bluuebunny/crossref_metadata_2025 huggingface dataset:
ECG classification using multifractal detrended moving average cross-correlation analysis
Authors: Wang Jian , Jiang Wenjing , Yan Yan , Chen Wenbing , Kim Junseok
Published: November 2021

Accurate detection of arrhythmia signal types is of great significance for the early detection of heart disease and its subsequent treatment. The primary purpose of this study is to explore an electrocardiogram (ECG) classification system to improve its performance and achieve excellent computing performance, especially for large sample datasets. We classified ECG signals using the Hurst exponent, which is an ECG feature extracted by multifractal detrended moving average cross-correlation analysis (MF-XDMA). In addition, we used multifractal methods such as multifractal detrended fluctuation analysis (MF-DFA), multifractal detrended cross-correlation analysis (MF-DCCA) and multifractal detrended moving average (MF-DMA) to extract the features of ECG signals, and we used a support vector machine (SVM) to classify the four types of feature data. The experimental results show that MF-XDMA-SVM has the best classification performance for atrial premature beat (APB) and bigeminy signals, which indicates that MF-XDMA-SVM is the most effective for the extraction of ECG signal sequence features among the four multifractal models.
Real subset sums and posets with an involution
Authors: Bisi Cinzia , Chiaselotti Giampiero , Gentile Tommaso
Published: November 2021

In this paper, we carry out in an abstract order context some real subset combinatorial problems. Specifically, let [Formula: see text] be a finite poset, where [Formula: see text] is an order-reversing and involutive map such that [Formula: see text] for each [Formula: see text]. Let [Formula: see text] be the Boolean lattice with two elements and [Formula: see text] the family of all the order-preserving 2-valued maps [Formula: see text] such that [Formula: see text] if [Formula: see text] for all [Formula: see text]. In this paper, we build a family [Formula: see text] of particular subsets of [Formula: see text], that we call [Formula: see text]-bases on [Formula: see text], and we determine a bijection between the family [Formula: see text] and the family [Formula: see text]. In such a bijection, a [Formula: see text]-basis [Formula: see text] on [Formula: see text] corresponds to a map [Formula: see text] whose restriction of [Formula: see text] to [Formula: see text] is the smallest 2-valued partial map on [Formula: see text] which has [Formula: see text] as its unique extension in [Formula: see text]. Next we show how each [Formula: see text]-basis on [Formula: see text] becomes, in a particular context, a sub-system of a larger system of linear inequalities, whose compatibility implies the compatibility of the whole system.
Emergent gravity and the quantum
Authors: Das Saurya , Sur Sourav
Published: November 2021

In this essay, we show that if one starts with a universe with some matter and a cosmological constant, then quantum mechanics naturally induces an attractive gravitational potential and an effective Newton’s coupling. Thus, gravity is an emergent phenomenon and what should be quantized are the fundamental degrees of freedom from which it emerges.
Nonlinearity Attack Against the Kirchhoff–Law–Johnson-Noise (KLJN) Secure Key Exchange Protocol
Authors: Chamon Christiana , Kish Laszlo B.
Published: November 2021

This paper introduces a new attack against the Kirchhoff–Law–Johnson-Noise (KLJN) secure key exchange scheme. The attack is based on the nonlinearity of the noise generators. We explore the effect of total distortion ([Formula: see text]) at the second order ([Formula: see text]), third order ([Formula: see text]) and a combination of the second and third orders ([Formula: see text]) on the security of the KLJN scheme. It is demonstrated that as little as 1% results in a notable power flow along the information channel, which leads to a significant information leak. We also show that decreasing the effective temperature (that is, the wire voltage) and, in this way reducing nonlinearity, results in the KLJN scheme approaching perfect security.
The monoploid chromosome complement of reconstructed ancestral genomes in a phylogeny
Authors: Xu Qiaoji , Zhang Xiaomeng , Zhang Yue , Zheng Chunfang , Leebens-Mack James H. , Jin Lingling , Sankoff David
Published: November 2021

Using RACCROCHE, a method for reconstructing gene content and order of ancestral chromosomes from a phylogeny of extant genomes represented by the gene orders on their chromosomes, we study the evolution of three orders of woody plants. The method retrieves the monoploid complement of each Ancestor in a phylogeny, consisting a complete set of distinct chromosomes, despite some of the extant genomes being recently or historically polyploidized. The three orders are the Sapindales, the Fagales and the Malvales. All of these are independently estimated to have ancestral monoploid number [Formula: see text].
Reformulation of elliptic equations for heat transfer and diffusion in solids with space-time algebra
Authors: Mironov Victor L.
Published: November 2021

In this paper, we demonstrate the application of non-commutative space-time algebra of sedeons to generalize the system of equations describing heat transfer and impurity diffusion in solids at finite velocity. It is shown that by analogy with electrodynamics, these transfer processes can be described using a compact second-order sedeonic equation for generalized scalar and vector potentials. On the one hand, this equation is reduced to the system of first-order differential equations for vortex-less mass and heat flows, and on the other hand, it can be transformed to the second-order elliptical equations for the profiles of temperature and impurity concentration. The comparison of peculiarities in transfer within the frames of parabolic and elliptic equations is discussed.
Analysis of Labor Embodied in China’s Inter-regional Trade in Value-Added: Re-Examination of Leontief’s Paradox from the Perspective of Energy Use
Authors: YAN Bingqian , WANG Zhenxia
Published: November 2021

