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An analysis of blood samples from thousands of study participants, led by researchers at UT Southwestern Medical Center, revealed 18 proteins associated with both heart failure and frailty, conditions that commonly develop in late life. Their findings, published in JAMA Cardiology, could lead to new strategies to jointly predict risk, administer preventive approaches, or treat these conditions, which often occur together.

“Our findings support shared biological pathways underlying both heart failure and frailty, suggesting interventions to prevent or treat one outcome may help decrease the burden of the other,” said study leader Amil Shah, M.D., M.P.H., Professor of Internal Medicine in the Division of Cardiology and in the Peter O’Donnell Jr. School of Public Health at UT Southwestern.

As the world’s population ages, so do the prevalence and incidence of heart failure and frailty, disorders that tend to occur in the seventh decade of life and beyond. Heart failure is characterized by an inability of the heart to keep up with the body’s demands; symptoms of frailty are a general loss of physical function, with features often including unintentional weight loss, physical exhaustion, and low physical activity. Frailty occurs in up to half of people with heart failure, and the risk of heart failure increases in people with frailty.

Although inflammation has been implicated in both of these multisystem disorders, whether heart failure and frailty share molecular pathways has been unknown.

By UT Southwestern Medical Center

Article can be accessed on: MedicalXpress

Patients with inflammatory bowel disease (IBD) endure abdominal pain, diarrhea, rectal bleeding, and weight loss. As these symptoms develop, the cellular environment in the gut undergoes a dramatic transformation. Yet, scientists know little about the cellular geographical landscape of this remodeling as the disease progresses.

To spatially map these cellular trajectories in the gut, a research team, led by single cell biologist Jeffrey Moffitt from Boston Children’s Hospital and immunologist Roni Nowarski from Brigham and Women’s Hospital, imaged the RNA molecules of cells within the gut in a mouse model of colitis, before, during, and after inflammation. In their study published in Cell, the team showed that as the disease progressed, there was a gradual spatial transformation of the gut, partially shaped by the presence and distribution of diverse subpopulations of inflammation-related fibroblasts. Weeks after the removal of the colitis-inducing drug, some of these fibroblasts retained a memory of the inflammation.

“Spatial context is important in biology,” said Kylie James, a mucosal immunologist at the Garvan Institute of Medical Research who did not participate in the study. Knowing where the cells sit in the gastrointestinal wall is important for understanding their roles in inflammatory processes and their contributions to disease. “Traditionally this information has been lost,” she explained, because researchers often analyze these cells once they have been removed from the tissue. While previous studies have used spatial transcriptomics to map cell signatures within the gut architecture, “One of the unique aspects here is that they also look throughout the trajectory of inflammation, doing it [at] multiple timepoints to understand how the cell signatures change,” said James.

In this study, researchers used multiplexed error-robust fluorescence in situ hybridization (MERFISH), a spatial transcriptomics technology, to follow the gene expression trajectories throughout the disease progression. They mapped 940 genes in the colons of mice prior to administration of the colitis-inducing drug (day zero), at the early disease period (day three), at the peak of inflammation (day nine), and after recovery (day 21 and day 35).

Using these data, they identified 25 tissue neighborhoods, defined statistically by recurrent local collections of cells. Each neighborhood was composed of a unique mixture of different cell types, such as epithelial, endothelial, immune, and fibroblasts, in specific proportions. Some neighborhoods were present at all stages (e.g., healthy and diseased) while others were unique to specific timepoints.

The researchers found that, as the disease progressed, the prevalence of many neighborhoods changed: the presence of some healthy neighborhoods lessened, while some inflammatory neighborhoods emerged. One of the signatures of most of these disease-emergent neighborhoods was the presence of diverse subpopulations of inflammation-associated fibroblasts, which arose from healthy fibroblasts. Fibroblasts are key immune regulators, and multiple studies previously hinted at some degree of heterogeneity in inflammatory fibroblasts during IBD. The present study identified inflammation-associated fibroblast subpopulations differing in gene expression, spatial location, and the disease stage at which they emerged.

“On a functional level, we still don’t understand very well what those different subsets of fibroblasts are doing,” said Nowarski. “What we were able to show in this work is that there is some unappreciated diversity of those fibroblast subsets.”

By Alejandra Manjarrez, PhD

Article can be accessed on: The Scientist

The human body’s sense of touch is so important it can be found throughout the body, not just on the skin. Two tiny sensors of touch, Piezo1 and Piezo2, signal the lightest pressures and can be found monitoring the circulatory system, telling the body where its limbs are in space, and even sounding the alarm for bladder pressure. But a new study from Duke University shows that Piezo1 works differently than everyone thought.

