98 research outputs found

    Ligand-biased ensemble receptor docking (LigBEnD): a hybrid ligand/receptor structure-based approach.

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    Ligand docking to flexible protein molecules can be efficiently carried out through ensemble docking to multiple protein conformations, either from experimental X-ray structures or from in silico simulations. The success of ensemble docking often requires the careful selection of complementary protein conformations, through docking and scoring of known co-crystallized ligands. False positives, in which a ligand in a wrong pose achieves a better docking score than that of native pose, arise as additional protein conformations are added. In the current study, we developed a new ligand-biased ensemble receptor docking method and composite scoring function which combine the use of ligand-based atomic property field (APF) method with receptor structure-based docking. This method helps us to correctly dock 30 out of 36 ligands presented by the D3R docking challenge. For the six mis-docked ligands, the cognate receptor structures prove to be too different from the 40 available experimental Pocketome conformations used for docking and could be identified only by receptor sampling beyond experimentally explored conformational subspace

    4D, N = 1 Supersymmetry Genomics (I)

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    Presented in this paper the nature of the supersymmetrical representation theory behind 4D, N = 1 theories, as described by component fields, is investigated using the tools of Adinkras and Garden Algebras. A survey of familiar matter multiplets using these techniques reveals they are described by two fundamental valise Adinkras that are given the names of the cis-Valise (c-V) and the trans-Valise (t-V). A conjecture is made that all off-shell 4D, N = 1 component descriptions of supermultiplets are associated with two integers - the numbers of c-V and t-V Adinkras that occur in the representation.Comment: 53 pages, 19 figures, Report-II of SSTPRS 2008 Added another chapter for clarificatio

    Soil organic carbon stocks in native forest of Argentina: a useful surrogate for mitigation and conservation planning under climate variability

