Tag Archives: #medicine

New Mechanism Revealed for Tumor-associated Macrophages to Regulate Fate of CD8+ T Cells (Medicine)

Immune checkpoint blockade therapy is an efficient way to reinvigorate CD8+ T cells, which has demonstrated clinical benefits in multiple types of cancer. However, many patients do not respond to immunotherapies effectively due to the irreversibly dysfunctional state of tumor-infiltrating T cells. Tumor-associated macrophages (TAMs) are the dominant population to induce T cells dysfunction. They are plastic and heterogeneous, and the plasticity could be precisely regulated by dynamic epitranscriptome, coordinately with transcriptional regulation.

As the most abundant modification in eukaryotic mRNA, N6-methyladenosine (m6A) could affect the fate of mRNA by regulating the half-life or translational efficacy of mRNA. Recent studies have pointed out that the m6A abundance and m6A modifiers are dysregulated in cancers. However, whether m6A modification is involved in regulating the function of tumor-infiltrating immune cells and orchestrating an immunosuppressive tumor microenvironment to induce T cells dysfunction is still unclear.

In a study published in Cancer Cell, a collaborative team led by Prof. HAN Dali from Beijing Institute of Genomics of the Chinese Academy of Sciences (China National Center for Bioinformation) and Prof. XU Michelle Meng from Tsinghua University revealed that the loss of m6A methylase METL14 in C1q+ macrophages leads to a decrease in m6A modification and an increase in expression level on Ebi3, which in turn induces the dysfunction of tumor-infiltrating CD8+ T cells.

The researchers revealed that C1q+ TAMs express a set of immunomodulatory ligands to interact with T cells. Notably, m6A methylation-associated genes, such as Mettl14, was highly enriched in C1q+ TAMs.

To investigate the function of m6A modification in macrophages, they specifically depleted Mettl14 in macrophages and found that the capacity to eliminate tumors was impaired and the proportion of CD8+ T cells decreased in Mettl14 deficient mice. Single cell RNA sequencing data demonstrated that Mettl14 deficiency in macrophages abolished the maintenance of effector and progenitor exhausted CD8+ T cell whereas increased the infiltration of dysfunctional transitory CD8+ T cells. Experiment for functional phenotype of tumor-infiltrating CD8+ T cells further validated that cytotoxic cytokine production of CD8+ T cells was impaired in Mettl14 deficient mice.

The loss of m6A in tumor-associated macrophages promotes CD8T cell dysfunction (Image by HAN Dali’s group and XU Michelle Meng’s group)

These data revealed that Mettl14 deficiency in macrophages control the bifurcation between divergent CD8+ T cell fates, dampening the effector CD8+ T cell activation and driving CD8+ T cell dysfunction.

Besides, the researchers found that the m6A abundance of Ebi3 was remarkably decreased and the mRNA and protein level of Ebi3 were markedly upregulated in Mettl14-deficient macrophages through integrated analysis of m6A-seq and RNA-seq data between wild-type and Mettl14-deficient macrophages. Subsequently, they treated tumor-bearing mice with an anti-EBI3 neutralizing antibody and found that T cell effector function was largely rescued in mice with Mettl14-deficient, which further improved the antitumor ability of Mettl14-deficient mice.

These findings supported that the loss of m6A in TAMs induces CD8+ T cell dysfunction by facilitating the accumulation of EBI3. To determine whether these findings can translate to human patients’ tumor samples, the researchers conducted multi-color immunohistochemistry and observed macrophages were close to CD8+ T cells in colon cancer patients.

In addition, they found that METTL14 expression level in stromal cells was positively correlated with the overall m6A level and CD8+ T cells infiltration within tumor. Furthermore, patients with higher m6A levels in stromal cells showed higher effector T cell signatures.

This study revealed a new mechanism that Mettl14 deficiency in macrophages can promote the accumulation of Ebi3, thereby driving CD8+ T cell dysfunction. It also showed that the function of macrophages was regulated by m6A modification at the epitranscriptomic level and emphasized that the functional plasticity of macrophages could be precisely switched through the dynamic epitranscriptome. Blocking the downstream molecules of Mettl14, such as EBI3, should be hopeful to restrict T cell dysfunction and improve the responsiveness of immune checkpoint blockade.


Provided by Chinese Academy of Sciences

Chronic Attack On the Aging Nervous System (Medicine)

Certain immune cells can cause damage to the aging central nervous system, according to a novel study by scientists of the University Hospital and the University of Würzburg.

Aging is the biggest risk factor for perturbation of the nervous system, even in the absence of distinct disease or trauma. For yet unknown reasons, the impulse conducting, myelinated projections and synaptic connections between nerve cells are especially vulnerable to aging-related degeneration. These pathological alterations often manifest as cognitive, sensory, and motor decline in older adults and represent a serious socio-economic challenge.

