Questions and controversies in innate immune research: what is the physiological role of NLRP3?

The NLRP3 inflammasome is a key component of the innate immune system that induces pro-inflammatory cytokine production and cell death. Although NLRP3 is activated by many pathogens, it only appears to be critical for host defense for a limited number of specific infections. NLRP3 is however strongly associated with the initiation and pathology of many inflammatory diseases. If NLRP3 function is largely redundant for host defense, but drives a number of inflammatory diseases, this raises the important question of why evolution has elected to maintain NLRP3 function. We propose that the primary physiological functions of NLRP3 in health are to engage pathways to clear noxious substances (e.g. protein aggregates and crystals), and to regulate metabolism. We discuss the newly identified functions for NLRP3 in metabolic homeostasis, and how NLRP3 beneficial functions in homeostasis may become detrimental during the onset of inflammatory and metabolic diseases. A common feature of most NLRP3-driven diseases is that they are associated with ageing or metabolic excess, and indeed, Nlrp3 deficiency promotes ‘healthspan’ in ageing mice. This suggests that beneficial functions of NLRP3 in youth may become increasingly countered by NLRP3-dependent pathology as an individual ages, and we propose a general model by which ageing or nutrient excess may provide a tipping point to switch NLRP3 function from beneficial to pathological. The physiological role of NLRP3 in healthy individuals remains incompletely understood and future research will need to address this if NLRP3 is to become a successful therapeutic target for the clinical management of inflammatory diseases

Variation within and between Frankliniella Thrips Species in Host Plant Utilization

Anthophilous flower thrips in the genus Frankliniella (Thysanoptera: Thripidae) exploit ephemeral plant resources and therefore must be capable of successfully locating appropriate hosts on a repeated basis, yet little is known of interspecific and intraspecific variation in responses to host plant type and nutritional quality. Field trials were conducted over two seasons to determine if the abundance of males and females of three common Frankliniella species, F. occidentalis (Pergande), F. tritici (Fitch) and F. bispinosa (Morgan), their larvae, and a key predator, Orius insidiosus (Say) (Hemiptera: Anthocoridae) were affected by host plant type and plant nutritional quality. Two host plants, pepper, Capsicum annuum L. (Solanales: Solanaceae) and tomato, Solanum lycopersicum L. that vary in suitability for these species were examined, and their nutritional quality was manipulated by applying three levels of nitrogen fertilization (101 kg/ha, 202 kg/ha, 404 kg/ha). F. occidentalis females were more abundant in pepper than in tomato, but males did not show a differential response. Both sexes of F. tritici and F. bispinosa were more abundant in tomato than in pepper. Larval thrips were more abundant in pepper than in tomato. Likewise, O. insidiosus females and nymphs were more abundant in pepper than in tomato. Only F. occidentalis females showed a distinct response to nitrogen fertilization, with abundance increasing with fertilization. These results show that host plant utilization patterns vary among Frankliniella spp. and should not be generalized from results of the intensively studied F. occidentalis. Given the different pest status of these species and their differential abundance in pepper and tomato, it is critical that scouting programs include species identifications for proper management

Fenamate NSAIDs inhibit the NLRP3 inflammasome and protect against Alzheimer's disease in rodent models.

Non-steroidal anti-inflammatory drugs (NSAIDs) inhibit cyclooxygenase-1 (COX-1) and COX-2 enzymes. The NLRP3 inflammasome is a multi-protein complex responsible for the processing of the proinflammatory cytokine interleukin-1β and is implicated in many inflammatory diseases. Here we show that several clinically approved and widely used NSAIDs of the fenamate class are effective and selective inhibitors of the NLRP3 inflammasome via inhibition of the volume-regulated anion channel in macrophages, independently of COX enzymes. Flufenamic acid and mefenamic acid are efficacious in NLRP3-dependent rodent models of inflammation in air pouch and peritoneum. We also show therapeutic effects of fenamates using a model of amyloid beta induced memory loss and a transgenic mouse model of Alzheimer's disease. These data suggest that fenamate NSAIDs could be repurposed as NLRP3 inflammasome inhibitors and Alzheimer's disease therapeutics

Meaning in Life as a Mediator of Ethnic Identity and Adjustment Among Adolescents from Latin, Asian, and European American Backgrounds

