Regulation of cell death receptor S-nitrosylation and apoptotic signaling by Sorafenib in hepatoblastoma cells

Nitric oxide (NO) plays a relevant role during cell death regulation in tumor cells. The overexpression of nitric oxide synthase type III (NOS-3) induces oxidative and nitrosative stress, p53 and cell death receptor expression and apoptosis in hepatoblastoma cells. S-nitrosylation of cell death receptor modulates apoptosis. Sorafenib is the unique recommended molecular-targeted drug for the treatment of patients with advanced hepatocellular carcinoma. The present study was addressed to elucidate the potential role of NO during Sorafenib-induced cell death in HepG2 cells. We determined the intra- and extracellular NO concentration, cell death receptor expression and their S-nitrosylation modifications, and apoptotic signaling in Sorafenib-treated HepG2 cells. The effect of NO donors on above parameters has also been determined. Sorafenib induced apoptosis in HepG2 cells. However, low concentration of the drug (10nM) increased cell death receptor expression, as well as caspase-8 and -9 activation, but without activation of downstream apoptotic markers. In contrast, Sorafenib (10 µM) reduced upstream apoptotic parameters but increased caspase-3 activation and DNA fragmentation in HepG2 cells. The shift of cell death signaling pathway was associated with a reduction of S-nitrosylation of cell death receptors in Sorafenib-treated cells. The administration of NO donors increased S-nitrosylation of cell death receptors and overall induction of cell death markers in control and Sorafenib-treated cells. In conclusion, Sorafenib induced alteration of cell death receptor S-nitrosylation status which may have a relevant repercussion on cell death signaling in hepatoblastoma cells.Instituto de Salud Carlos III PI13/00021Ministerio de Economía y Competitividad BFU2012-32056Consejería de Economía, Innovación, Ciencia y Empleo, Junta de Andalucía BIO-0216Consejería de Economía, Innovación, Ciencia y Empleo, Junta de Andalucía CTS-6264Consejería de Salud, Junta de Andalucía PI13/ 0002

What to consider when pseudohypoparathyroidism is ruled out: IPPSD and differential diagnosis

Background: Pseudohypoparathyroidism (PHP) is a rare disease whose phenotypic features are rather difficult to identify in some cases. Thus, although these patients may present with the Albright''s hereditary osteodystrophy (AHO) phenotype, which is characterized by small stature, obesity with a rounded face, subcutaneous ossifications, mental retardation and brachydactyly, its manifestations are somewhat variable. Indeed, some of them present with a complete phenotype, whereas others show only subtle manifestations. In addition, the features of the AHO phenotype are not specific to it and a similar phenotype is also commonly observed in other syndromes. Brachydactyly type E (BDE) is the most specific and objective feature of the AHO phenotype, and several genes have been associated with syndromic BDE in the past few years. Moreover, these syndromes have a skeletal and endocrinological phenotype that overlaps with AHO/PHP. In light of the above, we have developed an algorithm to aid in genetic testing of patients with clinical features of AHO but with no causative molecular defect at the GNAS locus. Starting with the feature of brachydactyly, this algorithm allows the differential diagnosis to be broadened and, with the addition of other clinical features, can guide genetic testing. Methods: We reviewed our series of patients (n = 23) with a clinical diagnosis of AHO and with brachydactyly type E or similar pattern, who were negative for GNAS anomalies, and classify them according to the diagnosis algorithm to finally propose and analyse the most probable gene(s) in each case. Results: A review of the clinical data for our series of patients, and subsequent analysis of the candidate gene(s), allowed detection of the underlying molecular defect in 12 out of 23 patients: five patients harboured a mutation in PRKAR1A, one in PDE4D, four in TRPS1 and two in PTHLH. Conclusions: This study confirmed that the screening of other genes implicated in syndromes with BDE and AHO or a similar phenotype is very helpful for establishing a correct genetic diagnosis for those patients who have been misdiagnosed with "AHO-like phenotype" with an unknown genetic cause, and also for better describing the characteristic and differential features of these less common syndromes

Comparison of different protocols for the extraction of microbial DNA from reef corals

