BET Inhibition Improves NASH and Liver Fibrosis.

Non-alcoholic fatty liver disease (NAFLD) is a leading form of chronic liver disease with large unmet need. Non-alcoholic steatohepatitis (NASH), a progressive variant of NAFLD, can lead to fibrosis, cirrhosis, and hepatocellular carcinoma. To identify potential new therapeutics for NASH, we used a computational approach based on Connectivity Map (CMAP) analysis, which pointed us to bromodomain and extra-terminal motif (BET) inhibitors for treating NASH. To experimentally validate this hypothesis, we tested a small-molecule inhibitor of the BET family of proteins, GSK1210151A (I-BET151), in the STAM mouse NASH model at two different dosing timepoints (onset of NASH and progression to fibrosis). I-BET151 decreased the non-alcoholic fatty liver disease activity score (NAS), a clinical endpoint for assessing the severity of NASH, as well as progression of liver fibrosis and interferon-γ expression. Transcriptional characterization of these mice through RNA-sequencing was consistent with predictions from the CMAP analysis of a human NASH signature and pointed to alterations in molecular mechanisms related to interferon signaling and cholesterol biosynthesis, as well as reversal of gene expression patterns linked to fibrotic markers. Altogether, these results suggest that inhibition of BET proteins may present a novel therapeutic opportunity in the treatment of NASH and liver fibrosis.

The purinergic receptor P2X5 regulates inflammasome activity and hyper-multinucleation of murine osteoclasts.

Excessive bone resorption by osteoclasts (OCs) can result in serious clinical outcomes, including bone loss that may weaken skeletal or periodontal strength. Proper bone homeostasis and skeletal strength are maintained by balancing OC function with the bone-forming function of osteoblasts. Unfortunately, current treatments that broadly inhibit OC differentiation or function may also interfere with coupled bone formation. We therefore identified a factor, the purinergic receptor P2X5 that is highly expressed during the OC maturation phase, and which we show here plays no apparent role in early bone development and homeostasis, but which is required for osteoclast-mediated inflammatory bone loss and hyper-multinucleation of OCs. We further demonstrate that P2X5 is required for ATP-mediated inflammasome activation and IL-1ß production by OCs, and that P2X5-deficient OC maturation is rescued in vitro by addition of exogenous IL-1ß. These findings identify a mechanism by which OCs react to inflammatory stimuli, and may identify purinergic signaling as a therapeutic target for bone loss-related inflammatory conditions.

Improving hospital preparedness for radiological terrorism: perspectives from emergency department physicians and nurses.

BACKGROUND: Hospital emergency department (ED) clinicians will play a crucial role in responding to any terrorist incident involving radioactive materials. To date, however, there has been a paucity of research focusing specifically on ED clinicians' perspectives regarding this threat. METHODS: At the request of the Centers for Disease Control and Prevention, researchers at the University of Alabama at Birmingham conducted a series of 10 focus groups (total participants, 77) with ED physicians and nurses at hospitals in 3 US regions. Participants considered a hypothetical "dirty bomb" scenario and discussed their perceptions, concerns, information needs, preferred information sources, and views of current guidance and informational materials. RESULTS: Study participants consistently expressed the view that neither EDs nor hospital facilities are sufficiently prepared for a terrorist event involving radioactive materials. Key clinician concerns included the possibility of the hospital being overwhelmed, safety of loved ones, potential staffing problems, readiness problems, and contamination and self-protection. Participants also expressed a need for additional information, strongly disagreed with aspects of current response guidance, and in some cases indicated they would not carry out current protocols. CONCLUSIONS: This study is the first to examine the views, perceptions, and information needs of hospital ED clinicians regarding radiological terrorism. As such, the findings may be useful in informing current and future efforts to improve hospital preparedness.

Communicating with the public about emerging health threats: lessons from the Pre-Event Message Development Project.

OBJECTIVES: We sought to better understand the challenges of communicating with the public about emerging health threats, particularly threats involving toxic chemicals, biological agents, and radioactive materials. METHODS: At the request of the Centers for Disease Control and Prevention, we formed an interdisciplinary consortium of investigative teams from 4 schools of public health. Over 2 years, the investigative teams conducted 79 focus group interviews with 884 participants and individual cognitive response interviews with 129 respondents, for a total sample of 1013 individuals. The investigative teams systematically compared their results with other published research in public health, risk communication, and emergency preparedness. RESULTS: We found limited public understanding of emerging biological, chemical, and radioactive materials threats and of the differences between them; demand for concrete, accurate, and consistent information about actions needed for protection of self and family; active information seeking from media, local authorities, and selected national sources; and areas in which current emergency messaging can be improved. CONCLUSIONS: The public will respond to a threat situation by seeking protective information and taking self-protective action, underlining the critical role of effective communication in public health emergencies.

Cometabolism of Cr(VI) by Shewanella oneidensis MR-1 produces cell-associated reduced chromium and inhibits growth.

Microbial reduction is a promising strategy for chromium remediation, but the effects of competing electron acceptors are still poorly understood. We investigated chromate (Cr(VI)) reduction in batch cultures of Shewanella oneidensis MR-1 under aerobic and denitrifying conditions and in the absence of an additional electron acceptor. Growth and Cr(VI) removal patterns suggested a cometabolic reduction; in the absence of nitrate or oxygen, MR-1 reduced Cr(VI), but without any increase in viable cell counts and rates gradually decreased when cells were respiked. Only a small fraction (1.6%) of the electrons from lactate were transferred to Cr(VI). The 48-h transformation capacity (Tc) was 0.78 mg (15 micromoles) Cr(VI) reduced. [mg protein](-1) for high levels of Cr(VI) added as a single spike. For low levels of Cr(VI) added sequentially, Tc increased to 3.33 mg (64 micromoles) Cr(VI) reduced. [mg protein](-1), indicating that it is limited by toxicity at higher concentrations. During denitrification and aerobic growth, MR-1 reduced Cr(VI), with much faster rates under denitrifying conditions. Cr(VI) had no effect on nitrate reduction at 6 microM, was strongly inhibitory at 45 microM, and stopped nitrate reduction above 200 microM. Cr(VI) had no effect on aerobic growth at 60 microM, but severely inhibited growth above 150 microM. A factor that likely plays a role in Cr(VI) toxicity is intracellular reduced chromium. Transmission electron microscopy (TEM) and electron energy loss spectroscopy (EELS) of denitrifying cells exposed to Cr(VI) showed reduced chromium precipitates both extracellularly on the cell surface and, for the first time, as electron-dense round globules inside cells.