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    Background The nationally determined contribution (NDC) presented by Argentina within the framework of the Paris Agreement is aligned with the decisions made in the context of the United Nations Framework Convention on Climate Change (UNFCCC) on the reduction of emissions derived from deforestation and forest degradation, as well as forest carbon conservation (REDD+). In addition, climate change constitutes one of the greatest threats to forest biodiversity and ecosystem services. However, the soil organic carbon (SOC) stocks of native forests have not been incorporated into the Forest Reference Emission Levels calculations and for conservation planning under climate variability due to a lack of information. The objectives of this study were: (i) to model SOC stocks to 30 cm of native forests at a national scale using climatic, topographic and vegetation as predictor variables, and (ii) to relate SOC stocks with spatial–temporal remotely sensed indices to determine biodiversity conservation concerns due to threats from high inter‑annual climate variability. Methods We used 1040 forest soil samples (0–30 cm) to generate spatially explicit estimates of SOC native forests in Argentina at a spatial resolution of approximately 200 m. We selected 52 potential predictive environmental covariates, which represent key factors for the spatial distribution of SOC. All covariate maps were uploaded to the Google Earth Engine cloud‑based computing platform for subsequent modelling. To determine the biodiversity threats from high inter‑annual climate variability, we employed the spatial–temporal satellite‑derived indices based on Enhanced Vegetation Index (EVI) and land surface temperature (LST) images from Landsat imagery. Results SOC model (0–30 cm depth) prediction accounted for 69% of the variation of this soil property across the whole native forest coverage in Argentina. Total mean SOC stock reached 2.81 Pg C (2.71–2.84 Pg C with a probability of 90%) for a total area of 460,790 km2, where Chaco forests represented 58.4% of total SOC stored, followed by Andean Patagonian forests (16.7%) and Espinal forests (10.0%). SOC stock model was fitted as a function of regional climate, which greatly influenced forest ecosystems, including precipitation (annual mean precipitation and precipitation of warmest quarter) and temperature (day land surface temperature, seasonality, maximum temperature of warmest month, month of maximum temperature, night land surface temperature, and monthly minimum temperature). Biodiversity was influenced by the SOC levels and the forest regions. Conclusions In the framework of the Kyoto Protocol and REDD+, information derived in the present work from the estimate of SOC in native forests can be incorporated into the annual National Inventory Report of Argentina to assist forest management proposals. It also gives insight into how native forests can be more resilient to reduce the impact of biodiversity loss.EEA Santa CruzFil: Peri, Pablo Luis. Instituto Nacional de Tecnología Agropecuaria (INTA). Estación Experimental Agropecuaria Santa Cruz; Argentina.Fil: Peri, Pablo Luis. Universidad Nacional de la Patagonia Austral; Argentina.Fil: Peri, Pablo Luis. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina.Fil: Gaitan, Juan José. Universidad Nacional de Luján. Buenos Aires; Argentina.Fil: Gaitan, Juan José. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina.Fil: Mastrangelo, Matias Enrique. Universidad Nacional de Mar del Plata. Facultad de Ciencias Agrarias. Grupo de Estudio de Agroecosistemas y Paisajes Rurales; Argentina.Fil: Mastrangelo, Matias Enrique. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina.Fil: Nosetto, Marcelo Daniel. Universidad Nacional de San Luis. Instituto de Matemática Aplicada San Luis. Grupo de Estudios Ambientales; Argentina.Fil: Nosetto, Marcelo Daniel. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina.Fil: Villagra, Pablo Eugenio. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto Argentino de Nivología, Glaciología y Ciencias Ambientales (IANIGLA); Argentina.Fil: Villagra, Pablo Eugenio. Universidad Nacional de Cuyo. Facultad de Ciencias Agrarias; Argentina.Fil: Balducci, Ezequiel. Instituto Nacional de Tecnología Agropecuaria (INTA). Estación Experimental Agropecuaria Yuto; Argentina.Fil: Pinazo, Martín Alcides. Instituto Nacional de Tecnología Agropecuaria (INTA). Estación Experimental Agropecuaria Montecarlo; Argentina.Fil: Eclesia, Roxana Paola. Instituto Nacional de Tecnología Agropecuaria (INTA). Estación Experimental Agropecuaria Paraná; Argentina.Fil: Von Wallis, Alejandra. Instituto Nacional de Tecnología Agropecuaria (INTA). Estación Experimental Agropecuaria Montecarlo; Argentina.Fil: Villarino, Sebastián. Universidad Nacional de Mar del Plata. Facultad de Ciencias Agrarias. Grupo de Estudio de Agroecosistemas y Paisajes Rurales; Argentina.Fil: Villarino, Sebastián. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina.Fil: Alaggia, Francisco Guillermo. Instituto Nacional de Tecnología Agropecuaria (INTA). Estación Experimental Agropecuaria Manfredi. Campo Anexo Villa Dolores; Argentina.Fil: Alaggia, Francisco Guillermo. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina.Fil: Gonzalez-Polo, Marina. Universidad Nacional del Comahue; Argentina.Fil: Gonzalez-Polo, Marina. Consejo Nacional de Investigaciones Científicas y Técnicas. INIBIOMA; Argentina.Fil: Manrique, Silvana M. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Investigaciones en Energía No Convencional. CCT Salta‑Jujuy; Argentina.Fil: Meglioli, Pablo A. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto Argentino de Nivología, Glaciología y Ciencias Ambientales (IANIGLA); Argentina.Fil: Meglioli, Pablo A. Universidad Nacional de Cuyo. Facultad de Ciencias Agrarias; Argentina.Fil: Rodríguez‑Souilla, Julián. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Austral de Investigaciones Científicas (CADIC); Argentina.Fil: Mónaco, Martín H. Ministerio de Ambiente y Desarrollo Sostenible. Dirección Nacional de Bosques; Argentina.Fil: Chaves, Jimena Elizabeth. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Austral de Investigaciones Científicas (CADIC); Argentina.Fil: Medina, Ariel. Ministerio de Ambiente y Desarrollo Sostenible. Dirección Nacional de Bosques; Argentina.Fil: Gasparri, Ignacio. Universidad Nacional de Tucumán. Instituto de Ecología Regional; Argentina.Fil: Gasparri, Ignacio. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina.Fil: Alvarez Arnesi, Eugenio. Universidad Nacional de Rosario. Instituto de Investigaciones en Ciencias Agrarias de Rosario; Argentina.Fil: Alvarez Arnesi, Eugenio. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Santa Fe; Argentina.Fil: Barral, María Paula. Universidad Nacional de Mar del Plata. Facultad de Ciencias Agrarias. Grupo de Estudio de Agroecosistemas y Paisajes Rurales; Argentina.Fil: Barral, María Paula. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina.Fil: Von Müller, Axel. Instituto Nacional de Tecnología Agropecuaria (INTA). Estación Experimental Agropecuaria Esquel Argentina.Fil: Pahr, Norberto Manuel. Instituto Nacional de Tecnología Agropecuaria (INTA). Estación Experimental Agropecuaria Montecarlo; Argentina.Fil: Uribe Echevarría, Josefina. Instituto Nacional de Tecnología Agropecuaria (INTA). Estación Experimental Agropecuaria Quimilí; Argentina.Fil: Fernandez, Pedro Sebastian. Instituto Nacional de Tecnología Agropecuaria (INTA). Estación Experimental Agropecuaria Famaillá; Argentina.Fil: Fernandez, Pedro Sebastian. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Ecología Regional; Argentina.Fil: Morsucci, Marina. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto Argentino de Nivología, Glaciología y Ciencias Ambientales (IANIGLA); Argentina.Fil: Morsucci, Marina. Universidad Nacional de Cuyo. Facultad de Ciencias Agrarias; Argentina.Fil: Lopez, Dardo Ruben. Instituto Nacional de Tecnología Agropecuaria (INTA). Estación Experimental Agropecuaria Manfredi. Campo Anexo Villa Dolores; Argentina.Fil: Lopez, Dardo Ruben. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina.Fil: Cellini, Juan Manuel. Universidad Nacional de la Plata (UNLP). Facultad de Ciencias Naturales y Museo. Laboratorio de Investigaciones en Maderas; Argentina.Fil: Alvarez, Leandro M. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto Argentino de Nivología, Glaciología y Ciencias Ambientales (IANIGLA); Argentina.Fil: Alvarez, Leandro M. Universidad Nacional de Cuyo. Facultad de Ciencias Agrarias; Argentina.Fil: Barberis, Ignacio Martín. Universidad Nacional de Rosario. Instituto de Investigaciones en Ciencias Agrarias de Rosario; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Santa Fe; Argentina.Fil: Barberis, Ignacio Martín. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Santa Fe; Argentina.Fil: Colomb, Hernán Pablo. Ministerio de Ambiente y Desarrollo Sostenible. Dirección Nacional de Bosques; Argentina.Fil: Colomb, Hernán. Administración de Parques Nacionales (APN). Parque Nacional Los Alerces; Argentina.Fil: La Manna, Ludmila. Universidad Nacional de la Patagonia San Juan Bosco. Centro de Estudios Ambientales Integrados (CEAI); Argentina.Fil: La Manna, Ludmila. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina.Fil: Barbaro, Sebastian Ernesto. Instituto Nacional de Tecnología Agropecuaria (INTA). Estación Experimental Agropecuaria Cerro Azul; Argentina.Fil: Blundo, Cecilia. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Ecología Regional; Argentina.Fil: Blundo, Cecilia. Universidad Nacional de Tucumán. Tucumán; Argentina.Fil: Sirimarco, Marina Ximena. Universidad Nacional de Mar del Plata. Grupo de Estudio de Agroecosistemas y Paisajes Rurales (GEAP); Argentina.Fil: Sirimarco, Marina Ximena. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina.Fil: Cavallero, Laura. Instituto Nacional de Tecnología Agropecuaria (INTA). Estación Experimental Agropecuaria Manfredi. Campo Anexo Villa Dolores; Argentina.Fil: Zalazar, Gualberto. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto Argentino de Nivología, Glaciología y Ciencias Ambientales (IANIGLA); Argentina.Fil: Zalazar, Gualberto. Universidad Nacional de Cuyo. Facultad de Ciencias Agrarias; Argentina.Fil: Martínez Pastur, Guillermo José. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Austral de Investigaciones Científicas (CADIC); Argentina

