Murine Anti-vaccinia Virus D8 Antibodies Target Different Epitopes and Differ in Their Ability to Block D8 Binding to CS-E

The IMV envelope protein D8 is an adhesion molecule and a major immunodominant antigen of vaccinia virus (VACV). Here we identified the optimal D8 ligand to be chondroitin sulfate E (CS-E). CS-E is characterized by a disaccharide moiety with two sulfated hydroxyl groups at positions 4′ and 6′ of GalNAc. To study the role of antibodies in preventing D8 adhesion to CS-E, we have used a panel of murine monoclonal antibodies, and tested their ability to compete with CS-E for D8 binding. Among four antibody specificity groups, MAbs of one group (group IV) fully abrogated CS-E binding, while MAbs of a second group (group III) displayed widely varying levels of CS-E blocking. Using EM, we identified the binding site for each antibody specificity group on D8. Recombinant D8 forms a hexameric arrangement, mediated by self-association of a small C-terminal domain of D8. We propose a model in which D8 oligomerization on the IMV would allow VACV to adhere to heterogeneous population of CS, including CS-C and potentially CS-A, while overall increasing binding efficiency to CS-E

Targeted mitochondrial therapy using MitoQ shows equivalent renoprotection to angiotensin converting enzyme inhibition but no combined synergy in diabetes.

Mitochondrial dysfunction is a pathological mediator of diabetic kidney disease (DKD). Our objective was to test the mitochondrially targeted agent, MitoQ, alone and in combination with first line therapy for DKD. Intervention therapies (i) vehicle (D); (ii) MitoQ (DMitoQ;0.6 mg/kg/day); (iii) Ramipril (DRam;3 mg/kg/day) or (iv) combination (DCoAd) were administered to male diabetic db/db mice for 12 weeks (n = 11-13/group). Non-diabetic (C) db/m mice were followed concurrently. No therapy altered glycaemic control or body weight. By the study end, both monotherapies improved renal function, decreasing glomerular hyperfiltration and albuminuria. All therapies prevented tubulointerstitial collagen deposition, but glomerular mesangial expansion was unaffected. Renal cortical concentrations of ATP, ADP, AMP, cAMP, creatinine phosphate and ATP:AMP ratio were increased by diabetes and mostly decreased with therapy. A higher creatine phosphate:ATP ratio in diabetic kidney cortices, suggested a decrease in ATP consumption. Diabetes elevated glucose 6-phosphate, fructose 6-phosphate and oxidised (NAD+ and NADP+) and reduced (NADH) nicotinamide dinucleotides, which therapy decreased generally. Diabetes increased mitochondrial oxygen consumption (OCR) at complex II-IV. MitoQ further increased OCR but decreased ATP, suggesting mitochondrial uncoupling as its mechanism of action. MitoQ showed renoprotection equivalent to ramipril but no synergistic benefits of combining these agents were shown

Work, life and time in the new economy: an introduction

International audienc

Assessing the carcinogenic potential of low-dose exposures to chemical mixtures in the environment: the challenge ahead.

Lifestyle factors are responsible for a considerable portion of cancer incidence worldwide, but credible estimates from the World Health Organization and the International Agency for Research on Cancer (IARC) suggest that the fraction of cancers attributable to toxic environmental exposures is between 7% and 19%. To explore the hypothesis that low-dose exposures to mixtures of chemicals in the environment may be combining to contribute to environmental carcinogenesis, we reviewed 11 hallmark phenotypes of cancer, multiple priority target sites for disruption in each area and prototypical chemical disruptors for all targets, this included dose-response characterizations, evidence of low-dose effects and cross-hallmark effects for all targets and chemicals. In total, 85 examples of chemicals were reviewed for actions on key pathways/mechanisms related to carcinogenesis. Only 15% (13/85) were found to have evidence of a dose-response threshold, whereas 59% (50/85) exerted low-dose effects. No dose-response information was found for the remaining 26% (22/85). Our analysis suggests that the cumulative effects of individual (non-carcinogenic) chemicals acting on different pathways, and a variety of related systems, organs, tissues and cells could plausibly conspire to produce carcinogenic synergies. Additional basic research on carcinogenesis and research focused on low-dose effects of chemical mixtures needs to be rigorously pursued before the merits of this hypothesis can be further advanced. However, the structure of the World Health Organization International Programme on Chemical Safety 'Mode of Action' framework should be revisited as it has inherent weaknesses that are not fully aligned with our current understanding of cancer biology

