Cancer Center, home to UT Health San Antonio MD Anderson Cancer Center. The program has specific focus on minority health and health disparities. Dr. Shah also serves as steering committee member, lead epidemiologist and patient advocacy co-chair for CCC19.
Structural racism
A framework of structural racism in the U.S. can explain the increased COVID-19 burden in Black patients, Dr. Shah and her co-authors wrote. Structural racism refers to the ways in which societies reinforce systems of health care, law enforcement, education, employment, benefits, media and housing, perpetuating discriminatory distribution of resources and attitudes, the authors wrote, citing a 2017 article by Zinzi D Bailey, ScD, et al., published in The Lancet.
“Race in medicine is largely a social construct because the majority of differences in health outcomes between Black patients and white patients are due to systematic racialization,” Dr. Shah said. “Some of the societal root causes of health disparities, including lack of access to health care, social determinants of health, preexisting comorbidities and access to clinical research, are common to both cancer and COVID-19, and together these two diseases create a perfect storm.”
Treatments
The researchers also noted differences in COVID-19 treatments provided to the two groups. Hydroxychloroquine was prescribed more in Black patients, and white patients had higher administration of remdesivir. Remdesivir is an antiviral drug approved by the U.S. Food and Drug Administration (FDA) to treat COVID-19 in adults and children 12 and older. Hydroxychloroquine, meanwhile, is a malaria drug. The FDA withdrew emergency use authorization of it after data indicated it is not effective in treating the coronavirus.

In a potential paradigm change for sepsis diagnostics, a new test predicted sepsis soon after infection in mice — well before blood clotting and organ failure — enabling early antibiotic treatment and markedly increased survival. The findings provide a platform to develop rapid and easy-to-perform clinical tests for early sepsis detection and clinical intervention in human patients.
The collaborative effort by a research team including scientists from UC Santa Barbara, UC San Diego, and Sanford Burnham Prebys Medical Discovery Institute (SBPMDI) is detailed in a new study published in the Lancet journal, eBioMedicine. The team succeeded in detecting a catastrophic shift in blood protein abundance soon after infection that can predict sepsis well before disease symptoms and organ damage arise.
The project was led by professor Michael Mahan of UC Santa Barbara, along with professors Dzung Le of UC San Diego, and Jeffrey Smith and Jamey Marth of SBPMDI. Additional collaborators include UCSB scientists Douglas Heithoff and Scott Mahan, as well as SBPMDI scientists Genaro Pimienta and Won Ho Yang, and University of Sydney veterinarian scientist John House.
Sepsis is the number one cause of death in U.S. hospitals. In the clinic, sepsis is diagnosed by a symptom-based approach that may include kidney or liver failure, blood clotting or bleeding — which often occurs well after permanent organ damage. Thus, molecular diagnostics that detect infection at early stages of disease to minimize host injury are sorely needed.
“The key finding was identifying proteins in the blood that arise very soon after infection — well before overt disease symptoms,” Mahan explained. “Early detection is critical for clinical intervention to increase survival in sepsis patients.”
To carry out the test, a small amount of blood was collected and analyzed for an increase in coagulation proteins that are induced but inactive at early stages of infection. Such detection enabled early antibiotic treatment — well before activated coagulation proteins induced blood clotting — resulting in markedly increased survival in mice. The technology is open source and freely accessible to all.
The study also demonstrated that antibiotics are less effective after blood proteins increase in response to infection. Treatment failure may be due to host injury triggered by excessive blood clotting, providing insight into why delays in antibiotic treatment in human sepsis are associated with increased risk for death.
“The future plan is to identify a biopanel of early sepsis blood proteins for incorporation into existing blood tests, enabling sepsis prediction well before excessive blood clotting and permanent organ damage,” Heithoff explained.
The researchers demonstrated that the changes in blood proteins soon after infection observed in mice were similar to that reported for human sepsis. Thus, they are optimistic that these findings are translatable for the early detection and treatment of sepsis in humans.
“Currently, one in four patients die of sepsis, with many survivors experiencing lifelong debilitation with cognitive decline,” Scott Mahan said. “We hope technologies like this offer new ways of delivering state-of-the-art molecular diagnostics that predict sepsis before permanent injury occurs.”
This research was funded by grants from the National Institutes of Health’s National Heart, Lung, and Blood Institute, Santa Barbara Cottage Hospital, and the U.S. Army Research Office via the Institute for Collaborative Biotechnologies cooperative agreement and contract.
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Materials provided by University of California – Santa Barbara. Original written by Sonia Fernandez. Note: Content may be edited for style and length.

Similar to a light switch, RNA switches (called riboswitches) determine which genes turn “on” and “off.” Although this may seem like a simple process, the inner workings of these switches have confounded biologists for decades.