    Canagliflozin and Cardiovascular and Renal Outcomes in Type 2 Diabetes Mellitus and Chronic Kidney Disease in Primary and Secondary Cardiovascular Prevention Groups

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    Background: Canagliflozin reduces the risk of kidney failure in patients with type 2 diabetes mellitus and chronic kidney disease, but effects on specific cardiovascular outcomes are uncertain, as are effects in people without previous cardiovascular disease (primary prevention). Methods: In CREDENCE (Canagliflozin and Renal Events in Diabetes With Established Nephropathy Clinical Evaluation), 4401 participants with type 2 diabetes mellitus and chronic kidney disease were randomly assigned to canagliflozin or placebo on a background of optimized standard of care. Results: Primary prevention participants (n=2181, 49.6%) were younger (61 versus 65 years), were more often female (37% versus 31%), and had shorter duration of diabetes mellitus (15 years versus 16 years) compared with secondary prevention participants (n=2220, 50.4%). Canagliflozin reduced the risk of major cardiovascular events overall (hazard ratio [HR], 0.80 [95% CI, 0.67-0.95]; P=0.01), with consistent reductions in both the primary (HR, 0.68 [95% CI, 0.49-0.94]) and secondary (HR, 0.85 [95% CI, 0.69-1.06]) prevention groups (P for interaction=0.25). Effects were also similar for the components of the composite including cardiovascular death (HR, 0.78 [95% CI, 0.61-1.00]), nonfatal myocardial infarction (HR, 0.81 [95% CI, 0.59-1.10]), and nonfatal stroke (HR, 0.80 [95% CI, 0.56-1.15]). The risk of the primary composite renal outcome and the composite of cardiovascular death or hospitalization for heart failure were also consistently reduced in both the primary and secondary prevention groups (P for interaction >0.5 for each outcome). Conclusions: Canagliflozin significantly reduced major cardiovascular events and kidney failure in patients with type 2 diabetes mellitus and chronic kidney disease, including in participants who did not have previous cardiovascular disease

