The First Swift Ultra-Violet/Optical Telescope GRB Afterglow Catalog

We present the first Swift Ultra-Violet/Optical Telescope (UVOT) gamma-ray burst (GRB) afterglow catalog. The catalog contains data from over 64,000 independent UVOT image observations of 229 GRBs first detected by Swift, the High Energy Transient Explorer 2 (HETE2), the INTErnational Gamma-Ray Astrophysics Laboratory (INTEGRAL), and the Interplanetary Network (IPN). The catalog covers GRBs occurring during the period from 2005 Jan 17 to 2007 Jun 16 and includes ~86% of the bursts detected by the Swift Burst Alert Telescope (BAT). The catalog provides detailed burst positional, temporal, and photometric information extracted from each of the UVOT images. Positions for bursts detected at the 3-sigma-level are provided with a nominal accuracy, relative to the USNO-B1 catalog, of ~0.25 arcseconds. Photometry for each burst is given in three UV bands, three optical bands, and a 'white' or open filter. Upper limits for magnitudes are reported for sources detected below 3-sigma. General properties of the burst sample and light curves, including the filter-dependent temporal slopes, are also provided. The majority of the UVOT light curves, for bursts detected at the 3-sigma-level, can be fit by a single power-law, with a median temporal slope (alpha) of 0.96, beginning several hundred seconds after the burst trigger and ending at ~1x10^5 s. The median UVOT v-band (~5500 Angstroms) magnitude at 2000 s for a sample of "well" detected bursts is 18.02. The UVOT flux interpolated to 2000 s after the burst, shows relatively strong correlations with both the prompt Swift BAT fluence, and the Swift X-ray flux at 11 hours after the trigger.Comment: 60 pages, 17 figures, 8 tables, accepted for publication by the Astrophysical Journa

Interleukin-23 engineering improves CAR T cell function in solid tumors

Cytokines that stimulate T cell proliferation, such as interleukin (IL)-15, have been explored as a means of boosting the antitumor activity of chimeric antigen receptor (CAR) T cells. However, constitutive cytokine signaling in T cells and activation of bystander cells may cause toxicity. IL-23 is a two-subunit cytokine known to promote proliferation of memory T cells and T helper type 17 cells. We found that, upon T cell antigen receptor (TCR) stimulation, T cells upregulated the IL-23 receptor and the IL-23α p19 subunit, but not the p40 subunit. We engineered expression of the p40 subunit in T cells (p40-Td cells) and obtained selective proliferative activity in activated T cells via autocrine IL-23 signaling. In comparison to CAR T cells, p40-Td CAR T cells showed improved antitumor capacity in vitro, with increased granzyme B and decreased PD-1 expression. In two xenograft and two syngeneic solid tumor mouse models, p40-Td CAR T cells showed superior efficacy in comparison to CAR T cells and attenuated side effects in comparison to CAR T cells expressing IL-18 or IL-15

Susceptible periods during embryogenesis of the heart and endocrine glands.

One of the original principles of teratology states that, "Susceptibility to teratogenesis varies with the developmental stage at the time of exposure to an adverse influence" [Wilson JG. Environment and Birth Defects. New York:Academic Press, 1973]. The time of greatest sensitivity encompasses the period of organ formation during weeks 3-8 following fertilization in human gestation. At this time, stem cell populations for each organ's morphogenesis are established and inductive events for the initiation of differentiation occur. Structural defects of the heart and endocrine system are no exception to this axiom and have their origins during this time frame. Although the function and maturation of these organs may be affected at later stages, structural defects and loss of cell types usually occur during these early phases of development. Thus, to determine critical windows for studying mechanisms of teratogenesis, it is essential to understand the developmental processes that establish these organs

Arsenic as an Endocrine Disruptor: Arsenic Disrupts Retinoic Acid Receptor–and Thyroid Hormone Receptor–Mediated Gene Regulation and Thyroid Hormone–Mediated Amphibian Tail Metamorphosis

Background: Chronic exposure to excess arsenic in drinking water has been strongly associated with increased risks of multiple cancers, diabetes, heart disease, and reproductive and developmental problems in humans. We previously demonstrated that As, a potent endocrine disruptor at low, environmentally relevant levels, alters steroid signaling at the level of receptor-mediated gene regulation for all five steroid receptors. Objectives: The goal of this study was to determine whether As can also disrupt gene regulation via the retinoic acid (RA) receptor (RAR) and/or the thyroid hormone (TH) receptor (TR) and whether these effects are similar to previously observed effects on steroid regulation. Methods and results: Human embryonic NT2 or rat pituitary GH3 cells were treated with 0.01–5 μM sodium arsenite for 24 hr, with or without RA or TH, respectively, to examine effects of As on receptor-mediated gene transcription. At low, noncytotoxic doses, As significantly altered RAR-dependent gene transcription of a transfected RAR response element–luciferase construct and the native RA-inducible cytochrome P450 CYP26A gene in NT2 cells. Likewise, low-dose As significantly altered expression of a transfected TR response element–luciferase construct and the endogenous TR-regulated type I deiodinase (DIO1) gene in a similar manner in GH3 cells. An amphibian ex vivo tail metamorphosis assay was used to examine whether endocrine disruption by low-dose As could have specific pathophysiologic consequences, because tail metamorphosis is tightly controlled by TH through TR. TH-dependent tail shrinkage was inhibited in a dose-dependent manner by 0.1– 4.0 μM As. Conclusions: As had similar effects on RAR- and TR-mediated gene regulation as those previously observed for the steroid receptors, suggesting a common mechanism or action. Arsenic also profoundly affected a TR-dependent developmental process in a model animal system at very low concentrations. Because RAR and TH are critical for both normal human development and adult function and their dysregulation is associated with many disease processes, disruption of these hormone receptor–dependent processes by As is also potentially relevant to human developmental problems and disease risk