Based on the multi-regional input-output framework, this paper analyzed the labor and energy transfer embodied in interregional trade in China. Meanwhile, through estimating the energy intensity per unit of labor embodied in final products in each region, this study examines whether the empirical results are consistent with the theoretical hypothesis and provides relevant explanations and industrial development suggestions. Results show that east coastal region and central region are the two main participants in interregional trade. As for the labor embodied in trade, east coastal region is the largest exporter of embodied labor, though it has the highest wage among eight regions; in contrast, north coastal and southwestern region, with relatively low wage, are the two largest importer of embodied labor. As for the energy embodied in trade, northwestern region is the largest exporter of embodied energy. Further analysis indicates that the energy intensity per unit of labor in region with relatively low GRP (such as northwestern region) is the highest, whereas those in Beijing-Tianjin Region and south coastal region (with relatively high GRP) are the lowest. By analyzing the Revealed Comparative Advantage in each region, the paper finds that the main reason for this inconsistency lies in the industrial structure in northwestern and north coastal region, which are highly dependent in primary industries. Improving the infrastructure and upgrading industrial structure are important steps for these regions to transform the extensive growth mode.
Emerging Complexity of Nuclear South Asia
Authors: Silva Sanath De
Published: November 2021

South Asia is a geo-political system which has its unique security characters. The emerging complex nature of a system could lead either to the security or insecurity of that system. India and Pakistan are the emerging nuclear powers of South Asia. The nuclear doctrines and behavior of India and Pakistan promote the advancement of their nuclear programs in both strategic and civil domains. Both countries desire stability, the balance of power and security through the possession of nuclear options. However, the author argues that South Asia’s existing nuclear environment and its emerging complexity have produced insecurity and instability in the region at large. This paper is an attempt to identify the complexity of actors and behaviors and their emerging threats to the security of the region. There is also a lack of literature to portray the nuclear risk that the non-nuclear states face in South Asia. This paper tries to fill that gap as well.
Research on Investment Environment Performance Evaluation of Blockchain Industry with Intuitionistic Fuzzy CODAS Method
Authors: Xu Yong
Published: November 2021

With global resource waste and environmental pollution becoming increasingly serious, corporate investment environmental performance (CIEP) of blockchain industry has received much attention from researchers over the past decade. As an important part of economic development, enterprises also pay increasing attention to environmental protection and pollution control. CIEP of blockchain industry is regarded as the result of corporate environmental management. Assessing CIEP of blockchain industry can not only make enterprises focus on the environmental protection and management but also promote sustainable social development. Also, it is always viewed as multiattribute group decision making (MAGDM). Thus, a new MAGDM model is used to tackle it. Based on the CODAS (combinative distance-based assessment) method and intuitionistic fuzzy sets (IFSs), this paper designs the distance-based IF-CODAS method to assess CIEP. Eventually, an application about CIEP evaluation is employed to show the superiority of the defined method. The results illustrate that the defined framework is very useful for assessing CIEP.
Equivalent Resilient Modulus Inversion and Calculation of Different Asphalt Pavement Structures
Authors: Cao Mingming , Huang Wanqing , Zou Yiwen , Wu Zhiyong
Published: November 2021

Based on the modulus inversion theory and the equivalent principle of deflection basin, by analyzing the deflection basin data of each structure layer measured by the FWD, the obtained equivalent resilient moduli of different structural layers in three different structures (a semirigid type Asphalt pavement and two inverted asphalt pavements) were compared. At the same time, the calculated equivalent resilient modulus of the top surface of the structural layer based on the inversion method was used to modify the existing theory formula. The results show that, with the inversion method and the theoretical calculation method, the calculated equivalent resilient modulus of the top surface of the cushion layer has a small error, but the theoretical calculation method overestimates the equivalent resilient modulus of the top surface of the cement stabilized crushed stone layer and the top surface of the graded crushed stone transition layer, especially for the inverted asphalt pavement; by contrast, the corresponding result of the inversion method is closer to the value in actual engineering. While determining the equivalent resilient modulus of the cushion layer, the influence of the thickness of the cement stabilized crushed stone layer needs to be considered, and the inverted asphalt pavement structure should adopt a thicker asphalt layer to reduce the modulus deviation; at the same time, the more the structural layers and the larger the difference in the interlayer modulus ratio, the larger the deviation of equivalent resilient modulus of the top surface of the base layer; for the inverted asphalt pavement and semirigid asphalt pavement, the correction coefficients of the calculation formula of the equivalent resilient modulus of the top surface of cement stabilized gravel layer are 0.35∼0.55 and 0.65∼0.75, respectively. The inversion method can be used to determine the equivalent resilient modulus of each structural layer of the inverted asphalt pavement and semirigid asphalt pavement, and its results can provide a basis for the design of the structure reconstruction of asphalt pavement.
Image Processing Technology in Remote Monitoring and Intelligent Medical System
Authors: Bao Kongjun , Bao Yaoxi
Published: November 2021

In order to study the application of image processing technology in remote monitoring and intelligent medical systems, the principle and implementation method of a remote intelligent image monitoring system based on virtual local area network is proposed; this method analyzes the key technologies to be considered in the remote realization of image monitoring, adopts advanced digital image compression coding and decoding technology and digital image transmission technology, and applies intelligent image processing and recognition technology to display, adjust, and track images; it overcomes the defects that the general monitoring system requires excessive intervention by monitoring personnel and low intelligence. After verification, the experimental results show that the proposed model can accurately and efficiently segment nonoverlapping cervical cell images, and compared with other existing models, this model has both higher segmentation accuracy and faster calculation speed. The application of multicast is still only in the laboratory or small local area network; with the further development of network technology, its application prospects will be very broad.
Fluid Equation-Based and Data-Driven Simulation of Special Effects Animation
Authors: Deng Yujuan
Published: November 2021

