bluuebunny/crossref_metadata_2025 huggingface dataset:
Landscape-level likelihood estimation of eastern spruce dwarf mistletoe (Arceuthobium pusillum) infestations in lowland black spruce (Picea mariana) forests of Minnesota, USA
Authors: Gray Ella R. , Russell Matthew B. , Windmuller-Campione Marcella A.
Published: October 2023

Biotic disturbance agents are important factors influencing forest dynamics; incorporating them into management planning requires a detailed understanding of their distribution, prevalence, and effects on stand dynamics. However, this information can be difficult to collect in remote forest systems, such as lowland black spruce ( Picea mariana (Mill.) B.S.P.) forests affected by eastern spruce dwarf mistletoe ( Arceuthobium pusillum Peck, hereafter ESDM). In such cases, predictive modeling is often needed to inform management decisions and address forest health questions. Here, we used two publicly available datasets to predict areas where black spruce is more likely to be infested with ESDM in northeastern Minnesota, USA. Using random forest modeling and logistic regression, we found location, stand age, basal area, site index, average diameter, and metrics of species composition to be among the most important predictors of ESDM occurrence. Predictions showed two regions of greater likelihood of infestation with distinct ecological characteristics and ownership patterns. By understanding how stand structural characteristics relate to ESDM infestations, managers can improve monitoring and management of ESDM at the stand and landscape scales. Additionally, our approach of using multiple datasets and modeling methods can serve as a framework for decision-making on other forest health concerns.
Nonrelativistic expansion of type IIA NS5 brane
Authors: Roychowdhury Dibakar
Published: October 2023

We carry out nonrelativistic expansion for NS5 brane based on a codimension two foliation of type IIA supergravity background. We simultaneously expand the world-volume fields in an appropriate $$ 1/c^2 $$

1
/

c
2

expansion together with the background fluxes. When put together, the resulting procedure yields a finite world-volume action for nonrelativistic NS5 brane that is coupled to String Newton-Cartan background.
Analytical solution for nuclear plus atomic Hulthén potential — A perturbative approach
Authors: Majumder M. , Laha U. , Panigrahi A.
Published: October 2023

In this work, we construct the analytical solution of the Schrödinger equation for a combined nuclear plus atomic Hulthén potential with different range parameters, using the Frobenius method. The atomic Hulthén potential acts as the screened Coulomb potential to represent the very short-range electromagnetic interaction. It is intended to emphasize how the impact of the combined potential in these situations is routinely examined within the context of nuclear physics. The Jost function is calculated from its integral representation in terms of the regular solution. From the phase of the Jost function, the scattering phase shifts for different partial waves, and further differential scattering cross-section and total cross-sections are calculated for alpha-proton and proton–proton systems. On comparing with the existing experimental data, we conclude that the results obtained are in close conformity with the previous works that exist in the literature.
Trustworthy Recommender Systems
Authors: Wang Shoujin , Zhang Xiuzhen , Wang Yan , Ricci Francesco
Published: October 2023

Recommender systems (RSs) aim at helping users to effectively retrieve items of their interests from a large catalogue. For a quite long time, researchers and practitioners have been focusing on developing accurate RSs. Recent years have witnessed an increasing number of threats to RSs, coming from attacks, system and user generated noise, and various types of biases. As a result, it has become clear that the focus on RS accuracy is too narrow, and the research must consider other important factors, particularly trustworthiness. A trustworthy recommender system (TRS) should not only be accurate but also transparent, unbiased, fair, and robust to noise and attacks. These observations actually led to a paradigm shift of the research on RSs: from accuracy-oriented RSs to TRSs. However, there is a lack of a systematic overview and discussion of the literature in this novel and fast-developing field of TRSs. To this end, in this article, we provide an overview of TRSs, including a discussion of the motivation and basic concepts of TRSs, a presentation of the challenges in building TRSs, and a perspective on the future directions in this area. We also provide a novel conceptual framework to support the construction of TRSs.
Use of Artificial Intelligence Techniques to Assist Individuals with Physical Disabilities
Authors: Pancholi Sidharth , Wachs Juan P. , Duerstock Bradley S.
Published: October 2023

Assistive technologies (AT) enable people with disabilities to perform activities of daily living more independently, have greater access to community and healthcare services, and be more productive performing educational and/or employment tasks. Integrating artificial intelligence (AI) with various agents, including electronics, robotics, and software, has revolutionized AT, resulting in groundbreaking technologies such as mind-controlled exoskeletons, bionic limbs, intelligent wheelchairs, and smart home assistants. This article provides a review of various AI techniques that have helped those with physical disabilities, including brain–computer interfaces, computer vision, natural language processing, and human–computer interaction. The current challenges and future directions for AI-powered advanced technologies are also addressed.
Authoritarian Legality and State Capitalism in China
Authors: Whiting Susan H.
Published: October 2023

This review addresses three questions surrounding authoritarian legality and state capitalism in China. First, what is legality, and does it exist in China's Leninist single-party state? Scholars who characterize the system as order maintenance find the absence of legality. Those employing dual-state and instrumentalist views of law find partial legality. Scholars promoting the notion of bare legality find complete legality. Second, does authoritarian legality strengthen regime legitimacy? Scholars agree that the state seeks legitimation through its embrace of authoritarian legality. Empirical research tests this claim. Third, is China in transition from plan to market, and what is the role of law in state capitalism? The teleology of the transition paradigm overlooks illiberal underpinnings of property rights and factor markets. Answers to these questions help explain regime resilience, economic growth, economic crisis, and inequality in China. Both the institution of the dual state and the perpetuation of plan elements reinforce state power.
Distributional Regression for Data Analysis
Authors: Klein Nadja
Published: October 2023

