Improving photon-hadron discrimination based on cosmic ray surface detector data

The search for photons at EeV energies and beyond has considerable astrophysical interest and will remain one of the key challenges for ultra-high energy cosmic ray (UHECR) observatories in the near future. Several upper limits to the photon flux have been established since no photon has been unambiguously observed up to now. An improvement in the reconstruction efficiency of the photon showers and/or better discrimination tools are needed to improve these limits apart from an increase in statistics. Following this direction, we analyze in this work the ability of the surface parameter Sb, originally proposed for hadron discrimination, for photon search. Semi-analytical and numerical studies are performed in order to optimize Sb for the discrimination of photons from a proton background in the energy range from 10^18.5 to 10^19.6 eV. Although not shown explicitly, the same analysis has been performed for Fe nuclei and the corresponding results are discussed when appropriate. The effects of different array geometries and the underestimation of the muon component in the shower simulations are analyzed, as well as the Sb dependence on primary energy and zenith angle.Comment: 9 pages, 19 Figures. Accepted in Astroparticle Physics on May 31th, 201

Ultra-deep pyrosequencing analysis of the hepatitis B virus preCore region and main catalytic motif of the viral polymerase in the same viral genome

Hepatitis B virus (HBV) pregenomic RNA contains a hairpin structure (ϵ) located in the preCore region, essential for viral replication. ϵ stability is enhanced by the presence of preCore variants and ϵ is recognized by the HBV polymerase (Pol). Mutations in the retrotranscriptase domain (YMDD) of Pol are associated with treatment resistance. The aim of this study was to analyze the preCore region and YMDD motif by ultra-deep pyrosequencing (UDPS). To evaluate the UDPS error rate, an internal control sequence was inserted in the amplicon. A newly developed technique enabled simultaneous analysis of the preCore region and Pol in the same viral genome, as well as the conserved sequence of the internal control. Nucleotide errors in HindIII yielded a UDPS error rate <0.05%. UDPS study confirmed the possibility of simultaneous detection of preCore and YMDD mutations, and demonstrated the complexity of the HBV quasispecies and cooperation between viruses. Thermodynamic stability of the ϵ signal was found to be the main constraint for selecting main preCore mutations. Analysis of ϵ-signal variability suggested the essential nature of the ϵ structural motif and that certain nucleotides may be involved in ϵ signal functions

Hepatitis B Virus Variants with Multiple Insertions and/or Deletions in the X Open Reading Frame 3 ' End: Common Members of Viral Quasispecies in Chronic Hepatitis B Patients

Hepatitis B virus; Insertions; Next-generation sequencingVirus de l'hepatitis B; Insercions; Seqüenciació de nova generacióVirus de la hepatitis B; Inserciones; Secuenciación de próxima generaciónDeletions in the 3′ end region of the hepatitis B virus (HBV) X open reading frame (HBX) may affect the core promoter (Cp) and have been frequently associated with hepatocellular carcinoma (HCC). The aim of this study was to investigate the presence of variants with deletions and/or insertions (Indels) in this region in the quasispecies of 50 chronic hepatitis B (CHB) patients without HCC. We identified 103 different Indels in 47 (94%) patients, in a median of 3.4% of their reads (IQR, 1.3–8.4%), and 25% (IQR, 13.1–40.7%) of unique sequences identified in each quasispecies (haplotypes). Of those Indels, 101 (98.1%) caused 44 different altered stop codons, the most commonly observed were at positions 128, 129, 135, and 362 (putative position). Moreover, 39 (37.9%) Indels altered the TATA-like box (TA) sequences of Cp; the most commonly observed caused TA2 + TA3 fusion, creating a new putative canonical TATA box. Four (8%) patients developed negative clinical outcomes after a median follow-up of 9.4 (8.7–12) years. In conclusion, we observed variants with Indels in the HBX 3′ end in the vast majority of our CHB patients, some of them encoding alternative versions of HBx with potential functional roles, and/or alterations in the regulation of transcription.This research was funded by Instituto de Salud Carlos III and co-financed by the European Regional Development Fund (ERDF), grant number PI18/01436; PI19/00301; and by the Centro para el Desarrollo Tecnológico Industrial (CDTI) from the Spanish Ministry of Economy and Business, grant number IDI-20200297. The APC was funded by the grant PI18/01436

Standardized Hepatitis B Virus RNA Quantification in Untreated and Treated Chronic Patients: a Promising Marker of Infection Follow-Up.

