Selective Vulnerability of Neurons in Layer II of the Entorhinal Cortex during Aging and Alzheimer's Disease

All neurons are not created equal. Certain cell populations in specific brain regions are more susceptible to age-related changes that initiate regional and system-level dysfunction. In this respect, neurons in layer II of the entorhinal cortex are selectively vulnerable in aging and Alzheimer's disease (AD). This paper will cover several hypotheses that attempt to account for age-related alterations among this cell population. We consider whether specific developmental, anatomical, or biochemical features of neurons in layer II of the entorhinal cortex contribute to their particular sensitivity to aging and AD. The entorhinal cortex is a functionally heterogeneous environment, and we will also review data suggesting that, within the entorhinal cortex, there is subregional specificity for molecular alterations that may initiate cognitive decline. Taken together, the existing data point to a regional cascade in which entorhinal cortical alterations directly contribute to downstream changes in its primary afferent region, the hippocampus

Possible X-ray diagnostic for jet/disk dominance in Type 1 AGN

Using Rossi X-ray Timing Explorer Seyfert 1 and 1.2 data spanning 9 years, we study correlations between X-ray spectral features. The sample consists of 350 time-resolved spectra from 12 Seyfert 1 and 1.2 galaxies. Each spectrum is fitted to a model with an intrinsic powerlaw X-ray spectrum produced close to the central black hole that is reprocessed and absorbed by material around the black hole. To test the robustness of our results, we performed Monte Carlo simulations of the spectral sample. We find a complex relationship between the iron line equivalent width (EW) and the underlying power law index (Gamma). The data reveal a correlation between Gamma and EW which turns over at Gamma <~ 2, but finds a weak anti-correlation for steeper photon indices. We propose that this relationship is driven by dilution of a disk spectrum (which includes the narrow iron line) by a beamed jet component and, hence, could be used as a diagnostic of jet-dominance. In addition, our sample shows a strong correlation between the reflection fraction (R) and Gamma, but we find that it is likely the result of modeling degeneracies. We also see the X-ray Baldwin effect (an anti-correlation between the 2-10 keV X-ray luminosity and EW) for the sample as a whole, but not for the individual galaxies and galaxy types.Comment: Accepted for publication in ApJ, 14 page

Molecular Functionalization of Carbon Nanotubes and Use as Substrates for Neuronal Growth

A cell and substrate system and nerve regeneration implant are disclosed including a carbon nanotube and a neuron growing on the carbon nanotube. Both unfunctionalized carbon nanotubes and carbon nanotubes functionalized with a neuronal growth promoting agent may be utilized in the invention. A method is also disclosed for promoting neuronal growth

Non-Newtonian fluid flow through three-dimensional disordered porous media

We investigate the flow of various non-Newtonian fluids through three-dimensional disordered porous media by direct numerical simulation of momentum transport and continuity equations. Remarkably, our results for power-law (PL) fluids indicate that the flow, when quantified in terms of a properly modified permeability-like index and Reynolds number, can be successfully described by a single (universal) curve over a broad range of Reynolds conditions and power-law exponents. We also study the flow behavior of Bingham fluids described in terms of the Herschel-Bulkley model. In this case, our simulations reveal that the interplay of ({\it i}) the disordered geometry of the pore space, ({\it ii}) the fluid rheological properties, and ({\it iii}) the inertial effects on the flow is responsible for a substantial enhancement of the macroscopic hydraulic conductance of the system at intermediate Reynolds conditions. This anomalous condition of ``enhanced transport'' represents a novel feature for flow in porous materials.Comment: 5 pages, 5 figures. This article appears also in Physical Review Letters 103 194502 (2009

XRCC1 protects against the lethality of induced oxidative DNA damage in nondividing neural cells

