bluuebunny/crossref_metadata_2025 huggingface dataset:
Regulating Striated Muscle Contraction: Through Thick and Thin
Authors: Brunello Elisabetta , Fusi Luca
Published: November 2023

Force generation in striated muscle is primarily controlled by structural changes in the actin-containing thin filaments triggered by an increase in intracellular calcium concentration. However, recent studies have elucidated a new class of regulatory mechanisms, based on the myosin-containing thick filament, that control the strength and speed of contraction by modulating the availability of myosin motors for the interaction with actin. This review summarizes the mechanisms of thin and thick filament activation that regulate the contractility of skeletal and cardiac muscle. A novel dual-filament paradigm of muscle regulation is emerging, in which the dynamics of force generation depends on the coordinated activation of thin and thick filaments. We highlight the interfilament signaling pathways based on titin and myosin-binding protein-C that couple thin and thick filament regulatory mechanisms. This dual-filament regulation mediates the length-dependent activation of cardiac muscle that underlies the control of the cardiac output in each heartbeat.
Transcendent Aspects of Proton Channels
Authors: DeCoursey Thomas E.
Published: November 2023

A handful of biological proton-selective ion channels exist. Some open at positive or negative membrane potentials, others open at low or high pH, and some are light activated. This review focuses on common features that result from the unique properties of protons. Proton conduction through water or proteins differs qualitatively from that of all other ions. Extraordinary proton selectivity is needed to ensure that protons permeate and other ions do not. Proton selectivity arises from a proton pathway comprising a hydrogen-bonded chain that typically includes at least one titratable amino acid side chain. The enormously diverse functions of proton channels in disparate regions of the phylogenetic tree can be summarized by considering the chemical and electrical consequences of proton flux across membranes. This review discusses examples of cells in which proton efflux serves to increase pHi, decrease pHo, control the membrane potential, generate action potentials, or compensate transmembrane movement of electrical charge.
Molecular Crowding: Physiologic Sensing and Control
Authors: Subramanya Arohan R. , Boyd-Shiwarski Cary R.
Published: November 2023

The cytoplasm is densely packed with molecules that contribute to its nonideal behavior. Cytosolic crowding influences chemical reaction rates, intracellular water mobility, and macromolecular complex formation. Overcrowding is potentially catastrophic; to counteract this problem, cells have evolved acute and chronic homeostatic mechanisms that optimize cellular crowdedness. Here, we provide a physiology-focused overview of molecular crowding, highlighting contemporary advances in our understanding of its sensing and control. Long hypothesized as a form of crowding-induced microcompartmentation, phase separation allows cells to detect and respond to intracellular crowding through the action of biomolecular condensates, as indicated by recent studies. Growing evidence indicates that crowding is closely tied to cell size and fluid volume, homeostatic responses to physical compression and desiccation, tissue architecture, circadian rhythm, aging, transepithelial transport, and total body electrolyte and water balance. Thus, molecular crowding is a fundamental physiologic parameter that impacts diverse functions extending from molecule to organism.
Diffusion and Creep in Lithium Metal Anodes Induced by Plating and Stripping Reactions
Authors: Hebert Kurt R.
Published: November 2023

Electrodeposition of lithium on lithium metal negative electrodes (anodes) of liquid cells produces filamentary deposits, resulting in poor cycling efficiency. Experiments suggest that filaments grow by extrusion of metal from the substrate, due to compressive stress introduced during deposition. A model is presented that explores the origin of stress generated in the anode during plating-stripping cycles. According to the model, plating or stripping reactions insert or remove lithium atoms at the interface between the metal and the solid electrolyte interphase (SEI) layer. Stress is induced by the resulting diffusion processes, with diffusion-induced strain accommodated by inelastic creep. Stress distributions during cycling are calculated, and are used in turn to predict curvature transients that would be measured in beam-deflection experiments. The calculations account for the three-dimensional surface morphology, since surface features that protrude above the surface plane do not contribute to curvature changes. Comparisons with recent curvature measurements demonstrate detailed agreement, with diffusion and creep parameters close to literature values. The results support the hypothesis that electrochemical reactions intrinsically generate stress. The model can serve as a framework for analysis of morphogical instability of the lithium anode interface in both liquid and solid-state cells.
Electrochemical Study of Corrosion Inhibition of Carbon Steel During Oil/Water Intermittent Wetting
Authors: He Yi , Wang Xi , Young David , Mohamed-Said Maalek , Ren Shuai , Singer Marc
Published: November 2023

Application of corrosion inhibitors in production systems containing oil and water is an economic method to protect carbon steel against internal corrosion. This study investigates how intermittent oil/water wetting of such a steel surface, simulating multiphase flow phenomena, impacts corrosion inhibition in exploration-production (high salinity with CO2) and refinery (low salinity without CO2) environments. The employed corrosion inhibitor was a pyrimidinium-type model compound, its effectiveness against corrosion being characterized using linear polarization resistance measurements and electrochemical impedance spectroscopy. Experimental results demonstrated that the presence of an aliphatic oil promotes corrosion inhibition in the exploration production condition, but failed to do so in the refinery condition. Electrochemical impedance spectroscopy revealed two different protection mechanisms in the presence of oil between the two environments. The inhibitor layer in refinery condition with oil was different from in the simulated exploration production environment after oil wetting. Results also demonstrated that the inhibitor in this study was physically adsorbed on the surface steel via electrostatic attraction. Anions, identified as chloride ions, played a critical role in inhibitor adsorption.
Exploring SEI Characteristics in Propylene Carbonate-Based Electrolyte with 2-Isocyanatoethyl Methacrylate at Graphite Electrode
Authors: Kim Yong-eun , Jung Cheolsoo
Published: November 2023

