Transporte de nicotinato y compuestos relacionados mediado por el transportador de monocarboxilatos acoplado a sodio (SMCT1)

63 p.Las proteínas de membrana tienen una gran importancia biológica, debido a que juegan un papel fundamental en distintos procesos que regulan una larga lista de enfermedades. Estas proteínas son cruciales para el transporte de sustratos en la célula, por lo que pueden actuar fácilmente como dianas biológicas, logrando desencadenar alguna respuesta farmacológica deseada. La familia SCL5, es una familia de cotransportadores de monocarboxilatos acoplado a sodio, que contempla 12 proteínas en el genoma humano. Existen varios estudios que reportan la importancia de esta familia en procesos de captación de azúcares, vitaminas y aminoácidos, sin embargo, los mecanismos estructurales asociados al transporte de solutos aún no son del todo caracterizados. Principalmente el gen SLC5A8, el cual codifica el transportador 1 de monocarboxilatos y cadenas cortas de ácidos grasos acoplado a sodio (SMCT1, del inglés Sodiumcoupled monocarboxylate transporter 1), ha sido asociado a la recaptación de monocarboxilatos en distintos órganos humanos. En este ámbito, investigaciones recientes a cerca del transporte de nicotinato, una vitamina del complejo B tipo monocarboxilato, han demostrado una reducción en el transporte de esta molécula debido a una mutación puntual en el residuo treonina 91 de SMCT1. En la presente investigación se utilizó una estrategia de modelado por homología de proteínas para generar un modelo del transportador SMCT1 en una conformación orientada hacia el medio externo. Acoplamiento molecular para la búsqueda de confórmeros que representaran el modo de unión de nicotinato y compuestos relacionados de variada afinidad para SMCT1, para finalmente aplicar metodologías de simulación molecular caracterizando estructuralmente los elementos claves que regulan la captación de estos compuestos, además de estudiar el efecto la mutación treonina 91 por glicina (T91G) y como esto incide en el transporte de sustratos. Los resultados obtenidos a lo largo de esta investigación sugieren que los residuos F65, F85, F88, Y92 y W253 son residuos importantes en la captación de compuestos, por otro lado, el residuo treonina 91 presenta un rol estructural en donde su mutación por glicina, que termina provocando la distorsión en las cadenas laterales de Y92 y W253 produce la inestabilidad de estos complejos. // ABSTRACT: Membrane proteins are of great biological importance, since they play a fundamental role in different processes that regulate a long list of diseases. These proteins are crucial for the transport of substrates in the cell, so they can easily act as biological targets, triggering a desired pharmacological response. The SCL5 family is a family of sodium-coupled monocarboxylate cotransporters, which includes 12 proteins in the human genome. There are several studies that report the importance of this family in the uptake of sugars, vitamins and amino acids; however, the structural mechanisms associated with solute transport have not yet been fully characterized. Mainly the SLC5A8 gene, which encodes the sodium-coupled monocarboxylate and short-chain fatty acid transporter 1 (SMCT1), has been associated with the reuptake of monocarboxylates in different human organs. In this field, recent research on the transport of nicotinate, a monocarboxylate-type B-complex vitamin, has demonstrated a reduction in the transport of this molecule due to a point mutation in the threonine 91 residue of SMCT1. In the present investigation, a protein homology modeling strategy was used to generate a model of the SMCT1 transporter in an externally oriented conformation. Molecular docking to search for confomers representing the binding mode of nicotinate and related compounds of varying affinity for SMCT1, to finally apply molecular simulation methodologies to structurally characterize the key elements that regulate the uptake of these compounds, in addition to studying the effect of the threonine 91 by glycine (T91G) mutation and how this affects the transport of substrates. The results obtained throughout this research suggest that residues F65, F85, F88, Y92 and W253 are important residues in the uptake of compounds, on the other hand, residue threonine 91 presents a structural role where its mutation by glycine, which ends up causing the distortion in the side chains of Y92 and W253 produces the instability of these complexes

Socioeconomic position, lifestyle habits and biomarkers of epigenetic aging: A multi-cohort analysis

Differences in health status by socioeconomic position (SEP) tend to be more evident at older ages, suggesting the involvement of a biological mechanism responsive to the accumulation of deleterious exposures across the lifespan. DNA methylation (DNAm) has been proposed as a biomarker of biological aging that conserves memory of endogenous and exogenous stress during life.We examined the association of education level, as an indicator of SEP, and lifestyle-related variables with four biomarkers of age-dependent DNAm dysregulation: the total number of stochastic epigenetic mutations (SEMs) and three epigenetic clocks (Horvath, Hannum and Levine), in 18 cohorts spanning 12 countries.The four biological aging biomarkers were associated with education and different sets of risk factors independently, and the magnitude of the effects differed depending on the biomarker and the predictor. On average, the effect of low education on epigenetic aging was comparable with those of other lifestyle-related risk factors (obesity, alcohol intake), with the exception of smoking, which had a significantly stronger effect.Our study shows that low education is an independent predictor of accelerated biological (epigenetic) aging and that epigenetic clocks appear to be good candidates for disentangling the biological pathways underlying social inequalities in healthy aging and longevity