    The Changing Landscape for Stroke\ua0Prevention in AF: Findings From the GLORIA-AF Registry Phase 2

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    Background GLORIA-AF (Global Registry on Long-Term Oral Antithrombotic Treatment in Patients with Atrial Fibrillation) is a prospective, global registry program describing antithrombotic treatment patterns in patients with newly diagnosed nonvalvular atrial fibrillation at risk of stroke. Phase 2 began when dabigatran, the first non\u2013vitamin K antagonist oral anticoagulant (NOAC), became available. Objectives This study sought to describe phase 2 baseline data and compare these with the pre-NOAC era collected during phase 1. Methods During phase 2, 15,641 consenting patients were enrolled (November 2011 to December 2014); 15,092 were eligible. This pre-specified cross-sectional analysis describes eligible patients\u2019 baseline characteristics. Atrial fibrillation disease characteristics, medical outcomes, and concomitant diseases and medications were collected. Data were analyzed using descriptive statistics. Results Of the total patients, 45.5% were female; median age was 71 (interquartile range: 64, 78) years. Patients were from Europe (47.1%), North America (22.5%), Asia (20.3%), Latin America (6.0%), and the Middle East/Africa (4.0%). Most had high stroke risk (CHA2DS2-VASc [Congestive heart failure, Hypertension, Age  6575 years, Diabetes mellitus, previous Stroke, Vascular disease, Age 65 to 74 years, Sex category] score  652; 86.1%); 13.9% had moderate risk (CHA2DS2-VASc = 1). Overall, 79.9% received oral anticoagulants, of whom 47.6% received NOAC and 32.3% vitamin K antagonists (VKA); 12.1% received antiplatelet agents; 7.8% received no antithrombotic treatment. For comparison, the proportion of phase 1 patients (of N = 1,063 all eligible) prescribed VKA was 32.8%, acetylsalicylic acid 41.7%, and no therapy 20.2%. In Europe in phase 2, treatment with NOAC was more common than VKA (52.3% and 37.8%, respectively); 6.0% of patients received antiplatelet treatment; and 3.8% received no antithrombotic treatment. In North America, 52.1%, 26.2%, and 14.0% of patients received NOAC, VKA, and antiplatelet drugs, respectively; 7.5% received no antithrombotic treatment. NOAC use was less common in Asia (27.7%), where 27.5% of patients received VKA, 25.0% antiplatelet drugs, and 19.8% no antithrombotic treatment. Conclusions The baseline data from GLORIA-AF phase 2 demonstrate that in newly diagnosed nonvalvular atrial fibrillation patients, NOAC have been highly adopted into practice, becoming more frequently prescribed than VKA in Europe and North America. Worldwide, however, a large proportion of patients remain undertreated, particularly in Asia and North America. (Global Registry on Long-Term Oral Antithrombotic Treatment in Patients With Atrial Fibrillation [GLORIA-AF]; NCT01468701

