bluuebunny/crossref_metadata_2025 huggingface dataset:
Prognostic role of myocardial inflammation in patients with undefined left ventricular arrhythmogenic cardiomyopathy
Authors: Peretto G , Casella M , Merlo M , Benedetti S , Cappelletto C , Rizzo S , Dello Russo A , Casari G , Basso C , Sala S , Sinagra G , Cooper LT , Della Bella P
Published: May 2022

Funding Acknowledgements

Type of funding sources: None.

Background

Etiology identification and risk stratification represent major issues for patients presenting with undefined left ventricular arrhythmogenic cardiomyopathy (ULVACM).

Purpose

To investigate the role of genetics and histology for ULVACM classification, management, and risk assessment.

Methods

We retrospectively analyzed a multicenter cohort of patients (screened n=1037) with ULVACM defined by ventricular arrhythmia (VA) onset, nonischemic late gadolinium enhancement (LGE) limited to the LV, and no severe dilated cardiomyopathy (LVEF≥40%). We selected patients undergoing both next generation sequencing (NGS) screening and endomyocardial biopsy (EMB) for etiology definition. When feasible, immunosuppressive therapy (IST) was used to target active myocardial inflammation (AMI). The study endpoint was a composite of cardiac death, heart transplantation and malignant VAs (VT, VF, appropriate ICD treatment).

Results

The study cohort is composed by 135 ULVACM patients (age 43±14 years, 63% males, LVEF 55±7 %). NGS identified pathogenic or likely-pathogenic variants (PVs/LPVs) consistent with ACM in 21 cases (16%), whereas EMB showed AMI in 78 patients (58%), including 13/21 PVs/LPVs+ (62%). After reclassification of 86 patients (64%), only 49 (36%) remained ULVACM. IST was started in 41/78 AMI patients (53%), including 9/13 PVs/LPVs+ (69%). Twenty patients (15%) met the study endpoint by 12 months, and 36 (27%) by the end of the study (60±27 months). Beyond malignant VT onset, AMI was the only predictor of events by 12 months (HR 5.0, 95%CI 1.4-18.1, p=0.007). No prognostic role was found for PVs/LPVs, except for the subgroup (n=77) with nonsustained VT onset. Among AMI patients, those treated by IST had a significantly lower occurrence of events, both by 12-months (1/41 vs. 16/37, p<0.001) and later (HR 0.05, 95%CI 0.01-0.21, p<0.001). Results were independently confirmed in PVs/LPVs+ and PVs/LPVs- cases. Excluding the IST population, the association of multiple factors among VT onset, PVs/LPVs, and AMI, resulted in an improved discrimination of arrhythmic risk profiles.

Conclusion

The combined genetic and histological workup allowed reclassification of up to 64% ULVACM patients, and substantially contributed into prognostic assessment. Furthermore, EMB identified suitable candidates for IST, who showed better outcomes irrespectively of their genotype.
Machine learning can identify hypertrophic cardiomyopathy in pediatric patients using electrocardiogram
Authors: Guerrier K , Gunturkun F , Bennie I , Akbilgic O , Davis R , Towbin J
Published: May 2022

Funding Acknowledgements

Type of funding sources: Public hospital(s). Main funding source(s): Le Bonheur Children’s Hospital

Background

Hypertrophic cardiomyopathy (HCM) is the most common genetic based heart disease and is associated with sudden cardiac death, particularly in young athletes. Standard measures of voltage abnormalities on electrocardiograms (ECGs) have demonstrated high false positive rates and poor correlation of LV thickness. Despite poor testing characteristics, ECGs continue to be part of most adolescent and family screening programs. While recent studies suggest that machine learning based analysis of ECGs may have utility in the identification of HCM in adult patients, there are limited data regarding its effectiveness in the pediatric population.

Purpose

The purpose of this study was to develop a deep learning model utilizing raw digital ECG data to accurately distinguish healthy pediatric patients from those with HCM.

Methods

ECGs from patients < 19 years with HCM were compared to ECGs from age- and sex-matched patients that underwent evaluation with ECG and echocardiogram for chest pain, sports clearance, syncope, or abnormal ECG between January 2011 and March 2021. Patients with a known clinical history of primary causes of left ventricular hypertrophy such as aortic stenosis, systemic hypertension, and glycogen storage disease were excluded from the study. Unsupervised signal processing tools including descriptive statistics and wavelet transformation were used to extract features from 12-lead ECG signals. A cascaded convolutional neural network was developed combining a residual neural network to extract features from waveform 12-lead ECG signals with a 2-layer dense neural network to embed features from signal processing tools. Model performance was evaluated by 10-fold stratified cross validation.

Results

The analytic sample included 181 patients (72% male; 63% Caucasian). Mean age was 12.3 ± 5.8 years. A cascaded deep learning model classified patients into healthy or HCM categories with a cross validation sensitivity of 77.7% and specificity of 81.6%. The positive predictive value was 82% and AUC of 0.89 (0.84-0.94).

Conclusion

This CNN trained with a relatively small number of images was able to accurately identify HCM in pediatric patients from standard 12-lead ECG. Evaluation of its potential utility in larger populations is needed.
An automatic single beat algorithm to discriminate farfield from nearfield bipolar voltage electrograms from the pulmonary veins
Authors: Schlageter V , Badertscher P , Krisai P , Spies F , Luca A , Osswald S , Vesin JM , Kuehne M , Sticherling C , Knecht S
Published: May 2022

Funding Acknowledgements

Type of funding sources: Public hospital(s). Main funding source(s): “Stiftung für Herzschrittmacher und Elektrophysiologie” Basel, Switzerland

Background

Confirmation of pulmonary vein (PV) isolation (PVI) during ablation of atrial fibrillation can be challenging due to superimposition of nearfield (NF) PV and farfield (FF) atrial bipolar voltage electrograms (BVE).