Pooled analysis of WHO Surgical Safety Checklist use and mortality after emergency laparotomy

Background The World Health Organization (WHO) Surgical Safety Checklist has fostered safe practice for 10 years, yet its place in emergency surgery has not been assessed on a global scale. The aim of this study was to evaluate reported checklist use in emergency settings and examine the relationship with perioperative mortality in patients who had emergency laparotomy. Methods In two multinational cohort studies, adults undergoing emergency laparotomy were compared with those having elective gastrointestinal surgery. Relationships between reported checklist use and mortality were determined using multivariable logistic regression and bootstrapped simulation. Results Of 12 296 patients included from 76 countries, 4843 underwent emergency laparotomy. After adjusting for patient and disease factors, checklist use before emergency laparotomy was more common in countries with a high Human Development Index (HDI) (2455 of 2741, 89.6 per cent) compared with that in countries with a middle (753 of 1242, 60.6 per cent; odds ratio (OR) 0.17, 95 per cent c.i. 0.14 to 0.21, P <0001) or low (363 of 860, 422 per cent; OR 008, 007 to 010, P <0.001) HDI. Checklist use was less common in elective surgery than for emergency laparotomy in high-HDI countries (risk difference -94 (95 per cent c.i. -11.9 to -6.9) per cent; P <0001), but the relationship was reversed in low-HDI countries (+121 (+7.0 to +173) per cent; P <0001). In multivariable models, checklist use was associated with a lower 30-day perioperative mortality (OR 0.60, 0.50 to 073; P <0.001). The greatest absolute benefit was seen for emergency surgery in low- and middle-HDI countries. Conclusion Checklist use in emergency laparotomy was associated with a significantly lower perioperative mortality rate. Checklist use in low-HDI countries was half that in high-HDI countries.Peer reviewe

Socioeconomic position, lifestyle habits and biomarkers of epigenetic aging: a multi-cohort analysis.

Differences in health status by socioeconomic position (SEP) tend to be more evident at older ages, suggesting the involvement of a biological mechanism responsive to the accumulation of deleterious exposures across the lifespan. DNA methylation (DNAm) has been proposed as a biomarker of biological aging that conserves memory of endogenous and exogenous stress during life.We examined the association of education level, as an indicator of SEP, and lifestyle-related variables with four biomarkers of age-dependent DNAm dysregulation: the total number of stochastic epigenetic mutations (SEMs) and three epigenetic clocks (Horvath, Hannum and Levine), in 18 cohorts spanning 12 countries.The four biological aging biomarkers were associated with education and different sets of risk factors independently, and the magnitude of the effects differed depending on the biomarker and the predictor. On average, the effect of low education on epigenetic aging was comparable with those of other lifestyle-related risk factors (obesity, alcohol intake), with the exception of smoking, which had a significantly stronger effect.Our study shows that low education is an independent predictor of accelerated biological (epigenetic) aging and that epigenetic clocks appear to be good candidates for disentangling the biological pathways underlying social inequalities in healthy aging and longevity

Global variation in anastomosis and end colostomy formation following left-sided colorectal resection

Background End colostomy rates following colorectal resection vary across institutions in high-income settings, being influenced by patient, disease, surgeon and system factors. This study aimed to assess global variation in end colostomy rates after left-sided colorectal resection. Methods This study comprised an analysis of GlobalSurg-1 and -2 international, prospective, observational cohort studies (2014, 2016), including consecutive adult patients undergoing elective or emergency left-sided colorectal resection within discrete 2-week windows. Countries were grouped into high-, middle- and low-income tertiles according to the United Nations Human Development Index (HDI). Factors associated with colostomy formation versus primary anastomosis were explored using a multilevel, multivariable logistic regression model. Results In total, 1635 patients from 242 hospitals in 57 countries undergoing left-sided colorectal resection were included: 113 (6·9 per cent) from low-HDI, 254 (15·5 per cent) from middle-HDI and 1268 (77·6 per cent) from high-HDI countries. There was a higher proportion of patients with perforated disease (57·5, 40·9 and 35·4 per cent; P < 0·001) and subsequent use of end colostomy (52·2, 24·8 and 18·9 per cent; P < 0·001) in low- compared with middle- and high-HDI settings. The association with colostomy use in low-HDI settings persisted (odds ratio (OR) 3·20, 95 per cent c.i. 1·35 to 7·57; P = 0·008) after risk adjustment for malignant disease (OR 2·34, 1·65 to 3·32; P < 0·001), emergency surgery (OR 4·08, 2·73 to 6·10; P < 0·001), time to operation at least 48 h (OR 1·99, 1·28 to 3·09; P = 0·002) and disease perforation (OR 4·00, 2·81 to 5·69; P < 0·001). Conclusion Global differences existed in the proportion of patients receiving end stomas after left-sided colorectal resection based on income, which went beyond case mix alone