Predictors of human PBDE body burdens for a UK cohort

Human exposure to polybrominated diphenyl ethers (PBDEs) was investigated in a cohort of 20 UK adults along with their anthropometric covariates and relevant properties such as room surveys, lifestyle, diet and activity details. Selected PBDE congeners were measured in matched samples of indoor dust (n = 41), vehicles (n = 8), duplicate diet (n = 24), serum (n = 24) and breast milk (n = 6).Combined exposure estimates via dust and diet revealed total PBDE intakes of 104 to 1,440 pg kg−1 bw d−1 for ΣBDEs3–7 and 1,170 to 17,000 pg kg−1 bw d−1 for BDE-209. These adult intakes are well within health reference doses suggested by the European Food Safety Authority (EFSA) and the US EPA. Diet was the primary source of intake of BDE3–7 congeners for the majority of the cohort, with dust the primary source of BDE-209. Primary sources of PBDE exposure vary between countries and regions with differing fire prevention regulations. Estimated infant exposures (ages 1.5–4.5 years) showed that BDE-99 intake for one of the households did not meet EFSA's recommended margin of exposure, a further two households had borderline PBDE exposures for high level dust and diet intake.Males and those having a lower body fat mass had higher serum BDE-153. Higher meat consumption was significantly correlated with higher BDEs3–7 in serum. A reduction in dietary BDEs3–7 would therefore result in the greatest reduction in BDE-99 exposure. Rooms containing PUF sofas or armchairs over 20 years old had more BDEs3–7 in their dust, and rooms with carpets or rugs of that age had higher dust BDE-209. Dusting rooms more frequently resulted in significantly lower concentrations of all major congeners in their dust. Correlation between BDE-209 body burden and dust or diet exposure was limited by its low bioaccessibility. Although vehicle dust contained the highest concentrations of BDEs3–7 and BDE-209, serum BDEs3–7 correlated most strongly with bedroom dust

Nuclear factor κB-inducing kinase activation as a mechanism of pancreatic β cell failure in obesity

The nuclear factor κB (NF-κB) pathway is a master regulator of inflammatory processes and is implicated in insulin resistance and pancreatic β cell dysfunction in the metabolic syndrome. Whereas canonical NF-κB signaling is well studied, there is little information on the divergent noncanonical NF-κB pathway in the context of pancreatic islet dysfunction. Here, we demonstrate that pharmacological activation of the noncanonical NF-κB-inducing kinase (NIK) disrupts glucose homeostasis in zebrafish in vivo. We identify NIK as a critical negative regulator of β cell function, as pharmacological NIK activation results in impaired glucose-stimulated insulin secretion in mouse and human islets. NIK levels are elevated in pancreatic islets isolated from diet-induced obese (DIO) mice, which exhibit increased processing of noncanonical NF-κB components p100 to p52, and accumulation of RelB. TNF and receptor activator of NF-κB ligand (RANKL), two ligands associated with diabetes, induce NIK in islets. Mice with constitutive β cell-intrinsic NIK activation present impaired insulin secretion with DIO. NIK activation triggers the noncanonical NF-κB transcriptional network to induce genes identified in human type 2 diabetes genome-wide association studies linked to β cell failure. These studies reveal that NIK contributes a central mechanism for β cell failure in diet-induced obesity

Deep dive into the chronic toxicity of tyre particle mixtures and their leachates.

This is the final version. Available from Elsevier via the DOI in this record. Data Availability: Data will be made available on request.Particles from the tread of vehicle tyres are a global pollutant, which are emitted into the environment at an approximate rate of 1.4 kg.year-1 for an average passenger-car. In this study, popular tyre brands were used to generate a tyre tread microparticle mixture. The chronic toxicity of both particles and chemical leachates were compared on a planktonic test species (Daphnia magna). Over 21 days of exposure, pristine tyre tread microparticles were more toxic (LC50 60 mg.L-1) than chemical lechates alone (LC50 542 mg.L-1). Microparticles and leachates showed distinct effects on reproduction and morphological development at environmentally relevant concentrations, with dose-dependent uptake of particles visible in the digestive tract. Chemical characterization of leachates revealed a metal predominance of zinc, titanium, and strontium. Of the numerous organic chemicals present, at least 54 were shared across all 5 tyre brands, with many classified to be very toxic. Our results provide a critically needed information on the toxicity of tyre tread particles and the associated chemicals that leach from them to inform future mitigation measures. We conclude that tyre particles are hazardous pollutants of particular concern that are close to or possibly above chronic environmental safety limits in some locations.Natural Environment Research Council (NERC

