Detailed immunohistochemical characterization of temporal and spatial progression of Alzheimer's disease-related pathologies in male triple-transgenic mice

<p>Abstract</p> <p>Background</p> <p>Several transgenic animal models genetically predisposed to develop Alzheimer's disease (AD)-like pathology have been engineered to facilitate the study of disease pathophysiology and the vetting of potential disease-modifying therapeutics. The triple transgenic mouse model of AD (3xTg-AD) harbors three AD-related genetic loci: human PS1^M146V, human APP^swe, and human tau^P301L. These mice develop both amyloid plaques and neurofibrillary tangle-like pathology in a progressive and age-dependent manner, while these pathological hallmarks are predominantly restricted to the hippocampus, amygdala, and the cerebral cortex the main foci of AD neuropathology in humans. This model represents, at present, one of the most advanced preclinical tools available and is being employed ever increasingly in the study of mechanisms underlying AD, yet a detailed regional and temporal assessment of the subtleties of disease-related pathologies has not been reported.</p> <p>Methods and results</p> <p>In this study, we immunohistochemically documented the evolution of AD-related transgene expression, amyloid deposition, tau phosphorylation, astrogliosis, and microglial activation throughout the hippocampus, entorhinal cortex, primary motor cortex, and amygdala over a 26-month period in male 3xTg-AD mice. Intracellular amyloid-beta accumulation is detectable the earliest of AD-related pathologies, followed temporally by phospho-tau, extracellular amyloid-beta, and finally paired helical filament pathology. Pathology appears to be most severe in medial and caudal hippocampus. While astrocytic staining remains relatively constant at all ages and regions assessed, microglial activation appears to progressively increase temporally, especially within the hippocampal formation.</p> <p>Conclusion</p> <p>These data fulfill an unmet need in the ever-widening community of investigators studying 3xTg-AD mice and provide a foundation upon which to design future experiments that seek to examine stage-specific disease mechanisms and/or novel therapeutic interventions for AD.</p

Far-Ultraviolet Emission from Elliptical Galaxies at z=0.33

We present far-ultraviolet (far-UV) images of the rich galaxy cluster ZwCl1358.1+6245, taken with the Space Telescope Imaging Spectrograph on board the Hubble Space Telescope (HST). When combined with archival HST observations, our data provide a measurement of the UV-to-optical flux ratio in 8 early-type galaxies at z=0.33. Because the UV flux originates in a population of evolved, hot, horizontal branch (HB) stars, this ratio is potentially one of the most sensitive tracers of age in old populations -- it is expected to fade rapidly with lookback time. We find that the UV emission in these galaxies, at a lookback time of 3.9 Gyr, is significantly weaker than it is in the current epoch, yet similar to that in galaxies at a lookback time of 5.6 Gyr. Taken at face value, these measurements imply different formation epochs for the massive ellipticals in these clusters, but an alternative explanation is a "floor" in the UV emission due to a dispersion in the parameters that govern HB morphology.Comment: 4 pages, Latex. 2 figures. Uses corrected version of emulateapj.sty and apjfonts.sty (included). Accepted for publication in ApJ Letter

Recommendations for reporting ion mobility Mass Spectrometry measurements

Here we present a guide to ion mobility mass spectrometry experiments, which covers both linear and nonlinear methods: what is measured, how the measurements are done, and how to report the results, including the uncertainties of mobility and collision cross section values. The guide aims to clarify some possibly confusing concepts, and the reporting recommendations should help researchers, authors and reviewers to contribute comprehensive reports, so that the ion mobility data can be reused more confidently. Starting from the concept of the definition of the measurand, we emphasize that (i) mobility values (K0) depend intrinsically on ion structure, the nature of the bath gas, temperature, and E/N; (ii) ion mobility does not measure molecular surfaces directly, but collision cross section (CCS) values are derived from mobility values using a physical model; (iii) methods relying on calibration are empirical (and thus may provide method‐dependent results) only if the gas nature, temperature or E/N cannot match those of the primary method. Our analysis highlights the urgency of a community effort toward establishing primary standards and reference materials for ion mobility, and provides recommendations to do so. © 2019 The Authors. Mass Spectrometry Reviews Published by Wiley Periodicals, Inc

Deposition of cupric oxide thin films by spin coating

Cupric oxide thin films were deposited onto soda lime glass by spin coating and subsequent annealing of copper nitrate dissolved in a glycerol–water solvent. It was found that the solution consistently gave reproducible films with good adhesion on glass. A range of band gaps were estimated between 0.8 and 1.17 eV, showing that this material has potential as a photoabsorber. Resistivity was successfully reduced from 1.47×105 to 7.02 Ω cm by doping the films with sodium. Dopant concentrations of 1 at-% gave the lowest resistivity, showing that the ideal doping is 1% or less. Film structure was found to improve with an increase in annealing time from 10 min to 1 h, although this did not have any noticeable effect on either the electrical or optical properties of the films

Epistatic Interactions Alter Dynamics of Multilocus Gene-for-Gene Coevolution

Fitness costs associated with resistance or virulence genes are thought to play a key role in determining the dynamics of gene-for-gene (GFG) host-parasite coevolution. However, the nature of interactions between fitness effects of multiple resistance or virulence genes (epistasis) has received less attention. To examine effects of the functional form of epistasis on the dynamics of GFG host-parasite coevolution we modified a classic multilocus GFG model framework. We show that the type of epistasis between virulence genes largely determines coevolutionary dynamics, and that coevolutionary fluctuations are more likely with acceleratingly costly (negative) than with linear or deceleratingly costly (positive) epistasis. Our results demonstrate that the specific forms of interaction between multiple resistance or virulence genes are a crucial determinant of host-parasite coevolutionary dynamics

