Biological Activity of CXCL8 Forms Generated by Alternative Cleavage of the Signal Peptide or by Aminopeptidase-Mediated Truncation

Posttranslational modification of chemokines is one of the mechanisms that regulate leukocyte migration during inflammation. Multiple natural NH(2)-terminally truncated forms of the major human neutrophil attractant interleukin-8 or CXCL8 have been identified. Although differential activity was reported for some CXCL8 forms, no biological data are available for others.status: publishe

Effect of Operating and Sampling Conditions on the Exhaust Gas Composition of Small-Scale Power Generators

Small stationary diesel engines, like in generator sets, have limited emission control measures and are therefore responsible for 44% of the particulate matter (PM) emissions in the United States. The diesel exhaust composition depends on operating conditions of the combustion engine. Furthermore, the measurements are influenced by the used sampling method. This study examines the effect of engine loading and exhaust gas dilution on the composition of small-scale power generators. These generators are used in different operating conditions than road-transport vehicles, resulting in different emission characteristics. Experimental data were obtained for gaseous volatile organic compounds (VOC) and PM mass concentration, elemental composition and nitrate content. The exhaust composition depends on load condition because of its effect on fuel consumption, engine wear and combustion temperature. Higher load conditions result in lower PM concentration and sharper edged particles with larger aerodynamic diameters. A positive correlation with load condition was found for K, Ca, Sr, Mn, Cu, Zn and Pb adsorbed on PM, elements that originate from lubricating oil or engine corrosion. The nitrate concentration decreases at higher load conditions, due to enhanced nitrate dissociation to gaseous NO at higher engine temperatures. Dilution on the other hand decreases PM and nitrate concentration and increases gaseous VOC and adsorbed metal content. In conclusion, these data show that operating and sampling conditions have a major effect on the exhaust gas composition of small-scale diesel generators. Therefore, care must be taken when designing new experiments or comparing literature results

Compound A, a Dissociated Glucocorticoid Receptor Modulator, Inhibits T-bet (Th1) and Induces GATA-3 (Th2) Activity in Immune Cells

Background: Compound A (CpdA) is a dissociating non-steroidal glucocorticoid receptor (GR) ligand which has antiinflammatory properties exerted by down-modulating proinflammatory gene expression. By favouring GR monomer formation, CpdA does not enhance glucocorticoid (GC) response element-driven gene expression, resulting in a reduced side effect profile as compared to GCs. Considering the importance of Th1/Th2 balance in the final outcome of immune and inflammatory responses, we analyzed how selective GR modulation differentially regulates the activity of T-bet and GATA-3, master drivers of Th1 and Th2 differentiation, respectively. Results: Using Western analysis and reporter gene assays, we show in murine T cells that, similar to GCs, CpdA inhibits T-bet activity via a transrepressive mechanism. Different from GCs, CpdA induces GATA-3 activity by p38 MAPK-induction of GATA-3 phosphorylation and nuclear translocation. CpdA effects are reversed by the GR antagonist RU38486, proving the involvement of GR in these actions. ELISA assays demonstrate that modulation of T-bet and GATA-3 impacts on cytokine production shown by a decrease in IFN-c and an increase in IL-5 production, respectively. Conclusions: Taken together, through their effect favoring Th2 over Th1 responses, particular dissociated GR ligands, fo

Cost-effectiveness of nurse-led self-help for recurrent depression in the primary care setting: design of a pragmatic randomized trial

