Structural Comparison of Allogeneic and Syngeneic T Cell Receptor–Peptide-Major Histocompatibility Complex Complexes: A Buried Alloreactive Mutation Subtly Alters Peptide Presentation Substantially Increasing Vβ Interactions

The crystal structures of the 2C/H-2Kbm3–dEV8 allogeneic complex at 2.4 Å and H-2Kbm3–dEV8 at 2.15 Å, when compared with their syngeneic counterparts, elucidate structural changes that induce an alloresponse. The Asp77Ser mutation that imbues H-2Kbm3–dEV8 with its alloreactive properties is located beneath the peptide and does not directly contact the T cell receptor (TCR). However, the buried mutation induces local rearrangement of the peptide itself to preserve hydrogen bonding interactions between the peptide and the α1 77 residue. The COOH terminus of the peptide main chain is tugged toward the α1-helix such that its presentation to the TCR is altered. These changes increase the stability of the allogeneic peptide-major histocompatibility complex (pMHC) complex and increase complementarity in the TCR–pMHC interface, placing greater emphasis on recognition of the pMHC by the TCR β-chain, evinced by an increase in shape complementarity, buried surface area, and number of TCR–pMHC contacting residues. A nearly fourfold increase in the number of β-chain–pMHC contacts is accompanied by a concomitant 64% increase in β-chain–pMHC shape complementarity. Thus, the allogeneic mutation causes the same peptide to be presented differently, temporally and spatially, by the allogeneic and syngeneic MHCs

Crystal Structure of the Carbohydrate Recognition Domain of the Human Macrophage Galactose C-Type Lectin Bound to GalNAc and the Tumor-Associated Tn Antigen

12/IA/1398 16/IA/4419 GOIPG/2016/858 IF/00780/2015 PTDC/BIA-MIB/31028/2017 UIDB/04378/2020 PD/BD/142847/2018 RTI2018-094751-B-C22 RTI2018-099592-B-C2.The human macrophage galactose lectin (MGL) is an endocytic type II transmembrane receptor expressed on immature monocyte-derived dendritic cells and activated macrophages and plays a role in modulating the immune system in response to infections and cancer. MGL contains an extracellular calcium-dependent (C-type) carbohydrate recognition domain (CRD) that specifically binds terminal N-acetylgalactosamine glycan residues such as the Tn and sialyl-Tn antigens found on tumor cells, as well as other N- and O-glycans displayed on certain viruses and parasites. Even though the glycan specificity of MGL is known and several binding glycoproteins have been identified, the molecular basis for substrate recognition has remained elusive due to the lack of high-resolution structures. Here we present crystal structures of the MGL CRD at near endosomal pH and in several complexes, which reveal details of the interactions with the natural ligand, GalNAc, the cancer-associated Tn-Ser antigen, and a synthetic GalNAc mimetic ligand. Like the asialoglycoprotein receptor, additional calcium atoms are present and contribute to stabilization of the MGL CRD fold. The structure provides the molecular basis for preferential binding of N-acetylgalactosamine over galactose and prompted the re-evaluation of the binding modes previously proposed in solution. Saturation transfer difference nuclear magnetic resonance data acquired using the MGL CRD and interpreted using the crystal structure indicate a single binding mode for GalNAc in solution. Models of MGL1 and MGL2, the mouse homologues of MGL, explain how these proteins might recognize LewisX and GalNAc, respectively.publishersversionpublishe

