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The study, “Endothelial TDP-43 Depletion Disrupts Core Blood-Brain Barrier Pathways in Neurodegeneration,” was published on March 14, 2025. The lead author, Omar Moustafa Fathy, an MD/Ph. D. candidate at the Center for Vascular Biology at UConn School of Medicine, conducted the research in the laboratory of senior author Dr. Patrick A. Murphy, associate professor and newly appointed interim director of the Center for Vascular Biology. The study was carried out in collaboration with Dr. Riqiang Yan, a leading expert in Alzheimer’s disease and neurodegeneration research.

This work provides a novel and significant exploration of how vascular dysfunction contributes to neurodegenerative diseases, exemplifying the powerful collaboration between the Center for Vascular Biology and the Department of Neuroscience. While clinical evidence has long suggested that blood-brain barrier (BBB) dysfunction plays a role in neurodegeneration, the specific contribution of endothelial cells remained unclear. The BBB serves as a critical protective barrier, shielding the brain from circulating factors that could cause inflammation and dysfunction. Though multiple cell types contribute to its function, endothelial cells—the inner lining of blood vessels—are its principal component.

“It is often said in the field that ‘we are only as old as our arteries’. Across diseases we are learning the importance of the endothelium. I had no doubt the same would be true in neurodegeneration, but seeing what these cells were doing was a critical first step,” says Murphy.

Omar, Murphy, and their team tackled a key challenge: endothelial cells are rare and difficult to isolate from tissues, making it even harder to analyze the molecular pathways involved in neurodegeneration.

To overcome this, they developed an innovative approach to enrich these cells from frozen tissues stored in a large NIH-sponsored biobank. They then applied inCITE-seq, a cutting-edge method that enables direct measurement of protein-level signaling responses in single cells—marking its first-ever use in human tissues.

This breakthrough led to a striking discovery: endothelial cells from three different neurodegenerative diseases—Alzheimer’s disease (AD), amyotrophic lateral sclerosis (ALS), and frontotemporal dementia (FTD)—shared fundamental similarities that set them apart from the endothelium in healthy aging. A key finding was the depletion of TDP-43, an RNA-binding protein genetically linked to ALS-FTD and commonly disrupted in AD. Until now, research has focused primarily on neurons, but this study highlights a previously unrecognized dysfunction in endothelial cells.

“It’s easy to think of blood vessels as passive pipelines, but our findings challenge that view,” says Omar. “Across multiple neurodegenerative diseases, we see strikingly similar vascular changes, suggesting that the vasculature isn’t just collateral damage—it’s actively shaping disease progression. Recognizing these commonalities opens the door to new therapeutic possibilities that target the vasculature itself.”

Continue reading “Endothelial TDP-43 depletion disrupts core blood–brain barrier pathways in neurodegeneration” | >

One of the most enduring questions humans have is how long we’re going to live. With this comes the question of how much of our lifespan is shaped by our environment and choices, and how much is predetermined by our genes.

A study recently published in the prestigious journal Nature Medicine has attempted for the first time to quantify the relative contributions of our environment and lifestyle versus our genetics in how we age and how long we live.

The findings were striking, suggesting our environment and lifestyle play a much greater role than our genes in determining our longevity.

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The landmark advance builds on a 2013 study by the team, published in Science, which described the construction of the first GRO. In that study, the researchers demonstrated new solutions for safeguarding genetically engineered organisms and for producing new classes of synthetic proteins and biomaterials with “unnatural,” or human-created, chemistries.

Ochre is a major step toward creating a non-redundant genetic code in E. coli, specifically, which is ideally suited to produce synthetic proteins containing multiple, different synthetic amino acids.

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A 69-year-old man with metastatic prostate adenocarcinoma, treated with chemotherapy 3 years ago, presented with pancytopenia (white blood cells, 3.1 × 109/L; hemoglobin, 11.1 g/L; platelets, 47 × 109/L). A bone marrow aspirate revealed increased blasts with folded nuclei, deeply basophilic cytoplasm, prominent nucleoli, perinuclear hofs, and occasional salmon-colored cytoplasmic granules without Auer rods (panel A, Giemsa stain, original magnification ×1000, lens objective 100×). The blasts were positive for CD34, CD13, CD19, CD25 (partial), CD33, CD38 (decreased), CD45 (dim), CD64 (partial), CD79a (dim), CD117, CD123, HLA-DR (bright), and myeloperoxidase and negative for CD7, CD10, CD14, CD20, CD22, CD36, CD56, cytoplasmic IgM and terminal deoxynucleotidyl transferase (panel B). Next-generation sequencing detected a DNMT3A mutation (F794del, variant allelic frequency 2%), likely representing bystander clonal hematopoiesis. Cytogenetic analysis revealed an abnormal karyotype (46,XY,+1,der(1;15)(q10;q10), t(16;21)(q24;q22)[20]) (panel C). Result of dual-color fusion fluorescence in situ hybridization (FISH) was negative for RUNX1::RUNX1T1. Nevertheless, 23% of the cells exhibited 3 copies of RUNX1, suggesting RUNX1 rearrangement with another partner (panel D); RUNX1 rearrangement was confirmed by FISH using a break-apart probe (panel E). Optical genome mapping confirmed the presence of RUNX1::CBFA2T3 (panel F). Acute myeloid leukemia (AML) with RUNX1::CBFA2T3 is a rare AML with characteristic morphologic and immunophenotypic features that overlap with AML with RUNX1::RUNX1T1. This case highlights the morphologic and immunophenotypic similarities between these AML subtypes and raises awareness of this rare entity.