Propylene carbonate (PC) has the advantage of a much lower melting point than ethylene carbonate (EC), but it cannot suppress the exfoliation of graphite layers because of its cointercalation with Li+ before forming a stable solid electrolyte interface (SEI). This paper introduces 2−isocyanatoethyl methacrylate (ICEMA) as an additive in PC−based electrolytes. ICEMA is a bifunctional monomer in which the isocyanate group is linked by the ethyl group to the acrylate group, which reacts through thermal polymerization. The isocyanate moiety is initiated as a radical during the initial charging process to induce electropolymerization and reaction with the PC radical. Radicals propagate through the entire reaction at the electrode to form a stable SEI. The modified interface suppresses the cointercalation of Li+−PC to graphite electrode. In situ Fourier transform infrared effectively showed the polymerization of the isocyanate and active reaction with the PC radical. Consequently, the reaction mechanisms to form the stable SEI in PC−based electrolytes were determined.
Endothelial cells differentially sense laminar and disturbed flows by altering the lipid order of their plasma and mitochondrial membranes
Authors: Yamamoto Kimiko , Shimogonya Yuji , Maeno Ryohei , Kawabe Kenshiroh , Ando Joji
Published: November 2023

How vascular endothelial cells (ECs) differentially sense laminar and disturbed flows and trigger intracellular signaling remains unclear. Here, we show that EC plasma membranes act as mechanosensors to discriminate between laminar and disturbed flows by undergoing opposite changes in their lipid order. Similar lipid order changes occur simultaneously in the mitochondrial membranes, which are linked to changes in mitochondrial function, that is, increased ATP production for laminar flow and increased H2O2 release for disturbed flow.
GPC3 Promotes Lung Squamous Cell Carcinoma Progression and HLA-A2-Restricted GPC3 Antigenic Peptide-Modified Dendritic Cell-Induced Cytotoxic T Lymphocytes to Kill Lung Squamous Cell Carcinoma Cells
Authors: Ning Jing , Ding Jianqiao , Wang Shu , Jiang Youhong , Wang Daqing , Jiang Shenyi
Published: November 2023

Lung squamous cell carcinoma (LUSC) is associated with poor clinical prognosis and lacks available targeted agents. GPC3 is upregulated in LUSC. Our study aimed to explore the roles of GPC3 in LUSC and the antitumor effects of HLA-A2-restricted GPC3 antigenic peptide-sensitized dendritic cell (DC)-induced cytotoxic T lymphocytes (CTLs) on LUSC. LUSC cells with GPC3 knockdown and overexpression were built using lentivirus packaging, and cell viability, clone formation, apoptosis, cycle, migration, and invasion were determined. Western blotting was used to detect the expression of cell cycle-related proteins and PI3K-AKT pathway-associated proteins. Subsequently, HLA-A2-restricted GPC3 antigenic peptides were predicted and synthesized by bioinformatic databases, and DCs were induced and cultured in vitro. Finally, HLA-A2-restricted GPC3 antigenic peptide-modified DCs were co-cultured with T cells to generate specific CTLs, and the killing effects of different CTLs on LUSC cells were studied. A series of cell function experiments showed that GPC3 overexpression promoted the proliferation, migration, and invasion of LUSC cells, inhibited their apoptosis, increased the number of cells in S phase, and reduced the cells in G2/M phase. GPC3 knockdown downregulated cyclin A, c-Myc, and PI3K, upregulated E2F1, and decreased the pAKT/AKT level. Three HLA-A2-restricted GPC3 antigenic peptides were synthesized, with GPC3522-530 FLAELAYDL and GPC3102-110 FLIIQNAAV antigenic peptide-modified DCs inducing CTL production, and exhibiting strong targeted killing ability in LUSC cells at 80 : 1 multiplicity of infection. GPC3 may advance the onset and progression of LUSC, and GPC3522-530 FLAELAYDL and GPC3102-110 FLIIQNAAV antigenic peptide-loaded DC-induced CTLs have a superior killing ability against LUSC cells.
Hybridization of Machine Learning Algorithms and an Empirical Regression Model for Predicting Debris-Flow-Endangered Areas
Authors: Wang Xiang , Tian Mi , Qin Qiang , Liang Jingwei
Published: November 2023

