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Computational models enable scientists to understand observed dynamics, uncover rules underlying behaviors, predict experimental outcomes, and generate new hypotheses. There are countless modeling approaches that can be used to characterize biological systems, further multiplied when accounting for the variety of model design choices. Many studies focus on the impact of model parameters on model output and performance; fewer studies investigate the impact of model design choices on biological insight. Here we demonstrate why model design choices should be deliberate and intentional in context of the specific research system and question. In this study, we analyze agnostic and broadly applicable modeling choices at three levels—system, cell, and environment—within the same agent-based modeling framework to interrogate their impact on temporal, spatial, and single-cell emergent dynamics. We identify key considerations when making these modeling choices, including the (i) differences between qualitative vs. quantitative results driven by choices in system representation, (ii) impact of cell-to-cell variability choices on cell-level and temporal trends, and (iii) relationship between emergent outcomes and choices of nutrient dynamics in the environment. This generalizable investigation can help guide the choices made when developing biological models that aim to characterize spatial-temporal dynamics.

Objectives To identify the most frequently used atrial fibrillation-specific quality of life (QoL) instruments across atrial fibrillation (AF) ablation studies and to perform a systematic review of the most frequently used instrument’s measurement properties. This study uses quality of life instruments as an overarching term for any patient reported outcome measure that assesses a person’s health related well-being, functional status, and disease related symptoms. Methods A literature mapping exercise was undergone to identify the most frequently used AF-specific QoL instruments across AF ablation studies published from 2016 to 2021. A systematic review of the most frequently used AF QoL instruments identified from the mapping exercise was performed using the COSMIN guidelines for systematic reviews of patient-reported outcome measurements. A systematic search was conducted in Ovid MEDLINE, Ovid Embase, Ovid PsycINFO, EBSCO CINAHL, and Cochrane CENTRAL. The search used variations of the keywords “atrial fibrillation”, “quality of life”, and “catheter ablation”. Results Forty-five instruments were identified via the literature mapping exercise. After excluding non-patient reported outcome instruments, non-AF specific instruments, and instruments appearing only once, six instruments were identified: AF Effect on QualiTy-of-Life (AFEQT), AF Severity Scale, Minnesota Living with Heart Failure Instrument, AF Quality of Life Instrument, Arrhythmia Specific instrument in Tachycardia and Arrhythmia (ASTA), and SCL (Arrhythmia Symptom Checklist, Frequency and Severity). A systematic review of these six AF-specific health related QoL instruments was performed. We screened 3221 articles and 17 studies were eligible for inclusion. Using the COSMIN guidelines, ASTA and AFEQT had the best ratings across measurement properties with both instruments having good ratings for instrument development and internal consistency. However, none of the 17 included articles assessed measurement error and cross-cultural validity. Conclusions AFEQT and ASTA had the strongest measurement properties but not all measurement properties were assessed. Considering the large number of indeterminate and insufficient ratings, future research should focus on cross-cultural validation, measurement error, responsiveness, and interpretability. This review summarizes the current evidence for AF QoL instruments across AF ablation studies and outlines areas for future research.

α-catenin is a key protein of adherens junctions (AJs) with mechanosensory properties. It also acts as a tumor suppressor that limits tissue growth. Here we analyzed the function of Drosophila α-Catenin (α-Cat) in growth regulation of the wing epithelium. We found that different α-Cat levels led to a differential activation of Hippo/Yorkie or JNK signaling causing tissue overgrowth or degeneration, respectively. α-Cat can modulate Yorkie-dependent tissue growth through recruitment of Ajuba, a negative regulator of Hippo signaling to AJs but also through a mechanism independent of Ajuba recruitment to AJs. Both mechanosensory regions of α-Cat, the M region and the actin-binding domain (ABD), contribute to growth regulation. Whereas M is dispensable for α-Cat function in the wing, individual M domains (M1, M2, M3) have opposing effects on growth regulation. In particular, M1 limits Ajuba recruitment. Loss of M1 causes Ajuba hyper-recruitment to AJs, promoting tissue-tension independent overgrowth. Although M1 binds Vinculin, Vinculin is not responsible for this effect. Moreover, disruption of mechanosensing of the α-Cat ABD affects tissue growth, with enhanced actin interactions stabilizing junctions and leading to tissue overgrowth. Together, our findings indicate that α-Cat acts through multiple mechanisms to control tissue growth, including regulation of AJ stability, mechanosensitive Ajuba recruitment, and dynamic direct F-actin interactions.

