bluuebunny/crossref_metadata_2025_split huggingface dataset:
Taurine activates delayed rectifier KV channels via a metabotropic pathway in retinal neurons
Authors: Bulley Simon , Liu Yufei , Ripps Harris , Shen Wen 
Published: October 2012

Key points
Although taurine is one of the most abundant amino acids in human tissues, and serves a number of important functions ranging from cell development to cytoprotection, its precise mode of action is often obscure.
Here we present evidence that, in the vertebrate retina, taurine regulates voltage‐gated potassium (KV) channels that are sensitive to the inhibitors of KV1, KV2 and KV4 subunits.
Taurine's effect was shown to be a metabotropic response, involving a G‐protein linked, PKC‐dependent intracellular pathway.
Noteworthy was the finding that responses to taurine were blocked by a specific antagonist of 5‐HT2A receptors. Taurine activation of 5‐HT2A receptors was further confirmed in HEK cells that expressed recombinant 5‐HT2A receptors.
Taurine has been shown to be beneficial in the management of a number of brain disorders. Its interaction with serotonergic pathways suggests that taurine may also play a role in various cognitive functions of the CNS.
Abstract  Taurine is one of the most abundant amino acids in the retina, throughout the CNS, and in heart and muscle cells. In keeping with its broad tissue distribution, taurine serves as a modulator of numerous basic processes, such as enzyme activity, cell development, myocardial function and cytoprotection. Despite this multitude of functional roles, the precise mechanism underlying taurine's actions has not yet been identified. In this study we report findings that indicate a novel role for taurine in the regulation of voltage‐gated delayed rectifier potassium (KV) channels in retinal neurons by means of a metabotropic receptor pathway. The metabotropic taurine response was insensitive to the Cl− channel blockers, picrotoxin and strychnine, but it was inhibited by a specific serotonin 5‐HT2A receptor antagonist, MDL11939. Moreover, we found that taurine enhanced KV channels via intracellular protein kinase C‐mediated pathways. When 5‐HT2A receptors were expressed in human embryonic kidney cells, taurine and AL34662, a non‐specific 5‐HT2 receptor activator, produced a similar regulation of KIR channels. In sum, this study provides new evidence that taurine activates a serotonin system, apparently via 5‐HT2A receptors and related intracellular pathways.
Relationship between membrane Cl− conductance and contractile endurance in isolated rat muscles
Authors: de Paoli Frank Vincenzo , Broch‐Lips Martin , Pedersen Thomas Holm , Nielsen Ole Bækgaard 
Published: October 2012