Malactivation leads to damage

Scientists have long assumed that inflammation plays an important role in this process. Mal- or overactivation of distinct cells belonging to the innate immune system – the microglia – appears to promote damage of nerve fibers and synapses in the aging central nervous system (CNS). In a recent project, scientists of the University Hospital Würzburg have now discovered an important role of the adaptive immune system.

The study was conducted at the Department of Neurology under corresponding author and lecturer Dr. Janos Groh from the section of “Developmental Neurobiology” (Prof. Dr. Rudolf Martini) in collaboration with Professor Wolfgang Kastenmüller (Institute for Systems Immunology) and Dr. Antoine-Emmanuel Saliba from the Helmholtz Institute for RNA-based Infection Research. The results of the study have now been published in the scientific journal Nature Aging.

T cells as mediators of neurodegeneration

“Cytotoxic CD8+ T cells normally recognize and fight infected or malignant cells. However, in case of autoimmune diseases like multiple sclerosis, they can also do unwanted damage in the nervous system”, says Janos Groh. The scientists could previously identify such CD8+ T cells as important disease amplifiers in models of various genetically mediated neurological disorders. Their role in the aging CNS, however, was so far poorly investigated on a functional level. In order to shed light on this question, the researchers investigated the impact of CD8+ T cells in aged mice, where these cells were found in increased numbers in fiber tracts.

“We show that the accumulation of CD8+ T cells leads to degeneration of nerve fibers in the CNS of normal aging mice, which contributes to motor and cognitive decline”, Groh summarizes the most important results of the study. Using modern gene expression analyses on the single-cell level, the team could for the first time characterize distinct populations of these CD8+ T cells in the brains of adult and aged mice in detail. This helped the scientists to subsequently clarify how the CD8+ T cells cause harm in the brain using precise immunological animal experiments.

Inflammation as a risk as well as therapeutic opportunity

“In addition, we show that T cell-mediated damage in aged but not adult mice is aggravated by systemic inflammation”, Groh adds. According to him, the study therefore confirms that CD8+ T cells are important effectors of inflammation-driven damage to the aging CNS, for example also after infections at more distant sites of the body. In future studies, the researchers want to clarify why and how exactly this inflammatory response is initiated.

Finally, the scientists could find very similar T cell reactions as observed in mice also in autopsies of CNS white matter from older humans. CD8+ T cells might therefore represent a putative target for therapeutic approaches to mitigate aging-related decline of structure and function of the nervous system. The study thus provides basic-scientific and translationally relevant insights into degenerative aging-related processes and another example for the complex interaction between the nervous and the immune system.

Featured image: Microscopic picture of a CD8+ T cell in the CNS of a two-year-old mouse. The cytotoxic T cell (red labelling) is located in immediate proximity to a damaged nerve fiber (green labelling) and is, according to the described results, involved in its damage. The cell nuclei of all cell bodies in the image are labelled in blue. Scale bar: 20 µm. (Image: Janos Groh / Reprinted by permission from Springer Nature)


Original publication

Accumulation of cytotoxic T cells in the aged CNS leads to axon degeneration and contributes to cognitive and motor decline. Janos Groh, Konrad Knöpper, Panagiota Arampatzi, Xidi Yuan, Lena Lößlein, Antoine-Emmanuel Saliba, Wolfgang Kastenmüller & Rudolf Martini. Nat Aging 1, 357–367 (2021). https://doi.org/10.1038/s43587-021-00049-z


Provided by University of Wurzburg

Asymmetric Synthesis of Aziridine with a New Catalyst Can Help Develop Novel Medicines (Chemistry)

Unless you’ve studied chemistry in college, it’s unlikely you’ve come across the name aziridine. An organic compound with the molecular formula, C2H4NH, aziridines are well-known among medicinal chemists, who make use of the compound to prepare pharmaceutical drugs such as Mitomycin C, a chemotherapeutic agent known for its anti-tumor activity. Specifically, aziridines are what chemists call “enantiomers”ーmolecules that are mirror images of each other and cannot be superposed on one another. A peculiarity with enantiomers is that the biological activity of one is different from its mirror image and only one of them is desirable for making drugs. Chemists, therefore, regularly opt for “asymmetric” or “enantioselective” synthesis techniques that yield the desired enantiomer in greater amounts.

One such technique that has recently attracted attention from the viewpoint of pharmaceutical synthesis involves the use of oxazolonesーchemical compounds with the molecular formula C3H3NO2ー to prepare aziridines. “Oxazolones are well-known for their versatility in affording biologically active compounds,” explains Professor Shuichi Nakamura from Nagoya Institute of Technology (NITech), Japan, who studies asymmetric reactions, “However, the enantioselective reactions of 2H-azirines with oxazolones have not been very fruitful, despite being touted as one of the most efficient methods to synthesize aziridines.

