The relation between hemispheric lateralisation and measures of immune competence and adherence in Human Immunodeficiency Virus Type 1 (HIV-1)

This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited - Copyright © 2012 Sumner et al

Upscaling of bottom-generated turbulence in large-scale 3D models for sediment transport in estuaries and coastal zones

Currently used 3D numerical sediment transport models still fail to make good quantitative predictions. To a great extent, this can be attributed to the inadequate description of physical processes which occur at the subgrid scale level. From flume experiments it is known that particle-turbulence interactions near the bed significantly change the effective roughness experienced by the overlying water column. This results in different transport rates if not accounted for.From a theoretical perspective, bed load transport, sheet flow and fluid mud flow are all occurrences of supersaturated suspension flow in the inner near-bed layer comprising the viscous sublayer and the transient layer. Its thickness increases with sediment load, since particle-particle interactions (four-way coupling effects) consume considerable amounts of the available stream power. In order to know how much energy is left over to compute the transport capacity of the outer, fully-developed layer, it is necessary to quantify the energy budget in the inner layer.This is a difficult task. Every modelling approach has its draw-backs and limitations. Lagrangean particle tracking is hopeless, since the required number of particles to approach field conditions is much too high, and the volumes occupied by the particles cannot be neglected. Grain sizes are non-uniform in nature and concentrations near the bed very high, making it very difficult to give an accurate description of the momentum exchange between fluid and solid phase, which accounts for particle collisions. Therefore, in view of large-scale applications, a one-fluid approach is adopted. This implies that the momentum equation is solved for the suspension, together with a turbulence closure model and the sediment mass balance.Since the thickness of the supersaturated inner layer mostly is very small relative to the water depth and the vertical discretization in large scale applications, it is not possible to resolve this layer with a traditional low-Reynolds model approach, which requires a very fine grid. A new approach is proposed, where a modified Prandtl-mixing length (PML) model is used for the bed layer, and a new low-Reynolds model is applied in the outer layers. In this way it is possible to obtain a correct behaviour for tidal oscillating flow in estuaries, where low-Re effects enter high in the water column during slack water.The correction factor for the PML eddy viscosity and the damping functions for the low-Re k-epsilon turbulence model are constructed based on theoretical constraints, DNS and LES generated data, as well as experimental flume data. In parallel, LES and improved two-layer low-Re models are developed to simulate flow over rough bottoms without and with sediment, in order to generate data very close to the bed surface, where no measurements can be made. These additional data are used to help interpret experimental flume data, which always show relatively high experimental errors, and to extend the new damping functions for the cases with bottom roughness and suspended sediment.Preliminary results of the new coarse grid RANS model for open-channel flow with various roughness conditions without and with suspended sediment will be shown, compared to LES results for flow over a wavy bottom, low-Reynolds RANS results over rough bottom and experimental flume data

Prospective Relationship between Hemispheric Lateralisation and CD4+ T Cells in Human Immunodeficiency Virus Type 1

Objectives: Neuromodulation of the immune system has been proposed to be influenced by hemispheric lateralisation (HL). The present study tested whether HL predicted CD4+ levels, statistically controlling for confounders. Methods: Employing two assessments of HL, 68 human immunodeficiency virus (HIV)-1+ patients were followed prospectively. Numerous exclusion criteria and confounder assessments were employed (e.g. age/medication). Results: Left HL significantly positively predicted CD4+ levels at follow-up, and this was qualified by medication (HAART) status: only in HAART-naïve patients did HL predict CD4 levels. Furthermore, HL significantly predicted whether patients had clinically significantly high/low CD4+ counts. Conclusions: Using a more rigorous methodology than a previous study, the present work partly corroborated the theory of HL influences on immunity, extended it to HIV immunity and identified a possible moderator: HAART medication. Implications for future research and treatments are provided

Postsynaptic dysfunction is associated with spatial and object recognition memory loss in a natural model of Alzheimer's disease

Alzheimer’s disease (AD) is an age-related neurodegenerative disorder associated with progressive memory loss, severe dementia, and hallmark neuropathological markers, such as deposition of amyloid-β (Aβ) peptides in senile plaques and accumulation of hyperphosphorylated tau proteins in neurofibrillary tangles. Recent evidence obtained from transgenic mouse models suggests that soluble, nonfibrillar Aβ oligomers may induce synaptic failure early in AD. Despite their undoubted value, these transgenic models rely on genetic manipulations that represent the inherited and familial, but not the most abundant, sporadic form of AD. A nontransgenic animal model that still develops hallmarks of AD would be an important step toward understanding how sporadic AD is initiated. Here we show that starting between 12 and 36 mo of age, the rodent Octodon degus naturally develops neuropathological signs of AD, such as accumulation of Aβ oligomers and phosphorylated tau proteins. Moreover, age-related changes in Aβ oligomers and tau phosphorylation levels are correlated with decreases in spatial and object recognition memory, postsynaptic function, and synaptic plasticity. These findings validate O. degus as a suitable natural model for studying how sporadic AD may be initiated

Genetically-controlled Vesicle-Associated Membrane Protein 1 expression may contribute to Alzheimer’s pathophysiology and susceptibility