This paper analyzes the simulation of special effects animation through fluid equations and data-driven methods. This paper also considers the needs of computer fluid animation simulation in terms of computational accuracy and simulation efficiency, takes high real-time, high interactivity, and high physical accuracy of simulation algorithm as the research focus and target, and proposes a solution algorithm and acceleration scheme based on deep neural network framework for the key problems of simulation of natural phenomena including smoke and liquid. With the deep development of artificial intelligence technology, deep neural network models are widely used in research fields such as computer image classification, speech recognition, and fluid detail synthesis with their powerful data learning capability. Its stable and efficient computational model provides a new problem-solving approach for computerized fluid animation simulation. In terms of time series reconstruction, this paper adopts a tracking-based reconstruction method, including target tracking, 2D trajectory fitting and repair, and 3D trajectory reconstruction. For continuous image sequences, a linear dynamic model algorithm based on pyramidal optical flow is used to track the feature centers of the objects, and the spatial coordinates and motion parameters of the feature points are obtained by reconstructing the motion trajectories. The experimental results show that in terms of spatial reconstruction, the matching method proposed in this paper is more accurate compared with the traditional stereo matching algorithm; in terms of time series reconstruction, the error of target tracking reduced. Finally, the 3D motion trajectory of the point feature object and the motion pattern at a certain moment are shown, and the method in this paper obtains more ideal results, which proves the effectiveness of the method.
Seepage Damage Statistical Model of Filled Fractured Rock considering Structural Surface and Failure Characteristic
Authors: Liu Xinyu , Tian Yuan , Zhu Zhende
Published: November 2021

Damage theory studies the whole process of initiation, propagation, and instability of microcracks in materials and provides an important basis for the estimation of the risk of materials. Therefore, it is assumed that the rock microunit strength is the damage variable of the medium and obeys the Weibull distribution. According to the tensile failure characteristics of filled fractured rock under the action of seepage stress, the maximum tensile strain criterion is used to define the rock microunit strength parameters, and the equivalent elastic modulus of the fractured rock is used to establish a new damage statistical model. This paper mainly studies the rationality and feasibility of using this new constitutive model to describe the seepage failure process and damage characteristics of filled fractured rock. The results indicate that (1) the accuracy of the equivalent elastic modulus is affected by the confining pressure and the characteristics of the structural surface. In the elastic phase, using the equivalent elastic modulus, EVRH has better fit. In the plastic phase, it is better to use the EV parameter. (2) The established Weibull distribution statistical model can better calculate the stress‐strain curve of fractured rocks with weak and soluble fillings. (3) The rock strength characteristics affected by different stress conditions and different filling fracture states calculated by the model are the same as the experimental data. (4) The model using equivalent elastic modulus parameters reflects the threshold characteristics of rock failure and the damage evolution process. After comparison, it is found that the model can accurately calculate the final damage value of the fractured rock with weak and soluble filling. However, the final damage value used to calculate the fractured rock of the hydraulic material filling is much higher and inaccurate.
Modeling of Hygro-Mechanical Behaviour through Raffia vinifera Fiber during the Water Diffusion Phenomenon
Authors: Takoudjou Harrond Nimjieu , Sikame Tagne Nicodème R. , Nwagoum Tuwa Peguy R. , Fogue Médard , Njeugna Ebenezer
Published: November 2021

In an industrial context where the use of friendly materials is encouraged, natural fibers of vegetable origin become more solicited for the reinforcement of composite materials. This work deals with the modeling of the hygro-mechanical behavior through raffia vinifera fiber during the diffusion phenomenon. The modeling of water diffusion through the raffia vinifera fiber is described by Fick’s second law and taking into account the swelling phenomenon of the fiber. The equation obtained is solved numerically by the finite difference method, and the evolution of the fiber radius as a function of time is obtained. By applying the Leibniz integration rule, a mathematical expression to predict the evolution of this radius as a function of time is proposed. It is observed numerically and analytically an increase of the dimensionless fiber radius with time up to a critical value after what one observes the saturation. This model allowed us to propose a mathematical model describing the absorption kinetics of the raffia vinifera fiber through its absorption ratio. By comparing the results of this model with the experimental results from the literature, one observes a good agreement. Moreover, the induced stresses in the fiber during the water diffusion can also be estimated with the proposed mathematical model expression of fiber. These stresses increase with time and can reach between 5 and 7 GPa. The results of this work can be used to predict the behavior of the raffia vinifera fiber inside a composite material during its development.
Changes in Gait Characteristics of Stroke Patients with Foot Drop after the Combination Treatment of Foot Drop Stimulator and Moving Treadmill Training
Authors: Peishun Chen , Haiwang Zhou , Taotao Li , Hongli Guan , Yu Min , Wanrong Zhang
Published: November 2021