    Canagliflozin and renal outcomes in type 2 diabetes and nephropathy

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    BACKGROUND Type 2 diabetes mellitus is the leading cause of kidney failure worldwide, but few effective long-term treatments are available. In cardiovascular trials of inhibitors of sodium–glucose cotransporter 2 (SGLT2), exploratory results have suggested that such drugs may improve renal outcomes in patients with type 2 diabetes. METHODS In this double-blind, randomized trial, we assigned patients with type 2 diabetes and albuminuric chronic kidney disease to receive canagliflozin, an oral SGLT2 inhibitor, at a dose of 100 mg daily or placebo. All the patients had an estimated glomerular filtration rate (GFR) of 30 to <90 ml per minute per 1.73 m2 of body-surface area and albuminuria (ratio of albumin [mg] to creatinine [g], >300 to 5000) and were treated with renin–angiotensin system blockade. The primary outcome was a composite of end-stage kidney disease (dialysis, transplantation, or a sustained estimated GFR of <15 ml per minute per 1.73 m2), a doubling of the serum creatinine level, or death from renal or cardiovascular causes. Prespecified secondary outcomes were tested hierarchically. RESULTS The trial was stopped early after a planned interim analysis on the recommendation of the data and safety monitoring committee. At that time, 4401 patients had undergone randomization, with a median follow-up of 2.62 years. The relative risk of the primary outcome was 30% lower in the canagliflozin group than in the placebo group, with event rates of 43.2 and 61.2 per 1000 patient-years, respectively (hazard ratio, 0.70; 95% confidence interval [CI], 0.59 to 0.82; P=0.00001). The relative risk of the renal-specific composite of end-stage kidney disease, a doubling of the creatinine level, or death from renal causes was lower by 34% (hazard ratio, 0.66; 95% CI, 0.53 to 0.81; P<0.001), and the relative risk of end-stage kidney disease was lower by 32% (hazard ratio, 0.68; 95% CI, 0.54 to 0.86; P=0.002). The canagliflozin group also had a lower risk of cardiovascular death, myocardial infarction, or stroke (hazard ratio, 0.80; 95% CI, 0.67 to 0.95; P=0.01) and hospitalization for heart failure (hazard ratio, 0.61; 95% CI, 0.47 to 0.80; P<0.001). There were no significant differences in rates of amputation or fracture. CONCLUSIONS In patients with type 2 diabetes and kidney disease, the risk of kidney failure and cardiovascular events was lower in the canagliflozin group than in the placebo group at a median follow-up of 2.62 years

    A multi-country test of brief reappraisal interventions on emotions during the COVID-19 pandemic.

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    The COVID-19 pandemic has increased negative emotions and decreased positive emotions globally. Left unchecked, these emotional changes might have a wide array of adverse impacts. To reduce negative emotions and increase positive emotions, we tested the effectiveness of reappraisal, an emotion-regulation strategy that modifies how one thinks about a situation. Participants from 87 countries and regions (n = 21,644) were randomly assigned to one of two brief reappraisal interventions (reconstrual or repurposing) or one of two control conditions (active or passive). Results revealed that both reappraisal interventions (vesus both control conditions) consistently reduced negative emotions and increased positive emotions across different measures. Reconstrual and repurposing interventions had similar effects. Importantly, planned exploratory analyses indicated that reappraisal interventions did not reduce intentions to practice preventive health behaviours. The findings demonstrate the viability of creating scalable, low-cost interventions for use around the world

    Omecamtiv mecarbil in chronic heart failure with reduced ejection fraction, GALACTIC‐HF: baseline characteristics and comparison with contemporary clinical trials

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    Aims: The safety and efficacy of the novel selective cardiac myosin activator, omecamtiv mecarbil, in patients with heart failure with reduced ejection fraction (HFrEF) is tested in the Global Approach to Lowering Adverse Cardiac outcomes Through Improving Contractility in Heart Failure (GALACTIC‐HF) trial. Here we describe the baseline characteristics of participants in GALACTIC‐HF and how these compare with other contemporary trials. Methods and Results: Adults with established HFrEF, New York Heart Association functional class (NYHA) ≥ II, EF ≤35%, elevated natriuretic peptides and either current hospitalization for HF or history of hospitalization/ emergency department visit for HF within a year were randomized to either placebo or omecamtiv mecarbil (pharmacokinetic‐guided dosing: 25, 37.5 or 50 mg bid). 8256 patients [male (79%), non‐white (22%), mean age 65 years] were enrolled with a mean EF 27%, ischemic etiology in 54%, NYHA II 53% and III/IV 47%, and median NT‐proBNP 1971 pg/mL. HF therapies at baseline were among the most effectively employed in contemporary HF trials. GALACTIC‐HF randomized patients representative of recent HF registries and trials with substantial numbers of patients also having characteristics understudied in previous trials including more from North America (n = 1386), enrolled as inpatients (n = 2084), systolic blood pressure < 100 mmHg (n = 1127), estimated glomerular filtration rate < 30 mL/min/1.73 m2 (n = 528), and treated with sacubitril‐valsartan at baseline (n = 1594). Conclusions: GALACTIC‐HF enrolled a well‐treated, high‐risk population from both inpatient and outpatient settings, which will provide a definitive evaluation of the efficacy and safety of this novel therapy, as well as informing its potential future implementation
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