Telescope to Observe Planetary Systems (TOPS): a high throughput 1.2-m visible telescope with a small inner working angle

The Telescope to Observe Planetary Systems (TOPS) is a proposed space mission to image in the visible (0.4-0.9 micron) planetary systems of nearby stars simultaneously in 16 spectral bands (resolution R~20). For the ~10 most favorable stars, it will have the sensitivity to discover 2 R_E rocky planets within habitable zones and characterize their surfaces or atmospheres through spectrophotometry. Many more massive planets and debris discs will be imaged and characterized for the first time. With a 1.2m visible telescope, the proposed mission achieves its power by exploiting the most efficient and robust coronagraphic and wavefront control techniques. The Phase-Induced Amplitude Apodization (PIAA) coronagraph used by TOPS allows planet detection at 2 lambda/d with nearly 100% throughput and preserves the telescope angular resolution. An efficient focal plane wavefront sensing scheme accurately measures wavefront aberrations which are fed back to the telescope active primary mirror. Fine wavefront control is also performed independently in each of 4 spectral channels, resulting in a system that is robust to wavefront chromaticity.Comment: 12 pages, SPIE conference proceeding, May 2006, Orlando, Florid

A non-canonical ESCRT pathway, including histidine domain phosphotyrosine phosphatase (HD-PTP), is used for down-regulation of virally ubiquitinated MHC class I.

The Kaposi's sarcoma-associated herpes virus (KSHV) K3 viral gene product effectively down-regulates cell surface MHC class I. K3 is an E3 ubiquitin ligase that promotes Lys(63)-linked polyubiquitination of MHC class I, providing the signal for clathrin-mediated endocytosis. Endocytosis is followed by sorting into the intralumenal vesicles (ILVs) of multivesicular bodies (MVBs) and eventual delivery to lysosomes. The sorting of MHC class I into MVBs requires many individual proteins of the four endosomal sorting complexes required for transport (ESCRTs). In HeLa cells expressing the KSHV K3 ubiquitin ligase, the effect of RNAi-mediated depletion of individual proteins of the ESCRT-0 and ESCRT-I complexes and three ESCRT-III proteins showed that these are required to down-regulate MHC class I. However, depletion of proteins of the ESCRT-II complex or of the ESCRT-III protein, VPS20 (vacuolar protein sorting 20)/CHMP6 (charged MVB protein 6), failed to prevent the loss of MHC class I from the cell surface. Depletion of histidine domain phosphotyrosine phosphatase (HD-PTP) resulted in an increase in the cell surface concentration of MHC class I in HeLa cells expressing the KSHV K3 ubiquitin ligase. Rescue experiments with wild-type (WT) and mutant HD-PTP supported the conclusion that HD-PTP acts as an alternative to ESCRT-II and VPS20/CHMP6 as a link between the ESCRT-I and those ESCRT-III protein(s) necessary for ILV formation. Thus, the down-regulation of cell surface MHC class I, polyubiquitinated by the KSHV K3 ubiquitin ligase, does not employ the canonical ESCRT pathway, but instead utilizes an alternative pathway in which HD-PTP replaces ESCRT-II and VPS20/CHMP6.This work was supported by an MRC research grant to J.P.L. (G0900113). M.D.J.P. and J.L.E. were MRC research students and S.P. a Wellcome Trust research student. K.B. was a British Heart Foundation Intermediate Fellow and P.J.L. is a Wellcome Trust Principal Fellow. The CIMR is supported by a Wellcome Trust Strategic Award 100140 and an electron microscope was purchased with Wellcome Trust grant 093026.This is the final version of the article. It first appeared from Portland Press via http://dx.doi.org/10.1042/BJ2015033

VprBP/DCAF1 Regulates the Degradation and Nonproteolytic Activation of the Cell Cycle Transcription Factor FoxM1

The oncogenic transcription factor FoxM1 plays a vital role in cell cycle progression, is activated in numerous human malignancies, and is linked to chromosome instability. We characterize here a cullin 4-based E3 ubiquitin ligase and its substrate receptor, VprBP/DCAF1 (CRL4VprBP), which we show regulate FoxM1 ubiquitylation and degradation. Paradoxically, we also found that the substrate receptor VprBP is a potent FoxM1 activator. VprBP depletion reduces expression of FoxM1 target genes and impairs mitotic entry, whereas ectopic VprBP expression strongly activates a FoxM1 transcriptional reporter. VprBP binding to CRL4 is reduced during mitosis, and our data suggest that VprBP activation of FoxM1 is ligase independent. This implies a nonproteolytic activation mechanism that is reminiscent of, yet distinct from, the ubiquitin-dependent transactivation of the oncoprotein Myc by other E3s. Significantly, VprBP protein levels were upregulated in high-grade serous ovarian patient tumors, where the FoxM1 signature is amplified. These data suggest that FoxM1 abundance and activity are controlled by VprBP and highlight the functional repurposing of E3 ligase substrate receptors independent of the ubiquitin system

A Galactic Bar to Beyond the Solar Circle and its Relevance for Microlensing

The Galactic kinematics of Mira variables have been studied using infrared photometry, radial velocities, and Hipparcos parallaxes and proper motions. For Miras in the period range 145 to 200 days (probably corresponding to [Fe/H] in the range -0.8 to -1.3) the major axes of the stellar orbits are concentrated in the first quadrant of Galactic longitude. This is interpreted as a continuation of the bar-like structure of the Galactic Bulge out to the solar circle and beyond.Comment: 6 pages, 2 figures. To be published in: Microlensing 2000. ASP Conference Series, Eds. J W Menzies, P Sacket