Axis elongation is a conserved process in which the head-to-tail or anterior-posterior (AP) axis of an embryo extends. In Drosophila, cellular rearrangements drive axis elongation. Cells exchange neighbours by converging into transient multicellular vertices which resolve through the assembly of new cell interfaces parallel to the AP axis. We found that new interfaces elongate in pulses correlated with periodic contractions of the surrounding cells. Inhibiting actomyosin contractility globally, or specifically in the cells around multicellular vertices, disrupted the rate and directionality of new interface assembly. Laser ablation indicated that new interfaces sustained greater tension than non-elongating ones. We developed a method to apply ectopic tension and found that increasing AP tension locally increased the elongation rate of new edges by more than twofold. Increasing dorsal-ventral tension resulted in vertex resolution perpendicular to the AP direction. We propose that local, periodic contractile forces polarize vertex resolution to drive Drosophila axis elongation. Tissues and organs form certain shapes that allow them to perform particular roles in the body. For example, the lungs form sacs that accommodate large volumes of air, while the skin forms a sheet to cover and protect our internal organs. One way to shape a tissue is for cells to swap places with their neighbours. During this rearrangement, the contacts between neighbouring cells break down before new contacts are formed with other cells. While the physical and molecular signals that guide the break down of cell contacts are well understood, less is known about how new contacts form. Early in development, animal embryos establish a head-to-tail 'axis' that helps to guide where each tissue and organ will form in the body. In fruit fly embryos, the cell rearrangements that drive this process involve cells exchanging places with their neighbours by gathering around a single point. These temporary cell clusters are then organised via new cell contacts that form parallel to the head-to-tail axis. Here, Yu and Fernandez-Gonzalez investigate the role of mechanical forces in forming new cell contacts as the head-tail axis elongates. The experiments show that disrupting the ability of the cells to generate mechanical forces inhibited the formation of new cell contacts and prevented cells from successfully swapping places. Conversely, when mechanical tension is applied at the rearrangement site, the assembly of new cell contacts happens faster. Furthermore, if the tension is applied in different orientations, new cell contacts form parallel to the direction of the mechanical force. Yu and Fernandez-Gonzalez thus show that local mechanical forces direct the assembly of new cell contacts as the head-to-tail axis forms. These forces are most likely generated by cell contractions that appear to create mechanical tension at sites of cell rearrangement. How such physical forces are converted into molecular signals remains a question for future work.

BackgroundGastric sleeve stenosis (GSS) is an adverse event following sleeve gastrectomy for which objective tools are needed for diagnosis and treatment. Endoscopic treatment with serial pneumatic balloon dilation may relieve symptoms and prevent the need for conversion to Roux-en-Y gastric bypass. Endoluminal functional impedance planimetry (EndoFLIP) is an endoscopic tool that measures luminal diameter and distensibility indices (DI) and could be used to characterize severity of GSS.MethodsThis was a retrospective analysis of a prospective database of patients referred for symptoms suggestive of GSS. Severity was determined at each endoscopy by a bariatric endoscopist blinded to EndoFLIP measurements. Successive pneumatic balloon dilations were performed until symptoms resolved; failure was defined as referral for conversion. EndoFLIP measurements of stenosis diameter and DI were obtained pre- and post-dilation. Primary outcomes were pre- and post-dilation luminal diameter and DI of GSS. Secondary outcomes were endoscopic severity of GSS, patient characteristics, and need for surgical revision.Results26 patients were included; 23 (85%) were female. Mean age was 45.3 (± 9.9) years. Mean number of dilations was 2.4 (± 1.3) and 10 (38%) patients were referred for conversion. Mild, moderate, and severe GSS was found in 10 (38%), 6 (23%), and 10 (38%) patients, respectively. Moderate and severe GSS underwent more dilations (2.5 ± 1.0 and 3.2 ± 1.6) than mild GSS (1.8 ± 0.8) and were more likely to be referred for conversion. Both pre- and post-dilation diameters were significantly larger in mild versus moderate or severe GSS. Additionally, pre- and post-dilation DI at 30 ml were significantly higher for mild compared to moderate and severe GSS.DiscussionEndoFLIP measurements correlate well with endoscopic assessment of GSS. While more data are needed to determine ideal balloon size and threshold measurements, our results suggest EndoFLIP may help expedite diagnosis and treatment of GSS.