XRCC1 is a critical scaffold protein that orchestrates efficient single-strand break repair (SSBR). Recent data has found an association of XRCC1 with proteins causally linked to human spinocerebellar ataxias—aprataxin and tyrosyl-DNA phosphodiesterase 1—implicating SSBR in protection against neuronal cell loss and neurodegenerative disease. We demonstrate herein that shRNA lentiviral-mediated XRCC1 knockdown in human SH-SY5Y neuroblastoma cells results in a largely selective increase in sensitivity of the nondividing (i.e. terminally differentiated) cell population to the redox-cycling agents, menadione and paraquat; this reduced survival was accompanied by an accumulation of DNA strand breaks. Using hypoxanthine–xanthine oxidase as the oxidizing method, XRCC1 deficiency affected both dividing and nondividing SH-SY5Y cells, with a greater effect on survival seen in the former case, suggesting that the spectrum of oxidative DNA damage created dictates the specific contribution of XRCC1 to cellular resistance. Primary XRCC1 heterozygous mouse cerebellar granule cells exhibit increased strand break accumulation and reduced survival due to increased apoptosis following menadione treatment. Moreover, knockdown of XRCC1 in primary human fetal brain neurons leads to enhanced sensitivity to menadione, as indicated by increased levels of DNA strand breaks relative to control cells. The cumulative results implicate XRCC1, and more broadly SSBR, in the protection of nondividing neuronal cells from the genotoxic consequences of oxidative stress

Nontelomeric TRF2-REST Interaction Modulates Neuronal Gene Silencing and Fate of Tumor and Stem Cells

SummaryRemoval of TRF2, a telomere shelterin protein, recapitulates key aspects of telomere attrition including the DNA-damage response and cell-cycle arrest [1]. Distinct from the response of proliferating cells to loss of TRF2 [2, 3], in rodent noncycling cells, TRF2 inhibition promotes differentiation and growth [4, 5]. However, the mechanism that couples telomere gene-silencing features [6–8] to differentiation programs has yet to be elucidated. Here we describe an extratelomeric function of TRF2 in the regulation of neuronal genes mediated by the interaction of TRF2 with repressor element 1-silencing transcription factor (REST), a master repressor of gene networks devoted to neuronal functions [9–12]. TRF2-REST complexes are readily detected by coimmunoprecipitation assays and are localized to aggregated PML-nuclear bodies in undifferentiated pluripotent human NTera2 stem cells. Inhibition of TRF2, either by a dominant-negative mutant or by RNA interference, dissociates TRF2-REST complexes resulting in ubiquitin-proteasomal degradation of REST. Consequentially, REST-targeted neural genes (L1CAM, β3-tubulin, synaptophysin, and others) are derepressed, resulting in acquisition of neuronal phenotypes. Notably, selective damage to telomeres without affecting TRF2 levels causes neither REST degradation nor cell differentiation. Thus, in addition to protecting telomeres, TRF2 possesses a novel role in stabilization of REST thereby controlling neural tumor and stem cell fate

Spin-dependent electrical transport in ion-beam sputter deposited Fe-Cr multilayers

The temperature dependence of the electrical resistivity and magnetoresistance of Xe-ion beam sputtered Fe-Cr multilayers has been investigated. The electrical resistivity between 5 and 300 K in the fully ferromagnetic state, obtained by applying a field beyond the saturation field (H_sat) necessary for the antiferromagnetic(AF)-ferromagnetic(FM) field-induced transition, shows evidence of spin-disorder resistivity as in crystalline Fe and an s-d scattering contribution (as in 3d metals and alloys). The sublattice magnetization m(T) in these multilayers has been calculated in terms of the planar and interlayer exchange energies. The additional spin-dependent scattering \Delta \rho (T) = \rho(T,H=0)_AF - \rho(T,H=H_sat)_FM in the AF state over a wide range of temperature is found to be proportional to the sublattice magnetization, both \Delta \rho(T) and m(T) reducing along with the antiferromagnetic fraction. At intermediate fields, the spin-dependent part of the electrical resistivity (\rho_s (T)) fits well to the power law \rho_s (T) = b - cT^\alpha where c is a constant and b and \alpha are functions of H. At low fields \alpha \approx 2 and the intercept b decreases with H much the same way as the decrease of \Delta \rho (T) with T. A phase diagram (T vs. H_sat) is obtained for the field- induced AF to FM transition. Comparisons are made between the present investigation and similar studies using dc magnetron sputtered and molecular beam epitaxy (MBE) grown Fe-Cr multilayers.Comment: 8 pages, 10 figures, to appear in Phys. Rev.

