Modeling Amyloid Beta Peptide Insertion into Lipid Bilayers

Inspired by recent suggestions that the Alzheimer's amyloid beta peptide (A beta) can insert into cell membranes and form harmful ion channels, we model insertion of the 40 and 42 residue forms of the peptide into cell membranes using a Monte Carlo code which is specific at the amino acid level. We examine insertion of the regular A-beta peptide as well as mutants causing familial Alzheimer's disease, and find that all but one of the mutants change the insertion behavior by causing the peptide to spend more simulation steps in only one leaflet of the bilayer. We also find that A-beta 42, because of the extra hydrophobic residues relative to A-beta 40, is more likely to adopt this conformation than A-beta 40 in both wild-type and mutant forms. We argue qualitatively why these effects happen. Here, we present our results and develop the hypothesis that this partial insertion increases the probability of harmful channel formation. This hypothesis can partly explain why these mutations are neurotoxic simply due to peptide insertion behavior. We further apply this model to various artificial A-beta mutants which have been examined experimentally, and offer testable experimental predictions contrasting the roles of aggregation and insertion with regard to toxicity of A-beta mutants. These can be used through further experiments to test our hypothesis.Comment: 14 pages; 8 figures; 2nd revisio

Introduction

Introduction to issu

Impediments to mixing classical and quantum dynamics

The dynamics of systems composed of a classical sector plus a quantum sector is studied. We show that, even in the simplest cases, (i) the existence of a consistent canonical description for such mixed systems is incompatible with very basic requirements related to the time evolution of the two sectors when they are decoupled. (ii) The classical sector cannot inherit quantum fluctuations from the quantum sector. And, (iii) a coupling among the two sectors is incompatible with the requirement of physical positivity of the theory, i.e., there would be positive observables with a non positive expectation value.Comment: RevTex, 21 pages. Title slightly modified and summary section adde

Sex-specific ultrasonic vocalization patterns and alcohol consumption in high alcohol-drinking (HAD-1) rats

Ultrasonic vocalizations (USVs) have been established as an animal model of emotional status and are often utilized in drug abuse studies as motivational and emotional indices. Further USV functionality has been demonstrated in our recent work showing accurate identification of selectively-bred high versus low alcohol-consuming male rats ascertained exclusively from 22 to 28 kHz and 50–55 kHz FM USV acoustic parameters. With the hypothesis that alcohol-sensitive sex differences could be revealed through USV acoustic parameters, the present study examined USVs and alcohol consumption in male and female selectively bred high-alcohol drinking (HAD-1) rats. For the current study, we examined USV data collected during a 12-week experiment in male and female HAD-1 rats. Experimental phases included Baseline (2 weeks), 4-h EtOH Access (4 weeks), 24-h EtOH Access (4 weeks) and Abstinence (2 weeks). Findings showed that both male and female HAD-1 rats spontaneously emitted a large number of 22–28 kHz and 50–55 kHz FM USVs and that females drank significantly more alcohol compared to males over the entire course of the experiment. Analyses of USV acoustic characteristics (i.e. mean frequency, duration, bandwidth and power) revealed distinct sex-specific phenotypes in both 50–55 kHz FM and 22–28 kHz USV transmission that were modulated by ethanol exposure. Moreover, by using a linear combination of these acoustic characteristics, we were able to develop binomial logistic regression models able to discriminate between male and female HAD-1 rats with high accuracy. Together these results highlight unique emotional phenotypes in male and female HAD-1 rats that are differentially modulated by alcohol experience

Alcohol-Naïve USVs Distinguish Male HAD-1 from LAD-1 Rat Strains

Ultrasonic vocalizations (USVs) are mediated through specific dopaminergic and cholinergic neural pathways and serve as real-time measures of positive and negative emotional status in rodents. Although most USV studies focus primarily on USV counts, each USV possesses a number of characteristics shown to reflect activity in the associated neurotransmitter system. In the present study, we recorded spontaneously emitted USVs from alcohol-naïve high alcohol drinking (HAD-1) and low alcohol drinking (LAD-1) rats. Using our recently developed WAAVES algorithm we quantified four acoustic characteristics (mean frequency, duration, power and bandwidth) from each 22 – 28 kHz and 50 – 55 kHz frequency modulated (FM) USV. This rich USV representation allowed us to apply advanced statistical techniques to identify the USV acoustic characteristics that distinguished HAD-1 from LAD-1 rats. Linear mixed models (LMM) examined the predictability of each USV characteristic in isolation and linear discriminant analysis (LDA) and binomial logistic regression examined the predictability of linear combinations of the USV characteristics as a group. Results revealed significant differences in acoustic characteristics between HAD-1 and LAD-1 rats in both 22 – 28 kHz and 50 – 55 kHz FM USVs. In other words, these rats selectively bred for high- and low-alcohol consumption can be identified as HAD-1 or LAD-1 rats with high classification accuracy (approx. 92-100%) exclusively on the basis of their emitted 22-28 kHz and 50-55 kHz FM USV acoustic characteristics. In addition, acoustic characteristics of 22 – 28 kHz and 50 – 55 kHz FM USVs emitted by alcohol-naïve HAD-1 and LAD-1 rats significantly correlate with their future alcohol consumption. Our current findings provide novel evidence that USV acoustic characteristics can be used to discriminate between alcohol-naïve HAD-1 and LAD-1 rats, and may serve as biomarkers in rodents with a predisposition for, or against, excessive alcohol intake