“Due to the mechanism that we found, we can basically say this signal that comes from Piezo is also picked up by other proteins, and therefore this really expands how mechanical forces are transduced,” said Jörg Grandl, an associate professor of neurobiology at Duke. “There are other signals that a cell can work with and further understand and interpret. So it opens up a new dimension of signaling.”

The discovery of the existence and ubiquity of Piezo1 and other touch sensors was part of the 2021 Nobel Prize in Physiology or Medicine and has become a hot research topic. Scientists all over the world are a pursuing deeper understanding of these crucial bits of physiology in the hope of being able to develop new therapies for pain and itching sensations and a host of other problems.

By  Karl Leif Bates, Duke University

Article can be accessed on: phys.org

Science has many historic examples of accidental discoveries that changed the world. In the modern laboratory, such moments continue to pave the way for scientific advances.

In one such recent occurrence, Caetano Reis e Sousa, an immunologist at The Francis Crick Institute, and his team happened upon a link between vitamin D and cancer through a bacterial ecosystem. They found that vitamin D acts through a binding protein, Gc globulin, and the gut resident Bacteroides fragilis to stimulate antitumor immunity in mice. These findings demonstrate for the first time a connection between vitamin D metabolism, a specific species of the microbiome, and the immune response to cancer in a living organism.

“It was pure serendipity, we were not interested in vitamin D,” noted Reis e Sousa, who published the findings in Science. 

Vitamin D is best known for its role in bone growth and development, where it facilitates the absorption of calcium, phosphate, and magnesium. More than a century ago, deficiency of this vitamin was identified as the cause of the bone disease rickets. Since then, researchers have found vitamin D to potentially play in a role in a number of other conditions, including cardiovascular diseases, autoimmunity, and cancer. However, vitamin D does not act alone. Recent evidence suggests that the gut microbiome, located at the interface of the intestinal lumen and epithelia where dietary vitamin D is absorbed, works synergistically with this vitamin to modulate the immune system.

At first, Reis e Sousa’s group was not looking at the microbiome either. An effective response to a foreign invasion depends on the ability of cells to mobilize immediately. The cytoskeletal protein actin is essential for cell mobility, as well as the changes in cell shape that characterize the cellular immune response. When Reis e Sousa and his team investigated the secreted form of the actin-severing protein gelsolin (sGSN), which is produced by damaged and cancerous cells, they found that lower levels of sGSN expression, or mutations in actin-associated proteins, correlated with enhanced antitumor immunity and increased patient survival.

“The serendipity comes from the fact that Gc globulin has a separate actin-binding domain and functions as an actin scavenger with secreted gelsolin,” he noted.

The researchers wondered if Gc globulin-deficient mice had similar tumor resistance to what they had observed for sGSN-deficient animals.

In their experiments, the team found that the Gc-deficient mice had enhanced immune-dependent resistance to transplanted tumors as well as a stronger response to immune checkpoint inhibitors. They then noticed that mice not deficient for Gc acquired this tumor resistance when co-housed with Gc-deficient mice, raising the possibility that this resistance depended on the mice’s gut microbiome. Next, they wanted to confirm this hypothesis experimentally. “We were worried that it could just be our mice, so we did fecal transplants from mice fed with high vitamin D into wild type mice from different sources and at two locations,” said Reis e Sousa. “It was like a detective story.”

The fecal transplant experiment confirmed that the tumor resistance was transmissible. The team also observed that treating the Gc-deficient mice with antibiotics diminished their tumor resistance following fecal transplant, further implicating the gut microbiome. They found that this resistance was enhanced when they fed the mice a high-vitamin D diet. The fact that they did not observe this effect in mice with deficiencies in other immunity-related genes that underwent the same treatments validated Gc as the protein linking vitamin D metabolism with the gut microbiome.

By Nicholas Miliaras, PhD

Article can be accessed on: The Scientist

Cholera infections caused by Vibrio cholerae bacteria can be life-threatening and the trigger is the cholera toxin produced by the bacteria. It binds to the surface of intestinal cells—more precisely, to certain “sugar lipids” (GM1 gangliosides, GM1) on the cell surfaces. This bond is one of the strongest known interactions between a protein—the toxin—and the sugar part of GM1. It enables the cholera toxin to penetrate the intestinal cells, which causes the very rapid loss of fluid.

In an interdisciplinary approach, a team from the University of Münster, ETH Zürich and Leibniz Universität Hannover has now analyzed a key component of the GM1 cholera toxin complex for the first time using a fluorinated GM1 analog. The findings on the molecular mechanisms of the strong interaction help to better understand the disease and could enable the development of novel drugs.

The work was published in the journal ACS Central Science.