The measurement and interpretation of HBV DNA and RNA levels in HBV infected patients treated with antiviral therapy supports the objective of HBV disease management. Here, we quantified circulating HBV RNA through a standardized and sensitive assay in follow-up samples from both naive and treated patients as a marker of infection evolution. HBV DNA (HBV DNA for use in Cobas 6800/8800 Automated Roche Molecular Systems), RNA (Roche HBV RNA Investigational Assay for use in the Cobas 6800/8800; Roche), HBeAg and HBsAg (Elycsys HBsAg chemiluminescence immunoassay by Cobas 8000; Roche), and core-related antigen (Lumipulse G chemiluminescence assay; Fujirebio) levels were measured in cohorts of untreated or nucleos(t)ide treated, HBV-infected subjects in an outpatient hospital setting. HBV DNA levels in untreated people were 3.6 log10 higher than corresponding RNA levels and were stable over 5 years of observation. While only five of 52 treated patients had DNA levels below the lower limit of quantification (10 IU/mL) at the end of follow-up, 13 had HBV RNA levels persistently above this limit, including eight with undetectable DNA. In samples with undetectable core-related antigen we observed a median HBsAg titer 2.7-fold higher than in samples with undetectable RNA (adjusted P = 0.012). Detectable HBV RNA with undetectable HBV DNA was a negative predictor of HBsAg decrease to a level ≤100 IU/mL (P = 0.03). In naive patients the difference between HBV DNA and RNA was higher than previously reported. HBV RNA rapidly decreased during treatment. However, in some cases, it was detectable even after years of effective therapy, being a negative predictor of HBsAg decrease. The investigational RNA assay for use on the Cobas 6800/8800 instruments is a sensitive and standardized method that could be applied in general management of HBV infection. IMPORTANCE This study focused on the quantification of circulating HBV RNA by using a standardized and sensitive assay. Thanks to this system we observed a higher difference between circulating HBV DNA and RNA than previously reported. In treated patients, HBV RNA decreased together with DNA, although some patients presented detectable levels even after years of successful antiviral treatment, suggesting a persistent viral transcription. Of note, the detection of viral RNA when HBV DNA is undetectable was a negative predictor of HBsAg decrease to a level ≤100 IU/mL. This assay could be extremely helpful in HBV patients management to study viral transcription and to identify those treated patients that may achieve sustained viral suppression

Heterogeneity and Clonal Evolution of Acquired PARP Inhibitor Resistance in TP53- and BRCA1-Deficient Cells

Homologous recombination (HR)-deficient cancers are sensitive to poly- ADP ribose polymerase inhibitors (PARPi), which have shown clinical efficacy in the treatment of high-grade serous cancers (HGSC). However, the majority of patients will relapse, and acquired PARPi resistance is emerging as a pressing clinical problem. Here we generated seven single-cell clones with acquired PARPi resistance derived from a PARPi-sensitive TP53(-/-) and BRCA1(-/-) epithelial cell line generated using CRISPR/Cas9. These clones showed diverse resistance mechanisms, and some clones presented with multiple mechanisms of resistance at the same time. Genomic analysis of the clones revealed unique transcriptional and mutational profiles and increased genomic instability in comparison with a PARPi-sensitive cell line. Clonal evolutionary analyses suggested that acquired PARPi resistance arose via clonal selection from an intrinsically unstable and heterogenous cell population in the sensitive cell line, which contained preexisting drug-tolerant cells. Similarly, clonal and spatial heterogeneity in tumor biopsies from a clinical patient with BRCA1-mutant HGSC with acquired PARPi resistance was observed. In an imaging-based drug screening, the clones showed heterogenous responses to targeted therapeutic agents, indicating that not all PARPi-resistant clones can be targeted with just one therapy. Furthermore, PARPi-resistant clones showed mechanism-dependent vulnerabilities to the selected agents, demonstrating that a deeper understanding on the mechanisms of resistance could lead to improved targeting and biomarkers for HGSC with acquired PARPi resistance. Significance: This study shows that BRCA1-deficient cells can give rise to multiple genomically and functionally heterogenous PARPi-resistant clones, which are associated with various vulnerabilities that can be targeted in a mechanism-specific manner.Peer reviewe