Establishing a sense of life meaning is a primary facet of well-being, yet is understudied in adolescent development. Using data from 579 adolescents (53% female) from Latin American, Asian, and European backgrounds, demographic differences in meaning in life, links with psychological and academic adjustment, and the role of meaning in explaining associations between ethnic identity and adjustment were examined. Although no generational or gender differences were found, Asian Americans reported higher search for meaning than Latin and European Americans. Presence of meaning was positively associated with self-esteem, academic adjustment, daily well-being, and ethnic belonging and exploration, whereas search for meaning was related to lower self-esteem and less stability in daily well-being. Presence of meaning mediated associations between ethnic identity and adjustment, explaining 28–52% of ethnic identity’s protective effect on development. Ethnic identity thus appears to affect adjustment, in part, through its role in fostering a positive sense of meaning in adolescents’ lives

Biochemical warfare on the reef : the role of glutathione transferases in consumer tolerance of dietary prostaglandins

© 2010 The Authors. This article is distributed under the terms of the Creative Commons Attribution License. The definitive version was published in PLoS ONE 5 (2010): e8537, doi:10.1371/journal.pone.0008537.Despite the profound variation among marine consumers in tolerance for allelochemically-rich foods, few studies have examined the biochemical adaptations underlying diet choice. Here we examine the role of glutathione S-transferases (GSTs) in the detoxification of dietary allelochemicals in the digestive gland of the predatory gastropod Cyphoma gibbosum, a generalist consumer of gorgonian corals. Controlled laboratory feeding experiments were used to investigate the influence of gorgonian diet on Cyphoma GST activity and isoform expression. Gorgonian extracts and semi-purified fractions were also screened to identify inhibitors and possible substrates of Cyphoma GSTs. In addition, we investigated the inhibitory properties of prostaglandins (PGs) structurally similar to antipredatory PGs found in high concentrations in the Caribbean gorgonian Plexaura homomalla. Cyphoma GST subunit composition was invariant and activity was constitutively high regardless of gorgonian diet. Bioassay-guided fractionation of gorgonian extracts revealed that moderately hydrophobic fractions from all eight gorgonian species examined contained putative GST substrates/inhibitors. LC-MS and NMR spectral analysis of the most inhibitory fraction from P. homomalla subsequently identified prostaglandin A2 (PGA2) as the dominant component. A similar screening of commercially available prostaglandins in series A, E, and F revealed that those prostaglandins most abundant in gorgonian tissues (e.g., PGA2) were also the most potent inhibitors. In vivo estimates of PGA2 concentration in digestive gland tissues calculated from snail grazing rates revealed that Cyphoma GSTs would be saturated with respect to PGA2 and operating at or near physiological capacity. The high, constitutive activity of Cyphoma GSTs is likely necessitated by the ubiquitous presence of GST substrates and/or inhibitors in this consumer's gorgonian diet. This generalist's GSTs may operate as ‘all-purpose’ detoxification enzymes, capable of conjugating or sequestering a broad range of lipophilic gorgonian compounds, thereby allowing this predator to exploit a range of chemically-defended prey, resulting in a competitive dietary advantage for this species.Financial support for this work was provided by the Ocean Life Institute Tropical Research Initiative Grant (WHOI) to KEW and MEH; the Robert H. Cole Endowed Ocean Ventures Fund (WHOI) to KEW; the National Undersea Research Center - Program Development Proposal (CMRC-03PRMN0103A) to KEW; Walter A. and Hope Noyes Smith, and a National Science Foundation Graduate Research Fellowship to KEW

The interaction between the proliferating macroalga Asparagopsis taxiformis and the coral Astroides calycularis induces changes in microbiome and metabolomic fingerprints

Mediterranean Sea ecosystems are considered as hotspots of biological introductions, exposed to possible negative effects of non-indigenous species. In such temperate marine ecosystems, macroalgae may be dominant, with a great percentage of their diversity represented by introduced species. Their interaction with temperate indigenous benthic organisms have been poorly investigated. To provide new insights, we performed an experimental study on the interaction between the introduced proliferative red alga Asparagopsis taxiformis and the indigenous Mediterranean coral Astroides calycularis. The biological response measurements included meta-barcoding of the associated microbial communities and metabolomic fingerprinting of both species. Significant changes were detected among both associated microbial communities, the interspecific differences decreasing with stronger host interaction. No short term effects of the macroalga on the coral health, neither on its polyp activity or its metabolism, were detected. In contrast, the contact interaction with the coral induced a change in the macroalgal metabolomic fingerprint with a significant increase of its bioactivity against the marine bacteria Aliivibrio fischeri. This induction was related to the expression of bioactive metabolites located on the macroalgal surface, a phenomenon which might represent an immediate defensive response of the macroalga or an allelopathic offense against coral.ERA-NET Biome project "SEAPROLIF"; CNRS; Provence Alpes Cote d'Azur Region; TOTAL Fundation; Fundacao para a Ciencia e a Tecnologia (FCT) [Netbiome/0002/2011]; FCT fellowships [SFRH/BPD/63703/2009, SFRH/BPD/107878/2015]info:eu-repo/semantics/publishedVersio

