Inhibition of REV-ERBs stimulates microglial amyloid-beta clearance and reduces amyloid plaque deposition in the 5XFAD mouse model of Alzheimer\u27s disease

A promising new therapeutic target for the treatment of Alzheimer\u27s disease (AD) is the circadian system. Although patients with AD are known to have abnormal circadian rhythms and suffer sleep disturbances, the role of the molecular clock in regulating amyloid-beta (Aβ) pathology is still poorly understood. Here, we explored how the circadian repressors REV-ERBα and β affected Aβ clearance in mouse microglia. We discovered that, at Circadian time 4 (CT4), microglia expressed higher levels of the master clock protein BMAL1 and more rapidly phagocytosed fibrillary A

A Multi-Chamber System for Analyzing the Outgassing, Deposition, and Associated Optical Degradation Properties of Materials in a Vacuum

We report on the Camera Materials Test Chamber, a multi-vessel apparatus which analyzes the outgassing consequences of candidate materials for use in the vacuum cryostat of a new telescope camera. The system measures the outgassing products and rates of samples of materials at different temperatures, and collects films of outgassing products to measure the effects on light transmission in six optical bands. The design of the apparatus minimizes potential measurement errors introduced by background contamination.Comment: 9 pages, 10 figures, published in RSI (minor edits made to match journal accepted version

Subgroups of cancer patients with unique pain and fatigue experiences during chemotherapy

Context. Some cancer patients experience pain and fatigue, whereas others experience only one of the two symptoms. Yet, it is not clear who experiences these unique patterns and why. Objectives. This study aimed to identify subgroups of cancer patients with unique pain and fatigue experiences in two different chemotherapy cycles to examine how selected factors influenced subgroup membership and identify how subgroups differed in concurrently measured functional limitation outcome. Methods. The sample included 276 patients with diverse cancer types from four U.S. sites. To investigate subgroups, latent profile analyses were performed. Multinomial logistic regression and one-way analysis of variance-type analyses were conducted to examine the influencing variables of subgroup membership and to examine differences among subgroups in patient outcome. Results. The high-pain/high-fatigue (HPHF) and low-pain/low-fatigue subgroups were found at both time points. The low-pain/high-fatigue subgroup was present only in the first chemotherapy cycle. Pain and fatigue levels significantly differentiated subgroups at each time point (all P \u3c 0.05). Across the two time points, experiencing higher depressed mood increased the risk to be in the HPHF subgroup (all P \u3c 0.01). The HPHF subgroup had the most serious limitations in activities (all P \u3c 0.01). Conclusion. This study confirmed the existence of a unique symptom experience of pain and fatigue. This pattern should be acknowledged for symptom assessment and management

Single copy/knock-in models of ALS SOD1 in C. elegans suggest loss and gain of function have different contributions to cholinergic and glutamatergic neurodegeneration

Mutations in Cu/Zn superoxide dismutase 1 (SOD1) lead to Amyotrophic Lateral Sclerosis (ALS), a neurodegenerative disease that disproportionately affects glutamatergic and cholinergic motor neurons. Previous work with SOD1 overexpression models supports a role for SOD1 toxic gain of function in ALS pathogenesis. However, the impact of SOD1 loss of function in ALS cannot be directly examined in overexpression models. In addition, overexpression may obscure the contribution of SOD1 loss of function in the degeneration of different neuronal populations. Here, we report the first single-copy, ALS knock-in models in C. elegans generated by transposon- or CRISPR/Cas9- mediated genome editing of the endogenous sod-1 gene. Introduction of ALS patient amino acid changes A4V, H71Y, L84V, G85R or G93A into the C. elegans sod-1 gene yielded single-copy/knock-in ALS SOD1 models. These differ from previously reported overexpression models in multiple assays. In single-copy/knock-in models, we observed differential impact of sod-1 ALS alleles on glutamatergic and cholinergic neurodegeneration. A4V, H71Y, G85R, and G93A animals showed increased SOD1 protein accumulation and oxidative stress induced degeneration, consistent with a toxic gain of function in cholinergic motor neurons. By contrast, H71Y, L84V, and G85R lead to glutamatergic neuron degeneration due to sod-1 loss of function after oxidative stress. However, dopaminergic and serotonergic neuronal populations were spared in single-copy ALS models, suggesting a neuronal-subtype specificity previously not reported in invertebrate ALS SOD1 models. Combined, these results suggest that knock-in models may reproduce the neurotransmitter-type specificity of ALS and that both SOD1 loss and gain of toxic function differentially contribute to ALS pathogenesis in different neuronal populations.Peer reviewe

Molecular functionalization of graphite surfaces : Basal Plane versus Step Edge electrochemical activity

