Macrophages on the run: Exercise balances macrophage polarization for improved health.

Objective: Exercise plays a crucial role in maintaining and improving human health. However, the precise molecular mechanisms that govern the body's response to exercise or/compared to periods of inactivity remain elusive. Current evidence appears to suggest that exercise exerts a seemingly dual influence on macrophage polarization states, inducing both pro-immune response M1 activation and cell-repair-focused M2 activation.

NetSci: A Library for High Performance Biomolecular Simulation Network Analysis Computation.

We present the NetSci program-an open-source scientific software package designed for estimating mutual information (MI) between data sets using GPU acceleration and a k-nearest-neighbor algorithm. This approach significantly enhances calculation speed, achieving improvements of several orders of magnitude over traditional CPU-based methods, with data set size limits dictated only by available hardware. To validate NetSci, we accurately compute MI for an analytically verifiable two-dimensional Gaussian distribution and replicate the generalized correlation (GC) analysis previously conducted on the B1 domain of protein G.

Multi-organ transcriptome atlas of a mouse model of relative energy deficiency in sport.

Insufficient energy intake to meet energy expenditure demands of physical activity can result in systemic neuroendocrine and metabolic abnormalities in activity-dependent anorexia and relative energy deficiency in sport (REDs). REDs affects >40% of athletes, yet the lack of underlying molecular changes has been a hurdle to have a better understanding of REDs and its treatment. To assess the molecular changes in response to energy deficiency, we implemented the "exercise-for-food" paradigm, in which food reward size is determined by wheel-running activity.

Multiscale modeling shows how 2'-deoxy-ATP rescues ventricular function in heart failure.

2'-deoxy-ATP (dATP) improves cardiac function by increasing the rate of crossbridge cycling and Ca[Formula: see text] transient decay. However, the mechanisms of these effects and how therapeutic responses to dATP are achieved when dATP is only a small fraction of the total ATP pool remain poorly understood. Here, we used a multiscale computational modeling approach to analyze the mechanisms by which dATP improves ventricular function.

Successful Cardiac Resynchronization Therapy Reduces Negative Septal Work in Patient-Specific Models of Dyssynchronous Heart Failure.

In patients with dyssynchronous heart failure (DHF), cardiac conduction abnormalities cause the regional distribution of myocardial work to be non-homogeneous. Cardiac resynchronization therapy (CRT) using an implantable, programmed biventricular pacemaker/defibrillator, can improve the synchrony of contraction between the right and left ventricles in DHF, resulting in reduced morbidity and mortality and increased quality of life. Since regional work depends on wall stress, which cannot be measured in patients, we used computational methods to investigate regional work distributions and their changes after CRT.

Network model of skeletal muscle cell signalling predicts differential responses to endurance and resistance exercise training.

Exercise-induced muscle adaptations vary based on exercise modality and intensity. We constructed a signalling network model from 87 published studies of human or rodent skeletal muscle cell responses to endurance or resistance exercise in vivo or simulated exercise in vitro. The network comprises 259 signalling interactions between 120 nodes, representing eight membrane receptors and eight canonical signalling pathways regulating 14 transcriptional regulators, 28 target genes and 12 exercise-induced phenotypes.

Impact of artificial intelligence arrhythmia mapping on time to first ablation, procedure duration, and fluoroscopy use.

Introduction: Artificial intelligence (AI) ECG arrhythmia mapping provides arrhythmia source localization using 12-lead ECG data; whether this information impacts procedural efficiency is unknown. We performed a retrospective, case-control study to evaluate the hypothesis that AI ECG mapping may reduce time to ablation, procedural duration, and fluoroscopy.

Materials And Methods: Cases in which system output was used were retrospectively enrolled according to IRB-approved protocols at each site.

A universal biventricular coordinate system incorporating valve annuli: Validation in congenital heart disease.