Now researchers led by Northwestern University and the University at Albany discovered one part of RNA smoothly invades and displaces another part of the same RNA, enabling the structure to rapidly and dramatically change shape. Called “strand displacement,” this mechanism appears to switch genetic expression from “on” to “off.”
Using a simulation they launched last year, the researchers made this discovery by watching a slow-motion simulation of a riboswitch up close and in action. Affectionately called R2D2 (short for “reconstructing RNA dynamics from data”), the new simulation models RNA in three dimensions as it binds to a compound, communicates along its length and folds to turn a gene “on” or “off.”
The findings could have potential implications for engineering new RNA-based diagnostics and for designing successful drugs to target RNA to treat illness and disease.
The research is described in a new paper published today (March 28) in the journal Nucleic Acids Research (NAR), which has designated the study as a “Breakthrough Article.” NAR reserves “Breakthrough Article” status for the most high-impact studies answering long-standing questions in nucleic acids research.
“We have found this strand displacement mechanism occurring in other types of RNA molecules, indicating this might be a potential generality of RNA folding,” said Northwestern’s Julius B. Lucks, who co-led the study. “We are starting to find similarities among different types of RNA molecules, which could eventually lead to RNA design rules for folding and function.”
Lucks is a professor of chemical and biological engineering in Northwestern’s McCormick School of Engineering and a member of the Center for Synthetic Biology and of the Chemistry of Life Processes Institute. He co-led the study with Alan Chen, an associate professor of chemistry at the University at Albany in New York.

A significant amount of genetic risk for asthma is likely mediated through altered gene expression within the airway epithelium. That is the conclusion of a National Jewish Health-led study to identify genetic variants that cause asthma by altering the function of airway cells. The team’s paper published March 28, 2022, in the journal Nature Communications.
“This work will help us identify targetable pathways to intervene for asthma, to stop mucus hypersecretion or type 2 airway inflammation, an allergic response that can exacerbate asthma,” said Max A. Seibold, PhD, professor of Pediatrics in the National Jewish Health Center for Genes, Environment and Health and senior author of the paper. “One of the banes of human existence is mucus, which plays a role in so many health conditions, everything from the common cold, to COVID, to chronic lung diseases like asthma and COPD. The more we know about what causes it, the better equipped we will be to develop impactful treatments.”
For the study, the team performed the first airway transcriptome-wide association study (TWAS) for childhood and adult onset asthma. The first step in a TWAS study is to build models that will allow prediction of how a person’s genes will function in a particular tissue, based solely on their genetic profile. Dr. Seibold and colleagues leveraged nasal airway samples and genetic data from a cohort of 700 children in Puerto Rico, who either were in good health or had asthma, to build these models for airway tissue.
The team then applied these models to genetic data from over 300,000 participants in the UK Biobank study, a large-scale biomedical database and research resource. This allowed them to test whether genetically altered function of airway genes is associated with asthma risk. The study data found over a third of identified genetic risk factors for asthma may confer their risk through alteration of the cells that line the airways (i.e. airway epithelium).
In particular, the researchers found genetic changes in a gene that forms the structure of mucus (MUC5AC), and another gene (FOXA3) that directs the production of mucus secretory cells. This is one of the first times anyone has found genetic variants that influence asthma risk through the alteration of mucus secretory function. The team also found that some of the key genes in the type 2 inflammatory pathway have genetic changes that increase their level of expression in the airway, increasing asthma risk.
This study was primarily funded by the National Heart, Lung, and Blood Institute (NHLBI). The Institute provides global leadership for research, training and education programs that promote the prevention and treatment of heart, lung, and blood diseases and enhance the health of all individuals so that they can live longer and more fulfilling lives. The NHLBI is one of the largest institutes within the National Institutes of Health (NIH).
“This study demonstrates how obtaining additional data on the expression of genes from participants in genome-wide association studies can shed light on their biological functions. It also shows that some genes may be expressed differently in different tissues,” said James P. Kiley, PhD, director of NHLBI’s Division of Lung Diseases. “Research like this moves us one step closer to developing personalized medicine treatments for asthma and other common diseases.”
Asthma is a major health crisis in the United States. The Centers for Disease Control estimates 26.5 million Americans, or 1 in 13 people, are living with the condition.
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Researchers have shown a new compound delivered in a nasal spray is highly effective in preventing and treating COVID-19 caused by the Delta variant in mice.
The researchers, including at UBC, Université de Sherbrooke, and Cornell University, believe this is the first treatment of its kind proven to be effective against all COVID-19 variants of concern reported to date, including alpha, beta, gamma and delta. Published today in Nature, the research opens the door to developing a therapeutic spray for humans.
