Elements of margin of safety,toxicity and action of sodium selenite in a lipopolysaccharide rat model

ProjectBoth septic shock and sodium selenite (Na₂SeO₃) lead to multiple organ failure through oxidation. Na₂SeO₃ has direct oxidant effects above the nutritional level and indirect anti-oxidant properties.In a lipopolysaccharide (LPS) rat model we assessed margin of safety, toxicity and beneficial effect of pentahydrate Na₂SeO₃ (5H₂O·Na₂SeO₃) at oxidant doses.ProcedureIn a three-step study on 204 rats we: (i) observed toxic effects of Na₂SeO₃ injected intraperitoneously (IP) and determined its Minimum Dose Without Toxic effect (MDWT) 0.25–0.35 mg/kg selenium (Se) content; (ii) injected IP LPS at 70% lethal dose (LD) followed, or not, one hour later by IP Na₂SeO₃ at MDWT and (iii) by doses > MDWT. At 48 h, in survivors, we measured plasma creatinine, lactate, aspartate and alanine aminotransferase (AST, ALT), nitric oxide (NO) and Se concentrations.Results(i) Na₂SeO₃ alone did not increase NO and lactate. Encephalopathy appeared at 1 mg Se/kg. Creatinine increased at 1–1.75 mg Se/kg, AST, ALT at 3–4.5 mg Se/kg, and the minimum LD was 3 mg Se/kg. (ii) Mortality after LPS was 37/50 (74%, [62–86%]) vs. 20/30 (67%, [50–84%]) when followed by Na₂SeO₃ at MDWT (p = 0.483) with a decreased in NO (−31%, p = 0.038) a trend for lactate decrease (−19%, p = 0.068) and an increased Se in plasma of survivals. (iii) All rats died at doses ≥0.6 mg/kg (p < 0.001).ConclusionMechanisms of LPS and Na₂SeO₃ toxicity differ (i.e. NO, lactate). In septic shock 5H₂O·Na₂SeO₃ toxicity increased, margin of safety decrease, but IP administration of dose considered as oxidant of 5H₂O·Na₂SeO₃ showed beneficial effects.     

A Hyaluronan Receptor for Endocytosis (HARE) Link Domain N-Glycan Is Required for Extracellular Signal-regulated Kinase (ERK) and Nuclear Factor-κB (NF-κB) Signaling in Response to the Uptake of Hyaluronan but Not Heparin,Dermatan Sulfate,or Acetylated Low Density Lipoprotein (LDL)

The human hyaluronan (HA) receptor for endocytosis (HARE; the 190-kDa C terminus of Stab2) is a major clearance receptor for multiple circulating ligands including HA, heparin (Hep), acetylated LDL (AcLDL), dermatan sulfate (DS), apoptotic debris, and chondroitin sulfate types A, C, D, and E. We previously found that HARE contains an N-glycan in the HA binding Link domain (at Asn²²⁸⁰), and cells expressing membrane-bound HARE(N2280A) bind and endocytose HA normally (Harris, E. N., Parry, S., Sutton-Smith, M., Pandey, M. S., Panico, M., Morris, H. R., Haslam, S. M., Dell, A., and Weigel, P. H. (2010) Glycobiology 20, 991–1001). Also, NF-κB-mediated signaling is activated by HARE-mediated endocytosis of HA, Hep, AcLDL, or DS but not by chondroitin sulfates (Pandey, M. S., and Weigel, P. H. (2014) J. Biol. Chem. 289, 1756–1767). Here we investigated the role of Link N-glycans in ligand uptake and NF-κB and ERK1/2 signaling. HA·HARE-mediated ERK1/2 activation was HA size- dependent, as found for NF-κB activation. HARE(N2280A) cells internalized HA, Hep, AcLDL, and DS normally. No ERK1/2 activation occurred during HA endocytosis by HARE(N2280A) cells, but activation did occur with Hep. Dual-luciferase recorder assays showed that NF-κB-mediated gene expression occurred normally in HARE(N2280A) cells endocytosing Hep, AcLDL, or DS but did not occur with HA. Activation of NF-κB by endogenous degradation of IκB-α was observed for HARE(N2280A) cells endocytosing Hep, AcLDL, or DS but not HA. We conclude that a Link domain complex N-glycan is required specifically for HARE·HA-mediated activation of ERK1/2 and NF-κB-mediated gene expression and that this initial activation mechanism is different from and independent of the initial mechanisms for HARE-mediated signaling in response to Hep, AcLDL, or DS uptake.     

On generalized Simes critical constants

We consider the problem treated by Simes of testing the overall null hypothesis formed by the intersection of a set of elementary null hypotheses based on ordered p‐values of the associated test statistics. The Simes test uses critical constants that do not need tabulation. Cai and Sarkar gave a method to compute generalized Simes critical constants which improve upon the power of the Simes test when more than a few hypotheses are false. The Simes constants can be viewed as the first order (requiring solution of a linear equation) and the Cai‐Sarkar constants as the second order (requiring solution of a quadratic equation) constants. We extend the method to third order (requiring solution of a cubic equation) constants, and also offer an extension to an arbitrary kth order. We show by simulation that the third order constants are more powerful than the second order constants for testing the overall null hypothesis in most cases. However, there are some drawbacks associated with these higher order constants especially for , which limits their practical usefulness.     

