Metalloproteinase-dependent TLR2 ectodomain shedding is involved in soluble toll-like receptor 2 (sTLR2) production

Toll-like receptor (TLR) 2, a type I membrane receptor that plays a key role in innate immunity, recognizes conserved molecules in pathogens, and triggering an inflammatory response. It has been associated with inflammatory and autoimmune diseases. Soluble TLR2 (sTLR2) variants have been identified in human body fluids, and the TLR2 ectodomain can negatively regulate TLR2 activation by behaving as a decoy receptor. sTLR2 generation does not involve alternative splicing mechanisms, indicating that this process might involve a post-translational modification of the full-length receptor; however, the specific mechanism has not been studied. Using CD14+ peripheral human monocytes and the THP-1 monocytic leukemia-derived cell line, we confirm that sTLR2 generation increases upon treatment with pro-inflammatory agents and requires a post-translational mechanism. We also find that the constitutive and ligand-induced release of sTLR2 is sensitive to pharmacological metalloproteinase activator and inhibitors leading us to conclude that metalloproteinase TLR2 shedding contributes to soluble receptor production. By expressing human TLR2 in ADAM10- or ADAM17-deficient MEF cells, we find both enzymes to be implicated in TLR2 ectodomain shedding. Moreover, using a deletion mutant of the TLR2 juxtamembrane region, we demonstrate that this domain is required for sTLR2 generation. Functional analysis suggests that sTLR2 generated by metalloproteinase activation inhibitsTLR2-induced cytokine production by this monocytic leukemia-derived cell line. The identification of the mechanisms involved in regulating the availability of soluble TLR2 ectodomain and cell surface receptors may contribute further research on TLR2-mediated processes in innate immunity and inflammatory disorders

Patterns of healthy lifestyle behaviours in older adults: findings from the Chilean National Health Survey 2009–2010

The purpose of this study was to investigate healthy lifestyle behaviours across age categories in the older population in Chile. Data from 1390 older adults (≥60 years), in the 2009–2010 Chilean National Health Survey were analyzed. We derived the following age categories: 60–65, 66–70, 71–75, 76–80 and >80 years. The association between age and compliance with healthy lifestyle behaviours (smoking, sitting time, physical activity, sleep duration and intake of salt, alcohol, fruit and vegetables) were investigated using logistic regression. The probability of meeting the guidelines for alcohol intake (OR trend: 1.35 [95% CI: 1.11; 1.64], p = 0.001) and smoking (OR trend: 1.23 [95% CI: 1.13; 1.33], p < 0.0001) increased with age, whereas spending <4 h per day sitting time or engaging in at least 150 min of physical activity per week or sleep on average between 7 and 9 h per day were less likely to be met with increasing age (OR trend: 0.77 [95% CI: 0.71; 0.83], p < 0.000; OR trend: 0.73 [95% CI: 0.67; 0.79], p < 0.0001, and OR trend: 0.89 [95% CI: 0.82; 0.96], p = 0.002, respectively). No significant trend across age categories was observed for fruit and vegetables, and salt intake. The probability of meeting at least 3 out of 7 healthy lifestyle behaviours across the age categories was also lower in older age categories compared to those aged 60 to 65 years. Overall, in older adults the probability of having the healthy lifestyle behaviours of physical activity, sitting time and sleeping behaviours was low but not for smoking or alcohol consumption. With an increasingly ageing population, these findings could inform stakeholders on which lifestyle behaviours could be targeted in the older adults and therefore which interventions should take place to promote healthy ageing

Regulation of the Intestinal Extra-Adrenal Steroidogenic Pathway Component LRH-1 by Glucocorticoids in Ulcerative Colitis

Ulcerative colitis (UC) is an inflammatory bowel disease (IBD) and can be treated with glucocorticoids (GC), although some patients are unresponsive to this therapy. The transcription factor LRH-1/NR5A2 is critical to intestinal cortisol production (intestinal steroidogenesis), being reduced in UC patients. However, the relationship between LRH-1 expression and distribution with altered corticosteroid responses is unknown. To address this, we categorized UC patients by their steroid response. Here, we found that steroid-dependent and refractory patients presented reduced glucocorticoid receptor (GR)-mediated intestinal steroidogenesis compared to healthy individuals and responder patients, possibly related to increased colonic mucosa GR isoform beta (GR beta) content and cytoplasmic LRH-1 levels in epithelial and lamina propria cells. Interestingly, an intestinal epithelium-specific GR-induced knockout (GR(iKO)) dextran sodium sulfate (DSS)-colitis mice model presented decreased epithelial LRH-1 expression, whilst it increased in the lamina propria compared to DSS-treated control mice. Mechanistically, GR directly induced NR5A2 gene expression in CCD841CoN cells and human colonic organoids. Furthermore, GR bound to two glucocorticoid-response elements within the NR5A2 promoter in dexamethasone-stimulated CCD841CoN cells. We conclude that GR contributes to intestinal steroidogenesis by inducing LRH-1 in epithelial cells, suggesting LRH-1 as a potential marker for glucocorticoid-impaired response in UC. However, further studies with a larger patient cohort will be necessary to confirm role of LRH-1 as a therapeutic biomarker

Thallium isotopes in early diagenetic pyrite – a paleoredox proxy?

