Soluble CD36 Ectodomain Binds Negatively Charged Diacylglycerol Ligands and Acts as a Co-Receptor for TLR2

BACKGROUND:Cluster of differentiation 36 (CD36) is a transmembrane glycoprotein involved in many biological processes, such as platelet biology, angiogenesis and in the aetiopathology of atherosclerosis and cardiovascular diseases. Toll-like receptors (TLRs) are one of the most important receptors of the innate immune system. Their main function is the recognition of conserved structure of microorganisms. This recognition triggers signaling pathways that activate transcription of cytokines and co-stimulatory molecules which participate in the generation of an immune response against microbes. In particular, TLR2 has been shown to recognize a broad range of ligands. Recently, we showed that CD36 serves as a co-receptor for TLR2 and enhances recognition of specific diacylglycerides derived from bacteria. METHODOLOGY/ PRINCIPAL FINDINGS:Here, we investigate the mechanism by which CD36 contributes to ligand recognition and activation of TLR2 signaling pathway. We show that the ectodomain of murine CD36 (mCD36ED) directly interacts with negatively charged diacylglycerol ligands, which explains the specificity and selectivity of CD36 as a TLR2 co-receptor. We also show that mCD36ED amplifies the pro-inflammatory response to lipoteichoic acid in macrophages of wild-type mice and restores the pro-inflammatory response of macrophages from mice deficient in CD36 (oblivious), but not from mice deficient in cluster of differentiation 14 (CD14) (heedless). CONCLUSION/ SIGNIFICANCE: These data indicate that the CD36 ectodomain is the only relevant domain for activation of TLR2 signaling pathway and that CD36 and CD14 have a non-redundant role for loading ligands onto TLR2 in the plasma-membrane. The pro-inflammatory role of soluble CD36 can be relevant in the activation of the immune response against pathogens, as well as in the progression of chronic diseases. Therefore, an increased level of soluble forms of CD36, which has been reported to be increased in type II diabetic patients, could accelerate atherosclerosis by increasing the pro-inflammatory response to diacylglycerol ligands

The Present and Future Role of Insect-Resistant Genetically Modified Maize in IPM

Commercial, genetically-modified (GM) maize was first planted in the United States (USA, 1996) and Canada (1997) but now is grown in 13 countries on a total of over 35 million hectares (\u3e24% of area worldwide). The first GM maize plants produced a Cry protein derived from the soil bacteriumBacillus thuringiensis (Bt), which made them resistant to European corn borer and other lepidopteran maize pests. New GM maize hybrids not only have resistance to lepidopteran pests but some have resistance to coleopteran pests and tolerance to specific herbicides. Growers are attracted to the Btmaize hybrids for their convenience and because of yield protection, reduced need for chemical insecticides, and improved grain quality. Yet, most growers worldwide still rely on traditional integrated pest management (IPM) methods to control maize pests. They must weigh the appeal of buying insect protection “in the bag” against questions regarding economics, environmental safety, and insect resistance management (IRM). Traditional management of maize insects and the opportunities and challenges presented by GM maize are considered as they relate to current and future insect-resistant products. Four countries, two that currently have commercialize Bt maize (USA and Spain) and two that do not (China and Kenya), are highlighted. As with other insect management tactics (e.g., insecticide use or tillage), GM maize should not be considered inherently compatible or incompatible with IPM. Rather, the effect of GM insect-resistance on maize IPM likely depends on how the technology is developed and used

Structural basis of 7SK RNA 5′ γ-phosphate methylation and retention by MePCE

Among RNA 5′-cap structures, γ-phosphate monomethylation is unique to a small subset of noncoding RNAs, 7SK and U6 in humans. 7SK is capped by methylphosphate capping enzyme (MePCE), which has a second non-enzymatic role as a core component of the 7SK RNP that is an essential regulator of RNA transcription. We report 2.0 and 2.1 Å X-ray crystal structures of human MePCE methyltransferase domain bound to S-adenosylhomocysteine (SAH) and uncapped or capped 7SK substrates, respectively. 7SK recognition is achieved by protein contacts to a 5′ hairpin-single-stranded RNA region, explaining MePCE specificity for 7SK and U6. The structures reveal SAH and product RNA in a near-transition state geometry. Surprisingly, binding experiments show that MePCE has higher affinity for capped vs uncapped 7SK, with kinetic data supporting a slow product release model. This work reveals the molecular mechanism of methyl transfer and 7SK retention by MePCE for subsequent assembly of 7SK RNP

Can a motivational intervention overcome an unsupportive environment for walking: Findings from the Step-by-Step Study

Background Interventions to promote walking have rarely examined how their effects varied by the attributes of the physical environment. Purpose The purpose of this study is to examine whether perceptions of environmental walkability predicted change in walking behavior following an individual-based intervention to promote walking and whether the intervention buffered the effects of unsupportive environment for walking. Methods Inactive adults (aged 30–65 years, 85% women) who completed a 3-month randomized control trial comparing the effect of a single mail-out of a theoretically based self-help walking program (WP, n = 102); the same program plus a pedometer (WPP, n  = 105); and a “no-treatment” control group (C, n = 107). Measures included change in self-reported walking time for all purposes and in the proportion of people reporting regular walking (i.e., ≥150 min/week and ≥5 sessions/wk). Perceptions of environmental esthetics, safety from crime, proximity to destinations, access to walking facilities, traffic, streetlights, connectivity, and hilliness were assessed at baseline and dichotomized into “low” or “high” by the median score. Covariates were social support, self-efficacy, intention to change behavior, and sociodemographic characteristics. Results Adjusting for baseline walking, significant covariates, and study groups, walking time at follow-up was lower if streetlights or esthetics were perceived to be “low” (−24% and −22%, respectively) compared with “high” (p