9 research outputs found
MINERvA neutrino detector response measured with test beam data
The MINERvA collaboration operated a scaled-down replica of the solid
scintillator tracking and sampling calorimeter regions of the MINERvA detector
in a hadron test beam at the Fermilab Test Beam Facility. This article reports
measurements with samples of protons, pions, and electrons from 0.35 to 2.0
GeV/c momentum. The calorimetric response to protons, pions, and electrons are
obtained from these data. A measurement of the parameter in Birks' law and an
estimate of the tracking efficiency are extracted from the proton sample.
Overall the data are well described by a Geant4-based Monte Carlo simulation of
the detector and particle interactions with agreements better than 4%, though
some features of the data are not precisely modeled. These measurements are
used to tune the MINERvA detector simulation and evaluate systematic
uncertainties in support of the MINERvA neutrino cross section measurement
program.Comment: as accepted by NIM
Plastid-to-Nucleus Retrograde Signals Are Essential for the Expression of Nuclear Starch Biosynthesis Genes during Amyloplast Differentiation in Tobacco BY-2 Cultured Cells1[W][OA]
Amyloplasts, a subtype of plastid, are found in nonphotosynthetic tissues responsible for starch synthesis and storage. When tobacco (Nicotiana tabacum) Bright Yellow-2 cells are cultured in the presence of cytokinin instead of auxin, their plastids differentiate from proplastids to amyloplasts. In this program, it is well known that the expression of nucleus-encoded starch biosynthesis genes, such as ADP-Glucose Pyrophosphorylase (AgpS) and Granule-Bound Starch Synthase (GBSS), is specifically induced. In this study, we investigated the roles of plastid gene expression in amyloplast differentiation. Microarray analysis of plastid genes revealed that no specific transcripts were induced in amyloplasts. Nevertheless, amyloplast development accompanied with starch biosynthesis was drastically inhibited in the presence of plastid transcription/translation inhibitors. Surprisingly, the expression of nuclear AgpS and GBSS was significantly repressed by the addition of these inhibitors, suggesting that a plastid-derived signal(s) that reflects normal plastid gene expression was essential for nuclear gene expression. A series of experiments was performed to examine the effects of intermediates and inhibitors of tetrapyrrole biosynthesis, since some of the intermediates have been characterized as candidates for plastid-to-nucleus retrograde signals. Addition of levulinic acid, an inhibitor of tetrapyrrole biosynthesis, resulted in the up-regulation of nuclear AgpS and GBSS gene expression as well as starch accumulation, while the addition of heme showed opposite effects. Thus, these results indicate that plastid transcription and/or translation are required for normal amyloplast differentiation, regulating the expression of specific nuclear genes by unknown signaling mechanisms that can be partly mediated by tetrapyrrole intermediates
Discovery of a First-in-Class Receptor Interacting Protein 1 (RIP1) Kinase Specific Clinical Candidate (GSK2982772) for the Treatment of Inflammatory Diseases
RIP1
regulates necroptosis and inflammation and may play an important role
in contributing to a variety of human pathologies, including immune-mediated
inflammatory diseases. Small-molecule inhibitors of RIP1 kinase that
are suitable for advancement into the clinic have yet to be described.
Herein, we report our lead optimization of a benzoxazepinone hit from
a DNA-encoded library and the discovery and profile of clinical candidate
GSK2982772 (compound <b>5</b>), currently in phase 2a clinical
studies for psoriasis, rheumatoid arthritis, and ulcerative colitis.
Compound <b>5</b> potently binds to RIP1 with exquisite kinase
specificity and has excellent activity in blocking many TNF-dependent
cellular responses. Highlighting its potential as a novel anti-inflammatory
agent, the inhibitor was also able to reduce spontaneous production
of cytokines from human ulcerative colitis explants. The highly favorable
physicochemical and ADMET properties of <b>5</b>, combined with
high potency, led to a predicted low oral dose in humans
NALP inflammasomes: a central role in innate immunity.
Inflammasomes are cytoplasmic multiprotein complexes that mediate the maturation of the proinflammatory cytokines interleukin-1beta (IL-1beta), IL-18, and possibly IL-33 by controlling the activation of the inflammatory caspases-1 and -5. Assembly of inflammasomes depends on NOD-like receptor (NLR) family members such as NALPs, NAIP, and IPAF. Various microbial and endogenous stimuli activate different types of inflammasomes. This article focuses on the Pyrin domain containing NLRs, known as NALP proteins. Recent findings provide exciting insights into how these proteins might be activated and also provide evidence of the critical role of the NALP inflammasomes in innate immunity and inflammatory diseases