Relativistic positioning: four-dimensional numerical approach in Minkowski space-time

We simulate the satellite constellations of two Global Navigation Satellite Systems: Galileo (EU) and GPS (USA). Satellite motions are described in the Schwarzschild space-time produced by an idealized spherically symmetric non rotating Earth. The trajectories are then circumferences centered at the same point as Earth. Photon motions are described in Minkowski space-time, where there is a well known relation, Coll, Ferrando & Morales-Lladosa (2010), between the emission and inertial coordinates of any event. Here, this relation is implemented in a numerical code, which is tested and applied. The first application is a detailed numerical four-dimensional analysis of the so-called emission coordinate region and co-region. In a second application, a GPS (Galileo) satellite is considered as the receiver and its emission coordinates are given by four Galileo (GPS) satellites. The bifurcation problem (double localization) in the positioning of the receiver satellite is then pointed out and discussed in detail.Comment: 16 pages, 9 figures, published (online) in Astrophys. Space Sc

Prevalence of vertebral fractures and their prognostic significance in the survival in patients with chronic kidney disease stages 3-5 not on dialysis

The prevalence of vertebral fractures (VF) and their association with clinical risk factors and outcomes are poorly documented in chronic kidney disease (CKD) cohorts. The aim of the study was to evaluate the prevalence of VF in patients with non-dialysis dependent CKD (NDD-CKD), their value in predicting mortality and its correlation with parameters of bone mineral metabolism and vascular calcification. 612 NDD 3-5 stage CKD patients participating in the OSERCE-2 study, a prospective, multicenter, cohort study, were prospectively evaluated and categorized into two groups according to presence or absence of VF at enrollment. VF were assessed with lateral radiographs and Genant semi-quantitative method was applied. Three radiologists specialized in musculoskeletal radiology performed consensual reading of individual images obtained using a Raim DICOM Viewer and a Canon EOS 350 camera to measure with Java Image software in those who had traditional acetate X-ray. Factors related to VF were assessed by logistic regression analysis. Association between VF and death over a 3-year follow-up was assessed by Kaplan-Meier survival curves and Cox-proportional hazard models. VF were detected in 110patients(18%). Serumphosphatelevels(OR0.719,95%CI0.532to0.972,p = 0.032),ankle-brachial index 3 and serum phosphate, the presence of VF (HR 1.983, 95% CI 1.009-3.898, p = 0.047) were an independent predictor of all-cause mortality. In our study 18% of patients with NDD-CKD have VF. Factors associated with VF were age, low serum phosphate levels and peripheral vascular disease. The presence of VF was an independent risk factor for mortality in stages 3-5 NDD-CKD patients. Clinical trials are needed to confirm whether this relationship is causal and reversible with treatment for osteoporosis

Therapeutic targeting of PD-1/PD-L1 blockade by novel small-molecule inhibitors recruits cytotoxic T cells into solid tumor microenvironment

© Author(s) (or their employer(s)) 2022.This is an open access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited, appropriate credit is given, any changes made indicated, and the use is non-commercial. See http://creativecommons.org/licenses/by-nc/4.0/.Background: Inhibiting programmed cell death protein 1 (PD-1) or PD-ligand 1 (PD-L1) has shown exciting clinical outcomes in diverse human cancers. So far, only monoclonal antibodies are approved as PD-1/PD-L1 inhibitors. While significant clinical outcomes are observed on patients who respond to these therapeutics, a large proportion of the patients do not benefit from the currently available immune checkpoint inhibitors, which strongly emphasize the importance of developing new immunotherapeutic agents. Methods: In this study, we followed a transdisciplinary approach to discover novel small molecules that can modulate PD-1/PD-L1 interaction. To that end, we employed in silico analyses combined with in vitro, ex vivo, and in vivo experimental studies to assess the ability of novel compounds to modulate PD-1/PD-L1 interaction and enhance T-cell function. Results: Accordingly, in this study we report the identification of novel small molecules, which like anti-PD-L1/PD-1 antibodies, can stimulate human adaptive immune responses. Unlike these biological compounds, our newly-identified small molecules enabled an extensive infiltration of T lymphocytes into three-dimensional solid tumor models, and the recruitment of cytotoxic T lymphocytes to the tumor microenvironment in vivo, unveiling a unique potential to transform cancer immunotherapy. Conclusions: We identified a new promising family of small-molecule candidates that regulate the PD-L1/PD-1 signaling pathway, promoting an extensive infiltration of effector CD8 T cells to the tumor microenvironment.C and RCA are supported by the Fundação para a Ciência e a Tecnologia, Ministério da Ciência, Tecnologia e Ensino Superior (FCT-MCTES) (PhD grants PD/BD/128238/2016 (RCA) and SFRH/BD/131969/2017 (BC)). The authors thank the funding received from the European Structural & Investment Funds through the COMPETE Programme and from National Funds through FCT under the Programme grant LISBOA-01-0145-FEDER016405 - SAICTPAC/0019/2015 (HF and RCG). HFF and RCA received additional support from FCT-MCTES (UIDB/04138/2020, PTDC/BTM-SAL/4350/2021 and UTAPEXPL/NPN/0041/2021; EXPL/MED-QUI/1316/2021, respectively). The MultiNano@MBM project was supported by The Israeli Ministry of Health, and FCTMCTES, under the frame of EuroNanoMed-II (ENMed/0051/2016; HF and RS-F). HF and RS-F thank the generous financial support from ‘La Caixa’ Foundation under the framework of the Healthcare Research call 2019 (NanoPanther; LCF/PR/HR19/52160021), as well as CaixaImpulse (Co-Vax; LCF/TR/CD20/52700005). MP thanks the financial support from Liga Portuguesa Contra o Cancro – Nucleo Regional do Sul and ‘iNOVA4Health – UIDB/04462/2020’, a program financially supported by Fundação para a Ciência e Tecnologia/Ministério da Educação e Ciência. RS-F thanks the following funding agencies for their generous support: the European Research Council (ERC) Advanced Grant Agreement No. (835227)–3DBrainStrom, ERC PoC Grant Agreement no. 862580 – 3DCanPredict, The Israel Science Foundation (Grant No. 1969/18), The Melanoma Research Alliance (MRA Established Investigator Award n°615808), the Israel Cancer Research Fund (ICRF) Professorship award (n° PROF-18-682), and the Morris Kahn Foundation.info:eu-repo/semantics/publishedVersio