In a new study recently published in Organic Letters, Prof. Nakamura along with his colleagues from NITech and Osaka University, Japan, explored this issue and, in a significant breakthrough, managed to obtain aziridine-oxazolone compounds in high yields (99%) as well as high enantioselectivity or purity (98%). In addition, the team used an original catalyst they developed to catalyze the reactions they studied.

The team started off by heating α-azideacrylates at 150°C in an organic solvent tetrahydrofuran (THF) to prepare 2H-azirines and then reacted them with oxazolones in presence of various organocatalysts to produce different aziridine-oxazolone compounds. In particular, the team examined the effect of the catalyst cinchonine and various heteroarenecarbonyl and heteroarenesulfonyl groups in organocatalysts derived from cinchona alkaloids and found that reactions using catalysts with either a 2-pyridinesulfonyl group or an 8-quinolinesulfonyl group gave both a high yield (81-99%) as well high enantiopurity (93-98%). In addition, scientists observed that the reaction between a 2H-azirine containing an ethyl ester group and an oxazolone with a 3, 5-dimethoxyphenyl group in presence of the catalyst with 8-quinolinesulfonyl group also gave high yields (98-99%) as well as enantiopurity (97-98%).

The team then moved on to exploring the reaction between 2H-azirine with ethyl ester group and a wider variety of oxazolones in presence of the catalyst with 8-quinolinesulfonyl group. In all of the reactions they observed high yields (77-99%) and enantiopurities (94-99%) except one for the case of an oxazolone bearing a benzyl group and the catalyst with 2-pyridylsulfonyl group that only produced a moderate yield (61%) and purity (86%). Moreover, they were able to convert the obtained aziridines into various other enantiomers without any loss of purity.

Finally, the team proposed a catalytic mechanism and a transition state for the reaction of 2H-azirines with oxazolones in which the catalyst activates both the oxazolone and the 2H-azirine, which then react to give an “addition product” that, in turn, yields the aziridine with regeneration of the catalyst.

While the detailed mechanism is yet to be clarified, scientists are excited by their findings and look forward to the method’s application in medicine and pharmacology. “It has the potential to provide people with new medicines and create new drugs as well as drug candidates that are currently difficult to synthesize. Moreover, the catalyst used in this study can be used for many other stereo-selective synthetic reactions,” observes an optimistic Prof. Nakamura.

Some fascinating consequences to contemplate for sure!

Featured image: Producing aziridines with high yield and high purity using novel catalyst. Scientists from Japan recently proposed a possible transition state for the reaction between aziridines and oxazolones in presence of a cinchona alkaloid sulfonamide catalyst, producing desirable aziridine-oxazolone compounds with high yields and enantioselectivity or purity. Image courtesy: Shuichi Nakamura from NITech


Reference

  • Title of original paper: Enantioselective Reaction of 2H‑Azirines with Oxazol-5-(4H)‑ones Catalyzed by Cinchona Alkaloid Sulfonamide Catalysts
  • Journal: Organic Letters
  • DOI: 10.1021/acs.orglett.1c00259 

Provided by Nagoya Institute of technology

The Tuberculosis Pathogen Releases its Toxin by a Novel Protein Transport System (Medicine)

This transport system may be widespread across many Gram-positive bacteria that contain proteins in the WXG100 superfamily. Tuberculosis kills 1 million people each year.

Six years ago, Michael Niederweis, Ph.D., described the first toxin ever found for the deadly pathogen Mycobacterium tuberculosis. This toxin, tuberculosis necrotizing toxin, or TNT, became the founding member of a novel class of previously unrecognized toxins present in more than 600 bacterial and fungal species, as determined by protein sequence similarity. The toxin is released as M. tuberculosis bacteria survive and grow inside their human macrophage host, killing the macrophage and allowing the escape and spread of the bacteria.

For 132 years, the lack of an identified toxin in M. tuberculosis had contrasted with nearly all other pathogenic bacteria whose toxins contribute to illness or death. M. tuberculosis infects 9 million people a year and kills more than 1 million.

Now, in another groundbreaking work, the University of Alabama at Birmingham researcher and colleagues describe how two small ESX proteins made by the M. tuberculosis bacteria mediate secretion of TNT by pore formation in the membranes that envelop the bacteria. This finding may have broad application because a distinctive three-amino acid motif found on EsxE and EsxF — tryptophan/any-amino-acid/glycine, known in shorthand as WXG — is also found on many other small mycobacterium proteins and on the large WXG100 superfamily of bacterial proteins that resemble EsxE and EsxF.

