MICU1 Interacts with the D-Ring of the MCU Pore to Control Its Ca2+ Flux and Sensitivity to Ru360

Proper control of the mitochondrial Ca2+ uniporter's pore (MCU) is required to allow Ca2+-dependent activation of oxidative metabolism and to avoid mitochondrial Ca2+ overload and cell death. The MCU's gatekeeping and cooperative activation is mediated by the Ca2+-sensing MICU1 protein, which has been proposed to form dimeric complexes anchored to the EMRE scaffold of MCU. We unexpectedly find that MICU1 suppresses inhibition of MCU by ruthenium red/Ru360, which bind to MCU's DIME motif, the selectivity filter. This led us to recognize in MICU1's sequence a putative DIME interacting domain (DID), which is required for both gatekeeping and cooperative activation of MCU and for cell survival. Thus, we propose that MICU1 has to interact with the D-ring formed by the DIME domains in MCU to control the uniporter. Copyright © 2018 Elsevier Inc. All rights reserved

Do patients with non-ulcer dyspepsia respond differently to Helicobacter pylori eradication treatments from those with peptic ulcer disease? A systematic review

Aim: It is controversial whether patients with non-ulcer dyspepsia (NUD) respond differently to Helicobacter pylori (H pylori) eradication treatment than those with peptic ulcer disease (PUD). To review the evidence for any difference in H pylori eradication rates between PUD and NUD patients. Methods: A literature search for full articles and meeting abstracts to July 2004 was conducted. We included studies evaluating the efficacy of a proton pump inhibitor (P) or ranitidine bismuth citrate (RBC) plus two antibiotics of clarithromycin (C), amoxicillin (A), metronidazole (M), or P-based quadruple therapies for eradicating the infection. Results: Twenty-two studies met the criteria. No significant difference in eradication rates was found between PUD and NUD patients when treated with 7-d RBCCA, 10-d PCA or P-based quadruple therapies. When the 7-d PCA was used, the pooled H pylori eradication rate was 82.1% (431/525) and 72.6% (448/617) for PUD and NUD patients, respectively, yielding a RR of 1.15 (95%CI 1.01-1.29). However, the statistically significant difference was seen only in meeting abstracts, but not in full publications. Conclusion: There is no convincing evidence to suggest that NUD patients respond to H pylori eradication treatments differently from those with PUD, although a trend exists with the 7-d PCA therapy. © 2005 The WJG Press and Elsevier Inc. All rights reserved.published_or_final_versio

Head-to-head comparison of H2-receptor antagonists and proton pump inhibitors in the treatment of erosive esophagitis: A meta-analysis

Aim: To systematically evaluate the efficacy of H2-receptor antagonists (H2RAs) and proton pump inhibitors in healing erosive esophagitis (EE). Methods: A meta-analysis was performed. A literature search was conducted in PubMed, Medline, Embase, and Cochrane databases to include randomized controlled head-to-head comparative trials evaluating the efficacy of H2RAs or proton pump inhibitors in healing EE. Relative risk (RR) and 95% confidence interval (CI) were calculated under a random-effects model. Results: RRs of cumulative healing rates for each comparison at 8 wk were: high dose vs standard dose H2RAs, 1.17 (95%CI, 1.02-1.33); standard dose proton pump inhibitors vs standard dose H2RAs, 1.59 (95%CI, 1.44-1.75); standard dose other proton pump inhibitors vs standard dose omeprazole, 1.06 (95%CI, 0.98-1.06). Proton pump inhibitors produced consistently greater healing rates than H2RAs of all doses across all grades of esophagitis, including patients refractory to H2RAs. Healing rates achieved with standard dose omeprazole were similar to those with other proton pump inhibitors in all grades of esophagitis. Conclusion: H2RAs are less effective for treating patients with erosive esophagitis, especially in those with severe forms of esophagitis. Standard dose proton pump inhibitors are significantly more effective than H2RAs in healing esophagitis of all grades. Proton pump inhibitors given at the recommended dose are equally effective for healing esophagitis. © 2005 The WJG Press and Elsevier Inc. All rights reserved.published_or_final_versio

