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In virtual reality, augmented reality, or animation, the goal is to represent the movement of deformable objects in the real world as similar as possible in the virtual world. Therefore, this paper proposed a method to automatically extract cloth stiffness values from video scenes, and then they are applied as material properties for virtual cloth simulation. We propose the use of deep learning (DL) models to tackle this issue. The Transformer model, in combination with pre-trained architectures like DenseNet121, ResNet50, VGG16, and VGG19, stands as a leading choice for video classification tasks. Position-Based Dynamics (PBD) is a computational framework widely used in computer graphics and physics-based simulations for deformable entities, notably cloth. It provides an inherently stable and efficient way to replicate complex dynamic behaviors, such as folding, stretching, and collision interactions. Our proposed model characterizes virtual cloth based on softness-to-stiffness labels and accurately categorizes videos using this labeling. The cloth movement dataset utilized in this research is derived from a meticulously designed stiffness-oriented cloth simulation. Our experimental assessment encompasses an extensive dataset of 3840 videos, contributing to a multi-label video classification dataset. Our results demonstrate that our proposed model achieves an impressive average accuracy of 99.50%. These accuracies significantly outperform alternative models such as RNN, GRU, LSTM, and Transformer.

Physically based cloth simulation requires a model that represents cloth as a collection of nodes connected by different types of constraints. In this paper, we present a coefficient prediction framework using a Deep Learning (DL) technique to enhance video summarization for such simulations. Our proposed model represents virtual cloth as interconnected nodes that are subject to various constraints. To ensure temporal consistency, we train the video coefficient prediction using Gated Recurrent Unit (GRU), Long-Short Term Memory (LSTM), and Transformer models. Our lightweight video coefficient network combines Convolutional Neural Networks (CNN) and a Transformer to capture both local and global contexts, thus enabling highly efficient prediction of keyframe importance scores for short-length videos. We evaluated our proposed model and found that it achieved an average accuracy of 99.01%. Specifically, the accuracy for the coefficient prediction of GRU was 20%, while LSTM achieved an accuracy of 59%. Our methodology leverages various cloth simulations that utilize a mass-spring model to generate datasets representing cloth movement, thus allowing for the accurate prediction of the coefficients for virtual cloth within physically based simulations. By taking specific material parameters as input, our model successfully outputs a comprehensive set of geometric and physical properties for each cloth instance. This innovative approach seamlessly integrates DL techniques with physically based simulations, and it therefore has a high potential for use in modeling complex systems.

Introduction: Individuals with chronic hypoparathyroidism managed with conventional therapy (active vitamin D and calcium) have an increased risk for renal dysfunction versus age- and sex-matched controls. Treatments that replace the physiologic effects of parathyroid hormone (PTH) while reducing the need for conventional therapy may help prevent a decline in renal function in this population. This post hoc analysis examined the impact of palopegteriparatide treatment on renal function in adults with chronic hypoparathyroidism., Methods: PaTHway is a phase 3 trial of palopegteriparatide in adults with chronic hypoparathyroidism that included a randomized, double-blind, placebo-controlled 26-week period followed by an ongoing 156-week open-label extension (OLE) period. Changes in renal function over 52 weeks (26 weeks blinded + 26 weeks OLE) were assessed using estimated glomerular filtration rate (eGFR). A subgroup analysis was performed with participants stratified by baseline eGFR < 60 or ≥ 60 mL/min/1.73 m 2 ., Results: At week 52, over 95% (78/82) of participants remained enrolled in the OLE and of those, 86% maintained normocalcemia and 95% achieved independence from conventional therapy (no active vitamin D and ≤ 600 mg/day of calcium), with none requiring active vitamin D. Treatment with palopegteriparatide over 52 weeks resulted in a mean (SD) increase in eGFR of 9.3 (11.7) mL/min/1.73 m 2 from baseline (P < 0.0001) and 43% of participants had an increase ≥ 10 mL/min/1.73 m 2 . In participants with baseline eGFR < 60 mL/min/1.73 m 2 , 52 weeks of treatment with palopegteriparatide resulted in a mean (SD) increase of 11.5 (11.3) mL/min/1.73 m 2 (P < 0.001). One case of nephrolithiasis was reported for a participant in the placebo group during blinded treatment; none were reported through week 52 with palopegteriparatide., Conclusion: In this post hoc analysis of the PaTHway trial, palopegteriparatide treatment was associated with significantly improved eGFR at week 52 in addition to previously reported maintenance and normalization of serum and urine biochemistries. Further investigation of palopegteriparatide for the preservation of renal function in hypoparathyroidism is warranted., Trial Registration: ClinicalTrials.gov NCT04701203., (© 2024. The Author(s).)

This study evaluated the efficacy and safety of IncobotulinumtoxinA 20 U for treatment of glabellar frown lines in Chinese subjects., Methods: This was a prospective, randomized, double-blind, active-controlled, phase-3 study conducted in China. Subjects with moderate to severe glabellar frown lines at maximum frown were randomized to receive IncobotulinumtoxinA (N = 336) or OnabotulinumtoxinA (N = 167)., Results: For the primary efficacy endpoint at day 30, response rates at maximum frown (score "none" or "mild") on the Merz Aesthetic Scales Glabella Lines - Dynamic were comparable between IncobotulinumtoxinA (92.5%) and OnabotulinumtoxinA (95.1%) per investigator's live rating. Noninferiority of IncobotulinumtoxinA versus OnabotulinumtoxinA was successfully demonstrated, as the two-sided 95% confidence interval of -0.97% to 0.43% for the difference in Merz Aesthetic Scales-based response rates (-0.27%) lay completely above the predefined noninferiority margin of -15%. For the secondary efficacy endpoints assessed at day 30, Merz Aesthetic Scales-based response rates (score "none" or "mild") at maximum frown were similarly comparable between both groups per subject (>85%) and independent review panel (>96%) rating. Per Global Impression of Change Scales, greater than 80% of subjects and greater than 90% of investigators in both groups rated treatment results as at least "much improved" at day 30 compared with baseline. Safety profiles were consistent between groups; IncobotulinumtoxinA was well tolerated, and no new safety concerns were identified in Chinese subjects., Conclusion: IncobotulinumtoxinA 20 U is safe and effective for treatment of moderate to severe glabellar frown lines at maximum frown in Chinese subjects and is noninferior to OnabotulinumtoxinA 20 U., Competing Interests: Bi Li was a consultant for Merz Aesthetics, Inc. as a member of the Aesthetics China Expert Group, serving on an advisory board for Belotero in China. Susanna Roll, Gudrun Klein, and Thorin Geister are employees of Merz Pharmaceuticals GmbH. Michael Makara is a former employee of Merz North America, Inc. Yan Wu has no conflict of interest to declare in relation to the content of this article. This study was supported by Merz Pharmaceuticals GmbH., (Copyright © 2023 The Authors. Published by Wolters Kluwer Health, Inc. on behalf of The American Society of Plastic Surgeons.)