“Here, we show for the first time that small Esx proteins of the WXG100 family have an important molecular function inside the Mtb cell by mediating toxin secretion,” said Niederweis, a professor in the UAB Department of Microbiology. “Our results suggest a dynamic mechanism of pore formation by small Esx proteins that might be applicable to other members of the large WXG100 protein family. Thus, our study not only represents a major advancement in our understanding of secretion of TNT and likely of other proteins in M. tuberculosis, but also describes a biological function for Esx-paralogs in M. tuberculosis and their homologs in the large WXG100 protein family in Gram-positive bacteria.”

TNT is one of two domains in the M. tuberculosis outer membrane protein CpnT; activity of the TNT domain of CpnT in the cytosol of the macrophage induces macrophage death by hydrolyzing NAD+. M. tuberculosis has an inner membrane and an outer membrane, and a protein needs to get through each layer to be secreted outside of the bacterium. How CpnT gets to the outer membrane was unknown.

EsxE and EsxF are part of the same gene segment as CpnT, and the UAB researchers hypothesized that the two small proteins might be involved in secretion of the toxin.

By creating different strains that lacked either EsxE or EsxF, they showed that both proteins were necessary for the translocation of CpnT to the cell surface of M. tuberculosis and for the secretion of TNT into the cytosol of macrophages infected with M. tuberculosis. Furthermore, EsxE and EsxF are surface-accessible proteins on M. tuberculosis as a membrane-associated complex.

To learn more about the mechanism of that translocation, the UAB team made mutants of each Esx protein, where the tryptophan amino acid of the single WXG motif on each protein was replaced by the amino acid alanine. The mutants showed that an intact WXG motif on EsxE and on EsxF were required for efficient CpnT translocation to the outer membrane of M. tuberculosis and subsequent TNT secretion into the cytosol of infected macrophages.

Purification of the water-soluble EsxE and EsxF proteins showed they formed EsxE-EsxF dimers, and five of these dimers assembled into star-shaped structures, as viewed by electron microscopy. Each was about 10 nanometers across, with a 3-nanometer central pore.

Experiments with planar lipid bilayers were key to understanding the molecular function of EsxE-EsxF, as they showed that the EsxE-EsxF pores formed channels through lipid membranes.

Finally, the researchers showed that the WXG motifs were required for pore formation and membrane disruption by the EsxE-EsxF complex, and the motifs mediated assembly of functional EsxE-EsxF oligomers. This now defines a biochemical role for the previously enigmatic WXG motif.

“EsxE and EsxF constitute the first known outer membrane components mediating protein secretion in M. tuberculosis,” Niederweis said. “However, it is unlikely that EsxE and EsxF are sufficient for TNT secretion, since an energy source is required in all known bacterial protein secretion systems. Therefore, it is possible that EsxE-EsxF associate with other proteins or protein complexes to achieve CpnT export and TNT secretion.”

The UAB researchers propose two models for the transport of CpnT by EsxE and EsxF. In the first, the EsxE-EsxF heterodimers form a pore in the inner membrane, and then form another pore in the outer membrane to create transmembrane channels. “Alternatively,” Niederweis said, “the inner membrane channel is extended to span the periplasm via filament formation, and connects to EsxE-EsxF pores in the outer membrane, exposing EsxF on the cell surface. In this model, the putative EsxE-EsxF channel tunnel enables export of the CpnT polypeptide to the outer membrane of M. tuberculosis, and subsequent secretion of TNT and EsxE-EsxF.”

Co-authors with Niederweis in the study, “Pore-forming Esx proteins mediate toxin secretion by Mycobacterium tuberculosis,” published in Nature Communications, are Uday Tak and Terje Dokland, UAB Department of Microbiology.

“This work was a remarkable achievement of an outstanding graduate student, Uday Tak, who did almost all of these experiments by himself,” Niederweis said. Uday Tak obtained his Ph.D. in November 2020 and is now a postdoctoral fellow at the University of Colorado-Boulder.

This paper was selected by the editor-in-chief as a highlight and is featured on a special website called “Microbiology and infectious diseases.”

Support came from National Institutes of Health grant AI121354. Electron microscopy data analysis was performed on the UAB CHEAHA supercomputer platform, which is supported by National Science Foundation grant OAC-1541310.

At UAB, Niederweis holds the Endowed Professorship in Bacteriology.

Featured image: Michael Niederweis © UAB


Reference: Tak, U., Dokland, T. & Niederweis, M. Pore-forming Esx proteins mediate toxin secretion by Mycobacterium tuberculosis. Nat Commun 12, 394 (2021). https://www.nature.com/articles/s41467-020-20533-1 https://doi.org/10.1038/s41467-020-20533-1


Provided by University of Alabama at Birmingham

Exosome-Coated Stent Heals Vascular Injury, Repairs Damaged Tissue (Medicine)

Researchers from North Carolina State University have developed an exosome-coated stent with a “smart-release” trigger that could both prevent reopened blood vessels from narrowing and deliver regenerative stem cell-derived therapy to blood-starved, or ischemic, tissue.

