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Biology subjects

Peluso, M.

Publications and source records attributed to Peluso, M..

4 recordsLinked to original sources

Susagi: A Microbiome World Model

MotivationAccurately modelling how microbial communities assemble and change across hosts and environments is essential for analysis and intervention. Typical pipelines capture limited generalisable structure and often depend on fixed ecological unit definitions. ResultsWe present Susagi (Set Unsupervised Assessment of Genetic Imposters), a permutation-invariant denoising transformer that operates directly on sets of bacterial SSU rRNA gene embeddings to learn a member-level stability function. The model was trained on [~] 2 x 106 bacterial community samples. We show that it reliably predicts community composition dynamics in a zero-shot (no training) setting, demonstrated here across three challenging microbiomes for which traditional ML methods do not exceed random expectation. The models stability scores capture biological structure: across datasets, higher scores are enriched for agricultural, cropland, and soil-associated habitats, consistent with microbial communities in these environments supporting positive diversity-stability relationships. The highest stability scores are only attained by communities with high Pielou evenness and large size, despite the fact that the model has never seen abundances suggesting it can recognise community dysbiosis from presence absence alone. Furthermore, they also track biological gradients such as subject age. Susagi is competitive with another Large Microbiome Model (Microbial General Model, MGM) on diverse classification tasks, without task-specific fine-tuning and with an increased parameter efficiency. Ultimately, our model will facilitate hypothesis generation for complex microbial processes, including deterministic assembly and microbial interactions, crucial for instance in the design of communities in silico. Availability and implementationEvaluation code and model weights can be found from https://github.com/the-puzzler/Microbiome-Modelling. Model weights can also be downloaded directly from https://huggingface.co/basilboy/microbiome-model. Interactive demo can be found here: https://huggingface.co/spaces/basilboy/microbiome-space.

systems biology↗

Mining the CRBN Target Space Redefines Rules for Molecular Glue-induced Neosubstrate Recognition

The CRL4CRBN ubiquitin ligase is leveraged by molecular glue degraders, small molecules that reprogram ligase specificity to induce degradation of clinically relevant neosubstrate proteins. Known CRBN neosubstrates share a generalizable {beta}-hairpin G-loop recognition motif, yet systematic exploration of the CRBN target landscape is still pending. Through computational mining of the human proteome using structure-based approaches, we predict over 1,400 CRBN-compatible {beta}-hairpin G-loop proteins across diverse target classes, identify novel mechanisms of neosubstrate recognition through structurally differentiated helical motifs and molecular surface mimicry, and validate 22 representative neosubstrates with clinical implications. This work broadens the CRBN target space, redefines rules for neosubstrate recognition and establishes a platform for the elimination of challenging drug targets by repurposing CRL4CRBN through next-generation molecular glue degraders.

biochemistry↗

The effect of circulating neutralizing antibodies on the replication of SARS-CoV-2 variants following post-vaccination infections.

The impact of pre-existing neutralizing antibodies (NAbs) titers on SARS-CoV-2 viral shedding dynamics in post-vaccination infection (PVI) are not well understood. We characterized viral shedding longitudinally in nasal specimens in relation to baseline (pre/peri-infection) serum neutralizing antibody titers in 125 participants infected with distinct SARS-CoV-2 variants. Among 68 participants who had received vaccinations, we quantified the effect of baseline serum NAb titers on maximum viral RNA titers and on the duration of infectivity. Baseline NAb titers were higher and efficiently targeted a broader range of variants in participants who received one or two monovalent ancestral booster vaccinations compared to those with a full primary vaccine series. In participants with Delta variant infections, baseline NAb titers targeting Delta were negatively correlated with maximum viral RNA copies. Per log10 increase in baseline NAb IC50, maximum viral load was reduced -2.43 (95% confidence interval [CI] -3.76, -1.11) log10 N copies and days of infectious viral shedding were reduced -2.79 [95% CI: -4.99, -0.60] days. By contrast, in those with Omicron infections (BA.1, BA.2, BA.4 or BA.5 lineages) baseline NAb responses against Omicron lineages did not predict viral outcomes. Our results provide robust estimates of the effect of baseline NAbs on the magnitude and duration of nasal viral replication after PVI (albeit with an unclear effect on transmission) and show how immune escape variants efficiently evade these modulating effects.

immunology↗

Markers of Fungal Translocation Are Elevated During Post-Acute Sequelae of SARS-CoV-2 Infection and Induce NF-κB Triggered Inflammation.

Long COVID, a type of Post-Acute Sequelae of SARS CoV-2 infection (PASC), has been associated with sustained elevated levels of immune activation and inflammation. However, the pathophysiological mechanisms that drive this inflammation remain unknown. Inflammation during acute Coronavirus Disease 2019 (COVID-19) could be exacerbated by microbial translocation (from the gut and/or lung) to the blood. Whether microbial translocation contributes to inflammation during PASC is unknown. We found higher levels of fungal translocation - measured as {beta}-glucan, a fungal cell wall polysaccharide - in the plasma of individuals experiencing PASC compared to those without PASC or SARS-CoV-2 negative controls. The higher {beta}-glucan correlated with higher levels of markers of inflammation and elevated levels of host metabolites involved in activating N-Methyl-D-aspartate receptors (such as metabolites within the tryptophan catabolism pathway) with established neuro-toxic properties. Mechanistically, {beta}-glucan can directly induce inflammation by binding to myeloid cells (via the Dectin-1 receptor) and activating Syk/NF-{kappa}B signaling. Using an in vitro Dectin-1/NF-{kappa}B reporter model, we found that plasma from individuals experiencing PASC induced higher NF-{kappa}B signaling compared to plasma from SARS-CoV-2 negative controls. This higher NF-{kappa}B signaling was abrogated by the Syk inhibitor Piceatannol. These data suggest a potential targetable mechanism linking fungal translocation and inflammation during PASC.

microbiology↗