Cell death in hepatocellular carcinoma: Pathogenesis and therapeutic opportunities

Hepatocellular carcinoma (HCC) is the most prevalent primary liver cancer and the third leading cause of cancer death worldwide. Closely associated with liver inflammation and fibrosis, hepatocyte cell death is a common trigger for acute and chronic liver disease arising from different etiologies, including viral hepatitis, alcohol abuse, and fatty liver. In this review, we discuss the con-tribution of different types of cell death, including apoptosis, necroptosis, pyroptosis, or autophagy, to the progression of liver disease and the development of HCC. Interestingly, inflammasomes have recently emerged as pivotal innate sensors with a highly pathogenic role in various liver diseases. In this regard, an increased inflammatory response would act as a key element promoting a pro-oncogenic microenvironment that may result not only in tumor growth, but also in the formation of a premetastatic niche. Importantly, nonparenchymal hepatic cells, such as liver sinusoidal endothelial cells, hepatic stellate cells, and hepatic macrophages, play an important role in establishing the tumor microenvironment, stimulating tumorigenesis by paracrine communication through cytokines and/or angiocrine factors. Finally, we update the potential therapeutic options to inhibit tumorige-nesis, and we propose different mechanisms to consider in the tumor microenvironment field for HCC resolution. © 2021 by the authors. Licensee MDPI, Basel, Switzerland

Protection from inflammatory disease in insulin resistance: the role of mannan-binding lectin

n/

Prompt emission and early optical afterglow of very-high-energy detected GRB 201015A and GRB 201216C : onset of the external forward shock

We present a detailed prompt emission and early optical afterglow analysis of the two very-high-energy (VHE) detected bursts GRB 201015A and GRB 201216C, and their comparison with a subset of similar bursts. Time-resolved spectral analysis of multistructured GRB 201216C using the Bayesian binning algorithm revealed that during the entire duration of the burst, the low-energy spectral index (αpt) remained below the limit of the synchrotron line of death. However, statistically some of the bins supported the additional thermal component. Additionally, the evolution of spectral parameters showed that both the peak energy (Ep) and αpt tracked the flux. These results were further strengthened using the values of the physical parameters obtained by synchrotron modeling of the data. Our earliest optical observations of both bursts using the F/Photometric Robotic Atmospheric Monitor Observatorio del Roque de los Muchachos and Burst Observer and Optical Transient Exploring System robotic telescopes displayed a smooth bump in their early optical light curves, consistent with the onset of the afterglow due to synchrotron emission from an external forward shock. Using the observed optical peak, we constrained the initial bulk Lorentz factors of GRB 201015A and GRB 201216C to Γ0 = 204 and Γ0 = 310, respectively. The present early optical observations are the earliest known observations constraining outflow parameters and our analysis indicate that VHE detected bursts could have a diverse range of observed luminosity within the detectable redshift range of present VHE facilities

Deep-sequencing reveals broad subtype-specific HCV resistance mutations associated with treatment failure

A percentage of hepatitis C virus (HCV)-infected patients fail direct acting antiviral (DAA)-based treatment regimens, often because of drug resistance-associated substitutions (RAS). The aim of this study was to characterize the resistance profile of a large cohort of patients failing DAA-based treatments, and investigate the relationship between HCV subtype and failure, as an aid to optimizing management of these patients. A new, standardized HCV-RAS testing protocol based on deep sequencing was designed and applied to 220 previously subtyped samples from patients failing DAA treatment, collected in 39 Spanish hospitals. The majority had received DAA-based interferon (IFN) a-free regimens; 79% had failed sofosbuvir-containing therapy. Genomic regions encoding the nonstructural protein (NS) 3, NS5A, and NS5B (DAA target regions) were analyzed using subtype-specific primers. Viral subtype distribution was as follows: genotype (G) 1, 62.7%; G3a, 21.4%; G4d, 12.3%; G2, 1.8%; and mixed infections 1.8%. Overall, 88.6% of patients carried at least 1 RAS, and 19% carried RAS at frequencies below 20% in the mutant spectrum. There were no differences in RAS selection between treatments with and without ribavirin. Regardless of the treatment received, each HCV subtype showed specific types of RAS. Of note, no RAS were detected in the target proteins of 18.6% of patients failing treatment, and 30.4% of patients had RAS in proteins that were not targets of the inhibitors they received. HCV patients failing DAA therapy showed a high diversity of RAS. Ribavirin use did not influence the type or number of RAS at failure. The subtype-specific pattern of RAS emergence underscores the importance of accurate HCV subtyping. The frequency of “extra-target” RAS suggests the need for RAS screening in all three DAA target regions

Observation of inverse Compton emission from a long γ-ray burst.

