Air-Liquid-Interface Differentiated Human Nose Epithelium: A Robust Primary Tissue Culture Model of SARS-CoV-2 Infection

The global urgency to uncover medical countermeasures to combat the COVID-19 pandemic caused by the severe acute respiratory syndrome-coronavirus 2 (SARS-CoV-2) has revealed an unmet need for robust tissue culture models that faithfully recapitulate key features of human tissues and disease. Infection of the nose is considered the dominant initial site for SARS-CoV-2 infection and models that replicate this entry portal offer the greatest potential for examining and demonstrating the effectiveness of countermeasures designed to prevent or manage this highly communicable disease. Here, we test an air–liquid-interface (ALI) differentiated human nasal epithelium (HNE) culture system as a model of authentic SARS-CoV-2 infection. Progenitor cells (basal cells) were isolated from nasal turbinate brushings, expanded under conditionally reprogrammed cell (CRC) culture conditions and differentiated at ALI. Differentiated cells were inoculated with different SARS-CoV-2 clinical isolates. Infectious virus release into apical washes was determined by TCID₅₀, while infected cells were visualized by immunofluorescence and confocal microscopy. We demonstrate robust, reproducible SARS-CoV-2 infection of ALI-HNE established from different donors. Viral entry and release occurred from the apical surface, and infection was primarily observed in ciliated cells. In contrast to the ancestral clinical isolate, the Delta variant caused considerable cell damage. Successful establishment of ALI-HNE is donor dependent. ALI-HNE recapitulate key features of human SARS-CoV-2 infection of the nose and can serve as a pre-clinical model without the need for invasive collection of human respiratory tissue samples.     

Comparing transmission potential networks based on social network surveys,close contacts and environmental overlap in rural Madagascar

Social and spatial network analysis is an important approach for investigating infectious disease transmission, especially for pathogens transmitted directly between individuals or via environmental reservoirs. Given the diversity of ways to construct networks, however, it remains unclear how well networks constructed from different data types effectively capture transmission potential. We used empirical networks from a population in rural Madagascar to compare social network survey and spatial data-based networks of the same individuals. Close contact and environmental pathogen transmission pathways were modelled with the spatial data. We found that naming social partners during the surveys predicted higher close-contact rates and the proportion of environmental overlap on the spatial data-based networks. The spatial networks captured many strong and weak connections that were missed using social network surveys alone. Across networks, we found weak correlations among centrality measures (a proxy for superspreading potential). We conclude that social network surveys provide important scaffolding for understanding disease transmission pathways but miss contact-specific heterogeneities revealed by spatial data. Our analyses also highlight that the superspreading potential of individuals may vary across transmission modes. We provide detailed methods to construct networks for close-contact transmission pathogens when not all individuals simultaneously wear GPS trackers.     

The Role of Interleukins in Recurrent Implantation Failure: A Comprehensive Review of the Literature

Recurrent implantation failure (RIF) is a multifactorial condition affecting 10–15% of in vitro fertilization (IVF) couples. Data suggest that functional dysregulation of the endometrial immune system constitutes one of the main pathophysiological mechanisms leading to RIF. The aim of this article is to provide a thorough presentation and evaluation of the role of interleukins (ILs) in the pathogenesis of RIF. A comprehensive literature screening was performed summarizing current evidence. During implantation, several classes of ILs are secreted by epithelial and stromal endometrial cells, including IL-6, IL-10, IL-12, IL-15, IL-18, and the leukemia inhibitory factor. These ILs create a perplexing network that orchestrates both proliferation and maturation of uterine natural killer cells, controls the function of regulatory T and B cells inhibiting the secretion of antifetal antibodies, and supports trophoblast invasion and decidua formation. The existing data indicate associations between ILs and RIF. The extensive analysis performed herein concludes that the dysregulation of the ILs network indeed jeopardizes implantation leading to RIF. This review further proposes a mapping of future research on how to move forward from mere associations to robust molecular data that will allow an accurate profiling of ILs in turn enabling evidence-based consultancy and decision making when addressing RIF patients.     

