Interleukin-1ß activates a short STAT-3 isoform in clonal insulin-secreting cells

Abstract Interleukin-1ß (IL-1ß) is a potent inflammatory cytokine involved in type 1 diabetes and acts through defined IL-1ß signaling pathways. In the present work we describe induction of DNA binding activity to signal transducer and activator of transcription (STAT) in response to IL-1ß in clonal insulin-secreting cells. Moreover, IL-1ß activates a short isoform of STAT-3 that potently stimulates transcription. Immunopre- cipitation studies reveal an interaction between the activated STAT-3 and the IL-1 receptor accessory protein indicating an association between the two signaling pathways. This may be a novel point of transduction cross talk and an additional mechanism utilised by IL-1ß in the pancreatic ß-cell during the process of type 1 diabetes. z 1999 Federation of European Biochemical Societies

Leptin signalling in pancreatic islets and clonal insulin-secreting cells

Leptin is a cytokine secreted from adipose tissue at a rate commensurate with the size of the body's fat stores. In addition to its anorectic and thermogenic central actions, leptin is known to act on peripheral tissues, including the pancreatic ß-cell where it inhibits insulin secretion and reduces insulin transcript levels. However, the role of leptin signalling through its full-length receptor, OB-Rb, in the ß-cell remains unclear. In the present study, we show that leptin activates a signal transducer and activator of transcription (STAT)3 signalling mechanism in pancreatic islets and in a rat model of the pancreatic ß-cell, RINm5F. Leptin induced DNA binding to a STAT consensus oligonucleotide and resulted in transcriptional activation from STAT reporter constructs in a manner consistent with STAT3 activation. Western blot analysis confirmed activation of STAT3 in RINm5F and isolated rat islets. Conditions that mimic increased metabolic activity resulted in attenuation of leptin-mediated STAT DNA binding but had no significant eVect on STAT3 tyrosine phosphorylation in RINm5F cells. In addition, leptin activated the mitogen activated protein (MAP) kinase pathway in RINm5F cells. The present study provides a framework for OB-Rb signalling mechanisms in the programming of the ß-cell by leptin and suggests that increased metabolic activity may modulate this function

Spatiotemporal Model-Based Estimation of High-Density Atrial Fibrillation Activation Map

Examination of activation maps using multi-electrode array (MEA) sensors can help to understand the mechanisms underlying atrial fibrillation (AF). Classically, creation of activation maps starts with detection of local activation times (LAT) based on recorded unipolar electrograms. LAT detection has a limited robustness and accuracy, and generally requires manual edition. In general, LAT detection ignores spatiotemporal information of activation embedded in the relation between electrode signals on the MEA mapping sensor. In this work, a unified approach to construct activation maps by simultaneous analysis of activation patterns from overlapping clusters of MEA electrodes is proposed. An activation model fits on the measured data by iterative optimization of the model parameters based on a cost function. The accuracy of the estimated activation maps was evaluated by comparison with audited maps created by expertelectrophysiologists during sinus rhythm (SR) and AF. During SR recordings, 25 activation maps (3100 LATs) were automatically determined resulting in an average LAT estimation error of -0.66 ±2.00msand a correlation of ¿s=0.98compared to the expert reference. During AF recordings (235 maps, 28226 LATs), the estimation error was -0.83 ±6.02mswith only a slightly lower correlation (¿s=0.93). In conclusion, complex spatial activation patterns can be decomposed into local activation patterns derived from fitting an activation model, allowing the creation of smooth and comprehensive high-density activation maps

Management of invasive thymoma at Groote Schuur Hospital, Cape Town

Fifteen patients (median age 55 years; range 23 - 69 years) with macroscopic invasive thymoma or thymic carcinoma were treated at Groote Schuur Hospital between 1969 and 1988. Stage 3 (macroscopically invasive) disease was present in 12 patients (80%) and stage 4 (metastatic disease) in 3 (20%). Ten of the patients with stage 3 disease were treated by combined surgery and full-dose mediastinal irradiation; in 2 resection was not possible and they were treated with irradiation alone. One of the patients with stage 3 disease developed progressive thymoma (median follow-up 74 months). This patient and 2 others died; 1 from mediastinitis after surgery for thymic carcinoma and 1 of unrelated disease. Both patients treated by irradiation alone were free of disease at follow-up. In the patients with stage 3 disease, the relapse rate was 8% (crude) and the 5-year disease-free survival rate 86% (life table). The patients with stage 4 disease received cisplatin-based combination chemotherapy, which was combined with further irradiation and debulking surgery in 2 of the 3 cases. These patients died of malignant disease at between 5 and 42 months, although 1 had a temporary response to chemotherapy. Tumour extent is the most important prognostic factor in these patients. A multidisciplinary approach to therapy is required

