Analyzing multitarget activity landscapes using protein-ligand interaction fingerprints: interaction cliffs.

This is the original submitted version, before peer review. The final peer-reviewed version is available from ACS at http://pubs.acs.org/doi/abs/10.1021/ci500721x.Activity landscape modeling is mostly a descriptive technique that allows rationalizing continuous and discontinuous SARs. Nevertheless, the interpretation of some landscape features, especially of activity cliffs, is not straightforward. As the nature of activity cliffs depends on the ligand and the target, information regarding both should be included in the analysis. A specific way to include this information is using protein-ligand interaction fingerprints (IFPs). In this paper we report the activity landscape modeling of 507 ligand-kinase complexes (from the KLIFS database) including IFP, which facilitates the analysis and interpretation of activity cliffs. Here we introduce the structure-activity-interaction similarity (SAIS) maps that incorporate information on ligand-target contact similarity. We also introduce the concept of interaction cliffs defined as ligand-target complexes with high structural and interaction similarity but have a large potency difference of the ligands. Moreover, the information retrieved regarding the specific interaction allowed the identification of activity cliff hot spots, which help to rationalize activity cliffs from the target point of view. In general, the information provided by IFPs provides a structure-based understanding of some activity landscape features. This paper shows examples of analyses that can be carried out when IFPs are added to the activity landscape model.M-L is very grateful to CONACyT (No. 217442/312933) and the Cambridge Overseas Trust for funding. AB thanks Unilever for funding and the European Research Council for a Starting Grant (ERC-2013- StG-336159 MIXTURE). J.L.M-F. is grateful to the School of Chemistry, Department of Pharmacy of the National Autonomous University of Mexico (UNAM) for support. This work was supported by a scholarship from the Secretariat of Public Education and the Mexican government

BMD loci contribute to ethnic and developmental differences in skeletal fragility across populations: Assessment of evolutionary selection pressures

Bone mineral density (BMD) is a highly heritable trait used both for the diagnosis of osteoporosis in adults and to assess bone health in children. Ethnic differences in BMD have been documented, with markedly higher levels in individuals of African descent, which partially explain disparity in osteoporosis risk across populations. To date, 63 independent genetic variants have been associated with BMD in adults of Northern-European ancestry. Here, we demonstrate that at least 61 of these variants are predictive of BMD early in life by studying their compound effect within two multiethnic pediatric cohorts. Furthermore, we show that within these cohorts and across populations worldwide the frequency of those alleles associated with increased BMD is systematically elevated in individuals of Sub-Saharan African ancestry. The amount of differentiation in the BMD genetic scores among Sub-Saharan and non-Sub-Saharan populations together with neutrality tests, suggest that these allelic differences are compatible with the hypothesis of selective pressures acting on the genetic determinants of BMD. These findings constitute an explorative contribution to the role of selection on ethnic BMD differences and likely a new example of polygenic adaptation acting on a human trait

Measurement of the cosmic ray spectrum above 4×10184{\times}10^{18} eV using inclined events detected with the Pierre Auger Observatory

A measurement of the cosmic-ray spectrum for energies exceeding $4{\times}10^{18}$ eV is presented, which is based on the analysis of showers with zenith angles greater than $60^{\circ}$ detected with the Pierre Auger Observatory between 1 January 2004 and 31 December 2013. The measured spectrum confirms a flux suppression at the highest energies. Above $5.3{\times}10^{18}$ eV, the "ankle", the flux can be described by a power law $E^{-\gamma}$ with index $\gamma=2.70 \pm 0.02 \,\text{(stat)} \pm 0.1\,\text{(sys)}$ followed by a smooth suppression region. For the energy ($E_\text{s}$) at which the spectral flux has fallen to one-half of its extrapolated value in the absence of suppression, we find $E_\text{s}=(5.12\pm0.25\,\text{(stat)}^{+1.0}_{-1.2}\,\text{(sys)}){\times}10^{19}$ eV.Comment: Replaced with published version. Added journal reference and DO

Catalytic Decomposition of n-C-7 Asphaltenes Using Tungsten Oxides-Functionalized SiO2 Nanoparticles in Steam/Air Atmospheres