Objective: Although symptom relief is a critical aspect for successful drug development in Sjögren's disease, patient experiences with Sjögren's-related symptoms are understudied. Our objective was to determine how pain, dryness, and fatigue, the cardinal symptoms of Sjögren's disease, drive cluster phenotypes., Methods: We used data from the Sjögren's International Collaborative Clinical Alliance (SICCA) Registry and a Sjögren's Foundation survey. We performed hierarchical clustering of symptoms by levels of dryness, fatigue, and pain. Using international and US cohorts, we performed multiple logistic regression analysis to compare the clusters, which included comparisons of differences in symptoms, quality of life (QoL), medication use, and systemic manifestations., Results: Four similar clusters were identified among 1,454 SICCA registrants and 2,920 Sjögren's Foundation survey participants: 1) low symptom burden in all categories (LSB); 2) dry with low pain and low fatigue (DLP); 3) dry with high pain and low to moderate fatigue (DHP); and 4) high symptom burden in all categories (HSB). Distribution of SICCA registrants matching the symptom profile for each cluster was 10% in the LSB cluster, 30% in the DLP cluster, 23% in the DHP cluster, and 37% in the HSB cluster. Distribution of survey participants matching the symptom profile for each cluster was 23% in the LSB cluster, 14% in the DLP cluster, 21% in the DHP cluster, and 42% in the HSB cluster. Individuals in the HSB cluster had more total symptoms and lower QoL but lower disease severity than those in the other clusters. Despite having milder disease as measured by laboratory tests and organ involvement, individuals in the HSB cluster received immunomodulatory treatment most often., Conclusion: We identified 4 symptom-based Sjögren's clusters and showed that symptom burden and immunomodulatory medication use do not correlate with Sjögren's end-organ or laboratory abnormalities. Findings highlight a discordance between objective measures and treatments and offer updates to proposed symptom-based clustering approaches., (© 2022 The Authors. Arthritis & Rheumatology published by Wiley Periodicals LLC on behalf of American College of Rheumatology.)

To gain insight into the Sjögren's disease (SjD) patient experience using a survey generated by patients and providers. We evaluated the results of the 2016 Sjögren's Foundation survey, with 25 questions designed in a collaborative effort between the Foundation, patients with SjD, SjD provider experts, and a marketing research company. We used descriptive statistics to provide a thorough understanding of SjD demographics, symptoms, quality of life (QoL), cost, and treatments. Analyses revealed high symptoms, QoL, and financial burdens in SjD. Dry mouth and eye were the most commonly reported symptoms (94 and 93%, respectively). The most frequent extra-glandular symptoms included fatigue, dry or itchy skin, and morning stiffness. The top three aspects of QoL most impaired included (i) sex life (53%), (ii) participating in hobbies/social activities/extracurricular activities (52%), and (iii) job/career or ability to work (49%). SjD respondents commonly reported taking health food supplements/remedies, vitamin D, and exercising, in addition to taking treatments for symptomatic dryness. SjD costs were high, including a total yearly cost, on average, of $2026 for dental care. SjD respondents reported that dryness and risk factors for lymphoma and fatigue are essential to address with new therapies. In this comprehensive overview of the SjD experience, we demonstrated a high burden of disease to SjD respondents, including symptoms, QoL, and financial burden. We also identify the top goals of therapy for new systemic SjD therapies. Key Points • The top three symptoms or signs that patients with Sjögren's hope new treatments will address are dryness, fatigue, and reduction in lymphoma or blood cancer risk • The top aspects of quality of life reported to be impaired by Sjögren's are sex life, hobbies, social activities and extracurricular activities, job/career or ability to work, and finding the correct word during conversations • Patients with Sjögren's have a yearly mean dental cost of $2026 but also have high costs associated with prescription medications, healthcare appointments, over-the-counter medications, alternative therapies, and medical equipment., (© 2022. The Author(s), under exclusive licence to International League of Associations for Rheumatology (ILAR).)

Zonula occludens-1 (ZO-1) is an intracellular scaffolding protein that orchestrates the anchoring of membrane proteins to the cytoskeleton in epithelial and specialized tissue including the heart. There is clear evidence to support the central role of intracellular auxiliary proteins in arrhythmogenesis and previous studies have found altered ZO-1 expression associated with atrioventricular conduction abnormalities. Here, using human cardiac tissues, we identified all three isoforms of ZO-1, canonical (Transcript Variant 1, TV1 ), CRA&#95;e (Transcript Variant 4, TV4 ), and an additionally expressed (Transcript Variant 3, TV3 ) in non-failing myocardium. To investigate the role of ZO-1 on ventricular arrhythmogenesis, we generated a haploinsufficient ZO-1 mouse model (ZO-1 +/- ). ZO-1 +/- mice exhibited dysregulated connexin-43 protein expression and localization at the intercalated disc. While ZO-1 +/- mice did not display abnormal cardiac function at baseline, adrenergic challenge resulted in rhythm abnormalities, including premature ventricular contractions and bigeminy. At baseline, ventricular myocytes from the ZO-1 +/- mice displayed prolonged action potential duration and spontaneous depolarizations, with ZO-1 +/- cells displaying frequent unsolicited (non-paced) diastolic depolarizations leading to spontaneous activity with multiple early afterdepolarizations (EADs). Mechanistically, ZO-1 deficient myocytes displayed a reduction in sodium current density ( I Na ) and an increased sensitivity to isoproterenol stimulation. Further, ZO-1 deficient myocytes displayed remodeling in I Ca current, likely a compensatory change. Taken together, our data suggest that ZO-1 deficiency results in myocardial substrate susceptible to triggered arrhythmias.

