Full Speed String Test On LM6000PF Gas Turbine Driven Refrigeration Compressors

LectureChevron Australia, as part of the Wheatstone Project, constructed a two train liquefied natural gas (LNG) facility and domestic gas plant at the Ashburton North Strategic Industrial Area, 12 kilometers west of Onslow on the Pilbara coast of Western Australia. A driver selection study was performed based on the ConocoPhillips Optimized Cascade® natural gas liquefaction process. Details of this driver selection study are covered by Shah et al [1]. This driver study evaluated a variety of project-specific parameters and resulted in the selection of a General Electric LM6000 PF aeroderivative gas turbine. The final decision to use the LM6000 engine was based on a detailed technology qualification program. Following the completion of the technology qualification, a detailed risk mitigation plan was developed. The plan was incorporated into the purchase order of the equipment and, subsequently, incorporated into the equipment manufacturer’s Failure Mode Effects Analysis (FMEA) process. The risk mitigation plan highlighted extensive testing requirements during the full-load, full-speed (FLFS) string test. This paper covers the details of the FLFS testing that was performed in the fourth quarter of 2013

Amyloid-β Oligomers Regulate ADAM10 Synaptic Localization Through Aberrant Plasticity Phenomena

A disintegrin and metalloproteinase 10 (ADAM10) is a synaptic enzyme that has been previously shown to limit amyloid-\u3b21-42 (A\u3b21-42) peptide formation in Alzheimer's disease (AD). Furthermore, ADAM10 participates to spine shaping through the cleavage of adhesion molecules and its activity is under the control of synaptic plasticity events. In particular, long-term depression (LTD) promotes ADAM10 synaptic localization triggering its forward trafficking to the synapse, while long-term potentiation elicits ADAM10 internalization. Here, we show that a short-term in vitro exposure to A\u3b21-42 oligomers, at a concentration capable of inducing synaptic depression and spine loss, triggers an increase in ADAM10 synaptic localization in hippocampal neuronal cultures. However, the A\u3b21-42 oligomers-induced synaptic depression does not foster ADAM10 delivery to the synapse, as the physiological LTD, but impairs ADAM10 endocytosis. Moreover, A\u3b21-42 oligomers-induced inhibition of ADAM10 internalization requires neuronal activity and the activation of the NMDA receptors. These data suggest that, at the synaptic level, A\u3b21-42 oligomers trigger an aberrant plasticity mechanism according to which A\u3b21-42 oligomers can downregulate A\u3b2 generation through the modulation of ADAM10 synaptic availability. Moreover, the increased activity of ADAM10 towards its synaptic substrates could also affect the structural plasticity phenomena. Overall, these data shed new lights on the strict and complex relationship existing between synaptic activity and the primary mechanisms of AD pathogenesis

Serum Total Tryptase Level Confirms Itself as a More Reliable Marker of Mast Cells Burden in Mast Cell Leukaemia (Aleukaemic Variant)

Mast cell leukemia (MCL) is a very rare form of systemic mastocytosis (SM) with a short median survival of 6 months. We describe a case of a 65-year-old woman with aleukaemic variant of MCL with a very high serum total tryptase level of 2255 μg/L at diagnosis, which occurred following an episode of hypotensive shock. She fulfilled the diagnostic criteria of SM, with a bone marrow smear infiltration of 50–60% of atypical mast cells (MCs). She tested negative for the KIT D816V mutation, without any sign of organ damage (no B- or C-findings) and only few mediator-related symptoms. She was treated with antihistamine alone and then with imatinib for the appearance of anemia. She maintained stable tryptase level and a very indolent clinical course for twenty-two months; then, she suddenly progressed to acute MCL with a serum tryptase level up to 12960 μg/L. The patient died due to haemorrhagic diathesis twenty-four months after diagnosis. This clinical case maybe represents an example of the chronic form of mast cell leukemia, described as unpredictable disease, in which the serum total tryptase level has confirmed itself as a reliable marker of mast cells burden regardless of the presence of other signs or symptoms