Objective. To study the changes in gait characteristics of stroke patients with foot drop after the combination treatment of foot drop stimulator and moving treadmill training and thus provide a basis for the improvement in a foot drop gait after stroke. Methods. Sixty patients with hemiplegia and foot drop caused by stroke were randomly divided into two groups of 30: the test group and the control group. Both groups received basic rehabilitation training. On this basis, the test group received the combination treatment of foot drop stimulator and moving treadmill training. The control group received foot drop stimulator training. Both groups received consecutive treatment for 3 weeks, five times a week, and every single time lasted for 30 minutes. Before and after the treatment, a gait watch three-dimensional gait analysis system was used to measure and record the maximum angles of flexion of the affected side’s hip, knee, and ankle; the pace; the step length asymmetry; the iEMG of the tibialis anterior muscle; the functional ambulation category; and Ashworth’s modified spasticity classification of the gastrocnemius. Results. After treatment, in the two groups, the maximum angles of flexion of the affected side’s hip, knee, and ankle improved, the pace increased, the step length asymmetry decreased, the iEMG of the tibialis anterior muscle increased, the functional ambulation category improved, and Ashworth’s modified spasticity classification of the gastrocnemius decreased, but the above changes in the test group were better than those in the control group. The difference is statistically significant (

p
<
0.05

). Conclusions. The combination treatment of the foot drop stimulator and moving treadmill can significantly improve stroke patients’ foot gait and promote the normalization of hip flexion, knee flexion, and ankle flexion. It can increase the pace, significantly reduce the step length asymmetry, reduce the muscle tone of the gastrocnemius, and improve walking function.
The First Case of Simultaneous Surgical Procedure for Mitral Valve Disease and Esophageal Cancer
Authors: Komarov Roman , Osminin Sergey , Ismailbaev Alisher , Ivashov Ivan , Agakina Yulia , Schekoturov Igor
Published: November 2021

Cardiological patients with malignant tumors belong to a complex category of patients. We present the world’s first case of simultaneous surgical treatment of severe mitral valve disease and esophageal cancer. The patient underwent simultaneous replacement of the mitral valve and the Ivor-Lewis procedure using right thoracotomy and upper midline laparotomy. The patient underwent 3 courses of chemotherapy (paclitaxel and 5-fluoroucil). Follow-up for 8 months showed no signs of tumor recurrence or cardiac problems. A dextral thoracotomy with the lung deprivation, supplemented by an upper median laparotomy, achieved us convenient access to the mitral valve and to all parts of the esophagus, including groups of compromised lymph nodes. This case demonstrates the modern possibilities of simultaneous cardio and oncosurgery that allows eliminating competitive fatal diseases in 1 surgical and anesthetic intervention.
Optical Coherence Tomography Prognostic Factors in Age-Related Macular Degeneration Patients with Peripapillary Choroidal Neovascularization
Authors: Rabina Gilad , Ayalon Anfisa , Mimouni Michael , Stanescu Nir , Moisseiev Elad , Nemet Arie Y. , Geffen Noa , Segal Ori
Published: November 2021

Purpose: The aim of the study was to investigate the correlation between optical coherence tomography (OCT) findings and visual acuity outcomes after treatment with intravitreal bevacizumab (IVB) injections for age-related macular degeneration (AMD) patients with peripapillary choroidal neovascularization (PPCNV). Methods: The study involved a retrospective case series of consecutive patients diagnosed with PPCNV secondary to AMD. All patients were treated with IVB injections with a follow-up time of 1 year. Data collected included best-corrected visual acuity (BCVA) and automated and manually measured OCT parameters. Results: A total of 68 eyes were diagnosed with PPMV. Of them, 30 eyes of 30 patients aged 84.3 ± 6.9 years of which 63.3% female gender were included. Baseline BCVA was 0.46 ± 0.62 logMAR (Snellen 20/57), average choroidal thickness was 193.2 ± 22 μm, and mean number of IVB injections was 7.2 ± 1.9. After 1 year, BCVA was 0.56 ± 0.78 logMAR (Snellen 20/72) (p = 0.28). Eyes with greater central retinal thickness (r = −0.36, p = 0.05), greater subretinal hyper-reflective material (SHRM) area (r = −0.37, p = 0.05), and greater sub-retinal fluid (SRF) area (r = −0.73, p < 0.001) had a significantly smaller improvement in BCVA. Eyes with pigment epithelium detachment (PED) (0.68 ± 0.90 vs. 0.21 ± 0.12, p = 0.03) had a significantly worse BCVA. Conclusions: Our data suggest that AMD-related PPCNV with greater foveal thickness, PED size, SHRM, and SRF areas have worse final BCVA prognosis.
Ticagrelor versus Prasugrel in Patients with Acute Coronary Syndrome Undergoing Percutaneous Coronary Intervention: Analysis from the Acute Coronary Syndrome Israeli Survey
Authors: Eliaz Ran , Mengesha Bethlehem , Ovdat Tal , Iakobishvili Zaza , Hasdai David , Kheifets Mark , Klempfner Robert , Beigel Roy , Kalmanovich Eran , Alcalai Ronny , Levi Amos
Published: November 2021

Introduction: We aimed to compare the outcomes of acute coronary syndrome (ACS) patients undergoing in-hospital percutaneous coronary intervention treated with prasugrel versus ticagrelor. Methods: Among 7,233 patients enrolled to the Acute Coronary Syndrome Israeli Survey (ACSIS) between 2010 and 2018, we identified 1,126 eligible patients treated with prasugrel and 817 with ticagrelor. Comparison between the groups was performed separately in ST-elevation myocardial infarction (STEMI) patients, propensity score matched (PSM) STEMI patients, and non-ST-elevation ACS (NSTE-ACS) patients. Results: In-hospital complication rates, including rates of stent thrombosis, were not significantly different between groups. In PSM STEMI patients, 30-day re-hospitalization rate (p < 0.05), 30-day MACE (the composite of death, MI, stroke, and urgent revascularization, p = 0.006), and 1-year mortality rates (p = 0.08) were higher in the ticagrelor group compared to the prasugrel group; in NSTE-ACS patients, outcomes were not associated with drug choice. In Cox regression analysis applied on the entire cohort, prasugrel was associated with lower 1-year mortality in STEMI patients but not in NSTE-ACS patients (p for interaction 0.03). Conclusions: Compared to ticagrelor, prasugrel was associated with superior clinical outcomes in STEMI patients, but not in NSTE-ACS patients.
Mono- and Biallelic Protein-Truncating Variants in Alpha-Actinin 2 Cause Cardiomyopathy Through Distinct Mechanisms
Authors: Lindholm Malene E. , Jimenez-Morales David , Zhu Han , Seo Kinya , Amar David , Zhao Chunli , Raja Archana , Madhvani Roshni , Abramowitz Sarah , Espenel Cedric , Sutton Shirley , Caleshu Colleen , Berry Gerald J. , Motonaga Kara S. , Dunn Kyla , Platt Julia , Ashley Euan A. , Wheeler Matthew T.
Published: November 2021