A wide range of technologies are being developed to increase oil recovery, reserves, and perform in situ upgrading of heavy crude oils. In this study, supported tungsten oxide nanoparticles were synthesized, characterized, and evaluated for adsorption and catalytic performance during wet in situ combustion (6% of steam in the air, in volumetric fraction) of n-C-7 asphaltenes. Silica nanoparticles of 30 nm in diameter were synthesized using a sol-gel methodology and functionalized with tungsten oxides, using three different concentrations and calcination temperatures: 1%, 3%, 5% (mass fraction), and 350 degrees C, 450 degrees C, and 650 degrees C, respectively. Equilibrium batch adsorption experiments were carried out at 25 celcius with model solutions of n-C-7 asphaltenes diluted in toluene at concentrations from 100 mg center dot L-1 to 2000 mg center dot L-1, and catalytic wet in situ combustion of adsorbed heavy fractions was carried out by thermogravimetric analysis coupled to FT-IR. The results showed improvements of asphaltenes decomposition by the action of the tungsten oxide nanoparticles due to the reduction in the decomposition temperature of the asphaltenes up to 120 degrees C in comparison with the system in the absence of WOX nanoparticles. Those synthesis parameters, such as temperature and impregnation dosage, play an important role in the adsorptive and catalytic activity of the materials, due to the different WOX-support interactions as were found through XPS. The mixture released during the catalyzed asphaltene decomposition in the wet air atmosphere reveals an increase in light hydrocarbons, methane, and hydrogen content. Hydrogen production was prioritized between 300 and 400 degrees C where, similarly, the reduction of CO, CH4, and the increase in CO2 content, associated with water-gas shift, and methane reforming reactions occur, respectively. The results show that these catalysts can be used either for in situ upgrading of crude oil, or any application where heavy fractions must be transformed

Energy Estimation of Cosmic Rays with the Engineering Radio Array of the Pierre Auger Observatory

The Auger Engineering Radio Array (AERA) is part of the Pierre Auger Observatory and is used to detect the radio emission of cosmic-ray air showers. These observations are compared to the data of the surface detector stations of the Observatory, which provide well-calibrated information on the cosmic-ray energies and arrival directions. The response of the radio stations in the 30 to 80 MHz regime has been thoroughly calibrated to enable the reconstruction of the incoming electric field. For the latter, the energy deposit per area is determined from the radio pulses at each observer position and is interpolated using a two-dimensional function that takes into account signal asymmetries due to interference between the geomagnetic and charge-excess emission components. The spatial integral over the signal distribution gives a direct measurement of the energy transferred from the primary cosmic ray into radio emission in the AERA frequency range. We measure 15.8 MeV of radiation energy for a 1 EeV air shower arriving perpendicularly to the geomagnetic field. This radiation energy -- corrected for geometrical effects -- is used as a cosmic-ray energy estimator. Performing an absolute energy calibration against the surface-detector information, we observe that this radio-energy estimator scales quadratically with the cosmic-ray energy as expected for coherent emission. We find an energy resolution of the radio reconstruction of 22% for the data set and 17% for a high-quality subset containing only events with at least five radio stations with signal.Comment: Replaced with published version. Added journal reference and DO

Measurement of the Radiation Energy in the Radio Signal of Extensive Air Showers as a Universal Estimator of Cosmic-Ray Energy

We measure the energy emitted by extensive air showers in the form of radio emission in the frequency range from 30 to 80 MHz. Exploiting the accurate energy scale of the Pierre Auger Observatory, we obtain a radiation energy of 15.8 \pm 0.7 (stat) \pm 6.7 (sys) MeV for cosmic rays with an energy of 1 EeV arriving perpendicularly to a geomagnetic field of 0.24 G, scaling quadratically with the cosmic-ray energy. A comparison with predictions from state-of-the-art first-principle calculations shows agreement with our measurement. The radiation energy provides direct access to the calorimetric energy in the electromagnetic cascade of extensive air showers. Comparison with our result thus allows the direct calibration of any cosmic-ray radio detector against the well-established energy scale of the Pierre Auger Observatory.Comment: Replaced with published version. Added journal reference and DOI. Supplemental material in the ancillary file

Factores de riesgo asociados a la aparición del linfedema en las pacientes mastectomizadas atendidas en el servicio de oncología del Hospital Julio C. Perrando entre los años 2011 y 2012

Se realizó una investigación cuantitativa, analítica de casos y controles, retrospectiva, transversal y observacional que tuvo como objetivo establecer la relación entre grupo etario, nivel de instrucción, tipo de cirugía, número de ganglios extirpados y la aparición del linfedema dentro del año posterior a la cirugía en pacientes mastectomizadas.Las unidades de análisis fueron pacientes mastectomizadas atendidas en el Servicio de Oncología del Hospital Julio C. Perrando de la Ciudad de Resistencia Chaco, entre 2011 y 2012.Los resultados mostraron que las pacientes mastectomizadas del grupo etario de 51 a 65 años tuvieron 1,22 veces más probabilidades de presentar linfedema; luego del año posterior a la cirugía.En cuanto al nivel de instrucción incompleto se asoció a la aparición del linfedema, presentándose como un factor de protección con un OR de 0,17 siendo estadísticamente significativo.Respecto al tipo de cirugía realizada, se constató que las pacientes que recibieron mastectomía radical obtuvieron un OR de 1,90 representó un factor de riesgo este tipo de cirugía; en cambio, las pacientes intervenidas quirúrgicamente con extirpación de más de 5 ganglios obtuvieron un OR de 2,5 presentándose como factor de riesgo para padecer linfedema