Key points
Excitable cells commonly regulate their ability to generate and propagate action potentials through modulating the properties of the membrane ion channels. Recently it was shown that muscle activity is associated with rapid, protein kinase C (PKC)‐dependent ClC‐1 Cl− channel inhibition.
Here the functional significance of this ClC‐1 inhibition for contractile endurance was determined in isolated slow‐ and fast‐twitch rat muscles.
Experiments showed that PKC inhibition led to reduced contractile endurance, an effect of PKC that disappeared when extracellular Cl− was removed or ClC‐1 channels were inhibited.
Experiments where resting Cl− conductance (GCl) was manipulated by reduction of solution Cl− or inhibition of ClC‐1 Cl− channels suggest a biphasic dependency of contractile endurance on GCl with an optimum close to the GCl observed in active muscles.
The biphasic relation between GCl and endurance seems to reflect that lowered GCl on one side increases muscle excitability but on the other side reduces the ability of the muscle fibres to maintain K+ homeostasis and membrane potential during contractions.
This study suggested that PKC‐dependent ClC‐1 Cl− channel regulation is important for the maintenance of contractile endurance in working muscle.
Abstract  Resting skeletal muscle fibres have a large membrane Cl− conductance (GCl) that dampens their excitability. Recently, however, muscle activity was shown to induce PKC‐mediated reduction in GCl in rat muscles of 40–90%. To examine the physiological significance of this PKC‐mediated GCl reduction for the function of muscles, this study explored effects of GCl reductions on contractile endurance in isolated rat muscles. Contractile endurance was assessed from the ability of muscle to maintain force during prolonged stimulation under conditions when GCl was manipulated by: (i) inhibition of PKC, (ii) reduction of solution Cl− or (iii) inhibition of ClC‐1 Cl− channels using 9‐anthracene‐carboxylic acid (9‐AC). Experiments showed that contractile endurance was optimally preserved by reductions in GCl similar to what occurs in active muscle. Contrastingly, further GCl reductions compromised the endurance. The experiments thus show a biphasic relationship between GCl and contractile endurance in which partial GCl reduction improves endurance while further GCl reduction compromises endurance. Intracellular recordings of trains of action potentials suggest that this biphasic dependency of contractile endurance on GCl reflects that lowering GCl enhances muscle excitability but low GCl also increases the depolarisation of muscle fibres during excitation and reduces their ability to re‐accumulate K+ lost during excitation. If GCl becomes very low, the latter actions dominate causing reduced endurance. It is concluded that the PKC‐mediated ClC‐1 channel inhibition in active muscle reduces GCl to a level that optimises contractile endurance during intense exercise.
Intrarectal Instillation of Clostridium difficile Toxin A Triggers Colonic Inflammation and Tissue Damage: Development of a Novel and Efficient Mouse Model of Clostridium difficile Toxin Exposure
Authors: Hirota Simon A. , Iablokov Vadim , Tulk Sarah E. , Schenck L. Patrick , Becker Helen , Nguyen Jimmie , Al Bashir Samir , Dingle Tanis C. , Laing Austin , Liu Jianrui , Li Yan , Bolstad Jeff , Mulvey George L. , Armstrong Glen D. , MacNaughton Wallace K. , Muruve Daniel A. , MacDonald Justin A. , Beck Paul L. 
Published: October 2012

ABSTRACTClostridium difficile, a major cause of hospital-acquired diarrhea, triggers disease through the release of two toxins, toxin A (TcdA) and toxin B (TcdB). These toxins disrupt the cytoskeleton of the intestinal epithelial cell, increasing intestinal permeability and triggering the release of inflammatory mediators resulting in intestinal injury and inflammation. The most prevalent animal model to study TcdA/TcdB-induced intestinal injury involves injecting toxin into the lumen of a surgically generated “ileal loop.” This model is time-consuming and exhibits variability depending on the expertise of the surgeon. Furthermore, the target organ ofC. difficileinfection (CDI) in humans is the colon, not the ileum. In the current study, we describe a new model of CDI that involves intrarectal instillation of TcdA/TcdB into the mouse colon. The administration of TcdA/TcdB triggered colonic inflammation and neutrophil and macrophage infiltration as well as increased epithelial barrier permeability and intestinal epithelial cell death. The damage and inflammation triggered by TcdA/TcdB isolates from the VPI and 630 strains correlated with the concentration of TcdA and TcdB produced. TcdA/TcdB exposure increased the expression of a number of inflammatory mediators associated with human CDI, including interleukin-6 (IL-6), gamma interferon (IFN-γ), and IL-1β. Finally, we were able to demonstrate that TcdA was much more potent at inducing colonic injury than was TcdB but TcdB could act synergistically with TcdA to exacerbate injury. Taken together, our data indicate that the intrarectal murine model provides a robust and efficient system to examine the effects of TcdA/TcdB on the induction of inflammation and colonic tissue damage in the context of human CDI.
Polymorphisms in the Fc Gamma Receptor IIIA and Toll-Like Receptor 9 Are Associated with Protection against Severe Malarial Anemia and Changes in Circulating Gamma Interferon Levels
Authors: Munde Elly O. , Okeyo Winnie A. , Anyona Samwel B. , Raballah Evans , Konah Stephen , Okumu Wilson , Ogonda Lilian , Vulule John , Ouma Collins 
Published: October 2012