Background:

ACTN2 (alpha-actinin 2) anchors actin within cardiac sarcomeres. The mechanisms linking
ACTN2
mutations to myocardial disease phenotypes are unknown. Here, we characterize patients with novel
ACTN2
mutations to reveal insights into the physiological function of ACTN2.

Methods:

Patients harboring ACTN2 protein-truncating variants were identified using a custom mutation pipeline. In patient-derived iPSC-cardiomyocytes, we investigated transcriptional profiles using RNA sequencing, contractile properties using video-based edge detection, and cellular hypertrophy using immunohistochemistry. Structural changes were analyzed through electron microscopy. For mechanistic studies, we used co-immunoprecipitation for ACTN2, followed by mass-spectrometry to investigate protein-protein interaction, and protein tagging followed by confocal microscopy to investigate introduction of truncated ACTN2 into the sarcomeres.

Results:

Patient-derived iPSC-cardiomyocytes were hypertrophic, displayed sarcomeric structural disarray, impaired contractility, and aberrant Ca
2+
-signaling. In heterozygous indel cells, the truncated protein incorporates into cardiac sarcomeres, leading to aberrant Z-disc ultrastructure. In homozygous stop-gain cells, affinity-purification mass-spectrometry reveals an intricate ACTN2 interactome with sarcomere and sarcolemma-associated proteins. Loss of the C-terminus of ACTN2 disrupts interaction with ACTN1 (alpha-actinin 1) and GJA1 (gap junction protein alpha 1), 2 sarcolemma-associated proteins, which may contribute to the clinical arrhythmic and relaxation defects. The causality of the stop-gain mutation was verified using CRISPR-Cas9 gene editing.

Conclusions:

Together, these data advance our understanding of the role of ACTN2 in the human heart and establish recessive inheritance of
ACTN2
truncation as causative of disease.
Abstract 117: Ponatinib Mediated Cardiotoxicity Is Driven By Pro-inflammatory S100A8/A9-NLRP3-IL-1β Signaling Circuit
Authors: Singh Anand P , Tousif Sultan , Umbarkar Prachi , Galindo Cristi L , Wheeler Nicholas , Zhang Qinkun , Prabhu Sumanth , Lal Hind
Published: November 2021

Background:
Ponatinib is a third-generation tyrosine kinase inhibitor (TKI) for chronic myelogenous leukemia (CML) treatment. Of note, ponatinib is the only treatment option for CML patients with T315I (gatekeeper) mutation. Unexpected clinical cardiotoxicity, including fatal myocardial infarction and congestive heart failure, has hampered its clinical use. Herein, we aimed to investigate the cardiotoxic mechanism of ponatinib and strategies to prevent the cardiotoxic manifestations.

Methods:
We employed wild-type C57BL/6, cardiovascular (CV) comorbidity models e.g., transverse aortic constriction (TAC)-pressure overload (cardiac comorbidity) and high-fat diet fed ApoE
-/-
(vascular comorbidity), to investigate the cardiotoxic mechanism of ponatinib. Echocardiography was performed to assess cardiac function. Comprehensive immune profiling was performed to identify ponatinib-induced immune dynamics using flow cytometry analysis.

Results:
Echocardiographic assessment of ponatinib treated high-fat diet fed ApoE
-/-
and pressure overload (PO) murine model showed significant decline in cardiac function, suggesting the key role of CV-comorbidities in ponatinib-induced cardiomyopathy. An unbiased RNA-Seq analysis identified the enrichment of dysregulated inflammatory genes, including a multi-fold upregulation of alarmins S100A8/A9 as a top hit in ponatinib-treated hearts. A combination of
in vitro
and
in vivo
mechanistic analysis, identified that ponatinib activates the S100A8/9-TLR4-NLRP3-IL-1β signaling pathway in cardiac and systemic myeloid cells (monocytes and neutrophils), thereby leading to excessive myocardial and systemic inflammation. Finally, we demonstrate that ponatinib-induced excessive inflammation is central to the cardiac pathology because a broad immunosuppressive agent dexamethasone abolished the adverse cardiac remodeling and dysfunction of ponatinib treated hearts.

