5,5′-[(1,4-Phenyl­enedimethyl­ene)bis­(sulfanedi­yl)]bis­(1-methyl-1H-1,2,3,4-tetra­zole)

The title mol­ecule, C12H14N8S2, has point symmetry since it is situated on a crystallographic centre of symmetry. The 1-meth­yl/5-thio groups are in an anti­periplanar conformation. The dihedral angle between the benzene and tetra­zole rings is 84.33 (2)°. In the crystal, C—H⋯N hydrogen bonds link mol­ecules into ladder-like chains running along the b axis. There are also C—H⋯π inter­actions present in the crystal structure

Region- or state-related differences in expression and activation of extracellular signal-regulated kinases (ERKs) in naïve and pain-experiencing rats

<p>Abstract</p> <p>Background</p> <p>Extracellular signal-regulated kinase (ERK), one member of the mitogen-activated protein kinase (MAPK) family, has been suggested to regulate a diverse array of cellular functions, including cell growth, differentiation, survival, as well as neuronal plasticity. Recent evidence indicates a role for ERKs in nociceptive processing in both dorsal root ganglion and spinal cord. However, little literature has been reported to examine the differential distribution and activation of ERK isoforms, ERK1 and ERK2, at different levels of pain-related pathways under both normal and pain states. In the present study, quantitative blot immunolabeling technique was used to determine the spatial and temporal expression of ERK1 and ERK2, as well as their activated forms, in the spinal cord, primary somatosensory cortex (SI area of cortex), and hippocampus under normal, transient pain and persistent pain states.</p> <p>Results</p> <p>In naïve rats, we detected regional differences in total expression of ERK1 and ERK2 across different areas. In the spinal cord, ERK1 was expressed more abundantly than ERK2, while in the SI area of cortex and hippocampus, there was a larger amount of ERK2 than ERK1. Moreover, phosphorylated ERK2 (pERK2), not phosphorylated ERK1 (pERK1), was normally expressed with a high level in the SI area and hippocampus, but both pERK1 and pERK2 were barely detectable in normal spinal cord. Intraplantar saline or bee venom injection, mimicking transient or persistent pain respectively, can equally initiate an intense and long-lasting activation of ERKs in all three areas examined. However, isoform-dependent differences existed among these areas, that is, pERK2 exhibited stronger response than pERK1 in the spinal cord, whereas ERK1 was more remarkably activated than ERK2 in the S1 area and hippocampus.</p> <p>Conclusion</p> <p>Taken these results together, we conclude that: (1) under normal state, while ERK immunoreactivity is broadly distributed in the rat central nervous system in general, the relative abundance of ERK1 and ERK2 differs greatly among specific regions; (2) under pain state, either ERK1 or ERK2 can be effectively phosphorylated with a long-term duration by both transient and persistent pain, but their response patterns differ from each other across distinct regions; (3) The long-lasting ERKs activation induced by bee venom injection is highly correlated with our previous behavioral, electrophysiological, morphological and pharmacological observations, lending further support to the functional importance of ERKs-mediated signaling pathways in the processing of negative consequences of pain associated with sensory, emotional and cognitive dimensions.</p

Propuesta de implementación de un sistema de gestión de seguridad y salud en el trabajo bajo la norma Ohsas 18001, para minimizar los factores de riesgo en la Institución Educativa Experimental Antonio Guillermo Urrelo

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Significance of the Balance between Regulatory T (Treg) and T Helper 17 (Th17) Cells during Hepatitis B Virus Related Liver Fibrosis

<div><h3>Background</h3><p>Hepatitis B virus-related liver fibrosis (HBV-LF) always progresses from inflammation to fibrosis. However, the relationship between these two pathological conditions is not fully understood. Here, it is postulated that the balance between regulatory T (Treg) cells and T helper 17 (Th17) cells as an indicator of inflammation may predict fibrosis progression of HBV-LF.</p> <h3>Methodology/Principal Findings</h3><p>The frequencies and phenotypes of peripheral Treg and Th17 cells of seventy-seven HBeAg-positive chronic hepatitis B (CHB) patients who underwent liver biopsies and thirty healthy controls were determined by flow cytometry. In the periphery of CHB patients, both Treg and Th17 frequencies were significantly increased and correlated, and a lower Treg/Th17 ratio always indicated more liver injury and fibrosis progression. To investigate exact effects of Treg and Th17 cells during HBV-LF, a series of <em>in vitro</em> experiments were performed using purified CD4⁺, CD4⁺CD25⁺, or CD4⁺CD25⁻ cells from the periphery, primary human hepatic stellate cells (HSCs) isolated from healthy liver specimens, human recombinant interleukin (IL)-17 cytokine, anti-IL-17 antibody and HBcAg. In response to HBcAg, CD4⁺CD25⁺ cells significantly inhibited cell proliferation and cytokine production (especially IL-17 and IL-22) by CD4⁺CD25⁻ cells in cell-contact and dose-dependent manners. In addition, CD4⁺ cells from CHB patients, compared to those from HC subjects, dramatically promoted proliferation and activation of human HSCs. Moreover, in a dramatically dose-dependent manner, CD4⁺CD25⁺ cells from CHB patients inhibited, whereas recombinant IL-17 response promoted the proliferation and activation of HSCs. Finally, <em>in vivo</em> evidence about effects of Treg/Th17 balance during liver fibrosis was obtained in concanavalin A-induced mouse fibrosis models via depletion of CD25⁺ or IL-17⁺ cells, and it’s observed that CD25 depletion promoted, whereas IL-17 depletion, alleviated liver injury and fibrosis progression.</p> <h3>Conclusions/Significance</h3><p>The Treg/Th17 balance might influence fibrosis progression in HBV-LF via increase of liver injury and promotion of HSCs activation.</p> </div

