Antinociceptive actions of honokiol and magnolol on glutamatergic and inflammatory pain

The antinociceptive effects of honokiol and magnolol, two major bioactive constituents of the bark of Magnolia officinalis, were investigated on animal paw licking responses and thermal hyperalgesia induced by glutamate receptor agonists including glutamate, N-methyl-D-aspartate (NMDA), and metabotropic glutamate 5 receptor (mGluR5) activator (RS)-2-chloro-5-hydroxyphenylglycine (CHPG), as well as inflammatory mediators such as substance P and prostaglandin E2 (PGE2) in mice. The actions of honokiol and magnolol on glutamate-induced c-Fos expression in the spinal cord dorsal horn were also examined. Our data showed that honokiol and magnolol blocked glutamate-, substance P- and PGE2-induced inflammatory pain with similar potency and efficacy. Consistently, honokiol and magnolol significantly decreased glutamate-induced c-Fos protein expression in superficial (I-II) laminae of the L4-L5 lumbar dorsal horn. However, honokiol was more selective than magnolol for inhibition of NMDA-induced licking behavioral and thermal hyperalgesia. In contrast, magnolol was more potent to block CHPG-mediated thermal hyperalgesia. These results demonstrate that honokiol and magnolol effectively decreased the inflammatory pain. Furthermore, their different potency on inhibition of nociception provoked by NMDA receptor and mGluR5 activation should be considered

利用日、月及年降雨量估算年降雨沖蝕指數

The Universal Soil Loss Equation (USLE) is presently one of the most widely used models for evaluating soil erosion. The rainfall amount is often used to estimate the R factor for Universal Soil Loss Equation (USLE) modeling. Daily, monthly, and annual rainfall data are commonly available. The purpose of the present study is to establish three models for estimating rainfall erosivity based on daily, monthly, and annual precipitation, respectively, and to identify the most suitable model in the Ailiao River watershed located in southern Taiwan. The data set consists of 2266 storm events, monitored by 6 rainfall stations there. The results show that the 6 stations indicate strong positive relationship (r2 > 0.75) between annual rainfall erosivity and annual rainfall with a 99% confidence level, which means the simplified estimation methods based on annual precipitation are useful for predicting long-term annual rainfall erosivity in most of locations in the Ailiao River watershed. The results also show that annual and monthly precipitation correlate with erosivity better than does daily precipitation based on the analysis results of root mean square error (RMSE) and mean absolute percentage error (MAPE) in the Ailiao River watershed.降雨沖蝕指數是通用土壤流失公式 (universal soil loss equation, USLE) 重要的參數之一，由於計算降雨沖蝕指數需要30 分鐘或更短量測間距的雨量資料，但大部分地區只有日、月或年雨量資料。因此利用何種降雨資料推估年平均降雨沖蝕指數較為接近30 分鐘雨量資料計算的年平均降雨沖蝕指數，是本研究的重點。本研究以隘寮溪集水區為研究區域，蒐集區域內6 個雨量站10 年 (2002-2011 年)10 分鐘等間隔的降雨資料，計算年平均降雨沖蝕指數 (Ryc)，另以日、月及年降雨資料，建立三種降雨量與降雨沖蝕指數關係式，利用RMSE、MAPE 及Bias 等誤差分析方法，評估三種降雨沖蝕指數推估關係式之適用性。研究結果顯示，利用年降雨資料推估年降雨沖蝕指數的適用性較好。本研究結果可提供缺乏短量測間距雨量資料地區年降雨沖蝕指數推估之參考依據

Clueless/CLUH regulates mitochondrial fission by promoting recruitment of Drp1 to mitochondria

Mitochondrial fission is critically important for controlling mitochondrial morphology, function, quality and transport. Drp1 is the master regulator driving mitochondrial fission, but exactly how Drp1 is regulated remains unclear. Here, we identified Drosophila Clueless and its mammalian orthologue CLUH as key regulators of Drp1. As with loss of drp1, depletion of clueless or CLUH results in mitochondrial elongation, while as with drp1 overexpression, clueless or CLUH overexpression leads to mitochondrial fragmentation. Importantly, drp1 overexpression rescues adult lethality, tissue disintegration and mitochondrial defects of clueless null mutants in Drosophila. Mechanistically, Clueless and CLUH promote recruitment of Drp1 to mitochondria from the cytosol. This involves CLUH binding to mRNAs encoding Drp1 receptors MiD49 and Mff, and regulation of their translation. Our findings identify a crucial role of Clueless and CLUH in controlling mitochondrial fission through regulation of Drp1

Honokiol Blocks Store Operated Calcium Entry in CHO Cells Expressing the M3 Muscarinic Receptor: Honokiol and Muscarinic Signaling

Background: Honokiol, a cell-permeable phenolic compound derived from the bark of magnolia trees and present in Asian herbal teas, has a unique array of pharmacological actions, including the inhibition of multiple autonomic responses. We determined the effects of honokiol on calcium signaling underlying transmission mediated by human M3 muscarinic receptors expressed in Chinese hamster ovary (CHO) cells. Receptor binding was determined in radiolabelled ligand binding assays; changes in intracellular calcium concentrations were determined using a fura-2 ratiometric imaging protocol; cytotoxicity was determined using a dye reduction assay. Results: Honokiol had a potent (EC50 ≈ 5 μmol/l) inhibitory effect on store operated calcium entry (SOCE) that was induced by activation of the M3 receptors. This effect was specific, rapid and partially reversible, and was seen at concentrations not associated with cytotoxicity, inhibition of IP3 receptor-mediated calcium release, depletion of ER calcium stores, or disruption of M3 receptor binding. Conclusions: It is likely that an inhibition of SOCE contributes to honokiol disruption of parasympathetic motor functions, as well as many of its beneficial pharmacological properties

