Cholesterol is a key component of eukaryotic cell membranes, promoting membrane stability and modulating the function of many membrane proteins, including ion channels. In our previous work using purified human voltage-gated proton channel proteins, we showed that cholesterol inhibits the hHv1 channel by altering the conformational dynamics of its S4 segment, the key element that senses membrane voltage to control proton permeation. In the present work, we examined the effects of cholesterol analogs and potential sites in the hHv1 channel mediating cholesterol inhibition using site-directed mutagenesis and docking simulations. Our results showed that desmosterol, the immediate precursor of cholesterol, markedly attenuates cholesterol inhibition. Using single-molecule Fluorescence Resonance Energy Transfer (smFRET), we showed that desmosterol attenuates cholesterol inhibition by promoting the intermediate and open state conformations of the S4 segment. Moreover, we identified multiple residues in the hHv1 channel that are critical for cholesterol inhibition, including Y141A in the S2 segment, which reduces cholesterol inhibition by nearly 3-fold. Our smFRET results showed that the Y141A mutation promotes the intermediate conformation in the S4 segment, which underlies the attenuation of cholesterol inhibition. Consistently, docking simulations also revealed multiple residues spanning the transmembrane domain, rather than clustered within a single localized pocket. Our work identified the key molecular determinant in the hHv1 channel that mediates cholesterol inhibition and also provided a mechanism linking the conversion between demosterol and cholesterol by DHCR24 to pH homeostasis in many cells, such as phagocytes, cardiomyocytes, neurons and microglial cells.
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