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Objective To examine the degree to which use of β blockers, statins, and diuretics in patients with impaired glucose tolerance and other cardiovascular risk factors is associated with new onset diabetes.Design Reanalysis of data from the Nateglinide and Valsartan in Impaired Glucose Tolerance Outcomes Research (NAVIGATOR) trial. Setting NAVIGATOR trial.Participants Patients who at baseline (enrolment) were treatment naïve to β blockers (n=5640), diuretics (n=6346), statins (n=6146), and calcium channel blockers (n=6294). Use of calcium channel blocker was used as a metabolically neutral control.Main outcome measures Development of new onset diabetes diagnosed by standard plasma glucose level in all participants and confirmed with glucose tolerance testing within 12 weeks after the increased glucose value was recorded. The relation between each treatment and new onset diabetes was evaluated using marginal structural models for causal inference, to account for time dependent confounding in treatment assignment.Results During the median five years of follow-up, β blockers were started in 915 (16.2%) patients, diuretics in 1316 (20.7%), statins in 1353 (22.0%), and calcium channel blockers in 1171 (18.6%). After adjusting for baseline characteristics and time varying confounders, diuretics and statins were both associated with an increased risk of new onset diabetes (hazard ratio 1.23, 95% confidence interval 1.06 to 1.44, and 1.32, 1.14 to 1.48, respectively), whereas β blockers and calcium channel blockers were not associated with new onset diabetes (1.10, 0.92 to 1.31, and 0.95, 0.79 to 1.13, respectively).

Lesion-mimic mutants (LMMs) provide a valuable tool to reveal the molecular mechanisms determining programmed cell death (PCD) in plants. Despite intensive research, the mechanisms behind PCD and the formation of lesions in various LMMs still remain to be elucidated. Here, we identified a rice (Oryza sativa) LMM, early lesion leaf 1 (ell1), cloned the causal gene by map-based cloning, and verified this by complementation. ELL1 encodes a cytochrome P450 monooxygenase, and the ELL1 protein was located in the endoplasmic reticulum. The ell1 mutant exhibited decreased chlorophyll contents, serious chloroplast degradation, upregulated expression of chloroplast degradation-related genes, and attenuated photosynthetic protein activity, indicating that ELL1 is involved in chloroplast development. RNA sequencing analysis showed that genes related to oxygen binding were differentially expressed in ell1 and wild-type plants; histochemistry and paraffin sectioning results indicated that hydrogen peroxide (H 2 O 2) and callose accumulated in the ell1 leaves, and the cell structure around the lesions was severely damaged, which indicated that reactive oxygen species (ROS) accumulated and cell death occurred in the mutant. TUNEL staining and comet experiments revealed that severe DNA degradation and abnormal PCD occurred in the ell1 mutants, which implied that excessive ROS accumulation may induce DNA damage and ROS-mediated cell death in the mutant. Additionally, lesion initiation in the ell1 mutant was light dependent and temperature sensitive. Our findings revealed that ELL1 affects chloroplast development or function, and that loss of ELL1 function induces ROS accumulation and lesion formation in rice.

Summary ATP ‐citrate lyases ( ACL ) play critical roles in tumour cell propagation, foetal development and growth, and histone acetylation in human and animals. Here, we report a novel function of ACL in cell death‐mediated pathogen defence responses in rice. Using ethyl methanesulphonate ( EMS ) mutagenesis and map‐based cloning, we identified an Oryza sativa ACL ‐A2 mutant allele, termed spotted leaf 30‐1 ( spl30‐1 ), in which an A‐to‐T transversion converts an Asn at position 343 to a Tyr (N343Y), causing a recessive mutation that led to a lesion mimic phenotype. Compared to wild‐type plants, spl30‐1 significantly reduces ACL enzymatic activity, accumulates high reactive oxygen species and increases degradation rate of nuclear deoxyribonucleic acids. CRISPR /Cas9‐mediated insertion/deletion mutation analysis and complementation assay confirmed that the phenotype of spl30‐1 resulted from the defective function of Os ACL ‐A2 protein. We further biochemically identified that the N343Y mutation caused a significant degradation of SPL 30 N343Y in a ubiquitin‐26S proteasome system ( UPS )‐dependent manner without alteration in transcripts of Os ACL ‐A2 in spl30‐1 . Transcriptome analysis identified a number of up‐regulated genes associated with pathogen defence responses in recessive mutants of Os ACL ‐A2, implying its role in innate immunity. Suppressor mutant screen suggested that Os SL , which encodes a P450 monooxygenase protein, acted as a downstream key regulator in spl30‐1 ‐mediated pathogen defence responses. Taken together, our study discovered a novel role of Os ACL ‐A2 in negatively regulating innate immune responses in rice.