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Employees’ protests against Trump science policies spread to NSF
Letter to key House Democrat follows declarations by scientists at NIH, EPA, and NASA
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Molecular Function of Midnolin and Its Relevance to Parkinson's Disease
Midnolin (Midn) was originally discovered as a gene expressed specifically in the mouse midbrain at the embryonic developmental stage; MIDN was localized in the nucleus/nucleolus. Although the pathophysiological roles of MIDN remained largely unknown for many years after its discovery, its molecular functions and relevance to diseases have gradually become clearer. In PC12 cells, a rat neuronal model cell line, liquidity factors that are necessary for neurite outgrowth are reported to induce...
Cell-type-directed network-correcting combination therapy for Alzheimer's disease
Alzheimer's disease (AD) is a multifactorial neurodegenerative disorder characterized by heterogeneous molecular changes across diverse cell types, posing significant challenges for treatment development. To address this, we introduced a cell-type-specific, multi-target drug discovery strategy grounded in human data and real-world evidence. This approach integrates single-cell transcriptomics, drug perturbation databases, and clinical records. Using this framework, letrozole and irinotecan were...
Spatial proteomics of Alzheimer's disease-specific human microglial states
Microglia are implicated in aging, neurodegeneration and Alzheimer's disease (AD). Low-plex protein imaging does not capture cellular states and interactions in the human brain, which differs from rodent models. Here we used multiplexed ion beam imaging to spatially map cellular states and niches in cognitively normal human brains, identifying a spectrum of proteomic microglial profiles. Defined by immune activation states that were skewed across brain regions and compartmentalized according to...
Combined single-cell profiling of chromatin-transcriptome and splicing across brain cell types, regions and disease state
Measuring splicing and chromatin accessibility simultaneously in frozen tissues remains challenging. Here we combined single-cell isoform RNA sequencing and assay for transposase accessible chromatin (ScISOr-ATAC) to interrogate the correlation between these modalities in single cells in human and rhesus macaque frozen cortical tissue samples. Applying a previous definition of four 'cell states' in which the transcriptome and chromatin accessibility are coupled or decoupled for each gene, we...
A genome-wide association study implicates the olfactory system in Drosophila melanogaster diapause-associated lifespan extension and fecundity
The effects of environmental stress on animal life are gaining importance with climate change. Diapause is a dormancy program that occurs in response to an adverse environment, followed by resumption of development and reproduction upon the return of favorable conditions. Diapause is a complex trait, so we leveraged the Drosophila Genetic Reference Panel (DGRP) lines and conducted a genome-wide association study (GWAS) to characterize the genetic basis of diapause. We assessed post-diapause and...
Variations in perfusion detectable in advance of microstructure in white matter aging
One of the most promising interventional targets for brain health is cerebral perfusion, but its link to white matter (WM) aging remains unclear. Motivated by existing literature demonstrating links between declining cortical perfusion and the development of WM hyperintensities, we posit that regional WM hypoperfusion precedes deteriorating WM integrity. Using the Human Connectome Project Aging (HCP-A) data set, we examine tract-wise associations between WM microstructural integrity (i.e....
Central memory T cells with key TCR repertoires and gene expression profiles dominate influenza CD8+ T cell pools across the human lifespan
Central memory CD8^(+) T cells (T(cm)) represent the prominent memory T cell subset in human blood, yet the persistence of T cell receptor (TCR) clonotypic and transcriptional features of epitope-specific T(cm) pools across the human lifespan remains unknown. We analyzed T(cm) CD8^(+) T cells specific for HLA-A*02:01-M1(58-66) (A2/M1(58); a prominent influenza epitope) in newborns, children, adults, and older adults directly ex vivo. Our data provide evidence that epitope-specific T(cm) CD8^(+)...
In vivo prime editing rescues alternating hemiplegia of childhood in mice
Alternating hemiplegia of childhood (AHC) is a neurodevelopmental disorder with no disease-modifying treatment. Mutations in ATP1A3, encoding an Na^(+)/K^(+) ATPase subunit, cause 70% of AHC cases. Here, we present prime editing (PE) and base editing (BE) strategies to correct ATP1A3 and Atp1a3 mutations in human cells and in two AHC mouse models. We used PE and BE to correct five prevalent ATP1A3 mutations with 43%-90% efficiency. AAV9-mediated in vivo PE corrects Atp1a3 D801N and E815K in the...
Accelerated brain ageing during the COVID-19 pandemic
The impact of SARS-CoV-2 and the COVID-19 pandemic on brain health is recognised, yet specific effects remain understudied. We investigate the pandemic's impact on brain ageing using longitudinal neuroimaging data from the UK Biobank. Brain age prediction models are trained from hundreds of multi-modal imaging features using a cohort of 15,334 healthy participants. These models are then applied to an independent cohort of 996 healthy participants with two magnetic resonance imaging scans: either...
Age mosaic of gut epithelial cells prevents aging
Improving gut health by altering the activity of intestinal stem cells is thought to have the potential to reverse aging. The aged Drosophila midgut undergoes hyperplasia and barrier dysfunction. However, it is still unclear how to limit hyperplasia to extend lifespan. Here, we show that early midgut injury prevents the abrupt onset of aging hyperplasia and extends lifespan in flies. Daily transcriptome profiling and lineage tracing analysis show that the abrupt onset of aging hyperplasia is due...
Spatial proteomics of Alzheimer's disease-specific human microglial states
Microglia are implicated in aging, neurodegeneration and Alzheimer's disease (AD). Low-plex protein imaging does not capture cellular states and interactions in the human brain, which differs from rodent models. Here we used multiplexed ion beam imaging to spatially map cellular states and niches in cognitively normal human brains, identifying a spectrum of proteomic microglial profiles. Defined by immune activation states that were skewed across brain regions and compartmentalized according to...
Neural features underlying high-accuracy classification of amnestic mild cognitive impairment using multi-sensory-evoked potentials
Early detection of amnestic mild cognitive impairment (aMCI) is crucial for timely interventions. This study combines scalp recordings of lateralized auditory, visual, and somatosensory stimuli with a flexible and interpretable support vector machine learning pipeline to differentiate individuals diagnosed with aMCI from healthy controls. Event-related potentials (ERPs) and functional connectivity (FC) matrices from each modality successfully predicted aMCI. Reduced ERP amplitude in aMCI...
People's brains aged faster during the COVID pandemic - even the uninfected
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Ageing stem cells in the knees drive arthritis damage
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Differences in patterns of functional and structural connectivity alterations of hippocampal subregions in patients on the Alzheimer's disease spectrum
The present study was conducted to construct structure connectivity (SC) and functional connectivity (FC) between different hippocampal subregions and the whole brain based on structural and function Magnetic Resonance Imaging, and to explore the changes in hippocampal subregions structural and functional connectivity in the different stages of Alzheimer's Disease (AD). 117 participants (75 female, 42 male) aged 60-88 years were recruited from the Sino-Longitudinal Study on Cognitive Decline in...
Demystifying common DNA methylation sites that promote the ability of CheekAge to associate with health and disease
We recently showed that the next-generation epigenetic aging clock CheekAge was significantly associated with 33 different health and disease signals across 25 publicly available MethylationEPIC datasets. We additionally uncovered DNA methylation sites that played a disproportionately important role in driving the ability of CheekAge to associate with each of these variables. We dubbed these "pro" CpGs because of their ability to promote a given association. Here, we identify 2639 common DNA...