Endoplasmic Reticulum Stress and Lipid Metabolism: Mechanisms and Therapeutic Potential

The endoplasmic reticulum (ER) plays a crucial role in protein folding, assembly, and secretion. Disruption of ER homeostasis may lead to accumulation of misfolded or unfolded proteins in the ER lumen, a condition referred to as ER stress. In response to ER stress, a signal transduction pathway known as the unfolded protein response (UPR) is activated. UPR activation allows the cell to cope with an increased protein-folding demand on the ER. Recent studies have shown that ER stress/UPR activation plays a critical role in lipid metabolism and homeostasis. ER-stress-dependent dysregulation of lipid metabolism may lead to dyslipidemia, insulin resistance, cardiovascular disease, type 2 diabetes, and obesity. In this paper, we examine recent findings illustrating the important role ER stress/UPR signalling pathways play in regulation of lipid metabolism, and how they may lead to dysregulation of lipid homeostasis

A phylogenetic analysis of variation in reproductive mode within an Australian lizard (Saiphos equalis, Scincidae)

Saiphos equalis, a semi-fossorial scincid lizard from south-eastern Australia, is one of only three reptile species world-wide that are known to display geographic variation in reproductive mode. Uniquely, Saiphos equalis includes populations with three reproductive modes: oviparous with long (15-day) incubation periods; oviparous with short (5-day) incubation periods; and viviparous (0-day incubation periods). No Saipho populations show \u27normal\u27 scincid oviparity (\u3e30-day incubation period). We used mitochondrial nucleotide sequences (ND2 and cytochrome b) to reconstruct relationships among populations from throughout the species\u27 distribution in New South Wales, Australia. Under the phylogenetic species concept, phylogenetic analyses are consistent with the oviparous and viviparous populations of S. equalis being conspecific. Phylogenetic analyses suggest that the long incubation period oviparous lineage is the sister group to all other populations; and that the viviparous populations belong to a cluster of weakly supported clades basal to the short-incubation-period oviparous clade. These clades correspond to variation in reproductive mode and geographic location. © 2001 The Linnean Society of London

Kentucky\u27s Perpetual Prisoner Machine: It\u27s about Money

Kentucky is currently facing a severe budget crisis and is seeking ways to lower its prison and community corrections costs. This article focuses on our study of the prison and parole experience of men and women in Kentucky. What we found is a virtual “perpetual incarceration machine” where prisoners are recycled from prison to parole and back to prison. The following discussion includes: Kentucky\u27s prison population continues to grow, parole failure, methods, description of interview samples, interview data, the structure producing parole failure, and Kentucky\u27s perpetual incarceration mechine. Based on our findings, several promising reforms are recommended that if implemented would serve to reduce the prison population and the rate of parole failure

Applying future industrialised processes to construction

Construction has traditionally relied on specifications and 2D drawings to convey material properties, performance details and location information. Advanced 3D solid modelling and digital fabrication methods are growing in construction. Iconic building design is driving the industry towards a new era of the Building Information Model (BIM) where a building is modelled entirely using 3D solid CAD tools containing all the required information for construction. CNC machinery can utilise this information to manufacture components enabling highly bespoke and non-repeating components to be cost competitive. Rapid Manufacturing machines also use this information to build components by selectively adding material rather than the traditional subtractive or formative processes. The BIM drives current machines for the production of models for inspection or to explore assembly issues. Recent developments are scaling up these processes so that whole building components can be built using a mega scale, additive machine. This paper explores some of the issues relating to the design of building components and discusses issues on the implementation of these process

Activation of mesangial cell MAPK in responseto homocysteine

Activation of mesangial cell MAPK in response to homocysteine.BackgroundAlteration in mesangial cell function is central to the progression of glomerular disease in numerous models of chronic renal failure (CRF). Animal models of chronic glomerular disease are characterized by mesangial cell proliferation and elaboration of extracellular matrix protein (ECM), resulting in glomerulosclerosis. Elevated plasma levels of homocysteine (Hcy) are seen in both animal models and humans with CRF, and have been proposed to contribute to the high prevalence of vascular disease in this group. Some of the pathogenetic effects of Hcy are thought to be mediated via the induction of endoplasmic reticulum stress. Thus, Hcy effects on mesangial cells could contribute to the progression of CRF. Previous work has shown Hcy- mediated induction of Erk mitogen-activated protein kinase (MAPK) in vascular smooth muscle cells (VSMCs). Erk induces increases in activator protein-1 (AP-1) transcription factor activity which may augment mesangial cell proliferation and ECM protein production. Consequently, we studied the effect of Hcy on mesangial cell Erk signaling.MethodsMesangial cells were exposed to Hcy after 24 hours of serum starvation and Erk activity assessed. Nuclear translocation of phospho-Erk was visualized by confocal microscopy. AP-1 nuclear protein binding was measured in response to Hcy by mobility shift assay. Hcy-induced mesangial cell calcium flux was measured in Fura-2 loaded cells. Mesangial cell DNA synthesis in response to Hcy was assessed by [3H]-thymidine incorporation and proliferation by Western blotting for proliferating cell nuclear antigen (PCNA). Expression of endoplasmic reticulum stress response genes were determined by Northern and Western analysis.ResultsHcy led to an increase in Erk activity that was maximal at 50 μmol/L and 20 minutes of treatment. Subsequent experiments used this concentration and time point. Erk activity in response to Hcy was insensitive to n-acetylcysteine and catalase, indicating oxidative stress did not play a role. However, Hcy50 μmol/L induced a brief increase in intracellular mesangial cell calcium within 5 minutes, and the calcium ionophores A23187 and ionomycin increased Erk activity while chelation of intracellular calcium with BAPTA-AM abrogated the Erk response to Hcy. Confocal microscopy of activated Erk nuclear translocation mirrored these results as did mesangial cell nuclear protein binding to AP-1 consensus sequences. Hcy- induced increases in thymidine incorporation and PCNA expression at 24 hours were Erk dependent. The expression of endoplasmic reticulum stress response genes was significantly elevated by Hcy in an Erk-dependent manner.ConclusionHcy increases Erk activity in mesangial cells via a calcium-dependent mechanism, resulting in increased AP-1 nuclear protein binding, cell DNA synthesis and proliferation and induction of endoplasmic reticulum stress. These observations suggest potential mechanisms by which Hcy may contribute to progressive glomerular injury