Parasitosis intestinales en escolares de la ciudad de Valencia. Encuesta de prevalencia.

Fundamento: La importancia de la lucha contra las infecciones intestinales entre las que se incluyen las parasitarias radica en su alta prevalencia y su distribución mundial. El objeto del estudio es conocer la prevalencia de parásitos en heces en la población escolar de la ciudad de Valencia y se justifica en el desconocimiento de la endemia parasitaria, combinada con los importantes cambios demográficos y sociales por el fenómeno inmigratorio.Material y método: Se realiza un estudio descriptivo, de corte transversal con distribución de características y atributos de los sujetos. Muestra asignada por conglomerados entre la población (64.200 alumnos) asistente a centros de Educación Infantil (3-5 años) y Primaria (6-11 años) segmentada por estacionalidad. Tamaño muestral 1.031 niños, prevalencia esperada 21,8% y error de muestreo 2,5%. Se aplicó encuesta auto-cumplimentada y toma de muestra única de heces: bote de recogida con fijador y cinta de Graham para detección de entero-parásitos. Resultados: En el segmento estacional primavera-otoño se recuperaron 523 sujetos, (29,8% son población inmigrante). La prevalencia general de infección fue 27,4%. (IC95%: 23,58-31,22), que alcanza el 40,52% (IC95%: 32,5-47,8) en inmigrantes, RP: 2,45 (IC95%: 1,64-3,67, p<0,0001). Se detectan 11 especies entero-parasitarias, la más frecuente Blastocystis hominis: 14,9%, de los que 57,33% corresponden a escolares inmigrantes RP: 3,16 (IC95%: 2,08-4,79, p<0,0001). Al comparar el origen de los infectados por ciclos escolares se observan diferencias en E.Primaria que se acentúan con la edad, OR1ºciclo: 2,6 (IC95%: 1,2-5,4), OR2ºciclo: 3,15 (IC95%: 1,3-7,3), OR3ªciclo: 6,44 (IC95%: 2,05-20,18). No se observan diferencias por género ni globalmente ni entre los inmigrantes.Conclusiones: La prevalencia general de parasitación observada resulta relevante. En general los datos conocidos coinciden con nuestra encuesta en que el 89% de las parasitosis son por protozoos. Los nematodos suponen un 9% y, de ellos, el más frecuente es E vermicularis. Con otros trabajos consultados, realizados en los años 90 se comprueba un cambio del patrón entero-parasitario y responde al cambio sociodemográfico producido por la inmigración. La fuerza de asociación y la relación infectados/edad en niños inmigrantes pone de manifiesto la necesidad de una especial vigilancia

Constraints on the steady and pulsed very high energy gamma-ray emission from observations of PSR B1951+32/CTB 80 with the MAGIC Telescope

We report on very high energy gamma-observations with the MAGIC Telescope of the pulsar PSR B1951+32 and its associated nebula, CTB 80. Our data constrain the cutoff energy of the pulsar to be less than 32 GeV, assuming the pulsed gamma-ray emission to be exponentially cut off. The upper limit on the flux of pulsed gamma-ray emission above 75 GeV is 4.3*10^-11 photons cm^-2 sec^-1, and the upper limit on the flux of steady emission above 140 GeV is 1.5*10^-11 photons cm^-2 sec^-1. We discuss our results in the framework of recent model predictions and other studies.Comment: 7 pages, 7 figures, replaced with published versio