Accurate delineation of debris-flow-endangered areas (e.g., the maximum runout distance) is a necessary prerequisite for the debris-flow risk assessment and countermeasures design. Recently, machine-learning models have been proved to be an effective tool in predicting debris-flow parameters. However, existing machine-learning models are generally developed based on a very limited number of observation data, which may result in the predictive model overfitting or underfitting. How to develop a robust model for accurate forecasting of debris-flow-endangered areas still remains a difficult task. This paper proposes a hybrid method for predicting debris-flow hazard zone by integrating machine-learning algorithms and an empirical regression model. The proposed method takes the calculated maximum runout distance obtained from the empirical model as supplementary inputs to increase the amount of training data to construct hybrid machine-learning models. Three commonly used machine-learning models (i.e., multivariate adaptive regression splines (MARS), random forest (RF), and support vector machine (SVM)) are developed based on the training datasets of a specific debris basin. Then, these three machine-learning models are combined with an empirical relationship developed using the same training datasets to generate corresponding hybrid models. Finally, the performance metrics (i.e., coefficient of determination (R2), root-mean-square error (RMSE), and mean absolute error (MAE)) of the proposed hybrid models are comprehensively investigated and compared with the single predictive model (i.e., MARS, RF, SVM, and the empirical model) under fivefold cross-validation. The proposed method is illustrated using 134 channelized debris-flow events in Sichuan province, China. Results show that compared with the three individual machine-learning models, hybridization of machine-learning algorithms and the empirical model results in R2, RMSE, and MAE improved by 70.5%, 32.9%, and 41.1%, respectively. In contrast to the empirical model, the R2, RMSE, and MAE value of the proposed hybrid models are improved by 29.6%, 22.3%, and 32.5%, respectively. The proposed hybrid models generally perform better than the single machine-learning and the empirical model, providing a promising tool for accurate forecasting of a debris-flow-endangered area.
Vitamin B6 Competition in the Tumor Microenvironment Hampers Antitumor Functions of NK Cells
Authors: He Chunbo , Wang Dezhen , Shukla Surendra K. , Hu Tuo , Thakur Ravi , Fu Xiao , King Ryan J. , Kollala Sai Sundeep , Attri Kuldeep S. , Murthy Divya , Chaika Nina V. , Fujii Yuki , Gonzalez Daisy , Pacheco Camila G. , Qiu Yudong , Singh Pankaj K. , Locasale Jason W. , Mehla Kamiya
Published: November 2023

Nutritional factors play crucial roles in immune responses. The tumor-caused nutritional deficiencies are known to affect antitumor immunity. Here, we demonstrate that pancreatic ductal adenocarcinoma (PDAC) cells can suppress NK-cell cytotoxicity by restricting the accessibility of vitamin B6 (VB6). PDAC cells actively consume VB6 to support one-carbon metabolism, and thus tumor cell growth, causing VB6 deprivation in the tumor microenvironment. In comparison, NK cells require VB6 for intracellular glycogen breakdown, which serves as a critical energy source for NK-cell activation. VB6 supplementation in combination with one-carbon metabolism blockage effectively diminishes tumor burden in vivo. Our results expand the understanding of the critical role of micronutrients in regulating cancer progression and antitumor immunity, and open new avenues for developing novel therapeutic strategies against PDAC.

Significance:

The nutrient competition among the different tumor microenvironment components drives tumor growth, immune tolerance, and therapeutic resistance. PDAC cells demand a high amount of VB6, thus competitively causing NK-cell dysfunction. Supplying VB6 with blocking VB6-dependent one-carbon metabolism amplifies the NK-cell antitumor immunity and inhibits tumor growth in PDAC models.

This article is featured in Selected Articles from This Issue, p. 5
Examining the Role of Estheticians in Skin Cancer Surveillance
Authors: Walker Amanda M. , Joseph Adrienne , Nelson Jacob , Orfaly Victoria E. , Stoos Elizabeth , Geller Allan , Bailey Elizabeth , Savory Stephanie , Leachman Sancy , Jacobe Heidi
Published: November 2023

Background: Melanoma and non-melanoma skin cancer are significant causes of mortality. Previous studies regarding skin cancer education in nonmedical professionals have shown increases in favorable attitudes and likelihood of approaching clients about concerning lesions with training. However, few studies have investigated the use of estheticians in skin cancer screening. Objectives: The objective of this study was to develop an education course to train estheticians to recognize concerning lesions, to assess the baseline knowledge of estheticians toward skin cancer detection, and to determine the effect that our curriculum has on lesion detection. Methods: We administered an education course and corresponding cross-sectional surveys to estheticians to evaluate current knowledge and assess for improvements in attitudes and behaviors regarding skin cancer detection. Results: Of 504 estheticians, most estheticians (85–98%) indicated the correct level of concern for “extremely concerning” lesions on pre- and post-training surveys. Estheticians were more likely to recommend that their client see a medical professional if they previously attended a course on skin cancer (p = 0.012) or had greater than 1 year of work experience (p < 0.001). After completion of the training module, most participants felt “very comfortable,” suggesting that clients see a doctor for a suspicious lesion. Conclusion: Our findings suggest that estheticians are capable of indicating the appropriate level of concern for abnormal lesions. Estheticians may serve as a valuable screening partner for dermatologists in the detection of skin cancer.
Ameloblastic Fibrosarcoma of the Jaw: Case Report, Genetic Profiling, and Literature Review
Authors: Barakeh Duna , Alsolami Afaf , Abedalthagafi Malak
Published: November 2023

