1,070 research outputs found

    JAK2 regulates mismatch repair protein‐mediated epigenetic alterations in response to oxidative damage

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    At sites of chronic inflammation epithelial cells undergo aberrant DNA methylation that contributes to tumorigenesis. Inflammation is associated with an increase in reactive oxygen species (ROS) that cause oxidative DNA damage, which has also been linked to epigenetic alterations. We previously demonstrated that in response to ROS, mismatch repair proteins MSH2 and MSH6 recruit epigenetic silencing proteins DNA methyltransferase 1 (DNMT1) and polycomb repressive complex 2 (PRC2) members to sites of DNA damage, resulting in transcriptional repression of tumor suppressor genes (TSGs). However, it was unclear what signal is unique to ROS that results in the chromatin binding of MSH2 and MSH6. Herein, we demonstrate that in response to hydrogen peroxide (H2O2), JAK2 localizes to the nucleus and interacts with MSH2 and MSH6. Inhibition or knockdown of JAK2 reduces the H2O2‐induced chromatin interaction of MSH2, MSH6, DNMT1, and PRC2 members, reduces H2O2‐induced global increase in trimethylation of lysine 27 of histone H3 (H3K27me3), and abrogates oxidative damage‐induced transcriptional repression of candidate TSGs. Moreover, JAK2 mRNA expression is associated with CpG island methylator phenotype (CIMP) status in human colorectal cancer. Our findings provide novel insight into the connection between kinase activation and epigenetic alterations during oxidative damage and inflammation. Environ. Mol. Mutagen. 2018. © 2018 Wiley Periodicals, Inc

    Franchise Law

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    The 2022 Annual Texas Survey on Franchise Law presents an assortment of novel and familiar legal issues in Texas state and federal courts. This year’s Survey period contains decisions favorable to franchisors, franchisees, and third parties associated with franchised businesses on disputes involving intellectual property rights, enforceability of forum selection clauses, the essential elements of common law and statutory claims, and remedies available to franchise parties involved in litigation, among other issues. As in prior years, the Survey showcases developments in franchise law that serve as helpful reminders to practitioners advising parties involved in any stage of a franchise relationship

    Histological Observation of Islet Hemorrhage Induced by Diagnostic Ultrasound with Contrast Agent in Rat Pancreas

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    Contrast enhanced diagnostic ultrasound CEDUS has been shown to induce capillary hemorrhage in heart and kidney. This study characterized the capillary hemorrhage induced in rat pancreas. The pancreata of anesthetized hairless rats were accessed by laparotomy. A 1.5 MHz diagnostic ultrasound probe with 2.3 MPa peak rarefactional pressure amplitude and 1 s intermittent trigger was used to scan the pancreas, located at the focus (3.8 cm), through saline coupling. The probe was swept to expose the entire organ in 5 min during infusion of DefinityÂź contrast agent at 10 ”L/kg/min, and this was repeated in a reverse sweep. The entire pancreas was removed, spread flat for fixation and histological slides were prepared from the mid-plane. Slides were scored blind for islet hemorrhage over the entire area of the organ. Intra-islet microlesions were evident and hemorrhage surrounded many islets. The hemorrhage often impacted nearby acini, and expanded into inter-lobular septa. In CEDUS pancreata removed soon after scanning, 76.2±11.8% (n = 6) of islets had evidence of hemorrhage and/or islet microlesions compared to 1.1±2.5% (n = 5) for sham CEDUS (P<0.001). In pancreata removed after 4 hr, fibrin formation was detected by immunohistology in the hemorrhage and intra-islet microlesions. Diagnostic ultrasound with contrast agent induced substantial capillary hemorrhage in rat pancreas, concentrated particularly in the islets

    The novel mu-opioid antagonist, GSK1521498, reduces ethanol consumption in C57BL/6J mice.

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    RATIONALE Using the drinking-in-the-dark (DID) model, we compared the effects of a novel mu-opioid receptor antagonist, GSK1521498, with naltrexone, a licensed treatment of alcohol dependence, on ethanol consumption in mice. OBJECTIVE We test the ability of GSK1521498 to reduce alcohol consumption and compare its intrinsic efficacy to that of naltrexone by comparing the two drugs at doses matched for equivalent receptor occupancy. METHODS Thirty-six C57BL/6J mice were tested in a DID procedure. In 2-day cycles, animals experienced one baseline, injection-free session, and one test session when they received two injections, one of test drug and one placebo. All animals received GSK1521498 (0, 0.1, 1 and 3 mg/kg, i.p., 30 min pre-treatment) and naltrexone (0, 0.1, 1 and 3 mg/kg, s.c. 10 min pre-treatment) in a cross-over design. Receptor occupancies following the same doses were determined ex vivo in separate groups by autoradiography, using [3H]DAMGO. Binding in the region of interest was measured integrally by computer-assisted microdensitometry and corrected for non-specific binding. RESULTS Both GSK1521498 and naltrexone dose-dependently decreased ethanol consumption. When drug doses were matched for 70-75 % receptor occupancy, GSK1521498 3 mg/kg, i.p., caused a 2.5-fold greater reduction in alcohol consumption than naltrexone 0.1 mg/kg, s.c. Both GSK1521498 and naltrexone significantly reduced sucrose consumption at a dose of 1 mg/kg but not 0.1 mg/kg. In a test of conditioned taste aversion, GSK1521498 (3 mg/kg) reduced sucrose consumption 24 h following exposure to a conditioning injection. CONCLUSIONS Both opioid receptor antagonists reduced alcohol consumption but GK1521498 has higher intrinsic efficacy than naltrexone

