Genetic variation in the TLL1 gene is not associated with fibrosis in patients with metabolic associated fatty liver disease

Metabolic associated fatty liver disease (MAFLD) is the most prevalent liver disease in Western nations, with high heritability. A recent study of Japanese patients with the disease suggested that TLL1 rs17047200 is associated with fibrosis; whether a similar association is observed in Caucasian patients with MAFLD is unknown. We investigated the association of the TLL1 rs17047200 polymorphism with liver fibrosis in a cohort of Caucasian patients with MAFLD (n = 728). We also investigated whether TLL1 expression is altered during liver injury in humans, in murine models of fibrosis, and in in-vitro. While TLL1 expression is upregulated in the liver of humans with MAFLD and in mice, the rs17047200 variant was not associated with fibrosis or any other histological features, or with hepatic TLL1 expression. In conclusion, the TLL1 rs17047200 variant is not a risk variant for fibrosis in Caucasian patients with MAFLD. However, TLL1 could be involved in the pathogenesis of liver fibrosis

Safety and effectiveness of shoulder arthroplasties in Spain: a systematic review.

The effectiveness and safety of shoulder arthroplasties in the general context of a Spanish patient population remains unclear. The aim of this study was to ascertain both the effectiveness and safety of primary shoulder arthroplasties and the prosthesis types used in Spain. A systematic review of all the available literature evaluating the effectiveness and safety of primary shoulder arthroplasties in Spain was performed. A narrative synthesis was performed, and evidence tables were created in four dimensions: study design, arthroplasty characteristics, safety, and effectiveness. Orthopaedic Data Evaluation Panel (ODEP) scores were used to evaluate prosthesis types. Twenty-one studies were selected that included a total of 1293 arthroplasties. The most common indication was fractures, while the prosthesis most frequently used was the Delta Xtend (ODEP 10A). The most common complication was scapular notching. Prosthesis revision rate was approximately 6% for follow-ups between 12 and 79 months. In addition, significant improvements were observed in the Constant-Murley test score after the intervention. Currently in Spain, shoulder arthroplasty can be considered a safe and effective procedure with functional recovery and pain reduction for eligible patients with humeral fracture, rotator cuff arthropathy, fracture sequelae and malunion of the proximal humerus, and degenerative disease. Future longitudinal research and population-based studies could serve to confirm these results and identify points of improvement.The article is freely available via the publisher's site, click on the Publisher URL to access

Copy number variation and expression of exportin-4 associates with severity of fibrosis in metabolic associated fatty liver disease

Background: Liver fibrosis risk is a heritable trait, the outcome of which is the net deposition of extracellular matrix by hepatic stellate cell-derived myofibroblasts. Whereas nucleotide sequence variations have been extensively studied in liver fibrosis, the role of copy number variations (CNV) in which genes exist in abnormal numbers of copies (mostly due to duplication or deletion) has had limited exploration. Methods: The impact of the XPO4 CNV on histological liver damage was examined in a cohort comprised 646 Caucasian patients with biopsy-proven MAFLD and 170 healthy controls. XPO4 expression was modulated and function was examined in human and animal models. Findings: Here we demonstrate in a cohort of 816 subjects, 646 with biopsy-proven metabolic associated liver disease (MAFLD) and 170 controls, that duplication in the exportin 4 (XPO4) CNV is associated with the severity of liver fibrosis. Functionally, this occurs via reduced expression of hepatic XPO4 that maintains sustained activation of SMAD3/SMAD4 and promotes TGF-β1-mediated HSC activation and fibrosis. This effect was mediated through termination of nuclear SMAD3 signalling. XPO4 demonstrated preferential binding to SMAD3 compared to other SMADs and led to reduced SMAD3-mediated responses as shown by attenuation of TGFβ1 induced SMAD transcriptional activity, reductions in the recruitment of SMAD3 to target gene promoters following TGF-β1, as well as attenuation of SMAD3 phosphorylation and disturbed SMAD3/SMAD4 complex formation. Interpretation: We conclude that a CNV in XPO4 is a critical mediator of fibrosis severity and can be exploited as a therapeutic target for liver fibrosis. Funding: ME and JG are supported by the Robert W. Storr Bequest to the Sydney Medical Foundation, University of Sydney; a National Health and Medical Research Council of Australia (NHMRC) Program Grant (APP1053206) and Project and ideas grants (APP2001692, APP1107178 and APP1108422). AB is supported by an Australian Government Research Training Program (RTP) scholarship. EB is supported by Horizon 2020 under grant 634413 for the project EPoS

Mistranslation Drives Alterations in Protein Levels and the Effects of a Synonymous Variant at the Fibroblast Growth Factor 21 Locus