滇龙胆与青叶胆环烯醚萜类物质计量特征分析?

龙胆科龙胆属滇龙胆( Gentiana rigescens)与獐牙菜属青叶胆( Swertia mileensis)为我国特有种。采用高效液相色谱法测定其中马钱苷酸、獐牙菜苦苷、龙胆苦苷和当药苷含量,结合多变量分析研究环烯醚萜类成分含量及其构成比例在龙胆科植物种内和种间的差异。研究结果显示,4种环烯醚萜类成分的计量特征呈现种间差异,依据环烯醚萜类成分含量及其构成比例,所有滇龙胆样品可分为4类。马钱苷酸含量与纬度呈极显著负相关( R＝－0?348, P<0?05),与海拔呈极显著正相关( R＝0?307, P<0?01);獐牙菜苦苷含量与经度呈极显著负相关( R＝－0?592, P<0?01),高海拔有利于植株中当药苷构成比例的增加( R＝0?245, P<0?05);地理因子对植株中龙胆苦苷含量变化影响不显著( P>0?05)。     

FDR control by the BH procedure for two-sided correlated tests with implications to gene expression data analysis

The multiple testing problem attributed to gene expression analysis is challenging not only by its size, but also by possible dependence between the expression levels of different genes resulting from coregulations of the genes. Furthermore, the measurement errors of these expression levels may be dependent as well since they are subjected to several technical factors. Multiple testing of such data faces the challenge of correlated test statistics. In such a case, the control of the False Discovery Rate (FDR) is not straightforward, and thus demands new approaches and solutions that will address multiplicity while accounting for this dependency. This paper investigates the effects of dependency between bormal test statistics on FDR control in two-sided testing, using the linear step-up procedure (BH) of Benjamini and Hochberg (1995). The case of two multiple hypotheses is examined first. A simulation study offers primary insight into the behavior of the FDR subjected to different levels of correlation and distance between null and alternative means. A theoretical analysis follows in order to obtain explicit upper bounds to the FDR. These results are then extended to more than two multiple tests, thereby offering a better perspective on the effect of the proportion of false null hypotheses, as well as the structure of the test statistics correlation matrix. An example from gene expression data analysis is presented.     

镍钛形状记忆合金环抱器内固定术对多发性肋骨骨折患者术后疼痛、呼吸功能及肺部感染的影响

目的:探讨多发性肋骨骨折患者采用镍钛形状记忆合金环抱器内固定术治疗的临床效果。方法:选取2016年1月-2018年1月期间我院收治的97例多发性肋骨骨折患者。按照不同的治疗方法将患者分为对照组(n=47)和研究组(n=50),对照组患者给予胸部护板外固定术,研究组患者给予镍钛形状记忆合金环抱器内固定术。比较两组患者术后7 d的临床疗效,比较两组术前、术后7 d疼痛程度及呼吸功能情况,记录两组术后并发症发生情况。结果:研究组患者治疗后总有效率为92.00%(46/50),高于对照组患者的76.60%(36/47)(P0.05)。两组患者术后7 d视觉疼痛模拟评分量表(VAS)评分均较术前降低,且研究组低于对照组(P0.05)。两组患者术后7 d最大自主通气量占预计值百分比(MVV%)较术前升高,且研究组高于对照组(P0.05);两组患者术后7 d第1秒用力呼气肺活量占预计值百分比(FEV1%)比较无差异(P0.05)。研究组患者术后并发症总发生率8.00%(4/50),低于对照组的23.40%(11/47)(P0.05)。结论:多发性肋骨骨折经镍钛形状记忆合金环抱器内固定术治疗安全、有效,可明显减轻患者术后疼痛及改善呼吸功能,临床应用价值较高。     

Prediction of herbage yield in grassland: How well do Ellenberg N‐values perform?

Question: How useful are Ellenberg N‐values for predicting the herbage yield of Central European grasslands in comparison to approaches based on ordination scores of plant species composition or on soil parameters? Location: Central Germany (11°00′‐11°37’E, 50°21‐50°34’N, 500–840 m a.s.l.). Methods: Based on data from a field survey in 2001, the following models were constructed for predicting herbage yield in montane Central European grasslands: (1) Linear regression of mean Ellenberg N‐, R‐ and F‐values; (2) Linear regression of ordination scores derived from Non‐metric Multidimensional Scaling (NMDS) of vegetation data; and (3) Multiple linear regression (MLR) of soil variables. Models were evaluated by cross‐validation and validation with additional data collected in 2002. Results: Best predictions were obtained with models based on species composition. Ellenberg N‐values and NMDS scores performed equally well and better than models based on Ellenberg R‐ or F‐values. Predictions based on soil variables were least accurate. When tested with data from 2002, models based on Ellenberg N‐values or on NMDS scores accurately predicted productivity rank order of sites, but not the actual herbage yield of particular sites. Conclusions: Mean Ellenberg N‐values, which are easy to calculate, are as accurate as ordination scores in predicting herbage yield from plant species composition. In contrast, models based on soil variables may be useful for generating hypotheses about the factors limiting herbage yield, but not for prediction. We support the view that Ellenberg N‐values should be called productivity values rather than nitrogen values.