The flexible modeling of an entire distribution as a function of covariates, known as distributional regression, has seen growing interest over the past decades in both the statistics and machine learning literature. This review outlines selected state-of-the-art statistical approaches to distributional regression, complemented with alternatives from machine learning. Topics covered include the similarities and differences between these approaches, extensions, properties and limitations, estimation procedures, and the availability of software. In view of the increasing complexity and availability of large-scale data, this review also discusses the scalability of traditional estimation methods, current trends, and open challenges. Illustrations are provided using data on childhood malnutrition in Nigeria and Australian electricity prices.
Synthesis and Characterization of Cr-Doped Pb2Fe2O5 Thin Films by Reactive Magnetron Sputtering
Authors: Beklešovas Benas , Stankus Vytautas , Abakevičienė Brigita , Link Joosep , Stern Raivo , Plyushch Artyom , Banys Jūras , Čyvienė Jurgita , Girčys Rolandas , Bašinskas Matas , Kalvaitis Evaldas
Published: October 2023

Multiferroic materials, which exhibit simultaneous ferroelectricity, ferromagnetism, and ferro-elasticity, have attracted significant attention due to their multifunctional properties. Coupling between ferroelectric and magnetic properties has led to the development of non-volatile memory devices, transducers, magnetic field sensors, and other applications. Pb2Fe2O5 (PFO) is a promising multiferroic material due to it simultaneously exhibiting ferroelectricity and ferromagnetism at room temperature. Doping with aliovalent ions, such as Cr3+, has been proposed as an effective method for enhancing the ferroelectric and magnetic properties, consequently leading to the enhancement of multiferroic properties. The investigation shows that the lead ferrite phase (220) was present in all samples, but its abundance reduced with increasing synthesis temperature due to lead desorption. Dielectric measurements revealed that PFO films with highest Cr concentration had the highest polarization (Pr) of 72.2 μC cm−2. The study also found that the magnetization of PFO films was up to 9.5·10−7
μAm2 at an ambient temperature of 5 K, and the magnetic ordering temperature was 363 K, corresponding to the magnetic ordering temperature of chromium oxides. The morphology of Cr doped PFO films changed with increasing chromium content, resulting in a reduction in grain size and an increase in the film density.
Premotor and Posterior Parietal Cortex Activity is Increased for Slow, as well as Fast Walking Poststroke: An fNIRS Study
Authors: Lim Shannon B. , Peters Sue , Yang Chieh-ling , Boyd Lara A. , Liu-Ambrose Teresa , Eng Janice J.
Published: October 2023

Background and Purpose. The ability to change gait speeds is important for interacting with the surrounding environment. Gait speed modulation poststroke is often impaired and is related to decreased walking independence after stroke. Assessment of brain activation during walking at different speeds can provide insight into important regions for facilitating gait recovery. The purpose is to determine: (1) the symmetry of brain activation as individuals increase or decrease their gait speed, (2) the activation levels in frontal to parietal brain regions during walking at different speeds, and (3) the relationship between an individual’s stroke impairment or their ability to modulate their gait speed and change in their brain activation. Methods. Twenty individuals in the chronic stage of stroke walked: (1) at their normal pace, (2) slower than normal, and (3) as fast as possible. Functional near-infrared spectroscopy was used to assess bilateral prefrontal, premotor, sensorimotor, and posterior parietal cortices during walking. Results. No significant differences in laterality were observed between walking speeds. The ipsilesional prefrontal cortex was overall more active than the contralesional prefrontal cortex. Premotor and posterior parietal cortex activity were larger during slow and fast walking compared to normal-paced walking with no differences between slow and fast walking. Greater increases in brain activation in the ipsilesional prefrontal cortex during fast compared to normal-paced walking related to greater gait speed modulation. Conclusions. Brain activation is not linearly related to gait speed. Ipsilesional prefrontal cortex, bilateral premotor, and bilateral posterior parietal cortices are important areas for gait speed modulation and could be an area of interest for neurostimulation.
Figure S3 from Targeting the Immunoglobulin IGSF9 Enhances Antitumor T-cell Activity and Sensitivity to Anti–PD-1 Immunotherapy
Authors: Liu Yifan , Wang Hongying , Zhao Xinyu , Zhang Jiashen , Zhao Zhiling , Lian Xia , Zhang Juan , Kong Feng , Hu Tao , Wang Ting , Li Xiaohua , Wang Lei , Wang Dapeng , Li Chunling , Luan Huiwen , Liu Xiaoli , Wang Chunyan , Jiang Yun , Li Xiaomin , Li Fangmin , Ji Shuhao , Wang Yaopeng , Li Zunling
Published: October 2023

Human IGSF9 was detected in myeloid cells of peripheral blood from healthy donors and tumor patients.
Supplementary Table S1 from Histone Methyltransferase NSD2 Activates PKCα to Drive Metabolic Reprogramming and Lenalidomide Resistance in Multiple Myeloma
Authors: Chong Phyllis S.Y. , Chooi Jing-Yuan , Lim Julia S.L. , Leow Aaron C.Y. , Toh Sabrina Hui Min , Azaman Irfan , Koh Mun Yee , Teoh Phaik Ju , Tan Tuan Zea , Chung Tae-Hoon , Chng Wee Joo
Published: October 2023

