Longitudinal Evaluation of an N-Ethyl-N-Nitrosourea-Created Murine Model with Normal Pressure Hydrocephalus

Normal-pressure hydrocephalus (NPH) is a neurodegenerative disorder that usually occurs late in adult life. Clinically, the cardinal features include gait disturbances, urinary incontinence, and cognitive decline.Herein we report the characterization of a novel mouse model of NPH (designated p23-ST1), created by N-ethyl-N-nitrosourea (ENU)-induced mutagenesis. The ventricular size in the brain was measured by 3-dimensional micro-magnetic resonance imaging (3D-MRI) and was found to be enlarged. Intracranial pressure was measured and was found to fall within a normal range. A histological assessment and tracer flow study revealed that the cerebral spinal fluid (CSF) pathway of p23-ST1 mice was normal without obstruction. Motor functions were assessed using a rotarod apparatus and a CatWalk gait automatic analyzer. Mutant mice showed poor rotarod performance and gait disturbances. Cognitive function was evaluated using auditory fear-conditioned responses with the mutant displaying both short- and long-term memory deficits. With an increase in urination frequency and volume, the mutant showed features of incontinence. Nissl substance staining and cell-type-specific markers were used to examine the brain pathology. These studies revealed concurrent glial activation and neuronal loss in the periventricular regions of mutant animals. In particular, chronically activated microglia were found in septal areas at a relatively young age, implying that microglial activation might contribute to the pathogenesis of NPH. These defects were transmitted in an autosomal dominant mode with reduced penetrance. Using a whole-genome scan employing 287 single-nucleotide polymorphic (SNP) markers and further refinement using six additional SNP markers and four microsatellite markers, the causative mutation was mapped to a 5.3-cM region on chromosome 4.Our results collectively demonstrate that the p23-ST1 mouse is a novel mouse model of human NPH. Clinical observations suggest that dysfunctions and alterations in the brains of patients with NPH might occur much earlier than the appearance of clinical signs. p23-ST1 mice provide a unique opportunity to characterize molecular changes and the pathogenic mechanism of NPH

Guidelines for the use and interpretation of assays for monitoring autophagy (4th edition)1.

In 2008, we published the first set of guidelines for standardizing research in autophagy. Since then, this topic has received increasing attention, and many scientists have entered the field. Our knowledge base and relevant new technologies have also been expanding. Thus, it is important to formulate on a regular basis updated guidelines for monitoring autophagy in different organisms. Despite numerous reviews, there continues to be confusion regarding acceptable methods to evaluate autophagy, especially in multicellular eukaryotes. Here, we present a set of guidelines for investigators to select and interpret methods to examine autophagy and related processes, and for reviewers to provide realistic and reasonable critiques of reports that are focused on these processes. These guidelines are not meant to be a dogmatic set of rules, because the appropriateness of any assay largely depends on the question being asked and the system being used. Moreover, no individual assay is perfect for every situation, calling for the use of multiple techniques to properly monitor autophagy in each experimental setting. Finally, several core components of the autophagy machinery have been implicated in distinct autophagic processes (canonical and noncanonical autophagy), implying that genetic approaches to block autophagy should rely on targeting two or more autophagy-related genes that ideally participate in distinct steps of the pathway. Along similar lines, because multiple proteins involved in autophagy also regulate other cellular pathways including apoptosis, not all of them can be used as a specific marker for bona fide autophagic responses. Here, we critically discuss current methods of assessing autophagy and the information they can, or cannot, provide. Our ultimate goal is to encourage intellectual and technical innovation in the field

Influence of Weld Toe Radii on Fatigue Life Prediction

A study was carried out to investigate the influence of the weld toe radii on the fatigue strength of butt welded joints loaded in bending and tension. Fatigue analysis starting from weld toe cracks in marine and offshore welded pipe specimens were conducted using cut-out four-point bend fatigue test specimens. Fatigue life can be enhanced by reducing the local stress concentration generated by weld toe radius effects. This study investigated the effect of different weld toe radii on the stress intensity factor at the region of the weld toe through Finite Element Analysis (FEA). FEA was used to model a butt welded steel plate extracted from a pipe subject to tension and four-point bend loading. Semi-elliptical surface (SESC) cracks were modeled at the weld toe region with different SESC crack depth and surface crack length. Four weld toe radii and two modes of loading were investigated. The stress intensity factors, weald toe magnification factors, or Mkc and Mka are reported and used for fatigue life prediction

Stacked Electron Diffusion Regions and Electron Kelvin-Helmholtz Vortices within the Ion Diffusion Region of Collisionless Magnetic Reconnection

The structure of the electron diffusion region (EDR) is essential for determining how fast the magnetic energy converts to plasma energy during magnetic reconnection. Conventional knowledge of the diffusion region assumes that the EDR is a single layer embedded within the ion diffusion region (IDR). This paper reports the first observation of two EDRs that stack in parallel within an IDR by the Magnetospheric Multiscale mission. The oblique tearing modes can result in these stacked EDRs. Intense electron flow shear in the vicinity of two EDRs induced electron Kelvin-Helmholtz vortices, which subsequently generated kinetic-scale magnetic peak and holes, which may effectively trap electrons. Our analyses show that both the oblique tearing instability and electron Kelvin-Helmholtz instability are important in three-dimensional reconnection since they can control the electron dynamics and structure of the diffusion region through cross-scale coupling

Application of Near Real-Time and Multiscale Three Dimensional Earth Observation Platforms in Disaster Prevention

Taiwan frequently experiences natural disasters such as typhoons, floods, landslides, debris flows, and earthquakes. Therefore, the instant acquisition of high-definition images and topographic or spatial data of affected areas as disasters occur is crucial for disaster response teams and making emergency aid decisions. The National Applied Research Laboratories has implemented the project “development of near real-time, high-resolution, global earth observation 3D platform for applications to environmental monitoring and disaster mitigation.” This developmental project integrates earth observation techniques, data warehousing, high-performance visualization displays, grids, and disaster prevention technology to establish a near real-time high-resolution three-dimensional (3D) disaster prevention earth observation application platform for Taiwan. The main functions of this platform include (1) integration of observation information, such as Formosat-2 satellite remote sensing, aerial photography, and 3D photography of disaster sites, to provide multidimensional information of the conditions at the affected sites; (2) disaster prevention application technologies, such as large-sized high-resolution 3D projection system, medium-sized active stereo projection systems, and small-sized personal computers with multiscale 3D display systems; (3) a 3D geographical information network platform that integrates data warehousing and cloud services, complies with the Open Geospatial Consortium (OGC) international standard for image data exchange and release processes, and includes image overlaying and added-value analysis of disasters; and (4) near real-time and automated simulation of image processing procedures, which accelerates orthophoto processing once raw data are received from satellites and provides appropriate images for disaster prevention decision-making within 3 to 6 h. This study uses the 88 Flood event of Typhoon Morakot in 2009, Typhoon Fanapi in 2011, and the 311 Earthquake of Japan in 2011 as examples to dissert the applications, functions and features of this platform for supporting disaster response and disaster recovery decision-making