Strigolactones (SLs) are a new class of carotenoid-derived phytohormones essential for developmental processes shaping plant architecture and interactions with parasitic weeds and symbiotic arbuscular mycorrhizal fungi. Despite the rapid progress in elucidating the SL biosynthetic pathway, the perception and signaling mechanisms of SL remain poorly understood. Here we show that DWARF53 (D53) acts as a repressor of SL signaling and SLs induce its degradation. We found that the rice d53 mutant, which produces an exaggerated number of tillers compared to wild type plants, is caused by a gain-of-function mutation and is insensitive to exogenous SL treatment. The D53 gene product shares predicted features with the class I Clp ATPase proteins and can form a complex with the α/β hydrolase protein DWARF14 (D14) and the F-box protein DWARF3 (D3), two previously identified signaling components potentially responsible for SL perception. We demonstrate that, in a D14- and D3-dependent manner, SLs induce D53 degradation by the proteasome and abrogate its activity in promoting axillary bud outgrowth. Our combined genetic and biochemical data reveal that D53 acts as a repressor of the SL signaling pathway, whose hormone-induced degradation represents a key molecular link between SL perception and responses.

Carriers of CYP2C19 loss-of-function alleles are at greater risk of stroke and composite vascular events than noncarriers among patients with ischemic stroke or TIA treated with clopidogrel.

AimStroke is the leading cause of disability and death in China. Ischaemic stroke accounts for about 60%–80% of all strokes. It is of considerable significance to carry out multidimensional management of ischaemic cerebrovascular diseases. This evidence-based guideline aims to provide the latest detailed and comprehensive recommendations on the diagnosis, treatment and secondary prevention of ischaemic cerebrovascular diseases.MethodsWe had performed comprehensive searches of MEDLINE (via PubMed) (before 30 June 2019), and integrated the relevant information into charts and distributed to the writing group. Writing group members discussed and determined the recommendations through teleconference. We used the level of evidence grading algorithm of Chinese Stroke Association to grade each recommendation. The draft was reviewed by the Guideline Writing Committee of Chinese Stroke Association Stroke and finalised. This guideline is fully updated every 3 years.ResultsThis evidence-based guideline is based on the treatment, care and prevention of ischaemic cerebrovascular diseases, which emphasises on pathogenesis evaluation, intravenous thrombolysis, endovascular therapy, antiplatelet therapy, prevention and treatment of complications, and risk factor management.ConclusionsThis updated guideline presents a framework for the management of ischaemic cerebrovascular diseases. Timely first-aid measures, professional care in the acute stage, and proactive secondary prevention will be helpful to patients.

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PurposeTo determine the prevalence and risk factors for diabetic retinopathy (DR) and sight-threatening diabetic retinopathy (STDR) in a multi-hospital-based DR screening programme among patients with diabetes in China, the Lifeline Express Diabetic Retinopathy Screening Program.MethodsPatients with diabetes in eight hospitals across mainland China (both southern and northern) from January 2014 to July 2016 were recruited in this programme. All participants underwent a standardised interview and examinations and received digital fundus photography. DR severity was graded from retinal fundus photographs by retina specialists in the reading centre of Joint Shantou International Eye Center, according to the grading standards of the English National Screening Programme. STDR was defined as the presence of preproliferative DR (R2), proliferative DR (R3) and/or maculopathy (M1).Results16 305 patients with diabetes were screened for DR in total. Fundus photographs were gradable for 15 078 patients (92.5%). The age–gender-standardised prevalence of any DR and STDR was 27.9% (95% CI, 27.2% to 28.6%) and 12.6% (95% CI, 12.1% to 13.1%), respectively. In the multiple logistic regression analysis, younger age (OR, 0.967), longer duration of diabetes (OR, 1.093), higher haemoglobin A1c (OR, 1.115), higher fasting plasma glucose (OR, 1.074), higher systolic blood pressure (OR, 1.014), faster heart rate (OR, 1.010), higher low-density lipoprotein (OR, 1.149), lower triglycerides (OR, 0.975), higher blood urea nitrogen (BUN) (OR, 1.012) and elevated serum creatinine level (OR, 1.003) were associated with the presence of DR. Similar risk factors, except for BUN and triglycerides, were found for STDR.ConclusionsThe prevalence of DR and STDR in diabetes was 27.9% and 12.6%, respectively in this multi-hospital-based population across China. Compared with Western population with diabetes, similar risk factors for DR and STDR were found in Chinese patients with diabetes.

Traffic forecasting is of great importance to transportation management and public safety, and very challenging due to the complicated spatial-temporal dependency and essential uncertainty brought about by the road network and traffic conditions. Latest studies mainly focus on modeling the spatial dependency by utilizing graph convolutional networks (GCNs) throughout a fixed weighted graph. However, edges, i.e., the correlations between pair-wise nodes, are much more complicated and interact with each other. In this paper, we propose the Multi-Range Attentive Bicomponent GCN (MRA-BGCN), a novel deep learning model for traffic forecasting. We first build the node-wise graph according to the road network distance and the edge-wise graph according to various edge interaction patterns. Then, we implement the interactions of both nodes and edges using bicomponent graph convolution. The multi-range attention mechanism is introduced to aggregate information in different neighborhood ranges and automatically learn the importance of different ranges. Extensive experiments on two real-world road network traffic datasets, METR-LA and PEMS-BAY, show that our MRA-BGCN achieves the state-of-the-art results.