<p>Abstract</p> <p>Background</p> <p>Major Depressive Disorder is a leading cause of disability, tends to run a recurrent course and is associated with substantial economic costs due to increased healthcare utilization and productivity losses. Interventions aimed at the prevention of recurrences may reduce patients' suffering and costs. Besides antidepressants, several psychological treatments such as preventive cognitive therapy (PCT) are effective in the prevention of recurrences of depression. Yet, many patients find long-term use of antidepressants unattractive, do not want to engage in therapy sessions and in the primary care setting psychologists are often not available. Therefore, it is important to study whether PCT can be used in a nurse-led self-help format in primary care. This study sets out to test the hypothesis that usual care plus nurse-led self-help for recurrent depression in primary care is feasible, acceptable and cost-effective compared to usual care only.</p> <p>Design</p> <p>Patients are randomly assigned to ‘nurse-led self-help treatment plus usual care’ (134 participants) or ‘usual care’ (134 participants). Randomisation is stratified according to the number of previous episodes (2 or 3 previous episodes versus 4 or more). The primary clinical outcome is the cumulative recurrence rate of depression meeting DSM-IV criteria as assessed by the Structured-Clinical-Interview-for-DSM-IV- disorders at one year after completion of the intervention. Secondary clinical outcomes are quality of life, severity of depressive symptoms, co-morbid psychopathology and self-efficacy. As putative effect-moderators, demographic characteristics, number of previous episodes, type of treatment during previous episodes, age of onset, self-efficacy and symptoms of pain and fatigue are assessed. Cumulative recurrence rate ratios are obtained under a Poisson regression model. Number-needed-to-be-treated is calculated as the inverse of the risk-difference. The economic evaluation is conducted from a societal perspective, both as a cost-effectiveness analysis (costs per depression free survival year) and as a cost-utility analysis (costs per quality adjusted life-year).</p> <p>Discussion</p> <p>The purpose of this paper is to outline the rationale and design of a nurse-led, cognitive therapy based self-help aimed at preventing recurrence of depression in a primary care setting. Only few studies have focused on psychological self-help interventions aimed at the prevention of recurrences in primary care patients.</p> <p>Trial registration</p> <p>NTR3001 (<url>http://www.trialregister.nl</url>)</p

Convergent genetic and expression data implicate immunity in Alzheimer's disease

Background Late–onset Alzheimer's disease (AD) is heritable with 20 genes showing genome wide association in the International Genomics of Alzheimer's Project (IGAP). To identify the biology underlying the disease we extended these genetic data in a pathway analysis. Methods The ALIGATOR and GSEA algorithms were used in the IGAP data to identify associated functional pathways and correlated gene expression networks in human brain. Results ALIGATOR identified an excess of curated biological pathways showing enrichment of association. Enriched areas of biology included the immune response (p = 3.27×10-12 after multiple testing correction for pathways), regulation of endocytosis (p = 1.31×10-11), cholesterol transport (p = 2.96 × 10-9) and proteasome-ubiquitin activity (p = 1.34×10-6). Correlated gene expression analysis identified four significant network modules, all related to the immune response (corrected p 0.002 – 0.05). Conclusions The immune response, regulation of endocytosis, cholesterol transport and protein ubiquitination represent prime targets for AD therapeutics

Call for emergency action to restore dietary diversity and protect global food systems in times of COVID-19 and beyond: Results from a cross-sectional study in 38 countries

Background: The COVID-19 pandemic has revealed the fragility of the global food system, sending shockwaves across countries\u27 societies and economy. This has presented formidable challenges to sustaining a healthy and resilient lifestyle. The objective of this study is to examine the food consumption patterns and assess diet diversity indicators, primarily focusing on the food consumption score (FCS), among households in 38 countries both before and during the first wave of the COVID-19 pandemic. Methods: A cross-sectional study with 37 207 participants (mean age: 36.70 ± 14.79, with 77 % women) was conducted in 38 countries through an online survey administered between April and June 2020. The study utilized a pre-tested food frequency questionnaire to explore food consumption patterns both before and during the COVID-19 periods. Additionally, the study computed Food Consumption Score (FCS) as a proxy indicator for assessing the dietary diversity of households. Findings: This quantification of global, regional and national dietary diversity across 38 countries showed an increment in the consumption of all food groups but a drop in the intake of vegetables and in the dietary diversity. The household\u27s food consumption scores indicating dietary diversity varied across regions. It decreased in the Middle East and North Africa (MENA) countries, including Lebanon (p \u3c 0.001) and increased in the Gulf Cooperation Council countries including Bahrain (p = 0.003), Egypt (p \u3c 0.001) and United Arab Emirates (p = 0.013). A decline in the household\u27s dietary diversity was observed in Australia (p \u3c 0.001), in South Africa including Uganda (p \u3c 0.001), in Europe including Belgium (p \u3c 0.001), Denmark (p = 0.002), Finland (p \u3c 0.001) and Netherland (p = 0.027) and in South America including Ecuador (p \u3c 0.001), Brazil (p \u3c 0.001), Mexico (p \u3c 0.0001) and Peru (p \u3c 0.001). Middle and older ages [OR = 1.2; 95 % CI = [1.125–1.426] [OR = 2.5; 95 % CI = [1.951–3.064], being a woman [OR = 1.2; 95 % CI = [1.117–1.367], having a high education (p \u3c 0.001), and showing amelioration in food-related behaviors [OR = 1.4; 95 % CI = [1.292–1.709] were all linked to having a higher dietary diversity. Conclusion: The minor to moderate changes in food consumption patterns observed across the 38 countries within relatively short time frames could become lasting, leading to a significant and prolonged reduction in dietary diversity, as demonstrated by our findings