ABSTRACTAn understanding of the immunogenetic basis of naturally acquired immunity toPlasmodium falciparuminfection would aid in the designing of a rationally based malaria vaccine. Variants within the Fc gamma receptors (FcγRs) mediate immunity through engagement of immunoglobulin G and other immune mediators, such as gamma interferon (IFN-γ), resulting in erythrophagocytosis and production of inflammatory cytokines in severe malarial anemia (SMA). The Toll-like receptors (TLRs) trigger transcription of proinflammatory cytokines and induce adaptive immune responses. Therefore, these receptors may condition malaria disease pathogenesis through alteration in adaptive and innate immune responses. To further delineate the impacts of FcγRIIIA and TLR9 in SMA pathogenesis, the associations between FcγRIIIA −176F/V and TLR9 −1237T/C variants, SMA (hemoglobin [Hb] < 6.0 g/dl), and circulating IFN-γ levels were investigated in children (n= 301) from western Kenya with acute malaria. Multivariate logistic regression analysis (controlling for potential confounders) revealed that children with the FcγRIIIA −176V/TLR9 −1237C (VC) variant combination had 64% reduced odds of developing SMA (odds ratio [OR], 0.36; 95% confidence interval [CI], 0.20 to 0.64;P= 0.001), while carriers of the FcγRIIIA −176V/TLR9 −1237T (VT) variant combination were twice as susceptible to SMA (OR, 2.04; 95% CI, 1.19 to 3.50;P= 0.009). Children with SMA had higher circulating IFN-γ levels than non-SMA children (P= 0.008). Hemoglobin levels were negatively correlated with IFN-γ levels (r= −0.207,P= 0.022). Consistently, the FcγRIIIA −176V/TLR9 −1237T (VT) carriers had higher levels of circulating IFN-γ (P= 0.011) relative to noncarriers, supporting the observation that higher IFN-γ levels are associated with SMA. These results demonstrate that FcγRIIIA-176F/V and TLR9 −1237T/C variants condition susceptibility to SMA and functional changes in circulating IFN-γ levels.
Interleukin 13 Exposure Enhances Vitamin D-Mediated Expression of the Human Cathelicidin Antimicrobial Peptide 18/LL-37 in Bronchial Epithelial Cells
Authors: Schrumpf J. A. , van Sterkenburg M. A. J. A. , Verhoosel R. M. , Zuyderduyn S. , Hiemstra P. S. 
Published: October 2012

ABSTRACT

Vitamin D is an important regulator of the expression of antimicrobial peptides, and vitamin D deficiency is associated with respiratory infections. Regulating expression of antimicrobial peptides, such as the human cathelicidin antimicrobial peptide 18 (hCAP18)/LL-37, by vitamin D in bronchial epithelial cells requires local conversion of 25(OH)-vitamin D
3
(25D
3
) into its bioactive metabolite, 1,25(OH)
2
-vitamin D
3
(1,25D
3
), by CYP27B1. Low circulating vitamin D levels in childhood asthma are associated with more-severe exacerbations, which are often associated with infections. Atopic asthma is accompanied by Th2-driven inflammation mediated by cytokines such as interleukin 4 (IL-4) and IL-13, and the effect of these cytokines on vitamin D metabolism and hCAP18/LL-37 expression is unknown. Therefore, we investigated this with well-differentiated bronchial epithelial cells. To this end, cells were treated with IL-13 with and without 25D
3
, and expression of hCAP18/LL-37, CYP27B1, the 1,25D
3
-inactivating enzyme CYP24A1, and vitamin D receptor was assessed by quantitative PCR. We show that IL-13 enhances the ability of 25D
3
to increase expression of hCAP18/LL-37 and CYP24A1. In addition, exposure to IL-13 resulted in increased CYP27B1 expression, whereas vitamin D receptor (VDR) expression was not significantly affected. The enhancing effect of IL-13 on 25D
3
-mediated expression of hCAP18/LL-37 was further confirmed using SDS-PAGE Western blotting and immunofluorescence staining. In conclusion, we demonstrate that IL-13 induces vitamin D-dependent hCAP18/LL-37 expression, most likely by increasing CYP27B1. These data suggest that Th2 cytokines regulate the vitamin D metabolic pathway in bronchial epithelial cells.
Intensity versus duration of physical activity: implications for the metabolic syndrome. A prospective cohort study
Authors: Laursen Adam Hoegsbro , Kristiansen Ole P , Marott Jacob Louis , Schnohr Peter , Prescott Eva 
Published: October 2012