Inhibition of organic anion-transporting polypeptide (OATP)1B function can lead to serious clinical drug-drug interactions, thus a thorough evaluation of the potential for this type of interaction must be completed during drug development. Therefore, sensitive and specific biomarkers for OATP function that could be used in conjunction with clinical studies are currently in demand. In the present study, preclinical evaluations were conducted to characterize the suitability of coproporphyrins (CPs) I and III as markers of hepatic OATP functional activity. Active uptake of CPs I and III was observed in human embryonic kidney (HEK) 293 cells singly expressing human OATP1B1 (hOATP1B1), hOATP1B3, cynomolgus monkey OATP1B1 (cOATP1B1), or cOATP1B3, as well as human and monkey hepatocytes. Cyclosporin A (100 mg/kg, oral) markedly increased the area under the curve (AUC) plasma concentrations of CPs I and III by 2.6-and 5.2-fold, while rifampicin (15 mg/kg, oral) increased the AUCs by 2.7-and 3.6-fold, respectively. As the systemic exposure increased, the excretion of both isomers in urine rose from 1.6-to 4.3-fold in monkeys. In agreement with this finding, the AUC of rosuvastatin (RSV) in cynomolgus monkeys increased when OATP1B inhibitors were coadministered. In Oatp1a/1b gene cluster knockout mice (Oatp1a/1b 2/2 ), CPs in plasma and urine were significantly increased compared with wild-type animals (7.1-to 18.4-fold; P , 0.001), which were also in agreement with the changes in plasma RSV exposure (14.6-fold increase). We conclude that CPs I and III in plasma and urine are novel endogenous biomarkers reflecting hepatic OATP function, and the measurements have the potential to be incorporated into the design of early clinical evaluation.

ObjectiveTo test the hypothesis that ticagrelor plus aspirin is safe and superior to clopidogrel plus aspirin for reducing high platelet reactivity at 90 days and stroke recurrence in patients with minor stroke or transient ischaemic attack, particularly in carriers of the CYP2C19 loss-of-function allele and patients with large artery atherosclerosis.DesignOpen label, blinded endpoint, randomised controlled phase II trial.SettingProspective studies conducted at 26 centres in China, August 2015 to March 2017.Participants675 patients with acute minor stroke or transient ischaemic attack.InterventionTicagrelor (180 mg loading dose, 90 mg twice daily thereafter) or clopidogrel (300 mg loading dose, 75 mg daily thereafter) on a background of aspirin (100 mg daily for the first 21 days) within 24 hours of symptom onset.Main outcome measuresPrimary outcome was the proportion of patients with high platelet reactivity at 90 days. High platelet reactivity was defined as P2Y12 reaction units of more than 208. Secondary outcomes included high platelet reactivity at 90 days (7 days either way) in patients carrying genetic variants that would affect clopidogrel metabolism, and any stroke (ischaemic or haemorrhagic) recurrence at 90 days (7 days either way), six months, and one year.ResultsAt 90 days, high platelet reactivity occurred in 35 (12.5%) of 280 patients in the ticagrelor/aspirin group and 86 (29.7%) of 290 patients in the clopidogrel/aspirin group (risk ratio 0.40; 95% confidence interval 0.28 to 0.56; P<0.001), and in 10.8% versus 35.4% (0.31; 0.18 to 0.49; P<0.001) of patients carrying CYP2C19 loss-of-function alleles. Stroke occurred in 21 (6.3%) of 336 patients in the ticagrelor/aspirin group and 30 (8.8%) of 339 patients in the clopidogrel/aspirin group (hazard ratio 0.70; 95% confidence interval 0.40 to 1.22; P=0.20). Patients with large artery atherosclerosis in the ticagrelor/aspirin group had a lower stroke recurrence at 90 days than those in the clopidogrel/aspirin group (6.0% v 13.1%; hazard ratio 0.45, 95% confidence interval 0.20 to 0.98; P=0.04). No difference was seen in the rates of major or minor haemorrhagic events between the ticagrelor/aspirin and clopidogrel/aspirin groups (4.8% v 3.5%; P=0.42).ConclusionPatients with minor stroke or transient ischaemic attack who are treated with ticagrelor plus aspirin have a lower proportion of high platelet reactivity than those who are treated with clopidogrel plus aspirin, particularly for those who are carriers of the CYP2C19 loss-of-function allele. The results of this study should be evaluated further in large scale, phase III trials and in different populations.Trial registrationClinicaltrials.gov NCT02506140.