The scale of population structure in Arabidopsis thaliana

The population structure of an organism reflects its evolutionary history and influences its evolutionary trajectory. It constrains the combination of genetic diversity and reveals patterns of past gene flow. Understanding it is a prerequisite for detecting genomic regions under selection, predicting the effect of population disturbances, or modeling gene flow. This paper examines the detailed global population structure of Arabidopsis thaliana. Using a set of 5,707 plants collected from around the globe and genotyped at 149 SNPs, we show that while A. thaliana as a species self-fertilizes 97% of the time, there is considerable variation among local groups. This level of outcrossing greatly limits observed heterozygosity but is sufficient to generate considerable local haplotypic diversity. We also find that in its native Eurasian range A. thaliana exhibits continuous isolation by distance at every geographic scale without natural breaks corresponding to classical notions of populations. By contrast, in North America, where it exists as an exotic species, A. thaliana exhibits little or no population structure at a continental scale but local isolation by distance that extends hundreds of km. This suggests a pattern for the development of isolation by distance that can establish itself shortly after an organism fills a new habitat range. It also raises questions about the general applicability of many standard population genetics models. Any model based on discrete clusters of interchangeable individuals will be an uneasy fit to organisms like A. thaliana which exhibit continuous isolation by distance on many scales

Presence of health risk nutrient tracers in food consumed by schoolchildren in Medellin

ABSTRACT: To identify the amount of carbohydrates, sugars, saturated fats and sodium present in the snacks and sugary drinks consumed by schoolchildren in Medellin. Method: A descriptive cross-sectional study in which tracer nutrient content of health risk in food available in school stores. A total of 130 products were analyzed: 38 snacks, 17 sweet 44 cakes, cookies and cereal bars, and softdrinks 31. These foods were selected for this study because of its high availability in school stores Medellin. Results: We found that products with higher sodium content are the snack food group and the highest content of sugars and carbohydrates found in softdrinks, followed by the group of biscuits, cakes and cereal bars, and this last group of foods that higher saturated fat content presented.RESUMEN: Identificar la cantidad de carbohidratos, azúcares, grasas saturadas y sodio, presentes en los snacks, tortas, galletas y barras de cereal, dulces y bebidas azucaradas consumidos por los escolares de Medellín. Método: se realizó un estudio descriptivo transversal en el cual se determinó el contenido de nutrientes trazadores de riesgo para la salud en los alimentos disponibles en las tiendas escolares. Se analizaron un total de 130 productos: 38 snacks, 17 dulces, 44 tortas, galletas y barras de cereal, y 31 bebidas azucaradas, en su presentación comercial. Estos alimentos fueron seleccionados por su alta disponibilidad en las tiendas escolares de la ciudad de Medellín. Resultados: los productos con mayor contenido de sodio son el grupo de alimentos de snacks y el mayor contenido de azúcares y carbohidratos se encuentra en las bebidas azucaradas, seguido por el grupo de galletas, ponqués y barras de cereal, siendo este último grupo de alimentos el que mayor contenido en grasas saturadas presenta

Classification of food consumed in school stores, as nutrient content tracers risk. Medellín - 2012

ABSTRACT: The aim this study was to establish a classification of the most consumed foods in school stores (snacks, cakes, cookies, candy and sugary drinks) according to the degree of health risk. A cross, by which nutritional components were identified and no nutrient declared in the nutrition label of the foods most consumed by school stores Medellin commercial lot, then your risk is classified according to the number and amount of these components. 38 snacks, 17 sweet 44 cakes, cookies and cereal bars, and sugary drinks 31: A total of 130 products were analysed. We found that severe risk foods have business presentations over 45 g, are foods with artificial flavors and colors, with fillings inside, with chocolates. And Food Without Risk presented opposite the above features, business presentations less than 20g, without artificial flavors and colors, all soft drinks were classified as moderate.RESUMEN: El objetivo de este estudio fue establecer una clasificación de los alimentos más consumidos en las tiendas escolares (snacks, ponqués, galletas, dulces y bebidas azucaradas) según el grado de riesgo para la salud. Estudio descriptivo transversal, por medio del cual se identificaron los componentes nutritivos y no nutritivos declarados en la etiqueta nutricional de los alimentos más consumidos en tiendas escolares de Medellín por porción comercial, y luego se clasificó su riesgo de acuerdo al número y cantidad de dichos componentes. Se analizaron un total de 130 Productos: 38 snacks, 17 dulces, 44 Tortas, galletas y barras de cereal, y 31 bebidas azucaradas. Se encontró que los alimentos con riesgo severo tienen presentaciones comerciales de más de 45g, son alimentos con sabores y colores artificiales, con rellenos en su interior, con chocolates. Y los alimentos sin riesgo presentan características opuestas a los anteriores, es decir, presentaciones comerciales de menos de 20g, y sin sabores y colores artificiales; todas las bebidas azucaradas se clasificaron en riesgo moderado, es decir, que ninguna se clasificó sin riesgo, debido a la adición de colorantes y al tamaño de las presentaciones comerciales