Ameloblastic fibrosarcoma (AFS) is considered a malignant progression resulting from dysplastic changes in an ameloblastic fibroma (AF). Both tumors are extremely rare, with only a few cases reported in the scientific literature. Notably, BRAF mutations have been identified in ameloblastomas, suggesting a connection between ameloblastic morphology and BRAF mutations, as AF is believed to be the precursor neoplasm leading to AFS. In this study, we present a case of AFS in a 25-year-old male. The tumor tissue underwent molecular analysis, specifically next-generation sequencing (NGS) using the Oncomine Comprehensive Assay v3 System. The analysis revealed pathogenic mutations in TP53 and RB genes, as well as copy number gains in NTRK1, MDM4, and BRAF. Additionally, we provide a summary of the literature’s findings from the analysis of 107 previously reported AFS cases. Our findings suggest the existence of a molecularly distinct subtype, emphasizing the importance of comprehensive molecular testing for these patients.
Discovery of Clinical Manifestations in Spontaneous Glaucoma Suspect Nonhuman Primates
Authors: Jia Xu , Yu Ziyu , Wu Jian , Hou Simeng , Du Yifan , Zhu Yingting , Li Zhidong , Tu Shu , Zhao Ling , Su Wenru , Wang Ningli , Zhuo Yehong
Published: November 2023

Introduction: The primary aim of this study was to assess the longitudinal changes in retinal nerve fiber layer (RNFL) thickness and relative ONH parameters using spectral-domain optical coherence tomography (SD-OCT) in the living eyes of nonhuman primates with spontaneous glaucoma. Methods: Totally 9 macaque subjects underwent a standard fundus photo and OCT examination, including 3 adult monkeys with stable elevated intraocular pressure (IOP) as the glaucoma suspect group and 6 normal IOP monkeys as the control group. Each eye of primates with IOP measurement was repeated three times. OCT measurements recorded RNFL, Bruch’s membrane opening (BMO) minimum rim width (MRW). The follow-up scan of glaucomatous subjects was undergone in 10 months. Results: The mean ages of glaucoma and healthy subjects are 19.33 ± 0.33 and 20.5 ± 1.46 years. Elevated IOP was achieved in three nonhuman primate eyes with an average increase of 10 mm Hg over the study period. Elevated IOP was associated with decreased RNFL thickness in all the regions and decreased RNFL phase retardation in the superior and inferior regions. When averaged over the entire retinal area, only the whole RNFL and temporal regions showed a significant decrease. The mean IPL thicknesses are 87.17 ± 2.15 μm in glaucomatous and 93.33 ± 1.51 μm in healthy eyes (p = 0.03). Lamina cribrosa parameters are measured from the OCT images and showed significant differences between glaucoma primates and normal primates. Conclusions: Of the measured parameters, decreased RNFL and MRW were correlated with glaucomatous damage. Natural glaucoma primate can be a natural glaucoma model which is closer to glaucoma in humans.
Urinary Post-Translationally Modified Fetuin-A Protein Is Associated with Increased Risk of Graft Failure in Kidney Transplant Recipients
Authors: Alkaff Firas F. , Kremer Daan , te Velde-Keyzer Charlotte A. , van den Born Jacob , Berger Stefan P. , Laverman Gozewijn D. , Chuang Lee-Ming , Tseng Tzu-Ling , Bakker Stephan J.L.
Published: November 2023

Introduction: Urinary fetuin-A has been identified as a biomarker for acute kidney injury and is proposed as a biomarker for early detection of kidney function decline. We investigated whether fetuin-A could serve as a marker of graft failure in kidney transplant recipients (KTRs). Methods: Data of KTR with a functioning graft ≥1 year that were enrolled in the TransplantLines Food and Nutrition Biobank and cohort study were used. Graft failure was defined as the need for re-transplantation or (re-)initiation of dialysis. Urinary fetuin-A was measured using an enzyme-linked immunosorbent assay kit that detected post-translationally modified fetuin-A in the urine (uPTM-FetA). In the main analyses, 24h uPTM-FetA excretion was used. In the sensitivity analyses, we excluded the outliers in 24h uPTM-FetA excretion, and we used uPTM-FetA concentration and uPTM-FetA concentration indexed for creatinine instead of 24h uPTM-FetA excretion. Results: A total of 627 KTRs (age 53 ± 13 years, 42% females) were included at 5.3 (1.9–12.2) years after transplantation. The estimated glomerular filtration rate (eGFR) was 52 ± 20 mL/min/1.73 m2 and uPTM-FetA excretion was 34 (17–74) µg/24 h. During a median follow-up of 5.3 (4.5–6.0) years after baseline measurements, 73 (12%) KTRs developed graft failure. The association of 24h uPTM-FetA excretion with increased risk of graft failure was not constant over time, with increased risk only observed after 3 years from baseline measurements, independent of potential confounders including kidney function and 24 h urinary protein excretion (hazard ratio per doubling of 24h uPTM-FetA excretion = 1.31; 95% confidence interval = 1.06–1.61). This finding was robust in the sensitivity analyses. Conclusions: Our findings suggest that uPTM-FetA can be used as a marker for early detection of graft failure in KTR. Further studies are needed to confirm our findings.
Effects of Breast-Conserving Surgery and Mastectomy on the Survival of Patients with Early-Stage (T1-2N0-1M0) HER2-Positive Breast Cancer: A Propensity Score-Matched Analysis
Authors: Zhan Qiaohui , Zhao Xuye , Zheng Guifeng , Liu Jiahui , Wu Songling , Huang Jiawen , Yu Liuwen , Fu Fangmeng
Published: November 2023

