Yeast (Saccharomyces cerevisiae) has an innate ability to withstand high levels of ethanol that would prove lethal to or severely impair the physiology of other organisms. Significant efforts have been undertaken to elucidate the biochemical and biophysical mechanisms of how ethanol interacts with lipid bilayers and cellular membranes. This research has implicated the yeast cellular membrane as the primary target of the toxic effects of ethanol. Analysis of model membrane systems exposed to ethanol has demonstrated ethanol's perturbing effect on lipid bilayers, and altering the lipid composition of these model bilayers can mitigate the effect of ethanol. In addition, cell membrane composition has been correlated with the ethanol tolerance of yeast cells. However, the physical phenomena behind this correlation are likely to be complex. Previous work based on often divergent experimental conditions and time-consuming low-resolution methodologies that limit large-scale analysis of yeast fermentations has fallen short of revealing shared mechanisms of alcohol tolerance in Saccharomyces cerevisiae. Lipidomics, a modern mass spectrometry-based approach to analyze the complex physiological regulation of lipid composition in yeast and other organisms, has helped to uncover potential mechanisms for alcohol tolerance in yeast. Recent experimental work utilizing lipidomics methodologies has provided a more detailed molecular picture of the relationship between lipid composition and ethanol tolerance. While it has become clear that the yeast cell membrane composition affects its ability to tolerate ethanol, the molecular mechanisms of yeast alcohol tolerance remain to be elucidated.

Establishment of the [GAR ⁺] prion in Saccharomyces cerevisiae reduces both transcriptional expression of the HXT3 hexose transporter gene and fermentation capacity in high sugar conditions. We evaluated the impact of deletion of the HXT3 gene on the expression of [GAR ⁺] prion phenotype in a vineyard isolate, UCD932, and found that changes in fermentation capacity were observable even with complete loss of the Hxt3 transporter, suggesting other cellular functions affecting fermentation rate may be impacted in [GAR ⁺] strains. In a comparison of isogenic [GAR ⁺] and [gar ^-] strains, localization of the Pma1 plasma membrane ATPase showed differences in distribution within the membrane. In addition, plasma membrane lipid composition varied between the two cell types. Oxygen uptake was decreased in prion induced cells suggesting membrane changes affect plasma membrane functionality beyond glucose transport. Thus, multiple cell surface properties are altered upon induction of the [GAR ⁺] prion in addition to changes in expression of the HXT3 gene. We propose a model wherein [GAR ⁺] prion establishment within a yeast population is associated with modulation of plasma membrane functionality, fermentation capacity, niche dominance, and cell physiology to facilitate growth and mitigate cytotoxicity under certain environmental conditions. Down-regulation of expression of the HXT3 hexose transporter gene is only one component of a suite of physiological differences. Our data show the [GAR ⁺] prion state is accompanied by multiple changes in the yeast cell surface that prioritize population survivability over maximizing metabolic capacity and enable progeny to establish an alternative adaptive state while maintaining reversibility.

A CsI salt-based cathode which is capable of producing a modest perveance, 10 s of A/cm2 electron beam for several microseconds pulse lengths, and has little susceptibility to diode closure has been experimentally characterized. This explosive field-emission CsI-coated carbon fiber cathode has operated in modest 10-5 Torr vacuums at voltages up to 160 kV, and can easily be configured to provide space-charge-limited solid or annular electron beams in arbitrarily large diameter configurations. The CsI cathode has demonstrated negligible closure for 2 μs pulses, and has operated for 200 shots with no degradation in cathode performance. Data on the operating performance of this salt cathode, including effective gap time history and streak photographs demonstrating uniformity of the current density, are presented. A comparison of CsI cathode performance with a velvet explosive field emitting cathode used in electron-beam production is also presented. © 1995 American Institute of Physics.

