Abstract Pharmacogene missense variants can disrupt protein stability, catalytic competence, or substrate handling through distinct mechanisms. General-purpose predictors estimate clinical pathogenicity as a single scalar, whereas pharmacogene interpretation requires knowing which biochemical dimension a variant perturbs, since that determines whether reduced function is substrate-dependent. Five deep mutational scanning datasets comprising 26,198 missense variants across CYP2C9, CYP2C19, and NUDT15 were assembled from MaveDB. Paired assays showed that this dimensionality dominates the data: 28% of CYP2C9 variants (1,236 of 4,421) decoupled catalytic activity from abundance, and 48% of NUDT15 variants (1,364 of 2,844) decoupled thiopurine sensitivity from stability, with CYP2C9 discordance concentrating at substrate-channel residues. AlphaMissense, a representative general-purpose pathogenicity predictor, scored these classes in line with its clinical training objective rather than the assayed biochemistry, assigning likely-benign scores to 38 of 195 stable-but-dead CYP2C9 variants and likely-pathogenic scores to 140 of 222 destabilized but thiopurine-resistant NUDT15 variants. To test whether this dimensionality is recoverable, a supervised ESM-2 sequence baseline was benchmarked against the ESM1v zero-shot ensemble and AlphaMissense under position-based 5-fold cross-validation, together with three architectural extensions: AlphaFold structural features, multi-task learning across paired assays, and contact-graph neural networks. The baseline reached Pearson r of 0.54–0.72, matching or marginally exceeding both comparators, and no extension improved upon it. Trained directly on each assay, it nonetheless recovered the paired-assay difference at r = 0.28 for CYP2C9 and 0.43 for NUDT15, separating discordant variants at AUROC 0.60 and 0.51. Pharmacogene interpretation therefore requires assay-specific, substrate-aware functional measurements rather than a single generic score.
This study constructed a pH-responsive P-TN/SF@Fe-Cur composite coating that demonstrated significant anti-infective, anti-inflammatory, antioxidant, pro-angiogenic, and pro-osteogenic effects in rat subcutaneous infection and femoral defect models.
The results show that alternative transcript diversity extensively enters translation-supported proteoform space and establish a systematic link between transcript variation and protein functional diversification.
Felicia T. Jiang, Dengwang Chen, Ziwei Wang et al.· bioRxiv· 1 citation
Protein therapeutic design and property prediction are frequently hampered by data scarcity. Here we propose a model, DyAb, that addresses these issues by leveraging a pair-wise representation to predict differences in binding affinity, rather than absolute values. DyAb is built on top of a pre-trained protein language model and achieves a Spearman rank correlation of up to 0.85 on binding affinity prediction across monoclonal antibodies targeting three different antigens (EGFR, IL-6, and an internal target), given as few as 100 training data. We employ DyAb in two design contexts: as a ranking model to score combinations of known mutations, and combined with a genetic algorithm to generate new sequences. Our method consistently generates antibody variants with high binding rates, including designs that improve on the binding affinity of the lead molecule by more than ten-fold. DyAb represents a powerful tool for optimizing antibody binding affinity in low data regimes common in early-stage drug development.
Joshua Yao-Yu Lin, Jennifer L. Hofmann, Andrew Leaver‐Fay et al.· mAbs· 1 citation
Due to its importance and wide adoption, wheat cultivation is promptly required to shift towards sustainable practices, reducing the dependency on chemical components. Among bio-based solutions aimed at securing the sustainability of wheat cultivation, biostimulants offer a versatile platform of eco-friendly tools assuring sustainability and profitability. Microalgae present a concrete example of a biostimulant source due to their richness in metabolites and high value products. Therefore, this study evaluated the biostimulant potential of eleven eco-extracts prepared from soil-isolated microalgae strains. Eco-extracts applied via soil drench at low dose (0.1 g/L) were investigated for their biostimulant effects on wheat growth, physiology, yield, and quality under controlled conditions. Results demonstrated significant ameliorations in treated plants as compared to the control, with no phytoinhibitory effects. Remarkable enhancements were notable in growth parameters such as shoot and root lengths (+40-70%), physiological traits such as total chlorophyll and stomatal conductance (+7-52%), yield components in the example of grain number per spike and thousand grain weight (+17-103%), and grain quality namely protein and polyphenol content (+2-fold to 4-fold). Similarly, phosphorus accumulation and uptake were significantly improved, while soil physicochemical status was ameliorated, indicating enhanced fertility. Multivariate analysis and composite index ranking marked Chlorella sp. GA18, Chlorella sp. GA65, Scenedesmus sp. GA69, and Chlorococcum sp. GA63 as eco-extracts with consistent performances across all plant traits. These findings highlighted the promising potential of integrating microalgae-based eco-friendly extracts in sustainable wheat cultivation.
Amer Chabili, Z. Hakkoum, F. Minaoui et al.· Plant Science· 1 citation
ProteinReasoner is developed, a multimodal generative protein foundation model that sequentially connects amino acid sequence, evolutionary constraints and three-dimensional structure within a shared autoregressive architecture and suggests a general route towards reasoning across interdependent representations in other scientific domains.
Chaozhong Liu, Linlin Chao, Shaomin Ji et al.· bioRxiv· 1 citation
HydroGym is introduced, a solver-independent reinforcement learning platform providing more than 60 validated, openly available flow control environments spanning from canonical laminar flows to complex turbulent flows, with systematic progression in the Reynolds number up to Re = 4 × 105, and Mach number variations in two and three dimensions.
Christian Lagemann, Sajeda Mokbel, Miro Gondrum et al.· Nature· 1 citation