Wei J. Wang, Sanam Loghavi; Acute myeloid leukemia with RUNX1:: CBFA2T3 fusion. Blood 2025; 145 (11): 1226. doi: https://doi.org/10.1182/blood.2024027698

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Moreover, among the 37 druggable genes supported by at least two pieces of genetic evidence, we have identified 28 drugs targeting MPL, CA4, TUBB, and RRM1, although neither in clinical trials nor reported previously have the potential to be repurposed for slowing down brain aging. Specifically, four drugs, namely, avatrombopag, eltrombopag, lusutrombopag, and romiplostim, which are typically used for thrombocytopenia, act as agonists for MPL. As mentioned above, MPL is a thrombopoietin receptor and has been linked to platelet count and brain morphology in the GWAS catalog. Notably, platelet signaling and aggregation pathway is enriched using the 64 MR genes. It is worth noting that platelet count decreases during aging and is lower in men compared to women (84). A recent study of platelets has also revealed that platelets rejuvenate the aging brain (85). Schroer et al. (86) found that circulating platelet-derived factors could potentially serve as therapeutic targets to attenuate neuroinflammation and improve cognition in aging mice (86). Park et al. (87) reported that longevity factor klotho induces multiple platelet factors in plasma, enhancing cognition in the young brain and decreasing cognitive deficits in the aging brain (87). Leiter et al. (88) found that platelet-derived platelet factor 4, highly abundant chemokine in platelets, ameliorates hippocampal neurogenesis, and restores cognitive function in aged mice. These findings suggest that the aforementioned drugs may enhance the expression of MPL, leading to increased platelet count and potentially contributing to a delay in brain aging. It is important to note that determining the significant tissue(s) for gene prioritization can be challenging. Although brain tissues may be more biologically relevant for brain aging, circulating proteins have the capability to modulate brain aging as well (89, 90). Six drugs (cladribine, clofarabine, gallium nitrate, gemcitabine, hydroxyurea, and tezacitabine) are inhibitors of RRM1, whereas 12 drugs (brentuximab vedotin, cabazitaxel, crolibulin, indibulin, ixabepilone, paclitaxel, plinabulin, podofilox, trastuzumab emtansine, vinblastine, vinflunine, and vinorelbine) are inhibitors of TUBB. Most of these drugs targeting RRM1 and TUBB are antineoplastic agents used in cancer treatment. In addition, six drugs (acetazolamide, brinzolamide, chlorothiazide, methazolamide, topiramate, and trichlormethiazide) are inhibitors of CA4 and most of them are used for hypertension.

There are a few limitations to this study: (i) The accurate estimation of brain age is hindered by the lack of ground-truth brain biological age and discrepancies between brain biological age and chronological age in supposedly healthy individuals. The estimated brain age derived from MRI data includes inherent biases (91). Although our model has shown better generalization performance compared to other models, there is always an expectation for a more accurate brain age estimation model that can deliver more robust outcomes for clinical applicants (3, 91). (ii) Potential data bias may affect the findings of this comprehensive study. For instance, the brain age estimation model and GWAS summary statistics primarily relied on cohorts of European white individuals, potentially overlooking druggable targets that would be effective in individuals of non-European ancestry. Validation using genomic and clinical data from more diverse populations could help remedy this limitation. (iii) Validation on independent discovery and replication cohorts would enhance the reliability of the identified genes as drug targets for the prevention of brain aging. Although we maximized statistical power using the UKB data as a large discovery cohort, the absence of a discovery-replication design is unavoidable. As large-scale datasets containing both MRI and genome-wide genotypes were not widely available, we used a combination of GWAS for BAG, MR with xQTL, colocalization analysis, MR-PheWAS, and the existing literature to carefully identify genetic targets that are supported by evidence for their involvement in brain aging. With the availability of more comprehensive proteomics platforms and the inclusion of more diverse non-European ancestry populations in studies, it is likely to replicate and validate our results. (iv) Brain aging is a complex process involving numerous potential causes, such as aging of cerebral blood vessels (92), atrophy of the cerebral cortex (93), etc. These causes may overlap and interweave, undergoing considerable changes during brain aging (48). Although our study demonstrates the utility of systematically analyzing GWAS alongside extensive brain imaging information and xQTL analysis to enrich the identification of drug targets, there remains a need for machine learning or statistical methods to address the various risk factors associated with brain aging. Fine-grained analysis is a must to comprehend the individualized causes and trajectories of brain aging, enabling the identification of effective drug targets and the use of precision medications for the purpose of slowing down or even preventing brain aging. There is also an increasing need for comprehensive studies spanning different tissues and organs to evaluate tissue-or organ-specific effects of targets, enabling the systematic prevention or treatment of human aging. (v) This study did not explore adverse effects of the rediscovered antiaging drugs. This is particularly important because healthy aging individuals should be encouraged to consider the potential risks associated with taking medications or supplements for slowing down aging as these interventions may have unintended negative consequences for both individuals and society. Alternatively, it is worthwhile to explore nonpharmacological interventions/digital therapies that can help preserve mental and physical fitness in people during aging.