ObjectivesTo explore the relative importance of leisure time physical activity (LTPA), walking and jogging on risk of developing the metabolic syndrome (MS).DesignA prospective cohort study.SettingThe Copenhagen City Heart Study.Participants10 135 men and women aged 21–98 years who attended an initial examination in 1991–1994 and were re-examined after 10 years.Outcome measuresThe association of LTPA, jogging, walking speed and walking volume with MS at baseline and at 10-year follow-up was investigated by multiple logistic regression analyses.ResultsBaseline prevalence of MS was 20.7% in women and 27.3% in men. In both women and men, MS prevalence was associated with lower LTPA and walking speed and was lower in joggers compared to non-joggers. In subjects free of MS at baseline, 15.4% had developed MS at 10-year follow-up. Risk of developing MS was reduced in subjects with moderate or high LTPA, higher walking speed and in joggers whereas a higher volume of walking was not associated with reduced risk. After multiple adjustment, odds ratio (OR) of developing MS in moderate/high LTPA was 0.71 (95% CI 0.50 to 1.01), fast walking speed 0.51 (0.33 to 0.80) and joggers 0.60 (0.37 to 0.95) and walking >1 h daily 1.22 (0.91 to 1.65).ConclusionsOur results confirm the role of physical activity in reducing MS risk and suggest that intensity more than volume of physical activity is important.
Unlocking the potential: longitudinal audit finds multifaceted education for general practice increases HIV testing and diagnosis
Authors: Pillay Timesh D , Mullineux Judith , Smith Colette J , Matthews Philippa 
Published: October 2012

BackgroundThis longitudinal study aimed to evaluate the impact of a multifaceted educational intervention (Sexual Health in Practice, SHIP) on general practice HIV testing rates in a high prevalence London area.InterventionSHIP offered training in sexual health clinical skills to general practitioners (GPs) and practice nurses (PNs) in Haringey. SHIP training aims to break down stigma in sexual health and provide sexual history and communication tools (e.g. differential diagnosis), and provides resources to practices (including condoms).DesignNumbers of GP HIV tests were collected from laboratories for 24 months prior, 19 months during and 5 months after training. Attendance data and practice list sizes were obtained.Results39 of 51 practices had at least one trained individual. These `trained' practices conducted an average 526 HIV tests p.a. before training began which rose to a projected 1556 p.a. (on the basis of the last 6 months of data). Testing rates of trained and untrained practices increased from 2.29 to 6.66 and 1.54 to 1.90 tests/1000 registered patients/year (p=0.0016 and p=0.5195) respectively. The rate of positive diagnosis was high in the trained group (18.0 and 16.7 positives/1000 tests before and after training began; p=0.7908). This equates to a rise from 9.5 to 22 new diagnoses p.a.ConclusionsThe training intervention has been found to significantly increase general practice HIV testing rates in the absence of financial incentives. Positivity rates are substantially higher than that found in pilots of screening in London, suggesting that the training nurtured and supplemented complex clinical skills.
Two-stage development of the Late Cretaceous to Late Eocene Darende Basin: implications for closure of Neotethys in central eastern Anatolia (Turkey)
Authors: Booth Matthew G. , Robertson Alastair H. F. , Tasli Kemal , İnan Nurdan , Ünlügenç Ulvi Can , Vincent Stephen 
Published: October 2012