Motion-based object segmentation using hysteresis and bidirectional inter-frame change detection in sequences with moving camera

We present an unsupervised motion-based object segmentation algorithm for video sequences with moving camera, employing bidirectional inter-frame change detection. For every frame, two error frames are generated using motion compensation. They are combined and a segmentation algorithm based on thresholding is applied. We employ a simple and effective error fusion scheme and consider spatial error localization in the thresholding step. We find the optimal weights for the weighted mean thresholding algorithm that enables unsupervised robust moving object segmentation. Further, a post processing step for improving the temporal consistency of the segmentation masks is incorporated and thus we achieve improved performance compared to the previously proposed methods. The experimental evaluation and comparison with other methods demonstrate the validity of the proposed method.     

Perceived versus objective urban opportunities and the migration of Venezuelan youths

A multivariate regression model incorporating both objective economic opportunity and objective quality-of-life measures is able to explain 65% of the variation in young adult in-migration rates for thirty Venezuelan cities in 1971. The objective variables mean annual temperature, level of secondary education, and objective income at the destination are largely responsible for this explanation. A second model, incorporating variables which measure perceived economic opportunity and perceived quality-of-life at the urban destination is then formulated. This perceptual model raises the level of explanation to 83%. Moreover, analysis of the regression coefficients for the objective variables in both models indicates that attractive factors are perceived correctly by migrants while repulsive factors are not.     

Dynamic elastic-plastic response of a containment vessel to fluid pressure pulses

The dynamic analysis of the wall of a fluid-filled unstiffened nuclear containment vessel, to the fluid pressure exerted on it when the relief valve discharge piping is cleared, is extended into the plastic range using two versions of an elastic-plastic shell theory.     

Discovery of [(2R,5R)-5-{[(5-fluoropyridin-2-yl)oxy]methyl}-2-methylpiperidin-1-yl][5-methyl-2-(pyrimidin-2-yl)phenyl]methanone (MK-6096): a dual orexin receptor antagonist with potent sleep-promoting properties

Insomnia is a common disorder that can be comorbid with other physical and psychological illnesses. Traditional management of insomnia relies on general central nervous system (CNS) suppression using GABA modulators. Many of these agents fail to meet patient needs with respect to sleep onset, maintenance, and next-day residual effects and have issues related to tolerance, memory disturbances, and balance. Orexin neuropeptides are central regulators of wakefulness, and orexin antagonism has been identified as a novel mechanism for treating insomnia with clinical proof of concept. Herein we describe the discovery of a series of α-methylpiperidine carboxamide dual orexin?1 and orexin?2 receptor (OX(1) R/OX(2) R) antagonists (DORAs). The design of these molecules was inspired by earlier work from this laboratory in understanding preferred conformational properties for potent orexin receptor binding. Minimization of 1,3-allylic strain interactions was used as a design principle to synthesize 2,5-disubstituted piperidine carboxamides with axially oriented substituents including DORA 28. DORA 28 (MK-6096) has exceptional in?vivo activity in preclinical sleep models, and has advanced into phase?II clinical trials for the treatment of insomnia.     

ITS-90 Density of Water Formulation for Volumetric Standards Calibration

A new formulation of the density of air-saturated water as a function of temperature on the 1990 International Temperature Scale (ITS-90) is presented. Also, a new equation for calculating isothermal compressibility as a function of temperature on ITS-90 was developed. The equations are to be used to calculate the density of water, in the temperature range 5 to 40 °C on ITS-90, used in the gravimetric determination of the volume of volumetric standards.     

The Constant Shape Parameter Assumption in Weibull Regression

ABSTRACT

The usual assumption in Weibull regression is that the scale parameter is a function of the predictor variables, and the shape parameter is constant. We consider the problem of estimating parameters in the presence of a nonconstant shape parameter and the effect of assuming a constant shape parameter when it really is not constant. We consider both classical and Bayesian methods of estimation. The misspecification of a constant shape parameter can lead to a loss of power for tests regarding the slope parameters. We find that prediction intervals can be inaccurate when the shape parameter is incorrectly assumed to be constant.