Capacitative Calcium Entry Deficits and Elevated Luminal Calcium Content in Mutant Presenilin-1 Knockin Mice

Dysregulation of calcium signaling has been causally implicated in brain aging and Alzheimer's disease. Mutations in the presenilin genes (PS1, PS2), the leading cause of autosomal dominant familial Alzheimer's disease (FAD), cause highly specific alterations in intracellular calcium signaling pathways that may contribute to the neurodegenerative and pathological lesions of the disease. To elucidate the cellular mechanisms underlying these disturbances, we studied calcium signaling in fibroblasts isolated from mutant PS1 knockin mice. Mutant PS1 knockin cells exhibited a marked potentiation in the amplitude of calcium transients evoked by agonist stimulation. These cells also showed significant impairments in capacitative calcium entry (CCE, also known as store-operated calcium entry), an important cellular signaling pathway wherein depletion of intracellular calcium stores triggers influx of extracellular calcium into the cytosol. Notably, deficits in CCE were evident after agonist stimulation, but not if intracellular calcium stores were completely depleted with thapsigargin. Treatment with ionomycin and thapsigargin revealed that calcium levels within the ER were significantly increased in mutant PS1 knockin cells. Collectively, our findings suggest that the overfilling of calcium stores represents the fundamental cellular defect underlying the alterations in calcium signaling conferred by presenilin mutations

Who knows best? A Q methodology study to explore perspectives of professional stakeholders and community participants on health in low-income communities

Abstract Background Health inequalities in the UK have proved to be stubborn, and health gaps between best and worst-off are widening. While there is growing understanding of how the main causes of poor health are perceived among different stakeholders, similar insight is lacking regarding what solutions should be prioritised. Furthermore, we do not know the relationship between perceived causes and solutions to health inequalities, whether there is agreement between professional stakeholders and people living in low-income communities or agreement within these groups. Methods Q methodology was used to identify and describe the shared perspectives (‘subjectivities’) that exist on i) why health is worse in low-income communities (‘Causes’) and ii) the ways that health could be improved in these same communities (‘Solutions’). Purposively selected individuals (n = 53) from low-income communities (n = 25) and professional stakeholder groups (n = 28) ranked ordered sets of statements – 34 ‘Causes’ and 39 ‘Solutions’ – onto quasi-normal shaped grids according to their point of view. Factor analysis was used to identify shared points of view. ‘Causes’ and ‘Solutions’ were analysed independently, before examining correlations between perspectives on causes and perspectives on solutions. Results Analysis produced three factor solutions for both the ‘Causes’ and ‘Solutions’. Broadly summarised these accounts for ‘Causes’ are: i) ‘Unfair Society’, ii) ‘Dependent, workless and lazy’, iii) ‘Intergenerational hardships’ and for ‘Solutions’: i) ‘Empower communities’, ii) ‘Paternalism’, iii) ‘Redistribution’. No professionals defined (i.e. had a significant association with one factor only) the ‘Causes’ factor ‘Dependent, workless and lazy’ and the ‘Solutions’ factor ‘Paternalism’. No community participants defined the ‘Solutions’ factor ‘Redistribution’. The direction of correlations between the two sets of factor solutions – ‘Causes’ and ‘Solutions’ – appear to be intuitive, given the accounts identified. Conclusions Despite the plurality of views there was broad agreement across accounts about issues relating to money. This is important as it points a way forward for tackling health inequalities, highlighting areas for policy and future research to focus on