Variants of concern, including the recent Omicron variants, have reduced vaccine effectiveness, but senior author Dr. François Jean, associate professor in the UBC department of microbiology and immunology, says early, still unpublished results from his team show promise that N-0385 is also effective at blocking Omicron variant infections in human lung cells. “Our unpublished results represent encouraging findings with the current rapid propagation of Omicron BA.2 around the world.”
“Unfortunately, with another wave of an Omicron variant hitting the U.K., Europe, and China and our knowledge of how these waves occur, this may be what we see in Canada in the near future. Once approved, this compound could be used in combination with already available drugs that inhibit the virus’ replication, to provide a stronger defense against COVID-19 variants of concern,” says Dr. Jean, founder of FINDER, the state-of-the-art level three biocontainment facility where the work on SARS-CoV-2 variants was conducted.
The specially designed compound, named N-0385, blocks a particular human enzyme’s activity, used by the virus to infect a host cell. The small molecule was developed by Drs. Richard Leduc, Éric Marsault, Pierre-Luc Boudreault and their team at Université de Sherbrooke. UBC researchers tested four variants, including Delta, in human lung cells and organoids, tissue cultures that can mimic the organ they’re taken from, and found that N-0385 inhibits infection, with no evidence of toxicity. “The compound is unique because it blocks entry at the cell surface, without having to get into the cell, which prevents it from causing any detectable cell damage. As well, it’s highly potent, in that it needs only a tiny amount to work very effectively,” says co-author Dr. Andrea Olmstead (she/her), research associate in the department of microbiology and immunology.
In a preprint, the researchers at Cornell University led by Associate Professor Hector Aguilar-Carreno showed that genetically engineered mice infected with the virus causing COVID-19 and given a daily dose of the compound in a nasal spray for four days. All ten of the treated mice survived infection, compared with only 20 per cent of the untreated mice.
In the newly published paper, N-0385 was tested against the Delta variant, and was found to not only help with prevention of COVID-19, but also treatment 12 hours after infection, including with infection-related weight loss, and levels of the virus in the mice lungs, compared with controls.
The enzyme which N-0385 targets is present in nasal cells, where the virus tends to enter, making a nasal spray the most practical and effective way to administer the compound. In addition, no mutations relating to the virus which causes COVID-19 have been found in this enzyme’s mechanism so far, as has occurred with other enzymes and COVID-19 variants, making it a useful target for defense against future strains of the virus, says Dr. Jean.
The compound has the potential to be used as a broad-spectrum treatment against other viruses which use the same mechanism, Dr. Jean says, including influenza viruses such as influenza A, H1N1, and influenza C. “Even not knowing what you’ve been infected with during flu season, you could potentially be prescribed a nasal spray to treat coronaviruses and the flu.”
However, the spray should be used in combination with other drugs already on the market, he says, as the compound is an entry inhibitor, blocking entry of the virus to cells while other drugs reduce replication. “The big picture is, there are multiple steps in the life cycle of a virus. The first step is entering a cell to pass on genetic material, then it goes on to replicate. So you would use both drugs: N-0385 could block most of the virus’ entry, making less work for the replicator drug.”
The project teams are working with Ebvia, a private company, to secure funding for clinical trials. Future avenues of research at UBC and Université de Sherbrooke include optimizing N-0385 when used in combination with recently approved drugs to treat COVID-19.
This work was partly funded by the Coronavirus Variants Rapid Response Network, CIHR’s SARS-COV-2 variants supplement, Stream 2, CIHR COVID-Rapid Research Funding, and Genome BC Rapid Response Funding (RRF) for COVID-19 Research and Innovation Projects.