Objective: To define the association between oral and systemic manifestations of Sjögren syndrome (SS) and quality of life (QOL)., Methods: We analyzed a cross-sectional survey conducted by the Sjögren's Foundation in 2016, with 2961 eligible responses. We defined oral symptom and sign exposures as parotid gland swelling, dry mouth, mouth ulcers/sores, oral candidiasis, trouble speaking, choking or dysphagia, sialolithiasis or gland infection, and dental caries. Systemic exposures included interstitial lung disease, purpura/petechiae/cryoglobulinemia, vasculitis, neuropathy, leukopenia, interstitial nephritis, renal tubular acidosis, autoimmune hepatitis, primary biliary cholangitis, or lymphoma. Outcomes included SS-specific QOL questions generated by SS experts and patients., Results: Using multivariable regression models adjusted for age, sex, race, and employment, we observed that mouth ulcers or sores, trouble speaking, and dysphagia were associated with poor quality of life. The following oral aspects had the greatest effect on the following QOL areas: (1) mouth ulcers/sores on the challenge and burden of living with SS (OR 4.26, 95% CI 2.89-6.28); (2) trouble speaking on memory and concentration (OR 4.24, 95% CI 3.28-5.48); and (3) dysphagia on functional interference (OR 4.25, 95% CI 3.13-5.79). In contrast, systemic manifestations were associated with QOL to a lesser extent or not at all., Conclusion: Oral manifestations of SS, particularly mouth ulcers or sores, trouble speaking, and dysphagia, were strongly associated with worse QOL. Further study and targeted treatment of these oral manifestations provides the opportunity to improve quality of life in patients with SS., (Copyright © 2021 by the Journal of Rheumatology.)

Synapse-associated protein 97 (SAP97) is a scaffolding protein crucial for the functional expression of several cardiac ion channels and therefore proper cardiac excitability. Alterations in the functional expression of SAP97 can modify the ionic currents underlying the cardiac action potential and consequently confer susceptibility for arrhythmogenesis. In this study, we generated a murine model for inducible, cardiac-targeted Sap97 ablation to investigate arrhythmia susceptibility and the underlying molecular mechanisms. Furthermore, we sought to identify human SAP97 ( DLG1 ) variants that were associated with inherited arrhythmogenic disease. The murine model of cardiac-specific Sap97 ablation demonstrated several ECG abnormalities, pronounced action potential prolongation subject to high incidence of arrhythmogenic afterdepolarizations and notable alterations in the activity of the main cardiac ion channels. However, no DLG1 mutations were found in 40 unrelated cases of genetically elusive long QT syndrome (LQTS). Instead, we provide the first evidence implicating a gain of function in human DLG1 mutation resulting in an increase in Kv4.3 current ( I to ) as a novel, potentially pathogenic substrate for Brugada syndrome (BrS). In conclusion, DLG1 joins a growing list of genes encoding ion channel interacting proteins (ChIPs) identified as potential channelopathy-susceptibility genes because of their ability to regulate the trafficking, targeting, and modulation of ion channels that are critical for the generation and propagation of the cardiac electrical impulse. Dysfunction in these critical components of cardiac excitability can potentially result in fatal cardiac disease. NEW & NOTEWORTHY The gene encoding SAP97 ( DLG1 ) joins a growing list of genes encoding ion channel-interacting proteins (ChIPs) identified as potential channelopathy-susceptibility genes because of their ability to regulate the trafficking, targeting, and modulation of ion channels that are critical for the generation and propagation of the cardiac electrical impulse. In this study we provide the first data supporting DLG1- encoded SAP97's candidacy as a minor Brugada syndrome susceptibility gene.

Tandem pore domain acid-sensitive K + (TASK) channels are present in cardiac tissue; however, their contribution to cardiac pathophysiology is not well understood. Here, we investigate the role of TASK-1 and TASK-3 in the pathogenesis of cardiac dysfunction using both human tissue and mouse models of genetic TASK channel loss of function. Compared with normal human cardiac tissue, TASK-1 gene expression is reduced in association with either cardiac hypertrophy alone or combined cardiac hypertrophy and heart failure. In a pressure overload cardiomyopathy model, TASK-1 global knockout (TASK-1 KO) mice have both reduced cardiac hypertrophy and preserved cardiac function compared with wild-type mice. In contrast to the TASK-1 KO mouse pressure overload response, TASK-3 global knockout (TASK-3 KO) mice develop cardiac hypertrophy and a delayed onset of cardiac dysfunction compared with wild-type mice. The cardioprotective effects observed in TASK-1 KO mice are associated with pressure overload-induced augmentation of AKT phosphorylation and peroxisome proliferator-activated receptor-γ coactivator-1α (PGC-1α) expression, with consequent augmentation of cardiac energetics and fatty acid oxidation. The protective effects of TASK-1 loss of function are associated with an enhancement of physiologic hypertrophic signaling and preserved metabolic functions. These findings may provide a rationale for TASK-1 channel inhibition in the treatment of cardiac dysfunction. NEW & NOTEWORTHY The role of tandem pore domain acid-sensitive K + (TASK) channels in cardiac function is not well understood. This study demonstrates that TASK channel gene expression is associated with the onset of human cardiac hypertrophy and heart failure. TASK-1 and TASK-3 strongly affect the development of pressure overload cardiomyopathies in genetic models of TASK-1 and TASK-3 loss of function. The effects of TASK-1 loss of function were associated with enhanced AKT phosphorylation and expression of peroxisome proliferator-activated receptor-γ coactivator-1 (PGC-1) transcription factor. These data suggest that TASK channels influence the development of cardiac hypertrophy and dysfunction in response to injury.