Introduction: Although breast-conserving therapy (BCT) promises at least a similar survival rate for patients with early breast cancer compared with mastectomy, its efficacy in patients with human epidermal growth factor receptor 2 (HER2)-positive tumors remains unclear. Therefore, we conducted this study to explore differential effects of BCT and mastectomy on survival outcomes of patients with early-stage HER2-positive breast cancer. Methods: Data were extracted from the Surveillance, Epidemiology, and End Results (SEER) database, and basic characteristics of patients who received either BCT or mastectomy were balanced using propensity score matching (PSM). Kaplan-Meier analysis, log-rank testing, and Cox proportional hazards regression were performed. Results: In total, 20,277 patients were diagnosed with T1-2N0-1M0 HER2-positive breast cancer between 2010 and 2015. After PSM, 6,185 pairs of patients were enrolled for further analysis. Compared with those undergoing mastectomy, patients receiving BCT had superior overall survival (OS) (hazard ratio [HR], 0.63; 95% confidence interval [CI]: 0.55–0.73; p < 0.001) and breast cancer-specific survival (BCSS) (HR: 0.59; 95% CI: 0.48–0.71; p < 0.001). The subgroup analyses revealed that survival outcomes (OS and BCSS) of BCT were better than those of mastectomy among estrogen receptor (ER)+/progesterone receptor (PR)+/HER2+, ER+/PR−/HER2+, and ER−/PR−/HER2+ subtypes (p < 0.05 for all); however, patients with ER−/PR+/HER2+ subtypes who underwent BCT had similar OS and BCSS (p > 0.05 for both) to those treated with mastectomy. Discussion/Conclusion: Despite the aggressiveness of the disease, we found that BCT may confer better long-term survival than mastectomy for patients with T1-2N0-1M0 HER2-positive breast cancer, particularly for those with ER+/PR+/HER2+, ER+/PR−/HER2+, and ER−/PR−/HER2+ subtypes. In addition, our study provided insights into the clinical applications of BCT. However, this retrospective study has introduced several inevitable limitations, and further prospective research is warranted to verify these conclusions.
Smartphone Photographs of Chronic Urticaria Taken by Patients Are of Good Quality and Useful in the Clinic
Authors: Ali Zarqa , Sørensen Jennifer Astrup , Zhang Ditte Georgina , Ghazanfar Misbah Noshela , Allerup Johan Anker Chrom , Maurer Marcus , Kocatürk Emek , Vestergaard Christian , Thomsen Simon Francis
Published: November 2023

Background: Chronic urticaria (CU) is characterized by transient wheals and angioedema, which are often not present when patients see their treating physician. Objective: The objective of this study was to evaluate the diagnostic value of smartphone photographs captured by patients prior to their first visit at an urticaria outpatient clinic. Methods: A survey regarding the quality and utility of smartphone photographs of urticarial skin lesions in patients with CU attending the outpatient clinic for the first time was conducted. Up to three random patient-selected photographs of skin lesions were evaluated by a physician. Results: Of 148 patients, 118 (79.7%) had taken photographs of their skin lesions prior to the consultation, and 75% took photographs with the intention of presenting it to their physician. The photographs were of wheals in 90% of the cases and angioedema in 8%. In total, 72% of the smartphone photographs had the skin lesion in focus, 64% had good resolution, and 48% had good lighting. Only 9% of the smartphone photographs were blurred, 10% had bad lighting, 4% had bad resolution, and 8% did not have the lesion in focus. Moreover, 86% of the smartphone photographs were found to be useful for clinical evaluation. At least one photograph of good/very good quality was presented by 86% of the patients, and 97% had at least one photograph that was useful for clinical evaluation. Conclusion: Patients with CU often take smartphone photographs of their skin lesions on their own initiative prior to their first consultation to present the photographs to their physician. These smartphone photographs are very often of good quality and suitable for clinical evaluation.
Somatostatin Receptor Imaging in Mice with Difference Positive Rate of SSTR2
Authors: Xie Qing , Zhou Wenyuan , Meng Xiangxi , Ding Jin , Li Dan , Lu Ming , Yang Zhi , Yu Jiangyuan
Published: November 2023

