Stress acts cumulatively to precipitate Alzheimer’s disease-like tau pathology and cognitive deficits

Stressful life experiences are likely tiological factors in sporadic forms of Alzheimer’s disease (AD). Many AD patients hypersecrete glucocorticoids (GCs), and their GC levels correlate with the rate of cognitive impairment and extent of neuronal atrophy. Severity of cognitive deficits in AD correlates strongly with levels of perphosphorylated forms of the cytoskeletal protein TAU, an essential mediator of the actions of amyloid Beta (ABeta ), another molecule with a key pathogenic role in AD. Our objective was to investigate the sequential interrelationships between these various pathogenic elements, in particular with respect to the mechanisms through which stress might precipitate cognitive decline. We thus examined whether stress, through the mediation of GCs, influences TAU hyperphosphorylation, a critical and early event in the cascade of processes leading to AD pathology. Results from healthy, wild-type, middle-aged rats show that chronic stress and GC induce abnormal hyperphosphorylation of TAU in the hippocampus and prefrontal cortex (PFC), with contemporaneous impairments of hippocampus- and PFC-dependent behaviors. Exogenous GC potentiated the ability of centrally infused ABeta to induce hyperphosphorylation of TAU epitopes associated with AD and cytoplasmic accumulation of TAU, while previous exposure to stress aggravated the biochemical and behavioral effects of GC in ABeta-infused animals. Thus, lifetime stress/GC exposure may have a cumulative impact on the onset and progress of AD pathology, with TAU hyperphosphorylation serving to transduce the negative effects of stress and GC on cognition.Marie Curie Training FellowshipsEU CRESCENDO Consortium contract FP6-018652University College, London.Max Planck Society and European Union (EU) German-Portuguese Luso-Alemas Program and the EU CRESCENDO Consortium (Contract FP6-018652).German-Portuguese Luso-Alemas Progra

NCAM180 Regulates Ric8A Membrane Localization and Potentiates β-Adrenergic Response

Cooperation between receptors allows integrated intracellular signaling leading to appropriate physiological responses. The Neural Cell Adhesion Molecule (NCAM) has three main isoforms of 120, 140 and 180 kDa, with adhesive and signaling properties, but their respective functions remains to be fully identified. Here we show that the human NCAM180 intracellular domain is a novel interactor of the human guanosine exchange factor (GEF) Ric8A using the yeast two hybrid system and immunoprecipitation. Furthermore, NCAM, Ric8A and Gαs form a tripartite complex. Colocalization experiments by confocal microscopy revealed that human NCAM180 specifically induces the recruitment of Ric8A to the membrane. In addition, using an in vitro recombinant system, and in vivo by comparing NCAM knock-out mouse brain to NCAM heterozygous and wild type brains, we show that NCAM expression dose dependently regulates Ric8A redistribution in detergent resistent membrane microdomains (DRM). Previous studies have demonstrated essential roles for Ric8 in Gα protein activity at G protein coupled receptors (GPCR), during neurotransmitter release and for asymmetric cell division. We observed that inhibition of Ric8A by siRNA or its overexpression, decreases or increases respectively, cAMP production following β-adrenergic receptor stimulation. Furthermore, in human HEK293T recombinant cells, NCAM180 potentiates the Gαs coupled β-adrenergic receptor response, in a Ric8A dependent manner, whereas NCAM120 or NCAM140 do not. Finally, in mouse hippocampal neurons expressing endogenously NCAM, NCAM is required for the agonist isoproterenol to induce cAMP production, and this requirement depends on Ric8A. These data illustrate a functional crosstalk between a GPCR and an IgCAM in the nervous system

