The Inheritance of Resistance Alleles in Multiple Sclerosis

Multiple sclerosis (MS) is a complex trait in which alleles at or near the class II loci HLA-DRB1 and HLA-DQB1 contribute significantly to genetic risk. HLA-DRB1*15 and HLA-DRB1*17-bearing haplotypes and interactions at the HLA-DRB1 locus increase risk of MS but it has taken large samples to identify resistance HLA-DRB1 alleles. In this investigation of 7,093 individuals from 1,432 MS families, we have assessed the validity, mode of inheritance, associated genotypes, and the interactions of HLA-DRB1 resistance alleles. HLA-DRB1*14-, HLA-DRB1*11-, HLA-DRB1*01-, and HLA-DRB1*10-bearing haplotypes are protective overall but they appear to operate by different mechanisms. The first type of resistance allele is characterised by HLA-DRB1*14 and HLA-DRB1*11. Each shows a multiplicative mode of inheritance indicating a broadly acting suppression of risk, but a different degree of protection. In contrast, a second type is exemplified by HLA-DRB1*10 and HLA-DRB1*01. These alleles are significantly protective when they interact specifically in trans with HLA-DRB1*15-bearing haplotypes. HLA-DRB1*01 and HLA-DRB1*10 do not interact with HLA-DRB1*17, implying that several mechanisms may be operative in major histocompatibility complex–associated MS susceptibility, perhaps analogous to the resistance alleles. There are major practical implications for risk and for the exploration of mechanisms in animal models. Restriction of antigen presentation by HLA-DRB1*15 seems an improbably simple mechanism of major histocompatibility complex–associated susceptibility

Melatonin administration in diabetes: regulation of plasma Cr, V, and Mg in young male Zucker diabetic fatty rats

The use of melatonin, a neurohormone present in plants, represents an exciting approach for the maintenance of optimum health conditions. Melatonin administration ameliorates glucose homeostasis in Zucker diabetic fatty (ZDF) rats. The objective of this study was to investigate the effects of melatonin in diabetes in relation to the levels and regulation of plasma chromium (Cr), vanadium (V), and magnesium (Mg) in Zucker diabetic fatty (ZDF) and Zucker lean (ZL) rats. At the age of 6 weeks, ZDF (n ¼ 30) and ZL (n ¼ 30) groups were each subdivided into three groups: control (C) (n ¼ 10), vehicle-treated (V 0 ) (n ¼ 10) and melatonin-treated (M) (10 mg kg À1 per day; n ¼ 10) groups for a 6 week period. After treatment, plasma mineral concentrations were measured by flame (Mg) and electrothermal (Cr and V) atomic absorption spectrometry. No significant differences were found between the C and V 0 groups (p > 0.05). Plasma Mg levels were significantly lower in C-ZDF vs. C-ZL rats, demonstrating the presence of hypomagnesemia in this diabetes mellitus model. Plasma V and Cr levels were significantly higher in M-ZDF vs. C-ZDF rats. Plasma Mg levels in ZDF rats were not affected by melatonin treatment (p > 0.05). Melatonin administration ameliorates the diabetic status of ZDF rats by enhancing plasma Cr and V concentrations. This appears to be the first report of a beneficial effect of melatonin treatment on plasma Cr and V regulation in ZDF rats

La experimentación del ECTS en trabajo social: la experiencia desde la Universidad de La Laguna

La experimentación del ECTS en trabajo social: la experiencia desde la Universidad de La Lagun

Feasibility study of reinforced concrete reinforced concrete buildings for upper stratum apartments in the city of Bogotá. A methodology to maximize profit