First bounds on the very high energy gamma-ray emission from Arp 220

Using the Major Atmospheric Gamma Imaging Cherenkov Telescope (MAGIC), we have observed the nearest ultra-luminous infrared galaxy Arp 220 for about 15 hours. No significant signal was detected within the dedicated amount of observation time. The first upper limits to the very high energy $\gamma$-ray flux of Arp 220 are herein reported and compared with theoretical expectations.Comment: Accepted for publication in Ap

Systematic search for VHE gamma-ray emission from X-ray bright high-frequency BL Lac objects

All but three (M87, BL Lac and 3C 279) extragalactic sources detected so far at very high energy (VHE) gamma-rays belong to the class of high-frequency peaked BL Lac (HBL) objects. This suggested to us a systematic scan of candidate sources with the MAGIC telescope, based on the compilation of X-ray blazars by Donato et al. (2001). The observations took place from December 2004 to March 2006 and cover sources on the northern sky visible under small zenith distances zd < 30 degrees at culmination. The sensitivity of the search was planned for detecting X-ray bright F(1 keV) > 2 uJy) sources emitting at least the same energy flux at 200 GeV as at 1 keV. In order to avoid strong gamma-ray attenuation close to the energy threshold, the redshift of the sources was constrained to values z<0.3. Of the fourteen sources observed, 1ES 1218+304 and 1ES 2344+514 have been detected in addition to the known bright TeV blazars Mrk 421 and Mrk 501. A marginal excess of 3.5 sigma from the position of 1ES 1011+496 was observed and has been confirmed as a source of VHE gamma-rays by a second MAGIC observation triggered by a high optical state (Albert et al. 2007). For the remaining sources, we present here the 99% confidence level upper limits on the integral flux above ~200 GeV. We characterize the sample of HBLs (including all HBLs detected at VHE so far) by looking for correlations between their multi-frequency spectral indices determined from simultaneous optical, archival X-ray, and radio luminosities, finding that the VHE emitting HBLs do not seem to constitute a unique subclass. The absorption corrected gamma-ray luminosities at 200 GeV of the HBLs are generally not higher than their X-ray luminosities at 1 keV.Comment: 15 pages, 7 figures, 5 tables, submitted to ApJ (revised version

Discovery of Very High Energy gamma-rays from 1ES 1011+496 at z=0.212

We report on the discovery of Very High Energy (VHE) gamma-ray emission from the BL Lacertae object 1ES1011+496. The observation was triggered by an optical outburst in March 2007 and the source was observed with the MAGIC telescope from March to May 2007. Observing for 18.7 hr we find an excess of 6.2 sigma with an integrated flux above 200 GeV of (1.58$\pm0.32) 10^{-11}$ photons cm$^{-2}$ s$^{-1}$. The VHE gamma-ray flux is >40% higher than in March-April 2006 (reported elsewhere), indicating that the VHE emission state may be related to the optical emission state. We have also determined the redshift of 1ES1011+496 based on an optical spectrum that reveals the absorption lines of the host galaxy. The redshift of z=0.212 makes 1ES1011+496 the most distant source observed to emit VHE gamma-rays up to date.Comment: 4 pages, 6 figures, minor changes to fit the ApJ versio

MAGIC upper limits on the very high energy emission from GRBs

The fast repositioning system of the MAGIC Telescope has allowed during its first data cycle, between 2005 and the beginning of year 2006, observing nine different GRBs as possible sources of very high energy gammas. These observations were triggered by alerts from Swift, HETE-II, and Integral; they started as fast as possible after the alerts and lasted for several minutes, with an energy threshold varying between 80 and 200 GeV, depending upon the zenith angle of the burst. No evidence for gamma signals was found, and upper limits for the flux were derived for all events, using the standard analysis chain of MAGIC. For the bursts with measured redshift, the upper limits are compatible with a power law extrapolation, when the intrinsic fluxes are evaluated taking into account the attenuation due to the scattering in the Metagalactic Radiation Field (MRF).Comment: 25 pages, 9 figures, final version accepted by ApJ. Changet title to "MAGIC upped limits on the VERY high energy emission from GRBs", re-organized chapter with description of observation, removed non necessaries figures, added plot of effective area depending on zenith angle, added an appendix explaining the upper limit calculation, added some reference

Upper limit for gamma-ray emission above 140 GeV from the dwarf spheroidal galaxy Draco

The nearby dwarf spheroidal galaxy Draco with its high mass to light ratio is one of the most auspicious targets for indirect dark matter searches. Annihilation of hypothetical DM particles can result in high-energy gamma-rays, e.g. from neutralino annihilation in the supersymmetric framework. With the MAGIC telescope a search for a possible DM signal originating from Draco was performed during 2007. The analysis of the data results in a flux upper limit of 1.1x10^-11 photons cm^-2 sec^-1 for photon energies above 140 GeV, assuming a point like source. Furthermore, a comparison with predictions from supersymmetric models is given. While our results do not constrain the mSUGRA phase parameter space, a very high flux enhancement can be ruled out.Comment: Accepted for publication by Astrophysical Journa