Supplementary Table S1
Supplementary Table S3 from Associations between AI-Assisted Tumor Amphiregulin and Epiregulin IHC and Outcomes from Anti-EGFR Therapy in the Routine Management of Metastatic Colorectal Cancer
Authors: Williams Christopher J.M. , Elliott Faye , Sapanara Nancy , Aghaei Faranak , Zhang Liping , Muranyi Andrea , Yan Dongyao , Bai Isaac , Zhao Zuo , Shires Michael , Wood Henry M. , Richman Susan D. , Hemmings Gemma , Hale Michael , Bottomley Daniel , Galvin Leanne , Cartlidge Caroline , Dance Sarah , Bacon Chris M. , Mansfield Laura , Young-Zvandasara Kathe , Sudan Ajay , Lambert Katy , Bibby Irena , Coupland Sarah E. , Montazeri Amir , Kipling Natalie , Hughes Kathryn , Cross Simon S. , Dewdney Alice , Pheasey Leanne , Leng Cathryn , Gochera Tatenda , Mangham D. Chas , Saunders Mark , Pritchard Martin , Stott Helen , Mukherjee Abhik , Ilyas Mohammad , Silverman Rafael , Hyland Georgina , Sculthorpe Declan , Thornton Kirsty , Gould Imogen , O'Callaghan Ann , Brown Nicholas , Turnbull Samantha , Shaw Lisa , Seymour Matthew T. , West Nicholas P. , Seligmann Jenny F. , Singh Shalini , Shanmugam Kandavel , Quirke Philip
Published: October 2023

Representativeness of study participants
Supplementary Figure S3 from Integrated Genomic and Transcriptomic Analysis Improves Disease Classification and Risk Stratification of MDS with Ring Sideroblasts
Authors: Todisco Gabriele , Creignou Maria , Bernard Elsa , Björklund Ann-Charlotte , Moura Pedro Luis , Tesi Bianca , Mortera-Blanco Teresa , Sander Birgitta , Jansson Monika , Walldin Gunilla , Barbosa Indira , Reinsbach Susanne E. , Hofman Isabel Juliana , Nilsson Christer , Yoshizato Tetsuichi , Dimitriou Marios , Chang David , Olafsdottir Svannildur , Venckute Larsson Sigita , Tobiasson Magnus , Malcovati Luca , Woll Petter , Jacobsen Sten Eirik W. , Papaemmanuil Elli , Hellström-Lindberg Eva
Published: October 2023

Overall survival of MDSRS+ with SRSF2 and TP53MH genotype stratified by RS burden. Cases (colored Kaplan-Meier curves) were compared to historical controls (gray curve) with similar clinical and molecular features and no RS (i.e. RS<5%) from two large studies evaluating clinical characteristics of SRSF2 and TP53MH -mutated MDS, respectively (ref. 2,3). SF3B1 mutated MDSRS+ were not considered for this analysis because of the small number of cases with RS between 5 and 15% (2 out of 82 SF3B1-mutated ones) and consolidated evidences in the literature showing no effect of RS burden on SF3B1-mutated MDS outcome (ref. 4,5); sample size also limited further analysis in the MDSRS+ NOS category.
Supplementary Data FS1 from Therapeutic Vaccination against Human Papillomavirus Type 16 for the Treatment of High-Grade Anal Intraepithelial Neoplasia in HIV+ Men
Authors: Gosens Karien C.M. , van der Burg Sjoerd H. , Welters Marij J.P. , Boekestijn Sanne , Loof Nikki M. , Quint Wim G.V. , van Noesel Carel J.M. , van der Wal Allard C. , Richel Olivier , Krebber Wilhelmus J.T.A. , Melief Cornelis J.M. , de Vries Henry J.C. , Prins Jan M.
Published: October 2023

Supplementary Figure S1: Trial Flowchart.
Supplementary Table S3 from Anlotinib in Locally Advanced or Metastatic Radioiodine-Refractory Differentiated Thyroid Carcinoma: A Randomized, Double-Blind, Multicenter Phase II Trial
Authors: Chi Yihebali , Zheng Xiangqian , Zhang Yuan , Shi Feng , Cheng Ying , Guo Zhuming , Ge Minghua , Qin Jianwu , Zhang Jiewu , Li Zhendong , Zhou Xiaohong , Huang Rui , Chen Xiaohong , Liu Hui , Cheng Ruochuan , Xu Zhengang , Li Dapeng , Tang Pingzhang , Gao Ming
Published: October 2023

Multivariable Cox regression analysis of determinants of OS (without consideration of crossover)
High In Vitro and In Vivo Activity of BI-847325, a Dual MEK/Aurora Kinase Inhibitor, in Human Solid and Hematologic Cancer Models
Authors: Vuaroqueaux Vincent , Musch Alexandra , Peille Anne-Lise , Kelter Gerhard , Weichert Loreen , Metz Thomas , Hendriks Hans R. , Fiebig Heinz-Herbert
Published: October 2023

BI-847325 is an ATP-competitive inhibitor of MEK/Aurora kinases with the potential to treat a wide range of cancers. In a panel of 294 human tumor cell lines in vitro, BI-847325 was found to be a highly selective inhibitor that was active in the submicromolar range. The most sensitive cancer types were acute lymphocytic and myelocytic leukemia, melanomas, bladder, colorectal, and mammary cancers. BI-847325 showed a broader range of activity than the MEK inhibitor GDC-0623. The high efficacy of BI-847325 was associated with but not limited to cell lines with oncogenic mutations in NRAS, BRAF, and MAP2K1.

The high antiproliferative activity of BI-847325 was validated in vivo using subcutaneous xenograft models. After oral administration of 80 and 40 mg/kg once weekly for 3 or 4 weeks, BI-847325 was highly active in four of five colorectal, two of two gastric, two of two mammary, and one of one pancreatic cancer models (test/control < 25%), and tumor regressions were observed in five of 11 cancer models. The treatment was well tolerated with no relevant lethality or body weight changes. In combination with capecitabine, BI-847325 displayed synergism over single-agent therapies, leading to complete remission in the triple-negative mammary model MAXFTN 401, partial regression in the colon model CXF 1103, and stasis in the gastric models GXA 3011 and GXA 3023. In conclusion, dual MEK/Aurora kinase inhibition shows remarkable potential for treating multiple types of hematologic and solid tumors. The combination with capecitabine was synergistic in colorectal, gastric, and mammary cancer.

