The Cytomegalovirus protein pUL37×1 targets mitochondria to mediate neuroprotection

There is substantial evidence that mitochondrial dysfunction plays a significant role in the pathogenesis of Parkinson disease (PD). This contribution probably encompasses defects of oxidative phosphorylation, mitochondrial turnover (mitophagy), mitochondrial derived oxidative stress, and apoptotic signalling. Human cytomegalovirus immediate-early protein pUL37 × 1 induces Bax mitochondrial translocation and inactivation to prevent apoptosis. Over-expressing pUL37 × 1 in neuronal cells protects against staurosporin and 6-hydroxydopamine induced apoptosis and cell death. Protection is not enhanced by bax silencing in pUL37 × 1 over-expressing cells, suggesting a bax-dependent mechanism of action. pUL37 × 1 increases glycolysis and induces mitochondrial hyperpolarization, a bax independent anti-apoptotic action. pUL37 × 1 increases glycolysis through activation of phosphofructokinase by a calcium-dependent pathway. The dual anti-apoptotic mechanism of pUL37 × 1 may be considered a novel neuroprotective strategy in diseases where mitochondrial dysfunction and apoptotic pathways are involved

Meclizine-induced enhanced glycolysis is neuroprotective in Parkinson disease cell models

Meclizine is a well-tolerated drug routinely used as an anti-histamine agent in the management of disequilibrium. Recently, meclizine has been assessed for its neuroprotective properties in ischemic stroke and Huntington disease models. We found that meclizine protected against 6-hydroxydopamine-induced apoptosis and cell death in both SH-SY5Y cells and rat primary cortical cultures. Meclizine increases the level of 6-phosphofructo-2-kinase/fructose-2,6-biphosphatase 3 (PFKFB3), which activates phosphofructokinase, a rate-determining enzyme of glycolysis. This protection is therefore mediated by meclizine's ability to enhance glycolysis and increase mitochondrial hyperpolarization. Meclizine represents an interesting candidate for further investigation to re-purpose for its potential to be neuroprotective in Parkinson disease

Soft-Boosted Self-Constructing Neural Fuzzy Inference Network

© 2013 IEEE. This correspondence paper proposes an improved version of the self-constructing neural fuzzy inference network (SONFIN), called soft-boosted SONFIN (SB-SONFIN). The design softly boosts the learning process of the SONFIN in order to decrease the error rate and enhance the learning speed. The SB-SONFIN boosts the learning power of the SONFIN by taking into account the numbers of fuzzy rules and initial weights which are two important parameters of the SONFIN, SB-SONFIN advances the learning process by: 1) initializing the weights with the width of the fuzzy sets rather than just with random values and 2) improving the parameter learning rates with the number of learned fuzzy rules. The effectiveness of the proposed soft boosting scheme is validated on several real world and benchmark datasets. The experimental results show that the SB-SONFIN possesses the capability to outperform other known methods on various datasets

Neuroprotection in Parkinson's Disease: Controlling Mitochondria-Dependent Apoptosis

Objective: To investigate the neuroprotective approach of controlling mitochondria-dependent apoptosis in Parkinson’s disease cellular models. Background: Parkinson’s disease is a neurodegenerative disease and there is evidence indicating that mitochondria-dependent apoptosis is related to dopaminergic neuron loss. pUL37x1, an immediate early protein expressed during cytomegalovirus infection, modulates mitochondria-dependent apoptosis by inactivating Bcl-2-associated X protein (Bax), and meclizine is believed to increase glycolysis and hyperpolarize mitochondria, which inhibits apoptosis. Methods: The neuroprotective and anti-apoptotic effects of pUL37x1 over-expression and meclizine were investigated in SH-SY5Y, a neuroblastoma cell line and primary rat cortical culture cells. Cell death was induced by either staurosporine or 6-hydroxydopamine and measured by lactate dehydrogenase release and propidium iodide binding assay. Apoptotic markers were measured by the release of cytochrome c and the activation of caspase-3. Mitochondrial membrane potential was measured by Tetramethylrhodamine, methyl ester fluorescence obtained by confocal microscope. Extracellular acidification rate (ECAR), a glycolytic activity parameter and oxygen consumption rate (OCR) were measured by XF analyser. Statistics was performed by either ANOVA with Dunnett’s post-hoc analysis or two-tailed Student’s t-test. Results: Both pUL37x1 over-expression and meclizine significantly protected against toxin-induced cell death in SH-SY5Y and rat primary cortical culture cells. Both approaches also down-regulated apoptosis. In terms of meclizine, the protection resulted from glycolysis-related mitochondrial hyperpolarization. Hyperpolarization and protection would decline following glycolytic inhibition. pUL37x1 over-expression prevented apoptotic cell death by two means: Bax-dependent and glycolysis-dependent mechanisms. First, pUL37x1 over-expression led to Bax mitochondria-translocation, and in contrast to control, Bax silencing did not provide more protection on pUL37x1 over-expressing cells. Second, pUL37x1 over-expression increased cellular glycolysis and hyperpolarized mitochondria, and glycolytic inhibitors attenuated the protection, indicating a glycolysis-dependent protective mechanism. Conclusions: The success of neuroprotection by pUL37x1 and meclizine in Parkinson’s disease cellular models not only confirms the significance of controlling mitochondria-dependent apoptosis, but also indicates two novel approaches to neuroprotection

