Heterologous prion-forming proteins interact to cross-seed aggregation in Saccharomyces cerevisiae

AbstractThe early stages of protein misfolding remain incompletely understood, as most mammalian proteinopathies are only detected after irreversible protein aggregates have formed. Cross-seeding, where one aggregated protein templates the misfolding of a heterologous protein, is one mechanism proposed to stimulate protein aggregation and facilitate disease pathogenesis. Here, we demonstrate the existence of cross-seeding as a crucial step in the formation of the yeast prion [PSI+], formed by the translation termination factor Sup35. We provide evidence for the genetic and physical interaction of the prion protein Rnq1 with Sup35 as a predominant mechanism leading to self-propagating Sup35 aggregation. We identify interacting sites within Rnq1 and Sup35 and determine the effects of breaking and restoring a crucial interaction. Altogether, our results demonstrate that single-residue disruption can drastically reduce the effects of cross-seeding, a finding that has important implications for human protein misfolding disorders.</jats:p

Precursor Analysis for Offshore Oil and Gas Drilling: From Prescriptive to Risk-Informed Regulation

The Oil Spill Commission’s chartered mission—to “develop options to guard against … any oil spills associated with offshore drilling in the future” (National Commission 2010)—presents a major challenge: how to reduce the risk of low-frequency oil spill events, and especially high-consequence events like the Deepwater Horizon accident, when historical experience contains few oil spills of material scale and none approaching the significance of the Deepwater Horizon. In this paper, we consider precursor analysis as an answer to this challenge, addressing first its development and use in nuclear reactor regulation and then its applicability to offshore oil and gas drilling. We find that the nature of offshore drilling risks, the operating information obtainable by the regulator, and the learning curve provided by 30 years of nuclear experience make precursor analysis a promising option available to the U.S. Bureau of Ocean Energy Management, Regulation and Enforcement (BOEMRE) to bring cost-effective, risk-informed oversight to bear on the threat of catastrophic oil spills.catastrophic oil spills, quantitative risk analysis, risk-informed regulation

Children’s episodic and generic reports of alleged abuse

With the present data, we explored the relations between the language of interviewer questions, children’s reports, and case and child characteristics in forensic interviews. Results clearly indicated that the type of questions posed by interviewers – either probing generic or episodic features of an event – was related to the specificity of information reported by children. Further, interviewers appeared to adjust their questioning strategies based on the frequency of the alleged abuse. Children alleging single instances of abuse were asked more episodic questions than those alleging multiple abuses. In contrast, children alleging multiple incidents of abuse were asked a greater proportion of generic questions. Given that investigators often seek forensically-relevant episodic information, it is recommended that training for investigators focus on recognition of prompt selection tendencies and developing strategies for posing non-suggestive, episodically focused questions

USING SATELLITE IMAGERY IN PREDICTING KANSAS FARMLAND VALUES

Can remotely sensed imagery improve hedonic land price models? A remotely sensed variable was added to a hedonic farmland value model as a proxy for land productivity. Land cover data were used to obtain urban and recreational effects as well. The urban and recreational effects were statistically significant but economically small. The remotely sensed productivity variable was statistically significant and economically large, indicating that knowing the "greenness" of the land increased the explanatory power of the hedonic price model. Thus, depending upon the cost of this information, including remotely sensed imagery in traditional hedonic land price models is economically beneficial.Land Economics/Use,

Prion-associated toxicity is rescued by elimination of cotranslational chaperones

The nascent polypeptide-associated complex (NAC) is a highly conserved but poorly characterized triad of proteins that bind near the ribosome exit tunnel. The NAC is the first cotranslational factor to bind to polypeptides and assist with their proper folding. Surprisingly, we found that deletion of NAC subunits in Saccharomyces cerevisiae rescues toxicity associated with the strong [PSI+] prion. This counterintuitive finding can be explained by changes in chaperone balance and distribution whereby the folding of the prion protein is improved and the prion is rendered nontoxic. In particular, the ribosome-associated Hsp70 Ssb is redistributed away from Sup35 prion aggregates to the nascent chains, leading to an array of aggregation phenotypes that can mimic both overexpression and deletion of Ssb. This toxicity rescue demonstrates that chaperone modification can block key steps of the prion life cycle and has exciting implications for potential treatment of many human protein conformational disorders

What is the Cost of a Preschool Program?

State and local governments that wish to establish or improve preschool programs need cost estimates to evaluate the magnitude of appropriations required. Yet even a casual scrutiny of available expenditure data reveals an enormous variance between the most expensive and least expensive preschool provisions. The purpose of this paper is to delineate the root causes of differences in per-student costs of states’ preschool programs and to suggest cost tradeoffs as different features such as smaller class size or longer school days are introduced or substituted for each other. These cost findings are contrasted with recent meta-analyses of the effectiveness of different program provisions. The goal of this paper is to advance the still nascent body of research on preschool cost effectiveness, and to aid state or local governments to assess the mix of characteristics that are most effective for any given budget constraint. The paper builds partially on the authors’ previous analysis of international preschool programs

The Cell and Molecular Biology of Neurodegenerative Diseases: An Overview

There is no abstract for this article

Comparing Costs of Early Childhood Care and Education Programs: An International Perspective

The purpose of this article is to outline the determinants of early childhood care and education (EccE) costs as well as a method for measuring them, and to set out available cost data provided by countries for their EccE endeavors. The analysis is based upon comparison of available data for 17 countries. We first address why costs may differ significantly for EccE from country to country. Second, we address why existing reporting of costs is highly inconsistent and typically incomplete, including an examination of disparities in reported EccE expenditures across countries. Third, we outline an appropriate way, known as the “ingredients method”, for determining costs that can provide consistent measurement for comparative purposes

Non-detection of L-band Line Emission from the Exoplanet HD189733b

We attempt to confirm bright non-local thermodynamic equilibrium (non-LTE) emission from the exoplanet HD 189733b at 3.25 μm, as recently reported by Swain et al. based on observations at low spectral resolving power (λ/δλ ≈ 30). Non-LTE emission lines from gas in an exoplanet atmosphere will not be significantly broadened by collisions, so the measured emission intensity per resolution element must be substantially brighter when observed at high spectral resolving power. We observed the planet before, during, and after a secondary eclipse event at a resolving power λ/δλ = 27, 000 using the NIRSPEC spectrometer on the Keck II telescope. Our spectra cover a spectral window near the peak found by Swain et al., and we compare emission cases that could account for the magnitude and wavelength dependence of the Swain et al. result with our final spectral residuals. To model the expected line emission, we use a general non-equilibrium formulation to synthesize emission features from all plausible molecules that emit in this spectral region. In every case, we detect no line emission to a high degree of confidence. After considering possible explanations for the Swain et al. results and the disparity with our own data, we conclude that an astrophysical source for the putative non-LTE emission is unlikely. We note that the wavelength dependence of the signal seen by Swain et al. closely matches the 2ν_2 band of water vapor at 300 K, and we suggest that an imperfect correction for telluric water is the source of the feature claimed by Swain et al