Significance:

We report the preclinical evaluation of BI-847325, a MEK/Aurora kinase inhibitor. Our data demonstrate that BI-847325 has potent antitumor activity in a broad range of human solid and hematologic cancer models in vitro and in vivo and is well tolerated in animal models. It also shows synergistic effect when combined with capecitabine. These findings provide a strong rationale for further development of BI-847325 as a potential therapeutic for patients with cancer.
Randomized Controlled Trial of Moderate‐ and High‐Intensity Exercise Training in Patients With Hypertrophic Cardiomyopathy: Effects on Fitness and Cardiovascular Response to Exercise
Authors: MacNamara James P. , Dias Katrin A. , Hearon Christopher M. , Ivey Erika , Delgado Vincent A. , Saland Sophie , Samels Mitchel , Hieda Michinari , Turer Aslan T. , Link Mark S. , Sarma Satyam , Levine Benjamin D.
Published: October 2023

Background

Moderate intensity exercise training (MIT) is safe and effective for patients with hypertrophic cardiomyopathy, yet the efficacy of high intensity training (HIT) remains unknown. This study aimed to compare the efficacy of HIT compared with MIT in patients with hypertrophic cardiomyopathy.

Methods and Results

Patients with hypertrophic cardiomyopathy were randomized to either 5 months of MIT, or 1 month of MIT followed by 4 months of progressive HIT. Peak oxygen uptake (V˙O
2
; Douglas bags), cardiac output (acetylene rebreathing), and arteriovenous oxygen difference (Fick equation) were measured before and after training. Left ventricular outflow gradient and volumes were measured by echocardiography. Fifteen patients completed training (MIT, n=8, age 52±7 years; HIT, n=7, age 42±8 years). Both HIT and MIT improved peak V˙O
2
by 1.3 mL/kg per min (
P
=0.009). HIT (+1.5 mL/kg per min) had a slightly greater effect than MIT (+1.1 mL/kg per min) but with no statistical difference (group×exercise
P
=0.628). A greater augmentation of arteriovenous oxygen difference occurred with exercise (Δ1.6 mL/100 mL
P
=0.005). HIT increased left ventricular end‐diastolic volume (+17 mL, group×exercise
P
=0.015) compared with MIT. No serious arrhythmias or adverse cardiac events occurred.

Conclusions

This randomized trial of exercise training in patients with hypertrophic cardiomyopathy demonstrated that both HIT and MIT improved fitness without clear superiority of either. Although the study was underpowered for safety outcomes, no serious adverse events occurred. Exercise training resulted in salutary peripheral and cardiac adaptations.

Registration

URL:
https://www.clinicaltrials.gov
; Unique identifier: NCT03335332.
Abstract EC.10: Transcriptional Heterogeneity Of The Postnatal Cardiac Conduction System
Authors: Oh Yena , Abid Rimshah , Dababneh Saif , Cook David , Park Jin , Vanderhyden Barbara , Munshi Nikhil , Kim Kyoung-Han
Published: October 2023

The cardiac conduction system (CCS) is a network of specialized cardiomyocytes responsible for the coordinated spreading of electrical impulses throughout the heart for synchronized contractions. The CCS is largely made up of the sinoatrial node (SAN), atrioventricular node (AVN) and the fast-conducting ventricular conduction system (VCS), which is further divided into the
His
bundle, Bundle branches and
Purkinje
fibers. Although these CCS structures were anatomically discovered >100 years ago, their molecular constituents are not fully known. In this study, CCS cells, making up ~0.05% of myocytes (~500 cells/heart), were isolated from early postnatal hearts (postnatal day 1 to 4) of fluorescent reporter mice (Cntn2-Cre;Rosa26TdTomato), purified using fluorescence-activated cell sorting, and subjected to single-cell RNA-sequencing. Unbiased cluster analysis on ~7000 CCS cells demonstrated distinct transcriptomic profiles in the SAN, AVN, proximal VCS (
His
bundle, bundle branches) and distal VCS (
Purkinje
fibers). Conforming to previous studies, global conduction markers, such as
Cntn2
and
Id2,
were present throughout the entire CCS, while a VCS-specific transcription factor,
Irx3
, was expressed only in the VCS. A comparison between proximal and distal VCS components revealed enrichments of
Igfbp7
,
Lyz2
and
Sfrp5
in the proximal VCS, and
Scn10a
,
Psd3
and
Wisp1
in the distal VCS. Sub-clustering analysis followed by validation with immunostaining further identified unique molecular profiles of the SAN (
Shox2
,
Vsnl1
), AVN (
Rspo3
),
His
bundle (
S100a6
,
Pcp4
) and bundle branches (
Nppa
,
Mest
). Data integrating publicly available ATAC-seq in SAN, AV junction, and atrial and ventricular cardiomyocytes as well as Tbx3-ChIP-seq, suggested that these regional markers are possibly regulated by two CCS-specific transcription factors,
Irx3
and
Tbx3
. More importantly, overexpressing
Irx3
and/or
Tbx3
in cultured neonatal mouse atrial and ventricular myocytes recapitulated these region-specific expression patterns in a dish. Together, our study provides a comprehensive view of the molecular profiles within the postnatal CCS at a high-resolution and show Irx3 and Tbx3 as genetic regulators establishing heterogeneities of the CCS.
Abstract P1002: Impact Of Maternal Diabetes-associated Oxidative Stress On The Developing Endocardium
Authors: Choudhury Talita Z , Greskovich Sarah , Girard Holly , Cameron Emily , Garg Vidu
Published: October 2023

