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The Azorhizobium nifA promoter (PnifA) is positively regulated by two physiological signal transduction pathways, NtrBC, which signals anabolic N status, and FixLJK, which signals prevailing O 2 status. Yet, PnifA response (gene product per unit time) to these two activating signals together is more than twice that of the summed, individual signals. In the absence of NIFA, a negative PnifA autoregulator, the fully induced PnifA response is more than 10-fold greater than that of summed, individual signals. Given this synergism, these two signal transduction pathways must interactively regulate PnifA activity. Unique among characterized bacteria, Azorhizobium caulinodans fixes N 2 at high rates both in free-living culture and in symbiosis with Sesbania spp. host legumes (17). Both structural and regulatory (nif) genes for N 2 fixation are strongly conserved across the Bacteria. Among the latter is the nifA gene, which encodes a master transcriptional activator. While nifA coding sequences are highly conserved, nifA expression patterns are quite different, even among related N 2 -fixing bacteria. Different nifA regulatory circuits reflect orthologous cisand trans-acting elements ''wired'' together quite differently (21). Klebsiella pneumoniae, a microaerophilic diazotroph, regulates nifA expression hierarchically through two signal transduction pathways. The primary pathway, low anabolic N signal 3 NTRB 3 NTRC 3 nifLA, allows NIFA synthesis, while a secondary pathway, high O 2 signal 3 NIFL Oٜ NIFA 3 nifLA, modulates NIFA levels (Oٜ, negative regulation; 3, positive regulation). In K. pneumoniae, both NTRB3NTRC and NIFL Oٜ NIFA constitute cognate pairs of environmental sensor and response regulator. The NTRB3NTRC pair, when stimulated by anabolic N limitation, activates transcription at specific targets, among them the nifLA operon (18). In an amplification cascade, K. pneumoniae NIFA so produced not only activates transcription at other nif operons, it also autoregulates its own transcription (7). NIFA negatively responds to its cognate environmental sensor, NIFL, which somehow monitors endogenous O 2 , and to high anabolic N levels (26,36). Both NIFA and NTRC specifically bind DNA and activate RNA polymerase 54 -type transcription initiation complexes. In K. pneumoniae, promoter targets carry distinct upstream activating elements which bind either NIFA or NTRC (8,47) as well as diagnostic Ϫ12 and Ϫ24 elements, which bind 54 initiator either alone or complexed with core RNA polymerase (5, 6). This integration of cis-and trans-acting elements allows global transcriptional control of targeted operons.In contrast, Rhizobium meliloti nif genes are regulated by physiological O 2 but not by anabolic N levels. In R. meliloti cultures, since nif gene products are only very weakly expressed and N 2 fixation is not observed, the nif genes probably respond to as-yet-uncharacterized symbiotic signals. While various Rhizobium species all carry a highly conserved NTRB3NTRC cognate pair, its targets do not include nif genes (57)...

Non-alcoholic steatohepatitis (NASH) is an emerging public health problem without effective therapies. Cytochrome P450 (CYP) epoxygenases metabolize arachidonic acid into bioactive epoxyeicosatrienoic acids (EETs), which have potent anti-inflammatory and protective effects. However, the functional relevance of the CYP epoxyeicosanoid metabolism pathway in the pathogenesis of NASH remains poorly understood. Our studies demonstrate that both mice with methionine-choline deficient (MCD) diet-induced NASH and humans with biopsy-confirmed NASH exhibited significantly higher free EET concentrations compared to healthy controls. Targeted disruption of Ephx2 (the gene encoding for soluble epoxide hydrolase) in mice further increased EET levels and significantly attenuated MCD diet-induced hepatic steatosis, inflammation and injury, as well as high fat diet-induced adipose tissue inflammation, systemic glucose intolerance and hepatic steatosis. Collectively, these findings suggest that dysregulation of the CYP epoxyeicosanoid pathway is a key pathological consequence of NASH in vivo, and promoting the anti-inflammatory and protective effects of EETs warrants further investigation as a novel therapeutic strategy for NASH.