Introduction: Imaging with [68Ga]Ga-DOTA-TATE, [68Ga]Ga-DOTA-JR11, and [18F]AlF-NOTA-JR11 was performed to analyze differences among the three probes and to analyze the correlation between the image and pathology parameters. Method: Tumor-bearing mice with different positive rates of somatostatin receptor II (SSTR2) were established with HEK293-SSTR2 and HEK293 cells, and imaging was performed on the same mouse with [68Ga]Ga-DOTA-TATE, [68Ga]Ga-DOTA-JR11, and [18F]AlF-NOTA-JR11 at 20, 60, and 120 min. The image parameters were obtained, including the maximum standard uptake value (SUVmax), mean standard uptake value (SUVmean), standard deviation of SUVmean, tumor volume, and coefficient of variation (CoV). Immunohistochemistry (IHC) of the tumor was performed after imaging to obtain positive rate of SSTR2. Statistical analysis was performed to analyze the differences among the three imaging techniques and the correlations between the relative imaging parameter and IHC. Result: The SUVmax of [18F]AlF-NOTA-JR11 at 20 min and 60 min was higher than that of [68Ga]Ga-DOTA-TATE (p = 0.0015, 0.0035) and [68Ga]Ga-DOTA-JR11 (p = 0.033, 0.019), and no significant difference was found in the other groups (p > 0.05). There was a significant positive correlation between the positive rate and SUVmean of tumors with three tracers (p < 0.05). However, a significant negative correlation between the positive rate and CoV was found only in the [68Ga]Ga-DOTA-TATE group at 60 min and 120 min (p = 0.048, 0.026). Conclusion: [18F]AlF-NOTA-JR11 is more suitable for SSTR imaging within an hour than other two tracers. SUVmean of whole tumor can become an indicator for evaluating the positive rate of IHC, and the higher SUVmean of three tracers means a higher positive rate. However, the CoV is not applicable to the two antagonist tracers for evaluating the positive rate.
Abstract 16901: A Computational Framework to Estimate the Consequences of Cardiac RNA Editing Events at Single-Cell Resolution
Authors: Srivastava Prashant , Hassani Mohamed , Ji Jiahui , Guan Yingshu , Punjabi Prakash , Emanueli Costanza
Published: November 2023

Introduction:
RNA is a highly dynamic molecule subject to various epigenetic modifications. One such process is RNA editing, a tightly regulated mechanism that introduces alterations to RNA nucleotides without affecting the DNA template. RNA editing serves as a mechanism for expanding and diversifying the functional repertoire of proteins. In the context of the heart, the RNA editors assume crucial roles in preserving cardiac function. Despite the importance of RNA editing, there are no framework to evaluate consequence of synonymous RNA editing events. Synonymous RNA editing events can affect mRNA stability, translation efficiency, protein folding, and even protein-protein interactions. These subtle changes in the coding region can influence gene expression, protein synthesis, and ultimately, cellular function.

Research question:
What are the functional consequences of RNA editing events in different types of cardiac cells?

Methods:
To estimate the RNA structural metrics, we employed the Vienna RNA package software. This comprehensive package provides a range of metrics for quantifying RNA secondary structures.

Results:
We have developed a framework to profile RNA editing and analyse synonymous events using new and existing single-cell datasets. Our framework enables users to explore the distribution of RNA editing events across different cell types and states, as well as analyse the functional consequences of these events. Here, to demonstrate its efficacy, we have applied our framework on healthy hearts. We identified highly edited cell types such as cardiomyocytes, fibroblasts, endothelial cells, macrophages, and pericytes, with over 1,000 edited sites. Interestingly, more than 50% of these edited sites enhanced secondary RNA structures, while 25% of the events destabilized the secondary structure.

Conclusions:
We have developed a comprehensive framework to estimate consequence of RNA editing events at single-cell resolution. Our results demonstrate the power of our framework in elucidating the impact of RNA editing on cellular processes. Synonymous RNA editing expands our understanding of the complexity of genetic regulation and its implications for cellular processes and disease.
Abstract 16904: Low-Dose Isoproterenol Administration in the Murine MDX Model Unmasks Progression of Duchenne-Associated Cardiomyopathy
Authors: Richards Alyssa M , Earl Conner C , Welc Steven S , Kowala Mark C , Markham Larry W , Goergen Craig J
Published: November 2023

Introduction:
The cardiovascular phenotype resulting from Duchenne muscular dystrophy (DMD) includes cardiomyopathy (CMP) leading to congestive heart failure and early mortality. CMP is the leading cause of death in DMD. Our
objective
was to characterize the progression of CMP in a murine model of DMD.
We hypothesized that a genetic mouse model of DMD will exhibit significantly lower function over time as measured by ejection fraction when given an isoproterenol (IPT) challenge.

Methods:
We examined a mouse model of DMD from the Jackson Laboratory: C57BL/10ScSn-
Dmd

mdx

/J (B10.mdx; n=6 female). The genetic group was paired with the wild type control strain C57BL/10ScSnJ (B10; n=6 female mice). B10.mdx (MDX) and B10 (WT) mice received intraperitoneal IPT administered via daily injections at 3 mg/kg. Cardiac function was assessed by 2D ultrasound using a Vevo3100 imaging system (FUJIFILM, VisualSonics) from the baseline, immediate effects of IPT injection at 1 minute, after 7, 14, and 21 days.

Results:
At 1 minute following the first IPT injection in WT and MDX, we observed increases in EF and HR for both groups (
Figure 1
). While the changes in EF were notable yet not reaching significance, the differences within groups between baseline and 1 minute after injection were significant due to HR response (
p
<0.05).We observed decreases in EF for both groups between baseline and day 7 following IPT injections (
Figure 1
). The changes in MDX EF between baseline and day 7 approached significance. The EF in both groups was maintained through day 7, day 14, and day 21. 2 deaths in MDX occurred during the treatment period and 1 death followed day 7. A WT sacrifice was made after day 14 due to severe dermatitis.