SharecloseShare pageCopy linkAbout sharingImage source, AFPThe head of the UN Aids agency, Winnie Byanyima, has spoken for the first time about her experience of sexual assault and harassment.”I was shocked, I was 18… This was an attempted rape,” Ms Byanyima said.She told the BBC’s Desert Island Discs programme she had never shared the story but it was a “defining” one.She said as a university student in Kampala in 1977, a lecturer went to her room and said if she became his girlfriend she would pass his exams.Ms Byanyima recalled she was “a confident little girl”. “I said: ‘I don’t need any help’ and I asked him to leave.”‘No word for abuse’She informed her parents, who thought she could not spend her university years being “blackmailed” and said she should leave.At the time, Uganda was under the rule of dictator Idi Amin. A family friend was on good terms with some generals, so he offered to help with her travel papers. Arrangements were made for her to go with him to the ministry of education.But he never took her to the ministry of education as he had promised. Instead, he drove her to his apartment, pretending he had forgotten something. “We got to his apartment, he put on some music on his player. The song was The First Cut Is The Deepest and he came to grab me,” she recalled.”I screamed, he was embarrassed, he stopped, put me in the car and dropped me back at the university and said I was stupid, I was childish. ‘These things happen’. He called it: ‘Things happen’.Listen to the full interview on Desert Island Discs”I was shocked, I was 18. I had never had a relation with a boy. This was an attempted rape.”At that time, there wasn’t even a word called sexual harassment or abuse. There was rape, but you felt ashamed to admit,” the UNAids chief recalled.She managed to get to the UK but upon arrival, she could not tell immigration officers what had happened to her. “I mentioned my cousin who’d been killed. I said I feared for my life. But I couldn’t say there was an attempt to rape me or abuse me sexually several times. It was too shameful,” she said.Life under AminShe returned to Uganda and became an MP before spending several years at the African Union and the UN. In 2013, Ms Byanyima became head of Oxfam International. At the time the charity was embroiled in a sexual misconduct scandal, which happened before her time at the helm of the organization.”The one time I broke down during that crisis, was during a radio interview by a Canadian journalist, who attacked me very hard,” Ms Byanyima said.”I was trying not to be defensive, to say I understand the pain of sexual abuse. She didn’t tell him about her personal experience “but in my heart it was there”, she said. “After the interview I cried because, I know the pain, or I knew it, and it all came back. That is why I couldn’t but apologise. I couldn’t defend staff, I defended the one who was abused.”Oxfam sex scandal – Baaba Maal stands down as ambassadorHow the Oxfam scandal unfoldedMs Byanyima also spoke of her childhood under Amin “seeing death, seeing violence”.”At school, when families would come to pull a girl out of class and take her away and then she’d come back after a week with her head shaved and in mourning. “Then we would know that her father has been killed or disappeared and we couldn’t talk about it,” Ms Byanyima said.”People would bury their dead at night because you have to pretend nobody has died. Because, if you do speak about it or show it, then they would come for you too,” she added.As an engineering student in Manchester in the late 1970s, Ms Byanyima campaigned against Amin and later went on to join a rebel group.”Being part of movements helped me channel my anger and to feel that I am with others, I think that saved me,” she added.She was appointed the head of UNAids in 2019.Africa Live: Updates from around the continent

A new study led by University of Cincinnati researchers provides new insights on how different risk factors following one of the most severe types of stroke can affect patient outcomes.
Daniel Woo, MD, said intracerebral hemorrhages (ICH) are caused when a blood vessel bursts inside the brain and causes bleeding in the brain. ICH strokes are often deadly and can cause high neurological disability.
Up to this point, many different factors have been generally reported to be associated with a higher likelihood of disability or death following an ICH stroke, but Woo said there was a need for more specific data.
To learn more, Woo led a cohort study analyzing outcome data three months after an ICH event from one of the largest-ever prospectively recruited group of patients, which included 1,000 non-Hispanic white, 1,000 non-Hispanic Black and 1,000 Hispanic patients. The results of the study were recently published in JAMA.
New insights
One of the avenues researchers used to assess risk factors were two clinical grading scales that have been previously developed.

The fallopian tube is the site of fertilization, where once a month for the duration of a female’s post-pubescent, pre-menopausal life, an egg is moved from the ovary, ready for fertilization by a sperm cell.
A new study from Michigan Medicine researchers creates a detailed “atlas” of the various cell types and their gene activities within the highly specialized fallopian tube, paving the way for new research into infertility and other diseases affecting this organ, including some cancers.
Using tissue samples from four premenopausal women, Saher Sue Hammoud, Ph.D., and Jun Li, Ph.D. from the Department of Human Genetics led a team at U-M to analyze almost 60,000 cells by single-cell RNA sequencing. They used the data to characterize the diversity of cells that make up the fallopian tube, including both the lining of the tube (the epithelium) and the deeper stromal layer, consisting of immune, blood, muscle, and other cells.
Hammoud and Li are joined by Ariella Shikanov, Ph.D., of the Department of Biomedical Engineering, Erica Marsh, M.D., of the Department of Obstetrics and Gynecology, and team members Nicole Ulrich, M.D., Yu-chi Shen, Ph.D., and Qianyi Ma, Ph.D. Their project is part of the Human Cell Atlas Seed Networks, an international effort supported by the Chan-Zuckerberg Initiative to map all cells in the human body as a resource for better understanding health and disease.
Prior to their work, “it was known that there are about four epithelial cell types in the fallopian tube,” said Hammoud. “We were able to reveal a deeper level of heterogeneity within these cells.”
Specifically, they identified 10 epithelial cell subtypes, including four of the finger-like ciliated cells responsible for moving the egg through the fallopian tube’s three sections before and after fertilization.