Angioplasty – a procedure that opens blocked arteries – often involves placing a metal stent to reinforce arterial walls and prevent them from collapsing once the blockage is removed. However, the stent’s placement usually causes some injury to the blood vessel wall, which stimulates smooth muscle cells to proliferate and migrate to the site in an attempt to repair the injury. The result is restenosis: a re-narrowing of the blood vessel previously opened by angioplasty.

“The inflammatory response that stents cause can decrease their benefit,” says Ke Cheng, corresponding author of the research. “Ideally, if we could stop smooth muscle cells from over-reacting and proliferating, but recruit endothelial cells to cover the stent, it would mitigate the inflammatory response and prevent restenosis.” Cheng is the Randall B. Terry Jr. Distinguished Professor in Regenerative Medicine at NC State and a professor in the NC State/UNC-Chapel Hill Joint Department of Biomedical Engineering.

There are drug-eluting stents currently in use coated with drugs that discourage cell proliferation, but these anti-proliferative drugs also delay stent coverage by endothelial cells – which are the cells healthcare providers want to coat the stent.

To solve this problem, Cheng and his team developed a stent coating composed of exosomes derived from mesenchymal stem cells. Exosomes are tiny nano-sized sacs secreted by most cell types. The idea behind the coating was two-fold: first, since the exosomes are composed of materials not much different from cell membranes they ‘camouflage’ the stent to trick smooth muscle cells and the body’s immune system. Second, the exosomes promote coverage of the stent by endothelial cells and, in the case of injury, travel downstream to the site to promote tissue repair.

To prevent premature depletion of the therapy, the stent releases exosomes when it encounters reactive oxygen species (ROS) – which are more prevalent during an inflammatory response.

“Think of it as a smart release function for the exosomes,” Cheng says. “Ischemic reperfusion injuries, which occur when blood flow is diminished and then reestablished, create a lot of ROS. Let’s say the heart is damaged by ischemia. The enhanced ROS will trigger the release of the exosomes on the stent, and regenerative therapy will travel through the blood vessel to the site of the injury.”

The research team performed in vitro testing to ensure biocompatibility and test the release mechanism. They found that in the presence of ROS, the exosomes released up to 60% of their secretions within 48 hours post-injury.

In a rat model of ischemic injury, the researchers compared their exosome-eluting stent (EES) to both a bare metal stent (BMS) and a drug-eluting stent (DES). They found that in comparison to the BMS, their stent performed better in both decreasing stenosis and promoting endothelial coverage. While the DES performed similarly to the EES in preventing restenosis, the EES was less injurious to the vessel wall and had better endothelial coverage overall. In addition, the exosomes released from EES promoted muscle regeneration in rats with hind limb ischemia. The researchers plan to test the stent in a large animal model with an eye toward eventual clinical trials.

“This bioactive stent promotes vascular healing and ischemic repair, and a patient wouldn’t need additional procedures for regenerative therapy after the stent is in place,” Cheng says. “The stent is the perfect carrier for exosomes, and the exosomes make the stent safer and more potent in tissue repair.”

The research appears in Nature Biomedical Engineering and was supported by the National Institutes of Health and the American Heart Association. NC State postdoctoral research scholars Shiqi Hu and Zhenhua Li are co-first authors.

Featured image: Exosomes (magenta) released from a stent in the blood vessel. Credit: Cheng Lab


Reference: Shiqi Hu, Zhenhua Li, Deliang Shen, Dashuai Zhu, Ke Huang, Teng Su, Phuong-Uyen Dinh, Jhon Cores, Ke Cheng, “Exosome-eluting stents for vascular healing after ischaemic injury”, Nature Biomedical Engineering, 2021. DOI: 10.1038/s41551-021-00705-0


Provided by NC State University

SARS-CoV-2 Hijacks Two Key Metabolic Pathways to Rapidly Replicate in Host Cells (Medicine)

Blocking folate metabolism with oral, prophylactic drugs could reduce viral replication in infected cells

When SARS-CoV-2, the virus that causes COVID-19, infects a human cell, it quickly begins to replicate by seizing the cell’s existing metabolic machinery. The infected cells churn out thousands of viral genomes and proteins while halting the production of their own resources. Researchers from Brigham and Women’s Hospital, Massachusetts General Hospital (MGH), and the Broad Institute, studying cultured cells shortly after infecting them with the virus, now have more insight into the metabolic pathways co-opted by the virus. The findings, published in Nature Communications, highlight the potential therapeutic benefit of drugs such as methotrexate, which inhibit folate and one-carbon metabolic pathways appropriated by the virus.