En el marco de la gerencia de proyectos y su fase de planeación se concibió e implementó una metodología para determinar la utilidad máxima que se puede obtener cuando se piensa en construir un edificio destinado a vivienda en estrato alto en la ciudad de Bogotá. La metodología que permitió alcanzar este objetivo fue la ciencia de investigación de operaciones, a través de la técnica de programación lineal. Esta metodología comprende la definición, planteamiento y resolución de modelos matemáticos para encontrar soluciones óptimas a través de las matemáticas y computadoras con el propósito de mitigar riesgos y facilitar la toma de decisiones. Conforme a la metodología seleccionada se formuló matemáticamente la expresión de la utilidad máxima esperada, la cual conjuntamente con otras fórmulas y variables de carácter comercial, técnico, normativo, económico y financiero, relacionadas con las restricciones propias del modelo, permitieron con la aplicación del Programa Solver de Excel obtener la solución deseada. Finalmente y teniendo en cuenta el cambiante y dinámico escenario de la industria de la construcción en la ciudad capital, se realizó el análisis de sensibilidad, que sometió los resultados óptimos obtenidos a escenarios alternativos para validar rechazar la aplicación de los mismos.INTRODUCCIÓN 19 ANTECEDENTES 22 DEFINICION DEL PROBLEMA DE INVESTIGACION 27 JUSTIFICACION 29 OBJETIVOS GENERALES Y ESPECIFICOS 30 HIPOTESIS O SUPUESTOS 32 1. MARCO TEORICO 34 1.1 CONTEXTO DE LA INVESTIGACIÓN 34 1.2 ENTORNO URBANO 35 1.3 DEFINICIÓN DE LA UTILIDAD DEL PROYECTO 39 1.4 ESTUDIO DE FACTIBILIDAD DEL PROYECTO 41 1.4.1 Factibilidad comercial 41 1.4.2 Factibilidad normativa 46 1.4.2.1 Indice de ocupación 47 1.4.2.2 Indice de construcción 48 1.4.2.3 Número máximo de pisos 49 1.4.3 Factibilidad técnica 51 1.4.3.1 Los estudios geotécnicos 51 1.4.3.2 El diseño arquitectónico 52 1.4.3.3 El diseño estructural 55 1.4.3.4 El diseño de la cimentación 66 1.4.4 Factibilidad económica 73 1.4.4.1 El lote y su valor comercial 74 1.4.4.2 Costos directos 75 1.4.4.3 Costos Indirectos 95 1.4.5 Factibilidad financiera 106 1.4.5.1 Bondad financiera del Proyecto 107 1.5 GERENCIA DE VALOR 112 1.5.1 Valor Económico Agregado. EVA. 112 2. METODOLOGIA 120 2.1 INVESTIGACIÓN DE OPERACIONES 120 2.1.1 Problema de programación lineal 124 2.1.2 Problema de Programación Lineal. Uso del Programa Solver de Excel 127 3. RESULTADOS DE LA INVESTIGACION 134 3.1 FORMULACIÓN DEL PROBLEMA DE LA INVESTIGACIÓN 136 3.2 PLANTEAMIENTO Y DESCRIPCIÓN PROBLEMA DE INVESTIGACIÓN 138 3.3 IDENTIFICACIÓN DE LOS DATOS DEL PROBLEMA 139 3.3.1 Información Comercial 139 3.3.2 Información Normativa 139 3.3.3 Información Técnica 140 3.3.4 Información Económica 141 3.3.5 Información Financiera 141 3.4 IDENTIFICACIÓN DEL CRITERIO DE DECISIÓN 142 3.5 IDENTIFICACIÓN DE LAS VARIABLES DE DECISIÓN 142 3.6 IDENTIFICACIÓN DE LA FUNCIÓN OBJETIVO 143 3.7 IDENTIFICACIÓN DE RESTRICCIONES CONCEPTUALES Y LÓGICAS 144 3.7.1 Restricción Comercial 144 3.7.2 Restricción Normativa 145 3.7.3 Restricción Técnica 146 3.7.4 Restricción Económica 150 3.7.5 Restricción Financiera 154 3.7.6 Restricciones lógicas 155 3.8 EVALUACIÓN FINANCIERA DEL PROYECTO. E.V.A. 156 3.9 OBTENCIÓN DE LA SOLUCIÓN ÓPTIMA 157 3.10.DESCRIPCIÓN, INTERPRETACIÓN Y ANÁLISIS SOLUCIÓN ÓPTIMA 160 3.11. ANÁLISIS DE SENSIBILIDAD Y PARAMÉTRICOS 174 3.11.1 Análisis de sensibilidad. Caso 1. Comercial 174 3.11.2 Análisis de sensibilidad. Caso 2. Técnica- económica 176 3.11.3 Análisis de sensibilidad. Caso 3. Financiera 178 3.11.4 Análisis de sensibilidad. Caso 4. Normativa 180 4. CONCLUSIONES 182 5. RECOMENDACIONES 199 BIBLIOGRAFIA 204 ANEXOS 210MaestríaWithin the framework of project management and its planning phase, a methodology was conceived and implemented to determine the maximum profit that can be obtained when thinking of constructing a building for upper-tier housing in the city of Bogotá. The methodology that allowed to achieve this objective was the science of operations research, through the linear programming technique. This methodology includes the definition, approach and resolution of mathematical models to find optimal solutions through mathematics and computers in order to mitigate risks and facilitate decision-making. In accordance with the selected methodology, the expression of the maximum expected profit was formulated mathematically, which together with other formulas and variables of a commercial, technical, regulatory, economic and financial nature, related to the model's own restrictions, allowed with the application of the Program. Excel solver get the desired solution. Finally, and taking into account the changing and dynamic scenario of the construction industry in the capital city, a sensitivity analysis was carried out, which submitted the optimal results obtained to alternative scenarios to validate reject their application.Modalidad Presencia