In summary, we present a systematic study for identify genetically supported targets and drugs for brain aging with deep learning-based brain age estimation, GWAS for BAG, analysis of the relation between BAG and brain disorders, prioritization of targets using MR and colorization analysis for BAG with xQTL data, drug repurposing for these targets of BAG, and PheWAS. Our results offer the potential to mitigate the risk associated with drug discovery by identifying genetically supported targets and repurposing approved drugs to attenuate brain aging. We anticipate that our findings will serve as a valuable resource for prioritizing drug development efforts for BAG, shedding light on the understanding of human brain aging and potentially extending the health span in humans.

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Researchers at Ruhr University Bochum, Germany, have studied the impact of two brain areas on the nature of memory content. The team from the Department of Neurophysiology showed in rats how the so-called locus coeruleus and the ventral tegmental area permanently alter brain activity in the hippocampus region, which is crucial for the formation of memory.

The two areas compete with each other for influence to determine, for example, in what way emotionally charged and meaningful experiences are stored. Dr. Hardy Hagena and Professor Denise Manahan-Vaughan conducted the study using optogenetics. In the process, they genetically modified rats so that certain nerve cells could be activated or deactivated with light.

They published their findings in the journal Proceedings of the National Academy of Sciences.

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Adding immunotherapy to a new type of inhibitor that targets multiple forms of the cancer-causing gene mutation KRAS kept pancreatic cancer at bay in preclinical models for significantly longer than the same targeted therapy by itself, according to researchers from the Perelman School of Medicine at the University of Pennsylvania and Penn Medicine’s Abramson Cancer Center. The results, published in Cancer Discovery, prime the combination strategy for future clinical trials.

Patients with pancreatic cancer have an overall poor prognosis: in most patients, the disease has already spread at the time of diagnosis, resulting in limited treatment options. Nearly 90 percent of pancreatic cancers are driven by KRAS mutations, the most common cancer-causing gene mutation across cancer types, which researchers long considered “undruggable.”

In 2021, the first KRAS inhibitor was approved to treat with KRAS G12C mutations, but with longer follow-up, it has become clear that KRAS-mutant cancers can quickly evolve to resist therapies targeted at one specific form of the gene mutation.

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Glial replication and proliferation support JC virus demyelination.

In HIV infected patients, JC virus (JCV) can cause a devastating demyelinating disease of the CNS known as progressive multifocal leukoencephalopathy (PML).

JCV replicates in human glial progenitor cells and astrocytes, which undergo viral T-antigen-triggered mitosis, enabling viral replication.

The authors were able to demonstrate that dividing human astrocytes supported JCV propagation to a substantially greater degree than did mitotically quiescent cells.

They also show that JCV infection greatly accentuated by cuprizone-induced demyelination and its associated mobilization of glial progenitor cells and triggered the death of both uninfected and infected glia, reflecting significant bystander death. https://sciencemission.com/JCV-infection-models

This scientific commentary refers to ‘JC virus spread is potentiated by glial replication and demyelination-linked glial proliferation’ by Li et al. (https://doi.org/10.1093/brain/awae252).

Continue reading “Bridging the gaps between JCV infection models and human disease” | >

DNA holds the key to understanding life itself… From genetics and the human genome to gene editing, it shapes our health, evolution, and future… Discover how CRISPR, forensic science, and genetic engineering are transforming medicine… Explore the mysteries of ancient DNA, the role of the microbiome, and the promise of gene therapy… Personalized medicine is revolutionizing healthcare, allowing treatments tailored to our genetic code… Learn how hereditary diseases are being decoded and cured through biotechnology and DNA sequencing… The future of medicine depends on genetic research, but genetic ethics raise profound questions… The genome project has paved the way for DNA fingerprinting, cloning, and synthetic biology… With genetic modification, we are reshaping evolution itself… Will genetic testing lead to designer babies or eliminate genetic disorders? As gene therapy advancements push the limits of precision medicine, are we ready for these medical breakthroughs and DNA discoveries?

Sources.
Watson, J. D., & Crick, F. H. C. (1953). Nature, 171(4356), 737–738.
Collins, F. S., & McKusick, V. A. (2001). Science, 291(5507), 1215–1220.
Jinek, M., Chylinski, K., Fonfara, I., Hauer, M., Doudna, J. A., & Charpentier, E. (2012). Science, 337(6096), 816–821.
Pääbo, S. (2014). Annual Review of Genetics, 38, 645–679.
Lander, E. S., Linton, L. M., Birren, B., et al. (2001). Nature, 409(6822), 860–921.

#DNABreakthroughs #GeneticsRevolution #HumanGenome #GeneTherapy #FutureOfMedicine.

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https://www.youtube.com/watch?v=bZWKW53XA0o.

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