Linking NMDA Receptor Synaptic Retention to Synaptic Plasticity and Cognition

NMDA receptor (NMDAR) subunit composition plays a pivotal role in synaptic plasticity at excitatory synapses. Still, the mechanisms responsible for the synaptic retention of NMDARs following induction of plasticity need to be fully elucidated. Rabphilin3A (Rph3A) is involved in the stabilization of NMDARs at synapses through the formation of a complex with GluN2A and PSD-95. Here we used different protocols to induce synaptic plasticity in the presence or absence of agents modulating Rph3A function. The use of Forskolin/Rolipram/Picrotoxin cocktail to induce chemical LTP led to synaptic accumulation of Rph3A and formation of synaptic GluN2A/Rph3A complex. Notably, Rph3A silencing or use of peptides interfering with the GluN2A/Rph3A complex blocked LTP induction. Moreover, in vivo disruption of GluN2A/Rph3A complex led to a profound alteration of spatial memory. Overall, our results demonstrate a molecular mechanism needed for NMDAR stabilization at synapses after plasticity induction and to trigger downstream signaling events necessary for cognitive behavior

MOLECULAR ASPECTS OF ALZHEIMER'S DISEASE PATHOGENESIS: FROM LOCAL SPINE TRAFFICKING TO LONG DISTANCE SPINE TO NUCLEUS SIGNALLING.'TOWARDS NEW THERAPEUTICS INTERVENTION'

The molecular pathogenesis of Alzheimer\u2019s disease (AD) is still controversial, although genetic and cell biology findings indicate accumulation of A\u3b2, especially in soluble oligomeric conformation, as the driving force of synaptic dysfunction with concomitant activation of complex cascade of molecular events leading to dementia. In the last few years, several studies aimed at understanding how A\u3b2 accumulation and assembly compromise synaptic structure and function of excitatory synapses. In this study, we evaluated how A\u3b2 can affect the local and the long-distance trafficking, since the alteration of these mechanisms could represent a key determinant for synaptic dysfunction. We focused the attention on ADAM10, which activity prevents A\u3b2 production. Notably the regulation of ADAM10 synaptic localization is neuronal activity-dependent, in particular LTP decrease, while LTD foster ADAM10 surface expression. Here we found that A\u3b242 (500nM, 30 min) exposure results in an increase of ADAM10 synaptic availability. In particular, A\u3b242 treatment leads to a decrease in the association between ADAM10 and AP2 complex, suggesting that the augment in ADAM10 synaptic localization is due to a decrease of the endocytosis. Interestingly, this mechanism is completely lost in the context of AD, suggesting that the increase in ADAM10 endocytosis, and thus the reduction of its activity towards APP, could be a synaptic mechanism of AD pathogenesis. In light of this consideration, we developed CPPs able to interfere with ADAM10 clathrin-mediated endocytosis and to restore the unbalance between exo- and endocytosis. This tool can be considered a potential disease-modifying strategy capable of modifying the progression of the disease and rescuing the pathological phenotype. Afterwards we describe a novel synapse-to-nucleus signaling pathway, involving the RNF10 protein, that specifically links activation of synaptic GluN2A-containing NMDARs to nuclear gene expression. In physiological conditions, RNF10 dissociates from the NMDAR complex in an activity-dependent manner and we provide compelling evidence for importin-dependent long-distance transport from synapto-dendritic compartments to the nucleus. These findings suggest that synaptonuclear trafficking of RNF10 is involved in the control of gene expression, which is necessary for synaptic plasticity in hippocampal neurons. Here we demonstrated that A\u3b2 can affect RNF10 long-distance trafficking. In particular, during acute exposure, A\u3b2 induces RNF10 translocation while in a chronic AD pathological context we found a reduction of the translocation, suggesting that RNF10 could be involved in AD pathogenesis

