The Intracellular Threonine of Amyloid Precursor Protein That Is Essential for Docking of Pin1 Is Dispensable for Developmental Function

Background: Processing of Ab-precursor protein (APP) plays an important role in Alzheimer’s Disease (AD) pathogenesis. Thr residue at amino acid 668 of the APP intracellular domain (AID) is highly conserved. When phosphorylated, this residue generates a binding site for Pin1. The interaction of APP with Pin1 has been involved in AD pathogenesis. Methodology/Principal Findings: To dissect the functions of this sequence in vivo, we created an APP knock-in allele, in which Thr 668 is replaced by an Ala (T 668 A). Doubly deficient APP/APP-like protein 2 (APLP2) mice present postnatal lethality and neuromuscular synapse defects. Previous work has shown that the APP intracellular domain is necessary for preventing early lethality and neuromuscular junctions (NMJ) defects. Crossing the T 668 A allele into the APLP2 knockout background showed that mutation of Thr 668 does not cause a defective phenotype. Notably, the T 668 A mutant APP is able to bind Mint1. Conclusions/Significance: Our results argue against an important role of the Thr 668 residue in the essential function of APP in developmental regulation. Furthermore, they indicate that phosphorylation at this residue is not functionally involved i

A benefit analysis of using a low-cost flight simulator for the MH-60R

Tactical proficiency in the Helicopter Maritime Strike community is pivotal in the United States National Defense Strategy. In an increasingly tight fiscal environment, flight hours available for training have been diminishing and will continue to diminish, despite an ever-growing battery of tactical requirements. The existing flight simulator for the MH-60R is highly capable; however, each hour of use is expensive, and not every capability of the simulator is required for every training event conducted. This thesis examines eight different configurations of a low-cost trainer, and analyzes the impact of each configuration on the utilization rates of the existing simulators. It uses the throughput data from the MH-60R Fleet Replacement Squadron to compare the configurations, as the Fleet Replacement Squadron is the single largest user of the devices. This thesis does not aim to determine an optimal configuration. It provides analytical evidence that the introduction of a low-cost trainer has the ability to make the existing devices significantly more available for events that require a high level of fidelity.http://archive.org/details/abenefitnalysiso1094550514Lieutenant, United States NavyApproved for public release; distribution is unlimited

Chromatin remodeling factor Brg1 supports the early maintenance and late responsiveness of nestin-lineage adult neural stem and progenitor cells

Insights from embryonic development suggest chromatin remodeling is important in adult neural stem cells (aNSCs) maintenance and self‐renewal, but this concept has not been fully explored in the adult brain. To assess the role of chromatin remodeling in adult neurogenesis, we inducibly deleted Brg1—the core subunit of SWI/SNF‐like Brg1/Brm‐associated factor chromatin remodeling complexes—in nestin‐expressing aNSCs and their progeny in vivo and in culture. This resulted in abnormal adult neurogenesis in the hippocampus, which initially reduced hippocampal aNSCs and progenitor maintenance, and later reduced its responsiveness to physiological stimulation. Mechanistically, deletion of Brg1 appeared to impair cell cycle progression, which is partially due to elevated p53 pathway and p21 expression. Knockdown of p53 rescued the neurosphere growth defects caused by Brg1 deletion. Our results show that epigenetic chromatin remodeling (via a Brg1 and p53/p21‐dependent process) determines the aNSCs and progenitor maintenance and responsiveness of neurogenesis

Chromatin remodeling factor Brg1 supports the early maintenance and late responsiveness of nestin-lineage adult neural stem and progenitor cells

Insights from embryonic development suggest chromatin remodeling is important in adult neural stem cells (aNSCs) maintenance and self‐renewal, but this concept has not been fully explored in the adult brain. To assess the role of chromatin remodeling in adult neurogenesis, we inducibly deleted Brg1—the core subunit of SWI/SNF‐like Brg1/Brm‐associated factor chromatin remodeling complexes—in nestin‐expressing aNSCs and their progeny in vivo and in culture. This resulted in abnormal adult neurogenesis in the hippocampus, which initially reduced hippocampal aNSCs and progenitor maintenance, and later reduced its responsiveness to physiological stimulation. Mechanistically, deletion of Brg1 appeared to impair cell cycle progression, which is partially due to elevated p53 pathway and p21 expression. Knockdown of p53 rescued the neurosphere growth defects caused by Brg1 deletion. Our results show that epigenetic chromatin remodeling (via a Brg1 and p53/p21‐dependent process) determines the aNSCs and progenitor maintenance and responsiveness of neurogenesis