Universal coordinate systems have been proposed to facilitate anatomic registration between three-dimensional images, data and models of the ventricles of the heart. However, current universal ventricular coordinate systems do not account for the outflow tracts and valve annuli where the anatomy is complex. Here we propose an extension to the 'Cobiveco' biventricular coordinate system that also accounts for the intervalvular bridges of the base and provides a tool for anatomically consistent registration between widely varying biventricular shapes.

Differential sensitivity to longitudinal and transverse stretch mediates transcriptional responses in mouse neonatal ventricular myocytes.

To identify how cardiomyocyte mechanosensitive signaling pathways are regulated by anisotropic stretch, micropatterned mouse neonatal cardiomyocytes were stretched primarily longitudinally or transversely to the myofiber axis. Four hours of static, longitudinal stretch induced differential expression of 557 genes, compared with 30 induced by transverse stretch, measured using RNA-seq. A logic-based ordinary differential equation model of the cardiac myocyte mechanosignaling network, extended to include the transcriptional regulation and expression of 784 genes, correctly predicted measured expression changes due to anisotropic stretch with 69% accuracy.

Multiscale computational modeling of the effects of 2'-deoxy-ATP on cardiac muscle calcium handling.

2'-Deoxy-ATP (dATP), a naturally occurring near analog of ATP, is a well-documented myosin activator that has been shown to increase contractile force, improve pump function, and enhance lusitropy in the heart. Calcium transients in cardiomyocytes with elevated levels of dATP show faster calcium decay compared with cardiomyocytes with basal levels of dATP, but the mechanisms behind this are unknown. Here, we design and utilize a multiscale computational modeling framework to test the hypothesis that dATP acts on the sarcoendoplasmic reticulum calcium-ATPase (SERCA) pump to accelerate calcium re-uptake into the sarcoplasmic reticulum during cardiac relaxation.

An Atlas-Based Analysis of Biventricular Mechanics in Tetralogy of Fallot.

The current study proposes an efficient strategy for exploiting the statistical power of cardiac atlases to investigate whether clinically significant variations in ventricular shape are sufficient to explain corresponding differences in ventricular wall motion directly, or if they are indirect markers of altered myocardial mechanical properties. This study was conducted in a cohort of patients with repaired tetralogy of Fallot (rTOF) that face long-term right ventricular (RV) and/or left ventricular (LV) dysfunction as a consequence of adverse remodeling. Features of biventricular end-diastolic (ED) shape associated with RV apical dilation, LV dilation, RV basal bulging, and LV conicity correlated with components of systolic wall motion (SWM) that contribute most to differences in global systolic function.

Monitoring AKT activity and targeting in live tissue and disease contexts using a real-time Akt-FRET biosensor mouse.

Aberrant AKT activation occurs in a number of cancers, metabolic syndrome, and immune disorders, making it an important target for the treatment of many diseases. To monitor spatial and temporal AKT activity in a live setting, we generated an Akt-FRET biosensor mouse that allows longitudinal assessment of AKT activity using intravital imaging in conjunction with image stabilization and optical window technology. We demonstrate the sensitivity of the Akt-FRET biosensor mouse using various cancer models and verify its suitability to monitor response to drug targeting in spheroid and organotypic models.

How can AI accelerate advances in physiology?

Combining machine learning with mechanistic computational modeling is enabling the discovery of novel genotype-phenotype relationships in heart disease.

Nuclear mechanosignaling in striated muscle diseases.

Mechanosignaling describes processes by which biomechanical stimuli are transduced into cellular responses. External biophysical forces can be transmitted structural protein networks that span from the cellular membrane to the cytoskeleton and the nucleus, where they can regulate gene expression through a series of biomechanical and/or biochemical mechanosensitive mechanisms, including chromatin remodeling, translocation of transcriptional regulators, and epigenetic factors. Striated muscle cells, including cardiac and skeletal muscle myocytes, utilize these nuclear mechanosignaling mechanisms to respond to changes in their intracellular and extracellular mechanical environment and mediate gene expression and cell remodeling.