Purpose

To develop an automatic algorithm allowing to discriminate PV nearfield (PV-NF) from atrial farfield (atrial-FF) BVE from a circular mapping catheter during cryoballoon (CB) PVI based on a single-heartbeat analysis.

Methods

BVEs from a decapolar inner-lumen diagnostic catheter (Achieve, Medtronic) during CB PVI were manually classified as PV-NF, atrial-FF and combined FF-NF signal based on the characteristics and disappearance of the PV signal during isolation (Figure, upper row). BVE power spectra were computed using the fast Fourier transform (FFT) and the automatic classification of PV-NF, atrial-FF and combined FF-NF signals was performed using the power in different frequency bands (Figure, lower row). Support vector machine classifier was used to identify PV-NF BVE due to its highest predictive accuracy for the two classes PV-NF+ (PV-NF only and combined FF-NF) and PV-NF- (atrial-FF only). Validation of the approach was performed by comparison of a subset of 80 random samples, which were classified in addition by five experienced electrophysiologists.

Results

We analysed a dataset of 355 BVEs from 57 patients. The examples were balanced between the two classes PV-NF+ and PV-NF-. The mean duration (95% CI) of the BVE was 58 ms (26 to 86), 70 ms (50 to 100) and 94 ms (71 to 139) for PV NF, atrial-FF and combined FF-NF, respectively. The overall balanced accuracy including BVE from all PVs was 82.7% (95% CI: 80.3% to 85.1%). The analysis on individual PVs showed an accuracy of 96.6%, 85.2%, 80.8%, and 76.9% for the right inferior, right superior, left inferior and left superior PV, respectively. Validation of the algorithm in the subset of 80 patients showed a comparable accuracy, sensitivity and specificity in PV-NF detection between the automatic algorithm and the experienced electrophysiologists (82.8%, 89.2%, and 76.3%, compared to 85.2%, 91.9%, and 78.5%, respectively).

Conclusion

A reliable automatic based classification algorithm to identify PV-NF BVE could be developed based on a single-beat analysis. Real-time applications as well as using other electrode configurations may improve local signal interpretation.
Validation of a novel smartphone-based photoplethysmographic method for ambulatory heart rhythm diagnostics
Authors: Fernstad J , Svennberg E , Aberg P , Kemp-Gudmundsdottir K , Jansson A , Rosenqvist M , Engdahl J
Published: May 2022

Funding Acknowledgements

Type of funding sources: Public grant(s) – National budget only. Main funding source(s): Vinnova - The Swedish Agency for Innovation Systems.

Region Stockholm Innovation Fund.

Introduction

Devices for long-term and ambulatory recording of heart rhythm have limited availability within health care systems worldwide, potentially leading to missed diagnoses and limitations in peri-procedural heart rhythm management. As smartphones are becoming ubiquitous the availability of heart rhythm diagnostics and management of atrial fibrillation (AF) using smartphone photoplethysmography (PPG) compared to electrocardiography (ECG) is increasing. Previous validation studies of smartphone-PPG applications have all been performed under supervision in healthcare settings. In addition, no previous study has validated smartphone-PPG compared to simultaneous ECG recordings, with manual heart rhythm interpretation of the PPG recordings nor have they included patients with atrial flutter (AFL).

Purpose

The aim of this study was to validate a novel smartphone-PPG method for heart rhythm diagnostics in patients with AF and/or AFL when in use unsupervised in an ambulatory setting.

Methods

Unselected patients undergoing direct current cardioversion at a University Hospital for treatment of AF or AFL were asked to perform one-minute heart rhythm recordings post-treatment at least twice daily for 30 days in their home environment. All included were provided with an unmodified iPhone 7 smartphone running the CORAI Heart Monitor PPG application simultaneously with a single-lead ECG recording (KardiaMobile). PPG and ECG recordings were interpreted independently by two readers.

Results

In total 280 patients, with median age of 69.0 years (31% women) were included from November 2018 to July 2020 and registered 18 005 simultaneous PPG and ECG recordings. Of the PPG recordings 96.9% had sufficient quality for diagnosis compared to 95.1% of the ECG recordings (p < 0.001). Precardioversion ECG recordings were interpreted as AF in 82.1%, AFL in 14.3% and as having insufficient quality for diagnosis in 3.6% of the patients. After removal of recordings with insufficient quality 69.7% of ECG recordings were interpreted as sinus rhythm, 28.2% as AF and 2.1 % as AFL. Manual interpretation of the PPG recordings diagnosed AF/AFL (sensitivity) in 97.7% and sinus rhythm (specificity) in 99.4% of the recordings compared to manually interpreted ECG recordings, with an overall accuracy of 98.9%. Results excluding recordings interpreted as AFL on ECG or PPG diagnosed AF (sensitivity) in 99.0% and sinus rhythm (specificity) in 99.7% of the recordings, with an overall accuracy of 99.5%.