Complement gene variants in relation to autoantibodies to beta cell specific antigens and type 1 diabetes in the TEDDY Study

M. Knip on TEDDY Study Grp -työryhmän jäsen.A total of 15 SNPs within complement genes and present on the ImmunoChip were analyzed in The Environmental Determinants of Diabetes in the Young (TEDDY) study. A total of 5474 subjects were followed from three months of age until islet autoimmunity (IA: n = 413) and the subsequent onset of type 1 diabetes (n = 115) for a median of 73 months (IQR 54-91). Three SNPs within ITGAM were nominally associated (p <0.05) with IA: rs1143678 [Hazard ratio; HR 0.80; 95% CI 0.66-0.98; p = 0.032], rs1143683 [HR 0.80; 95% CI 0.65-0.98; p = 0.030] and rs4597342 [HR 1.16; 95% CI 1.01-1.32; p = 0.041]. When type 1 diabetes was the outcome, in DR3/4 subjects, there was nominal significance for two SNPs: rs17615 in CD21 [HR 1.52; 95% CI 1.05-2.20; p = 0.025] and rs4844573 in C4BPA [HR 0.63; 95% CI 0.43-0.92; p = 0.017]. Among DR4/4 subjects, rs2230199 in C3 was significantly associated [HR 3.20; 95% CI 1.75-5.85; p = 0.0002, uncorrected] a significance that withstood Bonferroni correction since it was less than 0.000833 (0.05/60) in the HLA-specific analyses. SNPs within the complement genes may contribute to IA, the first step to type 1 diabetes, with at least one SNP in C3 significantly associated with clinically diagnosed type 1 diabetes.Peer reviewe

A multi-targeted approach to suppress tumor-promoting inflammation

Cancers harbor significant genetic heterogeneity and patterns of relapse following many therapies are due to evolved resistance to treatment. While efforts have been made to combine targeted therapies, significant levels of toxicity have stymied efforts to effectively treat cancer with multi-drug combinations using currently approved therapeutics. We discuss the relationship between tumor-promoting inflammation and cancer as part of a larger effort to develop a broad-spectrum therapeutic approach aimed at a wide range of targets to address this heterogeneity. Specifically, macrophage migration inhibitory factor, cyclooxygenase-2, transcription factor nuclear factor-κB, tumor necrosis factor alpha, inducible nitric oxide synthase, protein kinase B, and CXC chemokines are reviewed as important antiinflammatory targets while curcumin, resveratrol, epigallocatechin gallate, genistein, lycopene, and anthocyanins are reviewed as low-cost, low toxicity means by which these targets might all be reached simultaneously. Future translational work will need to assess the resulting synergies of rationally designed antiinflammatory mixtures (employing low-toxicity constituents), and then combine this with similar approaches targeting the most important pathways across the range of cancer hallmark phenotypes

Identification of Reference Genes across Physiological States for qRT-PCR through Microarray Meta-Analysis

The accuracy of quantitative real-time PCR (qRT-PCR) is highly dependent on reliable reference gene(s). Some housekeeping genes which are commonly used for normalization are widely recognized as inappropriate in many experimental conditions. This study aimed to identify reference genes for clinical studies through microarray meta-analysis of human clinical samples.After uniform data preprocessing and data quality control, 4,804 Affymetrix HU-133A arrays performed by clinical samples were classified into four physiological states with 13 organ/tissue types. We identified a list of reference genes for each organ/tissue types which exhibited stable expression across physiological states. Furthermore, 102 genes identified as reference gene candidates in multiple organ/tissue types were selected for further analysis. These genes have been frequently identified as housekeeping genes in previous studies, and approximately 71% of them fall into Gene Expression (GO:0010467) category in Gene Ontology.Based on microarray meta-analysis of human clinical sample arrays, we identified sets of reference gene candidates for various organ/tissue types and then examined the functions of these genes. Additionally, we found that many of the reference genes are functionally related to transcription, RNA processing and translation. According to our results, researchers could select single or multiple reference gene(s) for normalization of qRT-PCR in clinical studies

Telomere length is not a main factor for the development of islet autoimmunity and type 1 diabetes in the TEDDY study

The Environmental Determinants of Diabetes in the Young (TEDDY) study enrolled 8676 children, 3-4 months of age, born with HLA-susceptibility genotypes for islet autoimmunity (IA) and type 1 diabetes (T1D). Whole-genome sequencing (WGS) was performed in 1119 children in a nested case-control study design. Telomere length was estimated from WGS data using five tools: Computel, Telseq, Telomerecat, qMotif and Motif_counter. The estimated median telomere length was 5.10 kb (IQR 4.52-5.68 kb) using Computel. The age when the blood sample was drawn had a significant negative correlation with telomere length (P = 0.003). European children, particularly those from Finland (P = 0.041) and from Sweden (P = 0.001), had shorter telomeres than children from the U.S.A. Paternal age (P = 0.019) was positively associated with telomere length. First-degree relative status, presence of gestational diabetes in the mother, and maternal age did not have a significant impact on estimated telomere length. HLA-DR4/4 or HLA-DR4/X children had significantly longer telomeres compared to children with HLA-DR3/3 or HLA-DR3/9 haplogenotypes (P = 0.008). Estimated telomere length was not significantly different with respect to any IA (P = 0.377), IAA-first (P = 0.248), GADA-first (P = 0.248) or T1D (P = 0.861). These results suggest that telomere length has no major impact on the risk for IA, the first step to develop T1D. Nevertheless, telomere length was shorter in the T1D high prevalence populations, Finland and Sweden.</p