Effects of L-arginine on intestinal development and endogenous arginine-synthesizing enzymes in neonatal pigs

This study aimed to investigate the effects of dietary L-arginine supplementation on the intestinal development of neonatal piglets and the underlying mechanisms. 36 neonatal piglets were randomly allocated into three diet groups: control group (supplemented with 0% L-arginine), 0.4 and 0.8% Larginine groups. When compared with the control, dietary supplementation with L-arginine decreased (P<0.05) blood urea nitrogen (BUN), and improved (P<0.05) serum T3 and insulin level of the piglets on day 11. Arginine and its metabolites (citrulline and ornithine) were elevated, additionally, dietary supplementation with 0.8% L-arginine markedly enhanced jejunal villus height, villus area on day 11 and D-xylose absorption rate on day 19. Dietary supplementation with 0.8% L-arginine increased (P<0.05) activities of maltose and lactose on day 18, respectively. This effect correlated with profound change in enzyme activities as inducible nitric oxide synthetase (iNOS), glutamine synthetase (GS) and ornithine decarboxylase (ODC) were elevated on day 18. The concentrations of spermine was increased (P<0.05) by L-arginine supplementation on day 18. These results collectively suggest that dietary  Larginine supplementation improves protein synthesis and intestinal development of the neonatal pigs, the underlying mechanism includes dietary L-arginine supplementation which regulated the productions of intestinal polyamine in jejunum, and stimulated endogenous arginine-synthesizing enzymes in neonatal piglets.Key words: Neonatal pig, L-arginine, intestinal development, arginine-synthetases

The role of cardiac troponin T quantity and function in cardiac development and dilated cardiomyopathy

Background: Hypertrophic (HCM) and dilated (DCM) cardiomyopathies results from sarcomeric protein mutations, including cardiac troponin T (cTnT, TNNT2). We determined whether TNNT2 mutations cause cardiomyopathies by altering cTnT function or quantity; whether the severity of DCM is related to the ratio of mutant to wildtype cTnT; whether Ca2+ desensitization occurs in DCM; and whether absence of cTnT impairs early embryonic cardiogenesis. Methods and Findings: We ablated Tnnt2 to produce heterozygous Tnnt2+/ mice, and crossbreeding produced homozygous null Tnnt2-/-embryos. We also generated transgenic mice overexpressing wildtype (TGWT) or DCM mutant (TGK210Δ) Tnnt2. Crossbreeding produced mice lacking one allele of Tnnt2, but carrying wildtype (Tnnt2+/-/TGWT) or mutant (Tnnt2+/-/TGK210Δ) transgenes. Tnnt2+/-mice relative to wildtype had significantly reduced transcript (0.82 ± 0.06 [SD] vs. 1.00 ± 0.12 arbitrary units; p = 0.025), but not protein (1.01 ± 0.20 vs. 1.00 ± 0.13 arbitrary units; p = 0.44). Tnnt2+/-mice had normal hearts (histology, mass, left ventricular end diastolic diameter [LVEDD], fractional shortening [FS]). Moreover, whereas Tnnt2+/-/ TGK210Δ mice had severe DCM, TGK210Δ mice had only mild DCM (FS 18 ± 4 vs. 29 ± 7%; p < 0.01). The difference in severity of DCM may be attributable to a greater ratio of mutant to wildtype Tnnt2 transcript in Tnnt2+/-/TGK210Δ relative to TGK210Δ mice (2.42±0.08, p = 0.03). Tnnt2+/-/TGK210Δ muscle showed Ca2+ desensitization (pCa50 = 5.34 ± 0.08 vs. 5.58 ± 0.03 at sarcomere length 1.9 μm. p<0.01), but no difference in maximum force generation. Day 9.5 Tnnt2-/-embryos had normally looped hearts, but thin ventricular walls, large pericardial effusions, noncontractile hearts, and severely disorganized sarcomeres. Conclusions: Absence of one Tnnt2 allele leads to a mild deficit in transcript but not protein, leading to a normal cardiac phenotype. DCM results from abnormal function of a mutant protein, which is associated with myocyte Ca2+ desensitization. The severity of DCM depends on the ratio of mutant to wildtype Tnnt2 transcript. cTnT is essential for sarcomere formation, but normal embryonic heart looping occurs without contractile activity. © 2008 Ahmad et al

