Bonding as a Positive Youth Development Construct: A Conceptual Review

The concept of bonding as a positive youth development construct is reviewed in this paper. The goals are fourfold. First, theoretical perspectives of bonding are delineated. Secondly, the relationships among bonding to caregivers, friends, romantic partners, as well as teachers, and adolescents’ positive developmental outcomes are reviewed. Thirdly, with theoretical and empirical support, a discussion on how to promote bonding among adolescents is offered. Finally, a critical review on the cultural issues of bonding is provided

A high-resolution and observationally constrained OMI NO₂ satellite retrieval

This work presents a new high-resolution NO2 dataset derived from the NASA Ozone Monitoring Instrument (OMI) NO2 version 3.0 retrieval that can be used to estimate surface-level concentrations. The standard NASA product uses NO2 vertical profile shape factors from a 1.25°  ×  1° (∼  110 km  ×  110 km) resolution Global Model Initiative (GMI) model simulation to calculate air mass factors, a critical value used to determine observed tropospheric NO2 vertical columns. To better estimate vertical profile shape factors, we use a high-resolution (1.33 km  ×  1.33 km) Community Multi-scale Air Quality (CMAQ) model simulation constrained by in situ aircraft observations to recalculate tropospheric air mass factors and tropospheric NO2 vertical columns during summertime in the eastern US. In this new product, OMI NO2 tropospheric columns increase by up to 160 % in city centers and decrease by 20–50 % in the rural areas outside of urban areas when compared to the operational NASA product. Our new product shows much better agreement with the Pandora NO2 and Airborne Compact Atmospheric Mapper (ACAM) NO2 spectrometer measurements acquired during the DISCOVER-AQ Maryland field campaign. Furthermore, the correlation between our satellite product and EPA NO2 monitors in urban areas has improved dramatically: r2  =  0.60 in the new product vs. r2  =  0.39 in the operational product, signifying that this new product is a better indicator of surface concentrations than the operational product. Our work emphasizes the need to use both high-resolution and high-fidelity models in order to recalculate satellite data in areas with large spatial heterogeneities in NOx emissions. Although the current work is focused on the eastern US, the methodology developed in this work can be applied to other world regions to produce high-quality region-specific NO2 satellite retrievals

Accounting for variability in ion current recordings using a mathematical model of artefacts in voltage-clamp experiments

Mathematical models of ion channels, which constitute indispensable components of action potential models, are commonly constructed by fitting to whole-cell patch-clamp data. In a previous study, we fitted cell-specific models to hERG1a (Kv11.1) recordings simultaneously measured using an automated high-throughput system, and studied cell-cell variability by inspecting the resulting model parameters. However, the origin of the observed variability was not identified. Here, we study the source of variability by constructing a model that describes not just ion current dynamics, but the entire voltage-clamp experiment. The experimental artefact components of the model include: series resistance, membrane and pipette capacitance, voltage offsets, imperfect compensations made by the amplifier for these phenomena, and leak current. In this model, variability in the observations can be explained by either cell properties, measurement artefacts, or both. Remarkably, by assuming that variability arises exclusively from measurement artefacts, it is possible to explain a larger amount of the observed variability than when assuming cell-specific ion current kinetics. This assumption also leads to a smaller number of model parameters. This result suggests that most of the observed variability in patch-clamp data measured under the same conditions is caused by experimental artefacts, and hence can be compensated for in post-processing by using our model for the patch-clamp experiment. This study has implications for the question of the extent to which cell-cell variability in ion channel kinetics exists, and opens up routes for better correction of artefacts in patch-clamp data. This article is part of the theme issue 'Uncertainty quantification in cardiac and cardiovascular modelling and simulation'

Leak current, even with gigaohm seals, can cause misinterpretation of stem cell-derived cardiomyocyte action potential recordings

Background and AimsHuman induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs) have become an essential tool to study arrhythmia mechanisms. Much of the foundational work on these cells, and the computational models built from the resultant data, has overlooked the contribution of seal-leak current on the immature and heterogeneous phenotype that has come to define these cells. The aim of this study is to understand the effect of seal-leak current on recordings of action potential (AP) morphology.MethodsAPs were recorded in human iPSC-CMs using patch clamp and simulated using previously published mathematical models.ResultsOur in silico and in vitro studies demonstrate how seal-leak current depolarises APs, substantially affecting their morphology, even with seal resistances (Rseal) above 1 GΩ. We show that compensation of this leak current is difficult due to challenges with obtaining accurate measures of Rseal during an experiment. Using simulation, we show that Rseal measures: 1) change during an experiment, invalidating the use of pre-rupture values, and 2) are polluted by the presence of transmembrane currents at every voltage. Finally, we posit that the background sodium current in baseline iPSC-CM models imitates the effects of seal-leak current and is increased to a level that masks the effects of seal-leak current on iPSC-CMs.ConclusionBased on these findings, we make recommendations to improve iPSC-CM AP data acquisition, interpretation, and model-building. Taking these recommendations into account will improve our understanding of iPSC-CM physiology and the descriptive ability of models built from such data

