The normal microflora of the skin includes staphylococcal species that will induce inflammation when present below the dermis but are tolerated on the epidermal surface without initiating ...inflammation. Here we reveal a previously unknown mechanism by which a product of staphylococci inhibits skin inflammation. This inhibition is mediated by staphylococcal lipoteichoic acid (LTA) and acts selectively on keratinocytes triggered through Toll-like receptor 3(TLR3). We show that TLR3 activation is required for normal inflammation after injury and that keratinocytes require TLR3 to respond to RNA from damaged cells with the release of inflammatory cytokines. Staphylococcal LTA inhibits both inflammatory cytokine release from keratinocytes and inflammation triggered by injury through a TLR2-dependent mechanism. To our knowledge, these findings show for the first time that the skin epithelium requires TLR3 for normal inflammation after wounding and that the microflora can modulate specific cutaneous inflammatory responses.
Subcellular localization is emerging as an important mechanism for mTORC1 regulation. We report that the tuberous sclerosis complex (TSC) signalling node, TSC1, TSC2 and Rheb, localizes to ...peroxisomes, where it regulates mTORC1 in response to reactive oxygen species (ROS). TSC1 and TSC2 were bound by peroxisomal biogenesis factors 19 and 5 (PEX19 and PEX5), respectively, and peroxisome-localized TSC functioned as a Rheb GTPase-activating protein (GAP) to suppress mTORC1 and induce autophagy. Naturally occurring pathogenic mutations in TSC2 decreased PEX5 binding, and abrogated peroxisome localization, Rheb GAP activity and suppression of mTORC1 by ROS. Cells lacking peroxisomes were deficient in mTORC1 repression by ROS, and peroxisome-localization-deficient TSC2 mutants caused polarity defects and formation of multiple axons in neurons. These data identify a role for the TSC in responding to ROS at the peroxisome, and identify the peroxisome as a signalling organelle involved in regulation of mTORC1.
Plasmacytoid dendritic cells (pDCs) are specialized type I interferon (IFN-α/β)-producing cells that express intracellular toll-like receptor (TLR) 7 and TLR9 and recognize viral nucleic acids in the ...context of infections. We show that pDCs also have the ability to sense host-derived nucleic acids released in common skin wounds. pDCs were found to rapidly infiltrate both murine and human skin wounds and to transiently produce type I IFNs via TLR7- and TLR9-dependent recognition of nucleic acids. This process was critical for the induction of early inflammatory responses and reepithelization of injured skin. Cathelicidin peptides, which facilitate immune recognition of released nucleic acids by promoting their access to intracellular TLR compartments, were rapidly induced in skin wounds and were sufficient but not necessary to stimulate pDC activation and type I IFN production. These data uncover a new role of pDCs in sensing tissue damage and promoting wound repair at skin surfaces.
Water temperature is often monitored at water sources and treatment works; however, there is limited monitoring of the water temperature in the drinking water distribution system (DWDS), despite a ...known impact on physical, chemical and microbial reactions which impact water quality. A key parameter influencing drinking water temperature is soil temperature, which is influenced by the urban heat island effects. This paper provides critique and comprehensive summary of the current knowledge, policies and challenges regarding drinking water temperature research and presents the findings from a survey of international stakeholders. Knowledge gaps as well as challenges and opportunities for monitoring and research are identified. The conclusion of the study is that temperature in the DWDS is an emerging concern in various countries regardless of the water source and treatment, climate conditions, or network characteristics such as topology, pipe material or diameter. More research is needed, especially to determine (i) the effect of higher temperatures, (ii) a legislative limit on temperature and (iii) measures to comply with this limit.
Cathelicidins and other antimicrobial peptides are deployed at epithelial surfaces to defend against infection. These molecules have broad-spectrum killing activity against microbes and can have ...effects on specific mammalian cell types, potentially stimulating additional immune defense through direct chemotactic activity or induction of cytokine release. In humans, the cathelicidin hCAP18/LL-37 is processed to LL-37 in neutrophils, but on skin it can be further proteolytically processed to shorter forms. The influence of these cathelicidin peptides on keratinocyte function is not known. In the current study, DNA microarray analysis and confirmatory protein analysis showed that LL-37 affects the expression of several chemokines and cytokines by keratinocytes. Analysis of a synthetic peptide library derived from LL-37 showed that antimicrobial activity against bacterial, fungal, and viral skin pathogens resides within specific domains of the parent peptide, but antimicrobial activity does not directly correlate with the ability to stimulate IL-8 production in keratinocytes. IL-8 release was induced by d- and l-amino acid forms of cathelicidin and correlated with membrane permeability, suggesting that highly structure-specific binding to a cell surface receptor is not likely. However, this effect was inhibited by either pertussis toxin or AG1478, an epidermal growth factor receptor tyrosine kinase inhibitor, suggesting that cathelicidin may indirectly stimulate multiple signaling pathways associated with cell surface receptors. Taken together, these observations suggest that proteolytic processing may alter the balance between cathelicidin antimicrobial and host immunostimulatory functions.