Common variants at ABCA7, MS4A6A/MS4A4E, EPHA1, CD33 and CD2AP are associated with Alzheimer's disease

We sought to identify new susceptibility loci for Alzheimer's disease through a staged association study (GERAD+) and by testing suggestive loci reported by the Alzheimer's Disease Genetic Consortium (ADGC) in a companion paper. We undertook a combined analysis of four genome-wide association datasets (stage 1) and identified ten newly associated variants with P ≤ 1 × 10−5. We tested these variants for association in an independent sample (stage 2). Three SNPs at two loci replicated and showed evidence for association in a further sample (stage 3). Meta-analyses of all data provided compelling evidence that ABCA7 (rs3764650, meta P = 4.5 × 10−17; including ADGC data, meta P = 5.0 × 10−21) and the MS4A gene cluster (rs610932, meta P = 1.8 × 10−14; including ADGC data, meta P = 1.2 × 10−16) are new Alzheimer's disease susceptibility loci. We also found independent evidence for association for three loci reported by the ADGC, which, when combined, showed genome-wide significance: CD2AP (GERAD+, P = 8.0 × 10−4; including ADGC data, meta P = 8.6 × 10−9), CD33 (GERAD+, P = 2.2 × 10−4; including ADGC data, meta P = 1.6 × 10−9) and EPHA1 (GERAD+, P = 3.4 × 10−4; including ADGC data, meta P = 6.0 × 10−10)

CSF1R inhibitor JNJ-40346527 attenuates microglial proliferation and neurodegeneration in P301S mice.

Neuroinflammation and microglial activation are significant processes in Alzheimer's disease pathology. Recent genome-wide association studies have highlighted multiple immune-related genes in association with Alzheimer's disease, and experimental data have demonstrated microglial proliferation as a significant component of the neuropathology. In this study, we tested the efficacy of the selective CSF1R inhibitor JNJ-40346527 (JNJ-527) in the P301S mouse tauopathy model. We first demonstrated the anti-proliferative effects of JNJ-527 on microglia in the ME7 prion model, and its impact on the inflammatory profile, and provided potential CNS biomarkers for clinical investigation with the compound, including pharmacokinetic/pharmacodynamics and efficacy assessment by TSPO autoradiography and CSF proteomics. Then, we showed for the first time that blockade of microglial proliferation and modification of microglial phenotype leads to an attenuation of tau-induced neurodegeneration and results in functional improvement in P301S mice. Overall, this work strongly supports the potential for inhibition of CSF1R as a target for the treatment of Alzheimer's disease and other tau-mediated neurodegenerative diseases.Funded by a grant from the Wellcome Trust (Grant number: 104025/Z/14/Z), and by the NIHR Oxford Health Biomedical Research Centre

Genome-wide haplotype association study identifies the FRMD4A gene as a risk locus for Alzheimer's disease

Recently, several genome-wide association studies (GWASs) have led to the discovery of nine new loci of genetic susceptibility in Alzheimer's disease (AD). However, the landscape of the AD genetic susceptibility is far away to be complete and in addition to single-SNP (single-nucleotide polymorphism) analyses as performed in conventional GWAS, complementary strategies need to be applied to overcome limitations inherent to this type of approaches. We performed a genome-wide haplotype association (GWHA) study in the EADI1 study (n=2025 AD cases and 5328 controls) by applying a sliding-windows approach. After exclusion of loci already known to be involved in AD (APOE, BIN1 and CR1), 91 regions with suggestive haplotype effects were identified. In a second step, we attempted to replicate the best suggestive haplotype associations in the GERAD1 consortium (2820 AD cases and 6356 controls) and observed that 9 of them showed nominal association. In a third step, we tested relevant haplotype associations in a combined analysis of five additional case-control studies (5093 AD cases and 4061 controls). We consistently replicated the association of a haplotype within FRMD4A on Chr.10p13 in all the data set analyzed (OR: 1.68; 95% CI: (1.43-1.96); P=1.1 × 10 -10). We finally searched for association between SNPs within the FRMD4A locus and Aβ plasma concentrations in three independent non-demented populations (n=2579). We reported that polymorphisms were associated with plasma Aβ42/Aβ40 ratio (best signal, P=5.4 × 10 -7). In conclusion, combining both GWHA study and a conservative three-stage replication approach, we characterised FRMD4A as a new genetic risk factor of AD