Colorectal cancer survival among Malaysia population: data from the Malaysian National Cancer Registry

BackgroundColorectal cancer (CRC) is a major cause of cancer-related mortality worldwide. It is the second leading cause of cancer death in men and women in Malaysia and poses a major burden on society.AimsTo determine the overall survival rate of patients diagnosed with CRC and factors contributing to survival.MethodsData were obtained from the Malaysia National Cancer Registry. All patients with CRC were identified, and a total of 15,515 patients were screened. A total of 5,675 CRC patients were included from January 1, 2012, to December 31, 2016. Sex, age groups, ethnic groups, stage at diagnosis, cancer sites, and status of treatment received were analysed. The Kaplan–Meier analysis was performed to estimate the 1-, 3-, and 5-year survival of CRC. The log-rank test was conducted to compare the survival between sex, age groups, ethnic groups, stage at diagnosis, cancer sites, and status of treatment received. Multiple Cox regression was conducted to determine the risk of CRC death.ResultsOf 5,675, a total of 2,055 had died, 3,534 were censored, and another 86 were still alive within 5 years of CRC diagnosis. The 1-, 3-, and 5-year survival rates were 68.5%, 34.7%, and 18.4%, respectively with a median survival time of 24 months. Significant differences in survival rates of CRC were observed between age groups (p < 0.001), ethnic groups (p < 0.001), stages at diagnosis (p < 0.001), treatment status (p = 0.003), and treatment modalities (p < 0.001). No significant difference was observed in survival rates of CRC between sex (p = 0.235) and cancer sites (p = 0.410). Those who were 80 years old and above were found to be at higher risk of CRC death compared to those below 80 years old (adjusted hazard ratio (HR): 1.24, 95% CI 1.14–1.36). The risk of CRC death was also found four times higher among those with stage IV compared to those with stage 0 (adjusted HR: 4.28, 95% CI 3.26–5.62).ConclusionIn general, Malaysian patients with CRC had low survival rates. National health policies should focus on enhancing awareness of CRC, encouraging early screening, and developing strategies for early detection and management to reduce CRC-associated mortality

Вихретоковый анизотропный термоэлектрический первичный преобразователь лучистого потока

Представлена оригинальная конструкция первичного преобразователя лучистого потока, который может служить основой для создания приемника неселективного излучения с повышенной чувствительностью

Genetic drivers of heterogeneity in type 2 diabetes pathophysiology

Type 2 diabetes (T2D) is a heterogeneous disease that develops through diverse pathophysiological processes1,2 and molecular mechanisms that are often specific to cell type3,4. Here, to characterize the genetic contribution to these processes across ancestry groups, we aggregate genome-wide association study data from 2,535,601 individuals (39.7% not of European ancestry), including 428,452 cases of T2D. We identify 1,289 independent association signals at genome-wide significance (P &lt; 5 × 10-8) that map to 611 loci, of which 145 loci are, to our knowledge, previously unreported. We define eight non-overlapping clusters of T2D signals that are characterized by distinct profiles of cardiometabolic trait associations. These clusters are differentially enriched for cell-type-specific regions of open chromatin, including pancreatic islets, adipocytes, endothelial cells and enteroendocrine cells. We build cluster-specific partitioned polygenic scores5 in a further 279,552 individuals of diverse ancestry, including 30,288 cases of T2D, and test their association with T2D-related vascular outcomes. Cluster-specific partitioned polygenic scores are associated with coronary artery disease, peripheral artery disease and end-stage diabetic nephropathy across ancestry groups, highlighting the importance of obesity-related processes in the development of vascular outcomes. Our findings show the value of integrating multi-ancestry genome-wide association study data with single-cell epigenomics to disentangle the aetiological heterogeneity that drives the development and progression of T2D. This might offer a route to optimize global access to genetically informed diabetes care.</p

Search for dark matter produced in association with bottom or top quarks in √s = 13 TeV pp collisions with the ATLAS detector

A search for weakly interacting massive particle dark matter produced in association with bottom or top quarks is presented. Final states containing third-generation quarks and miss- ing transverse momentum are considered. The analysis uses 36.1 fb−1 of proton–proton collision data recorded by the ATLAS experiment at √s = 13 TeV in 2015 and 2016. No significant excess of events above the estimated backgrounds is observed. The results are in- terpreted in the framework of simplified models of spin-0 dark-matter mediators. For colour- neutral spin-0 mediators produced in association with top quarks and decaying into a pair of dark-matter particles, mediator masses below 50 GeV are excluded assuming a dark-matter candidate mass of 1 GeV and unitary couplings. For scalar and pseudoscalar mediators produced in association with bottom quarks, the search sets limits on the production cross- section of 300 times the predicted rate for mediators with masses between 10 and 50 GeV and assuming a dark-matter mass of 1 GeV and unitary coupling. Constraints on colour- charged scalar simplified models are also presented. Assuming a dark-matter particle mass of 35 GeV, mediator particles with mass below 1.1 TeV are excluded for couplings yielding a dark-matter relic density consistent with measurements