Flortaucipir (tau) PET in LGI1 antibody encephalitis

The contributors to persistent cognitive impairment and hippocampal atrophy in leucine-rich glioma-inactivated 1 antibody encephalitis (LGI1) patients are unknown. We evaluated whether tau neuropathology measured with

Implications of 36Cl exposure ages from Skye, northwest Scotland for the timing of ice stream deglaciation and deglacial ice dynamics

The French national AMS facility ASTER (CEREGE, Aix en Provence) is supported by the INSU/CNRS, the ANR through the "Projets thématiques d’excellence" program for the "Equipements d’excellence" ASTER-CEREGE action, IRD and CEA. The authors would like to thank Shasta Marrero for helpful and informative discussion on the CRONUScalc online calculator. DS was supported by a SAGES studentship and fieldwork by funds from the QRA and BSG.Geochronological constraints on the deglaciation of former marine based ice streams provide information on the rates and modes by which marine based ice sheets have responded to external forcing factors such as climate change. This paper presents new 36Cl cosmic ray exposure dating from boulders located on two moraines (Glen Brittle and Loch Scavaig) in southern Skye, northwest Scotland. Ages from the Glen Brittle moraines constrain deglaciation of a major marine terminating ice stream, the Barra-Donegal Ice Stream that drained the former British-Irish Ice Sheet, depending on choice of production method and scaling model this occurred 19.9 ± 1.5–17.6 ± 1.3 ka ago. We compare this timing of deglaciation to existing geochronological data and changes in a variety of potential forcing factors constrained through proxy records and numerical models to determine what deglaciation age is most consistent with existing evidence. Another small section of moraine, the Scavaig moraine, is traced offshore through multibeam swath-bathymetry and interpreted as delimiting a later stillstand/readvance stage following ice stream deglaciation. Additional cosmic ray exposure dating from the onshore portion of this moraine indicate that it was deposited 16.3 ± 1.3–15.2 ± 0.9 ka ago. When calculated using the most up-to-date scaling scheme this time of deposition is, within uncertainty, the same as the timing of a widely identified readvance, the Wester Ross Readvance, observed elsewhere in northwest Scotland. This extends the area over which this readvance has potentially occurred, reinforcing the view that it was climatically forced.PostprintPeer reviewe

Workshop on Environmental Research Needs in Support of Potential Virginia Offshore Oil and Gas Activities

The MMS, a bureau within the Department of the Interior, sponsored a workshop on the environmental research needs in support of potential Virginia offshore oil and gas activities 3 and 4 December 2008, in Williamsburg, Virginia. The focus of the workshop was to assess the existing scientific knowledgebase along the Virginia Coast and the information gaps that need to 2 be addressed should a lease sale for oil and gas activities be held for the Virginia outer continental shelf. This report summarizes the outcome of the workshop

Marine stratocumulus aerosol-cloud relationships in the MASE-II experiment: Precipitation susceptibility in eastern Pacific marine stratocumulus

Observational data on aerosol-cloud-drizzle relationships in marine stratocumulus are presented from the second Marine Stratus/Stratocumulus Experiment (MASE-II) carried out in July 2007 over the eastern Pacific near Monterey, California. Observations, carried out in regions of essentially uniform meteorology with localized aerosol enhancements due to ship exhaust (“ship tracks”), demonstrate, in accord with those from numerous other field campaigns, that increased cloud drop number concentration Nc and decreased cloud top effective radius r_e are associated with increased subcloud aerosol concentration. Modulation of drizzle by variations in aerosol levels is levels is clearly evident. Variations of cloud base drizzle rate R_(cb) are found to be consistent with the proportionality, R_(cb) / H^3/N_c, where H is cloud depth. Simultaneous aircraft and A-Train satellite observations are used to quantify the precipitation susceptibility of clouds to aerosol perturbations in the eastern Pacific region