Analysis of Gene Regulatory Networks in the Mammalian Circadian Rhythm

Circadian rhythm is fundamental in regulating a wide range of cellular, metabolic, physiological, and behavioral activities in mammals. Although a small number of key circadian genes have been identified through extensive molecular and genetic studies in the past, the existence of other key circadian genes and how they drive the genomewide circadian oscillation of gene expression in different tissues still remains unknown. Here we try to address these questions by integrating all available circadian microarray data in mammals. We identified 41 common circadian genes that showed circadian oscillation in a wide range of mouse tissues with a remarkable consistency of circadian phases across tissues. Comparisons across mouse, rat, rhesus macaque, and human showed that the circadian phases of known key circadian genes were delayed for 4–5 hours in rat compared to mouse and 8–12 hours in macaque and human compared to mouse. A systematic gene regulatory network for the mouse circadian rhythm was constructed after incorporating promoter analysis and transcription factor knockout or mutant microarray data. We observed the significant association of cis-regulatory elements: EBOX, DBOX, RRE, and HSE with the different phases of circadian oscillating genes. The analysis of the network structure revealed the paths through which light, food, and heat can entrain the circadian clock and identified that NR3C1 and FKBP/HSP90 complexes are central to the control of circadian genes through diverse environmental signals. Our study improves our understanding of the structure, design principle, and evolution of gene regulatory networks involved in the mammalian circadian rhythm

Integrative Gene Regulatory Network Analysis Reveals Light-Induced Regional Gene Expression Phase Shift Programs in the Mouse Suprachiasmatic Nucleus

We use the multigenic pattern of gene expression across suprachiasmatic nuclei (SCN) regions and time to understand the dynamics within the SCN in response to a circadian phase-resetting light pulse. Global gene expression studies of the SCN indicate that circadian functions like phase resetting are complex multigenic processes. While the molecular dynamics of phase resetting are not well understood, it is clear they involve a “functional gene expression program”, e.g., the coordinated behavior of functionally related genes in space and time. In the present study we selected a set of 89 of these functionally related genes in order to further understand this multigenic program. By use of high-throughput qPCR we studied 52 small samples taken by anatomically precise laser capture from within the core and shell SCN regions, and taken at time points with and without phase resetting light exposure. The results show striking regional differences in light response to be present in the mouse SCN. By using network-based analyses, we are able to establish a highly specific multigenic correlation between genes expressed in response to light at night and genes normally activated during the day. The light pulse triggers a complex and highly coordinated network of gene regulation. The largest differences marking neuroanatomical location are in transmitter receptors, and the largest time-dependent differences occur in clock-related genes. Nighttime phase resetting appears to recruit transcriptional regulatory processes normally active in the day. This program, or mechanism, causes the pattern of core region gene expression to transiently shift to become more like that of the shell region

Impact of Chikungunya Virus Infection on Health Status and Quality of Life: A Retrospective Cohort Study

BACKGROUND:Persistent symptoms, mainly joint and muscular pain and depression, have been reported several months after Chikungunya virus (CHIKV) infection. Their frequency and their impact on quality of life have not been compared with those of an unexposed population. In the present study, we aimed to describe the frequency of prolonged clinical manifestations of CHIKV infection and to measure the impact on quality of life and health care consumption in comparison with that of an unexposed population, more than one year after infection. METHODOLOGY/PRINCIPAL FINDINGS:In a retrospective cohort study, 199 subjects who had serologically confirmed CHIKV infection (CHIK+) were compared with 199 sero-negative subjects (CHIK-) matched for age, gender and area of residence in La Réunion Island. Following an average time of 17 months from the acute phase of infection, participants were interviewed by telephone about current symptoms, medical consumption during the last 12 months and quality of life assessed by the 12-items Short-Form Health Survey (SF-12) scale. At the time of study, 112 (56%) CHIK+ persons reported they were fully recovered. CHIK+ complained more frequently than CHIK- of arthralgia (relative risk = 1.9; 95% confidence interval: 1.6-2.2), myalgia (1.9; 1.5-2.3), fatigue (2.3; 1.8-3), depression (2.5; 1.5-4.1) and hair loss (3.8; 1.9-7.6). There was no significant difference between CHIK+ and CHIK- subjects regarding medical consumption in the past year. The mean (SD) score of the SF-12 Physical Component Summary was 46.4 (10.8) in CHIK+ versus 49.1 (9.3) in CHIK- (p = 0.04). There was no significant difference between the two groups for the Mental Component Summary. CONCLUSIONS/SIGNIFICANCE:More than one year following the acute phase of infection, CHIK+ subjects reported more disabilities than those who were CHIK-. These persistent disabilities, however, have no significant influence on medical consumption, and the impact on quality of life is moderate