Conclusions:
These findings uncover a novel mechanism of ponatinib-induced cardiac inflammation leading to cardiac dysfunction. Our results provide critical preclinical data and rationale for clinical investigation into immunosuppressive interventions to mitigate ponatinib-induced cardiotoxicity.
Abstract MP201: PKA Regulatory Subunit 1α As A Novel Necrosis Suppressor In Myocardial Ischemia/Reperfusion
Authors: Liu Yuening , Chen Jingrui , Xia Peng , Stratakis Constantine A , Cheng Zhaokang
Published: November 2021

Reperfusion therapy, the standard treatment for acute myocardial infarction, can trigger necrotic death of cardiomyocytes and provoke ischemia/reperfusion (I/R) injury. However, signaling pathways that regulate cardiomyocyte necrosis remain largely unknown. Our recent genome-wide RNAi screen has identified a potential necrosis suppressor gene
PRKAR1A
, which encodes PKA regulatory subunit 1α (R1α). R1α is primarily known for regulating PKA activity based on cAMP level, by restraining PKA catalytic subunits in the absence of cAMP. Here, we showed that disruption of R1α augmented cardiomyocyte necrosis
in vitro
and
in vivo
, resulting in exaggerated myocardial I/R injury and contractile dysfunction. Mechanistically, R1α loss repressed the Nrf2 antioxidant transcription factor and aggravated oxidative stress following I/R. Degradation of the endogenous Nrf2 inhibitor Keap1 through p62-dependent selective autophagy was blocked by R1α depletion. Phosphorylation of p62 at Ser349 by mammalian target of rapamycin complex 1 (mTORC1), a critical step in p62-Keap1 interaction, was induced by I/R, but diminished by R1α loss. Activation of PKA by forskolin or isoproterenol almost completely abolished hydrogen peroxide-induced p62 phosphorylation. In conclusion, R1α loss induces unrestrained PKA activation and impairs the mTORC1-p62-Keap1-Nrf2 antioxidant defense system, leading to aggravated oxidative stress, necrosis and myocardial I/R injury. Our findings uncover a novel role of PKA in oxidative stress and necrosis. Therefore, PKA signaling may be exploited to develop new cardioprotective therapies.
Abstract MP205: Human Induced Pluripotent Stem Cell Derived Cardiomyocyte And Fibroblast Patch To Treat Heart Failure
Authors: Lancaster Jordan J , Koevary Jennifer , Avery Ryan , Daugherty Sherry L , Fox Kenneth , Gorman Grace , LANCASTER Laryenth , McArthur Alice , Ref Jacob , Grijalva Adrian , Goldman Steven
Published: November 2021

Background:
We tested a tissue engineered (TE) patch composed of a biodegradable mesh embedded with human neonatal fibroblasts and seeded with human induced pluripotent stem cell derived cardiomyocytes (hiPSC-CMs) to treat heart failure in Yucatan mini swine receiving no immune suppression.

Methods:
Swine (N=12) underwent a 90-minute balloon occlusion/reperfusion of the left anterior descending coronary artery to create a myocardial infarction (MI). Following a 4-week recovery, the TE patch was implanted via a mini median sternotomy. The following were obtained: Cardiac Magnetic Resonance (CMR) imaging, cardiac catheterization, activity monitoring with FitBark collars, treadmill testing, 24/7 ECGs with implanted loop recorders.

Results:
At 4 weeks after MI, swine had increased left ventricular (LV) volumes, decreased end-systolic elastance (Ees), a shift of the diastolic pressure/volume (P/V) to the right of baseline and an increase in the LV mass/volume. After 6 months of treatment, the TE treated swine (N=7) compared to inert tissue treated swine (N=5): End-systolic volume (2% decrease vs 18% increase); End-diastolic volume (7% decrease vs 26% increase): Ees (1.0±0.2 vs 1.9±0.2 mmHg/mL, P=0.006); the diastolic P/V loops shifted back toward baseline with no change in slope, and LV mass decreased. There was no mortality related to treatment; the TE patch was well tolerated as assessed by CMR and histology. The loop recorders showed TE treated animals remained in sinus rhythm throughout with no ventricular arrhythmias, no change in heart rate and a 20% increase in daily activity levels and a 20% increase in exercise tolerance.

Conclusions:
This TE patch with human neonatal fibroblasts and hiPSC-CMs improves LV function, partially reverses LV remodeling and improves exercise in non-immune suppressed swine with heart failure after 6 months of treatment.
Abstract MP213: Activation Of Biosynthetic Pathways Regulates Cardiomyocyte Cell Cycle Induction In Human Cardiomyocyte
Authors: Abouleisa Riham , Mcnally Lindsey , Salama Abou B , Hammad Sally , Ou Qinghui , Wells Collin , Lorkiewicz Pawel , bolli Roberto , Mohamed Tamer , Hill Bradford G
Published: November 2021

Induction of cardiomyocyte proliferation is a promising therapeutic approach to treat heart failure. Several studies have identified metabolism as an important regulator of myocyte proliferation; however, the changes in metabolism during cardiomyocyte division remain unclear. Here, we use ectopic expression of cyclin B1, Cyclin D1, CDK1, and CDK4 (termed 4F) as a tool for understanding how metabolism influences cardiomyocyte proliferation. Mature hiPS-CMs stimulated to proliferate by 4F expression showed significant downregulation of oxidative phosphorylation genes, decreased glucose oxidation, and upregulation of genes that regulate biosynthetic pathways of glucose metabolism such as those involved in NAD(P)
+
synthesis (
NAMPT, NADK1, NNT
), the hexosamine biosynthetic pathway (HBP) and protein O-GlcNAcylation (
GFPT1
,
OGT, OGA
), and the serine biosynthesis pathway (SBP;
PHGDH
,
PSAT1
,
SHMT2
). In 4F-expressing hiPSC-CMs, stable isotope tracing indicated higher enrichment of glucose-derived
13
C in pentose phosphate intermediates, UDP-hexose, phospholipid precursors, NAD
+
, pyrimidines, UDP-HexNAc, and products of the serine biosynthesis pathway and one-carbon metabolism, suggesting that cell cycle induction activates biosynthetic pathways in cardiomyocytes. Knocking down nicotinamide phosphoribosyltransferase (NAMPT), a critical enzyme in the NAD
+
salvage pathway, 2 days before 4F overexpression significantly inhibited cell cycle progression in 4F-transduced hiPS-CMs. OGA overexpression, which catalyzes the hydrolytic cleavage of O-GlcNAc from post-transitionally modified proteins, completely abolished 4F-mediated cell cycle induction. Furthermore, NCT503, an inhibitor of the rate-limiting step in the serine biosynthesis pathway, abolished 4F-mediated increases in cell cycle markers. In a gain-of-function approach, we overexpressed phosphoenolpyruvate carboxykinase 2 (PCK2), which can drive carbon from the Krebs cycle to the glycolytic intermediate pool. PCK2 overexpression significantly augmented 4F-mediated cell cycle entry. These findings suggest that a metabolic shift from catabolic to anabolic activity is a critical step for cardiomyocyte cell cycle entry and is required to facilitate proliferation.
Abstract MP219: Hnrnpa2b1-dependent Selective Sorting Of Mir-486a-5p Into Msc-derived Exosomes Contributes To Cardioprotection
Authors: Jones Keith , Phan Ahn , Zhang Chongyu , Haar Lauren , Lynch Thomas
Published: November 2021