Congenital heart defects (CHD) affect 1% of all live births and are the leading cause of birth defect-related mortality. The etiology of CHD is multifactorial as genomic variation and environmental factors act as contributors. Among the environmental teratogens, maternal pre-gestational diabetes mellitus and its concurrent maternal hyperglycemia (matHG) is associated with a ~5-fold increased risk of CHD. Oxidative stress (Ox-Stress) due to generation of excess reactive oxygen species is observed in embryonic hearts exposed to matHG in animal models, but its teratogenic effect on cardiac development is not understood. Additionally, we observed murine embryonic hearts exposed to matHG have reduced expression of
Notch1,
which is highly expressed in endocardial cells (EC) and reported a gene-environment interaction between matHG and
Notch1
haploinsufficiency that results in CHD in mice. We hypothesize that matHG-induced Ox-Stress leads to the downregulation of endocardial Notch signaling and aberrant EC function leading to CHD. To investigate the effects of matHG-induced Ox-Stress on endocardial Notch signaling, we examined mouse embryos exposed to matHG with conditional deletion of
Notch1
in EC. We used lineage tracing to detect differences in EC-derived structures in hyperglycemia and normoglycemia-exposed embryonic hearts. Finally, we asked whether modulating intracellular levels of Ox-Stress can rescue the CHD phenotypes observed with matHG exposure by generating mouse embryos with overexpression of the antioxidant gene,
SOD1
. Results show conditional deletion of endocardial
Notch1
in embryos exposed to matHG leads to highly penetrant CHD. We found increased Ox-Stress and reduced number of EC-derived mesenchymal cells in endocardial cushions of mouse hearts exposed to matHG. Finally, embryos with SOD1 overexpression have reduced Ox-Stress and decreased incidence of CHD compared to non-SOD1 overexpressing littermates. This works shows that matHG-induced Ox-Stress may be associated with aberrant EC and EC-derived cell function via disruption of Notch signaling. Mitigating Ox-Stress during cardiac development may lead to rescue of Notch signaling and EC function to reduce CHD incidence from matHG exposure.
Abstract P1015: Functional Investigation Of The Coronary Artery Disease Risk Gene
Rest
In Atherosclerosis
Authors: Loferer Tobias D , Dang Tan A , Kessler Thorsten , Schunkert Heribert , Weydert Dina
Published: October 2023

Background:
GWAS discovered two CAD risk variants, rs17087335 and rs72627509, located downstream of
REST
(RE1-silencing transcription factor). So far, REST has been mainly associated with neurological diseases, while its role in vascular function remains unclear. Here, we aimed to explore the role of REST in atherosclerosis.

Methods and Results:
Transcriptome data from the GTEx consortium hinted towards an association of reduced
REST
expression in vascular tissues with the risk alleles of rs17087335 and rs72627509. We performed reporter gene assays in HEK293 cells using constructs that contain the
REST
promoter upstream and the SNP sequence (200 bp) downstream of the reporter gene. In line with the GTEx data, the luciferase assays showed reduced reporter gene activity with the risk alleles of both variants. We next studied the function of REST in different atherosclerosis-relevant vascular cell types, such as human vascular smooth muscle cells (HVSMC) and human vascular endothelial cells (HVEC). In HVEC, siRNA-mediated
REST
downregulation experiments revealed no changes in HVEC proliferation or migration. In HVSMC, in contrast, migration was significantly enhanced secondary to
REST
knockdown. Furthermore, reduced
REST
led to increased uptake of lipids into HVSMC under inflammatory conditions. To elucidate putative molecular pathways, we performed RNA sequencing in HVSMC secondary to
REST
downregulation. Surprisingly, we detected downregulation of
ATF6
(ActivatingTranscription Factor 6) upon
REST
knockdown, which was confirmed by qPCR.
In
silico
analysis revealed several REST binding sites at the
ATF6
promoter. ATF6 plays a role in endoplasmatic reticulum (ER) stress, which has been reported to contribute to a macrophage-/fibroblast-like lipid-loaden phenotype of SMC. In line with the findings for REST, we could show that decreased
ATF6
results in increased lipid uptake by HVSMC.

Conclusion and Outlook:
We provide first evidence that reduced
REST
expression may increase the risk of atherosclerosis and CAD via promoting HVSMC migration and a phenotypic switch towards macrophage-/fibroblast-like lipid-loaden SMC. These effects might be mediated via
ATF6
. Modulation of REST might be a new strategy for preventing and treating CAD.
Abstract P1034: Functional Modelling Of Arrhythmias With Human Cardiac Organoids
Authors: Pocock Mark , Fitzsimmons Rebecca , Lor Mary , Foster Simon , Doran Michael R , Mills Richard J , Hudson James E
Published: October 2023

Engineered heart tissues (EHTs) have become a well-established model of human cardiac muscle. Metabolic maturity, improved sarcoplasmic reticulum (SR) Ca2+ handling, and the incorporation of critical non-myocyte cell populations are advantages that EHTs provide over immature 2D cardiomyocyte models. Our human cardiac organoid-EHT hybrid (hCO) platform was developed to be compatible with standardized 96-well tissue culture formats to enable high-throughput functional screening, while retaining the physiological advantages of larger EHTs. Here, we explored the applicability of hCOs as a model of various arrhythmic mechanisms. QT-prolongation could be mimicked with LTCC agonist BayK8644 or hERG blocker dofetilide, which increased the relaxation time of the hCOs and induced arrhythmia at high concentrations. Ectopy was induced by perturbing SR Ca2+ cycling with ryanodine or caffeine. HCN4 blocker ivabradine slowed rate, and at high concentrations produced a complex pause-burst phenotype. Increasing the cardiomyocyte-to-fibroblast ratio with growth factors, or the addition of extra fibroblasts prolonged contraction duration and induced ectopy. Inflammatory cytokines also increased relaxation time and provoked ectopy. From this data we propose that hCOs are a sensitive and reliable platform for studying arrhythmias and we are currently exploring the impact of CPVT-linked RYR2 and CASQ2 mutations on hCO arrhythmogenesis.
Abstract P1037: Dysfunction Of N-terminal Acetylation Causes Multiple Electrical Abnormalities Leading To Long QT Syndrome And Dilated Cardiomyopathy
Authors: Yoshinaga Daisuke
Published: October 2023

