3-D struktura serumske paraoksonaze 1 objašnjava njezinu aktivnost, stabilnost, topljivost i kristalizaciju

Serum paraoxonases (PONs) exhibit a wide range of physiologically important hydrolytic activities, including drug metabolism and detoxification of nerve gases. PON1 and PON3 reside on high-density lipoprotein (HDL) (the “good cholesterol”), and are involved in the alleviation of atherosclerosis. Members of the PON family have been identified not only in mammals and other vertebrates, but also in invertebrates. We earlier described the first crystal structure of a PON family member, a directly-evolved variant of PON1, at 2.2 Å resolution. PON1 is a 6-bladed beta-propeller with a unique active-site lid which is also involved in binding to HDL. The 3-D structure, taken together with directed evolution studies, permitted analysis of mutations which enhanced the stability, solubility and crystallizability of this PON1 variant. The structure permits a detailed description of PON1’s active site and suggests possible mechanisms for its catalytic activity on certain substrates.Serumske paraoksonaze (PONs) imaju široki raspon fiziološki važnih hidrolitičkih aktivnosti uključujući metabolizam lijekova i detoksikaciju nervnih plinova. PON1 i PON3 smještene su na lipoproteinima visoke gustoće (engl. high-density lipoprotein; HDL - “dobri kolesterol”) i uključene su u ublažavanje ateroskleroze. Članovi skupine PON identificirani su ne samo u sisavaca i drugih kralježnjaka već i kod beskralješnjaka. Prije smo opisali prvu kristalnu strukturu člana PON skupine, direktno razrađenu varijantu PON1 pri rezoluciji 2,2 Å. PON1 je beta-propeler sa šest lopatica s jedinstvenim poklopcem aktivnog mjesta, koji je tako|er uključen u vezanje na HDL. 3-D struktura, gledana zajedno s direktnim razvojnim istraživanjima, omogućila je analizu mutacija koje povećavaju stabilnost, topljivost i kristalizaciju te PON1 varijante. Struktura dopušta detaljan opis aktivnog mjesta PON1 i sugerira moguće mehanizme za njezinu katalitičku aktivnost prema odre|enim supstratima

Mortality from gastrointestinal congenital anomalies at 264 hospitals in 74 low-income, middle-income, and high-income countries: a multicentre, international, prospective cohort study