Inhibition of TGF beta 1 and TGF beta 3 promotes hematopoiesis in Fanconi anemia

Fanconi anemia (FA) is a chromosome instability syndrome with congenital abnormalities, cancer predisposition and bone marrow failure (BMF). Although hematopoietic stem and progenitor cell (HSPC) transplantation is the recommended therapy, new therapies are needed for FA patients without suitable donors. BMF in FA is caused, at least in part, by a hyperactive growth-suppressive transforming growth factor beta (TGF beta) pathway, regulated by the TGF beta 1, TGF beta 2, and TGF beta 3 ligands. Accordingly, the TGF beta pathway is an attractive therapeutic target for FA. While inhibition of TGF beta 1 and TGF beta 3 promotes blood cell expansion, inhibition of TGF beta 2 is known to suppress hematopoiesis. Here, we report the effects of AVID200, a potent TGF beta 1- and TGF beta 3-specific inhibitor, on FA hematopoiesis. AVID200 promoted the survival of murine FA HSPCs in vitro. AVID200 also promoted in vitro the survival of human HSPCs from patients with FA, with the strongest effect in patients progressing to severe aplastic anemia or myelodysplastic syndrome (MDS). Previous studies have indicated that the toxic upregulation of the nonhomologous end-joining (NHEJ) pathway accounts, at least in part, for the poor growth of FA HSPCs. AVID200 downregulated the expression of NHEJ-related genes and reduced DNA damage in primary FA HSPC in vitro and in in vivo models. Collectively, AVID200 exhibits activity in FA mouse and human preclinical models. AVID200 may therefore provide a therapeutic approach to improving BMF in FA. (c) 2020 ISEH - Society for Hematology and Stem Cells. Published by Elsevier Inc. All rights reserved.Peer reviewe

Economía, Sociedad y Procesos Hegemónicos en la Provincia de Misiones (ESOHE). 16H328