Acne rosacea is an inflammatory skin disease that affects 3% of the US population over 30 years of age and is characterized by erythema, papulopustules and telangiectasia. The etiology of this ...disorder is unknown, although symptoms are exacerbated by factors that trigger innate immune responses, such as the release of cathelicidin antimicrobial peptides. Here we show that individuals with rosacea express abnormally high levels of cathelicidin in their facial skin and that the proteolytically processed forms of cathelicidin peptides found in rosacea are different from those present in normal individuals. These cathelicidin peptides are a result of a post-translational processing abnormality associated with an increase in stratum corneum tryptic enzyme (SCTE) in the epidermis. In mice, injection of the cathelicidin peptides found in rosacea, addition of SCTE, and increasing protease activity by targeted deletion of the serine protease inhibitor gene Spink5 each increases inflammation in mouse skin. The role of cathelicidin in enabling SCTE-mediated inflammation is verified in mice with a targeted deletion of Camp, the gene encoding cathelicidin. These findings confirm the role of cathelicidin in skin inflammatory responses and suggest an explanation for the pathogenesis of rosacea by demonstrating that an exacerbated innate immune response can reproduce elements of this disease.
Abstract
Background
The prevalence of childhood obesity has been increasing for several decades. Active video games (AVG) may be an effective intervention to help manage this rising health crisis. ...The aim of this review is to evaluate whether AVG are effective at reducing weight or improving body composition in overweight youths.
Method
Medline, Embase, SportDiscus, ASSIA, CINAHL Plus, CENTRAL, CDSR and PsychINFO databases were searched for studies assessing quantitative or qualitative impact of AVG in overweight adolescents published in English. Three authors screened the results using inclusion/exclusion criteria.
Results
A total of 12 studies met the inclusion criteria; 11 reported a significant decrease in at least one weight outcome. Results from seven randomized controlled trials were pooled by meta-analysis, which compared with controls subjects in AVG groups demonstrated greater body mass index (BMI) Z-score reduction (mean difference: −0.09 (−0.12, −0.05) I2 = 34%, P < 0.0001). The mean weight reduction (−2.66 Kg (−5.67, +0.35) I2 = 0%, P = 0.08) and BMI (−2.29 (−4.81, +0.22) I2 = 49%, P = 0.07) were greater in AVG groups but results did not reach statistical significance.
Conclusions
BMI Z-score was significantly reduced in the AVG group and the majority of included studies reported significant results in at least one weight outcome, suggesting AVG can be used to reduce weight or improve body composition in overweight youths. Further studies investigating the long-term sustainability of this change in body composition are needed.
Tuberous sclerosis complex (TSC) is a neurodevelopmental disease caused by TSC1 or TSC2 mutations and subsequent activation of the mTORC1 kinase. Upon mTORC1 activation, anabolic metabolism, which ...requires mitochondria, is induced, yet at the same time the principal pathway for mitochondrial turnover, autophagy, is compromised. How mTORC1 activation impacts mitochondrial turnover in neurons remains unknown. Here, we demonstrate impaired mitochondrial homeostasis in neuronal in vitro and in vivo models of TSC. We find that Tsc1/2-deficient neurons accumulate mitochondria in cell bodies, but are depleted of axonal mitochondria, including those supporting presynaptic sites. Axonal and global mitophagy of damaged mitochondria is impaired, suggesting that decreased turnover may act upstream of impaired mitochondrial metabolism. Importantly, blocking mTORC1 or inducing mTOR-independent autophagy restores mitochondrial homeostasis. Our study clarifies the complex relationship between the TSC-mTORC1 pathway, autophagy, and mitophagy, and defines mitochondrial homeostasis as a therapeutic target for TSC and related diseases.
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•Mitochondria, some of which are dysfunctional, accumulate in Tsc2-deficient neurons•Axonal mitochondria, including those captured at presynaptic sites, are depleted•Spatiotemporal dynamics of axonal mitophagy and global mitophagic flux are impaired•Enhancing mTOR-dependent and -independent autophagy restores mitochondrial turnover
Ebrahimi-Fakhari et al. show that mitochondrial dynamics and mitophagy are impaired in neuronal models of tuberous sclerosis complex. Axonal transport, turnover, and presynaptic capturing of mitochondria are compromised. Enhancing autophagic flux through mTORC1-dependent and -independent mechanisms restores mitochondrial homeostasis.
Aim of this study was to analyze the root canal configuration in mandibular central and lateral incisors in vivo using cone-beam computed tomography (CBCT) imaging.
A total of 487 mandibular central ...incisors and 491 mandibular lateral incisors from 250 patients were examined using CBCT imaging, previously taken for diagnosis and treatment. The number of roots, root canal system configuration, presence of apical confluences, distance between confluences and radiographic root end, symmetry between left and right elements were recorded and statistically analyzed.
All the examined teeth presented only one root. No significant differences were found between the prevalence of two root canals in mandibular central incisors (219 teeth, 45%) compared to lateral incisors (211 teeth, 43%).
The percentage of Vertucci type II configuration was higher than expected, being more frequent than type III. Type I was the prevalent, while other configurations were present but rare.
Cone-beam computed tomography, mandibular incisors, root canal anatomy, confluences.
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