Objective: To evaluate 3 doses of gadoxetic acid (Gd-EOB-DPTA) for hepatic CT and cholangiography in cats and to determine optimal timing for hepatobiliary image acquisition and evaluation of the contrast-enhanced hepatobiliary anatomy., Animals: 6 healthy cats., Procedures: Cats were anesthetized; sequential CT scans were performed 0, 5, 25, 45, 65, and 85 minutes after IV administration of Gd-EOB-DTPA at low (0.0125 mmol/kg), medium (0.1 mmol/kg), and high (0.3 mmol/kg) doses. Hepatobiliary enhancement for each dose was objectively assessed over time and by use of a subjective semiquantitative visual assessment score., Results: No contrast-related adverse effects were detected. Each increase in dose of contrast medium resulted in a significant increase in HU across the hepatobiliary system. The liver had a significantly higher number of HU at 45 minutes, with homogenous enhancement at all doses of contrast medium. Contrast-enhanced cystic and bile duct HU were significantly higher and maximal at 65 minutes. Contrast-enhanced gallbladder HU did not plateau by 85 minutes. At a high dose of contrast medium, 12 of 60 (20%) biliary tract scores indicated no enhancement, 34 (57%) indicated poor enhancement, and 14 (23%) indicated moderate enhancement. No cat had excellent enhancement of the biliary tract at any dose., Conclusions and Clinical Relevance: Gd-EOB-DTPA-enhanced hepatic CT and cholangiography in cats were safely performed and provided good hepatic enhancement but poor to moderate enhancement of the biliary tract. This technique may be useful for assessing the liver parenchyma in cats, but its value for assessing the biliary tract is questionable.

Ankyrin polypeptides are intracellular proteins responsible for targeting cardiac membrane proteins. Here, the authors demonstrate that ankyrin-G plays an unexpected role in normal compensatory physiological remodeling in response to myocardial stress and aging; the authors implicate disruption of ankyrin-G in human heart failure. Mechanistically, the authors illustrate that ankyrin-G serves as a key nodal protein required for cardiac myofilament integration with the intercalated disc. Their data define novel in vivo mechanistic roles for ankyrin-G, implicate ankyrin-G as necessary for compensatory cardiac physiological remodeling under stress, and implicate disruption of ankyrin-G in the development and progression of human heart failure.

The β 1 adrenergic receptor (β 1 AR) is recognized as a classical Gα s -coupled receptor. Agonist binding not only initiates G protein-mediated signaling but also signaling through the multifunctional adapter protein β-arrestin. Some βAR ligands, such as carvedilol, stimulate βAR signaling preferentially through β-arrestin, a concept known as β-arrestin-biased agonism. Here, we identify a signaling mechanism, unlike that previously known for any Gα s -coupled receptor, whereby carvedilol induces the transition of the β 1 AR from a classical Gα s -coupled receptor to a Gα i -coupled receptor stabilizing a distinct receptor conformation to initiate β-arrestin-mediated signaling. Recruitment of Gα i is not induced by any other βAR ligand screened, nor is it required for β-arrestin-bias activated by the β 2 AR subtype of the βAR family. Our findings demonstrate a previously unrecognized role for Gα i in β 1 AR signaling and suggest that the concept of β-arrestin-bias may need to be refined to incorporate the selective bias of receptors towards distinct G protein subtypes.

OBJECTIVE To evaluate the effect of gadoxetic acid (contrast) dose on biliary tract enhancement, determine the optimal time after contrast injection for CT image acquisition, and assess the feasibility of CT cholangiography in sedated dogs. ANIMALS 8 healthy dogs. PROCEDURES The study had 2 parts. In part 1, 4 dogs were anesthetized and underwent CT cholangiography twice. Gadoxetic acid was administered IV at a low dose (0.025 mmol/kg) for the first procedure and high dose (0.3 mmol/kg) for the second procedure. Serial CT scans were obtained at predetermined times after contrast injection. In part 2, 4 dogs were sedated and underwent CT angiography 85 minutes after IV administration of the high contrast dose. Contrast enhancement of the biliary tract on all scans was objectively assessed by measurement of CT attenuation and qualitatively assessed by use of a subjective 4-point scoring system by 3 independent reviewers. All measurements were compared over time and between contrast doses for the dogs of part 1. Subjective measurements were compared between the sedated dogs of part 2 and anesthetized dogs of part 1. RESULTS Enhancement of the biliary tract was positively associated with contrast dose and time after contrast injection. Optimal enhancement was achieved 65 minutes after contrast injection. Subjective visualization of most biliary structures did not differ significantly between sedated and anesthetized dogs. CONCLUSIONS AND CLINICAL RELEVANCE Results indicated CT cholangiography with gadoxetic acid was feasible in sedated dogs. The high contrast dose provided better visualization of biliary structures than the low dose; CT scans should be obtained 65 minutes after contrast injection.