Age-specific risk factor profiles of adenocarcinomas of the esophagus: A pooled analysis from the international BEACON consortium: Age-specific risk factors of esophageal adenocarcinomas

Esophageal (EA) and esophagogastric junction (EGJA) adenocarcinoma have been steadily increasing in frequency in younger people, however the etiology of these cancers is poorly understood. We therefore investigated associations of body- mass index (BMI), cigarette smoking, alcohol consumption, gastroesophageal reflux, and use of non-steroidal anti-inflammatory drugs (NSAIDs) in relation to age-specific risks of EA and EGJA. We pooled individual participant data from eight population-based, case-control studies within the international Barrett’s and Esophageal Adenocarcinoma Consortium (BEACON). The analysis included 1,363 EA patients, 1,472 EGJA patients, and 5,728 control participants. Multivariable logistic regression was used to estimate odds ratios (ORs) and 95% confidence intervals (CIs) for age-specific (<50, 50–59, 60–69, ≥70 years) cancer outcomes, as well as interactions by age. BMI, smoking status and pack-years, recurrent gastroesophageal reflux, and frequency of gastroesophageal reflux were positively associated with EA and EGJA in each age group. Early-onset EA (<50 years) had stronger associations with recurrent gastroesophageal reflux (OR=8.06, 95%CI: 4.52, 14.37; Peffect modification=0.01) and BMI (ORBMI ≥30 vs. <25=4.19, 95%CI: 2.23, 7.87; Peffect modification=0.04), relative to older age groups. In contrast, inverse associations of NSAID use were strongest in the oldest age group (≥70 years), although this apparent difference was not statistically significant. Age-specific associations with EGJA showed similar, but slightly weaker patterns and no statistically significant differences by age were observed. Our study provides evidence that associations between obesity and gastroesophageal reflux are stronger among earlier onset EA cancers

New genetic loci implicated in fasting glucose homeostasis and their impact on type 2 diabetes risk.

Levels of circulating glucose are tightly regulated. To identify new loci influencing glycemic traits, we performed meta-analyses of 21 genome-wide association studies informative for fasting glucose, fasting insulin and indices of beta-cell function (HOMA-B) and insulin resistance (HOMA-IR) in up to 46,186 nondiabetic participants. Follow-up of 25 loci in up to 76,558 additional subjects identified 16 loci associated with fasting glucose and HOMA-B and two loci associated with fasting insulin and HOMA-IR. These include nine loci newly associated with fasting glucose (in or near ADCY5, MADD, ADRA2A, CRY2, FADS1, GLIS3, SLC2A2, PROX1 and C2CD4B) and one influencing fasting insulin and HOMA-IR (near IGF1). We also demonstrated association of ADCY5, PROX1, GCK, GCKR and DGKB-TMEM195 with type 2 diabetes. Within these loci, likely biological candidate genes influence signal transduction, cell proliferation, development, glucose-sensing and circadian regulation. Our results demonstrate that genetic studies of glycemic traits can identify type 2 diabetes risk loci, as well as loci containing gene variants that are associated with a modest elevation in glucose levels but are not associated with overt diabetes

Inverse Association between Dietary Iron Intake and Gastric Cancer: A Pooled Analysis of Case-Control Studies of the Stop Consortium

Background: Inconsistent findings have been reported regarding the relationship between dietary iron intake and the risk of gastric cancer (GC). Methods: We pooled data from 11 case-control studies from the Stomach Cancer Pooling (StoP) Project. Total dietary iron intake was derived from food frequency questionnaires combined with national nutritional tables. We derived the odds ratios (ORs) and 95% confidence intervals (CIs) for quartiles of dietary iron through multivariable unconditional logistic regression models. Secondary analyses stratified by sex, smoking status, caloric intake, anatomical subsite and histological type were performed. Results: Among 4658 cases and 12247 controls, dietary iron intake was inversely associated with GC (per quartile OR 0.88; 95% CI: 0.83-0.93). Results were similar between cardia (OR = 0.85, 95% CI = 0.77-0.94) and non-cardia GC (OR = 0.87, 95% CI = 0.81-0.94), and for diffuse (OR = 0.79, 95% CI = 0.69-0.89) and intestinal type (OR = 0.88, 95% CI = 0.79-0.98). Iron intake exerted an independent effect from that of smoking and salt intake. Additional adjustment by meat and fruit/vegetable intake did not alter the results. Conclusions: Dietary iron is inversely related to GC, with no difference by subsite or histological type. While the results should be interpreted with caution, they provide evidence against a direct effect of iron in gastric carcinogenesis