An Extremes of outcome strategy provides evidence that multiple sclerosis severity is determined by alleles at the <i>HLA-DRB1</i> locus

Multiple sclerosis (MS) is a common inflammatory disease of the central nervous system unsurpassed for variability in disease outcome. A cohort of sporadic MS cases (n=63), taken from opposite extremes of the distribution of long-term outcome, was used to determine the role of the HLA-DRB1 locus on MS disease severity. Genotyping sets of benign and malignant MS patients showed that HLA-DRB1*01 was significantly underrepresented in malignant compared with benign cases. This allele appears to attenuate the progressive disability that characterizes MS in the long term. The observation was doubly replicated in (i) Sardinian benign and malignant patients and (ii) a cohort of affected sibling pairs discordant for HLA-DRB1*01. Among the latter, mean disability progression indices were significantly lower in those carrying the HLA-DRB1*01 allele compared with their disease-concordant siblings who did not. The findings were additionally supported by similar transmission distortion of HLA-DRB1*04 subtypes closely related to HLA-DRB1*01. The protective effect of HLA-DRB1*01 in sibling pairs may result from a specific epistatic interaction with the susceptibility allele HLA-DRB1*1501. A high-density (&gt;700) SNP examination of the MHC region in the benign and malignant patients could not identify variants differing significantly between the two groups, suggesting that HLA-DRB1 may itself be the disease-modifying locus. We conclude that HLA-DRB1*01, previously implicated in disease resistance, acts as an independent modifier of disease progression. These results closely link susceptibility to long-term outcome in MS, suggesting that shared quantitative MHC-based mechanisms are common to both, emphasizing the central role of this region in pathogenesis

Clathrin switches transforming growth factor-β role to pro-tumorigenic in liver cancer

