Mitochondrial Impairment in Cerebrovascular Endothelial Cells is Involved in the Correlation between Body Temperature and Stroke Severity

Stroke is the second leading cause of death worldwide. The prognostic influence of body temperature on acute stroke in patients has been recently reported; however, hypothermia has confounded experimental results in animal stroke models. This work aimed to investigate how body temperature could prognose stroke severity as well as reveal a possible mitochondrial mechanism in the association of body temperature and stroke severity. Lipopolysaccharide (LPS) compromises mitochondrial oxidative phosphorylation in cerebrovascular endothelial cells (CVECs) and worsens murine experimental stroke. In this study, we report that LPS (0.1 mg/kg) exacerbates stroke infarction and neurological deficits, in the mean time LPS causes temporary hypothermia in the hyperacute stage during 6 hours post-stroke. Lower body temperature is associated with worse infarction and higher neurological deficit score in the LPS-stroke study. However, warming of the LPS-stroke mice compromises animal survival. Furthermore, a high dose of LPS (2 mg/kg) worsens neurological deficits, but causes persistent severe hypothermia that conceals the LPS exacerbation of stroke infarction. Mitochondrial respiratory chain complex I inhibitor, rotenone, replicates the data profile of the LPS-stroke study. Moreover, we have confirmed that rotenone compromises mitochondrial oxidative phosphorylation in CVECs. Lastly, the pooled data analyses of a large sample size (n=353) demonstrate that stroke mice have lower body temperature compared to sham mice within 6 hours post-surgery; the body temperature is significantly correlated with stroke outcomes; linear regression shows that lower body temperature is significantly associated with higher neurological scores and larger infarct volume. We conclude that post-stroke body temperature predicts stroke severity and mitochondrial impairment in CVECs plays a pivotal role in this hypothermic response. These novel findings suggest that body temperature is prognostic for stroke severity in experimental stroke animal models and may have translational significance for clinical stroke patients - targeting endothelial mitochondria may be a clinically useful approach for stroke therapy

Three photosynthetic patterns characterized by cluster analysis of gas exchange data in two rice populations

AbstractPlant photosynthetic rate is affected by stomatal status and internal CO2 carboxylation. Understanding which process determines photosynthetic rate is essential for developing strategies for breeding crops with high photosynthetic efficiency. In this study, we identified different physiological patterns of photosynthetic rate in two different rice populations. Photosynthetic gas exchange parameters were measured during the flowering stage in two rice populations. Clustering and correlation analyses were performed on the resulting data. Five or six groups were defined by K-means clustering according to differences in net photosynthetic rates (Pn). According to differences in stomatal conductance (gs) and carboxylation efficiency (CE), each group was clustered into three subgroups characterized by physiological patterns stomatal pattern, carboxylation pattern, and intermediate pattern. Pn was significantly correlated with gs (r=0.810) and CE (r=0.531). Pn was also significantly correlated with gs and CE in the three physiological patterns. The correlation coefficients were highest in the stomatal pattern (0.905 and 0.957) and lowest in the carboxylation pattern (0.825 and 0.859). Higher correlation coefficients between Pn and gs or CE in the three physiological patterns indicate that clustering is very important for understanding factors limiting rice photosynthesis

Association between platelet distribution width and serum uric acid in Chinese population

© 2019 International Union of Biochemistry and Molecular Biology Platelet distribution width (PDW) is a simple and inexpensive parameter, which could predict activation of coagulation efficiently. And it has been confirmed to have a significant role in many diseases. We aimed to explore the association between PDW and hyperuricemia in a large Chinese cohort. This cross-sectional study recruited 61,091 ostensible healthy participants (29,259 males and 31,832 females) after implementing exclusion criteria. Clinical data of the enrolled population included anthropometric measurements and serum parameters. Database was sorted by gender, and the association between PDW and hyperuricemia was analyzed after dividing PDW into quartiles. Crude and adjusted odds ratios of PDW for hyperuricemia with 95% confidence intervals were analyzed using binary logistic regression models. We found no significant difference in PDW values between the genders. Males showed significantly higher incidence of hyperuricemia than females. From binary logistic regression models, significant hyperuricemia risks only were demonstrated in PDW quartiles 2 and 3 in males (P < 0.05). This study displayed close association between PDW and hyperuricemia as a risk factor. It is meaningful to use PDW as a clinical risk predictor for hyperuricemia in males. © 2019 BioFactors, 45(3):326–334, 2019

Evaluation of Tolerability, Pharmacokinetics and Pharmacodynamics of Vicagrel, a Novel P2Y12 Antagonist, in Healthy Chinese Volunteers