OBJECTIVE To evaluate the accuracy of estimating time to peak enhancement (TPE) of the aorta and liver parenchyma on the basis of contrast medium arrival time in the aorta, injection duration, and injection technique in dogs. ANIMALS 18 dogs of specific body weight categories (≥ 2 dogs/category) with no liver abnormalities detected via CT. PROCEDURES Dogs were randomly assigned within weight categories to receive contrast medium IV at a fixed injection rate (5 mL/s) or fixed injection duration (20 seconds). Time-contrast attenuation curves were generated from dynamic CT scans acquired at the hepatic hilus. Data collected for contrast medium arrival time and injection duration were used to estimate TPEs of the aorta and liver, and results were compared with the observed TPEs for the aorta and liver. RESULTS Contrast medium arrival time, injection duration, and injection technique were significantly associated with observed values for aortic TPE and explained 96.1% of variation in TPE. For the fixed rate technique, the regression equation for estimating aortic TPE was 0.8 × (injection duration + contrast medium arrival time) + 1.6. For the fixed duration technique, the regression equation changed by only the constant (-2.6). However, the hepatic TPE estimated from the 3 predictor variables was not significantly different from the mean of observed TPEs. CONCLUSIONS AND CLINICAL RELEVANCE Aortic TPE could be accurately estimated from contrast medium arrival time, injection duration, and injection technique in dogs with apparently healthy livers. The regression equations derived from this relationship can be used to improve the efficiency of dual-phase CT of the liver in dogs.

Background: Sepsis patients with cardiac dysfunction have significantly higher mortality. Although several pathways are associated with myocardial damage in sepsis, the precise cause(s) remains unclear and treatment options are limited. This study was designed to develop a new model to investigate the early events of cardiac damage during sepsis progression., Methods and Results: Francisella tularensis subspecies novicida (Ft.n) is a Gram-negative intracellular pathogen causing severe sepsis syndrome in mice. BALB/c mice (N=12) were sham treated or infected with Ft.n through the intranasal route. Serial electrocardiograms were recorded at multiple time points until 96 hours. Hearts were then harvested for histology and gene expression studies. Similar to septic patients, we illustrate both cardiac electrical and structural phenotypes in our murine Ft.n infection model, including prominent R' wave formation, prolonged QRS intervals, and significant left ventricular dysfunction. Notably, in infected animals, we detected numerous microlesions in the myocardium, previously observed following nosocomial Streptococcus infection and in sepsis patients. We show that Ft.n-mediated microlesions are attributed to cardiomyocyte apoptosis, increased immune cell infiltration, and expression of inflammatory mediators (tumor necrosis factor, interleukin [IL]-1β, IL-8, and superoxide dismutase 2). Finally, we identify increased expression of microRNA-155 and rapid degradation of heat shock factor 1 following cardiac Ft.n infection as a primary cause of myocardial inflammation and apoptosis., Conclusions: We have developed and characterized an Ft.n infection model to understand the pathogenesis of cardiac dysregulation in sepsis. Our findings illustrate novel in vivo phenotypes underlying cardiac dysfunction during Ft.n infection with significant translational impact on our understanding of sepsis pathophysiology., (© 2016 The Authors. Published on behalf of the American Heart Association, Inc., by Wiley Blackwell.)

Background: Human ANK2 (ankyrin-B) loss-of-function variants are directly linked with arrhythmia phenotypes. However, in atypical non-ion channel arrhythmia genes such as ANK2 that lack the same degree of robust structure/function and clinical data, it may be more difficult to assign variant disease risk based simply on variant location, minor allele frequency, and/or predictive structural algorithms. The human ankyrin-B p.L1622I variant found in arrhythmia probands displays significant diversity in minor allele frequency across populations., Objective: The objective of this study was to directly test the in vivo impact of ankyrin-B p.L1622I on cardiac electrical phenotypes and arrhythmia risk using a new animal model., Methods: We tested arrhythmia phenotypes in a new "knock-in" animal model harboring the human ankyrin-B p.L1622I variant., Results: Ankyrin-B p.L1622I displays reduced posttranslational expression in vivo, resulting in reduced cardiac ankyrin-B expression and reduced association with binding-partner Na/Ca exchanger. Ankyrin-B(L1622I/L1622I) mice display changes in heart rate, atrioventricular and intraventricular conduction, and alterations in repolarization. Furthermore, ankyrin-B(L1622I/L1622I) mice display catecholamine-dependent arrhythmias. At the cellular level, ankyrin-B(L1622I/L1622I) myocytes display increased action potential duration and severe arrhythmogenic afterdepolarizations that provide a mechanistic rationale for the arrhythmias., Conclusion: Our findings support in vivo arrhythmogenic phenotypes of an ANK2 variant with unusual frequency in select populations. On the basis of our findings and current clinical data, we support classification of p.L1622I as a "mild" loss-of-function variant that may confer arrhythmia susceptibility in the context of secondary risk factors including environment, medication, and/or additional genetic variation., (Copyright © 2016 Heart Rhythm Society. Published by Elsevier Inc. All rights reserved.)

Background: Cardiac arrhythmias are a leading cause of death in the US. Vast majority of these arrhythmias including catecholaminergic polymorphic ventricular tachycardia (CPVT) are associated with increased levels of circulating catecholamines and involve abnormal impulse formation secondary to aberrant Ca 2+ and Na + handling. However, the mechanistic link between β-AR stimulation and the subcellular/molecular arrhythmogenic trigger(s) remains elusive., Methods and Results: We performed functional and structural studies to assess Ca 2+ and Na + signaling in ventricular myocyte as well as surface electrocardiograms in mouse models of cardiac calsequestrin (CASQ2)-associated CPVT. We demonstrate that a subpopulation of Na + channels (neuronal Na + channels; nNa v ) that colocalize with RyR2 and Na + /Ca 2+ exchanger (NCX) are a part of the β-AR-mediated arrhythmogenic process. Specifically, augmented Na + entry via nNa v in the settings of genetic defects within the RyR2 complex and enhanced sarcoplasmic reticulum (SR) Ca 2+ -ATPase (SERCA)-mediated SR Ca 2+ refill is both an essential and a necessary factor for the arrhythmogenesis. Furthermore, we show that augmentation of Na + entry involves β-AR-mediated activation of CAMKII subsequently leading to nNa v augmentation. Importantly, selective pharmacological inhibition as well as silencing of Na v 1.6 inhibit myocyte arrhythmic potential and prevent arrhythmias in vivo ., Conclusion: These data suggest that the arrhythmogenic alteration in Na + /Ca 2+ handling evidenced ruing β-AR stimulation results, at least in part, from enhanced Na + influx through nNa v . Therefore, selective inhibition of these channels and Na v 1.6 in particular can serve as a potential antiarrhythmic therapy.