“One of the things we’re lacking in this pandemic is a pill that can be taken orally, as a prophylactic agent, before someone is hospitalized or even before they’re infected,” said corresponding author Benjamin Gewurz, MD, PhD, of the Division of Infectious Diseases. “Monoclonal antibodies have a lot of promise but need to be given intravenously. Blocking the metabolism pathways that viruses rely on to replicate could be a new strategy for treating patients at an early timepoint.”

To identify which metabolic pathways to target, the researchers obtained samples of the virus and cultivated them in a highly protected facility called a BSL-3 laboratory, located at the Broad Institute. They then paired up with the laboratory of co-senior author Vamsi Mootha, MD, of MGH, to apply mass spectrometry approaches to identify the resources being consumed and produced by healthy cells and infected cells. They studied the infected cells at an “eclipse point,” eight hours after infection, when the virus has begun manufacturing its RNA and proteins but has not yet exerted a serious effect on host cell growth and survival.

In analyzing the amino acids and thousands of chemical metabolites produced by the cells, the researchers observed that infected cells had depleted stores of glucose and folate. They demonstrated that the SARS-CoV-2 virus diverts building blocks from glucose production to the assembly of purine bases, which are necessary for creating large amounts of viral RNA. Additionally, they found that the 1-carbon pathway used to metabolize folate was hyperactive, thus supplying the virus with more carbon groups for making bases for DNA and RNA.

Drugs that inhibit folate metabolism, like methotrexate, are often used to treat autoimmune conditions like arthritis and could be therapeutic candidates for COVID-19. Methotrexate is currently being assessed as a treatment for the inflammation that accompanies more advanced COVID-19 infections, but the researchers suggest that it could also be beneficial early on. Their study also found that it could offer a synergistic effect when administered with the anti-viral drug remdesivir. Methotrexate’s immune-suppressing properties could make its proper administration as a prophylactic challenging, however. Researchers would need to determine how to maximize the drug’s antiviral effects without significantly compromising a patient’s natural immune response.

Still, Gewurz points out that oral antivirals are an important addition to an arsenal of therapies for COVID-19, serving both as an immediate treatment for infection as well as a defense against new variants and other coronaviruses.

“We’re hoping that, ultimately, we can find a way of preventing viruses from using cells’ metabolism pathways to replicate themselves because that could limit the ability of viruses to evolve resistance,” Gewurz said. “We’re starting to see new viral variants, and we’re hoping that we can stay ahead of that — treating patients before the virus has the chance to make copies of itself that could become resistant to antibodies.”

This work was supported by the National Institutes of Health (R01 AI137337, R01 CA228700, R35 GM122455), EMBO (ALTF 486-2018), a Burroughs Wellcome Career Award in Medical Sciences, the Howard Hughes Medical Institute and MassCPR. Gewurz and Mootha are listed as inventors on a patent application filed by the Broad Institute based on results from this manuscript.


Reference: Zhang, Y., Guo, R., Kim, S.H. et al. SARS-CoV-2 hijacks folate and one-carbon metabolism for viral replication. Nat Commun 12, 1676 (2021). https://www.nature.com/articles/s41467-021-21903-z https://doi.org/10.1038/s41467-021-21903-z


Provided by Brigham’s and Women’s Hospital

Aging-US: DNA- and Telomere-damage Does Not Limit Lifespan: Evidence From Rapamycin (Medicine)

Blagosklonny concluded in his Aging-US Research Output that here he discussed new evidence that normal aging is not caused by accumulation of molecular damage or telomere shortening

Aging-US published “DNA- and telomere-damage does not limit lifespan: evidence from rapamycin” which reported that failure of rapamycin to extend lifespan in DNA repair mutant and telomerase-knockout mice, while extending lifespan in normal mice, indicates that neither DNA damage nor telomere shortening limits normal lifespan or causes normal aging.

Dr. Mikhail V. Blagosklonny said, “As a provocative title has recently announced, ‘rapamycin fails to extend lifespan in DNA repair -deficient mice’ [1]. The word ‘fails’ implies bad news. Rapamycin tried but failed. Yet, it is expected that the anti-aging drug rapamycin should not restore lifespan of short-lived mice that fail to grow and die young from causes other than normal aging [2]. In such growth- retarded mice, rapamycin, an inhibitor of cell growth, further retards weight gain.”

While shortening lifespan by 18% in unnatural telomerase- deficient mice, in the same study in natural mice, rapamycin increased lifespan by 39% and healthspan by 58%.

In dozens of independent studies, rapamycin has not failed to extend lifespan in normal mice.

However, while extending lifespan in normal mice, rapamycin may fail to save animals dying young from cellular growth retardation.