Background & Aims: Upon ligand binding, tyrosine kinase receptors, such as epidermal growth factor receptor (EGFR), are recruited into clathrin-coated pits for internalization by endocytosis, which is relevant for signalling and/or receptor degradation. In liver cells, transforming growth factor-beta (TGF-beta) induces both pro- and anti-apoptotic signals; the latter are mediated by the EGFR pathway. Since EGFR mainly traffics via clathrin-coated vesicles, we aimed to analyse the potential role of clathrin in TGF-beta-induced signalling in liver cells and its relevance in liver cancer. Methods: Real-Time PCR and immunohistochemistry were used to analyse clathrin heavy-chain expression in human (CLTC) and mice (Cltc) liver tumours. Transient knockdown (siRNA) or overexpression of CLTC were used to analyse its role on TGF-beta and EGFR signalling in vitro. Bioinformatic analysis was used to determine the effect of CLTC and TGEB1 expression on prognosis and overall survival in patients with hepatocellular carcinoma (HCC). Results: Clathrin expression increased during liver tumorigenesis in humans and mice. CLTC knockdown cells responded to TGF-beta phosphorylating SMADs (canonical signalling) but showed impairment in the anti-apoptotic signals (EGFR transactivation). Experiments of loss or gain of function in HCC cells reveal an essential role for clathrin in inhibiting TGF-beta-induced apoptosis and upregulation of its pro-apoptotic target NOX4. Autocrine TGF-beta signalling in invasive HCC cells upregulates CLTC expression, switching its role to pro-tumorigenic. A positive correlation between TGEB1 and CLTC was found in HCC cells and patients. Patients expressing high levels of TGEB1 and CLTC had a worse prognosis and lower overall survival. Conclusions: This work describes a novel role for clathrin in liver tumorigenesis, favouring non-canonical pro-tumorigenic TGF-beta pathways. CLTC expression in human HCC samples could help select patients that would benefit from TGF-beta-targeted therapy. Lay summary: Clathrin heavy-chain expression increases during liver tumorigenesis in humans (CLTC) and mice (Mc), altering the cellular response to TGF-beta in favour of anti-apoptotic/pro-tumorigenic signals. A positive correlation between TGEB1 and CLTC was found in HCC cells and patients. Patients expressing high levels of TGEB1 and CLTC had a worse prognosis and lower overall survival. CLTC expression in HCC human samples could help select patients that would benefit from therapies targeting TGF-beta. (C) 2019 European Association for the Study of the Liver. Published by Elsevier B

MicroRNA Expression in Abdominal and Gluteal Adipose Tissue Is Associated with mRNA Expression Levels and Partly Genetically Driven

To understand how miRNAs contribute to the molecular phenotype of adipose tissues and related traits, we performed global miRNA expression profiling in subcutaneous abdominal and gluteal adipose tissue of 70 human subjects and characterised which miRNAs were differentially expressed between these tissues. We found that 12% of the miRNAs were significantly differentially expressed between abdominal and gluteal adipose tissue (FDR adjusted p<0.05) in the primary study, of which 59 replicated in a follow-up study of 40 additional subjects. Further, 14 miRNAs were found to be associated with metabolic syndrome case-control status in abdominal tissue and three of these replicated (primary study: FDR adjusted p<0.05, replication: p<0.05 and directionally consistent effect). Genome-wide genotyping was performed in the 70 subjects to enable miRNA expression quantitative trait loci (eQTL) analysis. Candidate miRNA eQTLs were followed-up in the additional 40 subjects and six significant, independent cis-located miRNA eQTLs (primary study: p<0.001; replication: p<0.05 and directionally consistent effect) were identified. Finally, global mRNA expression profiling was performed in both tissues to enable association analysis between miRNA and target mRNA expression levels. We find 22% miRNAs in abdominal and 9% miRNAs in gluteal adipose tissue with expression levels significantly associated with the expression of corresponding target mRNAs (FDR adjusted p<0.05). Taken together, our results indicate a clear difference in the miRNA molecular phenotypic profile of abdominal and gluteal adipose tissue, that the expressions of some miRNAs are influenced by cis-located genetic variants and that miRNAs are associated with expression levels of their predicted mRNA targets

Lack of EGFR catalytic activity in hepatocytes improves liver regeneration following DDC-induced cholestatic injury by promoting a pro-restorative inflammatory response