Background: Two-pore K(+) channels have emerged as potential targets to selectively regulate cardiac cell membrane excitability; however, lack of specific inhibitors and relevant animal models has impeded the effort to understand the role of 2-pore K(+) channels in the heart and their potential as a therapeutic target. The objective of this study was to determine the role of mechanosensitive 2-pore K(+) channel family member TREK-1 in control of cardiac excitability., Methods and Results: Cardiac-specific TREK-1-deficient mice (αMHC-Kcnk(f/f)) were generated and found to have a prevalent sinoatrial phenotype characterized by bradycardia with frequent episodes of sinus pause following stress. Action potential measurements from isolated αMHC-Kcnk2(f/f) sinoatrial node cells demonstrated decreased background K(+) current and abnormal sinoatrial cell membrane excitability. To identify novel pathways for regulating TREK-1 activity and sinoatrial node excitability, mice expressing a truncated allele of the TREK-1-associated cytoskeletal protein βIV-spectrin (qv(4J) mice) were analyzed and found to display defects in cell electrophysiology as well as loss of normal TREK-1 membrane localization. Finally, the βIV-spectrin/TREK-1 complex was found to be downregulated in the right atrium from a canine model of sinoatrial node dysfunction and in human cardiac disease., Conclusions: These findings identify a TREK-1-dependent pathway essential for normal sinoatrial node cell excitability that serves as a potential target for selectively regulating sinoatrial node cell function., (© 2016 The Authors. Published on behalf of the American Heart Association, Inc., by Wiley Blackwell.)

Protein phosphatase 2A (PP2A) is a serine/threonine-selective holoenzyme composed of a catalytic, scaffolding, and regulatory subunit. In the heart, PP2A activity is requisite for cardiac excitation-contraction coupling and central in adrenergic signaling. We found that mice deficient in the PP2A regulatory subunit B56α (1 of 13 regulatory subunits) had altered PP2A signaling in the heart that was associated with changes in cardiac physiology, suggesting that the B56α regulatory subunit had an autoinhibitory role that suppressed excess PP2A activity. The increase in PP2A activity in the mice with reduced B56α expression resulted in slower heart rates and increased heart rate variability, conduction defects, and increased sensitivity of heart rate to parasympathetic agonists. Increased PP2A activity in B56α(+/-) myocytes resulted in reduced Ca(2+) waves and sparks, which was associated with decreased phosphorylation (and thus decreased activation) of the ryanodine receptor RyR2, an ion channel on intracellular membranes that is involved in Ca(2+) regulation in cardiomyocytes. In line with an autoinhibitory role for B56α, in vivo expression of B56α in the absence of altered abundance of other PP2A subunits decreased basal phosphatase activity. Consequently, in vivo expression of B56α suppressed parasympathetic regulation of heart rate and increased RyR2 phosphorylation in cardiomyocytes. These data show that an integral component of the PP2A holoenzyme has an important inhibitory role in controlling PP2A enzyme activity in the heart., (Copyright © 2015, American Association for the Advancement of Science.)

Background: Social and spatial factors are an important part of individual and community health. The objectives were to identify food establishment sub-types and evaluate prevalence of diabetes, obesity, and recommended fruit and vegetable consumption in relation to these sub-types in the Washington DC metropolitan area., Methods: A cross-sectional study design was used. A measure of retail food environment was calculated as the ratio of number of sources of unhealthier food options (fast food, convenience stores, and pharmacies) to healthier food options (grocery stores and specialty food stores). Two categories were created: ≤ 1.0 (healthier options) and > 1.0 (unhealthier options). k-means clustering was used to identify clusters based on proportions of grocery stores, restaurants, specialty food, fast food, convenience stores, and pharmacies. Prevalence data for county-level diabetes, obesity, and consumption of five or more fruits or vegetables per day (FV5) was obtained from the Behavioral Risk Factor Surveillance System. Multiple imputation was used to predict block-group level health outcomes with US Census demographic and economic variables as the inputs., Results: The healthier options category clustered into three sub-types: 1) specialty food, 2) grocery stores, and 3) restaurants. The unhealthier options category clustered into two sub-types: 1) convenience stores, and 2) restaurants and fast food. Within the healthier options category, diabetes prevalence in the sub-types with high restaurants (5.9 %, p = 0.002) and high specialty food (6.1 %, p = 0.002) was lower than the grocery stores sub-type (7.1 %). The high restaurants sub-type compared to the high grocery stores sub-type had significantly lower obesity prevalence (28.6 % vs. 31.2 %, p < 0.001) and higher FV5 prevalence (25.2 % vs. 23.1 %, p < 0.001). Within the larger unhealthier options category, there were no significant differences in diabetes, obesity, or higher FV5 prevalence across the two sub-types. However, restaurants (including fast food) sub-type was significantly associated with lower diabetes and obesity, and higher FV prevalence compared to grocery store sub-type., Conclusions: These results suggest that there are sub-types within larger categories of food environments that are differentially associated with adverse health outcomes. These observations support the specific food establishment composition of an area may be an important component of the food establishment-health relationship.

