Biology subjects

Shahoha, M.

Publications and source records attributed to Shahoha, M..

3 recordsLinked to original sources

bioRxiv2026

ConvergeCELL: An end-to-end platform from patient transcriptomics to therapeutic hypotheses

Translating transcriptomic data into therapeutic hypotheses remains fragmented and labor-intensive. Here we present ConvergeCELL, a platform combining a patient representation model trained on over 20 million cells across 4,479 patients, an interpretability framework for gene discovery, and a large language model-driven workflow that classifies candidates along an evidence hierarchy and constructs mechanism-of-action hypotheses. Validated on held-out cohorts spanning lupus, multiple myeloma, and sepsis across single-cell and bulk modalities, ConvergeCELL recovers known disease-associated genes at or above differential expression, machine-learning, and patient-level foundation model (PaSCient) baselines. The advantage is most pronounced for clinically validated, disease-specific drug targets: ConvergeCELL ranks TNFSF13B (Belimumab; lupus), TNFRSF17/BCMA (Belantamab; myeloma), and CXCR4 (Plerixafor; myeloma) within the top 0.3% of its gene rankings - significantly outcompeting alternative approaches. ConvergeCELL delivers an end-to-end translational workflow with state-of-the-art performance on both disease-associated gene recovery and patient-level disease classification. The pretrained ConvergeCELL patient representation model and bulk distillation module are publicly available on Hugging Face (huggingface.co/ConvergeBio/virtual-cell-patient) under the Apache 2.0 license.

bioinformatics↗

bioRxiv2022

Hippocampal cAMP-dependent synaptic potentiation, ERK-dependent immediate-early gene activation, and context-dependent fear conditioning in mice are linked through dependence on the guanine nucleotide exchange factor RapGEF2

The MAP kinase ERK is important for neuronal plasticity underlying associative learning, yet specific molecular pathways for ERK activation in hippocampus are still largely undetermined. RapGEF2 has emerged as a neuron-specific cAMP sensor that mediates ERK activation. We investigated whether RapGEF2 might also be required for cAMP-dependent ERK activation leading to synaptic potentiation, and how this involvement might be penetrant to hippocampus-dependent learned behavior. We demonstrate that conditional knockout of Rapgef2 in forebrain neurons, specifically in dentate gyrus and CA1 of the hippocampus, leads to an attenuation of context-dependent fear conditioning, but not of cue-dependent fear conditioning, in mice. RapGEF2 knockout is associated with a reduction in cAMP-dependent synaptic potentiation at two central hippocampal synapses-the entorhinal cortex-granule cell synapse and the CA3-CA1 synapse. Furthermore, cAMP-induced postsynaptic potentiation requires both RapGEF2 and activation of ERK. Induction of Egr-1/Zif268 (and pERK), but not of c-Fos, immediately following fear conditioning, was abolished in CA1 and detate gyrus, in the absence of RapGEF2 expression in these hippocampal regions, thus revealing a link between learning (conditioning) and molecular pathways activated during conditioned fear memory formation. Hence, we suggest that contextual fear conditioning is mediated via RapGEF2-dependent ERK activation and downstream induction of Egr-1, via an underlying mechanism of cAMP-dependent long-term potentiation at hippocampal synapses. Cyclic AMP-dependent GEFs have been genetically associated as risk factors for schizophrenia, a disorder associated with cognitive deficits. This study provides a functional link between one of these cAMP-dependent GEFs, RapGEF2, and cognitive processes involved in associative learning.

neuroscience↗

bioRxiv2021

Effect of SARS-CoV-2 proteins on vascular permeability

SARS-CoV-2 infection leads to severe disease associated with cytokine storm, vascular dysfunction, coagulation, and progressive lung damage. It affects several vital organs, seemingly through a pathological effect on endothelial cells. The SARS-CoV-2 genome encodes 29 proteins, whose contribution to the disease manifestations, and especially endothelial complications, is unknown. We cloned and expressed 26 of these proteins in human cells and characterized the endothelial response to overexpression of each, individually. Whereas most proteins induced significant changes in endothelial permeability, nsp2, nsp5_c145a (catalytic dead mutant of nsp5) and nsp7 also reduced CD31, and increased von Willebrand factor expression and IL-6, suggesting endothelial dysfunction. Using propagation-based analysis of a protein-protein interaction (PPI) network, we predicted the endothelial proteins affected by the viral proteins that potentially mediate these effects. We further applied our PPI model to identify the role of each SARS-CoV-2 protein in other tissues affected by COVID-19. Overall, this work identifies the SARS-CoV-2 proteins that might be most detrimental in terms of endothelial dysfunction, thereby shedding light on vascular aspects of COVID-19.

cell biology↗