Resource limitation is a fundamental factor governing the composition and function of ecological communities. However, the role of resource supply in structuring the intestinal microbiome has not been established and represents a challenge for mammals that rely on microbial symbionts for digestion: too little supply might starve the microbiome while too much supply might starve the host. Here, we present evidence that microbiota occupy a habitat limited in total nitrogen supply within the large intestines of 30 mammal species. Furthermore, lowering dietary protein levels in mice reduced bacterial fecal concentrations. A gradient of stoichiometry along the length of the gut was consistent with the hypothesis that intestinal nitrogen limitation results from host absorption of dietary nutrients. Nitrogen availability though is also likely shaped by host-microbe interactions: levels of host-secreted nitrogen were altered in germfree mice and when bacterial loads were reduced via experimental antibiotic treatment. Single-cell spectrometry revealed that members of the phylum Bacteroidetes consumed nitrogen in the large intestine more readily than other commensal taxa. Collectively, our findings support a model where nitrogen limitation arises from preferential host utilization of dietary nutrients, and we speculate that this resource limitation could enable hosts to regulate microbial communities in the large intestine. Furthermore, commensal microbiota may have adapted to nitrogen-limited settings, suggesting why excess dietary protein has been associated with degraded gut microbial ecosystems.

To facilitate the study of renal proximal tubules, we generated a transgenic mouse strain expressing an improved Cre recombinase (iCre) under the control of the kidney androgen-regulated protein (KAP) promoter. The transgene was expressed in the kidney of male mice but not in female mice. Treatment of female transgenic mice with androgen induced robust expression of the transgene in the kidney. We confirmed the presence of Cre recombinase activity and the cell specificity by breeding the KAP2-iCRE mice with ROSA26 reporter mice. X-Gal staining of kidney sections from male double transgenic mice showed robust staining in the epithelial cells of renal proximal tubules. beta-Gal staining in female mice became evident in proximal tubules after administration of androgen. This model of inducible Cre recombinase in the renal proximal tubule should provide a novel useful tool for studying the physiological significance of genes expressed in the renal proximal tubule. This has advantages over other current models where Cre recombinase expression is constitutive, not inducible.

Non-alcoholic fatty liver disease (NAFLD) increases the risk of hepatobiliary carcinogenesis. However, the underlying mechanism remains unknown. Our study demonstrates that chronic inflammation suppresses hepatocyte expression of ESRP2, an adult RNA splicing factor that activates NF2. Thus, inactive (fetal) NF2 loses the ability to activate Hippo kinases, leading to the increased activity of downstream YAP/TAZ and promoting hepatobiliary carcinogenesis in chronically injured livers.

e Neisseria gonorrhoeae causes gonorrhea, a sexually transmitted infection characterized by inflammation of the cervix or urethra. However, a significant subset of patients with N. gonorrhoeae remain asymptomatic, without evidence of localized inflammation. Inflammatory responses to N. gonorrhoeae are generated by host innate immune recognition of N. gonorrhoeae by several innate immune signaling pathways, including lipooligosaccharide (LOS) and other pathogen-derived molecules through activation of innate immune signaling systems, including toll-like receptor 4 (TLR4) and the interleukin-1␤ (IL-1␤) processing complex known as the inflammasome. The lipooligosaccharide of N. gonorrhoeae has a hexa-acylated lipid A. N. gonorrhoeae strains that carry an inactivated msbB (also known as lpxL1) gene produce a penta-acylated lipid A and exhibit reduced biofilm formation, survival in epithelial cells, and induction of epithelial cell inflammatory signaling. We now show that msbB-deficient N. gonorrhoeae induces less inflammatory signaling in human monocytic cell lines and murine macrophages than the parent organism. The penta-acylated LOS exhibits reduced toll-like receptor 4 signaling but does not affect N. gonorrhoeae-mediated activation of the inflammasome. We demonstrate that N. gonorrhoeae msbB is dispensable for initiating and maintaining infection in a murine model of gonorrhea. Interestingly, infection with msbB-deficient N. gonorrhoeae is associated with less localized inflammation. Combined, these data suggest that TLR4-mediated recognition of N. gonorrhoeae LOS plays an important role in the pathogenesis of symptomatic gonorrhea infection and that alterations in lipid A biosynthesis may play a role in determining symptomatic and asymptomatic infections. L ipopolysaccharide (LPS) is an importance virulence factor in Gram-negative bacteria. LPS consists of a complex polysaccharide attached to a core saccharide consisting of 3-deoxy-Dmannooctulosonic acid (keto-deoxyoctulosonate [KDO]) and an acylated diglucosamine moiety known as lipid A. Neisseria species (as well as some other commensal and pathogenic bacteria) make LPS with a truncated polysaccharide structure, which is termed lipooligosaccharide (LOS). LOS is a potent mediator of inflammatory signaling and is known to activate several host innate immune signaling systems, including toll-like receptor 4 (TLR4) through the lipid A molecule, C-lectin receptors (particularly MGL and DC-SIGN) through the oligosaccharide structure, and the caspase-1 activating complex known as the NLRP3-inflammasome through mechanisms yet to be determined (1-4).Lipid A synthesis is largely carried out by a highly conserved set of enzymatic steps that include the acylation of glucosaminebased precursors followed by condensation of these acylated glucosamine structures into the tetra-acylated disaccharide backbone that is the core structure of lipid A. This core is further decorated by the addition of two KDOs (2) and a variety of other additional modifications of the lipidated dis...

Despite advances in the treatment of acute tissue ischemia significant challenges remain in effective cytoprotection from ischemic cell death. It has been documented that injected stem cells, such as mesenchymal stem cells (MSCs), can confer protection to ischemic tissue through the release of paracrine factors. The study of these factors is essential for understanding tissue repair and the development of new therapeutic approaches for regenerative medicine. We have recently shown that a novel factor secreted by MSCs, which we called HASF (Hypoxia and Akt induced Stem cell Factor), promotes cardiomyocyte proliferation. In this study we show that HASF has a cytoprotective effect on ischemia induced cardiomyocyte death. We assessed whether HASF could potentially be used as a therapeutic agent to prevent the damage associated with myocardial infarction. In vitro treatment of cardiomyocytes with HASF protein resulted in decreased apoptosis; tunel positive nuclei were fewer in number, caspase activation and mitochondrial pore opening were inhibited. Purified HASF protein was injected into the heart immediately following myocardial infarction. Heart function was found to be comparable to sham operated animals one month following injury and fibrosis was significantly reduced. In vivo and in vitro HASF activated protein kinase C ε (PKCε). Inhibition of PKCε blocked the HASF effect on apoptosis. Furthermore, the beneficial effects of HASF were lost in mice lacking PKCε. Collectively these results identify HASF as a protein of significant therapeutic potential, acting in part through PKCε.