Conclusion

A novel smartphone-PPG method can be used by patients unsupervised in their home environment for accurate heart rhythm diagnostics of AF and AFL with high sensitivity and specificity.
Quality of life instruments in atrial fibrillation: a systematic review of measurement properties
Authors: Sale A , Yu JJ
Published: May 2022

Funding Acknowledgements

Type of funding sources: Private company. Main funding source(s): Medtronic

Background

Atrial fibrillation (AF) is the most common arrhythmia worldwide. A key objective of AF management is symptom reduction, as quality of life (QoL) is lower for patients with AF. QoL outcomes are important for evaluating AF therapies primarily indicated for symptom control, including catheter ablation. The aim of this systematic review is to identify the most frequently used QoL instruments across AF ablation studies and to critically appraise their measurement properties.

Methods and results

A literature mapping exercise was completed to identify the most frequently used QoL instruments in AF ablation studies published in the past five years. A systematic review was then undertaken to critically appraise the measurement properties of the identified QoL instruments: EQ-5D, SF-36, AFEQT (AF Effect on QualiTy-of-Life), AFSS (AF Severity Scale), MLHF-Q (Minnesota Living with Heart Failure Questionnaire), AFQLQ (AF Quality of Life Questionnaire), ASTA (Arrhythmia Specific questionnaire in Tachycardia and Arrhythmia), and SCL (Arrhythmia Symptom Checklist, Frequency and Severity). The systematic review was designed using the COSMIN guidelines for systematic reviews of patient-reported outcome measurements, and was focused on the measurement properties of validity, reliability, and responsiveness. A systematic search of the literature was conducted in Ovid MEDLINE, Ovid Embase, Ovid PsycINFO, EBSCO CINAHL, and Cochrane CENTRAL. A meta-analysis was not feasible due to significant heterogeneity between studies and measurement properties, therefore results were synthesized qualitatively. 17 studies and 8 instruments were identified that met the eligibility criteria. ASTA and AFEQT had the best ratings across measurement properties with both instruments having good ratings for prom development and internal consistency. However, none of the studies assessed measurement error and cross-cultural validity. Measurement properties were inconsistent across different studies appraising the same instrument.

Conclusions

AFEQT and ASTA had the strongest measurement properties but not all measurement properties have been assessed. Considering the large number of indeterminate and insufficient ratings, future research should focus on cross-cultural validation, measurement error, responsiveness, and interpretability.
Virtual induction and treatment of arrhythmias (VITA): a fast automated computational tool to induce scar-related tachycardia and identify ablation targets
Authors: Campos F , Neic AN , Mendonca Costa CMC , Whitaker JW , O’neill MON , Razavi RR , Rinaldi CA , Scherr DS , Niederer SAN , Plank GP , Bishop MJB
Published: May 2022

Funding Acknowledgements

Type of funding sources: Public grant(s) – National budget only. Main funding source(s): British Heart Foundation, Wellcome Trust

Background

Catheter ablation therapy of post-infarction ventricular tachycardia (VT) is often a lengthy procedure, with a high risk profile, and VT recurrence remains common. While computational modeling may aid pre-procedure planning and target identification, state-of-the-art reaction diffusion (R-D) simulations require access to high performance computing facilities, making them incompatible with clinical workflows.

Purpose

To present the Virtual Induction and Treatment of Arrhythmias (VITA), a novel, fast and fully automated computational tool to induce VT and identify subsequent ablation targets.

Methods

VITA employs multisite pacing to automatically find split activation wavefronts associated with the presence of channel isthmuses of viable myocytes within the inexcitable scar. The algorithm probes for all possible associated reentrant pathways and refines these to obtain a set of unique circuits sustaining potential clinical VTs. VT sustenance is assessed by comparing the electrical wavelength with the anatomical circuit path length. Corresponding exit sites of susceptible circuits are automatically identified, and a minimal lesion set constructed for ablation targeting. VITA also allows for rapid simulation of ECGs for clinical comparison. A summary of the VITA is shown in the Figure. VITA was tested on a virtual cohort of 7 post-infarcted porcine hearts and results compared to R-D simulations.

Results

Using only a desktop computer, VITA successfully identified all possible scar-related VT circuits and optimal ablation targets in just 48mins (per model), compared to 68.5hrs using a high-performance computer required by the R-D approach. Furthermore, VITA consistently identified more VTs associated with intra-scar circuits than R-D (Figure C).

Conclusion

VITA provides the first near real-time computational tool to aid treatment of post-infarction VTs.
Dg-mapping as a tool to determine the spatial distribution of the focal sources and the number of reentries during torsade de pointes in the cavb dog model
Authors: Van Den Abeele R , Van Nieuwenhuyse E , Hendrickx S , Vos MA , Panfilov AV , Vandersickel N
Published: May 2022

Funding Acknowledgements

Type of funding sources: None.

Background

Torsade de Pointes (TdP) is a ventricular tachycardia that is still incompletely understood. While the origin of the arrhythmia is generally accepted to be caused by triggered activity, the perpetuation of such an episode is still under debate.

Purpose

We compare the difference in reentrant activity between self- and non-terminating(ST and NT) TdP episodes. In addition, we analyzed the distribution of the triggered activity for preferred locations.

Methods

A total of 5 dogs with Chronic Atrioventricular Block developed 54 episodes of TdP. These episodes were examined for reentry loops and focal sources. First, to detect loops, we used Directed Graph Mapping, a novel mapping technique based on principles from network theory. Subsequently, the number of simultaneous loops and the presence of (bi-)ventricular reentry was compared between the ST and NT groups. Second, focal sources were accumulated into heatmaps. The distribution of sources was compared to a randomly distributed model for the detection of preferred locations.