This study aimed to test different protocols for the extraction of microbial DNA from the coral Mussismilia harttii. Four different commercial kits were tested, three of them based on methods for DNA extraction from soil (FastDNA SPIN Kit for soil, MP Bio, PowerSoil DNA Isolation Kit, MoBio, and ZR Soil Microbe DNA Kit, Zymo Research) and one kit for DNA extraction from plants (UltraClean Plant DNA Isolation Kit, MoBio). Five polyps of the same colony of M. harttii were macerated and aliquots were submitted to DNA extraction by the different kits. After extraction, the DNA was quantified and PCR-DGGE was used to study the molecular fingerprint of Bacteria and Eukarya. Among the four kits tested, the ZR Soil Microbe DNA Kit was the most efficient with respect to the amount of DNA extracted, yielding about three times more DNA than the other kits. Also, we observed a higher number and intensities of DGGE bands for both Bacteria and Eukarya with the same kit. Considering these results, we suggested that the ZR Soil Microbe DNA Kit is the best adapted for the study of the microbial communities of corals

Measurement of the cosmic-ray energy spectrum above 2.5 x 10(18) eV using the Pierre Auger Observatory

We report a measurement of the energy spectrum of cosmic rays for energies above 2.5×10$^{18}$ eV based on 215,030 events recorded with zenith angles below 60°. A key feature of the work is that the estimates of the energies are independent of assumptions about the unknown hadronic physics or of the primary mass composition. The measurement is the most precise made hitherto with the accumulated exposure being so large that the measurements of the flux are dominated by systematic uncertainties except at energies above 5×10$^{19}$ eV. The principal conclusions are (1) The flattening of the spectrum near 5×10$^{18}$ eV, the so-called “ankle,” is confirmed. (2) The steepening of the spectrum at around 5×10$^{Z19}$ eV is confirmed. (3) A new feature has been identified in the spectrum: in the region above the ankle the spectral index γ of the particle flux (∝E$^{−γ }$) changes from 2.51±0.03 (stat)±0.05 (syst) to 3.05±0.05 (stat)±0.10 (syst) before changing sharply to 5.1±0.3 (stat)±0.1 (syst) above 5×10$^{19}$ eV. (4) No evidence for any dependence of the spectrum on declination has been found other than a mild excess from the Southern Hemisphere that is consistent with the anisotropy observed above 8×10$^{18}$ eV

An indication of anisotropy in arrival directions of utra-high-energy cosmic rays through comparison to the flux pattern of extragalactic gamma-ray sources

CNPQ - CONSELHO NACIONAL DE DESENVOLVIMENTO CIENTÍFICO E TECNOLÓGICOFINEP - FINANCIADORA DE ESTUDOS E PROJETOSFAPERJ - FUNDAÇÃO DE AMPARO À PESQUISA DO ESTADO DE RIO DE JANEIROFAPESP - FUNDAÇÃO DE AMPARO À PESQUISA DO ESTADO DE SÃO PAULOMCTIC - MINISTÉRIO DA CIÊNCIA, TECNOLOGIA, INOVAÇÕES E COMUNICAÇÕESA new analysis of the data set from the Pierre Auger Observatory provides evidence for anisotropy in the arrival directions of ultra-high-energy cosmic rays on an intermediate angular scale, which is indicative of excess arrivals from strong, nearby sources. The data consist of 5514 events above 20 EeV with zenith angles up to 80 degrees. recorded before 2017 April 30. Sky models have been created for two distinct populations of extragalactic gamma-ray emitters: active galactic nuclei from the second catalog of hard Fermi-LAT sources (2FHL) and starburst galaxies from a sample that was examined with Fermi-LAT. Flux-limited samples, which include all types of galaxies from the Swift-BAT and 2MASS surveys, have been investigated for comparison. The sky model of cosmic-ray density constructed using each catalog has two free parameters, the fraction of events correlating with astrophysical objects, and an angular scale characterizing the clustering of cosmic rays around extragalactic sources. A maximum-likelihood ratio test is used to evaluate the best values of these parameters and to quantify the strength of each model by contrast with isotropy. It is found that the starburst model fits the data better than the hypothesis of isotropy with a statistical significance of 4.0 sigma, the highest value of the test statistic being for energies above 39 EeV. The three alternative models are favored against isotropy with 2.7 sigma-3.2 sigma significance. The origin of the indicated deviation from isotropy is examined and prospects for more sensitive future studies are discussed.8532110CNPQ - CONSELHO NACIONAL DE DESENVOLVIMENTO CIENTÍFICO E TECNOLÓGICOFINEP - FINANCIADORA DE ESTUDOS E PROJETOSFAPERJ - FUNDAÇÃO DE AMPARO À PESQUISA DO ESTADO DE RIO DE JANEIROFAPESP - FUNDAÇÃO DE AMPARO À PESQUISA DO ESTADO DE SÃO PAULOMCTIC - MINISTÉRIO DA CIÊNCIA, TECNOLOGIA, INOVAÇÕES E COMUNICAÇÕESCNPQ - CONSELHO NACIONAL DE DESENVOLVIMENTO CIENTÍFICO E TECNOLÓGICOFINEP - FINANCIADORA DE ESTUDOS E PROJETOSFAPERJ - FUNDAÇÃO DE AMPARO À PESQUISA DO ESTADO DE RIO DE JANEIROFAPESP - FUNDAÇÃO DE AMPARO À PESQUISA DO ESTADO DE SÃO PAULOMCTIC - MINISTÉRIO DA CIÊNCIA, TECNOLOGIA, INOVAÇÕES E COMUNICAÇÕESSem informaçãoSem informaçãoSem informaçãoSem informaçãoSem informaçãoAgências de fomento estrangeiras apoiaram essa pesquisa, mais informações acesse artig

