TLR2 Signaling Contributes to Rapid Inflammasome Activation during F. novicida Infection

Early detection of microorganisms by the innate immune system is provided by surface-expressed and endosomal pattern recognition receptors (PRRs) such as Toll-like receptors (TLRs). Detection of microbial components by TLRs initiates a signaling cascade leading to the expression of proinflammatory cytokines including IL-6 and IL-1β. Some intracellular bacteria subvert the TLR response by rapidly escaping the phagosome and entering the cytosol. However, these bacteria may be recognized by the inflammasome, a multi-protein complex comprised of a sensor protein, ASC and the cysteine protease caspase-1. Inflammasome activation leads to release of the proinflammatory cytokines IL-1β and IL-18 and death of the infected cell, an important host defense that eliminates the pathogen's replicative niche. While TLRs and inflammasomes are critical for controlling bacterial infections, it is unknown whether these distinct host pathways cooperate to activate defenses against intracellular bacteria.Using the intracellular bacterium Francisella novicida as a model, we show that TLR2(-/-) macrophages exhibited delayed inflammasome activation compared to wild-type macrophages as measured by inflammasome assembly, caspase-1 activation, cell death and IL-18 release. TLR2 also contributed to inflammasome activation in response to infection by the cytosolic bacterium Listeria monocytogenes. Components of the TLR2 signaling pathway, MyD88 and NF-κB, were required for rapid inflammasome activation. Furthermore, TLR2(-/-) mice exhibited lower levels of cell death, caspase-1 activation, and IL-18 production than wild-type mice upon F. novicida infection.These results show that TLR2 is required for rapid inflammasome activation in response to infection by cytosolic bacterial pathogens. In addition to further characterizing the role of TLR2 in host defense, these findings broaden our understanding of how the host integrates signals from spatiotemporally separated PRRs to coordinate an innate response against intracellular bacteria

Ghrelin-induced food intake and adiposity depend on central mTORC1/S6K1 signaling.

Signaling through the mammalian target of rapamycin complex 1 (mTORC1) and its effectors the S6-kinases (S6K) in the hypothalamus is thought to be involved in nutrient sensing and control of food intake. Given the anatomical proximity of this pathway to circuits for the hormone ghrelin, we investigated the potential role of the mTORC1/S6K pathway in mediating the metabolic effects of ghrelin. We found that ghrelin promoted phosphorylation of S6K1 in the mouse hypothalamic cell line N-41 and in the rat hypothalamus after intracerebroventricular administration. Rapamycin, an inhibitor of mTORC1, suppressed ghrelin-induced phosphorylation of hypothalamic S6K1 and increased food intake and insulin in rats. Chronic peripheral administration of ghrelin induced a significant increase in body weight, fat mass and food efficiency in wild-type and S6K2-knockout but not in S6K1-knockout mice. We therefore propose that ghrelin-induced hyperphagia, adiposity and insulin secretion are controlled by a central nervous system involving the mTORC1/S6K1 pathway

Building Information Modelling (BIM) : a summary of some UK experiences as guide to adoption in Nigeria

Building information modelling (BIM) is a term that has been echoed around the world by researchers and practitioners alike. This is a new methodology (essentially electronic capture and focussed, timely distribution of relevant data) of project delivery that improves efficiency and quality of work. Although the word 'building' is used, BIM is equally applicable to civil engineering, utilities and infrastructure projects. Also, the word 'modelling' applies to the broad spectrum of process application not simply models produced by 3d software packages. The most important element in BIM is the 'information' and its beneficial capture and repeat usage. Every sector of the world economy is just looking for ways to produce more with fewer resources or making best use of the resources available. This paradigm shift has brought about the adoption of BIM in the construction industry. This paper will define BIM in simple terms; highlight its benefits and barriers; rationalise its workability, maturity levels and general ideas that it is based upon. The paper will also articulate some actual experiences from the UK at both the government and organisational level and the challenges overcome and some benefits achieved. Just like any other technology or methodology, BIM relies on collaboration for its successful implementation. This collaboration will create an avenue for construction teams to produce and make use of consistent unambiguous information, which will improve the overall efficiency in project delivery. For many people the question still remains. Will this be a solution to the all the problems in the industry? Or will it only solve particular problems? Just like every technology using it correctly will definitely yield benefits. Governments in many countries have recognised the usefulness of BIM and have intervened to make its implementation possible. As a developing country, Nigeria should not be far from making such efforts. There is need for construction industry to take proactive steps to overcome its problems. BIM implementation may not be a panacea to all the problems in the construction industry but it will surely make it better. Construction professionals may look at this idea with scepticism echoed, although it is now being overcome in countries adopting BIM. The earlier they realise that BIM will be the future of the industry the better