Summary Background Congenital anomalies are the fifth leading cause of mortality in children younger than 5 years globally. Many gastrointestinal congenital anomalies are fatal without timely access to neonatal surgical care, but few studies have been done on these conditions in low-income and middle-income countries (LMICs). We compared outcomes of the seven most common gastrointestinal congenital anomalies in low-income, middle-income, and high-income countries globally, and identified factors associated with mortality. Methods We did a multicentre, international prospective cohort study of patients younger than 16 years, presenting to hospital for the first time with oesophageal atresia, congenital diaphragmatic hernia, intestinal atresia, gastroschisis, exomphalos, anorectal malformation, and Hirschsprung’s disease. Recruitment was of consecutive patients for a minimum of 1 month between October, 2018, and April, 2019. We collected data on patient demographics, clinical status, interventions, and outcomes using the REDCap platform. Patients were followed up for 30 days after primary intervention, or 30 days after admission if they did not receive an intervention. The primary outcome was all-cause, in-hospital mortality for all conditions combined and each condition individually, stratified by country income status. We did a complete case analysis. Findings We included 3849 patients with 3975 study conditions (560 with oesophageal atresia, 448 with congenital diaphragmatic hernia, 681 with intestinal atresia, 453 with gastroschisis, 325 with exomphalos, 991 with anorectal malformation, and 517 with Hirschsprung’s disease) from 264 hospitals (89 in high-income countries, 166 in middleincome countries, and nine in low-income countries) in 74 countries. Of the 3849 patients, 2231 (58·0%) were male. Median gestational age at birth was 38 weeks (IQR 36–39) and median bodyweight at presentation was 2·8 kg (2·3–3·3). Mortality among all patients was 37 (39·8%) of 93 in low-income countries, 583 (20·4%) of 2860 in middle-income countries, and 50 (5·6%) of 896 in high-income countries (p<0·0001 between all country income groups). Gastroschisis had the greatest difference in mortality between country income strata (nine [90·0%] of ten in lowincome countries, 97 [31·9%] of 304 in middle-income countries, and two [1·4%] of 139 in high-income countries; p≤0·0001 between all country income groups). Factors significantly associated with higher mortality for all patients combined included country income status (low-income vs high-income countries, risk ratio 2·78 [95% CI 1·88–4·11], p<0·0001; middle-income vs high-income countries, 2·11 [1·59–2·79], p<0·0001), sepsis at presentation (1·20 [1·04–1·40], p=0·016), higher American Society of Anesthesiologists (ASA) score at primary intervention (ASA 4–5 vs ASA 1–2, 1·82 [1·40–2·35], p<0·0001; ASA 3 vs ASA 1–2, 1·58, [1·30–1·92], p<0·0001]), surgical safety checklist not used (1·39 [1·02–1·90], p=0·035), and ventilation or parenteral nutrition unavailable when needed (ventilation 1·96, [1·41–2·71], p=0·0001; parenteral nutrition 1·35, [1·05–1·74], p=0·018). Administration of parenteral nutrition (0·61, [0·47–0·79], p=0·0002) and use of a peripherally inserted central catheter (0·65 [0·50–0·86], p=0·0024) or percutaneous central line (0·69 [0·48–1·00], p=0·049) were associated with lower mortality. Interpretation Unacceptable differences in mortality exist for gastrointestinal congenital anomalies between lowincome, middle-income, and high-income countries. Improving access to quality neonatal surgical care in LMICs will be vital to achieve Sustainable Development Goal 3.2 of ending preventable deaths in neonates and children younger than 5 years by 2030

Aplicación de un sistema de análisis de peligros y control de puntos críticos en la nutrición enteral administrada en la unidad de cuidados intensivos

Indexación: ScieloSe aplicó un sistema de Análisis de Peligros y Control de Puntos Críticos (HACCP) en la administración de la nutrición enteral (NE) en la Unidad de Cuidados Intensivos (UCI) de un Hospital de alta complejidad, con la colaboración del personal que trabaja en la UCI, para garantizar la seguridad de la calidad en la preparación, almacenamiento y entrega de la nutrición enteral a pacientes hospitalizados. Se estudiaron los métodos de rutina de preparación de la nutrición enteral, su almacenamiento y entrega a pacientes y se realizó un diagrama de flujo del proceso de administración de la fórmula de NE, luego, se identificaron los peligros y se evaluó su gravedad. Se determinaron los Puntos Críticos de Control (PCC) y se establecieron los criterios de control. La abertura del envase de la Fórmula Enteral (FE) y la introducción del equipo de infusión a la FE constituyen los únicos PCC cuando se manipula una FE lista para colgar. Se monitorearon y se aplicaron límites críticos y medidas correctivas para cada uno de los PCC del proceso. Además, se tomaron muestras para realizar un análisis para medir la calidad microbiológica del producto en cada PCC del proceso y se controló su temperatura ambiental. El análisis estadístico del recuento bacteriano de Aerobios Mesófilos (RAM) y Coliformes totales (CT) al tiempo 0 y 48 horas señala que no existen diferencias estadísticamente significativas en el nivel RAM y CT (p<0,05) en esos tiempos de estudio. La aplicación del sistema HACCP en la manipulación de la FE listas para usar en pacientes hospitalizados en la UCI, demuestra que es un sistema eficaz que permite garantizar en forma efectiva y segura el empleo de NE en pacientes hospitalizadosA Hazard Analysis and Control of Critical Points (HACCP) was applied to enteral nutrition (EN) at the Intensive Care Unit (ICU) in a highly complex Hospital, with the collaboration of personnel working at the ICU to guarantee the certainty of the quality in the preparation, storage and delivery of enteral feeding solutions to hospitalized patients. Routine methods of food preparation, storage and delivery to patients were studied and a flux diagram of the process of the administration of the EN formula was draw; later, hazards were identified and their seriousness was evaluated. Critical Controls Points (CCP) were determined, and control criteria were established. The opening of the EN container and the introduction of infusion equipment are the only Critical Control Points (CCP) when a ready-to-hang EN preparation is manipulated. Critical limits and correction measures were monitored and applied for each of the CCP of the process. Moreover, samples were taken to analyze and measure the microbiologic quality of the product at each CCP of the process and room temperature was controlled. The statistical analysis of bacteria recount on enteral food shows that there are no statistically significant differences at RMA and TC levels (p< 0.05).http://www.scielo.cl/scielo.php?script=sci_arttext&pid=S0717-75182007000300010&nrm=is

