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Biology subjects

Kahn, S.

Publications and source records attributed to Kahn, S..

4 recordsLinked to original sources

Individual-specific recovery of the healthy human gut microbiota after antibiotics

Following disruption by broad-spectrum antibiotics, the human gut microbiome undergoes a prolonged recovery where coarse ecological features, such as species richness and diversity, are largely restored. However, as these features are shared by most healthy individuals, it remains unclear whether, even after strong perturbation, individuals preferentially return toward their own pre-treatment composition ('individual-specific recovery') or instead switch to alternative equally healthy states. Resolving this question is fundamental for evaluating the long-term impacts of antibiotics, because an individual's health is affected by their unique microbiome composition, affecting immune regulation and metabolic processing, so a state switch, even to a broadly healthy configuration, could carry unintended consequences. Here we compare each subject's post-antibiotic endpoint with their own baseline and with the baselines of every other subject, across four cohorts (n = 121) whose regimens ranged from a five-day fluoroquinolone course to a four-day three-drug combination given to deplete the gut community. The recovered community was significantly closer to the subject's own baseline than to the alternative healthy baselines in more than 90% of individuals under the mildest regimen and in two thirds of those under regimens that broadly target the gut anaerobes, remaining above chance in every cohort and the majority outcome even where most baseline taxa fell below detection during treatment. This specificity is not merely the persistence and fast regrowth of survivors: it persists among baseline taxa that remain undetected for weeks to months, and the same taxon re-establishes more readily in a host where it was previously detected than in one where it was not. Newly established taxa are consistently more functionally similar to the pre-treatment community than transient arrivals, and their identity correlates with the surviving community's composition in a substantial fraction of subjects. State switching, in contrast, was uncommon and occurred almost exclusively among subjects with the largest reduction in detected taxa during the treatment. Together, these observations reveal the individual-specific nature of the microbiome resilience to broad-spectrum antibiotics, whereas the compositional changes are not random but rather functionally and ecologically associated with the subject's baseline.

ecology↗

Evaluating a Standard Benchmark for Gene Prioritization: The InheriNext(R) Algorithm's Integration of Genomic and Phenotypic Information

This study presents a comprehensive benchmark analysis of InheriNext(R), a domain-specific, AI-powered tool designed for phenotype-driven pathogenic variant prioritization. For this study, 7,244 whole exome test cases were generated using phenotype and genotype data from Phenopackets, along with pools of variants from healthy individuals to serve as genomic backgrounds. Performance was evaluated across diverse testing scenarios and compared against four established tools. The results show InheriNext(R) achieving a 98.6% sensitivity in identifying pathogenic variants and consistent performance across diverse tests for variant types, phenotype counts, and disease groups--supporting the robustness and adaptability of its methodology. Sharing these benchmarking results and samples is intended to drive progress by assisting clinicians and researchers in evaluating interpretation tools and identifying areas for improvement.

genomics↗

Enhanced lentiviral gene delivery to mammalian cells via paired cell surface and viral envelope engineering

Lentiviral vectors that facilitate gene delivery to desired cell types have been widely used in routine laboratory research and therapeutic cell engineering. However, the lack of proper entry receptors on many cell types often results in poor gene delivery. Here, we present a simple paired virus-cell engineering approach that promotes lentiviral gene delivery into mammalian cells. Lentiviruses are dual-pseudotyped with VSV-G and a chimeric envelope protein specifically recognizing a small molecule fluorescein (FITC-Env), and target cells are transiently labelled with FITC to create surrogate receptors for lentivirus attachment. The synthetic interaction between FITC-labeled cells and FITC-binding LVs enables efficient LV docking, viral entry and stable transgene expression in a range of mammalian cell lines and primary T cells. We showed that this approach enabled efficient delivery of a CD19-targeted chimeric antigen receptor (CAR) into naive human T cells that are naturally refractory to conventional VSV-G LVs, which upon activation rapidly eradicated CD19+ leukemic cells. This paired cell surface and virus envelope engineering approach may serve as a universal method for engineering synthetic virus-cell interactions to improve lentiviral gene delivery to mammalian cells.

bioengineering↗

Identifying the core genome of the nucleus-forming bacteriophage family and characterization of Erwinia phage RAY

We recently discovered that some bacteriophages establish a nucleus-like replication compartment (phage nucleus), but the core genes that define nucleus-based phage replication and their phylogenetic distribution were unknown. By studying phages that encode the major phage nucleus protein chimallin, including previously sequenced yet uncharacterized phages, we discovered that chimallin-encoding phages share a set of 72 highly conserved genes encoded within seven distinct gene blocks. Of these, 21 core genes are unique to this group, and all but one of these unique genes encode proteins of unknown function. We propose that phages with this core genome comprise a novel viral family we term Chimalliviridae. Fluorescence microscopy and cryo-electron tomography studies of Erwinia phage vB_EamM_RAY confirm that many of the key steps of nucleus-based replication encoded in the core genome are conserved among diverse chimalliviruses, and reveal that non-core components can confer intriguing variations on this replication mechanism. For instance, unlike previously studied nucleus-forming phages, RAY doesnt degrade the host genome, and its PhuZ homolog appears to form a five-stranded filament with a lumen. This work expands our understanding of phage nucleus and PhuZ spindle diversity and function, providing a roadmap for identifying key mechanisms underlying nucleus-based phage replication.

microbiology↗