TNFR1 and TNFR2 regulate the extrinsic apoptotic pathway in myeloma cells by multiple mechanisms

The huge majority of myeloma cell lines express TNFR2 while a substantial subset of them failed to show TNFR1 expression. Stimulation of TNFR1 in the TNFR1-expressing subset of MM cell lines had no or only a very mild effect on cellular viability. Surprisingly, however, TNF stimulation enhanced cell death induction by CD95L and attenuated the apoptotic effect of TRAIL. The contrasting regulation of TRAIL- and CD95L-induced cell death by TNF could be traced back to the concomitant NFκB-mediated upregulation of CD95 and the antiapoptotic FLIP protein. It appeared that CD95 induction, due to its strength, overcompensated a rather moderate upregulation of FLIP so that the net effect of TNF-induced NFκB activation in the context of CD95 signaling is pro-apoptotic. TRAIL-induced cell death, however, was antagonized in response to TNF because in this context only the induction of FLIP is relevant. Stimulation of TNFR2 in myeloma cells leads to TRAF2 depletion. In line with this, we observed cell death induction in TNFR1-TNFR2-costimulated JJN3 cells. Our studies revealed that the TNF-TNF receptor system adjusts the responsiveness of the extrinsic apoptotic pathway in myeloma cells by multiple mechanisms that generate a highly context-dependent net effect on myeloma cell survival

Molecular signatures for CCN1, p21 and p27 in progressive mantle cell lymphoma

Mantle cell lymphoma (MCL) is a comparatively rare non-Hodgkin’s lymphoma characterised by overexpression of cyclin D1.Many patients present with or progress to advanced stage disease within 3 years. MCL is considered an incurable disease withmedian survival between 3 and 4 years. We have investigated the role(s) of CCN1 (CYR61) and cell cycle regulators inprogressive MCL. We have used the human MCL cell lines REC1 G519 > JVM2 cells by RQ-PCR, depicting a decrease in CCN1expression with disease progression. Investigation of CCN1 isoform expression by western blotting showed that whilst expres-sion of full-length CCN1 was barely altered in the cell lines, expression of truncated forms (18–20 and 28–30 kDa) decreasedwith disease progression. We have then demonstrated that cyclin D1 and cyclin dependent kinase inhibitors (p21CIP1and p27KIP1)are also involved in disease progression. Cyclin D1 was highly expressed in REC1 cells (OD: 1.0), reduced to one fifth in G519cells (OD: 0.2) and not detected by western blotting in JVM2 cells. p27KIP1followed a similar profile of expression as cyclin D1.Conversely, p21CIP1was absent in the REC1 cells and showed increasing expression in G519 and JVM2 cells. Subcellularlocalization detected p21CIP1/p27KIP1primarily within the cytoplasm and absent from the nucleus, consistent with altered roles in treatment resistance. Dysregulation of the CCN1 truncated forms are associated with MCL progression. In conjunction withreduced expression of cyclin D1 and increased expression of p21, this molecular signature may depict aggressive disease andtreatment resistance

Entlohnung und Produktionsentwicklung in der Stahlindustrie im Kaiserreich: Untersuchungen an ausgewaehlten rheinisch-westfaelischen Unternehmen

Available from Bibliothek des Instituts fuer Weltwirtschaft, ZBW, Duesternbrook Weg 120, D-24105 Kiel A 185849 / FIZ - Fachinformationszzentrum Karlsruhe / TIB - Technische InformationsbibliothekSIGLEDEGerman