Biology subjects

Salman, A.

Publications and source records attributed to Salman, A..

4 recordsLinked to original sources

bioRxiv2026

Mendel, a foundation model of human genetic variation, prioritizes regulatory variants and improves gene expression prediction

Human genome-wide association studies have identified hundreds of thousands of variant trait associations, but interpreting their mechanistic consequences at allele resolution remains a central bottleneck. DNA foundation models pretrained on genomic sequence corpora learn features predictive of regulatory activity, yet their training objectives are dominated by the conserved background common to all individuals, rather than the sparse variant sites at which human genetic variation is concentrated. Here we introduce Mendel, a DNA foundation model trained from scratch on human whole genome sequences using a variant-centric objective that concentrates supervision on allelic events within reference aligned sequence context. On held-out individuals, Mendel attains 0.984 micro-averaged SNV allele-prediction accuracy, compared with 0.311 for Evo 2. Mendel residual difficulty is selectively enriched at cis-eQTL variants, prioritizes fine-mapped causal variants (AUROC 0.731), where Evo 2 residuals performed near chance, and when converted into a cis-expression prior for modelling, improves prediction relative to an unweighted baseline in all 50 GTEx tissues.

genetics↗

bioRxiv2026

Molecular mechanisms of PDCD4-mediated modulation of translation initiation and termination

PDCD4 is a tumor suppressor, known to affect protein translation by binding to a component of the eIF4F complex, eIF4A, and reducing its helicase activity, which is necessary for the 48S preinitiation complex formation and scanning of the 5 untranslated region of mRNA. PDCD4 has also been shown to interact with the ribosome and with translation initiation factors eIF4G, eIF4G2, eIF3, and PABP, all of which participate both in initiation and the closed-loop structure that couples initiation and termination. To investigate whether PDCD4 modulates initiation and termination through these interactions, we used a reconstituted mammalian translation system and pre-termination complexes purified from rabbit reticulocyte lysate. We found that PDCD4 suppresses early initiation events prior to eIF4F complex binding to the cap structure on mRNA. Moreover, inhibition of the helicase activity of eIF4A by PDCD4 is lost when the 40S subunit is present. Inhibition of 48S complex formation was also observed in the presence of the truncated eIF4G fragment p50 or the eIF4G2 isoform, both of which interact with eIF4A but lack the eIF4E-binding domain. PDCD4-mediated inhibition of initiation persisted regardless of the presence of PABP. During translation termination, PDCD4 did not affect eIF4A activity, indicating that its regulatory function toward eIF4A is stage-specific and restricted to initiation. Finally, we discovered that PDCD4 additively stimulates peptide release together with eIF3, eIF4G2, and PABP, but competes with eIF4F. Thus, PDCD4 employs a complex molecular mechanism targeting multiple translation factors to regulate different stages of protein synthesis.

molecular biology↗

bioRxiv2025

Single-cell and spatial transcriptomic analyses of gene therapy-associatedretinal inflammation in non-human primates

Adeno-associated viral (AAV) vectors are rapidly advancing as gene therapies for inherited and common retinal disorders, but gene therapy-associated uveitis (GTAU) limits their broader application. To investigate the primate ocular immune response, we administered subretinal AAV gene therapy to two non-human primates (NHPs): NHP1 received AAV2-CAG-hRPE65 (voretigene neparvovec) bilaterally at clinical dose; NHP2 received AAV8-GRK1-hRPGRco alongside an analogous mScarlet reporter vector in separate blebs. Longitudinal assessments over three months included multimodal imaging, electroretinography and cytokine profiling, followed by immunohistological, single-cell and spatial transcriptomic analyses of retinal punches. Both therapies were well-tolerated, with preserved retinal structure and function. Single-cell RNA-sequencing revealed that the AAV8 vector transduced 80% of cones/rods in treated areas, while AAV2 targeted 30% of retinal pigment epithelium (RPE)/rods. Transgene expression did not correlate with apoptotic markers. Persistent immune infiltration (dominated by myeloid and T cells) suggested a type 1 cell-mediated response. Adjunctive intravitreal anti-TNF (adalimumab) did not appear to mitigate this anti-viral response. Spatial analysis highlighted microglia migration to the subretinal space, consistent with upregulated cytokines (MCP-1/CCL2, IP-10/CXCL10, IL-8/CXCL8, IL-6), which implicate monocytic phagocytes in driving local inflammation. These findings elucidate the mechanism of GTAU and identify potential therapeutic targets to prevent immune-mediated complications in retinal gene therapy.

immunology↗

bioRxiv2018

Determining the Quantitative Principles of T Cell Response to Antigenic Disparity: The Case of Stem Cell Transplant Donor-Recipient Exome Wide Mismatching and HLA Bound Alloreactive Peptides

Alloreactivity compromising clinical outcomes in stem cell transplantation is observed despite HLA matching of donors and recipients. This has its origin in the variation between the exomes of the two, which provides the basis for minor histocompatibility antigens (mHA). The mHA presented on the HLA class I and II molecules and the ensuing T cell response to these antigens results in graft versus host disease. In this paper, results of a whole exome sequencing study are presented, with resulting alloreactive polymorphic peptides and their HLA class I and HLA class II (DRB1) binding affinity quantified. Large libraries of potentially alloreactive recipient peptides binding both sets of molecules were identified, with HLA-DRB1 presenting an order of magnitude greater number of peptides. These results are used to develop a quantitative framework to understand the immunobiology of transplantation. A tensor-based approach is used to derive the equations needed to determine the alloreactive donor T cell response from the mHA-HLA binding affinity and protein expression data. This approach may be used in future studies to simulate the magnitude of expected donor T cell response and risk for alloreactive complications in HLA matched or mismatched hematopoietic cell and solid organ transplantation.

immunology↗