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Biology subjects

Venkatasubramanian, S.

Publications and source records attributed to Venkatasubramanian, S..

2 recordsLinked to original sources

Odyssey: reconstructing evolution through emergent consensus in the global proteome

We present Odyssey, a family of multimodal protein language models for sequence and structure generation, protein editing and design. We scale Odyssey to more than 102 billion parameters, trained over 1.1 x 1023 FLOPs. The Odyssey architecture uses context modalities, categorized as structural cues, semantic descriptions, and orthologous group metadata, and comprises two main components: a finite scalar quantizer for tokenizing continuous atomic coordinates, and a transformer stack for multimodal representation learning. Odyssey is trained via discrete diffusion, and characterizes the generative process as a time-dependent unmasking procedure. The finite scalar quantizer and transformer stack leverage the consensus mechanism, a replacement for attention that uses an iterative propagation scheme informed by local agreements between residues. Across various benchmarks, Odyssey achieves landmark performance for protein generation and protein structure discretization. Our empirical findings are supported by theoretical analysis.

synthetic biology↗

TOLLIP promotes durable alveolar macrophage-mediated immunity during Mycobacterium tuberculosis infection by resolving cellular stress from lipids.

Relative deficiency of TOLLIP expression in monocytes is associated with increased tuberculosis (TB) susceptibility in genetic studies, despite antagonizing host innate immune pathways that control Mycobacterium tuberculosis (Mtb) infection. In this study, we investigated the mechanisms by which TOLLIP influences Mtb immunity. Tollip-/- mice developed worsened disease, consistent with prior genetic observations, and developed large numbers of foam cells. Selective TOLLIP deletion in alveolar macrophages (AM) was sufficient to induce lipid accumulation and increased Mtb persistence 28 days after infection, despite increased antimicrobial responses. We analyzed sorted, Mtb-infected Tollip-/- AM from mixed bone marrow chimeric mice to measure global gene expression 28 days post-infection. We found transcriptional profiles consistent with increased EIF2 signaling. Selective lipid administration to Tollip-/- macrophages induced lipid accumulation, and Mtb infection of lipid laden, Tollip-/- macrophages induced cellular stress and impaired Mtb control. EIF2 activation induced increased Mtb replication within macrophages, irrespective of TOLLIP expression, and EIF2 kinases were enriched in human caseous granulomas. Our findings define a critical checkpoint for TOLLIP to prevent lipid-induced EIF2 activation and demonstrate an important mechanism for EIF2 signaling to permit Mtb replication within macrophages.

immunology↗