Public Health and Air Pollution in Asia (PAPA): A Multicity Study of Short-Term Effects of Air Pollution on Mortality

Background and Objectives: Although the deleterious effects of air pollution from fossil fuel combustion have been demonstrated in many Western nations, fewer studies have been conducted in Asia. The Public Health and Air Pollution in Asia (PAPA) project assessed the effects of short-term exposure to air pollution on daily mortality in Bangkok, Thailand, and in three cities in China: Hong Kong, Shanghai, and Wuhan. Methods: Poisson regression models incorporating natural spline smoothing functions were used to adjust for seasonality and other time-varying covariates that might confound the association between air pollution and mortality. Effect estimates were determined for each city and then for the cities combined using a random effects method. Results: In individual cities, associations were detected between most of the pollutants [nitrogen dioxide, sulfur dioxide, particulate matter ≤ 10 μm in aerodynamic diameter (PM 10), and ozone] and most health outcomes under study (i.e., all natural-cause, cardiovascular, and respiratory mortality). The city-combined effects of the four pollutants tended to be equal or greater than those identified in studies conducted in Western industrial nations. In addition, residents of Asian cities are likely to have higher exposures to air pollution than those in Western industrial nations because they spend more time outdoors and less time in air conditioning. Conclusions: Although the social and environmental conditions may be quite different, it is reasonable apply estimates derived from previous health effect of air pollution studies in the West to Asia.published_or_final_versio

Mapping the visible and invisible topgraphies of place and landscape through sacred mobilities

Different forms of mobility produce specific situated experiences, and consequently orient the subject differently in relation to those places at particular times. Places and landscapes are agential, evoking and provoking emotional-affective and, in some cases spiritual, engagement. In common with spirituality, emotional ties reach across time and place, ultimately they are both carried within and catalysed by meaningful places and embodied experience of landscape. Sacred mobilities are meaningful and meaning-making journeys and practices which have religious or spiritual intent. Sacred mobilities reflect and give meaning to place and landscape attributes, including place attachment. Embodied mobilities intersect with place, wider landscapes and perceived or virtual spiritual realms in varied ways, producing ‘deep maps’ of individual and collective sensory, emotional-affective and spiritual experience in material, embodied psychological and virtual spaces. Participant accounts of guided pilgrimage and prayer walks are used to explore experience of place and landscape

RNAseq Analyses Identify Tumor Necrosis Factor-Mediated Inflammation as a Major Abnormality in ALS Spinal Cord

ALS is a rapidly progressive, devastating neurodegenerative illness of adults that produces disabling weakness and spasticity arising from death of lower and upper motor neurons. No meaningful therapies exist to slow ALS progression, and molecular insights into pathogenesis and progression are sorely needed. In that context, we used high-depth, next generation RNA sequencing (RNAseq, Illumina) to define gene network abnormalities in RNA samples depleted of rRNA and isolated from cervical spinal cord sections of 7 ALS and 8 CTL samples. We aligned \u3e50 million 2X150 bp paired-end sequences/sample to the hg19 human genome and applied three different algorithms (Cuffdiff2, DEseq2, EdgeR) for identification of differentially expressed genes (DEG’s). Ingenuity Pathways Analysis (IPA) and Weighted Gene Co-expression Network Analysis (WGCNA) identified inflammatory processes as significantly elevated in our ALS samples, with tumor necrosis factor (TNF) found to be a major pathway regulator (IPA) and TNFα-induced protein 2 (TNFAIP2) as a major network “hub” gene (WGCNA). Using the oPOSSUM algorithm, we analyzed transcription factors (TF) controlling expression of the nine DEG/hub genes in the ALS samples and identified TF’s involved in inflammation (NFkB, REL, NFkB1) and macrophage function (NR1H2::RXRA heterodimer). Transient expression in human iPSC-derived motor neurons of TNFAIP2 (also a DEG identified by all three algorithms) reduced cell viability and induced caspase 3/7 activation. Using high-density RNAseq, multiple algorithms for DEG identification, and an unsupervised gene co-expression network approach, we identified significant elevation of inflammatory processes in ALS spinal cord with TNF as a major regulatory molecule. Overexpression of the DEG TNFAIP2 in human motor neurons, the population most vulnerable to die in ALS, increased cell death and caspase 3/7 activation. We propose that therapies targeted to reduce inflammatory TNFα signaling may be helpful in ALS patients

