Interaction of tau with the RNA-Binding Protein TIA1 Regulates tau Pathophysiology and Toxicity

Dendritic mislocalization of microtubule associated protein tau is a hallmark of tauopathies, but the role of dendritic tau is unknown. We now report that tau interacts with the RNA-binding protein (RBP) TIA1 in brain tissue, and we present the brain-protein interactome network for TIA1. Analysis of the TIA1 interactome in brain tissue from wild-type (WT) and tau knockout mice demonstrates that tau is required for normal interactions of TIA1 with proteins linked to RNA metabolism, including ribosomal proteins and RBPs. Expression studies show that tau regulates the distribution of TIA1, and tau accelerates stress granule (SG) formation. Conversely, TIA1 knockdown or knockout inhibits tau misfolding and associated toxicity in cultured hippocampal neurons, while overexpressing TIA1 induces tau misfolding and stimulates neurodegeneration. Pharmacological interventions that prevent SG formation also inhibit tau pathophysiology. These studies suggest that the pathophysiology of tauopathy requires an intimate interaction with RNA-binding proteins

Characterization of Maternal and Fetal CYP3A-Mediated Progesterone Metabolism

INTRODUCTION: Progesterone is critical for maintaining pregnancy and onset of labor. We evaluated CYP450-mediated progesterone meta-bolism, specifically the contribution of CYP3A isoforms. MATERIALS AND METHODS: In vitro progesterone metabolism was characterized in human liver microsomes (HLMs) with and without selective cytochrome P450 inhibitors and in recombinant CYP3A4, CYP3A5, and CYP3A7. 6β-hydroxyprogesterone (6β-OHP) and 16α-hydroxyprogesterone (16α-OHP) metabolites were quantified by HPLC/UV and fit to the Michaelis-Menten equation to determine Km and Vmax. The effect of CYP3A5 expression on progesterone clearance was determined by in vitro in vivo extrapolation. RESULTS: Ketoconazole inhibited formation of both 6β-OHP and 16α-OHP more than 95%. 6β-OHP and 16α-OHP were both produced by CYP3A4 (2.3 and 1.3 µL/min/pmol, respectively) to a greater extent than by CYP3A5 (0.09 and 0.003 µL/min/pmol) and CYP3A7 (0.004 and 0.003 µL/min/pmol). CONCLUSIONS: Maternal clearance of progesterone by hepatic CYP450's is driven primarily by CYP3A4, with limited contributions from CYP3A5 and CYP3A7

Commonwealth of Massachusetts Mill Building Repurposing Pilot Project (Twist Mill - Athol, MA)

The purpose of the UMass Amherst Department of Landscape Architecture and Regional Planning’s participation in this project is to establish a redevelopment action plan that incorporates the ownership’s clear vision for reuse of the site, proposes solutions to various obstacles that have hindered progress, and serves as a guiding model in terms of improving the feasibility of similar projects throughout the state. The project team gathered information from a variety of resources, and conducted three distinct phases of analysis in order to complete this redevelopment action plan. The Phase I: Inventory examines the physical, regulatory, and financial context surrounding the current site in order to gauge its condition as a viable location to foster desired economic development for the region. The Phase II: Assessment utilizes these inventory findings to identify clear challenges that impact the redevelopment potential of the site in an effort to reduce overall project roadblocks. The Phase III: Implementation provides strategies to alleviate these challenges moving forward, in the form of clear recommendations for local, regional, and state level regulatory improvements. Phases I and II were conducted in the fall of 2013, and Phase III was conducted in the spring of 2014. Particular thanks for guidance on this project are extended to L.P. Athol Corporation ownership, Dr. John Mullin of the UMass Amherst Center for Economic Development, State Representative Denise Andrews of the Franklin County Second District, State Senator Stephen Brewer, State Senator Stanley Rosenberg, Congressman James McGovern, and the Town of Athol

WSCLEAN: an implementation of a fast, generic wide-field imager for radio astronomy

Astronomical wide-field imaging of interferometric radio data is computationally expensive, especially for the large data volumes created by modern non-coplanar many-element arrays. We present a new wide-field interferometric imager that uses the w-stacking algorithm and can make use of the w-snapshot algorithm. The performance dependences of CASA's w-projection and our new imager are analysed and analytical functions are derived that describe the required computing cost for both imagers. On data from the Murchison Widefield Array, we find our new method to be an order of magnitude faster than w-projection, as well as being capable of full-sky imaging at full resolution and with correct polarization correction. We predict the computing costs for several other arrays and estimate that our imager is a factor of 2-12 faster, depending on the array configuration. We estimate the computing cost for imaging the lowfrequency Square Kilometre Array observations to be 60 PetaFLOPS with current techniques. We find that combining w-stacking with the w-snapshot algorithm does not significantly improve computing requirements over pure w-stacking. The source code of our new imager is publicly released

De novo assembly of the cattle reference genome with single-molecule sequencing.

