Neuronal response in Alzheimer's and Parkinson's disease: the effect of toxic proteins on intracellular pathways

Accumulation of protein aggregates is the leading cause of cellular dysfunction in neurodegenerative disorders. Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease, Prion disease and motor disorders such as amyotrophic lateral sclerosis, present with a similar pattern of progressive neuronal death, nervous system deterioration and cognitive impairment. The common characteristic is an unusual misfolding of proteins which is believed to cause protein deposition and trigger degenerative signals in the neurons. A similar clinical presentation seen in many neurodegenerative disorders suggests the possibility of shared neuronal responses in different disorders. Despite the difference in core elements of deposits in each neurodegenerative disorder, the cascade of neuronal reactions such as activation of glycogen synthase kinase-3 beta, mitogen-activated protein kinases, cell cycle re-entry and oxidative stress leading to a progressive neurodegeneration are surprisingly similar. This review focuses on protein toxicity in two neurodegenerative diseases, AD and PD. We reviewed the activated mechanisms of neurotoxicity in response to misfolded beta-amyloid and α-synuclein, two major toxic proteins in AD and PD, leading to neuronal apoptosis. The interaction between the proteins in producing an overlapping pathological pattern will be also discussed.Shohreh Majd, John H. Power and Hugh J.M. Grantha

Scaling Symmetries of Scatterers of Classical Zero-Point Radiation

Classical radiation equilibrium (the blackbody problem) is investigated by the use of an analogy. Scaling symmetries are noted for systems of classical charged particles moving in circular orbits in central potentials V(r)=-k/r^n when the particles are held in uniform circular motion against radiative collapse by a circularly polarized incident plane wave. Only in the case of a Coulomb potential n=1 with fixed charge e is there a unique scale-invariant spectrum of radiation versus frequency (analogous to zero-point radiation) obtained from the stable scattering arrangement. These results suggest that non-electromagnetic potentials are not appropriate for discussions of classical radiation equilibrium.Comment: 13 page

Cross-Lingual Classification of Crisis Data

Many citizens nowadays flock to social media during crises to share or acquire the latest information about the event. Due to the sheer volume of data typically circulated during such events, it is necessary to be able to efficiently filter out irrelevant posts, thus focusing attention on the posts that are truly relevant to the crisis. Current methods for classifying the relevance of posts to a crisis or set of crises typically struggle to deal with posts in different languages, and it is not viable during rapidly evolving crisis situations to train new models for each language. In this paper we test statistical and semantic classification approaches on cross-lingual datasets from 30 crisis events, consisting of posts written mainly in English, Spanish, and Italian. We experiment with scenarios where the model is trained on one language and tested on another, and where the data is translated to a single language. We show that the addition of semantic features extracted from external knowledge bases improve accuracy over a purely statistical model

Classifying Crises-Information Relevancy with Semantics

Social media platforms have become key portals for sharing and consuming information during crisis situations. However, humanitarian organisations and affected communities often struggle to sieve through the large volumes of data that are typically shared on such platforms during crises to determine which posts are truly relevant to the crisis, and which are not. Previous work on automatically classifying crisis information was mostly focused on using statistical features. However, such approaches tend to be inappropriate when processing data on a type of crisis that the model was not trained on, such as processing information about a train crash, whereas the classifier was trained on floods, earthquakes, and typhoons. In such cases, the model will need to be retrained, which is costly and time-consuming. In this paper, we explore the impact of semantics in classifying Twitter posts across same, and different, types of crises. We experiment with 26 crisis events, using a hybrid system that combines statistical features with various semantic features extracted from external knowledge bases. We show that adding semantic features has no noticeable benefit over statistical features when classifying same-type crises, whereas it enhances the classifier performance by up to 7.2% when classifying information about a new type of crisis

The impact of tau hyperphosphorylation at Ser(262) on memory and learning after global brain ischaemia in a rat model of reversible cardiac arrest

An increase in phosphorylated tau (p-tau) is associated with Alzheimer's disease (AD), and brain hypoxia. Investigation of the association of residue-specific tau hyperphosphorylation and changes in cognition, leads to greater understanding of its potential role in the pathology of memory impairment. The aims of this study are to investigate the involvement of the main metabolic kinases, Liver Kinase B1 (LKB1) and Adenosine Monophosphate Kinase Protein Kinase (AMPK), in tau phosphorylation-derived memory impairment, and to study the potential contribution of the other tau kinases and phosphatases including Glycogen Synthase Kinase (GSK-3β), Protein kinase A (PKA) and Protein Phosphatase 2A (PP2A). Spatial memory and learning were tested in a rat global brain ischemic model of reversible cardiac arrest (CA). The phosphorylation levels of LKB1, AMPK, GSK-3β, PP2A, PKA and tau-specific phosphorylation were assessed in rats, subjected to ischaemia/reperfusion and in clinically diagnosed AD and normal human brains. LKB1 and AMPK phosphorylation increased 4 weeks after CA as did AMPK related p-tau (Ser262). The animals showed unchanged levels of GSK-3β specific p-tau (Ser202/Thr205), phospho-PP2A (Tyr307), total GSK-3β, PP2A, phospho-cAMP response element-binding protein (CREB) which is an indicator of PKA activity, and no memory deficits. AD brains had hyperphosphorylated tau in all the residues of Ser262, Ser202 and Thr205, with increased phosphorylation of both AMPK (Thr172) and GSK-3β (Ser9), and reduced PP2A levels. Our data suggests a crucial role for a combined activation of tau kinases and phosphatases in adversely affecting memory and that hyperphosphorylation of tau in more than one specific site may be required to create memory deficits.Shohreh Majd, John H.T.Power, Simon A.Koblar, Hugh J.M.Grantha