Proper trafficking of membrane-bound ion channels and transporters is requisite for normal cardiac function. Endosome-based protein trafficking of membrane-bound ion channels and transporters in the heart is poorly understood, particularly in vivo. In fact, for select cardiac cell types such as atrial myocytes, virtually nothing is known regarding endosomal transport. We previously linked the C-terminal Eps15 homology domain-containing protein 3 (EHD3) with endosome-based protein trafficking in ventricular cardiomyocytes. Here we sought to define the roles and membrane protein targets for EHD3 in atria. We identify the voltage-gated T-type Ca(2+) channels (CaV3.1, CaV3.2) as substrates for EHD3-dependent trafficking in atria. Mice selectively lacking EHD3 in heart display reduced expression and targeting of both Cav3.1 and CaV3.2 in the atria. Furthermore, functional experiments identify a significant loss of T-type-mediated Ca(2+) current in EHD3-deficient atrial myocytes. Moreover, EHD3 associates with both CaV3.1 and CaV3.2 in co-immunoprecipitation experiments. T-type Ca(2+) channel function is critical for proper electrical conduction through the atria. Consistent with these roles, EHD3-deficient mice demonstrate heart rate variability, sinus pause, and atrioventricular conduction block. In summary, our findings identify CaV3.1 and CaV3.2 as substrates for EHD3-dependent protein trafficking in heart, provide in vivo data on endosome-based trafficking pathways in atria, and implicate EHD3 as a key player in the regulation of atrial myocyte excitability and cardiac conduction., (© 2015 by The American Society for Biochemistry and Molecular Biology, Inc.)

Aims: Sudden death resulting from cardiac arrhythmias is the most common consequence of cardiac disease. Certain arrhythmias caused by abnormal impulse formation including catecholaminergic polymorphic ventricular tachycardia (CPVT) are associated with delayed afterdepolarizations resulting from diastolic Ca2+ release (DCR) from the sarcoplasmic reticulum (SR). Despite high response of CPVT to agents directly affecting Ca2+ cycling, the incidence of refractory cases is still significant. Surprisingly, these patients often respond to treatment with Na+ channel blockers. However, the relationship between Na+ influx and disturbances in Ca2+ handling immediately preceding arrhythmias in CPVT remains poorly understood and is the object of this study., Methods and Results: We performed optical Ca2+ and membrane potential imaging in ventricular myocytes and intact cardiac muscles as well as surface ECGs on a CPVT mouse model with a mutation in cardiac calsequestrin. We demonstrate that a subpopulation of Na+ channels (neuronal Na+ channels; nNav) colocalize with ryanodine receptor Ca2+ release channels (RyR2). Disruption of the crosstalk between nNav and RyR2 by nNav blockade with riluzole reduced and also desynchronized DCR in isolated cardiomyocytes and in intact cardiac tissue. Such desynchronization of DCR on cellular and tissue level translated into decreased arrhythmias in CPVT mice., Conclusions: Thus, our study offers the first evidence that nNav contribute to arrhythmogenic DCR, thereby providing a conceptual basis for mechanism-based antiarrhythmic therapy., (Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2014. For permissions please email: journals.permissions@oup.com.)

The ability to dynamically regulate, traffic, retain, and recycle proteins within the cell membrane is fundamental to life and central to the normal function of the heart. In the cardiomyocyte, these pathways are essential for the regulation of Ca(2+), both at the level of the plasma membrane, but also in local cellular domains. One intracellular pathway often overlooked in relation to cardiovascular Ca(2+) regulation and signaling is the endosome-based trafficking pathway. Highlighting its importance, this system and its molecular components are evolutionarily conserved across all metazoans. However, remarkably little is known of how endosome-based protein trafficking and recycling functions within mammalian cells systems, especially in the heart. As the endosomal system acts to regulate the expression and localization of membrane proteins central for cardiac Ca(2+) regulation, understanding the in vivo function of this system in the heart is critical. This review will focus on endosome-based protein trafficking in the heart in both health and disease with special emphasis for the role of endocytic regulatory proteins, C-terminal Eps15 homology domain-containing proteins (EHDs).

Neuron-glia interactions establish functional membrane domains along myelinated axons. These include nodes of Ranvier, paranodal axoglial junctions and juxtaparanodes. Paranodal junctions are the largest vertebrate junctional adhesion complex, and they are essential for rapid saltatory conduction and contribute to assembly and maintenance of nodes. However, the molecular mechanisms underlying paranodal junction assembly are poorly understood. Ankyrins are cytoskeletal scaffolds traditionally associated with Na(+) channel clustering in neurons and are important for membrane domain establishment and maintenance in many cell types. Here we show that ankyrin-B, expressed by Schwann cells, and ankyrin-G, expressed by oligodendrocytes, are highly enriched at the glial side of paranodal junctions where they interact with the essential glial junctional component neurofascin 155. Conditional knockout of ankyrins in oligodendrocytes disrupts paranodal junction assembly and delays nerve conduction during early development in mice. Thus, glial ankyrins function as major scaffolds that facilitate early and efficient paranodal junction assembly in the developing CNS.

Rationale: Nav1.5 (SCN5A) is the primary cardiac voltage-gated Nav channel. Nav1.5 is critical for cardiac excitability and conduction, and human SCN5A mutations cause sinus node dysfunction, atrial fibrillation, conductional abnormalities, and ventricular arrhythmias. Further, defects in Nav1.5 regulation are linked with malignant arrhythmias associated with human heart failure. Consequently, therapies to target select Nav1.5 properties have remained at the forefront of cardiovascular medicine. However, despite years of investigation, the fundamental pathways governing Nav1.5 membrane targeting, assembly, and regulation are still largely undefined., Objective: Define the in vivo mechanisms underlying Nav1.5 membrane regulation., Methods and Results: Here, we define the molecular basis of an Nav channel regulatory platform in heart. Using new cardiac-selective ankyrin-G(-/-) mice (conditional knock-out mouse), we report that ankyrin-G targets Nav1.5 and its regulatory protein calcium/calmodulin-dependent kinase II to the intercalated disc. Mechanistically, βIV-spectrin is requisite for ankyrin-dependent targeting of calcium/calmodulin-dependent kinase II-δ; however, βIV-spectrin is not essential for ankyrin-G expression. Ankyrin-G conditional knock-out mouse myocytes display decreased Nav1.5 expression/membrane localization and reduced INa associated with pronounced bradycardia, conduction abnormalities, and ventricular arrhythmia in response to Nav channel antagonists. Moreover, we report that ankyrin-G links Nav channels with broader intercalated disc signaling/structural nodes, as ankyrin-G loss results in reorganization of plakophilin-2 and lethal arrhythmias in response to β-adrenergic stimulation., Conclusions: Our findings provide the first in vivo data for the molecular pathway required for intercalated disc Nav1.5 targeting/regulation in heart. Further, these new data identify the basis of an in vivo cellular platform critical for membrane recruitment and regulation of Nav1.5., (© 2014 American Heart Association, Inc.)