Results

Concerning reentry, during the time at which loops are present, a typical ST episode shows an average of 1.33(±0.66) reentry loops present at one time compared to an average of 2.72(±1.48) for a typical NT episode. Looking at the (bi-)ventricular reentry, only 1 of the 4 ST episodes (25%) shows the presence of this type of reentry and only 7.12 % of the total reentry duration, while all 9 NT episodes (100%) develop (bi-)ventricular reentry to a greater degree than in the one ST episode (Between 10.10% and 69.62% of their total reentry duration). Regarding the triggered activity, we see locations in the heatmaps containing up to 23% of all detected focal sources in the entire system. Compared to a random distribution of focal sources, the chances to get as many sources in one location as shown in the data are close to 0%.

Conclusion

Reentry in NT TdP differentiates itself from the reentry in ST cases on the basis of the number of simultaneous loops in the system and the presence of (bi-)ventricular reentry. Triggered activity in CAVB dogs occurs at preferred locations in the ventricles. Therefore, ablating these preferred regions could be a possible strategy to prevent TdP.
Atrial endomysial fibrosis is associated with sex, atrial fibrillation, heart failure and age in cardiac surgery patients: results from the Catch-Me consortium
Authors: Winters J , Isaacs A , Zeemering S , Casadei B , Fabritz L , Guasch E , Mont L , Hatem S , Kirchhof P , Verheule S , Schotten U
Published: May 2022

Funding Acknowledgements

Type of funding sources: Public grant(s) – EU funding. Main funding source(s): Horizon 2020

Background

Risk factors for atrial fibrillation (AF), such as ageing, heart failure and AF itself, enhance AF propensity partly by inducing atrial fibrosis. Atrial endomysial fibrosis, a type of reactive fibrosis occurring between cardiomyocytes, impairs transverse conduction in rapid atrial pacing animal models. The factors underlying transcriptional regulation of endomysial fibrosis are largely unknown.

Objective

To examine the contributions of age, sex, AF and heart failure to the development of endomysial fibrosis in the context of concurrent pathologies. To study genome-wide transcriptional changes associated with endomysial fibrosis in human left and right atrial appendage biopsies (LAA, n=95; RAA, n=76).

Methods

An algorithm for automated quantification of endomysial fibrosis following staining with wheat germ agglutinin (WGA) was employed. Linear mixed models were constructed to determine endomysial fibrosis quantity as a function of AF, heart failure, sex, age and four principal components that accounted for potential confounding effects of other clinical characteristics. RNA sequencing was used to study expression changes in the atrial transcriptome associated with endomysial fibrosis.

Results

Sex, persistent AF, heart failure and age were independently associated with endomysial fibrosis. We identified hundreds (LAA: 386, RAA: 311) of RNA transcripts associated with endomysial fibrosis. None of these associations were independent from the clinical phenotypes. However, explorative gene set enrichment analysis identified association of endomysial fibrosis with gene sets involved in extracellular matrix organization, immune response, cell motility, developmental processes, cardiac muscle contraction and proteostasis in LAA while in RAA only gene sets regulating contractile function were enriched.

Conclusion

Besides AF, female sex, age and heart failure are associated with endomysial fibrosis in the atria. While abundance of none of the differential genes were independently associated with endomysial fibrosis, gene set enrichment analysis suggests an involvement of extracellular matrix organization, immune response, cell motility, developmental processes and cardiac muscle contraction in endomysial fibrosis.
TNNI3K delays atrioventricular conduction and reduces connexin-45 gap junctional coupling
Authors: Pham C , Podliesna S , Verkerk AO , Wolswinkel R , Munoz-Martin N , Veldkamp MW , Beekman L , Wilde LMW , Remme CA , Bezzina CR , Lodder EM
Published: May 2022

Funding Acknowledgements

Type of funding sources: Public grant(s) – National budget only. Main funding source(s): The Dutch Research Council (NWO Talent Scheme)

Introduction

Cardiac conduction delay is the main substrate for triggering arrhythmias. Hence, prolongation of the PR interval on the electrocardiogram (ECG) is a strong predictor of atrial fibrillation, the most common cardiac arrhythmia. In previous research, cardiac troponin I-interacting kinase (TNNI3K) has been identified as a regulator of the PR interval. Various inbred mouse strains showed a correlation between Tnni3k expression levels and PR interval durations. Additionally, transgenic mice overexpressing hTNNI3K presented an extreme PR interval prolongation.

Objective

This study aims to unravel the mechanism underlying TNNI3K-driven PR interval prolongation.

Methods

ECG parameters were recorded in mice expressing physiological levels of Tnni3k (congenic), overexpressing hTNNI3K (TNNI3Ktg), or overexpressing kinase-dead hTNNI3K (TNNI3K-KDtg) and were compared to low-Tnni3k expressing DBA/2J control mice. Atrioventricular (AV) conduction was measured in Langendorff-perfused isolated hearts by electrical mapping. Cellular electrophysiology and conductance were measured using the (dual) patch-clamp technique. AV nodal collagen levels were identified by Pico Sirius Red staining. Candidate interactors were identified by immunoprecipitation of transfected HEK293A cell lysates. In stable HeLa-Connexin 45 (Cx45) cell lines expressing TNNI3K, Cx45 protein expression and phosphorylation levels were investigated by Western blot. Localisation of Cx45 was characterised by immunofluorescence.