Background: Vicagrel is a novel anti-platelet drug and hydrolyzed to the same intermediate as clopidogrel via esterase, instead of CYP2C19. Here we report the first clinical trial on the tolerability, pharmacokinetics and pharmacodynamics of different doses of vicagrel, and comparison with clopidogrel in healthy Chinese volunteers.Methods: This study was conducted in two parts. Study I was a dose-escalating (5–15 mg) study. For each dose, 15 participants were randomized into three groups (total n = 45); nine participants were given vicagrel, three were given clopidogrel, and three were given a placebo. Study II was conducted to assess interactions between vicagrel and aspirin in 15 healthy participants. The plasma concentrations of the metabolites of vicagrel and clopidogrel were determined using a LC-MS/MS method. Platelet aggregation was assessed using the VerifyNow-P2Y12 assay.Results: Vicagrel (5–15 mg per day) dosing for 10 days or addition of aspirin was well tolerated in healthy volunteers. The exposure of the active metabolite increased proportionally across the dose range and was higher (~10-fold) than clopidogrel. The levels of IPA dosing 75 mg clopidogrel were between the responses of 5 mg and 10 mg vicagrel. After a single loading dose of vicagrel (30 mg) and a once-daily maintenance dose (7.5 mg) for 8 days, the maximum inhibition of platelet aggregation was similar to that seen with the combined use of vicagrel and aspirin (100 mg/day).Conclusion: Oral vicagrel demonstrated a favorable safety profile and excellent anti-platelet activity, which could be a promising P2Y12 antagonist as anti-platelet drug and can be further developed in phase II/III studies, and marketing for the unmet medical needs of cardiovascular diseases. The study was registered at http://www.chictr.org.cn (ChiCTR-IIR-16009260)

Schizophrenia-associated somatic copy-number variants from 12,834 cases reveal recurrent NRXN1 and ABCB11 disruptions

While germline copy-number variants (CNVs) contribute to schizophrenia (SCZ) risk, the contribution of somatic CNVs (sCNVs)—present in some but not all cells—remains unknown. We identified sCNVs using blood-derived genotype arrays from 12,834 SCZ cases and 11,648 controls, filtering sCNVs at loci recurrently mutated in clonal blood disorders. Likely early-developmental sCNVs were more common in cases (0.91%) than controls (0.51%, p = 2.68e−4), with recurrent somatic deletions of exons 1–5 of the NRXN1 gene in five SCZ cases. Hi-C maps revealed ectopic, allele-specific loops forming between a potential cryptic promoter and non-coding cis-regulatory elements upon 5′ deletions in NRXN1. We also observed recurrent intragenic deletions of ABCB11, encoding a transporter implicated in anti-psychotic response, in five treatment-resistant SCZ cases and showed that ABCB11 is specifically enriched in neurons forming mesocortical and mesolimbic dopaminergic projections. Our results indicate potential roles of sCNVs in SCZ risk

The Single-Vendor Multibuyer Integrated Production-Delivery Model with Production Capacity under Stochastic Lead Time Demand

In this paper, we consider an integrated production-delivery model in which a vendor supplies the same product to multiple buyers. Unlike existing study, in this proposed model, we assume that the sum of all buyers’ demand rates is larger than the vendor’s production rate under normal work, but less than that under overtime. All buyers are independent of each other. For each buyer, the lead time demand is stochastic and the shortage during lead time is permitted. The main objective of this model is to determine the optimal production and delivery policies and the optimal overtime strategy, which minimize the joint expected annual cost of the system. Based on the genetic algorithm, we develop a solution procedure to find the optimal production, delivery, and overtime decision of this model. Computational experiments show the error rate between the objective values obtained by the proposed solution procedure and the solutions solved by the exhaustive method. The results indicate that the proposed mixed genetic algorithm is more effective and adoptable in comparison with the exhaustive method as it can be able to calculate the optimal solutions for at least 96% for the instances. Ultimately, an adequate numerical example is given to show the detailed process of the solution procedure, and sensitivity analysis of main parameters with managerial implication is discussed

Integrated Production-Delivery Lot Sizing Model with Limited Production Capacity and Transportation Cost considering Overtime Work and Maintenance Time

An extension of the integrated production-delivery lot sizing model with limited production capacity and transportation cost is investigated. We introduce the factor of overtime work into the model to improve the manufacturer’s production. In addition, when finishing a lot, the manufacturer has maintenance time to maintain and repair equipment for ensuring that the supply chain is operating continuously. By analyzing the integrated model, the solution procedure is provided to determine the optimal delivery and order policy. We conduct a numerical experiment and give sensitive analysis by varying some parameters to illustrate the problem and its solution procedure

Identification and functional characterization of a novel homozygous intronic variant in the fumarylacetoacetate hydrolase gene in a Chinese patient with tyrosinemia type 1

Abstract Background Hereditary tyrosinemia type 1 (HT1; OMIM# 276700) is a genetic metabolism disorder caused by disease-causing variants in the fumarylacetoacetate hydrolase (FAH) gene encoding the last enzyme of the tyrosine catabolic pathway. Herein, we describe the clinical features and genetic characteristics of HT1 in a five years and seven months old Chinese patient. Methods After clinical diagnosis of the proband with HT1, genetic testing was performed by Sanger sequencing of the FAH gene in all family members. Functional analysis of the disease-causing variant was performed by cDNA sequencing to understand the effect of the variant on FAH transcript. To further predict the variant effect, we used Human Splicing Finder (HSF) and PyMol in silico analysis. Results We identified a novel previously undescribed intronic variant in the FAH gene (c.914-1G>A). It was detected in a child who was homozygous for the variant and had the clinical presentation of HT1. cDNA sequencing showed that this splice-junction variant affected the transcription of FAH by formation of two different transcripts. Our observations and laboratory experiments were in line with in silico methods. Conclusions Our study provides new insight into the HT1 variant spectrum and a better understanding of this disease in the Chinese population. This will be useful for molecular diagnosis in our country in cases where premarital screening, prenatal diagnosis and preimplantation genetic diagnosis are planned