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Repositioning of polyubiquitin alters the pathologic tau filament structure

3 days 15 hours ago
Structurally diverse tau filaments form proteinaceous aggregates in a heterogeneous group of neurodegenerative diseases called tauopathies. The factors extrinsic to the highly ordered core structure that influence tau filament stability are not well understood. Here, we found that polyubiquitinated tau filaments from Alzheimer disease and vacuolar tauopathy human brain tissue exhibit distinct seeding patterns in mice, in association with differences in tau filament ultrastructure determined by...
Ryohei Watanabe

Mapping structural aging across human tissues reveals tissue-specific trajectories and coordinated deterioration

3 days 15 hours ago
Organ structure, including the organization of cells, vasculature and extracellular matrix, underpins its function, yet how structure changes with age remains mostly unknown. Here we developed PathStAR, a framework that quantifies tissue structural aging from routine histopathology images, without being trained to predict chronological age. Applying PathStAR to 25,306 post-mortem biopsies from 40 tissues in 970 donors aged 21-70 years revealed that organ structural aging progresses via distinct,...
Anamika Yadav

Sodium-glucose cotransporter 2 inhibitors are associated with reduced circulating activin A and modulation of BMP/activin signaling in ischemic cardiomyopathy with high echocardiographic probability of pulmonary hypertension

3 days 15 hours ago
Pulmonary hypertension (PH) frequently complicates heart failure with reduced ejection fraction (HFrEF), worsening prognosis despite limited therapeutic options. Whether sodium-glucose cotransporter 2 inhibitors (SGLT2i) improve PH beyond their established hemodynamic effects remains unclear. Seventy-four patients with ischemic HFrEF after acute myocardial infarction and a high echocardiographic probability of PH were prospectively enrolled in a single-center, non-randomized study. Patients...
Rosalinda Madonna

VAVL motor thalamus activity pattern changes following levodopa-induced dyskinesia in a rat model of Parkinson's disease

3 days 15 hours ago
Levodopa is the gold-standard treatment for Parkinson's disease, but chronic use results in levodopa-induced dyskinesia (LID) in approximately 80% of patients. Previous research has identified critical network changes in the cortico-basal ganglia pathway associated with LID; however, no study has extensively recorded motor thalamus single-cell activity in a LID model. The motor thalamus is a key node in the movement pathway, receiving basal ganglia and cerebellar inputs and projecting an...
Lily M Bentall

Inflammaging and cytokine-driven cardiovascular senescence in age-related myocardial infarction: mechanisms, biomarkers, and precision immunotherapy strategies

3 days 15 hours ago
Ageing is an independent, non-modifiable risk factor for myocardial infarction (MI). It is also characterized by chronic, low-grade inflammation (inflammaging) and progressive cardiovascular senescence. These ageing-associated processes alter cytokine networks and innate and adaptive immune-cell function, promote endothelial dysfunction, and compromise post-infarction repair, thereby increasing myocardial susceptibility to ischaemia and adverse cardiac remodelling in the elderly. Lifestyle...
Sithu Aung

RNA-binding protein OTUD1 maintains skeletal homeostasis by determining mesenchymal stem cell lineage commitment

3 days 15 hours ago
Mesenchymal stem cells (MSCs) maintain bone homeostasis through osteogenic differentiation. During aging, MSCs undergo a fate shift toward adipogenesis rather than osteogenesis, but the post-transcriptional mechanisms remain unclear. Here, we identify ovarian tumor domain-containing protein 1 (OTUD1) as an RNA-binding protein that controls MSC fate by stabilizing osteogenic transcripts. OTUD1 directly binds and stabilizes BMP2 mRNA, thereby supporting osteogenic differentiation. In vivo, OTUD1...
Jia Song

A cross-species drug-discovery platform to accelerate the identification of lifespan-extending interventions

3 days 15 hours ago
We develop an integrated, high-throughput platform to evaluate pharmacological lifespan-extending interventions across five model organisms spanning unicellular to mammalian biology including yeast, nematodes, fruit flies, killifish, and mice. By combining automated imaging, miniaturized assays, and deep-learning-based death detection, we evaluate over 400 compounds across thousands of conditions. In S. cerevisiae, a miniaturized PI/flow cytometry CLS assay enables scalable screening and...
Kevin Perez