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Hurwitz, B.

Publications and source records attributed to Hurwitz, B..

3 recordsLinked to original sources

The Aggregated Gut Viral Catalogue (AVrC): A Unified Resource for Exploring the Viral Diversity of the Human Gut

Despite the growing interest in the role of the gut virome in human health and disease, identifying viral sequences from human gut metagenomes remains computationally challenging due to underrepresentation of viral genomes in reference databases. Several recent large-scale efforts have mined human gut metagenomes to establish viral sequence catalogues, using varied computational tools and quality control criteria. However, there has been no consistent comparison of these catalogues quality, diversity, and completeness, nor unification into a comprehensive resource. Here, we systematically surveyed nine previously published human gut viral catalogues, assessing their quality and the overlap of the viral sequences retrieved. While these catalogues collectively screened >40,000 human fecal metagenomes, 82% of the recovered 345,613 viral sequences were unique to one catalogue, highlighting limited redundancy. We further expanded representation by mining 7,867 infant gut metagenomes, retrieving 1,205,739 additional putative viral sequences. From these datasets, we constructed the Aggregated Gut Viral Catalogue (AVrC), a unified modular resource containing 1,018,941 dereplicated viral sequences (449,859 species-level vOTUs). Detailed annotations were generated for sequence quality, taxonomy, predicted lifestyle, and putative host. The AVrC reveals the gut viromes substantial unexplored diversity, providing a pivotal resource for viral discovery. The AVrC is accessible as a relational database and through a web interface allowing customized querying and subset retrieval, enabling streamlined utilization by the research community and future expansions as novel data becomes available. Author summaryThe human gut is home to a vast array of viruses, collectively known as the gut virome, which play a crucial role in human health and disease. Recently, several research groups aiming at providing an overview of the Human gut viral diversity, have created catalogues of viral sequences found in the human gut by analyzing a large number of fecal samples from different individuals. In this study, we compared nine of these existing catalogues and found that there was surprisingly little overlap between them, with 82% of the viral sequences being unique to a single catalogue. To further expand the available data, we analyzed nearly 8,000 additional fecal samples from infants. By combining all this ressources, we created a unified resource called the Aggregated Gut Viral Catalogue (AVrC), which contains more than a million distinct viral sequences, representing nearly 450,000 different viral species. This catalogue, which is easily accessible to the scientific community through a user-friendly web interface, provides a valuable tool for exploring the vast diversity of the human gut virome and its potential implications for human health.

microbiology↗

A tissue injury repair pathway distinct but parallel to host pathogen defense

Pathogen infection and tissue injury are universal insults that disrupt homeostasis. Innate immunity senses microbial infections and induces interferons (IFNs) to activate resistance mechanisms. Applying unbiased phylogenetic analysis, we show that interleukin-24 (IL24) is among the closest evolutionary homologs to the IFN family and shares a common ancestral origin. However, in contrast to IFNs, IL24 induction occurs specifically in barrier epithelial progenitors after injury and is independent of microbiome or adaptive immunity. Surprisingly, Il24 ablation impedes not only epidermal proliferation and re-epithelialization, but also capillary and fibroblast regeneration within the dermal wound bed. Conversely, ectopic Il24 induction in homeostatic epidermis triggers global epithelial-mesenchymal tissue repair responses. Mechanistically, sustained Il24 expression depends upon both IL24 receptor/STAT3 signaling and also hypoxia-stabilized HIF1, which converge following injury. Thus, parallel to the IFN-mediated innate immune sensing of pathogens to resolve infections, epithelial stem cells sense injury signals to orchestrate IL24-mediated tissue repair.

immunology↗

The integrated stress response remodels the microtubule organizing center to clear unfolded proteins following proteotoxic stress

When cells encounter stressful situations, they activate the integrated stress response (ISR), which limits total protein synthesis and redirects translation to proteins that help the cells to cope. The ISR has also been implicated in cancers, but redundancies in the stress-sensing kinases that trigger the ISR have posed hurdles to dissecting physiological relevance. To overcome this challenge, we targeted the regulatory node of these kinases, namely the S51 phosphorylation site of eukaryotic translation initiation factor eIF2 and genetically replaced eIF2 with eIF2-S51A in squamous cell carcinoma (SCC) stem cells. While inconsequential under normal growth conditions, the vulnerability of this ISR-null state was unveiled when SCC stem cells experienced proteotoxic stress. Seeking mechanistic insights into the protective roles of the ISR, we combined ribosome profiling and functional approaches to identify and probe the functional importance of translational differences between ISR-competent and ISR-null SCC stem cells when exposed to proteotoxic stress. In doing so, we learned that the ISR redirects translation to centrosomal proteins that orchestrate the microtubule dynamics needed to efficiently concentrate unfolded proteins at the microtubule organizing center so that they can be cleared by the perinuclear degradation machinery. Thus, rather than merely maintaining survival during stress, the ISR also functions in promoting cellular recovery once the stress has subsided. This finding exposes a vulnerability to SCC stem cells that could be exploited therapeutically.

cell biology↗