Fibroblast growth factor 21 (FGF21) is a liver-derived hormone with pleiotropic beneficial effects on metabolism. Paradoxically, FGF21 levels are elevated in metabolic diseases. Interventions that restore metabolic homeostasis reduce FGF21. Whether abnormalities in FGF21 secretion or resistance in peripheral tissues is the initiating factor in altering FGF21 levels and function in humans is unknown. A genetic approach is used to help resolve this paradox. The authors demonstrate that the primary event in dysmetabolic phenotypes is the elevation of FGF21 secretion. The latter is regulated by translational reprogramming in a genotype- and context-dependent manner. To relate the findings to tissues outcomes, the minor (A) allele of rs838133 is shown to be associated with increased hepatic inflammation in patients with metabolic associated fatty liver disease. The results here highlight a dominant role for translation of the FGF21 protein to explain variations in blood levels that is at least partially inherited. These results provide a framework for translational reprogramming of FGF21 to treat metabolic diseases

Mitochondrial ATP fuels ABC transporter-mediated drug efflux in cancer chemoresistance

Chemotherapy remains the standard of care for most cancers worldwide, however development of chemoresistance due to the presence of the drug-effluxing ATP binding cassette (ABC) transporters remains a significant problem. The development of safe and effective means to overcome chemoresistance is critical for achieving durable remissions in many cancer patients. We have investigated the energetic demands of ABC transporters in the context of the metabolic adaptations of chemoresistant cancer cells. Here we show that ABC transporters use mitochondrial-derived ATP as a source of energy to efflux drugs out of cancer cells. We further demonstrate that the loss of methylation-controlled J protein (MCJ) (also named DnaJC15), an endogenous negative regulator of mitochondrial respiration, in chemoresistant cancer cells boosts their ability to produce ATP from mitochondria and fuel ABC transporters. We have developed MCJ mimetics that can attenuate mitochondrial respiration and safely overcome chemoresistance in vitro and in vivo. Administration of MCJ mimetics in combination with standard chemotherapeutic drugs could therefore become an alternative strategy for treatment of multiple cancers

Medios de comunicación y derecho a la información en Jalisco 2013

En el primer apartado, dedicado al sistema de medios en general, se presentan tres artículos: “Nuevos medios de comunicación en Jalisco”, “c7 ¿medio público o vocero del gobierno?” y “Réquiem por un ombudsman”. El segundo apartado está dedicado al tema de la libertad de expresión; se presentan aquí dos textos: “La vulnerabilidad en un ambiente de cambio. Los ataques a los medios de comunicación en Jalisco durante el año” y “Violaciones a la libertad de expresión de periodistas y trabajadores de medios en Jalisco, 1995-2013”. En el apartado “Derecho a la información, comunicación y política” se ofrecen cuatro textos de índole muy diversa: “La estrategia de comunicación del Gobierno del Estado”, “Diálogos públicos: la discusión de una nueva ley de transparencia para Jalisco”, “Cuando un niño desaparece, el peor enemigo es el tiempo…”, sobre la alerta Amber, y “2013: un año marcado por despidos en diversos periódicos de Guadalajara”. En la sección “Los que se fueron” se presenta la semblanza de Felipe Vicencio. Y en el apartado de “La investigación del observatorio de medios” se comparten los resultados de un trabajo sobre los columnistas de opinión jaliscienses que escriben en la prensa local.ITESO, A.C

Inter-Cellular Variation in DNA Content of Entamoeba histolytica Originates from Temporal and Spatial Uncoupling of Cytokinesis from the Nuclear Cycle

Accumulation of multiple copies of the genome in a single nucleus and several nuclei in a single cell has previously been noted in Entamoeba histolytica, contributing to the genetic heterogeneity of this unicellular eukaryote. In this study, we demonstrate that this genetic heterogeneity is an inherent feature of the cell cycle of this organism. Chromosome segregation occurs on a variety of novel microtubular assemblies including multi-polar spindles. Cytokinesis in E. histolytica is completed by the mechanical severing of a thin cytoplasmic bridge, either independently or with the help of neighboring cells. Importantly, cytokinesis is uncoupled from the nuclear division cycle, both temporally and spatially, leading to the formation of unequal daughter cells. Sorting of euploid and polyploid cells showed that each of these sub-populations acquired heterogeneous DNA content upon further growth. Our study conclusively demonstrates that genetic heterogeneity originates from the unique mode of cell division events in this protist

Receptor-Specific Mechanisms Regulate Phosphorylation of AKT at Ser473: Role of RICTOR in β1 Integrin-Mediated Cell Survival