RePlant Alfa: Integrating Google Earth Engine and R Coding to Support the Identification of Priority Areas for Ecological Restoration

Land degradation and climate change are among the main threats to the sustainability of ecosystems worldwide. As a result, the restoration of degraded landscapes is essential to maintaining the functionality of ecosystems, especially those with greater social, economic, and environmental vulnerability. Nevertheless, policymakers are frequently challenged by deciding where to prioritize restoration actions, which usually includes dealing with multiple and complex needs under an always limited budget. If these decisions are not taken based on proper data and processes, restoration implementation can easily fail. In order to help decision-makers take informed decisions on where to implement restoration activities, we have developed a semiautomatic geospatial platform to prioritize areas for restoration activities based on ecological, social, and economic variables. This platform takes advantage of the potential to integrate R coding, Google Earth Engine cloud computing, and GIS visualization services to generate an interactive geospatial decision-maker tool for restoration. Here, we present a prototype version called “RePlant alpha”, which was tested with data from the Central Zone of Chile. This exercise proved that integrating R and GEE was feasible, and that the analysis with at least six indicators for a specific region was also feasible to implement even from a personal computer. Therefore, the use of a virtual machine in the cloud with a large number of indicators over large areas is both possible and practical

RePlant Alfa: Integrating Google Earth Engine and R Coding to Support the Identification of Priority Areas for Ecological Restoration

Land degradation and climate change are among the main threats to the sustainability of ecosystems worldwide. As a result, the restoration of degraded landscapes is essential to maintaining the functionality of ecosystems, especially those with greater social, economic, and environmental vulnerability. Nevertheless, policymakers are frequently challenged by deciding where to prioritize restoration actions, which usually includes dealing with multiple and complex needs under an always limited budget. If these decisions are not taken based on proper data and processes, restoration implementation can easily fail. In order to help decision-makers take informed decisions on where to implement restoration activities, we have developed a semiautomatic geospatial platform to prioritize areas for restoration activities based on ecological, social, and economic variables. This platform takes advantage of the potential to integrate R coding, Google Earth Engine cloud computing, and GIS visualization services to generate an interactive geospatial decision-maker tool for restoration. Here, we present a prototype version called &ldquo;RePlant alpha&rdquo;, which was tested with data from the Central Zone of Chile. This exercise proved that integrating R and GEE was feasible, and that the analysis with at least six indicators for a specific region was also feasible to implement even from a personal computer. Therefore, the use of a virtual machine in the cloud with a large number of indicators over large areas is both possible and practical

Virtual screening leads to the discovery of novel non-nucleotide P2Y1 receptor antagonists

The P2Y(1) receptor (P2Y(1)R) is a G protein-coupled receptor naturally activated by extracellular ADP. Its stimulation is an essential requirement of ADP-induced platelet aggregation, thus making antagonists highly sought compounds for the development of antithrombotic agents. Here, through a virtual screening campaign based on a pharmacophoric representation of the common characteristics of known P2Y(1)R ligands and the putative shape and size of the receptor binding pocket, we have identified novel antagonist hits of µM affinity derived from a N,N’-bis-arylurea chemotype. Unlike the vast majority of known P2Y(1)R antagonists, these drug-like compounds do not have a nucleotidic scaffold or highly negatively charged phosphate groups. Hence, our compounds may provide a direction for the development of receptor probes with altered physicochemical properties