Alcohol-preferring P rats emit spontaneous 22-28 kHz ultrasonic vocalizations that are altered by acute and chronic alcohol experience

BACKGROUND: Emotional states are often thought to drive excessive alcohol intake and influence the development of alcohol use disorders. To gain insight into affective properties associated with excessive alcohol intake, we utilized ultrasonic vocalization (USV) detection and analyses to characterize the emotional phenotype of selectively bred alcohol-preferring (P) rats; an established animal model of excessive alcohol intake. USVs emitted by rodents have been convincingly associated with positive (50-55 kHz frequency-modulated [FM]) and negative (22-28 kHz) affective states. Therefore, we hypothesized that 50-55 and 22-28 kHz USV emission patterns in P rats would reveal a unique emotional phenotype sensitive to alcohol experience. METHODS: 50-55 kHz FM and 22-28 kHz USVs elicited from male P rats were assessed during access to water, 15 and 30% EtOH (v/v). Ethanol (EtOH; n = 12) or water only (Control; n = 4) across 8 weeks of daily drinking-in-the-dark (DID) sessions. RESULTS: Spontaneous 22-28 kHz USVs are emitted by alcohol-naïve P rats and are enhanced by alcohol experience. During DID sessions when alcohol was not available (e.g., "EtOH OFF" intervals), significantly more 22-28 kHz than 50-55 kHz USVs were elicited, while significantly more 50-55 kHz FM than 22-28 kHz USVs were emitted when alcohol was available (e.g., "EtOH ON" intervals). In addition, USV acoustic property analyses revealed chronic effects of alcohol experience on 22-28 kHz USV mean frequency, indicative of lasting alcohol-mediated alterations to neural substrates underlying emotional response. CONCLUSIONS: Our findings demonstrate that acute and chronic effects of alcohol exposure are reflected in changes in 22-28 and 50-55 kHz FM USV counts and acoustic patterns. These data support the notion that initiation and maintenance of alcohol intake in P rats may be due to a unique, alcohol-responsive emotional phenotype and further suggest that spontaneous 22-28 kHz USVs serve as behavioral markers for excessive drinking vulnerability

Dynamics of glomerular ultrafiltration: VI. Studies in the primate

Dynamics of glomerular ultrafiltration: VI. Studies in the primate. Pressures and flows were measured in accessible surface glomeruli of the squirrel monkey under conditions of normal hydropenia. Mean glomerular capillary hydrostatic pressure and the mean glomerular transcapillary hydrostatic pressure difference (ΔP) averaged approximately 45 mm Hg and 35 mm Hg, respectively. These findings are in close accord with recent direct estimates in the rat. The net driving force for ultrafiltration was found to decline from a maximum value of about 12 mm Hg at the afferent end of the glomerular capillary network essentially to zero by the efferent end, indicating that, in the monkey as in the rat, filtration pressure equilibrium is achieved under normal hydropenic conditions. The monkey differs from the rat in one important respect, however, in that, as has long been recognized, the monkey tends to have higher systemic total plasma protein concentrations (CA) than the rat. This is of interest since monkey, like man, is found to have lower filtration fractions than the rat. Since ΔP is found to be essentially similar in monkey and rat, and since, at filtration pressure equilibrium, filtration fraction is determined by ΔP and CA, these observed differences in filtration fraction between rodent and primate must therefore be due to these differences in CA

Alcohol enhances unprovoked 22-28 kHz USVs and suppresses USV mean frequency in High Alcohol Drinking (HAD-1) male rats

Heightened emotional states increase impulsive behaviors such as excessive ethanol consumption in humans. Though positive and negative affective states in rodents can be monitored in real-time through ultrasonic vocalization (USV) emissions, few animal studies have focused on the role of emotional status as a stimulus for initial ethanol drinking. Our laboratory has recently developed reliable, high-speed analysis techniques to compile USV data during multiple-hour drinking sessions. Since High Alcohol Drinking (HAD-1) rats are selectively bred to voluntarily consume intoxicating levels of alcohol, we hypothesized that USVs emitted by HAD-1 rats would reveal unique emotional phenotypes predictive of alcohol intake and sensitive to alcohol experience. In this study, male HAD-1 rats had access to water, 15% and 30% EtOH or water only (i.e., Controls) during 8 weeks of daily 7-h drinking-in-the-dark (DID) sessions. USVs, associated with both positive (i.e., 50-55 kHz frequency-modulated or FM) and negative (i.e., 22-28 kHz) emotional states, emitted during these daily DID sessions were examined. Findings showed basal 22-28 kHz USVs were emitted by both EtOH-Naïve (Control) and EtOH-experienced rats, alcohol experience enhanced 22-28 kHz USV emissions, and USV acoustic parameters (i.e., mean frequency in kHz) of both positive and negative USVs were significantly suppressed by chronic alcohol experience. These data suggest that negative affective status initiates and maintains excessive alcohol intake in selectively bred HAD-1 rats and support the notion that unprovoked emissions of negative affect-associated USVs (i.e., 22-28 kHz) predict vulnerability to excessive alcohol intake in distinct rodent models