A tight control over AKT/PKB activation is essential for cells, and they realise this in part by regulating the phosphorylation of Ser473 in the “hydrophobic motif” of the AKT carboxy-terminal region. The RICTOR-mTOR complex (TORC2) is a major kinase for AKT Ser473 phosphorylation after stimulation by several growth factors, in a reaction proposed to require p21-activated kinase (PAK) as a scaffold. However, other kinases may catalyse this reaction in stimuli-specific manners. Here we characterised the requirement of RICTOR, ILK, and PAK for AKT Ser473 phosphorylation downstream of selected family members of integrins, G protein-coupled receptors, and tyrosine-kinase receptors and analysed the importance of this phosphorylation site for adhesion-mediated survival. siRNA-mediated knockdown in HeLa and MCF7 cells showed that RICTOR-mTOR was required for phosphorylation of AKT Ser473, and for efficient phosphorylation of the downstream AKT targets FOXO1 Thr24 and BAD Ser136, in response to β1 integrin-stimulation. ILK and PAK1/2 were dispensable for these reactions. RICTOR knockdown increased the number of apoptotic MCF7 cells on β1 integrin ligands up to 2-fold after 24 h in serum-free conditions. β1 integrin-stimulation induced phosphorylation of both AKT1 and AKT2 but markedly preferred AKT2. RICTOR-mTOR was required also for LPA-induced AKT Ser473 phosphorylation in MCF7 cells, but, interestingly, not in HeLa cells. PAK was needed for the AKT Ser473 phosphorylation in response to LPA and PDGF, but not to EGF. These results demonstrate that different receptors utilise different enzyme complexes to phosphorylate AKT at Ser473, and that AKT Ser473 phosphorylation significantly contributes to β1 integrin-mediated anchorage-dependent survival of cells

A Proteomic and Cellular Analysis of Uropods in the Pathogen Entamoeba histolytica

Exposure of Entamoeba histolytica to specific ligands induces cell polarization via the activation of signalling pathways and cytoskeletal elements. The process leads to formation of a protruding pseudopod at the front of the cell and a retracting uropod at the rear. In the present study, we show that the uropod forms during the exposure of trophozoites to serum isolated from humans suffering of amoebiasis. To investigate uropod assembly, we used LC-MS/MS technology to identify protein components in isolated uropod fractions. The galactose/N-acetylgalactosamine lectin, the immunodominant antigen M17 (which is specifically recognized by serum from amoeba-infected persons) and a few other cells adhesion-related molecules were primarily involved. Actin-rich cytoskeleton components, GTPases from the Rac and Rab families, filamin, α-actinin and a newly identified ezrin-moesin-radixin protein were the main factors found to potentially interact with capped receptors. A set of specific cysteine proteases and a serine protease were enriched in isolated uropod fractions. However, biological assays indicated that cysteine proteases are not involved in uropod formation in E. histolytica, a fact in contrast to the situation in human motile immune cells. The surface proteins identified here are testable biomarkers which may be either recognized by the immune system and/or released into the circulation during amoebiasis

Effectiveness and Safety of the Sequential Use of a Second and Third Anti-TNF Agent in Patients with Inflammatory Bowel Disease: Results from the Eneida Registry

Background: The effectiveness of the switch to another anti-tumor necrosis factor (anti-TNF) agent is not known. The aim of this study was to analyze the effectiveness and safety of treatment with a second and third anti-TNF drug after intolerance to or failure of a previous anti-TNF agent in inflammatory bowel disease (IBD) patients. Methods: We included patients diagnosed with IBD from the ENEIDA registry who received another anti-TNF after intolerance to or failure of a prior anti-TNF agent. Results: A total of 1122 patients were included. In the short term, remission was achieved in 55% of the patients with the second anti-TNF. The incidence of loss of response was 19% per patient-year with the second anti-TNF. Combination therapy (hazard ratio [HR], 2.4; 95% confidence interval [CI], 1.8-3; P < 0.0001) and ulcerative colitis vs Crohn''s disease (HR, 1.6; 95% CI, 1.1-2.1; P = 0.005) were associated with a higher probability of loss of response. Fifteen percent of the patients had adverse events, and 10% had to discontinue the second anti-TNF. Of the 71 patients who received a third anti-TNF, 55% achieved remission. The incidence of loss of response was 22% per patient-year with a third anti-TNF. Adverse events occurred in 7 patients (11%), but only 1 stopped the drug. Conclusions: Approximately half of the patients who received a second anti-TNF achieved remission; nevertheless, a significant proportion of them subsequently lost response. Combination therapy and type of IBD were associated with loss of response. Remission was achieved in almost 50% of patients who received a third anti-TNF; nevertheless, a significant proportion of them subsequently lost response