Community-based governance: implications for ecosystem service supply in Berg en Dal, the Netherlands

Governance is an essential element in land-use decision-making and ecosystem management choices and thus for ecosystem service provisioning. Although a community-based approach, i.e. governance involving actors from all spheres of society (the state, market and civil society), is considered most appropriate for natural resource management, there is a lack of knowledge about its actual effects on environmental outcomes and ecosystem service supply in particular. To obtain insight in the effect of governance on ecosystem service provision in our study region (Berg en Dal, the Netherlands), we constructed ecosystem service maps for the period 1995 to 2012 using land-use maps. Also an inventory of the implemented governance models was created, based on interviews with stakeholders, supplemented with literature research. Our results show that 1) governance in Berg en Dal changed from top-down to more community-based models during the studied period; and 2) that the potential and actual supply of the majority of the investigated regulating, cultural and habitat ecosystem services increased during the studied period, at the expense of agricultural production. The interviewed local stakeholders also indicated that they have the perception that the landscape has improved during the last two decades. Although there is a clear connection between governance and improved ecosystem service supply, more research is needed to further develop causal relationships explaining the indirect effects and non-linear behavior within ecosystem service governance systems.FWN – Publicaties zonder aanstelling Universiteit Leide

Isolation and characterization of two specific regulatory Aspergillus niger mutants shows antagonistic regulation of arabinan and xylan metabolism

This paper describes two Aspergillus niger mutants (araA and araB) specifically disturbed in the regulation of the arabinanase system in response to the presence of L-arabinose. Expression of the three known L-arabinose-induced arabinanolytic genes, abfA, abfB and abnA, was substantially decreased or absent in the araA and araB strains compared to the wild-type when incubated in the presence of L-arabinose or L-arabitol. In addition, the intracellular activities Of L-arabitol dehydrogenase and L-arabinose reductase, involved in L-arabinose catabolism, were decreased in the araA and araB strains. Finally, the data show that the gene encoding D-xylulose kinase, xkiA, is also under control of the arabinanolytic regulatory system. L-Arabitol, most likely the true inducer of the arabinanolytic and L-arabinose catabolic genes, accumulated to a high intracellular concentration in the araA and araB mutants. This indicates that the decrease of expression of the arabinanolytic genes was not due to lack of inducer accumulation. Therefore, it is proposed that the araA and araB mutations are localized in positive-acting components of the regulatory system involved in the expression of the arabinanase-encoding genes and the genes encoding the L-arabinose catabolic pathway

Analysis of regulation of pentose utilisation in Aspergillus niger reveals evolutionary adaptations in Eurotiales

Aspergilli are commonly found in soil and on decaying plant material. D-xylose and L-arabinose are highly abundant components of plant biomass. They are released from polysaccharides by fungi using a set of extracellular enzymes and subsequently converted intracellularly through the pentose catabolic pathway (PCP)

Regulation of pentose catabolic pathway genes of Aspergillus niger

The aim of this study was to obtain a better understanding of the pentose catabolism in Aspergillus niger and the regulatory systems that affect it. To this end, we have cloned and characterised the genes encoding A. niger L-arabitol dehydrogenase (ladA) and xylitol dehydrogenase (xdhA), and compared the regulation of these genes to other genes of the pentose catabolic pathway. This demonstrated that activation of the pathway depends on two transcriptional regulators, the xylanolytic activator (XlnR) and an unidentified L-arabinose specific regulator (AraR). These two regulators affect those genes of the pentose catabolic pathway that are related to catabolic conversion of their corresponding inducers (D-xylose and L-arabinose, respectively)