Abstract

The Darende Basin is an excellent example of an important, but little known, type of sedimentary basin that can form on the top of emplaced ophiolites prior to and during continental collision. The basin formation was preceded by southward emplacement of accretionary mélange and ophiolites onto the Tauride carbonate platform during latest Cretaceous. Sedimentation began during the Maastrichtian with non-marine clastic sediments accumulating in palaeovalleys. This was followed by a Maastrichtian marine transgression, triggered by extension along the basin margins. Rudist-rich patch reefs and a carbonate shelf developed in different areas. A second transgression during the Mid-Eocene was preceded by emergence, a hiatus (Paleocene), localized faulting and low-angle (<5–10°) tilting. Middle Eocene hemipelagic marls, shallow-marine
Nummulites
-rich carbonates, calciturbidites and sparse alkaline volcanism culminated in Late Eocene shallowing, emergence and then deformation. The first phase of basin development (Maastrichtian) is seen as extensional, related to slab-pull that resulted from northward subduction of remnant oceanic lithosphere beneath Eurasia in the Pontides to the north. The second phase of basin development (Mid–Late Eocene) is explained by crustal downflexure to form an under-filled foreland basin during the final collision of the Tauride continent with Eurasia. Basin uplift was delayed until after a Mid-Miocene marine incursion.

Supplementary material:

Full results of the palaeontological determination of collected samples from the Eocene aged sedimentary rocks of the Darende Basin are available at
www.geolsoc.org.uk/SUP18544
Molecular Analysis of HER2 Signaling in Human Breast Cancer by Functional Protein Pathway Activation Mapping
Authors: Wulfkuhle Julia D. , Berg Daniela , Wolff Claudia , Langer Rupert , Tran Kai , Illi Julie , Espina Virginia , Pierobon Mariaelena , Deng Jianghong , DeMichele Angela , Walch Axel , Bronger Holger , Becker Ingrid , Waldhör Christine , Höfler Heinz , Esserman Laura ,   on behalf of the I-SPY 1 TRIAL Investigators, Liotta Lance A. , Becker Karl-Friedrich , Petricoin Emanuel F. 
Published: October 2012

Abstract
Purpose: Targeting of the HER2 protein in human breast cancer represents a major advance in oncology but relies on measurements of total HER2 protein and not HER2 signaling network activation. We used reverse-phase protein microarrays (RPMA) to measure total and phosphorylated HER2 in the context of HER family signaling to understand correlations between phosphorylated and total levels of HER2 and downstream signaling activity.
Experimental Design: Three independent study sets, comprising a total of 415 individual patient samples from flash-frozen core biopsy samples and formalin-fixed and paraffin-embedded (FFPE) surgical and core samples, were analyzed via RPMA. The phosphorylation and total levels of the HER receptor family proteins and downstream signaling molecules were measured in laser capture microdissected (LCM) enriched tumor epithelium from 127 frozen pretreatment core biopsy samples and whole-tissue lysates from 288 FFPE samples and these results were compared with FISH and immunohistochemistry (IHC).
Results: RPMA measurements of total HER2 were highly concordant (&gt;90% all sets) with FISH and/or IHC data, as was phosphorylation of HER2 in the FISH/IHC+ population. Phosphorylation analysis of HER family signaling identified HER2 activation in some FISH/IHC− tumors and, identical to that seen with FISH/IHC+ tumors, the HER2 activation was concordant with EGF receptor (EGFR) and HER3 phosphorylation and downstream signaling endpoint activation.
Conclusions: Molecular profiling of HER2 signaling of a large cohort of human breast cancer specimens using a quantitative and sensitive functional pathway activation mapping technique reveals IHC−/FISH−/pHER2+ tumors with HER2 pathway activation independent of total HER2 levels and functional signaling through HER3 and EGFR. Clin Cancer Res; 18(23); 6426–35. ©2012 AACR.
Mutation Profiling and Microsatellite Instability in Stage II and III Colon Cancer: An Assessment of Their Prognostic and Oxaliplatin Predictive Value
Authors: Gavin Patrick G. , Colangelo Linda H. , Fumagalli Debora , Tanaka Noriko , Remillard Matthew Y. , Yothers Greg , Kim Chungyeul , Taniyama Yusuke , Kim Seung Il , Choi Hyun Joo , Blackmon Nicole L. , Lipchik Corey , Petrelli Nicholas J. , O'Connell Michael J. , Wolmark Norman , Paik Soonmyung , Pogue-Geile Kay L. 
Published: October 2012