Conclusion:
Murine mdx models exhibit DMD-associated CMP comparable to humans. Associated humanlike phenotype includes decreased EF, FS, ESV, EDS, and SV. A low dose of IPT in MDW mice has the potential to unmask these changes within 7 days, reducing the need for longer term murine studies.
Abstract 16915: Considerations in Management of Cocaine-Induced Coronary Disease and Embolism
Authors: Huffaker Tyler , Asif Anum , Almomani Ahmed
Published: November 2023

Background:
Coronary embolism accounts for ~3% of cases of myocardial infarction (MI). We describe a case of a young patient with cocaine abuse with coronary thrombus resulting in acute coronary syndrome (ACS).

Case:
33-year-old male with no known medical history seen in the ER with one hour of typical chest pain. EKG showed ST-segment elevations in inferior leads. Coronary angiogram demonstrated a hazy filling defect in the distal RCA as well as a 100% thrombotic occlusion of the right posterolateral branch of RCA likely due to distal embolization. Aspiration thrombectomy was performed with no residual stenosis. All other vessels were angiographically normal.

Decision-Making:
Our patient had no traditional coronary artery disease risk factors. Work-up for other coronary embolism causes and genetic thrombophilia was negative. We aspirated the thrombi rather than stenting, as stent thrombosis risk is >10-fold in cocaine users in absence of any residual stenosis. Dual antiplatelet therapy was initiated given ACS presentation.

Conclusion:
Acute coronary thrombosis is a life-threatening complication of cocaine abuse. In lack of residual stenosis post-aspiration thrombectomy, stenting can be avoided due to high stent thrombosis risk in this patient population.
Abstract 16919: Analysis of Astrocyte Activation and Reduction of Motor Deficits Following hSOX2 Gene Therapy Delivered Using PAMAM Dendrimer Nanomolecules in Ischemic Stroke
Authors: Srinageshwar Bhairavi , Stadler Justin , Andrews Melissa , MacDonald Bethany , Toth Alexa , Poudel Arjun , Schalau Raegan , Malkowski Clayton , Schurr Harrison , Hellrung Joseph , Swanson Douglas , Sharma Ajit , Dunbar Gary , Rossignol Julien
Published: November 2023

PAMAM dendrimers are 3-dimensional nanomolecules which have the capability to deliverbiomolecules and gene therapy to the cells
in
vitro
and
in
vivo
. We have previously used the generation-4 surface-modified PAMAM dendrimers having 90% hydroxyl groups and 10% amine groups (G4-90/10) which are safe, cross the blood-brain barrier and deliver the biomolecules into the cells. In thecurrent study, we utilized G4-90/10 PAMAM dendrimers to deliver a gene therapy to the infarct in aischemic stroke brain in rats. Following an ischemic stroke, glial cells (such as astrocytes) are recruitedat the infarct region to perform maintenance functions, creating severe neuroinflammation. The goalof this study was to reprogram some of the astrocytes into neuronal lineage and repopulate the infarctregion. In addition, we also analyzed the temporal profile of astrocyte activation following ischemicstroke in the striatal and cortical regions to determine the time-point at which the maximum gliosisoccurs. This gives us a crucial timeline for treatment intervention to achieve astrocytereprogramming. We have used a transcription factor (hSOX2 gene), which was then delivered to thestroke brain in rats using the G4-90/10 dendrimers. Our results showed that the maximum glial cellactivation occurs in striatal and cortical regions on day 4 following ischemic stroke. Following genetherapy intervention, our initial analyses indicated that there was recovery from behavioral deficits inthe stroked rats compared to the vehicle-treated stroked rats and sham controls. Overall, these resultsshow that PAMAM dendrimers have significant potential delivering therapeutic molecules for treatingstroke and other neurological conditions.

Support for this study was provided by the American Heart Association (18AIREA 33990094),Neuroscience program, the College of Medicine, department of Chemistry and Biochemistry, the JohnG. Kulhavi Professorship and the E. Malcolm Field and Gary Leo Dunbar Endowed Chair of Neuroscience at Central Michigan University.
Abstract 16935: Distressed Community Index in Patients Undergoing Carotid Artery Stenting in Medicare-Linked Vascular Quality Initiative Registry
Authors: Pajarillo Carmen S , Romain Gaelle , Cleman Jacob , Scierka Lindsey , Grubman Scott , Schenck Christopher , Kluger Jonathan , Smolderen Kim G , Mena-Hurtado Carlos
Published: November 2023

Introduction:
Patients with high community-level socioeconomic distress have worse cardiovascular outcomes, yet its impact on carotid artery stenting (CAS) outcomes is unknown. We assessed the association between the Distressed Community Index (DCI), a zip-code level measure of community distress, with post-CAS mortality and stroke.

Methods:
We used the Vascular Quality Initiative database linked with Medicare claims outcomes data to identify patients undergoing CAS between 2015 and 2019. From a time-dependent ROC curve and using Youden index, we classified patients as high community distress if DCI≥65. Thirty-six-month cumulative mortality incidence using Kaplan-Meier by DCI groups, and hierarchical Cox regression with random intercept for site for linear DCI were used. For stroke, we used 36-month cumulative incidence function by DCI groups, and Fine and Gray models accounting for competing risk of death for linear DCI. Models were later adjusted for patient and procedural characteristics.

