Castromackinnon8343

Although our findings do not exclude the importance of other signaling differences between BBζ and 28ζ CARs, they demonstrate the necessary and nonredundant role of ncNF-κB signaling in promoting the survival of BBζ CAR T cells, which likely underlies the engraftment persistence observed with this CAR design. Copyright © 2020 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.Biased agonism at G protein-coupled receptors describes the phenomenon whereby some drugs can activate some downstream signaling activities to the relative exclusion of others. Descriptions of biased agonism focusing on the differential engagement of G proteins versus β-arrestins are commonly limited by the small response windows obtained in pathways that are not amplified or are less effectively coupled to receptor engagement, such as β-arrestin recruitment. At the μ-opioid receptor (MOR), G protein-biased ligands have been proposed to induce less constipation and respiratory depressant side effects than opioids commonly used to treat pain. However, it is unclear whether these improved safety profiles are due to a reduction in β-arrestin-mediated signaling or, alternatively, to their low intrinsic efficacy in all signaling pathways. Here, we systematically evaluated the most recent and promising MOR-biased ligands and assessed their pharmacological profile against existing opioid analgesics in assays not confounded by limited signal windows. We found that oliceridine, PZM21, and SR-17018 had low intrinsic efficacy. We also demonstrated a strong correlation between measures of efficacy for receptor activation, G protein coupling, and β-arrestin recruitment for all tested ligands. By measuring the antinociceptive and respiratory depressant effects of these ligands, we showed that the low intrinsic efficacy of opioid ligands can explain an improved side effect profile. Our results suggest a possible alternative mechanism underlying the improved therapeutic windows described for new opioid ligands, which should be taken into account for future descriptions of ligand action at this important therapeutic target. Copyright © 2020 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.KRAS4b is a small guanosine triphosphatase (GTPase) protein that regulates several signal transduction pathways that underlie cell proliferation, differentiation, and survival. KRAS4b function requires prenylation of its C terminus and recruitment to the plasma membrane, where KRAS4b activates effector proteins including the RAF family of kinases. The Ca2+-sensing protein calmodulin (CaM) has been suggested to regulate the localization of KRAS4b through direct, Ca2+-dependent interaction, but how CaM and KRAS4b functionally interact is controversial. Here, we determined a crystal structure, which was supported by solution nuclear magnetic resonance (NMR), that revealed the sequestration of the prenyl moiety of KRAS4b in the hydrophobic pocket of the C-terminal lobe of Ca2+-bound CaM. Our engineered fluorescence resonance energy transfer (FRET)-based biosensor probes (CaMeRAS) showed that, upon stimulation of Ca2+ influx by extracellular ligands, KRAS4b reversibly translocated in a Ca2+-CaM-dependent manner from the plasma membrane to the cytoplasm in live HeLa and HEK293 cells. These results reveal a mechanism underlying the inhibition of KRAS4b activity by Ca2+ signaling pathways. Copyright © 2020 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.The time, extent, and genomic impact of the introgressions from archaic humans into ancestors of extant human populations remain one of the most exciting venues of population genetics research in the last decade. Several studies have shown population-specific signatures of introgression events from Neanderthals, Denisovans, and potentially other unknown hominin populations in different human groups. Moreover, it was shown that these introgression events may have contributed to phenotypic variation in extant humans, with biomedical and evolutionary consequences. In this study, we present a comprehensive analysis of the unusually divergent haplotypes in the Eurasian genomes and showed that they can be traced back to multiple introgression events. In parallel, we document hundreds of deletion polymorphisms shared with Neanderthals. A locus-specific analysis of one such shared deletion suggests the existence of a direct introgression event from the Altai Neanderthal lineage into the ancestors of extant East Asian populations. Overall, our study is in agreement with the emergent notion that various Neanderthal populations contributed to extant human genetic variation in a population-specific manner. Copyright © 2020, Genetics.BACKGROUND/AIM Hepatitis B core (HBc) antibody positivity indicates a history of hepatitis B virus (HBV) infection and latent infection. PATIENTS AND METHODS We conducted a retrospective case-control study of 512 and 495 head and neck cancer (HNC) and non-HNC patients treated at the Okayama University Hospital, Head and Neck Cancer Center from 2008-2017. Demographic data and risk factors that might affect HNC diagnosis were analyzed to assess their effects. RESULTS Cancer diagnosis was found to correlate with HBc antibody positivity [odds ratio (OR)=1.50, 95% confidence interval (CI)=1.09-2.08], smoking (OR=3.03, 95%CI=2.16-4.25), and a previous history of cancer (OR=4.12, 95%CI=2.79-6.09). The HBs antigen positivity rate in both groups was very close to that observed in the general Japanese population. The HBc antibody positivity rate was very high only in the HNC group. CONCLUSION HBc antibody positivity and HNC are epidemiologically correlated. BACKGROUND For patients with esophageal squamous cell carcinoma (ESCC) with oligo-recurrence (OR) after previous curative radiotherapy and not eligible for radical resection, the role of radical re-irradiation was not clear. Therefore, we aimed to investigate the outcome and prognostic factors of such patients. PATIENTS AND METHODS We identified patients with OR of ESCC after previous curative radiotherapy and were treated with radical re-irradiation within 2012-2018 via an in-house prospectively established database. The characteristics of patients, disease, treatment, and outcome were retrospectively obtained via chart review. The first day of re-irradiation was defined as the index date. Overall survival was calculated via the Kaplan-Meier method. Log-rank test was used for univariate analysis and Cox regression method was used for multivariable analysis. 12-O-Tetradecanoylphorbol-13-acetate mw RESULTS We identified thirty patients for analyses. After a median follow-up of 9 (range=2-76) months, the 5-year overall survival rate was 21%. Four patients with possible radiotherapy-related complication in need of inpatient care were identified.