Exosomes (Exo) are a class of extracellular vesicles and involvement of stem cell-derived Exo in cardiac repair and cardioprotection is thought to be an important in the heart. Our HYPOTHESIS Is that specific microRNAs (miRs) from mesenchymal stem cell (MSC)-derived exosomes are actively and selectively sorted into Exo by RNA binding proteins and motifs on the miR, to serve specific functions of the Exo, including Cardioprotection.

Methods:
We characterized the miR populations of parental MSCs and their Exo via RNA Seq and confirmed by QRT-PCR the subpopulation of miRs that is increased in Exo
vs
. MSC cells. We then used Multiple Em for Motif Elicitation (MEME) Version 5.3.3 and determined the predicted conserved motifs. From these, we predicted RNA binding protein sites from the literature. In parallel, we performed mass spectrometry and western blot analyses to determine RNA binding proteins in MSC and Exo. Predicting that hnRNPA2B1 was a likely RNA binding protein for the new motif, we knocked out the cognate gene (CRISPR) in MSC and evaluated the KO Exo vs. the WT Exo by RNA Seq and QRT-PCR. We performed protein and RNA pulldowns, and EMSA to validate binding of hnRNPA2B1 to several of the miRs, and investigated the effects of these miRs on cell survival after simIR and in an
in vivo
mouse model of MI.

Results:
We found a set of eight miRs that are selectively concentrated in the MSC Exo. MEME software predicted a conserved binding motif of gAGu, which is close to canonical sites for binding of hnRNPA2B1 and hnRNPA1. We determined hnRNPA2B1 was in MSC and Exo and showed KO hnRNPA2B1 cells and Exo had no compensatory perturbation of other RNA binding proteins. The KO MSC Exo show reduction of the selective sorting of the miRs of interest. Pulldowns and binding assay results verify binding of hnRNPA2B1 to both miR-486a-5p and miR-122a. Finally, we showed that miR-486a-5p is protective in H9C2 cells submitted to simIR and results in significant 68% reduction of infarct size (n=7, P=0.0175) in vivo in association with repression of PDCD4 expression and apoptosis.

Conclusions:
We determined that a set of miRs is selectively concentrated in MSC Exo and demonstrated the necessity of hnRNPA2B1 in that process. This appears to involve a conserved RNA sequence motif (mutational analysis underway). A major miR affected is miR-486a-5p, which is strongly cardioprotective. Our results support that miR-486a-5p is selectively concentrated in MSC Exo and contributes to cardioprotection by reducing PDCD4 activity in apoptosis.
Abstract MP227: Single Cell RNA Sequencing Analysis Reveals Insulin Signaling Defects In Cardiomyocytes Derived From A Novel Mouse Model Of Heart Failure With Preserved Ejection Fraction
Authors: Huang Jijun , Xiong Zhaojun , Ren Shuxun , Cao Nancy , Liu Jianfang , Wang Yibin , Gao Chen
Published: November 2021

Heart failure with preserved ejection fraction (HFpEF) is an emerging form of heart failure worldwide with no effective therapies in contrast with heart failure with reserved ejection fraction (HFrEF). To simulate multiple risk-factors associated with HFpEF in clinic, we developed a HFpEF mouse model by introducing cardiac hypertrophy with transverse aortic constriction (TAC) in ObOb (
Lep
ob/ob
) mice, which has intrinsic systemic metabolic dysfunctions including obesity and insulin resistance. We first validated pathological changes in diastolic but not systolic parameters in the Ob-TAC vs. Ob-sham mice up to 10 weeks post-TAC by echocardiography. To evaluate the global transcriptome change in difference cell types, we conducted single nuclei RNA sequencing (snRNA-seq) from whole hearts of lean mice (c57), ObOb, and Ob-TAC mice (male only). 10x genomic 3’ GEM kit was used to generate the cDNA library and sequencing was done by Novaseq SP platform. A total of 13k nuclei were recovered from QC, nFeature RNA (< 2500) and mitochondrial gene (< 5%) filtering. By UMAP dimension reduction analysis, we annotated major cardiac cell types in the integrated snRNA-seq dataset, including 3 clusters of Cardiomyocytes (CMs). By pathway analysis of the differentially expressed genes in each CM clusters, we found that insulin resistance and glucagon pathway were enriched among the up regulated genes in CMs in HFpEF vs. lean control, while cell migration, signal transduction including insulin substrates were down regulated. Thus, we hypothesized that the altered crosstalk between glucagon and insulin signaling might contribute to the development of HFpEF in this mouse modal. This hypothesis was validated in a proof-of-concept study showing significant improvement of HFpEF features by inhibiting the glucagon receptors post-TAC with injection of a glucagon receptor antagonist.
Abstract MP228: The Role Of Gut Microbiome Secreted Short Chain Fatty Acids In The Development Of Heart Failure With Preserved Ejection Fraction HFpEF
Authors: Hatahet Jomana , Bonomo Raiza , Cook Tyler , White Chelsea R , Gavini Chaitanya , Mansuy-Aubert Virginie , Aubert Gregory
Published: November 2021