Features of the energy spectrum of cosmic rays above 2.5×1018 eV using the pierre auger observatory

We report a measurement of the energy spectrum of cosmic rays above 2.5×10$^{18}$ eV based on 215 030 events. New results are presented: at about 1.3×10$^{19}$ eV, the spectral index changes from 2.51±0.03(stat)±0.05(syst) to 3.05±0.05(stat)±0.10(syst), evolving to 5.1±0.3(stat)±0.1(syst) beyond 5×10$^{19}$ eV, while no significant dependence of spectral features on the declination is seen in the accessible range. These features of the spectrum can be reproduced in models with energy-dependent mass composition. The energy density in cosmic rays above 5×10$^{18}$ eV is [5.66±0.03(stat)±1.40(syst)]×10$^{53}$ erg Mpc$^{-3}$

The observation of lightning-related events with the Surface Detector of the Pierre Auger Observatory

The Pierre Auger Observatory, designed to detect ultra-high energy cosmic rays, can be a valid instrument at the ground to study phenomena related to the atmospheric electricity. The fluorescence detector is a powerful instrument to observe ELVES thanks to its excellent time resolution, while peculiar events with a large number of triggered stations have been recorded by the surface detector. The characteristic signal of these events lasts more than 10 mu s, about two orders of magnitude more than the duration of a signal produced by a cosmic muon. Moreover, each of these events has at least one station with a signal dominated by a high-frequency noise that could be related with a lightning-induced signal. Stations with a long-lasting signal are arranged in a disk shape. There are "big" events characterized by a radius of about 6 km and few "small" events with a radius of about 2-3 km. The signal, generated by a source very close to the ground, first reaches the innermost stations and then spreads outwards. In the "big" events, a lack of signal in some of the central stations was observed. Further studies and checks are in progress to understand the origin of the lack of signal and what mechanisms occurring during the lightning evolution may provide for electric fields capable of generating and accelerating particles that can produce Cherenkov light in the stations of the surface detector

Direct measurement of the muonic content of extensive air showers between 2×1017\mathbf { 2\times 10^{17}} and 2×1018 \mathbf {2\times 10^{18}}~eV at the Pierre Auger Observatory

The hybrid design of the Pierre Auger Observatory allows for the measurement of the properties of extensive air showers initiated by ultra-high energy cosmic rays with unprecedented precision. By using an array of prototype underground muon detectors, we have performed the first direct measurement, by the Auger Collaboration, of the muon content of air showers between 2×10$^{17}$ and 2×10$^{18}$ eV. We have studied the energy evolution of the attenuation-corrected muon density, and compared it to predictions from air shower simulations. The observed densities are found to be larger than those predicted by models. We quantify this discrepancy by combining the measurements from the muon detector with those from the Auger fluorescence detector at 10$^{17.5}$eV and 10$^{18}$eV. We find that, for the models to explain the data, an increase in the muon density of 38% ±4%(12%) ± (21%)¦(18%) for EPOS-LHC, and of 50%(53%) ±4%(13%) ± (23%)¦(20%) for QGSJetII-04, is respectively needed

Analysis of ELVES at the Pierre Auger Observatory

In the last six years, the Fluorescence Detector (FD) of the Auger Observatory has been exploited for the study of transient luminous events occuring high above thunderstorms at large distances (250 to more than 1000 km) from the Observatory. The first ELVES candidate was discovered during a night shift in 2005, and further studies based on auxiliary subtriggers allowed to modify the third level trigger of the observatory in order to acquire them with reasonable efficiency. This report aims to briefly review the studies underway on the >4000 ELVES triggers harvested in the years 2013-18 by the Observatory