Despite the well-known hepatoprotective role of the epidermal growth factor receptor (EGFR) pathway upon acute damage, its specific actions during chronic liver disease, particularly cholestatic injury, remain ambiguous and unresolved. Here, we analyzed the consequences of inactivating EGFR signaling in the liver on the regenerative response following cholestatic injury. For that, transgenic mice overexpressing a dominant negative mutant human EGFR lacking tyrosine kinase activity (ΔEGFR) in albumin-positive cells were submitted to liver damage induced by 3,5-diethoxycarbonyl-1,4-dihydrocollidine (DDC), an experimental model resembling human primary sclerosing cholangitis. Our results show an early activation of EGFR after 1–2 days of a DDC-supplemented diet, followed by a signaling switch-off. Furthermore, ΔEGFR mice showed less liver damage and a more efficient regeneration following DDC injury. Analysis of the mechanisms driving this effect revealed an enhanced activation of mitogenic/survival signals, AKT and ERK1/2-MAPKs, and changes in cell turnover consistent with a quicker resolution of damage in response to DDC. These changes were concomitant with profound differences in the profile of intrahepatic immune cells, consisting of a shift in the M1/M2 balance towards M2 polarity, and the Cd4/Cd8 ratio in favor of Cd4 lymphocytes, overall supporting an immune cell switch into a pro-restorative phenotype. Interestingly, ΔEGFR livers also displayed an amplified ductular reaction, with increased expression of EPCAM and an increased number of CK19-positive ductular structures in portal areas, demonstrating an overexpansion of ductular progenitor cells. In summary, our work supports the notion that hepatocyte-specific EGFR activity acts as a key player in the crosstalk between parenchymal and non-parenchymal hepatic cells, promoting the pro-inflammatory response activated during cholestatic injury and therefore contributing to the pathogenesis of cholestatic liver disease. © 2022 The Pathological Society of Great Britain and Ireland.This work was supported by the Ministry of Science,Innovation and Universities (MICIU) and AgenciaEstatal de Investigacion (AEI), Spain (co-funded byFEDER funds/Development Fund–a Way to BuildEurope): RTI2018-099098-B-100 to AS/BH andRTI2018-094052-B-100 to AMV; and the RamonAreces Foundation: 20th National Competition forScientific and Technical Research in Life and MatterScience (2020) to IF. NL and JGS were recipients ofresearch assistant contracts linked to grant SAF2015-69145-R and RTI2018-099098-B-100, respectively. CMR was the recipient of a researchcontract (PEJD-2019-POST/BMD-16090) from the Education, Universities, Research and Spokesperson Counseling of the Community of Madrid

Stratospheric connection to the abrupt end of the 2016/2017 iberian drought

Southwestern Europe experienced extraordinary rainy and windy conditions in March 2018, leading to the end of the most severe drought since 1970 at continental scale. This anomalous weather was linked to a persistent negative North Atlantic Oscillation pattern. Two weeks earlier a sudden stratospheric warming (SSW) took place, preceded by the strongest planetary wave activity on record. In this study, we explore the connection between the SSW and the weather shift by employing a weather regime approach and flow analogues. The timing of the downward propagation of the stratospheric anomalies, the transition to and persistence of the negative North Atlantic Oscillation weather regime, and the sudden precipitation increase are all consistent with the typical tropospheric state after SSWs. Our results evidence a significant role of the 2018 SSW in the record-breaking precipitation event

Methylation of class II transactivator gene promoter IV is not associated with susceptibility to Multiple Sclerosis

<p>Abstract</p> <p>Background</p> <p>Multiple sclerosis (MS) is a complex trait in which alleles at or near the class II loci <it>HLA-DRB1 </it>and <it>HLA-DQB1 </it>contribute significantly to genetic risk. The MHC class II transactivator (<it>MHC2TA</it>) is the master controller of expression of class II genes, and methylation of the promoter of this gene has been previously been shown to alter its function. In this study we sought to assess whether or not methylation of the <it>MHC2TA </it>promoter pIV could contribute to MS disease aetiology.</p> <p>Methods</p> <p>In DNA from peripheral blood mononuclear cells from a sample of 50 monozygotic disease discordant MS twins the <it>MHC2TA </it>promoter IV was sequenced and analysed by methylation specific PCR.</p> <p>Results</p> <p>No methylation or sequence variation of the <it>MHC2TA </it>promoter pIV was found.</p> <p>Conclusion</p> <p>The results of this study cannot support the notion that methylation of the pIV promoter of <it>MHC2TA </it>contributes to MS disease risk, although tissue and timing specific epigenetic modifications cannot be ruled out.</p