Background Alzheimer’s disease is a neurodegenerative disorder in which extracellular deposition of β-amyloid (Aβ) oligomers causes synaptic injury resulting in early memory loss, altered homeostasis, accumulation of hyperphosphorylated tau and cell death. Since proteins in the SNAP (Soluble N-ethylmaleimide-sensitive factor Attachment Protein) REceptors (SNARE) complex are essential for neuronal Aβ release at pre-synaptic terminals, we hypothesized that genetically controlled SNARE expression could alter neuronal Aß release at the synapse and hence play an early role in Alzheimer’s pathophysiology. Results Here we report 5 polymorphisms in Vesicle-Associated Membrane Protein 1 (VAMP1), a gene encoding a member of the SNARE complex, associated with bidirectionally altered cerebellar VAMP1 transcript levels (all p < 0.05). At the functional level, we demonstrated that control of VAMP1 expression by heterogeneous knockdown in mice resulted in up to 74% reduction in neuronal Aβ exocytosis (p < 0.001). We performed a case-control association study of the 5 VAMP1 expression regulating polymorphisms in 4,667 Alzheimer’s disease patients and 6,175 controls to determine their contribution to Alzheimer’s disease risk. We found that polymorphisms associated with increased brain VAMP1 transcript levels conferred higher risk for Alzheimer’s disease than those associated with lower VAMP1 transcript levels (p = 0.03). Moreover, we also report a modest protective association for a common VAMP1 polymorphism with Alzheimer’s disease risk (OR = 0.88, p = 0.03). This polymorphism was associated with decreased VAMP1 transcript levels (p = 0.02) and was functionally active in a dual luciferase reporter gene assay (p < 0.01). Conclusions Genetically regulated VAMP1 expression in the brain may modify both Alzheimer’s disease risk and may contribute to Alzheimer’s pathophysiology

A critical role for the self-assembly of Amyloid-β1-42 in neurodegeneration

Amyloid β1-42 (Aβ1-42) plays a central role in Alzheimer’s disease. The link between structure, assembly and neuronal toxicity of this peptide is of major current interest but still poorly defined. Here, we explored this relationship by rationally designing a variant form of Aβ1-42 (vAβ1-42) differing in only two amino acids. Unlike Aβ1-42, we found that the variant does not self-assemble, nor is it toxic to neuronal cells. Moreover, while Aβ1-42 oligomers impact on synaptic function, vAβ1-42 does not. In a living animal model system we demonstrate that only Aβ1-42 leads to memory deficits. Our findings underline a key role for peptide sequence in the ability to assemble and form toxic structures. Furthermore, our non-toxic variant satisfies an unmet demand for a closely related control peptide for Aβ1-42 cellular studies of disease pathology, offering a new opportunity to decipher the mechanisms that accompany Aβ1-42-induced toxicity leading to neurodegeneration

Sensitive detection of Aβ protofibrils by proximity ligation - relevance for Alzheimer's disease

<p>Abstract</p> <p>Background</p> <p>Protein aggregation plays important roles in several neurodegenerative disorders. For instance, insoluble aggregates of phosphorylated tau and of Aβ peptides are cornerstones in the pathology of Alzheimer's disease. Soluble protein aggregates are therefore potential diagnostic and prognostic biomarkers for their cognate disorders. Detection of the aggregated species requires sensitive tools that efficiently discriminate them from monomers of the same proteins. Here we have established a proximity ligation assay (PLA) for specific and sensitive detection of Aβ protofibrils via simultaneous recognition of three identical determinants present in the aggregates. PLA is a versatile technology in which the requirement for multiple target recognitions is combined with the ability to translate signals from detected target molecules to amplifiable DNA strands, providing very high specificity and sensitivity.</p> <p>Results</p> <p>For specific detection of Aβ protofibrils we have used a monoclonal antibody, mAb158, selective for Aβ protofibrils in a modified PLA, where the same monoclonal antibody was used for the three classes of affinity reagents required in the assay. These reagents were used for detection of soluble Aβ aggregates in solid-phase reactions, allowing detection of just 0.1 pg/ml Aβ protofibrils, and with a dynamic range greater than six orders of magnitude. Compared to a sandwich ELISA setup of the same antibody the PLA increases the sensitivity of the Aβ protofibril detection by up to 25-fold. The assay was used to measure soluble Aβ aggregates in brain homogenates from mice transgenic for a human allele predisposing to Aβ aggregation.</p> <p>Conclusions</p> <p>The proximity ligation assay is a versatile analytical technology for proteins, which can provide highly sensitive and specific detection of Aβ aggregates - and by implication other protein aggregates of relevance in Alzheimer's disease and other neurodegenerative disorders.</p

The Molecular Assembly of Amyloid Aβ Controls Its Neurotoxicity and Binding to Cellular Proteins

Accumulation of β-sheet-rich peptide (Aβ) is strongly associated with Alzheimer's disease, characterized by reduction in synapse density, structural alterations of dendritic spines, modification of synaptic protein expression, loss of long-term potentiation and neuronal cell death. Aβ species are potent neurotoxins, however the molecular mechanism responsible for Aβ toxicity is still unknown. Numerous mechanisms of toxicity were proposed, although there is no agreement about their relative importance in disease pathogenesis. Here, the toxicity of Aβ 1–40 and Aβ 1–42 monomers, oligomers or fibrils, was evaluated using the N2a cell line. A structure-function relationship between peptide aggregation state and toxic properties was established. Moreover, we demonstrated that Aβ toxic species cross the plasma membrane, accumulate in cells and bind to a variety of internal proteins, especially on the cytoskeleton and in the endoplasmatic reticulum (ER). Based on these data we suggest that numerous proteins act as Aβ receptors in N2a cells, triggering a multi factorial toxicity