The failure of rapamycin to extend lifespan in these short- lived mice, dying from DNA damage, rules out the damage theory of aging and to illustrate this point the author first discusses what limits animal lifespan by providing commentary on 1. Quasi-programmed (hyperfunctional) aging and 2. How molecular damage can become life- limiting

Blagosklonny concluded in his Aging-US Research Output that here he discussed new evidence that normal aging is not caused by accumulation of molecular damage or telomere shortening: while extending normal lifespan in mice, rapamycin failed to do so in mice dying from molecular damage.

Previously, several lines of evidence suggested that molecular damage does not cause normal aging. Their detailed discussion is beyond the focus of this article, so he just mentions some of them, without referencing them.

1. Overexpression of enzymes that decrease damage does not extend lifespan in most studies. Similarly, antioxidants do not extend lifespan in animals and may increase mortality in humans. Furthermore, even data that support damage theory can be explained by other mechanisms. For example, N-Acetyl-L-Cysteine, a commonly used anti- oxidant, can inhibit mTOR.
2. According to calculations, molecular damage, especially mtDNA mutations and telomere shortening, cannot reach a deadly threshold during animal lifetime.
3. Genetic knockout of signaling pathways can extend lifespan without affecting molecular damage. Similarly, pharmacological interventions can extend life without affecting damage accumulation.
4. Dramatic intra- and inter-species differences in lifespan poorly correlate with the rate of molecular damage.
5. Nuclear transfer and nuclear reprogramming both rule out DNA damage as a cause of aging. Following adult somatic cell nuclear transfer, cloned animals are healthy and have normal lifespan.
6. Low levels of molecular damage may increase longevity. This phenomenon is known as hormesis. Regardless of mechanistic explanations, this indicates that molecular damage is not-life-limiting even when moderately increased.
7. Rapamycin increases lifespan in all normal animals tested, indicating that mTORC1-dependent quasi-program is life-limiting.

Once again, damage accumulates and must cause death eventually, but quasi-programmed aging terminates life first. Molecular damage can become life-limiting, when artificially accelerated or, potentially, when quasi-programmed aging is decelerated.

Featured image: Rapamycin extends lifespan in natural but not progeroid mice. (A) Natural mice. Hyperfunctional aging (green/yellow/red arrow) progresses from development (green) to diseases (red), reaching death threshold and limiting lifespan. Accumulation of molecular damage (gray arrow) is slow and does not reach death threshold in animal lifetime. It would take longer to die from molecular damage. Treatment with rapamycin (RAPA) extends lifespan by slowing down mTOR-driven aging (B) Progeroid, telomerase- or DNA-repair-deficient mice. Accumulation of molecular damage (gray arrow) is artificially accelerated to become life-limiting. Treatment with rapamycin (RAPA) cannot extend lifespan. Copyright: © 2021 Blagosklonny


Reference: Blagosklonny MV. DNA- and telomere-damage does not limit lifespan: evidence from rapamycin. Aging (Albany NY). 2021; 13:3167-3175. DOI – https://doi.org/10.18632/aging.202674 Full Text – https://www.aging-us.com/article/202674/text


Provided by Impact Journals LLC

Researchers Discover New Potential For Functional Recovery After Spinal Cord Injury (Medicine)

Researchers at Indiana University School of Medicine have successfully reprogrammed a glial cell type in the central nervous system into new neurons to promote recovery after spinal cord injury—revealing an untapped potential to leverage the cell for regenerative medicine.

The group of investigators published their findings March 5 in Cell Stem Cell. This is the first time scientists have reported modifying a NG2 glia—a type of supporting cell in the central nervous system—into functional neurons after spinal cord injury, said Wei Wu, PhD, research associate in neurological surgery at IU School of Medicine and co-first author of the paper.

Wu and Xiao-Ming Xu, PhD, the Mari Hulman George Professor of Neuroscience Research at IU School of Medicine, worked on the study with a team of scientists from the University of Texas Southwestern Medical Center. Xu is also a primary member of Stark Neurosciences Research Institute, where he leads the Indiana Spinal Cord and Brain Injury Research Group.

Spinal cord injuries affect hundreds of thousands of people in the United States, with thousands more diagnosed each year. Neurons in the spinal cord don’t regenerate after injury, which typically causes a person to experience permanent physical and neurological ailments.

“Unfortunately, effective treatments for significant recovery remain to be developed,” Xu said. “We hope that this new discovery will be translated to a clinically relevant repair strategy that benefits those who suffer from a spinal cord injury.”

When the spinal cord is injured, glial cells, of which there are three types—astrocyte, ependymal and NG2—respond to form glial scar tissue.

“Only NG2 glial cells were found to exhibit neurogenic potential in the spinal cord following injury in adult mice, but they failed to generate mature neurons,” Wu said. “Interestingly, by elevating the critical transcription factor SOX2, the glia-to-neuron conversion is successfully achieved and accompanied with a reduced glial scar formation and increased functional recovery following spinal cord injury.”