Effect of atomic ordering on hydrogen dissociation on Ni₃Fe surfaces

2008-2009 > Academic research: refereed > Publication in refereed journalVersion of RecordPublishe

The ReaxFF reactive force-field : development, applications and future directions

The reactive force-field (ReaxFF) interatomic potential is a powerful computational tool for exploring, developing and optimizing material properties. Methods based on the principles of quantum mechanics (QM), while offering valuable theoretical guidance at the electronic level, are often too computationally intense for simulations that consider the full dynamic evolution of a system. Alternatively, empirical interatomic potentials that are based on classical principles require significantly fewer computational resources, which enables simulations to better describe dynamic processes over longer timeframes and on larger scales. Such methods, however, typically require a predefined connectivity between atoms, precluding simulations that involve reactive events. The ReaxFF method was developed to help bridge this gap. Approaching the gap from the classical side, ReaxFF casts the empirical interatomic potential within a bond-order formalism, thus implicitly describing chemical bonding without expensive QM calculations. This article provides an overview of the development, application, and future directions of the ReaxFF method

High glucose up-regulates ENaC and SGK1 expression in HCD-cells

Background/Aim: Diabetic nephropathy is associated with progressive renal damage, leading to impaired function and end-stage renal failure. Secondary hypertension stems from a deranged ability of cells within the kidney to resolve and appropriately regulate sodium resorption in response to hyperglycaemia. However, the mechanisms by which glucose alters sodium re-uptake have not been fully characterised. Methods: Here we present RT-PCR, western blot and immunocytochemistry data confirming mRNA and protein expression of the serum and glucocorticoid inducible kinase (SGK1) and the a conducting subunit of the epithelial sodium channel (ENaC) in a model in vitro system of the human cortical collecting duct (HCD). We examined changes in expression of these elements in response to glucose challenge, designed to mimic hyperglycaemia associated with type 2 diabetes mellitus. Changes in Na+ concentration were assessed using single-cell microfluorimetry. Results: Incubation with glucose, the Ca2+-ionophore ionomycin and the cytokine TGF-beta 1 were all found to evoke significant and time-dependent increases in both SGK1 and alpha ENaC protein expression. These molecular changes were correlated to an increase in Na+-uptake at the single-cell level. Conclusion: Together these data offer a potential explanation for glucose-evoked Na+-resorption and a potential contributory role of SGK1 and ENaCs in development of secondary hypertension, commonly linked to diabetic nephropathy

Effects of sea level rise on salinity and tidal flooding patterns in the Guadiana Estuary

Sea level rise is a worldwide concern as a high percentage of the population accommodates coastal areas. The focus of this study is the impact of sea level rise in the Guadiana Estuary, an estuary in the Iberian Peninsula formed at the interface of the Guadiana River and the Gulf of Cadiz. Estuaries will be impacted by sea level rise as these transitional environments host highly diverse and complex marine ecosystems. The major consequences of sea level rise are the intrusion of salt from the sea into fresh water and an increase in flooding area. As the physical, chemical, and biological components of estuaries are sensitive to changes in salinity, the purpose of this study is to further evaluate salt intrusion in the Guadiana Estuary caused by sea level rise. Hydrodynamics of the Guadiana Estuary were simulated in a two-dimensional numerical model with the MOHID water modeling system. A previously developed hydrodynamic model was implemented to further examine changes in salinity distribution in the estuary in response to sea level rise. Varying tidal amplitudes, freshwater discharge from the Guadiana River and bathymetries of the estuary were incorporated in the model to fully evaluate the impacts of sea level rise on salinity distribution and flooding areas of the estuary. Results show an overall increase in salinity and land inundation in the estuary in response to sea level rise.info:eu-repo/semantics/publishedVersio

Measurement of Tau Filament Fragmentation Provides Insights into Prion-like Spreading.

The ordered assembly of amyloidogenic proteins causes a wide spectrum of common neurodegenerative diseases, including Alzheimer's and Parkinson's diseases. These diseases share common features with prion diseases, in which misfolded proteins can self-replicate and transmit disease across different hosts. Deciphering the molecular mechanisms that underlie the amplification of aggregates is fundamental for understanding how pathological deposits can spread through the brain and drive disease. Here, we used single-molecule microscopy to study the assembly and replication of tau at the single aggregate level. We found that tau aggregates have an intrinsic ability to amplify by filament fragmentation, and determined the doubling times for this replication process by kinetic modeling. We then simulated the spreading time for aggregates through the brain and found this to be in good agreement with both the observed time frame for spreading of pathological tau deposits in Alzheimer's disease and in experimental models of tauopathies. With this work we begin to understand the physical parameters that govern the spreading rates of tau and other amyloids through the human brain

Evaluating three decades of the European Capital of Culture programme: a difference-in-differences approach

We measure the regional impact of the European Capital of Culture programme using a difference-in-differences approach. We compare the regions of cities that hosted the event with the regions of cities that tried to host it but did not succeed. GDP per capita in hosting regions is 4.5 percent higher compared to non-hosting regions during the event and the effect persists more than 5 years after it. This result suggests that the economic dimension of the event is important and supports claims that the event serves as catalyst for urban regeneration and development