bluuebunny/crossref_metadata_2025_split huggingface dataset:
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

Abstract

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

Abstract

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

Abstract

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

Abstract

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

Abstract

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&lt;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

Abstract
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

SUMMARY
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

ABSTRACT
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

ABSTRACTThe 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

ABSTRACT
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.