The chemical functionalization of carbon surfaces has myriad applications, from tailored sensors to electrocatalysts. Here, the adsorption and electrochemistry of anthraquinone-2,6-disulfonate (AQDS) is studied on highly oriented pyrolytic graphite (HOPG) as a model sp2 surface. A major focus is to elucidate whether adsorbed electroactive AQDS can be used as a marker of step edges, which have generally been regarded as the main electroactive sites on graphite electrode surfaces. First, the macroscopic electrochemistry of AQDS is studied on a range of surfaces differing in step edge density by more than 2 orders of magnitude, complemented with ex situ tapping mode atomic force microscopy (AFM) data. These measurements show that step edges have little effect on the extent of adsorbed electroactive AQDS. Second, a new fast scan cyclic voltammetry protocol carried out with scanning electrochemical cell microscopy (SECCM) enables the evolution of AQDS adsorption to be followed locally on a rapid time scale. Subsequent AFM imaging of the areas probed by SECCM allows a direct correlation of the electroactive adsorption coverage and the actual step edge density of the entire working area. The amount of adsorbed electroactive AQDS and the electron transfer kinetics are independent of the step edge coverage. Last, SECCM reactive patterning is carried out with complementary AFM measurements to probe the diffusional electroactivity of AQDS. There is essentially uniform and high activity across the basal surface of HOPG. This work provides new methodology to monitor adsorption processes at surfaces and shows unambiguously that there is no correlation between the step edge density of graphite surfaces and the observed coverage of electroactive AQDS. The electroactivity is dominated by the basal surface, and studies that have used AQDS as a marker of steps need to be revised

Synthesis of Cell-Adhesive Anisotropic Multifunctional Particles by Stop Flow Lithography and Streptavidin–Biotin Interactions

Cell-adhesive particles are of significant interest in biotechnology, the bioengineering of complex tissues, and biomedical research. Their applications range from platforms to increase the efficiency of anchorage-dependent cell culture to building blocks to loading cells in heterogeneous structures to clonal-population growth monitoring to cell sorting. Although useful, currently available cell-adhesive particles can accommodate only homogeneous cell culture. Here, we report the design of anisotropic hydrogel microparticles with tunable cell-adhesive regions as first step toward micropatterned cell cultures on particles. We employed stop flow lithography (SFL), the coupling reaction between amine and N-hydroxysuccinimide (NHS) and streptavidin–biotin chemistry to adjust the localization of conjugated collagen and poly-l-lysine on the surface of microscale particles. Using the new particles, we demonstrate the attachment and formation of tight junctions between brain endothelial cells. We also demonstrate the geometric patterning of breast cancer cells on particles with heterogeneous collagen coatings. This new approach avoids the exposure of cells to potentially toxic photoinitiators and ultraviolet light and decouples in time the microparticle synthesis and the cell culture steps to take advantage of the most recent advances in cell patterning available for traditional culture substrates.National Institutes of Health (U.S.) (GM092804)National Science Foundation (U.S.) (CMMI-1120724 and DMR-1006147)Samsung Scholarship Foundatio

Intrinsic Absorption in the Spectrum of NGC 7469: Simultaneous Chandra, FUSE, and STIS Observations

We present simultaneous X-ray, far-ultraviolet, and near-ultraviolet spectra of the Seyfert 1 galaxy NGC 7469 obtained with the Chandra X-Ray Observatory, the Far Ultraviolet Spectroscopic Explorer, and the Space Telescope Imaging Spectrograph on the Hubble Space Telescope. Previous non-simultaneous observations of this galaxy found two distinct UV absorption components, at -560 and -1900 km/s, with the former as the likely counterpart of the X-ray absorber. We confirm these two absorption components in our new UV observations, in which we detect prominent O VI, Ly alpha, N V, and C IV absorption. In our Chandra spectrum we detect O VIII emission, but no significant O VIII or O VII absorption. We also detect a prominent Fe K alpha emission line in the Chandra spectrum, as well as absorption due to hydrogen-like and helium-like neon, magnesium, and silicon at velocities consistent with the -560 km/s UV absorber. The FUSE and STIS data reveal that the H I and C IV column densities in this UV- and X-ray- absorbing component have increased over time, as the UV continuum flux decreased. We use measured H I, N V, C IV, and O VI column densities to model the photoionization state of both absorbers self-consistently. We confirm the general physical picture of the outflow in which the low velocity component is a highly ionized, high density absorber with a total column density of 10^20 cm^-2, located near the broad emission line region, although due to measurable columns of N V and C IV, we assign it a somewhat smaller ionization parameter than found previously, U~1. The high velocity UV component is of lower density, log N=18.6, and likely resides farther from the central engine as we find its ionization parameter to be U=0.08.Comment: Minor correction to abstract; STScI eprint #1683; 50 pages, incl. 19 figures, 4 tables; Accepted to Ap