More than 50% of patients with heart failure are diagnosed with heart failure with preserved ejection fraction (HFpEF), and 80% of them are obese. It is a prominent disease with no available treatments. It is characterized by diastolic dysfunction that involves increase in left ventricle stiffness and decrease in its relaxation during diastole. To better understand the pathogenesis of obesity associated HFpEF, our studies focus on the early asymptomatic changes in cardiac mechanics that occurs before the increases in intracardiac pressure. Therefore, we have developed an obesity associated mouse model that we called pre-HFpEF where mice were fed either Normal Chow or Western Diet for 14 weeks. Our echocardiography measurements indicated the presence of early cardiac dysfunction consistent with obesity associated pre-HFpEF phenotype. Mice on WD had decrease in Global Longitudinal Strain (%GLS) and Longitudinal strain rate reverse (LSRr) indicating early signs of systolic and diastolic dysfunction, as well as increase in left ventricle anterior and posterior wall thickness during diastole (LVAWd, LVPWd). Obesity is also known to cause microbiome imbalance, which plays a significant role in the development of cardiovascular diseases through changes in short chains fatty acids, which are products of dietary fiber fermentation by the gut bacteria. In order to study the association between gut microbiome imbalance and HFpEF development, we treated our obese pre-HFpEF mice with fecal matter transplantation (FMT) from either lean or obese mice, and we found that FMT from lean mice led to significant improvements in systolic and diastolic dysfunction by increasing %GLS and LSRr and preventing hypertrophy by decreasing LVAWd and LVPWd. In addition, WD reduced butyrate producing bacteria, however circulating levels of butyrate were significantly increased with lean FMT treatment. Using an
in-vitro
approach to mimic WD we found butyrate treatment to inhibit the activation of NLRP3 inflammasome and NF-KB. Therefore, since FMT treatment improved cardiac dysfunction in obesity associated pre-HFpEF mice, and that butyrate is increased after FMT and can play a role in metabolic homeostasis, we predict that butyrate could be an important player in FMT improvements through cardiac metabolic regulation and cardiac inflammation suppression
Abstract MP231: Long Non-coding Rna Camirt Plays A Sentinel Role In Aging-related Heart Failure Via Interaction With Phb2 To Modulate Mitophagy Signaling In The Heart
Authors: Wang Xiao-Liang , LI XIUCHUN , Ong Hannah L , Ko Jae-Kyun , Sun Nuo , Miano Joseph M , Ma Jianjie , Cai Chuanxi
Published: November 2021

Background:
Mitochondrial dysfunction is an important risk factor for heart failure in elderly people. Mitophagy, a physiological process that controls the removal of damaged mitochondria, is compromised in aging or failing hearts. In this study, we examined the physiological role of a cardiac-specific lncRNA Camirt that can potentially modulate mitophagy in the heart.

Methods and Results:
RNA-seq analysis and RT-PCR reveal a lncRNA is highly expressed in both mouse and human hearts, with undetectable levels in other vital organs. Furthermore, Real time qPCR was used to examine the expression of lncRNA in different animal models and in human hearts, which results showed that the expression of this lncRNA is decreased in aging mouse and human hearts, and failing mouse hearts induced by isoproterenol and doxorubicin. RNA pull-down and RNA-binding protein immunoprecipitation assays identify prohibitin-2 (Phb2), a known mitophagy receptor, as a binding partner for this lncRNA. Thus, we name this novel lncRNA as a cardiac-specific mitophagy-associated RNA transcript (Camirt). Camirt conditional (flox) knockout mice were created via CRISPR /Cas9 technology, and subjected to the longitudinal echocardiographic and survival studies. Mice with cardiac specific deletion of Camirt (Camirt-cKO) display progressive heart failure and die within 12 month after birth. RNA sequencing and gene ontology analysis revealed that genes involved in mitophagy signaling were significantly altered in the Camirt-cKO hearts compared with the littermate wild type mice. Transmission electron microscopy were used to examine the mitochondrial morphology in mouse hearts, and reveal excessive accumulation of mitolysosomes in cardiomyocytes derived from the Camirt-cKO mice. In vitro study with Annexin-V/PI staining showed an increased number of live cells and decreased number of apoptotic cells in cultured neonatal cardiomyocytes with overexpression of Camirt following oxidative stress induced by treatment with H2O2. Increased autophagy (or mitophagy) activity was observed in HL-1 cells with stable overexpression of Camirt and in the presence of chloroquine (an inhibitor for the lysosome degradation). While reduced Camirt expression via shRNA knock-down leads to compromised mitophagy activity in HL-1 cells. Further biochemical studies support the function of Camirt/Phb2 in maintenance of mitochondria function and mitophagy signaling under stress conditions.

Conclusion:
Overall, our results suggested that Camirt plays a sentinel role in aging-related heart failure via interaction with Phb2 to modulate mitophagy signaling in the heart. Future studies will focus on elucidating the in vivo role and mechanisms of Camirt in modulation of mitophagy under natural aging or stress-induced pathologic conditions using the loss- or gain-of-function of Camirt mouse models.