Semiconductors, featuring tunable electrical transport, and magnets, featuring tunable spin configurations, form the basis of many information technologies. A long-standing challenge has been to realize materials that integrate and connect these two distinct properties. Two-dimensional (2D) materials offer a platform to realize this concept, but known 2D magnetic semiconductors are electrically insulating in their magnetic phase. Here we demonstrate tunable electron transport within the magnetic phase of the 2D semiconductor CrSBr and reveal strong coupling between its magnetic order and charge transport. This provides an opportunity to characterize the layer-dependent magnetic order of CrSBr down to the monolayer via magnetotransport. Exploiting the sensitivity of magnetoresistance to magnetic order, we uncover a second regime characterized by coupling between charge carriers and magnetic defects. The magnetoresistance within this regime can be dynamically and reversibly tuned by varying the carrier concentration using an electrostatic gate, providing a mechanism for controlling charge transport in 2D magnets. A ferromagnetic transition in CrSBr is attributed to ordering of magnetic defects, and can be electrostatically manipulated.

Computational models are most impactful when they explain and characterize biological phenomena that are non-intuitive, unexpected, or difficult to study experimentally. Countless equation-based models have been built for these purposes, but we have yet to realize the extent to which rules-based models offer an intuitive framework that encourages computational and experimental collaboration. We develop ARCADE, a multi-scale agent-based model to interrogate emergent behavior of heterogeneous cell agents within dynamic microenvironments and demonstrate how complexity of intracellular metabolism and signaling modules impacts emergent dynamics. We perform in silico case studies on context, competition, and heterogeneity to demonstrate the utility of our model for gaining computational and experimental insight. Notably, there exist (i) differences in emergent behavior between colony and tissue contexts, (ii) linear, non-linear, and multimodal consequences of parameter variation on competition in simulated co-cultures, and (iii) variable impact of cell and population heterogeneity on emergent outcomes. Our extensible framework is easily modified to explore numerous biological systems, from tumor microenvironments to microbiomes.

INTRODUCTION:Gastric sleeve stenosis (GSS) is an increasingly common adverse event following sleeve gastrectomy for which objective diagnostic criteria are lacking. Impedance planimetry measurements show promise in characterizing GSS, though normal and abnormal benchmark values have never been established.METHODS:This was a retrospective analysis of upper endoscopies performed with impedance planimetry for suspected GSS. A bariatric endoscopist, blind to impedance planimetry measurements, assessed gastric sleeve anatomy and graded GSS severity. Impedance planimetry of diameter and distensibility index (DI) were obtained using 3 different balloon volumes (30, 40, and 50 mL).RESULTS:A total of 110 upper endoscopies were included. Distribution of GSS was graded as none, mild, moderate, and severe in 19 (17%), 27 (25%), 34 (31%), and 30 (27%) procedures, respectively. In normal gastric sleeve anatomy, mean (±SD) diameter and DI measurements using consecutive balloon volumes ranged from 19.1 (±5.5) to 23.2 (±1.7) and 16.8 (±4.9) to 23.1 (±10.9), respectively. In severe GSS, mean diameter and DI measurements ranged from 10.3 (±3.0) to 16.6 (±2.1) and 7.5 (±2.4) to 7.7 (±2.4), respectively. When stratified by severity, impedance planimetry measurements of diameter and DI were significantly lower with each subsequent increase in GSS grade regardless of balloon fill volumes (P ≤ 0.001).DISCUSSION:Impedance planimetry measurements provide objective assessment in the diagnosis of GSS and correlate with luminal narrowing. A diameter ≥20 mm and a DI ≥15 mm2/mm Hg, as measured by impedance planimetry, are predictive of normal gastric sleeve anatomy. This study provides new benchmark values for the diagnosis and severity of GSS.