Results

At six weeks of age, congenic and TNNI3Ktg mice show a 17% and 35% prolonged PR interval duration, respectively. Nonetheless, the PR interval of TNNI3K-KDtg mice did not change. Electrical mapping experiments on TNNI3Ktg mouse hearts show a corresponding AV conduction delay, which was neither driven by changes in cellular atrial cardiomyocyte electrophysiology nor driven by AV-nodal fibrosis. We next identified Cx45, a highly expressed connexin in the AV node, as a potential TNNI3K interactor. HeLa-Cx45 cells expressing TNNI3K demonstrated a reduced Cx45 conductance compared to controls without changes in kinetics. Moreover, we observed relatively decreased Cx45 phosphorylation and increased Cx45 intracellular accumulation.

Conclusion

We here present TNNI3K as a kinase-driven modulator of PR interval prolongation and AV conduction delay, which is independent of atrial electrophysiology and AV nodal fibrosis. We further identified Cx45 as a novel interactor of TNNI3K. The presence of TNNI3K reduces Cx45 gap junctional conductance and promotes intracellular Cx45 protein accumulation, which could explain the PR interval prolongation in vivo. Altogether, this study implies a crucial role for TNNI3K in AV nodal conduction.
Regulation of APD and force by Na+/Ca2+ exchanger in hiPSC-cardiomyocytes
Authors: Ismaili D , Gurr K , Horvath A , Yuan L , Lemoine MD , Schulz C , Sani J , Petersen J , Reichenspurner H , Kirchhof P , Jespersen T , Eschenhagen T , Hansen A , Koivumaki JT , Christ T
Published: May 2022

Funding Acknowledgements

Type of funding sources: Public grant(s) – National budget only. Main funding source(s): BMBF

Introduction

Human induced pluripotent stem cell-derived cardiomyocytes (HiPSC-CM) are an emerging, powerful tool to study human cardiac physiology, pharmacology and toxicology, to model cardiovascular diseases or even to use for cardiac repair. Understanding the similarities and differences between hiPSC-CM and adult human cardiomyocytes is critical for their use. Here we focus on sodium calcium exchanger (NCX) who plays a crucial role in the Ca2+-homeostasis in the mammalian heart. Importantly, alterations in NCX expression in human heart are associated with various cardiac pathologies such as heart failure or arrhythmias. In order to investigate whether hiPSC-CM could serve as model for adult human heart NCX we measured the properties of NCX in hiPSC-CM and human ventricular tissue. Rat ventricular tissue was used for comparison.

Methods

HiPSC-CM were differentiated from a healthy iPSC line and dissociated from engineered heart tissue (EHT). Adult human and rat cardiomyocytes were digested from ventricular samples. We measured NCX current by the whole-cell patch clamp technique at 37 °C. Standard sharp microelectrodes were used to record action potentials (AP). Contractile force in human and rat ventricular samples was measured isometrically. A video-optical contractility test system was used to measure force in EHT. SEA0400 (10 µM) was used to block NCX.

Results

NCX currents could be measured in every hiPSC-CM. The NCX current densities in hiPSC-CM were larger than in human ventricular cardiomyocytes (3.2±0.2 pA/pF n=28 vs. 1.3±0.2 pA/pF n=15, p<0.05), but lower than reported for rat left ventricular cardiomyocytes using the same protocol. SEA0400 shortened APD90 markedly in EHT (264.1±24.9 ms to 191±31.6 ms, n=4) and to a lesser extent in rat ventricular tissue (54.4±3.9 ms to 48.9±4.2 ms, n=7). Shortening in human left ventricular preparations was tiny (320±22.1 ms to 305.5±20.3 ms, n=6) and not different from time-matched controls (TMC). Resting membrane potential, action potential amplitude and upstroke velocity were not affected neither in EHT nor in left ventricular preparations (rat and human). Force was significantly increased by NCX block in rat ventricle (by 31±5.4%, n=18) and EHT (by 20.8±3.9%, n=4), but in human left ventricular preparations there was only a tendency to attenuate spontaneous run-down (-3.7±4.3% n=8 with SEA vs. -6.2±3.7% n=12 in TMC).

Conclusion

HiPSC-CM possess NCX in the physiological range. HiPSC-CM show NCX-effects on APD and force as predicted from rat ventricle and in full accordance with cardiac physiology. Lack of NCX effect in human adult ventricles that had been already reported previously needs further investigations.
Defining characteristics and conservation of poorly annotated genes in Caenorhabditis elegans using WormCat 2.0
Authors: Higgins Daniel P , Weisman Caroline M , Lui Dominique S , D’Agostino Frank A , Walker Amy K
Published: May 2022

Omics tools provide broad datasets for biological discovery. However, the computational tools for identifying important genes or pathways in RNA-seq, proteomics, or GWAS (Genome-Wide Association Study) data depend on Gene Ontogeny annotations and are biased toward well-described pathways. This limits their utility as poorly annotated genes, which could have novel functions, are often passed over. Recently, we developed an annotation and category enrichment tool for Caenorhabditis elegans genomic data, WormCat, which provides an intuitive visualization output. Unlike Gene Ontogeny-based enrichment tools, which exclude genes with no annotation information, WormCat 2.0 retains these genes as a special UNASSIGNED category. Here, we show that the UNASSIGNED gene category enrichment exhibits tissue-specific expression patterns and can include genes with biological functions identified in published datasets. Poorly annotated genes are often considered to be potentially species-specific and thus, of reduced interest to the biomedical community. Instead, we find that around 3% of the UNASSIGNED genes have human orthologs, including some linked to human diseases. These human orthologs themselves have little annotation information. A recently developed method that incorporates lineage relationships (abSENSE) indicates that the failure of BLAST to detect homology explains the apparent lineage specificity for many UNASSIGNED genes. This suggests that a larger subset could be related to human genes. WormCat provides an annotation strategy that allows the association of UNASSIGNED genes with specific phenotypes and known pathways. Building these associations in C. elegans, with its robust genetic tools, provides a path to further functional study and insight into these understudied genes.
Effect of temperature on elastic properties of biotite and biotite-rich rocks: estimation from experiment and molecular dynamics simulation
Authors: Kitamura Keigo , Sakuma Hiroshi , Nishizawa Osamu
Published: May 2022