Two-phase noble liquid detectors, with large target masses and effective background reduction, are currently leading the dark matter direct detection for WIMP masses above a few GeV. Due to their sensitivity to single ionized electron signals, these detectors were shown to also have strong constraints for sub-GeV dark matter via their scattering on electrons. In fact, the most stringent direct detection constraints for sub-GeV dark matter down to as low as 5 MeV come from noble liquid detectors, namely XENON10, DarkSide-50, XENON100 and XENON1T, although these experiments still suffer from high background at single or a few electron level. LBECA is a planned 100-kg scale liquid xenon detector with significant reduction of the single and a few electron background. The experiment will improve the sensitivity to sub-GeV dark matter by three orders of magnitude compared to the current best constraints.

Background: Despite the substantial burden of asthma-related emergency department (ED) visits, there have been no recent multicenter efforts to characterize this high-risk population. Objective: We aimed to characterize patients with asthma according to their frequency of ED visits and to identify factors associated with frequent ED visits. Methods: A multicenter chart review study of 48 EDs across 23 US states. We identified ED patients ages 18 to 54 years with acute asthma during 2011 and 2012. Primary outcome was frequency of ED visits for acute asthma in the past year, excluding the index ED visit. Results: Of the 1890 enrolled patients, 863 patients (46%) had 1 or more (frequent) ED visits in the past year. Specifically, 28% had 1 to 2 visits, 11% had 3 to 5 visits, and 7% had 6 or more visits. Among frequent ED users, guideline-recommended management was suboptimal. For example, of patients with 6 or more ED visits, 85% lacked evidence of prior evaluation by an asthma specialist, and 43% were not treated with inhaled corticosteroids. In a multivariable model, significant predictors of frequent ED visits were public insurance, no insurance, and markers for chronic asthma severity (all P < .05). Stronger associations were found among those with a higher frequency of asthma-related ED visits (eg, 6 or more ED visits). Conclusion: This multicenter study of US adults with acute asthma demonstrated many frequent ED users and suboptimal preventive management in this high-risk population. Future reductions in asthma morbidity and associated health care utilization will require continued efforts to bridge these majorgaps in asthma care.

The Majorana Collaboration is operating an array of high-purity Ge detectors to search for the neutrinoless double-β decay of Ge76. The Majorana Demonstrator consists of 44.1 kg of Ge detectors (29.7 kg enriched to 88% in Ge76) split between two modules constructed from ultraclean materials. Both modules are contained in a low-background shield at the Sanford Underground Research Facility in Lead, South Dakota. We present updated results on the search for neutrinoless double-β decay in Ge76 with 26.0±0.5 kg yr of enriched exposure. With the Demonstrator's energy resolution of 2.53 keV FWHM at Qββ, which is the best among all neutrinoless double-β decay experiments, we observe one event in the region of interest with 0.65 events expected from the estimated background, resulting in a lower limit on the Ge76 neutrinoless double-β decay half-life of 2.7×1025 yr [90% confidence level (CL)] with a median sensitivity of 4.8×1025 yr (90% CL). Depending on the matrix elements used, a 90% CL upper limit on the effective Majorana neutrino mass in the range of 200-433 meV is obtained. The measured background in the configurations with full shielding and optimized grounding is 11.9±2.0 counts/(FWHM t yr).

Introduction

Cluster randomized crossover trials are often faced with a dilemma when selecting an optimal model of consent, as the traditional model of obtaining informed consent from participant's before initiating any trial related activities may not be suitable. We describe our experience of engaging patient advisors to identify an optimal model of consent for the PREP-IT trials. This paper also examines surrogate measures of success for the selected model of consent.

Methods

The PREP-IT program consists of two multi-center cluster randomized crossover trials that engaged patient advisors to determine an optimal model of consent. Patient advisors and stakeholders met regularly and reached consensus on decisions related to the trial design including the model for consent. Patient advisors provided valuable insight on how key decisions on trial design and conduct would be received by participants and the impact these decisions will have.

Results

Patient advisors, together with stakeholders, reviewed the pros and cons and the requirements for the traditional model of consent, deferred consent, and waiver of consent. Collectively, they agreed upon a deferred consent model, in which patients may be approached for consent after their fracture surgery and prior to data collection. The consent rate in PREP-IT is 80.7%, and 0.67% of participants have withdrawn consent for participation.

Discussion

Involvement of patient advisors in the development of an optimal model of consent has been successful. Engagement of patient advisors is recommended for other large trials where the traditional model of consent may not be optimal.