Developing a single-domain assay to identify individuals at high risk of future events is a priority for multi-disease and mortality prevention. By training a neural network, we developed a disease/mortality-specific proteomic risk score (ProRS) based on 1461 Olink plasma proteins measured in 52,006 UK Biobank participants. This integrative score markedly stratified the risk for 45 common conditions, including infectious, hematological, endocrine, psychiatric, neurological, sensory, circulatory, respiratory, digestive, cutaneous, musculoskeletal, and genitourinary diseases, cancers, and mortality. The discriminations witnessed high accuracies achieved by ProRS for 10 endpoints (e.g., cancer, dementia, and death), with C-indexes exceeding 0.80. Notably, ProRS produced much better or equivalent predictive performance than established clinical indicators for almost all endpoints. Incorporating clinical predictors with ProRS enhanced predictive power for most endpoints, but this combination only exhibited limited improvement when compared to ProRS alone. Some proteins, e.g., GDF15, exhibited important discriminative values for various diseases. We also showed that the good discriminative performance observed could be largely translated into practical clinical utility. Taken together, proteomic profiles may serve as a replacement for complex laboratory tests or clinical measures to refine the comprehensive risk assessments of multiple diseases and mortalities simultaneously. Our models were internally validated in the UK Biobank; thus, further independent external validations are necessary to confirm our findings before application in clinical settings.

Abscisic acid (ABA) regulates plant stress responses and development. However, how the ABA signal is transmitted in response to stresses remains largely unclear, especially in monocots. In this study, we found that rice (Oryza sativa) OsPM1 (PLASMA MEMBRANE PROTEIN 1), encoded by a gene of AWPM-19 like family, mediates ABA influx through the plasma membrane. OsPM1 is predominantly expressed in vascular tissues, guard cells and mature embryos. Phenotypic analysis of overexpression, RNA interference (RNAi), and knock out (KO) lines showed that OsPM1 is involved in drought responses and seed germination regulation. 3H-(±)ABA transport activity and FRET (Fluorescence Resonance Energy Transfer) assays both demonstrated that OsPM1 facilitates ABA uptake into cells. The physiological isomer of ABA, (+)-ABA, is the preferred substrate of OsPM1. Higher ABA accumulation and faster stomatal closure in response to ABA treatment were observed in the overexpression lines compared to the wild-type control. Many ABA-responsive genes were up-regulated more in the OsPM1-overexpression lines but less in the RNAi lines compared to wild-type plants. Further investigation revealed that OsPM1 expression is regulated by the AREB/ABF family transcription factor OsbZIP46. Our results thus revealed that OsPM1 is an ABA influx carrier that plays an important role in drought responses.

Plants are immobile and often face stressful environmental conditions, prompting the evolution of genes regulating environmental responses. Such evolution is achieved largely through gene duplication and subsequent divergence. One of the most important gene families involved in regulating plant environmental responses and development is the AP2/ERF superfamily; however, the evolutionary history of these genes is unclear across angiosperms and in major angiosperm families adapted to various ecological niches. Specifically, the impact on gene copy number of whole-genome duplication events occurring around the time of the origins of several plant families is unknown. Here, we present the first angiosperm-wide comparative study of AP2/ERF genes, identifying 75 Angiosperm OrthoGroups (AOGs), each derived from an ancestral angiosperm gene copy. Among these AOGs, 21 retain duplicates with increased copy number in many angiosperm lineages, while the remaining 54 AOGs tend to maintain low copy number. Further analyses of multiple species in the Brassicaceae family indicated that family-specific duplicates experienced differential selective pressures in coding regions, with some paralogs showing signs of positive selection. Further, cis regulatory elements also exhibit extensive divergence between duplicates in Arabidopsis. Moreover, comparison of expression levels suggested that AP2/ERF genes with frequently retained duplicates are enriched for broad expression patterns, offering increased opportunities for functional diversification via changes in expression patterns, and providing a mechanism for repeated duplicate retention in some AOGs. Our results represent the most comprehensive evolutionary history of the AP2/ERF gene family, and support the hypothesis that AP2/ERF genes with broader expression patterns are more likely to be retained as duplicates than those with narrower expression profiles, which could lead to a higher chance of duplicate gene subfunctionalization. The greater tendency of some AOGs to retain duplicates, allowing expression and functional divergence, may facilitate the evolution of complex signaling networks in response to new environmental conditions.