Biology subjects

YANG, X.

Publications and source records attributed to YANG, X..

4 recordsLinked to original sources

bioRxiv2026

Alpha Spatial: Language-guided prediction of single-cell spatial gene expression from histology

Routine histology preserves tissue architecture but leaves its molecular organization largely unmeasured. Recovering this information requires learning across heterogeneous gene panels and constraining a biologically ill-posed morphology-to-expression mapping. Here we present Alpha Spatial (AS), a language-conditioned framework that predicts cell-level gene expression from histology while jointly learning from different tissues and panels. Matched biological context improved prediction over omitted context, whereas incompatible context reduced accuracy. Multi-tissue learning further improved breast-tissue prediction, and AS outperformed the evaluated methods while preserving molecular-state organization. In breast cancer, AS recovered POSTN-associated stromal programmes and HER2-associated molecular and spatial differences. Exploratory patient-level analyses identified a CXCL14-associated spatial state whose abundance was associated with non-response to trastuzumab-containing treatment and larger residual invasive tumours. These findings establish a framework for reusing heterogeneous molecular observations to investigate tissue organization and treatment-associated microenvironments in archived histology.

bioinformatics↗

bioRxiv2026

Structural insights into DHODH-mediated catalysis and drug resistance

Dihydroorotate dehydrogenase (DHODH), which catalyzes the rate-limiting step in de novo pyrimidine biosynthesis, is a validated therapeutic target in cancer, autoimmune disorders and infectious diseases. DHODH is hypothesized to utilize a ping-pong catalytic mechanism. However, available crystal structures of DHODH in complex with small molecule inhibitors are irreconcilable with this model, showing simultaneous occupancy of both substrate binding sites. To elucidate the structural basis for DHODH-mediated catalysis, we resolved the structures of two DHODH holoenzymes. These structures capture novel conformational states that show mutually exclusive substrate binding. The holoenzyme structures also suggest that conformational changes in the catalytic loop of DHODH play a critical role in regulating enzyme activity. To map the functional landscape underlying DHODH inhibitor resistance, we performed deep mutational scanning drug-resistance screens with two clinically-relevant structurally distinct DHODH inhibitors, BAY2402234 and brequinar. Resistance variants cluster in the inhibitor binding site and at a previously unappreciated surface pocket on DHODH that allosterically regulates ubiquinone binding. Together, our findings provide structural evidence for the ping pong model of catalysis, define the mutational landscape governing inhibitor resistance, and reveal novel structural vulnerabilities in DHODH that can be utilized for future drug development.

biochemistry↗

bioRxiv2024

Muscle and intestine innexins with muscle Deg/Enac channels promote muscle coordination and embryo elongation

Body axis elongation represents a fundamental morphogenetic process in development, which involves cell shape changes powered by mechanical forces. How mechanically interconnected tissues coordinate in organismal development remains largely unexplored. During C. elegans elongation, cyclic forces generated by muscle contractions induce remodeling of adherens junctions and the actin cytoskeleton in the epidermis, facilitating gradual embryo lengthening. While previous studies have identified key players in epidermal cells, understanding how muscle cells coordinate their activity for proper embryo elongation remains unsolved. Using a Calcium sensor to monitor muscle activity during elongation, we identified two cells in each muscle quadrant with a leader cell function that orchestrate muscle activity within their respective quadrants. Strikingly, ablation of these cells halted muscle contractions and delayed elongation. A targeted RNAi screen focusing on communication channels identified two innexins and two Deg channels regulating muscle activity, which proved required for normal embryonic elongation. Interestingly, one innexin exhibits specific expression in intestinal cells. Our findings provide novel insights into how embryonic body wall muscles coordinate their activity and how interconnected tissues ensure proper morphogenesis.

developmental biology↗

bioRxiv2022

Testing the Growth Rate and Temperature Compensation Hypotheses in Marine Bacterioplankton

Two different hypotheses have been raised as to how temperature affects resource allocation in microorganisms. The translation-compensation hypothesis (TCH) predicts that the increase in enzymatic efficiency with temperature results in fewer required ribosomes per cell and lower RNA:protein ratio. In contrast, the growth rate hypothesis (GRH) predicts that increasing growth rate with temperature requires more ribosomes and hence a higher cellular RNA:protein. We tested these two hypotheses in lab cultures of Prochlorococcus and Alteromonas as well as over an annual cycle in the Eastern Mediterranean Sea. The RNA:protein of Alteromonas mostly decreased with temperature in accordance with the TCH, while that of Prochlorococcus increased with temperature, as predicted by the GRH. No support was found for either hypotheses in surface waters from the Eastern Mediterranean, whereas the fraction of phosphorus in RNA was positively correlated with per-cell bacterial production in the deep chlorophyll maximum, supporting the GRH in this niche. A considerable part of the cellular phosphorus was not allocated to RNA, DNA, phospholipids or polyphosphate, raising the question which cellular molecules contain these P reserves. While macromolecular quotas differed significantly between laboratory cultures and field samples, these were connected through a power law, suggesting common rules of resource allocation. Originality-Significance statementWe investigated whether the translation-compensation hypothesis (TCH) or growth rate hypothesis (GRH) affect the macromolecular composition and phosphorus allocation in both lab cultures of Prochlorococcus and Alteromonas as well as in seawater with natural microbial communities. Our results highlight that the TCH and GRH may each be applicable to different organisms (autotroph or heterotroph), physiological states or environmental conditions. Testing the applicability of theoretical models such as the TCH and GRH in lab cultures and field samples is an important step toward mechanistic models of bacterial physiology. This is especially important to our understanding of how bacterioplankton allocate resources in response to changes in environmental conditions such as temperature and nutrient stress, which are likely to expand due to the predicted global changes.

microbiology↗