Early glycogen synthase kinase-3beta and protein phosphatase 2A independent tau dephosphorylation during global brain ischaemia and reperfusion following cardiac arrest and the role of the adenosine monophosphate kinase pathway

Abnormal tau phosphorylation (p-tau) has been shown after hypoxic damage to the brain associated with traumatic brain injury and stroke. As the level of p-tau is controlled by Glycogen Synthase Kinase (GSK)-3β, Protein Phosphatase 2A (PP2A) and Adenosine Monophosphate Kinase (AMPK), different activity levels of these enzymes could be involved in tau phosphorylation following ischaemia. This study assessed the effects of global brain ischaemia/reperfusion on the immediate status of p-tau in a rat model of cardiac arrest (CA) followed by cardiopulmonary resuscitation (CPR). We reported an early dephosphorylation of tau at its AMPK sensitive residues, Ser(396) and Ser(262) after 2 min of ischaemia, which did not recover during the first two hours of reperfusion, while the tau phosphorylation at GSK-3β sensitive but AMPK insensitive residues, Ser(202) /Thr(205) (AT8), as well as the total amount of tau remained unchanged. Our data showed no alteration in the activities of GSK-3β and PP2A during similar episodes of ischaemia of up to 8 min and reperfusion of up to 2 h, and 4 weeks recovery. Dephosphorylation of AMPK followed the same pattern as tau dephosphorylation during ischaemia/reperfusion. Catalase, another AMPK downstream substrate also showed a similar pattern of decline to p-AMPK, in ischaemic/reperfusion groups. This suggests the involvement of AMPK in changing the p-tau levels, indicating that tau dephosphorylation following ischaemia is not dependent on GSK-3β or PP2A activity, but is associated with AMPK dephosphorylation. We propose that a reduction in AMPK activity is a possible early mechanism responsible for tau dephosphorylation.Shohreh Majd, John H. T. Power, Simon A. Koblar and Hugh J. M. Grantha

On the effects of mass and momentum transfer from droplets impacting on steady two-dimensional rimming flow in a horizontal cylinder

Motivated by applications in aero-engines, steady two-dimensional thin-filmflow on the inside of a circular cylinder is studied when the filmsurface is subject to mass and momentum transfer from impacting droplets. Asymptotic analysis is used systematically to identify distinguished limits that incorporate these transfer effects at leading order and to provide a new mathematical model. Applying both analytical and numerical approaches to the model, a set of stable steady, two-dimensional solutions that fit within the rational framework is determined. A number of these solutions feature steep fronts and associated recirculating pools, which are undesirable in an aeroengine since oil may be stripped away from the steep fronts when there is a core flow external to the film, and recirculation may lead to oil degradation. The model, however, provides a means of investigating whether the formation of the steep fronts on the filmsurface and of internal recirculation pools can be delayed, or inhibited altogether, by designing jets to deliver prescribed distributions of oil droplets or by the judicious siting of oil sinks. Moreover, by studying pathlines, oil-residence times can be predicted and systems optimized

Dark Matter Halo Profiles in Scale-Free Cosmologies

We explore the dependence of the central logarithmic slope of dark matter halo density profiles $\alpha$ on the spectral index $n$ of the linear matter power spectrum $P(k)$ using cosmological $N$-body simulations of scale-free models (i.e. $P(k) \propto k^n$). For each of our simulations we identify samples of well resolved haloes in dynamical equilibrium and we analyse their mass profiles. By parameterising the mass profile using a ``generalised'' Navarro, Frenk & White profile in which the central logarithmic slope $\alpha$ is allowed to vary while preserving the $r^{-3}$ asymptotic form at large radii, we obtain preferred central slopes for haloes in each of our models. There is a strong correlation between $\alpha$ and $n$, such that $\alpha$ becomes shallower as $n$ becomes steeper. However, if we normalise our mass profiles by $r_{-2}$, the radius at which the logarithmic slope of the density profile is -2, we find that these differences are no longer present. We conclude that there is no evidence for convergence to a unique central asymptotic slope, at least on the scales that we can resolve.Comment: 9 pages, 4 figures. Accepted for publication in MNRA