    Mood instability, mental illness and suicidal ideas : results from a household survey

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    Purpose: There is weak and inconsistent evidence that mood instability (MI) is associated with depression, post traumatic stress disorder (PTSD) and suicidality although the basis of this is unclear. Our objectives were first to test whether there is an association between depression and PTSD, and MI and secondly whether MI exerts an independent effect on suicidal thinking over and above that explained by common mental disorders. Methods: We used data from the Adult Psychiatric Morbidity Survey 2007 (N = 7,131). Chi-square tests were used to examine associations between depression and PTSD, and MI, followed by regression modelling to examine associations between MI and depression, and with PTSD. Multiple logistic regression analyses were used to assess the independent effect of MI on suicidal thinking, after adjustment for demographic factors and the effects of common mental disorder diagnoses. Results: There are high rates of MI in depression and PTSD and the presence of MI increases the odds of depression by 10.66 [95 % confidence interval (CI) 7.51–15.13] and PTSD by 8.69 (95 % CI 5.90–12.79), respectively, after adjusting for other factors. Mood instability independently explained suicidal thinking, multiplying the odds by nearly five (odds ratio 4.82; 95 % CI 3.39–6.85), and was individually by some way the most important single factor in explaining suicidal thoughts. Conclusions: MI is strongly associated with depression and PTSD. In people with common mental disorders MI is clinically significant as it acts as an additional factor exacerbating the risk of suicidal thinking. It is important to enquire about MI as part of clinical assessment and treatment studies are required

    Software systems for operation, control, and monitoring of the EBEX instrument

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    We present the hardware and software systems implementing autonomous operation, distributed real-time monitoring, and control for the EBEX instrument. EBEX is a NASA-funded balloon-borne microwave polarimeter designed for a 14 day Antarctic flight that circumnavigates the pole. To meet its science goals the EBEX instrument autonomously executes several tasks in parallel: it collects attitude data and maintains pointing control in order to adhere to an observing schedule; tunes and operates up to 1920 TES bolometers and 120 SQUID amplifiers controlled by as many as 30 embedded computers; coordinates and dispatches jobs across an onboard computer network to manage this detector readout system; logs over 3~GiB/hour of science and housekeeping data to an onboard disk storage array; responds to a variety of commands and exogenous events; and downlinks multiple heterogeneous data streams representing a selected subset of the total logged data. Most of the systems implementing these functions have been tested during a recent engineering flight of the payload, and have proven to meet the target requirements. The EBEX ground segment couples uplink and downlink hardware to a client-server software stack, enabling real-time monitoring and command responsibility to be distributed across the public internet or other standard computer networks. Using the emerging dirfile standard as a uniform intermediate data format, a variety of front end programs provide access to different components and views of the downlinked data products. This distributed architecture was demonstrated operating across multiple widely dispersed sites prior to and during the EBEX engineering flight.Comment: 11 pages, to appear in Proceedings of SPIE Astronomical Telescopes and Instrumentation 2010; adjusted metadata for arXiv submissio

    EBEX: A balloon-borne CMB polarization experiment

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    EBEX is a NASA-funded balloon-borne experiment designed to measure the polarization of the cosmic microwave background (CMB). Observations will be made using 1432 transition edge sensor (TES) bolometric detectors read out with frequency multiplexed SQuIDs. EBEX will observe in three frequency bands centered at 150, 250, and 410 GHz, with 768, 384, and 280 detectors in each band, respectively. This broad frequency coverage is designed to provide valuable information about polarized foreground signals from dust. The polarized sky signals will be modulated with an achromatic half wave plate (AHWP) rotating on a superconducting magnetic bearing (SMB) and analyzed with a fixed wire grid polarizer. EBEX will observe a patch covering ~1% of the sky with 8' resolution, allowing for observation of the angular power spectrum from \ell = 20 to 1000. This will allow EBEX to search for both the primordial B-mode signal predicted by inflation and the anticipated lensing B-mode signal. Calculations to predict EBEX constraints on r using expected noise levels show that, for a likelihood centered around zero and with negligible foregrounds, 99% of the area falls below r = 0.035. This value increases by a factor of 1.6 after a process of foreground subtraction. This estimate does not include systematic uncertainties. An engineering flight was launched in June, 2009, from Ft. Sumner, NM, and the long duration science flight in Antarctica is planned for 2011. These proceedings describe the EBEX instrument and the North American engineering flight.Comment: 12 pages, 9 figures, Conference proceedings for SPIE Millimeter, Submillimeter, and Far-Infrared Detectors and Instrumentation for Astronomy V (2010
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