Biology subjects

Epstein, A.

Publications and source records attributed to Epstein, A..

4 recordsLinked to original sources

bioRxiv2025

Spatiotemporal profiling reveals the impact of caloric restriction on mammalian brain aging

Aging induces functional declines in the mammalian brain, increasing its vulnerability to cognitive impairments and neurodegenerative disorders. Among various interventions to slow the aging process, caloric restriction (CR) has consistently demonstrated the ability to extend lifespan and enhance brain function across different species. Yet the precise molecular and cellular mechanisms by which CR benefits the aging brain remain elusive, especially at region-specific and cell type-specific resolution. In this study, we performed spatiotemporal profiling of mouse brains to elucidate the detailed mechanisms driving the anti-aging effects of CR. Utilizing highly scalable single-nucleus genomics and spatial transcriptomics platforms, EasySci and IRISeq, we profiled over 500,000 cells from 36 mouse brains across three age groups and conducted spatial transcriptomic analysis on twelve brain sections from aged mice under CR and control conditions. This comprehensive approach allowed us to explore the impact of CR on over 300 cellular states and assess region-specific molecular alterations. Our findings reveal that CR effectively modulates key aging-associated changes, notably by delaying the expansion of inflammatory cell populations and preserving cells critical to the neurovascular system and myelination pathways. Moreover, CR significantly reduced the expression of aging-associated genes involved in oxidative stress, unfolded protein stress, and DNA damage stress across various cell types and regions. A notable reduction in senescence-associated genes and restoration of circadian rhythm genes were observed, particularly in ventricles and white matter. Furthermore, CR exhibited region-specific restoration in genes linked to cognitive function and myelin maintenance, underscoring its targeted effects on brain aging. In summary, the integration of single-nucleus and spatial genomics provides a novel framework for understanding the complex effects of anti-aging interventions at the cellular and molecular levels, offering potential therapeutic targets for aging and neurodegenerative diseases.

genomics↗

bioRxiv2025

The origin, invasion history and resistance architecture of Anopheles stephensi in Africa.

The invasion of Africa by the Asian urban malaria vector, Anopheles stephensi, endangers 126 million people across a rapidly urbanising continent where malaria is primarily a rural disease. Control of An. stephensi requires greater understanding of its origin, invasion dynamics, and mechanisms of widespread resistance to vector control insecticides. We present a genomic surveillance study of 551 An. stephensi sampled across the invasive and native ranges in Africa and Asia. Our findings support a hypothesis that an initial invasion from Asia to Djibouti seeded separate incursions to Sudan, Ethiopia, and Yemen before spreading inland, aided by favourable temperature, vegetation cover, and human transit conditions. Insecticide resistance in invasive An. stephensi is conferred by detoxification genes introduced from Asia. These findings, and a companion genomic data catalogue, will form the foundation of an evidence base for surveillance and management strategies for An. stephensi.

genomics↗

bioRxiv2023

Clustering Protein Binding Pockets and Identifying Potential Drug Interactions: A Novel Ligand-based Featurization Method

Protein-ligand interactions are essential to drug discovery and drug development efforts. Desirable on-target or multi-target interactions are a first step in finding an effective therapeutic; undesirable off-target interactions are a first step in assessing safety. In this work, we introduce a novel ligand-based featurization and mapping of human protein pockets to identify closely related protein targets, and to project novel drugs into a hybrid protein-ligand feature space to identify their likely protein interactions. Using structure-based template matches from PDB, protein pockets are featurized by the ligands which bind to their best co-complex template matches. The simplicity and interpretability of this approach provides a granular characterization of the human proteome at the protein pocket level instead of the traditional protein-level characterization by family, function, or pathway. We demonstrate the power of this featurization method by clustering a subset of the human proteome and evaluating the predicted cluster associations of over 7,000 compounds.

synthetic biology↗

bioRxiv2022

A global view of aging and Alzheimer's pathogenesis-associated cell population dynamics and molecular signatures in the human and mouse brains

Conventional single-cell genomics approaches are limited by throughput and thus may have failed to capture aspects of the molecular signatures and dynamics of rare cell types associated with aging and diseases. Here, we developed EasySci, an extensively improved single-cell combinatorial indexing strategy, for investigating the age-dependent dynamics of transcription and chromatin accessibility across diverse brain cell types. We profiled [~]1.5 million single-cell transcriptomes and [~]400,000 single-cell chromatin accessibility profiles across mouse brains spanning different ages, genotypes, and both sexes. With a novel computational framework designed for characterizing cellular subtypes based on the expression of both genes and exons, we identified > 300 cell subtypes and deciphered their underlying molecular programs and spatial locations especially for rare cell types (e.g., pinealocytes, tanycytes). Leveraging these data, we generated a global readout of age-dependent changes at cell subtype resolution, providing insights into cell types that expand (e.g., rare astrocytes and vascular leptomeningeal cells in the olfactory bulb, reactive microglia, and oligodendrocytes) or are depleted (e.g., neuronal progenitors, neuroblasts, committed oligodendrocyte precursors) as age progresses. Furthermore, we explored cell-type-specific responses to genetic perturbations associated with Alzheimers disease (AD) and identified rare cell types depleted (e.g., mt-Cytb+, mt-Rnr2+ choroid plexus epithelial cells) or enriched (e.g., Col25a1+, Ndrg1+ interbrain and midbrain neurons) in both AD models. Key findings are consistent between males and females, validated across the transcriptome, chromatin accessibility, and spatial analyses. Finally, we profiled a total of 118,240 single-nuclei transcriptomes from twenty-four post-mortem human brain samples derived from control and AD patients, revealing highly cell-type-specific and region-specific gene expression changes associated with AD pathogenesis. Critical AD-associated gene signatures were validated in both human and mice. In summary, these data comprise a rich resource for exploring cell-type-specific dynamics and the underlying molecular mechanisms in normal and pathological mammalian aging.

genomics↗