Divergent Modulation of Neuronal Differentiation by Caspase-2 and -9

Human Ntera2/cl.D1 (NT2) cells treated with retinoic acid (RA) differentiate towards a well characterized neuronal phenotype sharing many features with human fetal neurons. In view of the emerging role of caspases in murine stem cell/neural precursor differentiation, caspases activity was evaluated during RA differentiation. Caspase-2, -3 and -9 activity was transiently and selectively increased in differentiating and non-apoptotic NT2-cells. SiRNA-mediated selective silencing of either caspase-2 (si-Casp2) or -9 (si-Casp9) was implemented in order to dissect the role of distinct caspases. The RA-induced expression of neuronal markers, i.e. neural cell adhesion molecule (NCAM), microtubule associated protein-2 (MAP2) and tyrosine hydroxylase (TH) mRNAs and proteins, was decreased in si-Casp9, but markedly increased in si-Casp2 cells. During RA-induced NT2 differentiation, the class III histone deacetylase Sirt1, a putative caspase substrate implicated in the regulation of the proneural bHLH MASH1 gene expression, was cleaved to a ∼100 kDa fragment. Sirt1 cleavage was markedly reduced in si-Casp9 cells, even though caspase-3 was normally activated, but was not affected (still cleaved) in si-Casp2 cells, despite a marked reduction of caspase-3 activity. The expression of MASH1 mRNA was higher and occurred earlier in si-Casp2 cells, while was reduced at early time points during differentiation in si-Casp9 cells. Thus, caspase-2 and -9 may perform opposite functions during RA-induced NT2 neuronal differentiation. While caspase-9 activation is relevant for proper neuronal differentiation, likely through the fine tuning of Sirt1 function, caspase-2 activation appears to hinder the RA-induced neuronal differentiation of NT2 cells

Immunocytochemical assessment of bone marrow aspirates for monitoring response to chemotherapy in small-cell lung cancer patients

Recent reports have suggested that tumour cell immunodetection in bone marrow of small-cell lung cancer patients is by far more frequent than found cytohistologically and may have clinical relevance. This study evaluates primarily the efficacy of chemotherapy as method of in vivo purging, but also the relationship of marrow involvement with survival. A total of 112 bone marrow aspirates from 30 chemo-naïve patients were stained twice using anti-NCAM antibodies, first at diagnosis and then after chemotherapy (24 patients) or at disease progression (six patients). Marrow contamination was associated with lower survival (P = 0.002), and was also detected in 7/17 patients conventionally staged as having limited disease. At multivariate analysis, marrow involvement was an independent factor of unfavourable prognosis (P = 0.033). The amount of tumour contamination, before and after chemotherapy, remained unchanged also in responders and even in the subset of patients with apparent limited disease. Following chemotherapy, bone marrow became tumour negative only in 25% of initially positive responders and in none of non-responders. Our results indicate that (i) chemotherapy is not effective in purging bone marrow even in chemo-responsive patients and (ii) a subset of patients with limited disease and negative bone marrow aspirates might have a more favourable prognosis. © 1999 Cancer Research Campaig

ALCAM Regulates Motility, Invasiveness, and Adherens Junction Formation in Uveal Melanoma Cells

ALCAM, a member of the immunoglobulin superfamily, has been implicated in numerous developmental events and has been repeatedly identified as a marker for cancer metastasis. Previous studies addressing ALCAM’s role in cancer have, however, yielded conflicting results. Depending on the tumor cell type, ALCAM expression has been reported to be both positively and negatively correlated with cancer progression and metastasis in the literature. To better understand how ALCAM might regulate cancer cell behavior, we utilized a panel of defined uveal melanoma cell lines with high or low ALCAM levels, and directly tested the effects of manipulating these levels on cell motility, invasiveness, and adhesion using multiple assays. ALCAM expression was stably silenced by shRNA knockdown in a high-ALCAM cell line (MUM-2B); the resulting cells displayed reduced motility in gap-closure assays and a reduction in invasiveness as measured by a transwell migration assay. Immunostaining revealed that the silenced cells were defective in the formation of adherens junctions, at which ALCAM colocalizes with N-cadherin and ß-catenin in native cells. Additionally, we stably overexpressed ALCAM in a low-ALCAM cell line (MUM-2C); intriguingly, these cells did not exhibit any increase in motility or invasiveness, indicating that ALCAM is necessary but not sufficient to promote metastasis-associated cell behaviors. In these ALCAM-overexpressing cells, however, recruitment of ß-catenin and N-cadherin to adherens junctions was enhanced. These data confirm a previously suggested role for ALCAM in the regulation of adherens junctions, and also suggest a mechanism by which ALCAM might differentially enhance or decrease invasiveness, depending on the type of cadherin adhesion complexes present in tissues surrounding the primary tumor, and on the cadherin status of the tumor cells themselves