Hyperleptinemia Is Required for the Development of Leptin Resistance

Leptin regulates body weight by signaling to the brain the availability of energy stored as fat. This negative feedback loop becomes disrupted in most obese individuals, resulting in a state known as leptin resistance. The physiological causes of leptin resistance remain poorly understood. Here we test the hypothesis that hyperleptinemia is required for the development of leptin resistance in diet-induced obese mice. We show that mice whose plasma leptin has been clamped to lean levels develop obesity in response to a high-fat diet, and the magnitude of this obesity is indistinguishable from wild-type controls. Yet these obese animals with constant low levels of plasma leptin remain highly sensitive to exogenous leptin even after long-term exposure to a high fat diet. This shows that dietary fats alone are insufficient to block the response to leptin. The data also suggest that hyperleptinemia itself can contribute to leptin resistance by downregulating cellular response to leptin as has been shown for other hormones

Emotional problems in preadolescents in Norway: the role of gender, ethnic minority status, and home- and school-related hassles

<p>Abstract</p> <p>Background</p> <p>"The gender gap" refers to a lifelong higher rate of emotional problems in girls, as compared to boys, that appears during adolescence. The gender gap is a well-replicated finding among older adolescents and is assumed to be a cross-cultural phenomenon. However, these cross-cultural studies have not investigated the gender gap in ethnic minorities but sampled ethnic majority adolescents in different countries. Some studies that investigated the gender gap across ethnic groups indirectly (by presenting emotional problem scores stratified by gender and ethnic group) indicate that the gender gap is less prominent or even absent among minorities. The aims of this study were to assess whether the gender gap is found in both majority and minority preadolescents, and to investigate whether a possible (gender and ethnic) group difference can be accounted for by differences in home or school hassles.</p> <p>Methods</p> <p>Participants were 902 preadolescent students (aged 10 to 12) from two cities in Norway. We collected self-report measures of emotional problems and home and school hassles. Using mediated moderation analysis we tested whether the interaction effect between gender and ethnic minority background on emotional problems was mediated by home or school hassles.</p> <p>Results</p> <p>The gender gap in emotional problems was restricted to ethnic majority preadolescents. School hassles but not home hassles accounted in part for this effect.</p> <p>Conclusions</p> <p>The absence of the gender gap among minority as opposed to majority preadolescents may indicate that social circumstances may postpone or hamper the emergence and magnitude of the gender gap in ethnic minority preadolescents. In this study, school hassles partly accounted for the combined gender and ethnic group differences on emotional problems. This indicates that school hassles may play a role in the higher levels of emotional problems in preadolescent minority boys and consequently the absence of a gender gap found in our minority sample.</p

Hormonal signaling in cnidarians : do we understand the pathways well enough to know whether they are being disrupted?

Author Posting. © The Author, 2006. This is the author's version of the work. It is posted here by permission of Springer for personal use, not for redistribution. The definitive version was published in Ecotoxicology 16 (2007): 5-13, doi:10.1007/s10646-006-0121-1.Cnidarians occupy a key evolutionary position as basal metazoans and are ecologically important as predators, prey and structure-builders. Bioregulatory molecules (e.g., amines, peptides and steroids) have been identified in cnidarians, but cnidarian signaling pathways remain poorly characterized. Cnidarians, especially hydras, are regularly used in toxicity testing, but few studies have used cnidarians in explicit testing for signal disruption. Sublethal endpoints developed in cnidarians include budding, regeneration, gametogenesis, mucus production and larval metamorphosis. Cnidarian genomic databases, microarrays and other molecular tools are increasingly facilitating mechanistic investigation of signaling pathways and signal disruption. Elucidation of cnidarian signaling processes in a comparative context can provide insight into the evolution and diversification of metazoan bioregulation. Characterizing signaling and signal disruption in cnidarians may also provide unique opportunities for evaluating risk to valuable marine resources, such as coral reefs