Actividades desarrolladas durante el período: Desde mediados de año se ha instalado un Taller Continuo que funciona los días viernes destinado a la puesta en común de información y la discusión de la marcha general del proyecto. El taller, se ha constituido en caja de resonancia de los avances y dificultades que se presentan y como el espacio donde se distribuyen tareas y responsabilices, se analizan las actividades y los aportes personales o de los integrantes de cada grupo responsable de alguna línea de investigación y se incorporan ideas y señalamientos. En este marco, se ha programado también un Ciclo de Lecturas teóricas y metodológicas que colaboran en la construcción de un lenguaje y una mirada común, necesaria para armonizar la labor de investigadores y becarios de postgrado con trayectorias disciplinares y experiencias muy disímiles; En la investigación sobre la historia económica de Misiones se ha avanzado en los siguientes puntos: Construcción de una periodización basada en ciclos económicos. Se trabaja en el reconocimiento y exploración de repositorios y fuentes escritas existentes a nivel local. exhaustivo relevamiento de las tesis de grado y postgrado, tanto en historia como en Antropología, existentes en las bibliotecas de la UNaM, referidas a temas empresariales y o al funcionamiento de las elites del poder. Se ha tomado contacto y accedido a ámbitos empresariales como las cámaras de la construcción, que en Misiones son 5, de PyMES y la Delegación Provincial de la Cámara Argentina de la Construcción que reúne a grandes empresas; Un grupo de investigadores y auxiliares del ESOHE está investigando los procesos de transformación del sistema educativo provincial (incluyendo tanto la componente pública como la privada), entendiendo que el sistema escolar es una de las instancias donde se socializa ideológicamente a la población y se promueven “sentidos de la realidad”; Entre las tareas en ejecución cabe mencionar: Lectura y fichaje de materia bibliográfico destinado a la actualización reajuste del encuadre teórico-metodológico. Identificación y caracterización de diferentes actores: funcionarios gubernamentales, empresas constructoras, e inmobiliarias, medios de comunicación, asociaciones civiles y otras organizaciones, grupos de interés y afectados por las obras que intervienen en la producción, disputa, apropiación y uso del espacio urbano en las ciudades de Encarnación y Posadas, Garupá y Candelaria. Elección y contacto de informantes calificados. Relevamiento de políticas y/o programas de intervención urbana a ambos lados de la frontera y sus procesos resultantes. Geo-referenciamiento de áreas de revalorización urbana, comerciales, de relegación y desplazamiento, así como de asentamientos precarios y zonas residenciales para sectores de alto poder adquisitivo. El trabajo realizado en esta primera etapa ha permitido avanzar en: Revisión bibliográfica; Redefinición del marco teórico de la investigación; Análisis de algunas relaciones concretas establecidas entre el estado y el sector civil organizado, en particular en el campo de las actividades económicas del tercer sector y en el marco de la implementación de planes y programas públicos; Análisis de las tensiones entre prácticas políticas y económicas que se desatan en el proceso de generación y funcionamiento de los emprendimientos productivos auto-gestionados y cooperativas de trabajo

Highlights from the Pierre Auger Observatory

The Pierre Auger Observatory is the world's largest cosmic ray observatory. Our current exposure reaches nearly 40,000 km$^2$ str and provides us with an unprecedented quality data set. The performance and stability of the detectors and their enhancements are described. Data analyses have led to a number of major breakthroughs. Among these we discuss the energy spectrum and the searches for large-scale anisotropies. We present analyses of our X$_{max}$ data and show how it can be interpreted in terms of mass composition. We also describe some new analyses that extract mass sensitive parameters from the 100% duty cycle SD data. A coherent interpretation of all these recent results opens new directions. The consequences regarding the cosmic ray composition and the properties of UHECR sources are briefly discussed.Comment: 9 pages, 12 figures, talk given at the 33rd International Cosmic Ray Conference, Rio de Janeiro 201

Update on the correlation of the highest energy cosmic rays with nearby extragalactic matter

Data collected by the Pierre Auger Observatory through 31 August 2007 showed evidence for anisotropy in the arrival directions of cosmic rays above the Greisen-Zatsepin-Kuz'min energy threshold, \nobreak{$6\times 10^{19}$eV}. The anisotropy was measured by the fraction of arrival directions that are less than $3.1^\circ$ from the position of an active galactic nucleus within 75 Mpc (using the V\'eron-Cetty and V\'eron $12^{\rm th}$ catalog). An updated measurement of this fraction is reported here using the arrival directions of cosmic rays recorded above the same energy threshold through 31 December 2009. The number of arrival directions has increased from 27 to 69, allowing a more precise measurement. The correlating fraction is $(38^{+7}_{-6})$, compared with $21$ expected for isotropic cosmic rays. This is down from the early estimate of $(69^{+11}_{-13})$. The enlarged set of arrival directions is examined also in relation to other populations of nearby extragalactic objects: galaxies in the 2 Microns All Sky Survey and active galactic nuclei detected in hard X-rays by the Swift Burst Alert Telescope. A celestial region around the position of the radiogalaxy Cen A has the largest excess of arrival directions relative to isotropic expectations. The 2-point autocorrelation function is shown for the enlarged set of arrival directions and compared to the isotropic expectation.Comment: Accepted for publication in Astroparticle Physics on 31 August 201