Abstract
Purpose: The purpose of this study was to examine the prognostic and oxaliplatin predictive value of mismatch repair (MMR) status and common hot spot mutations, which we previously identified in stage II and III colon cancer.
Experimental Design: Mutations in BRAF, KRAS, NRAS, MET, and PIK3CA were profiled in 2,299 stage II and III colon tumors from National Surgical Adjuvant Breast and Bowel Project (NSABP) clinical trials C-07 (n = 1,836) and C-08 (n = 463) with Type Plex chemistry and mass spectrometry. C-07 tested the worth of adding oxaliplatin to 5-fluorouracil plus leucovorin, and C-08 tested the worth of adding bevacizumab to FOLFOX. Cox proportional hazard models were used to assess prognostic or oxaliplatin predictive value of mutations for tumor recurrence, overall survival (OS), and survival after recurrence (SAR).
Results: BRAF mutations were associated with MMR-deficient tumors (P &lt; 0.0001), poor OS [HR, 1.46; 95% confidence interval (CI), 1.20–1.79; P ≤ 0.0002], and poor SAR (HR, 2.31; 95% CI, 1.83–2.95; P &lt; 0.0001). Mutations in KRAS, NRAS, MET, and PIK3CA were not associated with recurrence, OS, or SAR. MMR-deficient tumors were associated with an improved prognosis based on recurrence (HR, 0.48; 95% CI, 0.33–0.70; P &lt; 0.0001). Mutations and MMR status were not predictive for oxaliplatin benefit.
Conclusions: This study shows that BRAF mutations profiled from stage II and III colon cancer tumors were associated with poor SAR and validates and explains, at least in part, previous observations associating it with poor OS. Profiling of all of these mutations is warranted for future clinical trials testing new targeted therapies that block relevant signaling pathways. Such clinical trials are under development at NSABP. Clin Cancer Res; 18(23); 6531–41. ©2012 AACR.
Adverse childhood experiences among women prisoners: Relationships to suicide attempts and drug abuse
Authors: Friestad Christine , Åse-Bente Rustad , Kjelsberg Ellen 
Published: October 2012

Background: Women prisoners are known to suffer from an accumulation of factors known to increase the risk for several major health problems. This study examines the prevalence of adverse childhood experiences (ACE) and the relationship between such experiences and suicide attempts and drug use among incarcerated women in Norway. Methods: A total of 141 women inmates (75% of all eligible) were interviewed using a structured interview guide covering information on demographics and a range of ACE related to abuse and neglect, and household dysfunction. The main outcome variables were attempted suicide and adult drug abuse. Results: Emotional, physical and sexual abuse during childhood was experienced by 39%, 36% and 19%, respectively, and emotional and physical neglect by 31% and 33%, respectively. Looking at the full range of ACE, 17% reported having experienced none, while 34% reported having experienced more than five ACEs. After controlling for age, immigrant background and marital status, the number of ACEs significantly increased the risk of attempted suicide and current drug abuse. Conclusion: The associations observed between early life trauma and later health risk behaviour indicate the need for early prevention. The findings also emphasize the important role of prison health services in secondary prevention among women inmates.