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

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

Core drilling on Vernagtferner (Oetztal Alps, Austria) in 1979: Tritium contents

In March 1979, on Vernagtferner (Oetztal Alps, Austria) two cores, I (81 m) and II (45 m), had been drilled the 3H content of which was measured. The cores show clearly the increase of the 3H content in the deposited precipitation due to the nuclear weapon tests which were performed mainly in the time between 1953 and 1962. However, it is difficult to correlate the 3H profiles of core I and II for the layers below 15 m. From the results of core lone can calculate a mean net accumulation rate of 0.7 m water equivalent per year during the time period 1952-1977, the corresponding value of core II being about 0.9 m w. e. per year. The 3H content of former precipitation and of core I is in agreement. Comparing the 3H content of core I with that of a core drilled in 1976 on Vernagtferner one finds general agreement but the concentration peaks do not very well coincide. Traces of up to 10 TV were measured in samples of ice of core I which were taken randomly from depths below. These are supposed to originate from young meltwater penetrating into the glacier

Determination of groundwater movement by means of environmental isotopes: state of the art.

The present state of analytical techniques enables measurements of the heavy isotope content of the water molecules as well as of specific isotopes in solutes like HCO- 3, CO2, Cl-, and noble gases, with high detection sensitivity and low detection limit. Labelling of water with the environmental isotopes mentioned above occurs in the atmosphere and upper soil layers by isotopic fractionation effects during phase transitions or by uptake of cosmic-ray produced or manmade isotopes. -from Author

Environmental isotope studies of an alpine snowpack ( Weissfluhsoch Switzerland).

At the experimental plot of Weissfluhjoch in Switzerland, 2540m a.s.l., tritium, deuterium and oxygen-18 have been used to study exchange processes during the build-up and ablation of the snow cover as well as the hydrological balance. Selected results from the period 1971-79 are presented

Model tests to study groundwater flows using radioisotopes and dye tracers.

This chapter is an observation on the model tests studying the behavior of groundwater flows, in particular near borings, two types of flow models, three-dimensional models and quasi-two-dimensional model, built on a scale of 1:1. Tracer experiments are performed to measure the velocity distribution over the cross section of the models; potential distribution can be followed continuously by pressure measuring points on the bottom and on the walls. Both measurements revealed a constant velocity over the model cross section. Quasi-two-dimensional model on which any section through the aquifer is represented. The model consists of a steel frame supporting Plexiglass panes sandwiching the aquifer. Inflow and outflow, along with control and measurement of the water flowing through, are similar to the three-dimensional models. The tracer solution (dye or radioactive tracer) can be introduced in the aquifer through nozzles to produce flow lines, or injected at any desired point (for instance, in a simulated boring). The chapter discusses the models used in developing single-well tracer methods to determine filtration velocity and the direction of flow in the unpumped aquifier. The models are being employed for exploratory measurements on vertical flows in boreholes whose evaluation and explanation are apt, shedding new light on the hydrological phenomena