We measured the P-wave velocities (VP) of mafic high-grade metamorphic rocks at 1.0 GPa pressure and a range of temperatures from 25 to 400 °C, along orthogonal directions corresponding to macroscopic fabric elements in the specimen. Our results showed that biotite-rich rocks (over 15 vol per cent biotite) displayed a strong decrease in VP with increasing temperature whereas biotite-free rocks did not. The anisotropy of VP (AVP) in biotite-rich rocks also increased with increasing temperature because of differential VP reduction, indicating a thermal dependence of the elastic properties of biotite. We conducted molecular dynamics simulations to investigate the effect of temperature on the elastic stiffness constants (Cij) of phlogopite, an end member of the biotite solid-solution series. The simulations indicated that Cij of phlogopite have a strong anisotropy and temperature dependence. We then estimated Cij of the bulk rock by using the Voigt–Reuss–Hill average procedure based on the estimated Cij of phlogopite, reference values for Cij of hornblende and plagioclase and measured crystal preferred orientations. From the resulting values of bulk-rock Cij, we calculated the quasi-VP and anisotropy parameter ε, under the assumption of transverse isotropy, and confirmed that temperature had a clear effect on velocity whereas AVP remained stable. This result suggests that the thermal effect on VP of biotite-rich rocks can be explained by the thermal dependence of Cij of phlogopite, which we attribute to a lattice rearrangement in phlogopite. This finding implies that the elastic properties of micas may change and affect the elastic properties of bulk rocks in the absence of mechanical breakage, dehydration reactions or phase changes. The thermal effect on AVP of biotite-rich rocks cannot be explained by a thermal dependency of the elastic constants of phlogopite. We speculate that the local concentration of thermal stress on biotite may account for the thermal dependency of AVP of biotite-rich rocks.
Effects of a Gonadotropin-Releasing Hormone Agonist on Sex Behavior in Females of the Southern Giant Pouched Rat
Authors: Lo Beverly , Freeman Angela R , Singh Bhupinder , Hanadari-Levy Amit , Berman Jacquelyn , Chaves Alexandra , Choudhry Aumena , Ophir Alexander G
Published: May 2022

Synopsis

In general, males should be particularly attentive to cues of sexual availability and females should advertize accordingly. Vaginal patency (i.e., the openness of the vagina) is a reliable indicator of sexual maturity; if the vagina is closed, the female is unable to copulate. The southern giant pouched rat (Cricetomys ansorgei) is unusual because females can have fully fused vaginal openings (i.e., vaginal nonpatency) despite being considered “adults” by other metrics. Moreover, some females reversibly close their vaginal openings. Thus, vaginal patency in the pouched rat is a “flexible” reproductive state. We subcutaneously implanted a long-acting GnRH agonist (deslorelin), which over time inhibits sex steroid secretion, to better understand the endocrinology and social behavior relating to vaginal patency in this species. We hypothesized that altering GnRH would impact both patency and behavior through its effects on circulating levels of estradiol. Six months of deslorelin treatment did not alter vaginal patency. Behaviorally, deslorelin-treated females spent less time interacting with, and were more aggressive towards males (compared to controls). Notably, deslorelin did not alter female scent marking. We conclude that behavioral receptivity, but not vaginal patency, is impacted by GnRH hormonal cascades in the pouched rat.
First Light And Reionisation Epoch Simulations (flares) – IV. The size evolution of galaxies at z ≥ 5
Authors: Roper William J , Lovell Christopher C , Vijayan Aswin P , Marshall Madeline A , Irodotou Dimitrios , Kuusisto Jussi K , Thomas Peter A , Wilkins Stephen M
Published: May 2022

We present the intrinsic and observed sizes of galaxies at z ≥ 5 in the First Light And Reionisation Epoch Simulations (flares). We employ the large effective volume of flares to produce a sizeable sample of high-redshift galaxies with intrinsic and observed luminosities and half-light radii in a range of rest-frame ultraviolet (UV) and visual photometric bands. This sample contains a significant number of intrinsically ultracompact galaxies in the far-UV (1500 Å), leading to a negative intrinsic far-UV size–luminosity relation. However, after the inclusion of the effects of dust these same compact galaxies exhibit observed sizes that are as much as 50 times larger than those measured from the intrinsic emission, and broadly agree with a range of observational samples. This increase in size is driven by the concentration of dust in the core of galaxies, heavily attenuating the intrinsically brightest regions. At fixed luminosity we find a galaxy size redshift evolution with a slope of m = 1.21–1.87 depending on the luminosity sample in question, and we demonstrate the wavelength dependence of the size–luminosity relation that will soon be probed by the James Webb Space Telescope.
Impact of bar resonances in the velocity–space distribution of the solar neighbourhood stars in a self-consistentN-body Galactic disc simulation
Authors: Asano Tetsuro , Fujii Michiko S , Baba Junichi , Bédorf Jeroen , Sellentin Elena , Portegies Zwart Simon
Published: May 2022