Modellierung solarbetriebener Dampfstrahlkältemaschinen und Untersuchung des dynamischen Betriebsverhaltens

The rising standard of living and the changing situation in the energy sector have led to the development of solar cooling systems in the last years. Previously only "sorptive" cooling systems, which means absorption chillers, adsorption chillers and Desiccative Evaporative Cooling, have been used for solar cooling. These cooling systems are very complicated and there is still a high demand for research and development. Another interesting alternative to the only "sorptive" cooling systems used is a solar driven steam jet ejector, which has a simple construction design and a high coefficient of performance in part load. However, the concept of a solar driven steam jet ejector chiller has only been investigated theoretically or by small test rigs. Up to now there are no demonstration or pilot plants, so that no operational experiences are available. The few existing models for calculation are used to identify parameters for the nominal load and do not describe the operational behaviour. Because of the lack of systems realised and the respective calculation models, the operational behaviour of solar driven steam jet ejector chillers has not been investigated under changing operational conditions yet. This publication first of all gives an overview of the possibilities of solar cooling systems and describes briefly the different techniques. Furthermore, theoretical and practical works concerning solar collectors and steam jet ejectors are presented. Subsequently, a dynamic model of a solar driven steam jet ejector chiller is presented and described. The model is structured into model components, which correspond to the device components. These model components can be combined in different ways to one cooling plant. Consequently, different plant concepts can be modelled and investigated. The validation of the model is done by values taken from literature and measurement data of a small test rig. The validation proves that the model presented simulates the dynamic operational behaviour of a solar driven steam jet ejector chiller. At the end of the work, a concept of a solar driven steam jet ejector chiller for air conditioning is investigated for the location of St. Katrine in Egypt. The concept consists of parabolic trough collectors and a two stage steam jet ejector chiller with a cold capacity of 100 kW. The cooling plant is modelled and its operational behaviour is simulated and discussed. There are three simulations: normal operation of the plant, a start-up of the stand-by mode and a step responds of the plant. The three simulations prove a functional concept of a solar cooling system with a quick dynamic operational behaviour and a high coefficient of performance in part load

Paraffin O/W emulsion for cold storage and distribution applications

"Phase Change Slurry (PCS) is a multifunctional fluid consisting of a Phase Change Material (PCM) as dispersed phase and a carried fluid as continuous phase. PCS can store or transfer amounts of thermal energy by using the latent heat capacity of the used PCM. In this paper, paraffin oil-in-water emulsion has been studied as PCS for comfort cooling applications in the temperature range beween 0-20 °C. The heat transfer capacity and the rheological behaviours of a paraffin emulsion have been investigated in test rigs and the results are presented here.

Experimental study on the performance of a solar driven steam jet ejector chiller

"This study experimentally investigated the performance of a solar driven (by parabolic trough collector) steam jet ejector chiller (SJEC) having a cooling capacity of 1 kW. The experiments show the particular characteristics of a SJEC with the strong influence of the condenser temperature, Tcond, and evaporator temperature, Tevap, on the coefficient of performance (COP). A decrease in the condenser temperature by 12 °C, in case of an evaporator temperature of Tevap = 7 °C the COP was increased by 57%, while for Tevap = 13 °C the COP was increased by 41% and for Tevap = 17 °C the COP was increased by 34.4%, respectively. While at a constant condensation temperature an increase in the evaporator temperature, Tevap, from 7 to 13 °C, leads to increased COP values ranging from 14% to 56.7%, and increases Tevap from 7 to 17 °C, lead to increases in COP values ranging from 53% to 132%, respectively. These results in general indicate that the COP increases with decreasing condenser temperature, which is determined by the source temperature of the cooling medium and it has the limiting factors controlling the operation of the solar steam ejector refrigeration system.