Acetylcholinesterase Inhibition of Diversely Functionalized Quinolinones for Alzheimer's Disease Therapy

In this communication, wereport the synthesis and cholinesterase (ChE)/monoamine oxidase (MAO) inhibition of 19 quinolinones (QN1-19) and 13 dihydroquinolinones (DQN1-13) designed as potential multitarget small molecules (MSM) for Alzheimer¿s disease therapy. Contrary to our expectations, none of them showed significant human recombinant MAO inhibition, but compounds QN8, QN9, and DQN7 displayed promising human recombinant acetylcholinesterase (hrAChE) and butyrylcholinesterase (hrBuChE) inhibition. In particular, molecule QN8 was found to be a potent and quite selective non-competitive inhibitor of hrAChE (IC50 = 0.29 M), with Ki value in nanomolar range (79 nM). Pertinent docking analysis confirmed this result, suggesting that this ligand is an interesting hit for further investigation.R.A., M.S., P.B., and K.M. were supported by European Regional Development Fund/European Social Fund (ERDF/ESF, project PharmaBrain, no. CZ.02.1.01/0.0/0.0/16_025/0007444), University of Hradec Kralove (no. SV2113-2019, VT2019-2021), and EU COST action CA15135 MuTaLig. J.M.C. thanks Ministerio de Economía (MINECO, SAF2015-65586-R) and Universidad Camilo José Cela (UCJC, grants UCJC 2020-03, and UCJC 2020-33) for support

Search for very-high-energy emission from Gamma-ray Bursts using the first 18 months of data from the HAWC Gamma-ray Observatory

The High Altitude Water Cherenkov (HAWC) Gamma-ray Observatory is an extensive air shower detector operating in central Mexico, which has recently completed its first two years of full operations. If for a burst like GRB 130427A at a redshift of 0.34 and a high-energy component following a power law with index -1.66, the high-energy component is extended to higher energies with no cut-off other than from extragalactic background light attenuation, HAWC would observe gamma rays with a peak energy of $\sim$300 GeV. This paper reports the results of HAWC observations of 64 gamma-ray bursts (GRBs) detected by $\mathit{Swift}$ and $\mathit{Fermi}$, including three GRBs that were also detected by the Large Area Telescope ($\mathit{Fermi}$-LAT). An ON/OFF analysis method is employed, searching on the time scale given by the observed light curve at keV-MeV energies and also on extended time scales. For all GRBs and time scales, no statistically significant excess of counts is found and upper limits on the number of gamma rays and the gamma-ray flux are calculated. GRB 170206A, the third brightest short GRB detected by the Gamma-ray Burst Monitor on board the $\mathit{Fermi}$ satellite ($\mathit{Fermi}$-GBM) and also detected by the LAT, occurred very close to zenith. The LAT measurements can neither exclude the presence of a synchrotron self-Compton (SSC) component nor constrain its spectrum. Instead, the HAWC upper limits constrain the expected cut-off in an additional high-energy component to be less than $100~\rm{GeV}$ for reasonable assumptions about the energetics and redshift of the burst.Comment: 19 pages, 6 figures, published in Ap

Métodos para la identificación del antígeno de histocompatibilidad HLA-B27: comparación de cuatro protocolos técnicos

Introducción: La asociación del HLA-B27 y las Espondiloartritis, ha hecho evidente que la tipificación del HLA-B27 sea considerada como un apoyo en el diagnóstico de estas enfermedades. Los métodos más empleados para la determinación del antígeno HLA-B27 en los laboratorios clínicos y en investigación son: la microlinfocitotoxicidad (MCTX), la citometría de flujo digital (CMFd), la citometría de flujo análoga (CMFa) y la reacción en cadena de la polimerasa con primers de secuencia específicos (PCR-SSP).Objetivo: Comparar MCTX con la CMFd, la CMFa con la CMFd, y la técnica de CMFd frente a PCR-SSP.Métodos para la identificación del antígeno de histocompatibilidad hla-b27 Métodos: Se analizaron 4109 solicitudes de HLA-B27 en población con manifestaciones sugestivas de EAS remitidas entre 2009 y 2012 al Hospital Militar Central y al Instituto de Referencia Andino. Se evaluaron las frecuencias obtenidas por Chi cuadrado (X2); para estimar la concordancia metodológica se utilizó el Coeficiente de Correlación Intraclase (CCI). Los análisis se realizaron con el paquete estadístico SPSS V18.Resultados: Al evaluar 467 datos por la técnica de CMFa frente a PCR-SSP, la CMFa mostró 239 resultados entre positivos y en rango indeterminado, de los cuales, luego de ser confirmados PCRSSP, solo 213 demostraron la expresión de HLA-B27 (p<0.05). Se obtuvieron 208 resultados realizados por CMFd y PCR-SSP simultáneamente, observándose una alta correspondencia entre estas técnicas (p<0.05). Para evaluar la concordancia entre la MCTX y CMFd se analizaron 34 datos,revelando un 100% de correspondencia entre esta dos metodologías CCI=1,p<0.05).Conclusión: La citometría de flujo digital es un método rápido que presenta un desempeño altamente confiable para la identificación de HLA-B27, resultados que se recomiendan confirmar por PCR SSP