As one of the most abundant biomolecule classes on the plant, carbohydrates are essential in all areas of biology and medicine. From determining blood groups to regulating the immune system and supplying cells with energy—the complexity of these sugar molecules offers great potential for the development of next-generation drugs. However, their interaction with the target proteins is often too weak to be utilized for therapeutic purposes.

By Hanna Dieckmann, University of Münster

Article can be accessed on: phys.org

Clinicians routinely administer antibiotics before surgeries to reduce the risk of infection. However, with the rise of antimicrobial resistance worldwide and the lack of new antibiotics, bacterial infections are becoming a growing challenge for the medical field. “We have a super lean antibiotic pipeline now that is being populated [mostly] by analogs of existing drug classes,” said Jon Stokes, a biochemist at McMaster University. Without the development of structurally and functionally novel antibacterial drugs, researchers predict that the mortality rate associated with antimicrobial-resistant bacteria will continue to rise reaching up to 10 million deaths annually by the year 2050.

In a recently published Nature Machine Intelligence paper, Stokes and his team enlisted the help of artificial intelligence (AI) to design structurally novel antibiotics that they could easily synthesize in the laboratory. This approach could help accelerate both antibiotic development and drug discovery.

Scientists are particularly concerned about six highly virulent and drug-resistant bacterial species, Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa, and Enterobacter species, known as the ESKAPE pathogens. One of these pathogens, A. baumannii, is a desiccation- and disinfectant-resistant microbe that is responsible for life-threatening, hospital-acquired infections of the skin, lungs, urinary tract, brain, bloodstream, and soft tissues. Because of the gravity of its threat to global health, the World Health Organization ranked this pathogen as a critical priority for new treatment and diagnostic tool development.

To address this need, Stokes and his team decided to use AI to discover novel small molecules with antibacterial activity against A. baumannii. Traditionally used property prediction AI models forecast the characteristics of chemicals to allow researchers to find synthesizable compounds with the desired properties, but they screen only existing chemical libraries. On the other hand, new generative AI models allow scientists to produce novel chemical compounds with the required qualities, but this approach is not without its own pitfalls. “A lot of generative algorithms for de novo molecular design exist. The problem is they tend to build molecules, atom by atom, which means in a computer you can draw amazing, beautiful compounds, but you cannot bring them into the laboratory because you cannot make them. They are synthetically intractable. I always compare it to kids when they draw wild stuff, like a giraffe flying a spaceship. It is a really cool picture, but we cannot make that happen,” said Stokes.

By Charlene Lancaster, PhD

Article can be accessed on: The Scientist

Human bodies are teeming with trillions of microbial cells that comprise the microbiome, many of them bacteria. Although they may be small, some of these bacteria maintain health, but others promote sickness. These differences often come down to the genes in each bacterial genome, but it can be challenging to find and sequence rare strains.

Gang Fang, a geneticist at the Icahn School of Medicine at Mount Sinai, has proposed a new solution called mEnrich-seq that draws on his decade of bacterial epigenomic research to distinguish different species’ DNA for metagenomic studies. In an interview with The Scientist, Fang describes his vision for how mEnrich-seq can help scientists answer hard questions about humans’ bacterial companions.

What are some challenges associated with studying the human microbiome with metagenomics?

We have a lot of technologies to understand the microbiome in many different ways, but there is a common problem. If a bacterial species is abundant in a sample, then we can learn almost anything about it, but if the abundance of a species is really low, it is very hard to study. There may even be two or three coexisting strains of the same species, and the important strain may not be the one that is relatively more abundant. These different strains are often very similar in terms of their genomes, so it is extremely hard to differentiate between them.

What motivated you to develop mEnrich-seq?

If a target is rare, most of the sequencing throughput will be consumed by the more abundant species. The moment we sequence, we have already lost this battle, so we needed a new strategy before sequencing. The natural epigenetic barcodes in bacteria give us a unique way to solve this problem. Even though different species and strains have similar genomes, they often encode different DNA methyltransferases, which determine their DNA methylation patterns. Bacteria do this to differentiate between self and foreign DNA. We can use this to differentiate between species’ or strains’ genomes based on the global methylation pattern.

If we want to target a certain genome and we know its methylation pattern, we can rationally choose restriction enzymes that will cut at a certain sequence called the methylation motif. The enzymes will digest the vast majority of the background DNA that does not have this matching methylation. With mEnrich-seq, we can enrich bacteria of interest over 100-fold.

By Aparna Nathan, PhD

Article can be accessed on: The Scientist

Researchers led by Yasuhiro Murakawa at the RIKEN Center for Integrative Medical Sciences (IMS) and Kyoto University in Japan and IFOM ETS in Italy have discovered several rare types of helper T cells that are associated with immune disorders such as multiple sclerosis, rheumatoid arthritis, and even asthma.