Leak current, even with gigaohm seals, can cause misinterpretation of stem cell-derived cardiomyocyte action potential recordings

Aims: Human-induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs) have become an essential tool to study arrhythmia mechanisms. Much of the foundational work on these cells, as well as the computational models built from the resultant data, has overlooked the contribution of seal-leak current on the immature and heterogeneous phenotype that has come to define these cells. The aim of this study is to understand the effect of seal-leak current on recordings of action potential (AP) morphology. Methods and results: Action potentials were recorded in human iPSC-CMs using patch clamp and simulated using previously published mathematical models

Resolving artefacts in voltage-clamp experiments with computational modelling: an application to fast sodium current recordings

Cellular electrophysiology is the foundation of many fields, from basic science in neurology, cardiology, oncology to safety critical applications for drug safety testing, clinical phenotyping, etc. Patch-clamp voltage clamp is the gold standard technique for studying cellular electrophysiology. Yet, the quality of these experiments is not always transparent, which may lead to erroneous conclusions for studies and applications. Here, we have developed a new computational approach that allows us to explain and predict the experimental artefacts in voltage-clamp experiments. The computational model captures the experimental procedure and its inadequacies, including: voltage offset, series resistance, membrane capacitance and (imperfect) amplifier compensations, such as series resistance compensation and supercharging. The computational model was validated through a series of electrical model cell experiments. Using this computational approach, the artefacts in voltage-clamp experiments of cardiac fast sodium current, one of the most challenging currents to voltage clamp, were able to be resolved and explained through coupling the observed current and the simulated membrane voltage, including some typically observed shifts and delays in the recorded currents. We further demonstrated that the typical way of averaging data for current-voltage relationships would lead to biases in the peak current and shifts in the peak voltage, and such biases can be in the same order of magnitude as those differences reported for disease-causing mutations. Therefore, the presented new computational pipeline will provide a new standard of assessing the voltage-clamp experiments and interpreting the experimental data, which may be able to rectify and provide a better understanding of ion channel mutations and other related applications

Microarray-Based Analysis of Differential Gene Expression between Infective and Noninfective Larvae of Strongyloides stercoralis

Strongyloides stercoralis is a soil-transmitted helminth that affects an estimated 30–100 million people worldwide. Chronically infected persons who are exposed to corticosteroids can develop disseminated disease, which carries a high mortality (87–100%) if untreated. Despite this, little is known about the fundamental biology of this parasite, including the features that enable infection. We developed the first DNA microarray for this parasite and used it to compare infective third-stage larvae (L3i) with non-infective first stage larvae (L1). Using this method, we identified 935 differentially expressed genes. Functional characterization of these genes revealed L3i biased expression of heat shock proteins and genes with products that have previously been shown to be immunoreactive in infected humans. Genes putatively involved in transcription were found to have L1 biased expression. Potential chemotherapeutic and vaccine targets such as far-1, ucr 2.1 and hsp-90 were identified for further study

Emerging interdependence between stock values during financial crashes

To identify emerging interdependencies between traded stocks we investigate the behavior of the stocks of FTSE 100 companies in the period 2000-2015, by looking at daily stock values. Exploiting the power of information theoretical measures to extract direct influences between multiple time series, we compute the information flow across stock values to identify several different regimes. While small information flows is detected in most of the period, a dramatically different situation occurs in the proximity of global financial crises, where stock values exhibit strong and substantial interdependence for a prolonged period. This behavior is consistent with what one would generally expect from a complex system near criticality in physical systems, showing the long lasting effects of crashes on stock markets

Metamorphic testing: a review of challenges and opportunities

Metamorphic testing is an approach to both test case generation and test result verification. A central element is a set of metamorphic relations, which are necessary properties of the target function or algorithm in relation to multiple inputs and their expected outputs. Since its first publication, we have witnessed a rapidly increasing body of work examining metamorphic testing from various perspectives, including metamorphic relation identification, test case generation, integration with other software engineering techniques, and the validation and evaluation of software systems. In this paper, we review the current research of metamorphic testing and discuss the challenges yet to be addressed. We also present visions for further improvement of metamorphic testing and highlight opportunities for new research