Reproducibility of hospital rankings based on centers for Medicare & Medicaid Services Hospital Compare measures as a function of measure reliability

Importance: Unreliable performance measures can mask poor-quality care and distort financial incentives in value-based purchasing. Objective: To examine the association between test-retest reliability and the reproducibility of hospital rankings. Design, Setting, and Participants: In a cross-sectional design, Centers for Medicare & Medicaid Services Hospital Compare data were analyzed for the 2017 (based on 2014-2017 data) and 2018 (based on 2015-2018 data) reporting periods. The study was conducted from December 13, 2020, to September 30, 2021. This analysis was based on 28 measures, including mortality (acute myocardial infarction, congestive heart failure, pneumonia, and coronary artery bypass grafting), readmissions (acute myocardial infarction, congestive heart failure, pneumonia, and coronary artery bypass grafting), and surgical complications (postoperative acute kidney failure, postoperative respiratory failure, postoperative sepsis, and failure to rescue). Exposures: Measure reliability based on test-retest reliability testing. Main Outcomes and Measures: The reproducibility of hospital rankings was quantified by calculating the reclassification rate across the 2017 and 2018 reporting periods after categorizing the hospitals into terciles, quartiles, deciles, and statistical outliers. Linear regression analysis was used to examine the association between the reclassification rate and the intraclass correlation coefficient for each of the classification systems. Results: The analytic cohort consisted of 28 measures from 4452 hospitals with a median of 2927 (IQR, 2378-3160) hospitals contributing data for each measure. The hospitals participating in the Inpatient Prospective Payment System (n = 3195) had a median bed size of 141 (IQR, 69-261), average daily census of 70 (IQR, 24-155) patients, and a median disproportionate share hospital percentage of 38.2% (IQR, 18.7%-36.6%). The median intraclass correlation coefficient was 0.78 (IQR, 0.72-0.81), ranging between 0.50 and 0.85. The median reclassification rate was 70% (IQR, 62%-71%) when hospitals were ranked by deciles, 43% (IQR, 39%-45%) when ranked by quartiles, 34% (IQR, 31%-36%) when ranked by terciles, and 3.8% (IQR, 2.0%-6.2%) when ranked by outlier status. Increases in measure reliability were not associated with decreases in the reclassification rate. Each 0.1-point increase in the intraclass correlation coefficient was associated with a 6.80 (95% CI, 2.28-11.30; P = .005) percentage-point increase in the reclassification rate when hospitals were ranked into performance deciles, 4.15 (95% CI, 1.16-7.14; P = .008) when ranked into performance quartiles, 1.47 (95% CI, 1.84, 4.77; P = .37) when ranked into performance terciles, and 3.70 (95% CI, 1.30-6.09; P = .004) when ranked by outlier status. Conclusions and Relevance: In this study, more reliable measures were not associated with lower rates of reclassifying hospitals using test-retest reliability testing. These findings suggest that measure reliability should not be assessed with test-retest reliability testing

An Extremely Deep Wide-Field Near-Infrared Survey: Bright Galaxy Counts and Local Large Scale Structure

We present a deep, wide-field near-infrared (NIR) survey over five widely separated fields at high Galactic latitude covering a total of ~ 3 deg^2 in J, H, and Ks. The deepest areas of the data (~ 0.25 deg^2) extend to a 5 sigma limiting magnitude of JHKs > 24 in the AB magnitude system. Although depth and area vary from field to field, the overall depth and large area of this dataset make it one of the deepest wide-field NIR imaging surveys to date. This paper discusses the observations, data reduction, and bright galaxy counts in these fields. We compare the slope of the bright galaxy counts with the Two Micron All Sky Survey (2MASS) and other counts from the literature and explore the relationship between slope and supergalactic latitude. The slope near the supergalactic equator is sub- Euclidean on average pointing to the possibility of a decreasing average space density of galaxies by ~ 10-15% over scales of ~ 250-350 Mpc. On the contrary, the slope at high supergalactic latitudes is strongly super-Euclidean on average suggesting an increase in the space density of galaxies as one moves from the voids just above and below the supergalactic plane out to distances of ~ 250-350 Mpc. These results suggest that local large scale structure could be responsible for large discrepancies in the measured slope between different studies in the past. In addition, the local universe away from the supergalactic plane appears to be underdense by ~ 25-100% relative to the space densities of a few hundred megaparsecs distant. Subject headings: cosmology: observations and large scale structure of universe-galaxies: fundamental parameters (counts)-infrared: galaxiesComment: Accepted to ApJS, 18 Pages, 14 Figures, 8 Table