Biology subjects

Torres, S.

Publications and source records attributed to Torres, S..

5 recordsLinked to original sources

bioRxiv2026

Protein-DNA mesh assembly drives dsDNA-specific and duplex length-dependent activation of cGAS

Cyclic G/AMP synthase (cGAS) forms condensates on dysregulated double-stranded (ds) DNA to trigger inflammatory responses. Currently, how it specifically recognizes dsDNA and why activation depends on duplex length remain poorly understood. Using cryo-electron microscopy, biochemical assays, and single-molecule methods, we show that full-length cGAS assembles a protein*dsDNA mesh by reiteratively propagating dimers-of-dimers, driving an associative phase transition. Previously uncharacterized N- and C-terminal interactions, together with inter-dimer junction-loops, track the B-form groove and bend dsDNA to build an extensive mesh network spanning multiple duplexes. These interactions are critical for cross-stabilizing active cGAS, revealing why higher-order assembly on long duplexes maximizes signaling activity. Remarkably, cGAS can build the protein*dsDNA mesh on a single contiguous duplex by entangling its oligomerization platform, resulting in a mechanically resilient and kinetically stable signaling platform. Together, our findings establish higher-order mesh assembly of cGAS as the foundation for dsDNA selectivity, duplex-length-dependent activation, and condensate formation.

biophysics↗

bioRxiv2026

Towards molecular-based functional classification of fetal bovine serum

Quality and price of fetal bovine serum (FBS) are traditionally determined by geographical origin and parameters listed in the Certificate of Analysis (CoA). Despite its central role in cell culture, selecting suitable FBS batches remains costly and labor-intensive due to substantial batch-to-batch variation. We propose a molecular assessment strategy based on transcriptomic and cytokine profiling of cells cultured in different FBS batches to evaluate performance more reliably. Analysis of differential gene expression in three cell lines - MRC-5, Jurkat, and THP-1 - enables batch grouping and reveals pathway-specific effects, with immune-related pathways showing the most pronounced variability. Although CoA parameters can stratify batches by origin, they do not consistently correlate with cytokine secretion or gene expression across cell lines. These findings demonstrate that geographical origin is an inadequate predictor of functional FBS performance and that molecular profiling provides a more robust and informative assessment.

molecular biology↗

bioRxiv2026

A Sensitized ENU Mutagenesis Screen for Thrombosis Modifiers Identifies Suppressor Variants in Non-mutagenized Parental Generations Due to Antithrombotic Selective Pressures

Thrombosis is a leading cause of morbidity and mortality. We used a mouse forward genetic ENU screen to identify genomic variants that suppress F5L/L Tfpi+/- lethal thrombosis. Surviving F5L/L Tfpi+/- mice from our Modifier of Factor 5 Leiden 16 (MF5L16) ENU line were subjected to whole-genome sequencing analysis. This revealed that instead of an ENU-induced mutation, four mutations introduced from our F5L/L breeding stock were responsible for survival, which we named sMF5L1-4 for spontaneous Modifier of Factor 5 Leiden. In our colony, F5L/L female breeders carrying all four sMF5L mutations produced more litters and offspring than breeders with three or fewer mutations (p<0.006). Genotyping of 13 additional MF5L lines demonstrated that the four sMF5L mutations were present in all lines and were consistently associated with survival. Of these four mutations, a single G to A intergenic variant on Chromosome 18 (Chr18A, sMF5L4), was most significantly associated with survival (p=0.003), with [~]15% penetrance for conferring the survival phenotype. Furthermore, platelet aggregation was significantly reduced in Chr18A mice, suggesting an additional mechanism by which Chr18A could suppress lethal thrombosis. Comparative transcriptomics analysis of livers from Chr18A mice versus wildtype littermate controls revealed a small number of differentially expressed genes both known and unknown to affect thrombosis. In summary, we have identified four variants exerting a significant selective breeding advantage along with antithrombotic effects. Superimposing our mutagenesis screen on a selective background illustrates the interplay of natural strain background variants and de novo ENU mutations in suppressing F5L/L Tfpi+/- lethal thrombosis.

genetics↗

bioRxiv2024

Condensin-mediated restriction of retrotransposable elements facilitates brain development in Drosophila melanogaster.

Neural stem and progenitor cell (NSPC) maintenance are essential for ensuring that organisms are born with proper brain volumes and head sizes. Microcephaly is a disorder in which babies are born with significantly smaller head sizes and cortical volumes. Mutations in subunits of the DNA organizing complexes, condensins have been identified in microcephaly patients. However the molecular mechanisms by which condensin insufficiency causes microcephaly remain elusive. We previously identified conserved roles for condensins in repression of retrotransposable elements (RTEs). Here, we show that condensin subunit knockdown in NSPCs of the Drosophila larval central brain increases RTE expression and mobility which causes cell death, and significantly decreases adult head sizes and brain volumes. These findings suggest that unrestricted RTE expression and activity may lead to improper brain development in condensin insufficient organisms, and lay the foundation for future exploration of causative roles for RTEs in other microcephaly models.

neuroscience↗

bioRxiv2021

Intercellular crosstalk regulating ARRB2/RARRES1 is involved in transition from fibrosis to cancer

Progressive fibrogenesis in chronic liver injury is often associated with cancer development. Beta-arrestin-2 (ARRB2) is a regulator of the profibrotic Angiotensin II type 1 receptor (AGTR1). The role of ARRB2 in liver fibrosis and in the transition from fibrosis to cancer is not fully understood and was investigated in this study. This study demonstrates that upregulation of the retinoic acid receptor responder 1 (RARRES1) in HSC mediated by ARRB2 leads to fibrosis. This process is driven by exosomal ARRB2 transfer to HSC, major fibrosis contributors, from injured hepatocytes, which highly express ARRB2. By contrast, downregulation of RARRES1 in hepatocytes induces malignant transformation and hepatocellular carcinoma (HCC) development. Consequently, Arrb2-deficient mice show higher number and size of liver tumors than wild-type mice in a hepatocellular carcinoma model with fibrosis. The identified relationship between ARRB2 and RARRES1 was observed in at least two species, including human cells and tissues in fibrosis and HCC and has a predictive value for survival in cancer patients. This study describes the discovery of a novel molecular pathway mediating the transition from fibrosis to cancer offering potential diagnostics and therapeutics.

molecular biology↗