Malaria en niños: discusión de algunos aspectos clínicos, diagnósticos y terapéuticos

Malaria infections in children often present dificulties in diagnosis and chemotherapy. Here we describe three cases of malaria with several considerations about the diagnosis, course of infection and post-treatment evolution. The first case was a 2 month old girl with a severe malnutrition and a post-transfusional Plasmodium vivax infection. Three different regimens of chloroquine were required to clear the infection. The second case was a 25 day-old boy who developed a Plasmodium vivax infection and methahemoglobinemia after treatment with primaquine. The last patient was a 8 year-old boy in fected with a chloroquine-resistent Plasmodium folciparum. After radical treatment with sulfadoxine-pyrimethamine and due to the presence of circualting gametocytes the patient received at the hospital 4 different therapeutic schemes including 10 days of I.V. quinine, sulfadoxine-pyrimethamine and trimethorpim-sulfamethoxazol.Se describen 3 casos de malaria en niños incluyendo el diagnóstico y tratamiento, la evolución y las complicaciones. El primer caso corresponde a una lactante menor con un avanzado estado de desnutrición y una infección post-transfusional por Plasmodium vivax. La respuesta a la cloroquina no fue adecuada requiriendo 2 ciclos adicionales para eliminar los parásitos circulantes. El segundo caso describe un neonato de 25 días de edad con una infección por Plasmodium vivax cuyo mecanismo de transmisión pudo ser transplacentario aunque no se descartó la transmisión natural. La madre fue positiva pera Plasmodium vivax durante el embarazo y puerperio. El paciente presentó además un metahemaglobinemia como complicación del tratamiento con primaquina. Finalmente se presenta el caso de un escolar con una malaria por Plasmodium falciparum resistente a la cloroquina tratada en forma inadecuada con 4 esquemas terapéuticos diferentes, que incluyen quinina intravenosa, trimetoprim-sulfametoxazol y sulfadoxina-pirimetamina

Validación de una metodología analítica para la cuantificación de polifenoles totales, en procesos de extracción asistida por microondas sobre frutos de la especie colombiana Vaccinium meridionale

En este trabajo se muestra el desarrollo y la validación de un método analítico para la cuantificación de polifenoles totales con el reactivo de Folin-Ciocalteu (F–C),en procesos de extracción asistida por microondas (MAE), sobre frutos de la especie colombiana Vaccinium meridionale. Los resultados obtenidos en los parámetros selectividad, linealidad, repetibilidad y exactitud muestran que la metodología propuesta es confiable para evaluar el efecto de las condiciones de extracción sobre la cantidad de polifenoles removidos.The in vitro pharmacological model of P. falciparum culture is crucial in the initial screening for substances or plant extracts with possible antiplasmodial activity. The parasite density can be determined by varied methods, however have been described numerous advantages and disadvantages associated with each of them.The incubation time required for staining and the use of synchronous or asynchronous cultures were assessed for optimal settings; showing optimal time of 2 h, and lower limits of detection and quantification in asynchronous cultures. Employing the FCB2 and FCR3 strains, was evidenced a background noise of 12% and 38% respectively; linearity showed a good correlation, r2 of 0.9644 (FCR3) and 0.9841 (FCB2) and a slope of 1761.8 and 852.4, respectively. It was evidenced agreement between the methods, fluorometric with SYBR Green I (SYBRG I) and microscopic with Giemsa, the mean difference was 0.00002% and 0.09109% respectively for FCR3 and FCB2, The limits of detection and quantification were 0.5% and 1.5% of parasitaemia. The Z factor was 0.376 with FCB2, whereas with FCR3 reached 0.702. The inhibitory concentration 50 (IC50) against P. falciparum FCR3, generated by chloroquine (CQ), was 0.37 mcg/mL by microscopy and 0.35 mcg/mL by fluorometry.Our findings suggest that the SYBRG I fluorescence based assay, by using fluorometers commonly available in many laboratories, is precise, robust, fast and accurate; for the in vitro evaluation of substances or extracts with possible antiplasmodial activity