Nutrient and microbial water quality of the upper Ganga river, India: identification of pollution sources

The Ganga River is facing mounting environmental pressures due to rapidly increasing human population, urbanisation, industrialisation and agricultural intensification, resulting in worsening water quality, ecological status and impacts on human health. A combined inorganic chemical, algal and bacterial survey (using flow cytometry and 16S rRNA gene sequencing) along the upper and middle Ganga (from the Himalayan foothills to Kanpur) was conducted under pre-monsoon conditions. The upper Ganga had total phosphorus (TP) and total dissolved nitrogen concentrations of less than 100 μg l−1 and 1.0 mg l−1, but water quality declined at Kannauj (TP = 420 μg l−1) due to major nutrient pollution inputs from human-impacted tributaries (principally the Ramganga and Kali Rivers). The phosphorus and nitrogen loads in these two tributaries and the Yamuna were dominated by soluble reactive phosphorus and ammonium, with high bacterial loads and large numbers of taxa indicative of pathogen and faecal organisms, strongly suggesting sewage pollution sources. The high nutrient concentrations, low flows, warm water and high solar radiation resulted in major algal blooms in the Kali and Ramganga, which greatly impacted the Ganga. Microbial communities were dominated by members of the Phylum Proteobacteria, Bacteriodetes and Cyanobacteria, with communities showing a clear upstream to downstream transition in community composition. To improve the water quality of the middle Ganga, and decrease ecological and human health risks, future mitigation must reduce urban wastewater inputs in the urbanised tributaries of the Ramganga, Kali and Yamuna Rivers

Genome-wide association and functional studies identify a role for matrix Gla protein in osteoarthritis of the hand

Objective Osteoarthritis (OA) is the most common form of arthritis and the leading cause of disability in the elderly. Of all the joints, genetic predisposition is strongest for OA of the hand; however, only few genetic risk loci for hand OA have been identified. Our aim was to identify novel genes associated with hand OA and examine the underlying mechanism. Methods We performed a genome-wide association study of a quantitative measure of hand OA in 12 784 individuals (discovery: 8743, replication: 4011). Genome-wide significant signals were followed up by analysing gene and allele-specific expression in a RNA sequencing dataset (n=96) of human articular cartilage. Results We found two significantly associated loci in the discovery set: at chr12 (p=3.5 × 10⁻¹⁰) near the matrix Gla protein (MGP) gene and at chr12 (p=6.1×10⁻⁹) near the CCDC91 gene. The DNA variant near the MGP gene was validated in three additional studies, which resulted in a highly significant association between the MGP variant and hand OA (rs4764133, Betameta=0.83, Pmeta=1.8*10⁻¹⁵). This variant is high linkage disequilibrium with a coding variant in MGP, a vitamin K-dependent inhibitor of cartilage calcification. Using RNA sequencing data from human primary cartilage tissue (n=96), we observed that the MGP RNA expression of the hand OA risk allele was significantly lowercompared with the MGP RNA expression of the reference allele (40.7%, p<5*10⁻¹⁶). Conclusions Our results indicate that the association between the MGP variant and increased risk for hand OA is caused by a lower expression of MGP, which may increase the burden of hand OA by decreased inhibition of cartilage calcification

The United Kingdom and British Empire: A Figurational Approach

Drawing upon the work of Norbert Elias and the process [figurational] sociology perspective, this article examines how state formation processes are related to, and, affected by, expanding and declining chains of international interdependence. In contrast to civic and ethnic conceptions, this approach focuses on the emergence of the nation/nation-state as grounded in broader processes of historical and social development. In doing so, state formation processes within the United Kingdom are related to the expansion and decline of the British Empire. That is, by focusing on the functional dynamics that are embedded in collective groups, one is able to consider how the UK’s ‘state’ and ‘imperial’ figurations were interdependently related to changes in both the UK and the former British Empire. Consequently, by locating contemporary UK relations in the historical context of former imperial relationships, nationalism studies can go ‘beyond’ the nation/nation-state in order to include broader processes of imperial expansion and decline. Here, the relationship between empire and nationalism can offer a valuable insight into contemporary political movements, especially within former imperial groups