Rationale: Cardiac function is dependent on the coordinate activities of membrane ion channels, transporters, pumps, and hormone receptors to tune the membrane electrochemical gradient dynamically in response to acute and chronic stress. Although our knowledge of membrane proteins has rapidly advanced during the past decade, our understanding of the subcellular pathways governing the trafficking and localization of integral membrane proteins is limited and essentially unstudied in vivo. In the heart, to our knowledge, there are no in vivo mechanistic studies that directly link endosome-based machinery with cardiac physiology., Objective: To define the in vivo roles of endosome-based cellular machinery for cardiac membrane protein trafficking, myocyte excitability, and cardiac physiology., Methods and Results: We identify the endosome-based Eps15 homology domain 3 (EHD3) pathway as essential for cardiac physiology. EHD3-deficient hearts display structural and functional defects including bradycardia and rate variability, conduction block, and blunted response to adrenergic stimulation. Mechanistically, EHD3 is critical for membrane protein trafficking, because EHD3-deficient myocytes display reduced expression/localization of Na/Ca exchanger and L-type Ca channel type 1.2 with a parallel reduction in Na/Ca exchanger-mediated membrane current and Cav1.2-mediated membrane current. Functionally, EHD3-deficient myocytes show increased sarcoplasmic reticulum [Ca], increased spark frequency, and reduced expression/localization of ankyrin-B, a binding partner for EHD3 and Na/Ca exchanger. Finally, we show that in vivo EHD3-deficient defects are attributable to cardiac-specific roles of EHD3 because mice with cardiac-selective EHD3 deficiency demonstrate both structural and electric phenotypes., Conclusions: These data provide new insight into the critical role of endosome-based pathways in membrane protein targeting and cardiac physiology. EHD3 is a critical component of protein trafficking in heart and is essential for the proper membrane targeting of select cellular proteins that maintain excitability., (© 2014 American Heart Association, Inc.)

Objective: To evaluate and compare healing, with and without the use of bone graft, of the gap created during tibial tuberosity advancement (TTA)., Study Design: Prospective study and case series., Animals: Dogs treated with TTA (n=67)., Methods: Prospective study: Mediolateral radiographic projections (6 weeks and 4 months) after TTA without use of bone graft (group I, n=14) were compared with radiographs of consecutive TTA in which the gap was filled with autologous cancellous bone graft (group II, n=14). Two scoring techniques (A, B) were used. Score A was used to grade the overall osteotomy healing (0=no healing, 4=healed osteotomy). Score B evaluated, independently of each other, healing in 3 sites: proximal to the cage (B1), between cage and plate (B2), and distal to the plate (B3)., Case Series: nongrafted TTA (4-25 weeks, n=39) were evaluated for healing (Score A). Data was analyzed using t-tests and ANOVA. Significance was set at P≤.05., Results: Prospective study: Score A, B2, and B3 showed no difference in healing between groups at 6.8 weeks and 4.2 months. Score B1 revealed, in both rechecks, a significantly higher density in group II. case series: Radiographs at 11.59±5.99 weeks scored 3.3 (2-4). No healing related complications were observed., Conclusion: The osteotomy gap created during TTA healed within expected time regardless of bone graft use., (© Copyright 2010 by The American College of Veterinary Surgeons.)

Objective: To compare racemic ketamine and S-ketamine as induction agents prior to isoflurane anaesthesia., Study Design: Prospective, blinded, randomized experimental study., Animals: Thirty-one healthy adult goats weighing 39-86 kg., Methods: Goats were premedicated with xylazine (0.1 mg kg(-1)) intravenously (IV) given over 5 minutes. Each goat was assigned randomly to one of two treatments for IV anaesthetic induction: group RK (15 goats) racemic ketamine (3 mg kg(-1)) and group SK (16 goats) S-ketamine (1.5 mg kg(-1)). Time from end-injection to recumbency was measured and quality of anaesthetic induction and condition for endotracheal intubation were scored. Anaesthesia was maintained with isoflurane in oxygen for 90 minutes. Heart rate, invasive arterial blood pressure, oxygen saturation, temperature, end-tidal carbon dioxide and isoflurane were recorded every 5 minutes. Arterial blood samples were taken for analysis every 30 minutes. Recovery time to recurrence of swallowing reflex, to first head movement and to standing were recorded and recovery quality was scored. Two-way repeated measures anova, Mann-Whitney and a Mantel-Cox tests were used for statistical analysis as relevant with a significance level set at p<0.05., Results: Induction of anaesthesia was smooth and uneventful in all goats. There was no statistical difference between groups in any measured parameter. Side effects following anaesthetic induction included slight head or limb twitching, moving forward and backward, salivation and nystagmus but were minimal. Endotracheal intubation was achieved in all goats at first or second attempt. Recovery was uneventful on all occasions. All goats were quiet and needed only one or two attempts to stand., Conclusions and Clinical Relevance: S-ketamine at half the dose rate of racemic ketamine in goats sedated with xylazine and thereafter anaesthetised with isoflurane induces the same clinically measurable effects., (© 2010 The Authors. Veterinary Anaesthesia and Analgesia © 2010 Association of Veterinary Anaesthetists and the American College of Veterinary Anesthesiologists.)