Biventricular shape modes discriminate pulmonary valve replacement in tetralogy of Fallot better than imaging indices.

Current indications for pulmonary valve replacement (PVR) in repaired tetralogy of Fallot (rTOF) rely on cardiovascular magnetic resonance (CMR) image-based indices but are inconsistently applied, lead to mixed outcomes, and remain debated. This study aimed to test the hypothesis that specific markers of biventricular shape may discriminate differences between rTOF patients who did and did not require subsequent PVR better than standard imaging indices. In this cross-sectional retrospective study, biventricular shape models were customized to CMR images from 84 rTOF patients.

Signaling network model of cardiomyocyte morphological changes in familial cardiomyopathy.

Familial cardiomyopathy is a precursor of heart failure and sudden cardiac death. Over the past several decades, researchers have discovered numerous gene mutations primarily in sarcomeric and cytoskeletal proteins causing two different disease phenotypes: hypertrophic (HCM) and dilated (DCM) cardiomyopathies. However, molecular mechanisms linking genotype to phenotype remain unclear.

Performance Evaluation of the Microfluidic Antigen LumiraDx SARS-CoV-2 and Flu A/B Test in Diagnosing COVID-19 and Influenza in Patients with Respiratory Symptoms.

Introduction: Coronavirus disease 2019 (COVID-19) and influenza share similar symptoms, which hampers diagnosis. Given that they require different containment and treatment strategies, fast and accurate distinction between the two infections is needed. This study evaluates the sensitivity and specificity of the microfluidic antigen LumiraDx SARS-CoV-2 and Flu A/B Test for simultaneous detection of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and influenza A/B from a single nasal swab.

Forward-Solution Noninvasive Computational Arrhythmia Mapping: The VMAP Study.

Background: The accuracy of noninvasive arrhythmia source localization using a forward-solution computational mapping system has not yet been evaluated in blinded, multicenter analysis. This study tested the hypothesis that a computational mapping system incorporating a comprehensive arrhythmia simulation library would provide accurate localization of the site-of-origin for atrial and ventricular arrhythmias and pacing using 12-lead ECG data when compared with the gold standard of invasive electrophysiology study and ablation.

Methods: The VMAP study (Vectorcardiographic Mapping of Arrhythmogenic Probability) was a blinded, multicenter evaluation with final data analysis performed by an independent core laboratory.

Le Cœur en Sabot: shape associations with adverse events in repaired tetralogy of Fallot.

Background: Maladaptive remodelling mechanisms occur in patients with repaired tetralogy of Fallot (rToF) resulting in a cycle of metabolic and structural changes. Biventricular shape analysis may indicate mechanisms associated with adverse events independent of pulmonary regurgitant volume index (PRVI). We aimed to determine novel remodelling patterns associated with adverse events in patients with rToF using shape and function analysis.

Right Ventricular Flow Vorticity Relationships With Biventricular Shape in Adult Tetralogy of Fallot.

Remodeling in adults with repaired tetralogy of Fallot (rToF) may occur due to chronic pulmonary regurgitation, but may also be related to altered flow patterns, including vortices. We aimed to correlate and quantify relationships between vorticity and ventricular shape derived from atlas-based analysis of biventricular shape. Adult rToF ( = 12) patients underwent 4D flow and cine MRI imaging.

Subcellular Remodeling in Filamin C Deficient Mouse Hearts Impairs Myocyte Tension Development during Progression of Dilated Cardiomyopathy.

Dilated cardiomyopathy (DCM) is a life-threatening form of heart disease that is typically characterized by progressive thinning of the ventricular walls, chamber dilation, and systolic dysfunction. Multiple mutations in the gene encoding filamin C (FLNC), an actin-binding cytoskeletal protein in cardiomyocytes, have been found in patients with DCM. However, the mechanisms that lead to contractile impairment and DCM in patients with FLNC variants are poorly understood.