The velocity–space distribution of the solar neighbourhood stars shows complex substructures. Most of the previous studies use static potentials to investigate their origins. Instead we use a self-consistent N-body model of the Milky Way, whose potential is asymmetric and evolves with time. In this paper, we quantitatively evaluate the similarities of the velocity–space distributions in the N-body model and that of the solar neighbourhood, using Kullback–Leibler divergence (KLD). The KLD analysis shows the time evolution and spatial variation of the velocity–space distribution. The KLD fluctuates with time, which indicates the velocity–space distribution at a fixed position is not always similar to that of the solar neighbourhood. Some positions show velocity–space distributions with small KLDs (high similarities) more frequently than others. One of them locates at $(R,\phi)=(8.2\,\,\rm{\mathrm{kpc}}, 30^\circ)$, where R and ϕ are the distance from the galactic centre and the angle with respect to the bar’s major axis, respectively. The detection frequency is higher in the inter-arm regions than in the arm regions. In the velocity maps with small KLDs, we identify the velocity–space substructures, which consist of particles trapped in bar resonances. The bar resonances have significant impact on the stellar velocity–space distribution even though the galactic potential is not static.
Dust diffusion in SPH simulations of an isolated galaxy
Authors: Romano Leonard E C , Nagamine Kentaro , Hirashita Hiroyuki
Published: May 2022

We compute the evolution of the grain size distribution (GSD) in a suite of numerical simulations of an isolated Milky Way-like galaxy using the N-body/smoothed-particle-hydrodynamics code gadget4-osaka. The full GSD is sampled on a logarithmically spaced grid with 30 bins, and its evolution is calculated self-consistently with the hydrodynamical and chemical evolution of the galaxy using a state-of-the-art star formation and feedback model. In previous versions of this model, the GSD tended to be slightly biased towards larger grains and the extinction curve had a tendency to be flatter than the observations. This work addresses these issues by considering the diffusion of dust and metals through turbulence on subgrid scales and introducing a multiphase subgrid model that enables a smoother transition from diffuse to dense gas. We show that diffusion can significantly enhance the production of small grains and improve the agreement with the observed dust extinction curve in the Milky Way.
The co-evolution of molecular hydrogen and the grain size distribution in an isolated galaxy
Authors: Romano Leonard E C , Nagamine Kentaro , Hirashita Hiroyuki
Published: May 2022

Understanding the evolution of dust and molecular hydrogen (H2) is a critical aspect of galaxy evolution, as they affect star formation and the spectral energy distribution of galaxies. We use the N-body/smoothed particle hydrodynamics code gadget4-osaka to compute the evolution of dust and H2 in a suite of numerical simulations of an isolated Milky Way-like galaxy. The evolution of the full grain size distribution (GSD) is solved by sampling the grain size on a logarithmically spaced grid with 30 bins. The evolution of a primordial chemistry network with 12 species is solved consistently with the hydrodynamic evolution of the system, including star formation, metal and energy ejections from stars into the interstellar medium through supernova feedback, and stellar winds. The formation model for H2 considers the GSD and photodissociation through the UV radiation of young stars. We identify the processes needed for producing a sizeable amount of H2, verify that the resulting star formation law in the later stages of galaxy evolution is consistent with observations of local spirals, and show that our model manages to produce a galactic molecular gas fraction in line with observations of Milky Way-like galaxies. We stress the importance of the co-evolution of the GSD and H2, as models assuming a fixed MRN shape for the GSD overestimate the production of H2 in regimes where the dust abundance is dominated by large grains and underestimate it in the regime where the dust is dominated by small grains, both of which are realized in simulations of dust evolution.
A revised simplified scattering model for the moonlit sky brightness profile based on photometry at SAAO
Authors: Winkler Hartmut
Published: May 2022

This paper presents multifilter measurements of the night sky brightness at the South African Astronomical Observatory (SAAO) in Sutherland in the presence of a bright moon. The observations cover a wide range of sky directions, lunar phases, and lunar positions. A revised simplified scattering model is developed for estimating the sky brightness due to moonlight that more accurately reflects the atmospheric extinction of the lunar beam compared to models frequently applied in astronomical studies. Contributions to night sky brightness due to sources other than moonlight are quantified and subtracted from the total sky background radiation to determine the spectral intensity and angular distribution of scattered moonlight. The atmospheric scattering phase function is then derived by comparing the sky brightening to the strength of the incoming lunar beam, estimated using a novel approach. The phase function is shown to be an excellent match to the combined theoretical Rayleigh and Mie scattering functions, the latter with a Henyey–Greenstein form instead of the exponential angular relationship often used in previous studies. Where deviations between measured and model sky brightness are evident in some bands, these are explained by contributions from multiple scattering or airglow, and are quantified accordingly. The model constitutes an effective tool to predict sky brightness at SAAO in optical photometric bands, especially with a bright moon present. The methodology can also be readily be adapted for use at other astronomical sites. The paper furthermore presents UBV(RI)c and Strömgren photometry for 49 stars, most with no prior such data.
Cross helicity of interplanetary coronal mass ejections at 1 au
Authors: Good S W , Hatakka L M , Ala-Lahti M , Soljento J E , Osmane A , Kilpua E K J
Published: May 2022