Author Posting. © The Author(s), 2011. This is the author's version of the work. It is posted here by permission of Elsevier B.V. for personal use, not for redistribution. The definitive version was published in Geochimica et Cosmochimica Acta 75 (2011): 6690-6704, doi:10.1016/j.gca.2011.07.047.This paper presents the first study of Tl isotopes in early diagenetic pyrite. Measurements from two sections deposited during the Toarcian Ocean Anoxic Event (T-OAE, ~183Ma) are compared with data from Late Neogene (<10Ma) pyrite samples from ODP legs 165 and 167 that were deposited in relatively oxic marine environments. The Tl isotope compositions of Late Neogene pyrites are all significantly heavier than seawater, which most likely indicates that Tl in diagenetic pyrite is partially sourced from ferromanganese oxy-hydroxides that are known to display relatively heavy Tl isotope signatures. One of the T-OAE sections from Peniche in Portugal displays pyrite thallium isotope compositions indistinguishable from Late Neogene samples, whereas samples from Yorkshire in the UK are depleted in the heavy isotope of Tl. These lighter compositions are best explained by the lack of ferromanganese precipitation at the sediment–water interface due the sulphidic (euxinic) conditions thought to be prevalent in the Cleveland Basin where the Yorkshire section was deposited. The heavier signatures in the Peniche samples appear to result from an oxic water column that enabled precipitation of ferromanganese oxy-hydroxides at the sediment–water interface. The Tl isotope profile from Yorkshire is also compared with previously published molybdenum isotope ratios determined on the same sedimentary succession. There is a suggestion of an anti-correlation between these two isotope systems, which is consistent with the expected isotope shifts that occur in seawater when marine oxic (ferromanganese minerals) fluxes fluctuate. The results outlined here represent the first evidence that Tl isotopes in early diagenetic pyrite have potential to reveal variations in past ocean oxygenation on a local scale and potentially also for global oceans. However, much more information about Tl isotopes in different marine environments, especially in anoxic/euxinic basins, is needed before Tl isotopes can be confidently utilized as a paleo-redox tracer.SGN is funded by a NERC fellowship

Effects of different doses of high-speed resistance training on physical performance and quality of life in older women: a randomized controlled trial.

Objective: This study aimed to compare the effects of two frequencies of high-speed resistance training (HSRT) on physical performance and quality of life of older women. Methods: A total of 24 older women participated in a 12-week HSRT program composed of either two or three sessions/week (equated for volume and intensity). Women were randomized into three arms: a control group (CG, n=8), a resistance training group performing two sessions/week (RT2, n=8), and a resistance training group performing three sessions/week (RT3, n=8). The training program for both experimental groups included exercises that required high-speed concentric muscle actions. Results: No baseline differences were observed among groups. Compared with the CG, both training groups showed similar small to moderate improvements (P<0.05) in muscle strength, power, functional performance, balance, and quality of life. Conclusion: These results suggest that equated for volume and intensity, two and three training sessions/week of HSRT are equally effective for improving physical performance and quality of life of older women

Association of leisure time and occupational physical activity with obesity and cardiovascular risk factors in Chile

The aim of this study was to investigate the association between physical activity (PA), both occupational (OPA) and during leisure time (LTPA), with obesity and cardiovascular risk factors in Chilean adults. 5,157 participants from the Chilean National Health Survey 2009–2010 were included in this study. OPA and LTPA levels were assessed using the Global Physical Activity Questionnaire. The association between both PA with obesity and cardiovascular risk factors was determined using logistic regression. Our findings showed a significant trend between higher LTPA and lower odds for obesity (OR 0.64 [95% CI: 0.53; 0.76], central obesity 0.52 [0.44; 0.61]) and other cardiovascular risk factors including diabetes (OR: 0.72 [0.55; 0.94]), hypertension (OR: 0.59 [0.50; 0.71]) and metabolic syndrome (OR: 0.62 [0.50; 0.78]). In contrast, OPA was only associated with lower odds of diabetes (OR: 0.79 [0.65; 0.98]) and hypertension (0.85 [0.74; 0.98]). In conclusion, LTPA was associated with a lower risk of all major cardiovascular risk factors, whereas OPA was only associated with a lower risk of diabetes and hypertension

Conservation planning in a fire-prone Mediterranean region: threats and opportunities for bird species