Chronic Exposure to Arsenic and Markers of Cardiometabolic Risk: A Cross-Sectional Study in Chihuahua, Mexico

BackgroundExposure to arsenic (As) concentrations in drinking water > 150 μg/L has been associated with risk of diabetes and cardiovascular disease, but little is known about the effects of lower exposures.ObjectiveThis study aimed to examine whether moderate As exposure, or indicators of individual As metabolism at these levels of exposure, are associated with cardiometabolic risk.MethodsWe analyzed cross-sectional associations between arsenic exposure and multiple markers of cardiometabolic risk using drinking-water As measurements and urinary As species data obtained from 1,160 adults in Chihuahua, Mexico, who were recruited in 2008–2013. Fasting blood glucose and lipid levels, the results of an oral glucose tolerance test, and blood pressure were used to characterize cardiometabolic risk. Multivariable logistic, multinomial, and linear regression were used to assess associations between cardiometabolic outcomes and water As or the sum of inorganic and methylated As species in urine.ResultsAfter multivariable adjustment, concentrations in the second quartile of water As (25.5 to < 47.9 μg/L) and concentrations of total speciated urinary As (< 55.8 μg/L) below the median were significantly associated with elevated triglycerides, high total cholesterol, and diabetes. However, moderate water and urinary As levels were also positively associated with HDL cholesterol. Associations between arsenic exposure and both dysglycemia and triglyceridemia were higher among individuals with higher proportions of dimethylarsenic in urine.ConclusionsModerate exposure to As may increase cardiometabolic risk, particularly in individuals with high proportions of urinary dimethylarsenic. In this cohort, As exposure was associated with several markers of increased cardiometabolic risk (diabetes, triglyceridemia, and cholesterolemia), but exposure was also associated with higher rather than lower HDL cholesterol.CitationMendez MA, González-Horta C, Sánchez-Ramírez B, Ballinas-Casarrubias L, Hernández Cerón R, Viniegra Morales D, Baeza Terrazas FA, Ishida MC, Gutiérrez-Torres DS, Saunders RJ, Drobná Z, Fry RC, Buse JB, Loomis D, García-Vargas GG, Del Razo LM, Stýblo M. 2016. Chronic exposure to arsenic and markers of cardiometabolic risk: a cross-sectional study in Chihuahua, Mexico. Environ Health Perspect 124:104–111; http://dx.doi.org/10.1289/ehp.140874

The non-Verbal Structure of Patient Case Discussions in Multidisciplinary Medical Team Meetings

Meeting analysis has a long theoretical tradition in social psychology, with established practical rami?cations in computer science, especially in computer supported cooperative work. More recently, a good deal of research has focused on the issues of indexing and browsing multimedia records of meetings. Most research in this area, however, is still based on data collected in laboratories, under somewhat arti?cial conditions. This paper presents an analysis of the discourse structure and spontaneous interactions at real-life multidisciplinary medical team meetings held as part of the work routine in a major hospital. It is hypothesised that the conversational structure of these meetings, as indicated by sequencing and duration of vocalisations, enables segmentation into individual patient case discussions. The task of segmenting audio-visual records of multidisciplinary medical team meetings is described as a topic segmentation task, and a method for automatic segmentation is proposed. An empirical evaluation based on hand labelled data is presented which determines the optimal length of vocalisation sequences for segmentation, and establishes the competitiveness of the method with approaches based on more complex knowledge sources. The effectiveness of Bayesian classi?cation as a segmentation method, and its applicability to meeting segmentation in other domains are discusse

Effect of aspirin on cancer incidence and mortality in older adults.