Introduction:
NAA10-related syndrome is characterized by long QT syndrome (LQTS), cardiomyopathy, hypotonia, and neurodevelopmental delay. NAA10 complexes with the regulatory subunit NAA15 to make the post-translationally modifying N-terminal acetyltransferase, NatA. Despite the association of LQTS and NAA10 mutations, the mechanism is unknown.

Hypothesis:
NAA10 dysfunction affects the function of cardiac ion channels or related proteins causing LQTS, and sarcomere abnormalities causing cardiomyopathy.

Methods:
Target sequencing of large kindred with multiple family members who had LQTS and sudden death revealed a segregating mutation in NAA10 (c.10C>A; p.R4S). Somatic cell reprogramming was used to create an induced pluripotent stem cell (iPSC) line from a gene-positive male patient with LQTS and dilated cardiomyopathy (pNAA10
R4S
). Genome-editing was used to create the control iPSC line (eNAA10
R4S
). iPSC lines were differentiated into cardiomyocytes (iPSC-CMs) for further analysis. In addition, we performed biochemical assays to investigate the enzymatic activities of the NAA10-R4S mutation.

Results:
The NAA10-R4S mutation had reduced enzymatic activity, decreased expression levels of NAA10/NAA15 and destabilized the NatA complex. Action potential duration was prolonged in pNAA10
R4S
- and eNAA10
R4S
-iPSC-CMs as compared to WT iPSC-CMs (498.9 ± 38.8 ms and 514.1 ± 52.9 ms, vs 316.7 ± 48.2 ms; p<0.05). Investigation of the underlying ion channel currents revealed increased late I
Na
(Late I
Na
/ Peak I
Na
: pNAA10
R4S
: 0.062 ± 0.010 % and eNAA10
R4S
: 0.074 ± 0.020 % vs. WT: 0.026 ± 0.005 %; p<0.05) and reduced I
Ks
(pNAA10
R4S
: 0.18 ± 0.05 pA/pF and eNAA10
R4S
: 0.26 ± 0.04 pA/pF vs. WT: 0.61 ± 0.15 pA/pF; p<0.05). There were no significant differences in I
Kr
and I
CaL
. Diastolic Ca
2+
levels were increased in mutant iPSC-CMs (F340/F380: 0.18 ± 0.02 vs 0.04 ± 0.01; p<0.05) consistent with impaired Ca
2+
handling. Plating iPSC-CMs on micro-contact printed islands revealed alterations in sarcomeric structure.

Conclusion:
We demonstrate that the NAA10 mutation cause abnormalities in ion channels and sarcomere development. Our data indicated a novel role for N-terminal acetylation in cardiac ion channel regulation leading to cardiovascular disorders.
Abstract P1046: Twenty-year Single-center Experience Of Catheter Ablation Of Ventricular Tachycardia And Progression To Heart Transplantation
Authors: Mullis Danielle M , Obafemi Oluwatomisin O , Kumar Sean , Kang Augustine , Aparicio Valenzuela Joy , Pelissero Ornella , Haddad Francois , Lee Anson M
Published: October 2023

Objective:
Orthotopic heart transplantation (OHT) is often used as salvage therapy after failed catheter ablation for ventricular tachycardia (VT). Little is published on the results of OHT after VT ablation, and predicting which ablation patients need transplantation is difficult. The purpose of this study is to examine the effect of OHT as a therapy for failed VT ablation and to identify echocardiographic measurements that might predict the need for transplantation.

Methods:
All adult patients who received VT ablations at our institution between 2001 and 2021 were identified. Follow-up data was collected until mid-2022. Echocardiograms obtained at the time of ablation were analyzed by hand tracing and Phillips QLab Advanced Quantification Software (Amsterdam, Netherlands). Survival distributions were compared using a Log Rank test. Continuous variables were analyzed using independent samples T-tests.

Results:
205 adult patients underwent an elective VT ablation between 2001 and 2021. Of these patients, 40 were referred for heart transplant evaluation. Of these 40 patients, 18 underwent OHT. There was a significant survival benefit after VT ablation for those who underwent OHT versus those who were referred but did not undergo OHT. There was a mean of 2.42 years of increased survival after VT ablation for the patients who were referred and transplanted versus those referred and not transplanted (p=0.016). The mean survival of patients not referred for transplantation was 4.6 ± 3.4 years. The most common barrier to transplant was obesity (n=6). Factors significantly predictive for referral to transplantation after VT ablation were lower ejection fraction (EF) (33.8% versus 45.6%), increased global longitudinal strain, and decreased fractional shortening (p<0.01, p<0.001, and p=0.001, respectively).

