1,728 research outputs found
J R SOC INTERFACE
Enzymes are dynamic entities, and their dynamic properties are clearly linked to their biological function. It follows that dynamics ought to play an essential role in enzyme evolution. Indeed, a link between conformational diversity and the emergence of new enzyme functionalities has been recognized for many years. However, it is only recently that state-of-the-art computational and experimental approaches are revealing the crucial molecular details of this link. Specifically, evolutionary trajectories leading to functional optimization for a given host environment or to the emergence of a new function typically involve enriching catalytically competent conformations and/or the freezing out of non-competent conformations of an enzyme. In some cases, these evolutionary changes are achieved through distant mutations that shift the protein ensemble towards productive conformations. Multifunctional intermediates in evolutionary trajectories are probably multi-conformational, i.e. able to switch between different overall conformations, each competent for a given function. Conformational diversity can assist the emergence of a completely new active site through a single mutation by facilitating transition-state binding. We propose that this mechanism may have played a role in the emergence of enzymes at the primordial, progenote stage, where it was plausibly promoted by high environmental temperatures and the possibility of additional phenotypic mutationsDepartment of Chemistry, BMC, Uppsala University, Box 576, 751 23 Uppsala, Sweden
Departamento de Quimica Fisica, Facultad de Ciencias, University of Granada, 18071 Granada, SpainWallenberg Academy Fellowship to S.C.L.K. from the Knut and Alice Wallenberg Foundation (KAW 2013.0124)Grant RGP0041/2017 from the Human Frontier Science ProgramFEDER Funds and grant BIO2015–66426-R to J.M.S.R. from the Spanish Ministry of Economy and Competitivenes
HEMIC Project: Design of a Clinical Information Modelling Tool Based on ISO13972 Technical Specification
The Andalusian Health Service is the public healthcare provider for 8.302.923 inhabitants in the South Spain. This organization coordinates primary and specialized care with an IT infrastructure composed by multiple Electronic Health Record Systems. According to the large volume of healthcare professionals involved, there is a need for providing a consistent management of information through multiple locations and systems. The HEMIC project aims to address this need developing and validating a methodology based on a software tool for standardizing information contained within EHR systems. The developed tool has been designed for supporting the participation of healthcare professionals the establishment of mechanisms for information governance. This research presents the requirements and designs for of a software tool focused on the adoption of recognized best practice in clinical information modeling. The designed tool has a Service Oriented Architecture that will be able to integrate terminology servers and repositories of clinical information models as part of the modeling process. Moreover, the defined tool organizes clinicians, IT developers and terminology experts involved in the modeling process in three levels to promote their coordination in the definition, specialization and validation of clinical information models. In order to ensure the quality of the developed clinical information models, the defined tool is based on the requirements defined in the ISO13972 Technical Specification
Evaluation of Linked Determinants Between Diabetes and Caries
Dental caries and diabetes mellitus, represent two chronic diseases of public health that present statistics of high prevalence worldwide. One of the main problems that affect these conditions is demography, since the least developed countries are those that have less access to public health services and are limited by the economic costs that represent the treatments. In this work is presented the univariate analysis, of a set of demographic determinants obtained from the National Health and Nutrition Examination Surveys (NHANES), in order to identify those that present the most significant information related to estimation of these diseases. According to the results, the age of the subjects is the main determinant describing the simultaneous presence of these diseases, obtaining an area under the curve (AUC) value ≥ 0.846, concluding that age can be used as tool for their preventive diagnosis
Pumped double quantum dot with spin-orbit coupling
We study driven by an external electric field quantum orbital and spin dynamics of electron in a one-dimensional double quantum dot with spin-orbit coupling. Two types of external perturbation are considered: a periodic field at the Zeeman frequency and a single half-period pulse. Spin-orbit coupling leads to a nontrivial evolution in the spin and orbital channels and to a strongly spin- dependent probability density distribution. Both the interdot tunneling and the driven motion contribute into the spin evolution. These results can be important for the design of the spin manipulation schemes in semiconductor nanostructures
Measurement of finite-frequency current statistics in a single-electron transistor
Electron transport in nano-scale structures is strongly influenced by the
Coulomb interaction which gives rise to correlations in the stream of charges
and leaves clear fingerprints in the fluctuations of the electrical current. A
complete understanding of the underlying physical processes requires
measurements of the electrical fluctuations on all time and frequency scales,
but experiments have so far been restricted to fixed frequency ranges as
broadband detection of current fluctuations is an inherently difficult
experimental procedure. Here we demonstrate that the electrical fluctuations in
a single electron transistor (SET) can be accurately measured on all relevant
frequencies using a nearby quantum point contact for on-chip real-time
detection of the current pulses in the SET. We have directly measured the
frequency-dependent current statistics and hereby fully characterized the
fundamental tunneling processes in the SET. Our experiment paves the way for
future investigations of interaction and coherence induced correlation effects
in quantum transport.Comment: 7 pages, 3 figures, published in Nature Communications (open access
VALORACIÓN NUTRICIONAL EN LACTANTES DE ENTRE 8 A 12 MESES DE VIDA
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Safety outcomes during pediatric GH therapy: final results from the prospective GeNeSIS observational program
CONTEXT: Safety concerns regarding premature mortality, diabetes, neoplasia and cerebrovascular disease in association with growth hormone (GH) therapy have been raised.
OBJECTIVE: To assess incidence of key safety outcomes.
DESIGN: Prospective, multinational, observational study (1999-2015).
SETTING: 22,311 GH-treated children from 827 investigative sites in 30 countries.