Daily monitoring of TeV gamma-ray emission from Mrk 421, Mrk 501, and the Crab Nebula with HAWC

We present results from daily monitoring of gamma rays in the energy range $\sim0.5$ to $\sim100$ TeV with the first 17 months of data from the High Altitude Water Cherenkov (HAWC) Observatory. Its wide field of view of 2 steradians and duty cycle of $>95$% are unique features compared to other TeV observatories that allow us to observe every source that transits over HAWC for up to $\sim6$ hours each sidereal day. This regular sampling yields unprecedented light curves from unbiased measurements that are independent of seasons or weather conditions. For the Crab Nebula as a reference source we find no variability in the TeV band. Our main focus is the study of the TeV blazars Markarian (Mrk) 421 and Mrk 501. A spectral fit for Mrk 421 yields a power law index $\Gamma=2.21 \pm0.14_{\mathrm{stat}}\pm0.20_{\mathrm{sys}}$ and an exponential cut-off $E_0=5.4 \pm 1.1_{\mathrm{stat}}\pm 1.0_{\mathrm{sys}}$ TeV. For Mrk 501, we find an index $\Gamma=1.60\pm 0.30_{\mathrm{stat}} \pm 0.20_{\mathrm{sys}}$ and exponential cut-off $E_0=5.7\pm 1.6_{\mathrm{stat}} \pm 1.0_{\mathrm{sys}}$ TeV. The light curves for both sources show clear variability and a Bayesian analysis is applied to identify changes between flux states. The highest per-transit fluxes observed from Mrk 421 exceed the Crab Nebula flux by a factor of approximately five. For Mrk 501, several transits show fluxes in excess of three times the Crab Nebula flux. In a comparison to lower energy gamma-ray and X-ray monitoring data with comparable sampling we cannot identify clear counterparts for the most significant flaring features observed by HAWC.Comment: 18 pages, 10 figures, accepted for publication in The Astrophysical Journa

Extended gamma-ray sources around pulsars constrain the origin of the positron flux at Earth

The unexpectedly high flux of cosmic ray positrons detected at Earth may originate from nearby astrophysical sources, dark matter, or unknown processes of cosmic-ray secondary production. We report the detection, using the HighAltitude Water Cherenkov Observatory (HAWC), of extended tera-electron volt gamma-ray emission coincident with the locations of two nearby middle-aged pulsars (Geminga and PSR B0656+14). The HAWC observations demonstrate that these pulsars are indeed local sources of accelerated leptons, but the measured tera-electron volt emission profile constrains the diffusion of particles away from these sources to be much slower than previously assumed. We demonstrate that the leptons emitted by these objects are therefore unlikely to be the origin of the excess positrons, which may have a more exotic origin.Comment: 16 pages (including supplementary material), 5 figure

2013. Documento Sevilla de Consenso sobre Alternativas a la Transfusión de Sangre Alogénica. Actualización del Documento Sevilla

La transfusión de sangre alogénica (TSA) no es inocua, y como consecuencia han surgido múltiples alternativas a la misma (ATSA). Existe variabilidad respecto a las indicaciones y buen uso de las ATSA. Dependiendo de la especialidad de los médicos que tratan a los pacientes, el grado de anemia, la política transfusional, la disponibilidad de las ATSA y el criterio personal, estas se usan de forma variable. Puesto que las ATSA tampoco son inocuas y pueden no cumplir criterios de coste-efectividad, la variabilidad en su uso es inaceptable. Las sociedades españolas de Anestesiología y Reanimación (SEDAR), Hematología y Hemoterapia (SEHH), Farmacia Hospitalaria (SEFH), Medicina Intensiva y Unidades Coronarias (SEMICYUC), Trombosis y Hemostasia (SETH) y Transfusiones Sanguíneas (SETS) han elaborado un documento de consenso para el buen uso de la ATSA. Un panel de expertos de las 6 sociedades ha llevado a cabo una revisión sistemática de la literatura médica y elaborado el 2013. Documento Sevilla de Consenso sobre Alternativas a la Transfusión de Sangre Alogénica. Solo se contempla las ATSA dirigidas a disminuir la transfusión de concentrado de hematíes. Se definen las ATSA como toda medida farmacológica y no farmacológica encaminada a disminuir la transfusión de concentrado de hematíes, preservando siempre la seguridad del paciente. La cuestión principal que se plantea en cada ítem se formula, en forma positiva o negativa, como: «La ATSA en cuestión reduce/no reduce la tasa transfusional». Para formular el grado de recomendación se ha usado la metodología Grades of Recommendation Assessment, Development and Evaluation (GRADE)

Mannose-binding lectin-deficient genotypes as a risk factor of pneumococcal meningitis in infants