Conclusion:
Patients ultimately referred for OHT after VT ablation had significantly more cardiac dysfunction at the time of ablation. Once referred, morbid obesity was the most common barrier to transplantation. Lower EF, along with increased strain, was predictive of the need for transplantation. Earlier counseling of weight loss for morbidly obese patients with VT and ventricular dysfunction might lead to better survival.
Abstract P1047: The Extracellular Matrix Metalloproteinase Inducer And The Membrane Type 1 Matrix Metalloproteinase In Marfan Syndrome Related Thoracic Aortic Aneurysm
Authors: Peterson Andrew R , Alexander Kyle C , Anderson Carlton , Parrish Joseph , Boutros Jacob G , Shah Syed Mohsin , Cannon John H , Peterson Jarret , Townsend Jaleel , McGlamery Dalton J , Ikonomidis John S , Akerman Adam W
Published: October 2023

Objectives:
Marfan Syndrome (MFS) is a connective tissue disorder commonly associated with Thoracic Aortic Aneurysms (TAAs). TAAs occur because of abnormal remodeling of the aortic extracellular matrix (ECM). The balance between matrix metalloproteinases (MMPs) and the Tissue Inhibitors of MMPs (TIMPs), regulates these processes. The extracellular MMP inducer (EMMPRIN), is a widely expressed glycoprotein capable of stimulating the production of various MMPs, suggesting a direct role in driving pathology. The Membrane Type-1 MMP (MT1-MMP) can cause proteolytic shedding of EMMPRIN. Therefore, we investigated this relationship in MFS TAA tissue and plasma and tested the hypothesis that a unique proteolytic profile may exist.

Methods:
Levels of EMMPRIN, MT1-MMP, MMP-2, MMP-9, MMP-3, MMP-8, TIMP-1, and TIMP-2 were measured in aortic tissue and plasma from MFS patients with TAA and compared to healthy controls. Following modification of the abundance and location of MT1-MMP in isolated primary aortic fibroblasts, secreted EMMPRIN was measured in conditioned culture media.

Results:
Compared to controls, EMMPRIN is elevated in MFS TAA tissue and reduced in the plasma. Elevation of EMMPRIN abundance in tissue does not induce MMP-3, MMP-8, or TIMP-1 expression. MT1-MMP and TIMP-2 are elevated in MFS TAA tissue. MMP-2 and MMP-9 are reduced in MFS TAA tissue while increased in the plasma. In aortic fibroblasts we found that MT1-MMP must be internalized from the plasma membrane for EMMPRIN secretion.

Conclusions:
Our findings indicate that the pathological consequences of MFS cause the shedding of EMMPRIN and its secretion from cells to be blocked, which leads to higher EMPRINN abundance in MFS TAA tissue. This process depends upon the cellular location of MT1-MMP. Taken together, these observations suggest that internalization of MT1-MMP from the plasma membrane is required for the cellular secretion of EMMPRIN from aortic fibroblasts.
Abstract P1052: Development Of A Porcine Model Of Arteriovenous Fistula For The Evaluation Of Radiopaque Polymeric Vascular Wrap
Authors: Klusman Carleigh , Martin Benjamin , Perez Joy , Del Mundoa Huckie , Damasco Jossana , San Valentin Erin Marie , Bernardino Marvin , Barcena Allan , Williams Malea , Parrish Steve , Norton William , Chintalapani Gouthami , Fowlkes Natalie , Huynh Tam , Huang Steven , Melancon Marites P
Published: October 2023

Purpose:
The success and clinical utility of arteriovenous fistulas (AVF) are complicated by neointimal hyperplasia (NIH). Radiopaque and drug-eluting perivascular wraps have demonstrated attenuation of NIH in a rat model, but these constructs have yet to be tested in a large animal. This study aims to create an AVF model in pigs to evaluate the radiopacity and patency of a novel absorbable medical device made of rosuvastatin (ROSU) and gold nanoparticle (AuNP)-loaded polycaprolactone (PCL).

Materials and Methods:
A solution containing PCL, AuNP, and ROSU was electrospun into 6 x 5 x 0.2 cm scaffolds, and physicochemical properties were characterized over 8 weeks. AVFs with and without implantation of PCL wrap were surgically created in the neck and groin of 3 pigs.
In vivo
ultrasound (US) and computed tomography (CT) imaging were obtained at weeks 2 and 4.

Results:
PCL and PCL-Au-ROSU polymeric wraps were successfully fabricated using an electrospinning system. Figure 1 demonstrates successful creation of AVFs in pigs.
In vivo
Doppler US of AVF at weeks 2 and 4 with or without perivascular wrap showed arterial-venous communication with high-velocity flow and arterialized waveforms in draining veins. CT imaging demonstrated persistent radiopacity of PCL-Au-ROSU wraps through week 4.

Conclusion:
Outcomes suggest that surgical implantation of PCL wraps during AVF creation is feasible in a pig model. The increased radiopacity seen with AuNPs supports the efficacy of embedded metallic particles for device visualization. Ongoing in vivo studies will focus on optimization of the polymeric perivascular wrap and the evaluation of its efficacy in maintaining AVF patency.
Abstract P1072: Microneedle Patch Loaded With Il-4 Macroparticles Facilitates Heart Repair Through Macrophages Mediated Cardiomyocyte Phenotype Transition
Authors: Huang Ke
Published: October 2023

Ischemic heart disease remains the leading cause of mortality worldwide, but significant progress has been made in optimizing the treatment of acute myocardial infarction (MI) with percutaneous coronary intervention techniques. However, the increased pool of post-MI survivors has led to a higher prevalence of heart failure (HF) secondary to coronary artery disease, making it a major public health issue. Monocytes recruited from circulation differentiate into pro-inflammatory macrophages (M1-like) responsible for post-MI inflammation and cellular debris removal. As a unique Th2 cell cytokine, Interleukin 4 (IL-4) has been widely established as a powerful agent for the polarization of anti-inflammatory macrophages that promote tissue repair. However, there are limitations such as local and targeted delivery have hampered the successful translation of IL-4 therapy. In this study, we created an IL-4 microparticle-loaded microneedle patch (IL-4 MP-MN) for localized delivery of IL-4 to the MI region and tested the therapeutic effects in a rat model of MI. Our preliminary data suggested that IL-4 MP-MN treatment promoted cardiomyocyte proliferation and induced an anti-inflammatory microenvironment, which further led to a cardiomyocyte phenotype shift from "self-rescue" to "assisted-rescue" mode. Additionally, we successfully translated the therapeutic effects of IL-4 MP-MN in a porcine model of MI for testing therapeutic feasibility, safety, and efficacy.
Abstract P1075: Igf-1 Signaling And Nuclear Localization Of Pdgfralpha Tyrosine Kinase Activity Control The Fibrotic Response Of Mesenchymal Stromal Cells To Myocardial Ischemia
Authors: Santini Maria Paola P , Ishikawa Kiyotake , Azeloglu Evren U
Published: October 2023