Interplanetary coronal mass ejections (ICMEs) contain magnetic field and velocity fluctuations across a wide range of scales. These fluctuations may be interpreted as Alfvénic wave packets propagating parallel or antiparallel to the background magnetic field, with the difference in power between counterpropagating fluxes quantified by the cross helicity. We have determined the cross helicity of inertial range fluctuations at 10−3 to 10−2 Hz in 226 ICME flux ropes and 176 ICME sheaths observed by the Wind spacecraft at 1 au during 1995–2015. The flux ropes and sheaths had mean, normalized cross helicities of 0.18 and 0.24, respectively, with positive values here indicating net antisunward fluxes. While still tipped towards the antisunward direction on average, fluxes in ICMEs tend to be more balanced than in the solar wind at 1 au, where the mean cross helicity is larger. Superposed epoch profiles show cross helicity falling sharply in the sheath and reaching a minimum inside the flux rope near the leading edge. More imbalanced, solar wind-like cross helicity was found towards the trailing edge and laterally further from the rope axis. The dependence of cross helicity on flux rope orientation and the presence of an upstream shock are considered. Potential origins of the low cross helicity in ICMEs at 1 au include balanced driving of the closed-loop flux rope at the Sun and ICME–solar wind interactions in interplanetary space. We propose that low cross helicity of fluctuations is added to the standard list of ICME signatures.
The Chosen One
Authors: Waters Matt
Published: May 2022

Cyrus the Great’s conquest of Babylonia in 539 had important implications, not least among them being that Cyrus now ruled more territory than any previous king. In both Babylonian and Judean traditions, Cyrus was identified as the chosen agent of the deity, Marduk and Yahweh, respectively. Through the royal inscriptions Cyrus commissioned in Babylonia, especially the Cyrus Cylinder from Babylon, it is possible to see how he shaped his ideological messaging for a Mesopotamian audience and, further, how subtle modifications to age-old Mesopotamia formulae laid the foundations for a nascent, unique Persian vision of rule for his successors. Facilitating the return of exiled Judeans to Jerusalem is one example of Cyrus’ magnanimity.
Legacies
Authors: Waters Matt
Published: May 2022

Cyrus was a prominent reference point in later Greek and Latin literature, both as a major historical figure and as an idealized ruler. Through the Roman period in their relations with Parthian and Sasanians, contemporary conflicts were often cast through the lens of the conflicts between Achaemenid Persians and Greeks, especially Xerxes’ invasion of Greece in 480–479. It is notable that Cyrus alone of the early Persian kings retained positive press in almost all sources, from any region, that spoke about him. Ironically, Cyrus became almost invisible, but his legacy still powerful, within indigenous Near Eastern traditions for several centuries. Memories of the Achaemenids were lost or conflated, or subsumed to the Zoroastrian traditions of eastern Iran, which were adopted and promulgated by the Sasanians in particular. Nonetheless, Cyrus the Great remains a historical touchstone, a universally admired figure who left a deep imprint on both European and Middle Eastern history, the first emperor to unite almost the entirety of the then-known world.
Berkeley and the Language of Philosophy
Authors: Townsend Chris
Published: May 2022

This chapter outlines the backdrop against which Berkeley’s thought comes into focus, including the philosophy of John Locke and the subsequent ‘free-thinking’ movement. It offers a preliminary sketch of Berkeley’s central and enduring ideas, and especially those that would resurface in the works of the Romantic poets, and particular emphasis on the areas of his work concerning the workings and ends of language. Central here is the argument that nature is a divinely authored text—a notion that would inspire some of the most celebrated Romantic verse. The chapter offers a new reading of Berkeley in light of the ongoing developments in the forms and style of his writing, and argues that Berkeley’s expanded theory of the rhetorical uses of language—and important area where Berkeley advanced past Locke’s language philosophy—opens the door for future arguments concerning the usefulness of poetic language.
Inside Outness in Coleridge
Authors: Townsend Chris
Published: May 2022

Coleridge’s reading in philosophy is often thought of as a process of ‘ousting’, where Hartley was surpassed by Berkeley, and Berkeley by Kant. This chapter shows that, whilst Kant did irrevocably change Coleridge’s philosophical views and drew him away from what he came to call Berkeley’s ‘dogmatic idealism’, elements of his reading of Berkeley lived on after Coleridge’s exposure to German philosophy. Central here is the experience Coleridge called ‘outness’—the sense that the world around us is external, even if it might actual exist in our minds. After reconstructing our knowledge of Coleridge’s reading of Berkeley, this chapter argues that Coleridge took from Berkeley the notion of ‘outness’ and a rhetoric of semblance that would animate his poetry and theological prose well after his Kantian turn.
Introduction
Authors: Sarker Sonita
Published: May 2022

The introduction explicates how the concept of “N/native” (and the distinction between “Native” and “native”), set in the prevailing discourses about History and Time in the early twentieth century, is the basis for the cultural and political participation of the six women featured in this study. The introduction argues that definitions of the “new” and “now,” dominant tropes of Anglophone literary modernist studies, depend on the position of N/natives who are themselves situated in the distinct but related categories of Time and History. Extending from this premise, the discussion proposes that belonging, not exile, is the defining feature of these particular women’s writing in the modernist era. It presents the ways in which Lineage, Land, Learning, and Labor, the material conditions of cultural and political belonging, inform the six women’s positions as N/natives and their narratives.