Long-duration γ-ray bursts (GRBs) originate from ultra-relativistic jets launched from the collapsing cores of dying massive stars. They are characterized by an initial phase of bright and highly variable radiation in the kiloelectronvolt-to-megaelectronvolt band, which is probably produced within the jet and lasts from milliseconds to minutes, known as the prompt emission1,2. Subsequently, the interaction of the jet with the surrounding medium generates shock waves that are responsible for the afterglow emission, which lasts from days to months and occurs over a broad energy range from the radio to the gigaelectronvolt bands1-6. The afterglow emission is generally well explained as synchrotron radiation emitted by electrons accelerated by the external shock7-9. Recently, intense long-lasting emission between 0.2 and 1 teraelectronvolts was observed from GRB 190114C10,11. Here we report multi-frequency observations of GRB 190114C, and study the evolution in time of the GRB emission across 17 orders of magnitude in energy, from 5 × 10-6 to 1012 electronvolts. We find that the broadband spectral energy distribution is double-peaked, with the teraelectronvolt emission constituting a distinct spectral component with power comparable to the synchrotron component. This component is associated with the afterglow and is satisfactorily explained by inverse Compton up-scattering of synchrotron photons by high-energy electrons. We find that the conditions required to account for the observed teraelectronvolt component are typical for GRBs, supporting the possibility that inverse Compton emission is commonly produced in GRBs

Supplement: "Localization and broadband follow-up of the gravitational-wave transient GW150914" (2016, ApJL, 826, L13)

This Supplement provides supporting material for Abbott et al. (2016a). We briefly summarize past electromagnetic (EM) follow-up efforts as well as the organization and policy of the current EM follow-up program. We compare the four probability sky maps produced for the gravitational-wave transient GW150914, and provide additional details of the EM follow-up observations that were performed in the different bands

Localization and Broadband Follow-up of the Gravitational-wave Transient GW150914

A gravitational-wave (GW) transient was identified in data recorded by the Advanced Laser Interferometer Gravitational-wave Observatory (LIGO) detectors on 2015 September 14. The event, initially designated G184098 and later given the name GW150914, is described in detail elsewhere. By prior arrangement, preliminary estimates of the time, significance, and sky location of the event were shared with 63 teams of observers covering radio, optical, near-infrared, X-ray, and gamma-ray wavelengths with ground- and space-based facilities. In this Letter we describe the low-latency analysis of the GW data and present the sky localization of the first observed compact binary merger. We summarize the follow-up observations reported by 25 teams via private Gamma-ray Coordinates Network circulars, giving an overview of the participating facilities, the GW sky localization coverage, the timeline, and depth of the observations. As this event turned out to be a binary black hole merger, there is little expectation of a detectable electromagnetic (EM) signature. Nevertheless, this first broadband campaign to search for a counterpart of an Advanced LIGO source represents a milestone and highlights the broad capabilities of the transient astronomy community and the observing strategies that have been developed to pursue neutron star binary merger events. Detailed investigations of the EM data and results of the EM follow-up campaign are being disseminated in papers by the individual teams. </p

Who are the end-use(r)s of smart cities?: A synthesis of conversations in Amsterdam

Amsterdam has historically been and continues to be a thriving “global city,” acting as a commercial and financial hub, and has made significant advances in digitizing, automatizing, and datafying urban life. Withdrawing from digital space would mean giving up on countless pleasures and conveniences afforded by communication and navigation devices. The research was conducted through expert interviews and focus groups in Amsterdam during 2015. The majority of focus group participants acknowledged the conveniences afforded by the smart city: be it the fast and easy finding of the next train connection through online apps or the convenience afforded by using digital calendars. The residents of a smart city are often referred to as the “users,” “end-users,” consumers or beneficiaries. Creating a democratic city livable for its citizens, questions beyond the labels of “convenience, efficiency, and security” need to be addressed through continued public debate

Dome control with fuzzy logic

This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.This article describes a fuzzy logic-based method optimized for the dome control of a robotic astronomical observatory. A Mamdani inference has been developed in order to make the decision to open or close the dome. The input variables are obtained from data received from a weather station besides the percentage of cloudy sky as derived by two allsky cameras. The software has been tested at the BOOTES-1 observatory as part of the BOOTES Global Network of Robotic Telescopes led by IAA-CSIC. © 2022 Castellón, Larrubia, Castillo, Castro-Tirado, Fernández-García, Pérez del Pulgar, Reina and Castillo-Carrión.C-T acknowledges support from the Spanish Ministry Project PID 2020-118491GB-I00, Junta de Andalucía Project P20-01068, and the “Center of Excellence Severo Ochoa” award for the Instituto de Astrofísica de Andalucía (SEV-2017-0709).Peer reviewe