Background and Hypothesis:
The role of mesenchymal stromal cells expressing the platelet-derived growth factor alpha (PDGFRα
+
MSCs) has been associated with fibro-adipogenic pathologies. Based on our previous data in regenerating skeletal muscle and the data herein described, we hypothesized that specific and distinct mesenchymal stromal cells exist in the heart, which will retain regenerative capacities by modulating the spatiotemporal distribution of the PDGFRα tyrosine kinase activity and the re-expression of specific regenerative molecules.

Methods:
Myocardial ischemia/reperfusion (I/R) was induced in mice with standard procedures and in compliance with the regulations of the NIH and the local institutional animal care.

Results:
Confocal imaging and immunophenotyping analyses showed that cardiac PDGFRα
+
MSCs exist as two distinct sub-populations expressing markers of specialized and differentiated cells, such as endothelial (60.3%±7.9% expressing CD31) and cardiomyocyte cell-cell anchoring markers (89%± 0.6% of population expressing desmocollin 2/3), while also retaining the expression of mesenchymal markers. Importantly, whereas PDGFRα
+
MSCs organized in vessel-like structures expressing CD31 during the acute phase after I/R, they transitioned into myofibroblast-like cells in ischemic subacute conditions. Identifying the mechanisms regulating PDGFRα
+
MSCs dual function remains a critical roadblock. In addressing this gap, we discovered that the transition to myofibroblast-like cells was associated to nuclear shuttling of PDGFRα C-terminal tyrosine kinase domain and ligand-dependent increased nuclear area, suggesting receptor-mediated activation of chromatin remodeling. Furthermore, we discovered that therapeutic re-expression of downregulated paracrine factors, such as the IGF-1Ea splice variant, correlated with long-term organization of PDGFRα
+
/CD31
+
in small capillaries, overcoming the late ischemic transition to fibrotic cells.

Conclusions:
Taken together, these data suggest that by modulating PDGFRα intracellular shuttling or altering the expression of regenerating genes, may therapeutically direct PDGFRα
+
MSCs duality to reduce fibrosis, while harnessing their beneficial properties.
Abstract P1078: Cardiomyocyte-fibroblast Interaction Regulates Ferroptosis And Fibrosis After Myocardial Injury
Authors: Li Shuang , Mohr Mary , Tao Ge
Published: October 2023

Neonatal mouse hearts have transient renewal capacity which is lost in juvenile and adult hearts. After myocardial infarction (MI) in neonatal hearts, an initial loss of cardiomyocytes occurs but it is unclear through which type of regulated cell death (RCD). In the current studies, we induced MI in neonatal and juvenile mouse hearts, and show that ischemic cardiomyocytes primarily undergo ferroptosis, a non-apoptotic and iron-dependent form of RCD. We demonstrate that cardiac fibroblasts (CFs) protect cardiomyocytes from ferroptosis through paracrine factors and direct cell-cell interaction. CFs show strong resistance to ferroptosis due to high ferritin expression. Meanwhile, the fibrogenic role of CFs, typically considered detrimental to heart function, is negatively regulated by paired-like homeodomain 2 (Pitx2) signaling from cardiomyocytes. In addition, Pitx2 prevents ferroptosis in cardiomyocytes by regulating ferroptotic genes. Understanding the regulatory mechanisms of cardiomyocyte survival and death can identify potentially translatable therapeutic strategies for MI.
Abstract P1098: Molecular Maturation Of Engrafted Human Pluripotent Stem Cell-derived Cardiomyocytes
Authors: Gomez Juliana , Jiang Wenlei , Qiang Beiping , Bader Gary , Laflamme Michael A
Published: October 2023

The transplantation of human pluripotent stem cell derived cardiomyocytes (hPSC-CMs) represents an attractive strategy to regenerate myocardium lost following injury and mitigate the pathological remodeling that ultimately leads to heart failure. However, in vitro hPSC-CMs have an immature phenotype that likely contributes to the transient arrhythmias observed during the initial weeks following hPSC-CM transplantation in large-animal models, hindering safe translation into the clinic. We hypothesized that maturational changes in hPSC-CMs in vivo facilitate the improved electrophysiological behavior of graft tissue observed at later time-points. Because the changing phenotype of hPSC-CM graft tissue remains largely unexplored, we used single nucleus RNA sequencing to evaluate the transcriptional dynamics and cell population heterogeneity of hPSC-CMs prior to transplantation and at 2- and 8-weeks following transplantation in a guinea pig cardiac cryoinjury model (n=3). We used methods based on the sorting of nuclei labeled by a genetically-encoded fluorescent reporter to enrich the proportion of human nuclei sequenced from the graft site and created a comprehensive atlas (> 20,000 cells) of host and graft cells present at the implantation site at both time-points. We identified an upregulation of genes involved in intracellular calcium handling, AMPK, and cAMP signaling pathways, as well as a metabolic shift in engrafted hPSC-CMs that we speculate supports their growth and enhanced electrophysiological function. Our study includes a comprehensive description of the temporal changes in hPSC-CM graft tissue at the single-cell resolution and provides unique insights into how these cells adapt to the injured heart environment and mature in vivo.