BACKGROUND: ASPirin in Reducing Events in the Elderly (ASPREE), a randomized double-blind placebo-controlled trial (RCT) of daily low-dose aspirin (100 mg) in older adults, showed an increase in all-cause mortality, primarily due to cancer. In contrast prior RCTs, mainly involving younger individuals, demonstrated a delayed cancer benefit with aspirin. We now report a detailed analysis of cancer incidence and mortality. METHODS: 19,114 Australian and U.S. community-dwelling participants aged 70+ years (U.S. minorities 65+ years) without cardiovascular disease, dementia or physical disability were randomized and followed for a median of 4.7 years. Fatal and non-fatal cancer events, a prespecified secondary endpoint, were adjudicated based on clinical records. RESULTS: 981 cancer events occurred in the aspirin and 952 in the placebo groups. There was no statistically significant difference between groups for all incident cancers (HR = 1.04, 95% CI = 0.95 to 1.14), hematological cancer (HR = 0.98, 95% CI = 0.73 to 1.30), or all solid cancers (HR = 1.05, 95% CI = 0.95 to 1.15), including by specific tumor type. However, aspirin was associated with an increased risk of incident cancer that had metastasized (HR = 1.19, 95% CI = 1.00 to 1.43) or was stage 4 at diagnosis (HR = 1.22, 95% CI = 1.02 to 1.45), and with higher risk of death for cancers that presented at stages 3 (HR = 2.11, 95% CI = 1.03 to 4.33) or 4 (HR = 1.31, 95% CI = 1.04 to 1.64). CONCLUSIONS: In older adults, aspirin treatment had an adverse effect on later stages of cancer evolution. These findings suggest that in older persons, aspirin may accelerate the progression of cancer and thus, suggest caution with its use in this age group

Nocturnal Oximetry-based Evaluation of Habitually Snoring Children

Rationale: The vast majority of children around the world undergoing adenotonsillectomy for obstructive sleep apnea–hypopnea syndrome (OSA) are not objectively diagnosed by nocturnal polysomnography because of access availability and cost issues. Automated analysis of nocturnal oximetry (nSpO2), which is readily and globally available, could potentially provide a reliable and convenient diagnostic approach for pediatric OSA. Methods: DeidentifiednSpO2 recordings froma total of 4,191 children originating from13 pediatric sleep laboratories around the worldwere prospectively evaluated after developing and validating an automated neural network algorithm using an initial set of single-channel nSpO2 recordings from 589 patients referred for suspected OSA. Measurements and Main Results: The automatically estimated apnea–hypopnea index (AHI) showed high agreement with AHI from conventional polysomnography (intraclass correlation coefficient, 0.785) when tested in 3,602 additional subjects. Further assessment on the widely used AHI cutoff points of 1, 5, and 10 events/h revealed an incremental diagnostic ability (75.2, 81.7, and 90.2% accuracy; 0.788, 0.854, and 0.913 area under the receiver operating characteristic curve, respectively). Conclusions: Neural network–based automated analyses of nSpO2 recordings provide accurate identification of OSA severity among habitually snoring children with a high pretest probability of OSA. Thus, nocturnal oximetry may enable a simple and effective diagnostic alternative to nocturnal polysomnography, leading to more timely interventions and potentially improved outcomes.Supported in part by project VA037 U16 from the Consejer´ıa de Educacio´ n de la Junta de Castilla y Leo´ n and the European Regional Development Fund (FEDER), project RTC-2015-3446-1 from the Ministerio de Econom´ıa y Competitividad and FEDER, and project 153/2015 of the Sociedad Espan˜ ola de Neumolog´ıa y Cirug´ıa Tora´ cica (SEPAR). L.K.-G. is supported by NIH grant 1R01HL130984. M.F.P. was supported by a Fellowship Educational grant award from the Kingdom of Saudi Arabia. D.´A. was in receipt of a Juan de la Cierva grant from the Ministerio de Econom´ıa y Competitividad. The funders played no role in the study design, data collection, data analysis, interpretation, and writing of the manuscript