Published in Science, the discoveries were made possible by a newly developed technology they call ReapTEC, which identified genetic enhancers in rare T cell subtypes that are linked to specific immune disorders. The new T cell atlas is publicly available and should help in the development of new drug therapies for immune-mediated diseases.

Helper T cells are a kind of white blood cell that make up a large part of the immune system. They recognize pathogens and regulate the immune response. Many immune-mediated diseases are caused by abnormal T cell function. In autoimmune diseases like multiple sclerosis, they mistakenly attack parts of the body as if they were pathogens.

In the case of allergies, T cells overreact to harmless substances in the environment like pollen. We know of several common T cells, but recent studies have shown that rare and specialized types of T cells exist, and they might be related to immune-mediated diseases.

Within all cells, including T cells, there are regions of DNA called “enhancers.” This DNA does not code for proteins. Instead, it codes for small pieces of RNA, and enhances the expression of other genes.

By RIKEN

Article can be accessed on: MedicalXpress

A team of researchers has established a ribonucleic acid (RNA)-based method that drives cells in the body to produce therapeutic proteins and secrete them into the bloodstream. The approach could potentially extend the lifespan of drugs in the body, reducing the burden on patients who require frequent drug administrations.

The researchers, based at UT Southwestern Medical Center, leveraged a naturally occurring biomolecule called a signal peptide that determines where cells send proteins—acting like a shipping label—to release proteins into the blood that would normally remain in the cell.

In their paper, published in Proceedings of the National Academy of Sciences, the new approach enabled secretion and increased the circulation time of a therapeutic protein compared to standard injections in a mouse model of psoriasis, demonstrating beneficial effects in these mice and separately, in animal models of cancer.

The modular nature of the technique suggests that it could be adapted to address a wide range of diseases.

“This could potentially be a powerful platform technology. By linking a signal peptide to any particular protein—insulin for patients with diabetes for example—you could very easily tailor this technique to different disease conditions,” said Jermont Chen, Ph.D., a program director in the National Institute of Biomedical Imaging and Bioengineering (NIBIB) Division of Discovery Science and Technology.

By National Institutes of Health

Article can be accessed on: phys.org

Targeted genomic editing made great strides in recent decades, especially thanks to the advent of endonuclease-based gene-editing systems such as CRISPR-Cas9. However, targeted insertion of larger payloads remains problematic, hampering what researchers can do in terms of capability and throughput. Richard Davis, a stem cell researcher at Leiden University Medical Center (LUMC) and associate investigator at The Novo Nordisk Foundation Center for Stem Cell Medicine (reNEW), believes that a new strategy, termed serine and tyrosine recombinase-assisted integration of genes for high-throughput investigation (STRAIGHT-IN), can give scientists a powerful new tool for research and clinical applications.

Precision genome editing relies on homology-directed repair (HDR) to incorporate donor DNA into targeted regions. However, HDR targeting efficiency decreases significantly as insert size increases, so inserting multi-kilobase payloads remains difficult. Site-specific recombination can address this issue, and Davis and his team from LUMC used the strengths of two major site-specific recombinase (SSR) classes to build STRAIGHT-IN. “Serine recombinases can rapidly introduce constructs, but the whole vector—backbone, plasmid, everything—will integrate,” Davis said. “We knew from experience that if these [unnecessary] sequences were retained, there will be silencing down the road preventing expression. So, we used tyrosine recombinases to excise these auxiliary sequences which were not required in the final cell line.”

Davis and his team’s findings, published in Cell Reports Methods, showed that STRAIGHT-IN facilitated the targeted integration or substitution of multi-kilobase genomic fragments while leaving only traces (under 300 basepairs) of plasmid backbone DNA. This capability is important for creating more physiologically relevant systems. “We wanted to keep all of the [endogenous] introns and regulatory elements; to retain the entire genomic context of the gene,” Davis explained. Davis also noted that in the past, inserting large payloads often required potentially phenotype-altering manipulations of cellular genomes. This was particularly problematic for stem cell researchers. “These additional modifications could involve knocking out or overexpressing certain genes, which would then affect their phenotype and their ability to differentiate,” said Davis.

The researchers designed STRAIGHT-IN with human induced pluripotent stem cells (hiPSCs) in mind, as the cells’ potential for disease research had been hampered because they were more difficult to genetically modify compared to immortalized cell lines. “STRAIGHT-IN technology is going to play a role in making [hiPSC] models more useful,” said David Largaespada, a geneticist at the University of Minnesota Medical School who was not associated with this study. “For example, we have trouble mimicking what happens in human cancer genomes in mice because murine chromosomes are different. With hiPSC models, we could potentially model things more relevant to human cancer like gene amplification events, enhancer hijacking events, and so on.”

By Nathan Ni, PhD

Article can be accessed on: The Scientist