Comparative Transcriptomics Uncovers Upstream Factors Regulating BnFAD3 Expression and Affecting Linolenic Acid Biosynthesis in Yellow-Seeded Rapeseed (Brassica napus L.).

α-Linolenic acid (ALA) is an important nutrient component in rapeseed oil, and rapeseed breeders want to either restrain or enhance the function of fatty acid desaturases (FADs) in the ALA biosynthesis pathway. To determine the reason for the upregulation of rapeseed BnFAD genes in two high-ALA accessions, R8Q10 and YH25005, we compared their transcriptome profiles in the seed at 24 days after pollination (DAP) with those of two low-ALA lines, A28 and SW. The expression levels of twenty-eight important genes in the seed samples at 20, 27, and 34 DAP were also investigated using an RT-qPCR. The expression levels of genes involved in flavonoid and proanthocyanidin synthesis, including BnCHS, BnCHI, BnDFR, BnFLS1, BnLDOX, BnBAN, BnTT10, and BnTT12 and genes encoding the transcription factors BnTT1, BnTT2, BnTT8, and BnTT16 were lower in R8Q10 and YH25005 than in A28 and SW. The expression levels of genes encoding master transcription factors in embryo development, such as BnLEC1, BnABI3, BnFUS3, BnL1L, BnAREB3, and BnbZIP67, were elevated significantly in the two high-ALA accessions. Combined with previous results in the Arabidopsis and rapeseed literature, we speculated that the yellow-seededness genes could elevate the activity of BnLEC1, BnABI3, BnFUS3, and BnbZIP67, etc., by reducing the expression levels of several transparent testa homologs, resulting in BnFAD3 and BnFAD7 upregulation and the acceleration of ALA synthesis. Yellow-seededness is a favorable factor to promote ALA synthesis in the two high-ALA accessions with the yellow-seeded trait. These findings provide initial insights into the transcriptomic differences between high-/low-ALA germplasms and a theoretic basis for seed quality breeding.

Understanding inter-individual variability in pharmacokinetics/pharmacodynamics of aripiprazole in children with tic disorders: Individualized administration based on physiological development and CYP2D6 genotypes.

Objective: This study aims to develop a combined population pharmacokinetic (PPK) model for aripiprazole (ARI) and its main active metabolite dehydroaripiprazole (DARI) in pediatric patients with tic disorders (TD), to investigate the inter-individual variability caused by physiological and genetic factors in pharmacokinetics of ARI and optimize the dosing regimens for pediatric patients. Methods: A prospective PPK research was performed in Chinese children with TD. Totally 84 patients aged 4.83-17.33 years were obtained for the pharmacokinetic analysis. 27 CYP2D6 and ABCB1 gene alleles were detected. Moreover, the clinical efficacy was evaluated according to reduction rate of Yale Global Tic Severity Scale (YGTSS) score at the 12th week comparing with the baseline. Monte Carlo simulations were used to evaluate and optimize dosing regimens. Results: The PPK model was established to predict the concentrations of ARI and DARI. Body weight and CYP2D6 genotype were the significant covariates affecting the clearance of ARI. The DARI/ARI metabolic ratios (MRs) of AUC24h, Cmin and Cmax at the steady state of results were ultra-rapid metabolizers (UMs) > normal metabolizers (NMs) > intermediated metabolizers (IMs). MRs could be used to distinguish UMs or IMs from other patients. The best predictor of clinical efficacy for TD was the trough concentration of ARI and the cut-off point was 101.636 ng/ml. Conclusion: The pharmacokinetics of ARI and DARI in pediatric TD were significantly influenced by body weight and CYP2D6 genotype. Individualized dosing regimens were recommended for pediatric patients with TD to ensure clinical efficacy.

Circ_USP36 Silencing Attenuates Oxidized Low-Density Lipoprotein-Induced Dysfunction in Endothelial Cells in Atherosclerosis Through Mediating miR-197-3p/ROBO1 Axis.

ABSTRACT: Circular RNAs (circRNAs) are reported to play pivotal regulatory roles in atherosclerosis progression. In the present study, we explored the biological role of circRNA ubiquitin-specific peptidase 36 (circ_USP36; hsa_circ_0003204) in oxidized low-density lipoprotein (ox-LDL)-induced dysfunction of endothelial cells (ECs). RNA and protein levels were determined by reverse transcription-quantitative polymerase chain reaction and Western blot assay, respectively. Cell proliferation was analyzed by 5-ethynyl-2'-deoxyuridine assay and 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay. Flow cytometry was conducted to analyze cell cycle progression and cell apoptosis. The release of tumor necrosis factor α in the supernatant was measured by enzyme linked immunosorbent assay. Cell death was evaluated by lactate dehydrogenase assay. Intermolecular interaction was verified by dual-luciferase reporter assay. Circ_USP36 expression was significantly up-regulated in the serum of atherosclerosis patients and ox-LDL-stimulated HUVECs than that in their corresponding controls. ox-LDL exposure inhibited the proliferation ability and cell cycle progression and triggered the apoptosis and inflammation of HUVECs, and these effects were largely overturned by the knockdown of circ_USP36. microRNA-197-3p (miR-197-3p) was a target of circ_USP36, and circ_USP36 knockdown-mediated protective role in ox-LDL-induced HUVECs was largely counteracted by the silence of miR-197-3p. miR-197-3p interacted with the 3' untranslated region of roundabout guidance receptor 1 (ROBO1). Circ_USP36 knockdown reduced ROBO1 expression partly by up-regulating miR-197-3p in HUVECs. ROBO1 overexpression reversed miR-197-3p accumulation-mediated effects in ox-LDL-induced HUVECs. In conclusion, circ_USP36 interference alleviated ox-LDL-induced dysfunction in HUVECs by targeting miR-197-3p/ROBO1 axis.