The researchers reprogrammed the NG2 cells from the mouse model using elevated levels of SOX2—a transcription factor found inside the cell that’s essential for neurogenesis—to neurons. This conversion has two purposes, Xu said: generate neurons to replace those lost due to a spinal cord injury and reduce the size of the glial scars in the lesion area of the damaged tissue.

This discovery, Wu said, serves as an important target in the future for potential therapeutic treatments of spinal cord injury.

The partnership between the laboratory of Chun-Li Zhang, PhD, professor at UT Southwestern Medical Center, and Xu’s laboratory at IU School of Medicine greatly benefited the research, Xu added, by offering complementary expertise in neuronal reprogramming and in spinal cord injury, respectively.

“Such a collaboration will be continued between the two laboratories to address neuronal remodeling and functional recovery after successful conversion of glial cells into functional neurons in future,” Xu said.


Reference: Wenjiao Tai, Wei Wu, Lei-Lei Wang et al., “In vivo reprogramming of NG2 glia enables adult neurogenesis and functional recovery following spinal cord injury”, Cell stem cell, 2021. DOI: https://doi.org/10.1016/j.stem.2021.02.009


Provided by IU School of Medicine


About IU School of Medicine

IU School of Medicine is the largest medical school in the U.S. and is annually ranked among the top medical schools in the nation by U.S. News & World Report. The school offers high-quality medical education, access to leading medical research and rich campus life in nine Indiana cities, including rural and urban locations consistently recognized for livability.

Researchers Uncover Link Between Racial, Ethnic & Socioeconomic Factors & Likelihood of Getting Effective Treatment for Atrial Fibrillation

Findings show Black, Latinx, and lower income patients receive less rhythm control

Even though the use of rhythm control strategies for treating Paroxysmal Atrial Fibrillation (AF), a common abnormal heart rhythm, have increased overall in the United States, patients from racial and ethnic minority groups and those with lower income were less likely to receive rhythm control treatment – often the preferred treatment – according to new research from the Perelman School of Medicine at the University of Pennsylvania. The study is published in the JAMA Network Open.

“Research has demonstrated the pervasive impact of structural racism on health outcomes among minoritized patients. We know, for instance, that there is less use of novel cardiovascular therapies among Black, Latinx, and patients of lower socioeconomic status,” said the study’s lead author, Lauren Eberly, MD, MPH, a cardiology fellow at the University of Pennsylvania. “That’s why we wanted to evaluate the rates of antiarrhythmic drugs and catheter ablation and investigate for the presence of inequities to see how we can do better from an equity standpoint.”

Atrial Fibrillation is the most common sustained heart rhythm disorder, and is the cause of significant complications including heart failure and stroke, which can be deadly for some patients. The two forms of rhythm control are antiarrhythmic drugs and catheter ablation, which aims to eliminate the sources of atrial fibrillation. Evidence suggests that when doctors pursue these rhythm control strategies early in the course of the patient’s disease, they are more likely to successfully control the condition, and long term cardiovascular outcomes are improved.

Researchers examined data from October 2015 to June 2019 from more than 100,000 diverse, commercially insured patients, and found that from 2016 to 2019 the cumulative percentage of patients treated with antiarrhythmic drugs and catheter ablation increased from 1.6 percent to 3.8 percent. Despite this overall increase, patients with Latinx ethnicity and those who lived in zip codes with lower median household income were less likely to receive catheter ablation treatment, and Black and lower-income patients were less likely to be prescribed antiarrhythmic drugs or treated with catheter ablation.

Overall, patients living in areas with median household incomes of less than $50,000 were 39 percent less likely to receive catheter ablation compared with those with a median household income of $100,000 or more.

According to researchers, the number of cardiology visits by each patient was one of the strongest factors associated with rhythm control and catheter ablation use, stressing the importance of access to care. The findings suggest that reduced access to specialty care, including cardiovascular care for Black patients, is a potential reason for differences in treatments.

“As evidence builds regarding the benefits of early rhythm control and particularly catheter ablation, we must ensure that all our patients benefit equally” said the study’s senior author, David Frankel, MD, Associate Professor of Medicine and Director of the Cardiac Electrophysiology Fellowship.

Eberly also hopes that in addition this awareness will push primary care providers and non-cardiac providers to more readily consider rhythm-control strategies or referral to a specialist, particularly for those patients who have been historically marginalized by the healthcare system.

Funding was provided by the Mark Marchlinski Research and Education Fund.


Reference: Lauren A. Eberly, Lohit Garg, Lin Yang, et al, “Racial/Ethnic and Socioeconomic Disparities in Management of Incident Paroxysmal Atrial Fibrillation”, JAMA Netw Open. 2021;4(2):e210247. doi: 10.1001/jamanetworkopen.2021.0247


Provided by Penn Medicine