OBJECTIVES: The objective of this study was to evaluate to evaluate the role of mannose-binding-lectin deficient genotypes in pneumococcal meningitis (PM) in children. METHODS: We performed a 16-year retrospective study (January 2001 to March 2016) including patients ≤ 18 years with PM. Variables including attack rate of pneumococcal serotype (high or low invasive capacity) and MBL2 genotypes associated with low serum MBL levels were recorded. RESULTS: Forty-eight patients were included in the study. Median age was 18.5 months and 17/48 episodes (35.4%) occurred in children ≤ 12 months old. Serotypes with high-invasive disease potential were identified in 15/48 episodes (31.2%). MBL2 deficient genotypes accounted for 18.8% (9/48). Children ≤ 12 months old had a 7-fold risk (95% CI: 1.6-29.9; p 12 months old. A sub-analysis of patients by age group revealed significant proportions of carriers of MBL2 deficient genotypes among those ≤ 12 months old with PM caused by opportunistic serotypes (54.5%), admitted to the PICU (Pediatric Intensive Care Unit) (46.7%) and of White ethnicity (35.7%). These proportions were significantly higher than in older children (all p<0.05). CONCLUSIONS: Our results suggest that differences in MBL2 genotype in children ≤12 months old affects susceptibility to PM, and it may have an important role in the episodes caused by non-high invasive disease potential serotypes

Código Cáncer: resultados preliminares

Antecedentes: Los retrasos en la atención de personas con cáncer impactan negativamente su calidad de vida y aumentan los costos al sistema de salud. / Objetivo: Describir las fases del proyecto Código Cáncer y sus resultados preliminares. / Métodos: Se organizaron siete grupos de investigación para: a) entender las causas de los retrasos que enfrentan las personas con cáncer en México, sus trayectorias y costos asociados; b) conocer los mecanismos de referencia formales e informales que constituyen su trayectoria en el sistema de salud, y c) entender la infraestructura existente y la necesaria para responder a las necesidades epidemiológicas del país. / Resultados: Estos resultados sientan las bases para la implementación de un programa de referencia rápida de pacientes. / Conclusión: Las políticas de diagnóstico y tratamiento oportuno del cáncer basadas en la evidencia son imprescindibles para atender los retrasos en la atención. Código Cáncer representa un proyecto innovador para lograr este objetivo en México

Medios de comunicación y derecho a la información en Jalisco, 2020

Este informe de medios hace una mirada crítica al pasado reciente de lo ocurrido en el 2020 y destaca el trabajo de la comunicación pública para combatir la crisis epistemológica que enfrentó la sociedad durante el inicio de la pandemia. Destaca las nuevas formas de hacer periodismo por parte de los medios independientes, que se abren paso en medio de un mercado laboral periodístico mermado drásticamente por despidos masivos y cada vez más precarias remuneraciones. También presenta un análisis del Sistema de Radio y Televisión de Jalisco y, a partir de estándares internacionales, profundiza cronológica y críticamente sus publicaciones en contrapunto con los cambios político-partidistas vividas en el estado. En su apartado final, presenta semblanzas biográficas de personajes relacionados con el derecho a la información y los medios de comunicación en Jalisco, que fallecieron durante 2020.ITESO, A.C

The Fourteenth Data Release of the Sloan Digital Sky Survey: First Spectroscopic Data from the extended Baryon Oscillation Spectroscopic Survey and from the second phase of the Apache Point Observatory Galactic Evolution Experiment

The fourth generation of the Sloan Digital Sky Survey (SDSS-IV) has been in operation since July 2014. This paper describes the second data release from this phase, and the fourteenth from SDSS overall (making this, Data Release Fourteen or DR14). This release makes public data taken by SDSS-IV in its first two years of operation (July 2014-2016). Like all previous SDSS releases, DR14 is cumulative, including the most recent reductions and calibrations of all data taken by SDSS since the first phase began operations in 2000. New in DR14 is the first public release of data from the extended Baryon Oscillation Spectroscopic Survey (eBOSS); the first data from the second phase of the Apache Point Observatory (APO) Galactic Evolution Experiment (APOGEE-2), including stellar parameter estimates from an innovative data driven machine learning algorithm known as "The Cannon"; and almost twice as many data cubes from the Mapping Nearby Galaxies at APO (MaNGA) survey as were in the previous release (N = 2812 in total). This paper describes the location and format of the publicly available data from SDSS-IV surveys. We provide references to the important technical papers describing how these data have been taken (both targeting and observation details) and processed for scientific use. The SDSS website (www.sdss.org) has been updated for this release, and provides links to data downloads, as well as tutorials and examples of data use. SDSS-IV is planning to continue to collect astronomical data until 2020, and will be followed by SDSS-V.Comment: SDSS-IV collaboration alphabetical author data release paper. DR14 happened on 31st July 2017. 19 pages, 5 figures. Accepted by ApJS on 28th Nov 2017 (this is the "post-print" and "post-proofs" version; minor corrections only from v1, and most of errors found in proofs corrected