BackgroundMajor advances in selection progress for cattle have been made following the introduction of genomic tools over the past 10-12 years. These tools depend upon the Bos taurus reference genome (UMD3.1.1), which was created using now-outdated technologies and is hindered by a variety of deficiencies and inaccuracies.ResultsWe present the new reference genome for cattle, ARS-UCD1.2, based on the same animal as the original to facilitate transfer and interpretation of results obtained from the earlier version, but applying a combination of modern technologies in a de novo assembly to increase continuity, accuracy, and completeness. The assembly includes 2.7 Gb and is >250× more continuous than the original assembly, with contig N50 >25 Mb and L50 of 32. We also greatly expanded supporting RNA-based data for annotation that identifies 30,396 total genes (21,039 protein coding). The new reference assembly is accessible in annotated form for public use.ConclusionsWe demonstrate that improved continuity of assembled sequence warrants the adoption of ARS-UCD1.2 as the new cattle reference genome and that increased assembly accuracy will benefit future research on this species

Earthquake Input Motions and Seismic Site Response in a Centrifuge Test Examining SFSI Effects

This paper describes the ground motion selection process and reports observed seismic site response and SFSI effects during a dynamic centrifuge test (Test-1). The centrifuge test is the first in a series of tests examining the effects of SFSI in dense urban environments. The objective of Test-1 is to examine SFSI effects for two structures that are located a significant distance apart and essentially isolated. The model structures represent a three-story building founded on spread footings and a nine-story structure founded on a threestory basement. The structures are sited on a dry, dense bed of Nevada Sand. The centrifuge model is subjected to a series of shaking events that represent near-fault and “ordinary” ground motions at a site in Los Angeles. Results show that site periods degrade as ground motion intensity increases with more pronounced degradation observed for near-fault ground motions as compared with ordinary ground motions. Additionally, the results indicate the importance of kinematic effects of embedded structures when considering SFSI effects

Seismic Performance Assessment in Dense Urban Environments: Evaluation of Nonlinear Building-Foundation Systems Using Centrifuge Tests

In dense urban areas, buildings are generally constructed in clusters, forming city blocks. New buildings are designed assuming their response is independent of adjacent buildings, which ignores potentially important structure-soil-structure-interaction (SSSI) effects. Although a few studies have revealed the significance of SSSI effects, validated simulation and design tools do not exist. In this paper, we present the results from the first in a series of centrifuge tests intended to investigate SSSI effects. Results herein are focused on the design and measured response of two model building-foundation systems placed on dense dry Nevada sand and tested at 55-g. The two models represent prototypical nine-story and three-story special moment resisting frame buildings, with the former structure supported by a three-level basement-mat and the later on isolated spread footings. Nonlinear response-history simulations are performed to aid in the design of the models, with particular attention to reproducing prototype building periods and nonlinear characteristics. Yielding of the model buildings is achieved using custom-designed fuses placed strategically throughout the superstructures. At present, the two models are placed as far apart as possible to characterize soil-structure interaction on individual buildings; subsequent experiments will move the structures in near proximity, allowing direct experimental assessment of structuresoil- structure-interaction

High School Quality is Associated with Cognition 58 Years Later

We leveraged a unique school-based longitudinal cohort—the Project Talent Aging Study—to examine whether attending higher quality schools is associated with cognitive performance among older adults in the United States (mean age = 74.8). Participants (n = 2,289) completed telephone neurocognitive testing. Six indicators of high school quality, reported by principals at the time of schooling, were predictors of respondents’ cognitive function 58 years later. To account for school-clustering, multilevel linear and logistic models were applied. We found that attending schools with a higher number of teachers with graduate training was the clearest predictor of later-life cognition, and school quality mattered especially for language abilities. Importantly, Black respondents (n = 239; 10.5 percentage) were disproportionately exposed to low quality high schools. Therefore, increased investment in schools, especially those that serve Black children, could be a powerful strategy to improve later life cognitive health among older adults in the United States

Interaction of tau with the RNA-Binding Protein TIA1 Regulates tau Pathophysiology and Toxicity

Dendritic mislocalization of microtubule associated protein tau is a hallmark of tauopathies, but the role of dendritic tau is unknown. We now report that tau interacts with the RNA-binding protein (RBP) TIA1 in brain tissue, and we present the brain-protein interactome network for TIA1. Analysis of the TIA1 interactome in brain tissue from wild-type (WT) and tau knockout mice demonstrates that tau is required for normal interactions of TIA1 with proteins linked to RNA metabolism, including ribosomal proteins and RBPs. Expression studies show that tau regulates the distribution of TIA1, and tau accelerates stress granule (SG) formation. Conversely, TIA1 knockdown or knockout inhibits tau misfolding and associated toxicity in cultured hippocampal neurons, while overexpressing TIA1 induces tau misfolding and stimulates neurodegeneration. Pharmacological interventions that prevent SG formation also inhibit tau pathophysiology. These studies suggest that the pathophysiology of tauopathy requires an intimate interaction with RNA-binding proteins