Antidiabetic compounds 8a, 8b, 8k, and 9h enhance insulin secretion: activity and mechanism.

PURPOSE: This study primarily investigated the effects of hypoglycemic compounds (Imeglimin derivatives) on insulin secretion in type 2 diabetes mellitus (T2DM), and further explored the possible mechanism underlying these effects. METHODS: Firstly, Metformin was used as the initiating compound to synthesize three sets of derivatives which contained Imeglimin structure core. At the cellular level, we screened compounds with better effect on the activity of insulin receptor tyrosine protein kinase (IFcTPK) after the islet ß cells were treated with the compounds of different concentrations. The insulin secretion was assessed using radioimmunoassay and the cytotoxicity to islet ß cells was evaluated by means of MTT assay following treatment with the compounds. The Ca2+-related mechanism by which these compounds promote insulin secretion was elucidated with whole cell recordings from current-clamp mode. RESULTS: Totally, 48 synthesized compounds were generated, wherein 10 compounds could increase the activity of IFcTPK in HIT-T15 cells better among these compounds. The modified Imeglimin, especially in the structure of hydrophilic hydroxyl or piperidine rings, could improve the activity of the compound to promote insulin secretion. Furthermore, the compounds 8a, 8b, 8k, and 9h revealed high insulin secretion-promoting activity. These compounds enhanced insulin secretion in islet ß cells by repressing the ATP-sensitive K(+) and voltage-gated K+ pathway. CONCLUSIONS: Our findings indicate that the hypoglycemic compounds 8a, 8b, 8k, and 9h confer better promotive effect on insulin secretion, which provides a reference for the development of drugs with better hypoglycemic activity.

Intensive glucose control for critically ill patients: an updated meta-analysis.

This meta-analysis aims to update the evidence for the effects of intensive glucose control (IGC) on the outcomes among critically ill patients. We performed a systematic literature review from inception through December, 2017 by two independent authors by searching PubMed, EMBASE and Cochrane Library. Randomized clinical trials of the effects of IGC compared with conventional glucose control were selected. Random-effect models were applied to calculate summary relative risks (RRs) for the related outcomes. Of 4247 records identified, we abstracted data from 27 relevant trials for meta-analysis. Compared with patients receiving conventional glucose control (controls), patients with IGC did not have significantly decreased risk of short-term mortality (in-hospital mortality or intensive care unit (ICU) mortality) (RR 0.99, 95% CI 0.92-1.06) or 3- to 6-month mortality (RR 1.02, 95% CI 0.97-1.08). These results remained constant among different study settings including surgical ICUs, medical ICUs or mixed ICUs. Similarly, we also found that patients with IGC did not have significantly lower risk of sepsis (RR 1.00, 95% CI 0.89-1.11) or new need for dialysis (RR 0.97, 95% CI 0.84-1.11). However, patients with IGC had almost 4-fold increase in risk of hypoglycemia (RR 4.86, 95% CI 3.16-7.46). In conclusion, in this updated meta-analysis of published trials, critically ill patients receiving IGC were found to be at neutral risk for short-term or 3- 6-month mortality, risk of sepsis or new need for dialysis, but at higher risk of hypoglycemia.

[Epidemiological survey of mental illnesses in the people aged 15 and older in Zhejiang Province, China].

OBJECTIVE: To describe the current prevalence and distribution of all types of mental disorders in Zhejiang Province and use this data to develop a provincial mental health plan. METHODS: Stratified multi-stage cluster randomization was used to identify 14 counties (cities), 70 townships (urban districts), 140 villages (urban neighborhoods) and 15,000 subjects > or = 15 years of age. Psychiatric nurses used an expanded version of the General Health Questionnaire (GHQ) to identify subgroups of subjects at high, moderate and low risk of having a mental disorder, then psychiatrists determined their diagnoses by administering a structured psychiatric examination (SCID) that employs American diagnostic criteria for mental disorders (DSM-IV) to 100% of high-risk, 40% of moderate-risk and 10% of low-risk subjects. RESULTS: 14 639 subjects completed the screening and 4,788 completed the psychiatric examination. The adjusted overall current rate of mental disorders was 17.3% (95% CI = 16.0%-18.7%), which dropped to 13.4% (12.2%-14.7%) if the non-specific (NOS) disorders were excluded. The most common diagnostic groups were affective disorders (8.6%, 7.9%-9.5%), anxiety disorders (4.3%, 3.6%-5.1%), and substance use disorders (3.0%, 2.4%-3.8%). The most common specific disorders were major depressive disorder (4.3%, 3.7%-4.9%), alcohol use disorder (2.9%, 2.3%-3.7%), dysthymia (1.6%, 1.3%-1.9%) and specific phobias (1.2%, 0.8%-1.8%). The overall prevalence was higher in rural than in urban areas (RR = 1.23, 95% CI = 1.11-1.37) and slightly higher in women than in men (RR = 1.11, 1.00-1.22). CONCLUSIONS: Mental disorders seriously affect the social and economic development of Zhejiang Province; they are a major public health problem that urgently needs to be addressed. To do this, it is necessary to develop and implement a comprehensive province-wide mental health plan and regularly evaluate its effectiveness.