Stilbene derivatives promote Ago2-dependent tumour-suppressive microRNA activity

It is well known that natural products are a rich source of compounds for applications in medicine, pharmacy, and biology. However, the exact molecular mechanisms of natural agents in human health have not been clearly defined. Here, we demonstrate for the first time that the polyphenolic phytoalexin resveratrol promotes expression and activity of Argonaute2 (Ago2), a central RNA interference (RNAi) component, which thereby inhibits breast cancer stem-like cell characteristics by increasing the expression of a number of tumour-suppressive miRNAs, including miR-16, -141, -143, and -200c. Most importantly, resveratrol-induced Ago2 resulted in a long-term gene silencing response. We also found that pterostilbene, which is a natural dimethylated resveratrol analogue, is capable of mediating Ago2-dependent anti-cancer activity in a manner mechanistically similar to that of resveratrol. These findings suggest that the dietary intake of natural products contributes to the prevention and treatment of diseases by regulating the RNAi pathway

Predictors of HIV and Syphilis among Men Who Have Sex with Men in a Chinese Metropolitan City: Comparison of Risks among Students and Non-Students

Men who have sex with men (MSM) are at a substantial risk of HIV, given rising HIV prevalence in urban China. Adolescent and adult students often take HIV-related risk as part of sexual exploration. We compared the risks of HIV and syphilis infections and risky sexual behaviors between student and non-student among urban MSM.Respondent driven sampling approach was used to recruit men who were self-identified as MSM in Chongqing Metropolitan City in southwestern China in 2009. Each participant completed a computer-assisted self-interview which collected demographic and behavioral data, and provided blood specimens for HIV and syphilis testing. Multivariable logistic regression analyses identified predictors for HIV and syphilis infections while comparing student and non-student MSM.Among 503 MSM participants, 36.4% were students, of whom 84.2% were in college. The adjusted prevalence of HIV infection was 5.5% (95% confidence interval [CI]: 2.1%-10.2%) in students and 20.9% (95% CI: 13.7%-27.5%) in non-students; the adjusted prevalence of syphilis was 4.4% (95% CI: 0.7%-9.0%) in students and 7.9% (95% CI: 3.6%-12.9%) in non-students (P = 0.12). Two groups had similar risky sexual behaviors such as number of sexual partners and exchanging sex for money. Multivariate analysis showed that students had lower HIV prevalence than non-students (adjusted odds ratio [AOR]: 0.3; 95% CI: 0.1-0.8) adjusting for age, ethnicity and other variables.Student MSM have lower HIV and similar syphilis prevalence compared with non-student MSM. However, due to a shorter duration of sexual experience and high prevalence of at-risk sexual behaviors among student MSM, HIV risk might be quite high in students as in non-students

Rhaponticum acaule (L) DC essential oil: chemical composition, in vitro antioxidant and enzyme inhibition properties

Background: α-glucosidase is a therapeutic target for diabetes mellitus (DM) and α-glucosidase inhibitors play a vital role in the treatments for the disease. Furthermore, xanthine oxidase (XO) is a key enzyme that catalyzes hypoxanthine and xanthine to uric acid which at high levels can lead to hyperuricemia which is an important cause of gout. Pancreatic lipase (PL) secreted into the duodenum plays a key role in the digestion and absorption of fats. For its importance in lipid digestion, PL represents an attractive target for obesity prevention. Methods: The flowers essential oil of Rhaponticum acaule (L) DC (R. acaule) was characterized using gas chromatography-mass spectrometry (GC-MS). The antioxidant activities of R. acaule essential oil (RaEO) were also determined using 2,2’-azinobis-3-ethylbenzothiazoline-6-sulfonic acid (ABTS), reducing power, phosphomolybdenum, and DNA nicking assays. The inhibitory power of RaEO against α-glucosidase, xanthine oxidase and pancreatic lipase was evaluated. Enzyme kinetic studies using Michaelis-Menten and the derived Lineweaver-Burk (LB) plots were performed to understand the possible mechanism of inhibition exercised by the components of this essential oil. Results: The result revealed the presence of 26 compounds (97.4%). The main constituents include germacrene D (49.2%), methyl eugenol (8.3%), (E)-β-ionone (6.2%), β-caryophyllene (5.7%), (E,E)-α-farnesene (4.2%), bicyclogermacrene (4.1%) and (Z)-α-bisabolene (3.7%). The kinetic inhibition study showed that the essential oil demonstrated a strong α-glucosidase inhibiton and it was a mixed inhibitor. On the other hand, our results evidenced that this oil exhibited important xanthine oxidase inhibitory effect, behaving as a non-competitive inhibitor. The essential oil inhibited the turkey pancreatic lipase, with maximum inhibition of 80% achieved at 2 mg/mL. Furthermore, the inhibition of turkey pancreatic lipase by RaEO was an irreversible one. Conclusion: The results revealed that the RaEO is a new promising potential source of antioxidant compounds, endowed with good practical applications for human health. Keywords: α-glucosidase, Antioxidant activity, Chemical composition, Pancreatic lipase inhibition, Rhaponticum acaule essential oil, Xanthine oxidase