PATIENTS: Children with growth disorders.
INTERVENTIONS: GH treatment.
MAIN OUTCOME MEASURES: Standardized mortality (SMR) and incidence (SIR) ratios with 95% confidence intervals (CI) for mortality, diabetes, and primary cancer, using general population registries.
RESULTS: Predominant short stature diagnoses were GH deficiency (63%), idiopathic short stature (13%), and Turner syndrome (8%), with mean±SD follow-up of 4.2±3.2 years (∼92,000 person-years [PY]). Forty-two deaths occurred in patients with follow-up, with SMR (95% CI) of 0.61 (0.44-0.82); the SMR was elevated for patients with cancer-related organic GH deficiency (5.87 [3.21-9.85]). Based on 18 cases, Type 2 diabetes (T2DM) risk was elevated (SIR 3.77 [2.24-5.96]), but 72% had risk factors. In patients without cancer history, 14 primary cancers were observed (SIR 0.71 [0.39-1.20]). Second neoplasms occurred in 31/622 (5.0%) cancer survivors (10.7 [7.5-15.2] cases/1000 PY), and intracranial tumor recurrences in 67/823 (8.1%) tumor survivors (16.9 [13.3-21.5] cases/1000 PY). All 3 hemorrhagic stroke cases had risk factors.
CONCLUSIONS: GeNeSIS data support the favourable safety profile of pediatric GH treatment. Overall risk for death or primary cancer was not elevated in GH-treated children, and no hemorrhagic strokes occurred in patients without risk factors. T2DM incidence was elevated compared to the general population, but most cases had diabetes risk factors
Synthesis and Biological Evaluation of Phenanthrenes as Cytotoxic Agents with Pharmacophore Modeling and ChemGPS-NP Prediction as Topo II Inhibitors
In a structure-activity relationship (SAR) study, 3-methoxy-1,4-phenanthrenequinones, calanquinone A (6a), denbinobin (6b), 5-OAc-calanquinone A (7a) and 5-OAc-denbinobin (7b), have significantly promising cytotoxicity against various human cancer cell lines (IC50 0.08–1.66 µg/mL). Moreover, we also established a superior pharmacophore model for cytotoxicity (r = 0.931) containing three hydrogen bond acceptors (HBA1, HBA2 and HBA3) and one hydrophobic feature (HYD) against MCF-7 breast cancer cell line. The pharmacophore model indicates that HBA3 is an essential feature for the oxygen atom of 5-OH in 6a–b and for the carbonyl group of 5-OCOCH3 in 7a–b, important for their cytotoxic properties. The SAR for moderately active 5a–b (5-OCH3), and highly active 6a–b and 7a–b, are also elaborated in a spatial aspect model. Further rational design and synthesis of new cytotoxic phenanthrene analogs can be implemented via this model. Additionally, employing a ChemGPS-NP based model for cytotoxicity mode of action (MOA) provides support for a preliminary classification of compounds 6a–b as topoisomerase II inhibitors
Enriching Peptide Libraries for Binding Affinity and Specificity Through Computationally Directed Library Design
Peptide reagents with high affinity or specificity for their target protein interaction partner are of utility for many important applications. Optimization of peptide binding by screening large libraries is a proven and powerful approach. Libraries designed to be enriched in peptide sequences that are predicted to have desired affinity or specificity characteristics are more likely to yield success than random mutagenesis. We present a library optimization method in which the choice of amino acids to encode at each peptide position can be guided by available experimental data or structure-based predictions. We discuss how to use analysis of predicted library performance to inform rounds of library design. Finally, we include protocols for more complex library design procedures that consider the chemical diversity of the amino acids at each peptide position and optimize a library score based on a user-specified input model.National Institute of General Medical Sciences (U.S.) (Award R01 GM110048
Caracterización fisicoquÃmica, actividad antioxidante y contenido de fenoles y flavonoides totales de nopal morado (Opuntia gosseliniana) en dos etapas de coloración
Nopal (Opuntia gosseliniana) is considered a food product of interest due to its functional properties, including its antioxidant activity. The objective of this work was to evaluate the physical-chemical properties (color, pH and total soluble solids), antioxidant activity (DPPH, ABTS and FRAP), content of total phenols and flavonoids and betalain content of ethanolic extracts of nopal in two stages of coloration: green and purple. The highest values for total phenols and flavonoids were found in the purple samples, with values of 2.31 mg EAG/gps and 3.06 mg EQ/gps, respectively. Similarly, in the antioxidant activity (in the three techniques used) and betalain content, higher values were obtained in the purple color stage. Therefore, this species of cacti could be a potential source of antioxidants and pigments of agroindustrial interest.El nopal (Opuntia gosseliniana) es considerado un producto alimenticio de interés debido a sus propiedades funcionales, incluyendo su actividad antioxidante. El objetivo de este trabajo fue evaluar las propiedades fÃsico-quÃmicas (color, pH y sólidos solubles totales), actividad antioxidante (DPPH, ABTS y FRAP), contenido de fenoles y flavonoides totales y contenido de betalaÃnas extractos etanólicos de nopal en dos etapas de coloración: verde y morado. Los valores más altos para fenoles y flavonoides totales se encontraron en las muestras de color morado, con valores de 2.31 mg EAG/gps y 3.06 mg EQ/gps, respectivamente. De igual manera, en la actividad antioxidante se obtuvieron valores más altos en la etapa de color morado en las tres técnicas utilizadas. Por lo que, esta especie de cactácea podrÃa ser una fuente potencial de antioxidantes y pigmentos de interés agroindustrial
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