In response to the processes threatening biodiversity such as habitat loss, effective selection of priority conservation areas is required. However, reserve selection methods usually ignore the drivers of future habitat changes, thus compromising the effectiveness of conservation. In this work, we formulated an approach to explicitly quantify the impact of fire on conservation areas, considering such disturbance as a driver of land-cover changes. The estimated fire impact was integrated as a constraint in the reserve selection process to tackle the likely threats or opportunities that fire disturbance might cause to the targeted species depending on their habitat requirements. In this way, we selected conservation areas in a fire-prone Mediterranean region for two bird assemblages: forest and open-habitat species. Differences in conservation areas selected before and after integrating the impact of fire in the reserve selection process were assessed. Integration of fire impact for forest species moved preferences towards areas that were less prone to burn. However, a larger area was required to achieve the same conservation goals. Conversely, integration of fire impacts for open-habitat species shifted preferences towards conservation areas in locations where the persistence of their required habitat is more likely (i.e. shrublands). In other words, we prioritized the conservation of not only the current distribution of open-habitat birds, but also the disturbance process (i.e. fire) that favours their preferred habitat and distributions in the long term. Finally, this work emphasizes the need to consider the opposing potential impacts of wildfires on species for an effective conservation planning

Resistance of Asian Cryptococcus neoformans Serotype A Is Confined to Few Microsatellite Genotypes

Contains fulltext : 109375.pdf (publisher's version ) (Open Access)BACKGROUND: Cryptococcus neoformans is a pathogenic yeast that causes cryptococcosis, a life threatening disease. The prevalence of cryptococcosis in Asia has been rising after the onset of the AIDS epidemic and estimates indicate more than 120 cases per 1,000 HIV-infected individuals per year. Almost all cryptococcal disease cases in both immunocompromised and immunocompetent patients in Asia are caused by C. neoformans var. grubii. Epidemiological studies on C. neoformans in pan-Asia have not been reported. The present work studies the genetic diversity of the fungus by microsatellite typing and susceptibility analysis of approximately 500 isolates from seven Asian countries. METHODOLOGY/PRINCIPAL FINDINGS: Genetic diversity of Asian isolates of C. neoformans was determined using microsatellite analysis with nine microsatellite markers. The analysis revealed eight microsatellite complexes (MCs) which showed different distributions among geographically defined populations. A correlation between MCs and HIV-status was observed. Microsatellite complex 2 was mainly associated with isolates from HIV-negative patients, whereas MC8 was associated with those from HIV-positive patients. Most isolates were susceptible to amphotericin B, itraconazole, voriconazole, posaconazole, and isavuconazole, but 17 (3.4%) and 10 (2%) were found to be resistant to 5-flucytosine and fluconazole, respectively. Importantly, five Indonesian isolates (approximately 12.5% from all Indonesian isolates investigated and 1% from the total studied isolates) were resistant to both antifungals. The majority of 5-flucytosine resistant isolates belonged to MC17. CONCLUSIONS: The findings showed a different distribution of genotypes of C. neoformans var. grubii isolates from various countries in Asia, as well as a correlation of the microsatellite genotypes with the original source of the strains and resistance to 5-flucytosine

COVID-19 outbreaks in a transmission control scenario: challenges posed by social and leisure activities, and for workers in vulnerable conditions, Spain, early summer 2020

Severe acute respiratory syndrome coronavirus 2 community-wide transmission declined in Spain by early May 2020, being replaced by outbreaks and sporadic cases. From mid-June to 2 August, excluding single household outbreaks, 673 outbreaks were notified nationally, 551 active (>6,200 cases) at the time. More than half of these outbreaks and cases coincided with: (i) social (family/friends’ gatherings or leisure venues) and (ii) occupational (mainly involving workers in vulnerable conditions) settings. Control measures were accordingly applied

Diversity of Cl− Channels

Cl− channels are widely found anion pores that are regulated by a variety of signals and that play various roles. On the basis of molecular biologic findings, ligand-gated Cl− channels in synapses, cystic fibrosis transmembrane conductors (CFTRs) and ClC channel types have been established, followed by bestrophin and possibly by tweety, which encode Ca2+-activated Cl− channels. The ClC family has been shown to possess a variety of functions, including stabilization of membrane potential, excitation, cellvolume regulation, fluid transport, protein degradation in endosomal vesicles and possibly cell growth. The molecular structure of Cl− channel types varies from 1 to 12 transmembrane segments. By means of computer-based prediction, functional Cl− channels have been synthesized artificially, revealing that many possible ion pores are hidden in channel, transporter or unidentified hydrophobic membrane proteins. Thus, novel Cl−-conducting pores may be occasionally discovered, and evidence from molecular biologic studies will clarify their physiologic and pathophysiologic roles