Synaptic dysfunction in Alzheimer's disease : from the role of amyloid β-peptide to the α-secretase ADAM10

Alzheimer's disease (AD) is emerging as the most prevalent and socially disruptive illness of aging populations as more people live long enough to become affected. Although AD is placing a considerable and increasing burden on patients, caregivers and society, it represents the largest unmet medical need in neurology, because it is currently incurable. In the last few years, the amyloid hypothesis, which points to amyloid \u3b2-peptide (A\u3b2) as the initiating factor in AD, had a central role in the development of therapeutic strategies for AD. However, the recent clinical trials targeting A\u3b2 have been disappointing. The need to obtain a comprehensive picture of AD pathogenesis is strong as ever. In this framework, this review focuses on A\u3b2 effects on the synapses and on ADAM10, the enzyme able to prevent A\u3b2 formation, analysing its function in the synapse, its contribution to AD pathology and discussing its potential as pharmacological target

Trafficking in neurons: Searching for new targets for Alzheimer's disease future therapies

Alzheimer's disease (AD) is the most common cause of dementia and no cure is available at the moment. As the disease progresses, patients become increasingly dependent, needing constant supervision and care. Prevention or delay of AD onset is among the most urgent moral, social, economic and scientific imperatives in industrialized countries. A better understanding of the pathogenic mechanisms leading to the disease and the consequent identification of new pharmacological targets are now a need. One of the most prominent molecular events occurring in AD patients' brains is the deposition of a peptide named amyloid-\u3b2 (A\u3b2). A\u3b2 derives from the concerted action of \u3b2-secretase, which mediates the amyloid precursor protein (APP) shedding at A\u3b2 N-terminus, and \u3b3-secretase, responsible for APP C-terminal stub cleavage. The production of A\u3b2 can be prevented by the cleavage of ADAM10 on APP. In regard of AD pathogenesis, it is notable that neurons are the cell type affected in AD and that APP and the secretases are all integral transmembrane proteins, and so they are dynamically sorted in neurons. Therefore, neuronal sorting mechanisms responsible for APP and the secretases colocalization in the same membranous compartment play important roles in the regulation of A\u3b2 production. In light of these considerations, this review provides an overview on the actual knowledge of the trafficking mechanisms involved in the regulation of APP and secretases localization, paying particular attention to the specific neuronal setting

ADAM10 in Synaptic Physiology and Pathology

Generation of amyloid-\u3b2 peptide is at the beginning of a cascade that leads to Alzheimer's disease. Amyloid precursor protein (APP) as well as \u3b2- and \u3b3-secretases are the principal players involved in amyloid-\u3b2 (A\u3b2) production, while \u3b1-secretase cleavage on APP prevents A\u3b2 deposition. A disintegrin and metalloproteinase 10 (ADAM10) has been demonstrated to act as \u3b1-secretase in neurons. Objective: Although localization of ADAM10 in the synaptic membrane is the key for its shedding activity, currently, very little is known about the mechanisms that control the synaptic abundance of ADAM10. Results: Two established forms of long-term activity-dependent plasticity, i.e. long-term potentiation and long-term depression (LTD), differentially regulate the synaptic availability and activity of ADAM10. Long-term potentiation decreases ADAM10 surface levels and activity by promoting its endocytosis. This process is mediated by activity-regulated association of ADAM10 with the clathrin adaptor protein 2 (AP2) complex. Conversely, LTD fosters ADAM10 insertion in the membrane and stimulates its activity. Furthermore, ADAM10 interaction with synapse-associated protein 97 (SAP97) is necessary for LTD-induced ADAM10 trafficking and required for LTD maintenance and LTD-induced spine morphology changes. Conclusions: Regulated interaction of ADAM10 with SAP97 and AP2 discloses a novel physiological mechanism of ADAM10 activity regulation at the synapses. This phenomenon produces a situation whereby synaptically regulated ADAM10 activity is positioned to modulate synaptic functionin