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

Beam Solar Irradiation Assessment for Sonora, Mexico

AbstractLocated in north western Mexico, the State of Sonora has an excellent quality solar resource, with the highest solar irradiation levels in the country. In less than 1% of its vast arid territory, it receives enough solar power to satisfy the energy demand of the entire country. In spite of its huge solar potential, there has been little work on the measurement of solar radiation in this area. At a few locations, global solar radiation has been measured for some years. Also there have been some works reporting evaluation of solar irradiation based on empirical models or satellite images. Because of the very small amount of precipitation on most of its territory, Sonora is ideal for the implementation of concentrated solar power (CSP). Beam solar radiation data is necessary for the sizing and assessment of CSP plants. Unfortunately, very little information is available on this solar radiation component for Sonora. The present work reports on the results of recent measurements of beam and solar global radiation for the area of the city of Hermosillo, in the center of the state. The obtained results are compared with other available information obtained by indirect methods, such as satellite based or empirical climate data based models. The yearly available energy as well as the utilizable energy for certain irradiance levels is evaluated

A single-domain bispecific antibody targeting CD1d and the NKT T-cell receptor induces a potent antitumor response

Antibody-mediated modulation of major histocompatibility complex (MHC) molecules, or MHC class I-like molecules, could constitute an effective immunotherapeutic approach. We describe how single-domain antibodies (VHH), specific for the human MHC class I-like molecule CD1d, can modulate the function of CD1d-restricted T cells and how one VHH (1D12) specifically induced strong type I natural killer T (NKT) cell activation. The crystal structure of the VHH1D12-CD1d(α-GalCer)-NKT T-cell receptor (TCR) complex revealed that VHH1D12 simultaneously contacted CD1d and the type I NKT TCR, thereby stabilizing this interaction through intrinsic bispecificity. This led to greatly enhanced type I NKT cell-mediated antitumor activity in in vitro, including multiple myeloma and acute myeloid leukemia patient-derived bone marrow samples, and in vivo models. Our findings underscore the versatility of VHH molecules in targeting composite epitopes, in this case consisting of a complexed monomorphic antigen-presenting molecule and an invariant TCR, and represent a generalizable antitumor approach

Study of the level structure of 108Ag

The high spin structure of 108Ag nucleus has been studied using the reaction 11B + 100Mo at 39 MeV with Indian National Gamma Array (INGA) at TIFR-BARC accelerator facility. From the two- and higher-fold coincidence analysis of the emitted γ-rays, the level structure of the nucleus is built, with addition of around ∼ 60 new transitions. A new positive parity dipole band has been observed and significant additions have been made in the low spin region. A pair of nearly degenerate, negative parity, dipole bands is established, which is studied using the triaxial projected shell model (TPSM)