A multi-functional PEGylated gold(iii) compound: potent anti-cancer properties and self-assembly into nanostructures for drug co-delivery

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Helicobacter pylori infection is associated with increased expression of macrophage migratory inhibitory factor - by epithelial cells, T cells, and macrophages - in gastric mucosa

The macrophage migratory inhibitory factor (MIF) plays a pivotal role in inflammatory and immune diseases; however, its role in gastrointestinal diseases has not been clarified. This study intended to determine the expression of MIF, by gastric epithelial cells, T cells, and macrophages, in Helicobacter pylori-induced gastritis. Sixty-four patients (30 males, 34 females; mean age, 47 years) referred for upper endoscopy were recruited. Biopsy specimens from the gastric antrum and corpus were obtained for (1) detection of H. pylori and histological examination, (2) single and double immunostaining to test for expression of MIF protein in epithelial cells, T cells, and macrophages, and (2) in situ hybridization for expression of MIF mRNA within the lamina propria. In mucosal specimens from each of the 2 sites, both the percentage of MIF + epithelial cells and the numbers of MIF mRNA+ inflammatory cells, MIF+ T cells, and MIF+ macrophages were significantly higher in H. pylori-positive patients than in H. pylori-negative patients. Overall, the percentage of MIF+ epithelial cells and the numbers of MIF mRNA+ cells, MIF+ T cells, and MIF+ macrophages were higher in the antrum than in the corpus. The percentage of MIF+ epithelial cells and the numbers of MIF mRNA+ cells, MIF+ T cells, and MIF+ macrophages increased in chronic gastritis, but, in the absence of H. pylori infection, this increase disappeared for all except MIF+ T cells. Therefore, H. pylori infection is associated with increased expression of the MIF protein and MIF mRNA in gastric epithelial and inflammatory cells; along with other cytokines, MIF may play a significant role in gastric inflammation related to H. pylori infection.published_or_final_versio

Application of analytic tools for theory testing in organizational behaviour research

Best paper award in ManagementTrack: ManagementMany management journals insist on having a strong theoretical perspective for empirical studies. The purpose of this paper is to investigate the conditions under which one can claim that a study is theory-driven. The basic premise of our approach is to develop hypotheses that map directly onto the explanatory mechanisms that are employed to explain why a phenomenon would occur. We provide both conceptual and technical tools for ...published_or_final_versio

Penetration and intracellular uptake of poly(glycerol-adipate)nanoparticles into 3-dimensional brain tumour cell culture models

Nanoparticle (NP) drug delivery systems may potentially enhance the efficacy of therapeutic agents. It is difficult to characterise many important properties of NPs in vivo and therefore attempts have been made to use realistic in vitro multicellular spheroids instead. In this paper we have evaluated poly(glycerol-adipate) (PGA) NPs as a potential drug carrier for local brain cancer therapy. Various 3-dimensional (3-D) cell culture models have been used to investigate the delivery properties of PGA NPs. Tumour cells in 3-D culture showed a much higher level of endocytic uptake of NPs than a mixed normal neonatal brain cell population. Differences in endocytic uptake of NPs in 2-D and 3-D models strongly suggest that it is very important to use in vitro 3-D cell culture models for evaluating this parameter. Tumour penetration of NPs is another important parameter which could be studied in 3-D cell models. The penetration of PGA NPs through 3-D cell culture varied between models, which will therefore require further study to develop useful and realistic in vitro models. Further use of 3-D cell culture models will be of benefit in the future development of new drug delivery systems, particularly for brain cancers which are more difficult to study in vivo

Expression of macrophage migration inhibitory factor in Helicobacter pylori-induced gastritis and peptic ulcer disease

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