Cholesterol-Dependent Anaplasma phagocytophilum Exploits the Low-Density Lipoprotein Uptake Pathway

In eukaryotes, intracellular cholesterol homeostasis and trafficking are tightly regulated. Certain bacteria, such as Anaplasma phagocytophilum, also require cholesterol; it is unknown, however, how this cholesterol-dependent obligatory intracellular bacterium of granulocytes interacts with the host cell cholesterol regulatory pathway to acquire cholesterol. Here, we report that total host cell cholesterol increased >2-fold during A. phagocytophilum infection in a human promyelocytic leukemia cell line. Cellular free cholesterol was enriched in A. phagocytophilum inclusions as detected by filipin staining. We determined that A. phagocytophilum requires cholesterol derived from low-density lipoprotein (LDL), because its replication was significantly inhibited by depleting the growth medium of cholesterol-containing lipoproteins, by blocking LDL uptake with a monoclonal antibody against LDL receptor (LDLR), or by treating the host cells with inhibitors that block LDL-derived cholesterol egress from late endosomes or lysosomes. However, de novo cholesterol biosynthesis is not required, since inhibition of the biosynthesis pathway did not inhibit A. phagocytophilum infection. The uptake of fluorescence-labeled LDL was enhanced in infected cells, and LDLR expression was up-regulated at both the mRNA and protein levels. A. phagocytophilum infection stabilized LDLR mRNA through the 3′ UTR region, but not through activation of the sterol regulatory element binding proteins. Extracellular signal–regulated kinase (ERK) was up-regulated by A. phagocytophilum infection, and inhibition of its upstream kinase, MEK, by a specific inhibitor or siRNA knockdown, reduced A. phagocytophilum infection. Up-regulation of LDLR mRNA by A. phagocytophilum was also inhibited by the MEK inhibitor; however, it was unclear whether ERK activation is required for LDLR mRNA up-regulation by A. phagocytophilum. These data reveal that A. phagocytophilum exploits the host LDL uptake pathway and LDLR mRNA regulatory system to accumulate cholesterol in inclusions to facilitate its replication

Porphyromonas gingivalis suppresses adaptive immunity in periodontitis, atherosclerosis and Alzheimer’s disease

Porphyromonas gingivalis, a keystone pathogen in chronic periodontitis, has been found to associate with remote body organ inflammatory pathologies including atherosclerosis and Alzheimer’s disease (AD). Although P. gingivalis has a plethora of virulence factors, much of its pathogenicity is surprisingly related to the overall immunosuppression of the host. This review focuses on P. gingivalis aiding suppression of the host’s adaptive immune system involving manipulation of cellular immunological responses specifically T- and B-cells in periodontitis and related conditions. In periodontitis this bacterium inhibits the synthesis of IL-2 and increases humoral responses. This reduces inflammatory responses related to T- and B-cell activation, and subsequent IFN-ɤ secretion by a subset of T cells. The T cells further suppresses upregulation of programmed cell death-1 (PD-1)-receptor on CD+-cells and its ligand PD-L1 on CD11b+- subset of T-cells. IL-2 down-regulates immune response-regulated genes, induces a cytokine pattern in which the Th17 lineage is favored thereby modulating the Th17/ T-regulatory cell (Treg) imbalance. The suppression of IFN-ɤ stimulated release of interferon-inducible protein-10 (IP-10) chemokine ligands [ITAC (CXCL11) and Mig (CXCL9)] by P. gingivalis capsular serotypes, triggers distinct T-cell responses, and contributes to local immune evasion by release of its outer membrane vesicles. In atherosclerosis P. gingivalis reduces Tregs and transforming growth factor beta-1 (TGF-1) and causes imbalance in the Th17 lineage of the Treg population. In Alzheimer’s disease P. gingivalis may affect the blood-brain barrier permeability, and inhibit local IFN-ɤ response by preventing entry of immune cells into the brain. The scarcity of adaptive immune cells in Alzheimer’s disease neuropathology implies P. gingivalis infection of the brain likely causes impaired clearance of insoluble amyloid and induces immunosuppression. By the effective manipulation of the armory of adaptive immune suppression through a plethora of virulence factors P. gingivalis may act as a keystone organism in periodontitis and in related systemic diseases and other remote body inflammatory pathologies