Results:
The final complete-case cohort included 8,595 patients (2,580/30% DCI≥65), had a mean age of 74.7 (±7.8) years, was 92.7% white and 97.6% non-Hispanic/Latino. The 36-month cumulative mortality incidence was similar in both groups (26.0% vs 22.5%, P=0.236). A 10-point increase in DCI did not increase mortality risk (unadjusted HR 1.00; 95% CI 0.98-1.03 and adjusted HR 1.01; 95% CI 0.87-1.17). At 36 months the high community distress group experienced higher stroke risk (29.8% vs 22.9%, P=0.008). However, a 10-point increase in DCI did not increase stroke risk (unadjusted sub-HR: 1.01; 95% CI 0.99-1.03, adjusted sub-HR: 1.00; 95% CI 0.98-1.02).

Conclusions:
In this selective set of patients with underrepresentation of demographic groups, for those who get prioritized to CAS, higher community distress was associated with an increased unadjusted 36-month stroke risk by DCI group. However, a 10-point increase in DCI was nonsignificant regardless of adjustment.
Abstract 16945: Aberrant Citric Acid Cycle Metabolites Temporally Coincide With Myocardial Dysfunction in a Rat Model of Stress Cardiomyopathy
Authors: Iyengar Amit , Weingarten Noah , Dominic Jessica , Meldrum Danika , Wilson Rachel , Belec Andrew , Ho Joyce , Seiberlich Melissa , Atluri Pavan
Published: November 2023

Introduction:
Stress cardiomyopathy is characterized by transient contractile dysfunction with a poorly understood mechanism. Targeting metabolic derangements has proven efficacious in chronic heart failure, but the role of metabolism in acute cardiac dysfunction is ill-defined.

Hypothesis:
Characterizing any metabolic alterations in stress cardiomyopathy may help identify potential therapeutic targets.

Methods:
Sprague-Dawley rats (350 ± 57 g) were given a single intraperitoneal injection of 75 mg/kg isoprenaline. Animals were allocated into groups (N=30 each) based on designated time-points for assessment after injection: control (no injection), day 1, 3, and 7. Rats underwent left ventricular PV loop catheterization followed by harvesting of apical ventricular tissue. Targeted metabolomic analyses were performed via LC-MS and supplemented with enzyme activity assays, qPCR, and Western blotting.

Results:
Stroke work, cardiac output, and ejection fraction were all significantly reduced by day 1 with recovery by day 7 (Figure A, all p<0.05). Targeted tissue metabolomics revealed peaks in nearly all citric acid cycle metabolites, pyruvate, and lactate that similarly correlated with illness (Figure B). In tandem, anaplerotic amino acids rose with injury while tissue triglycerides decreased. Pyruvate dehydrogenase phosphorylation decreased with decreased expression of pyruvate dehydrogenase kinase (Figure C). However, no differences were noted in tissue acylcarnitine levels despite increased serum fatty acids (all p>0.05).

Conclusions:
Profound rises in citric acid metabolites with accompanying increases in anaplerotic amino acids are suggestive of metabolic reprogramming in the setting of energetic deficits. Notably, these trends differ from those found in chronic heart failure, and represent a novel phenotypic characterization of stress cardiomyopathy with potential therapeutic implications.
Abstract 16949: The Effects of the Technology-Based Family-Centered Empowerment (T-FamE) Heart Failure Transitional Program: Preliminary Analysis of a Randomized Controlled Trial
Authors: yu Doris S , Li Polly Wai Chi W , Wong Chi Wing , Cheng Victor
Published: November 2023

Introduction:
Health digitization and advanced dyadic science offer new opportunities to enhance the transitional care model for heart failure (HF). The T-FamE program a transitional care model integrating digital health and optimized carer support to enhance the post-discharge outcomes of HF patients.

Hypothesis:
The T-FamE was more effective than usual care to enhance self-care, perceived control, family function, HRQoL and hospital readmission of HF patients.

Methods:
From Aug 2021 to March 2022, a RCT randomized 170 post-discharge HF patients (mean age = 69.0; SD=11.5; NYHA Grade II/III/IV = 53.9/40.6/.5.5%. LVEF<40% =58.5%) to the T-FamE or usual care. The 12-week nurse-delivered T-FamE comprises an interactive mobile Apps, which allows i) proactive health monitoring with tailored autonomous guideline-based feedback; ii) family-centerd goal-setting on self-care, iii) personalized drug education, iv) mobile access to nurse, v) video-based HF compass for rehabilitation and self-care. The cardiac nurse conducted three monthly visits for family-based empowerment on disease management. Outcome evaluation by Self-care Heart Failure index, Self-care Self-Efficacy Scale, Control Attitude Scale, Family Functioning Device and EuroQoL at baseline and post-test.

Results:
Two-way analysis of covariance showed significant greater improvement of T-FamE group on self-care maintenance (F=21.46, p<0.001, η
2
p
=0.113), management (F=22.52, p=0.01, η
2
p
=0.118), symptom perception (F=69.70, p<0.001, η
2
p
=0.29) and confidence (F=13.36, p<0.001, η
2
p
=0.073) than the control. They have greater improvement in EuroQoL (F=5.78, p=0.017, η
2
p
=0.033) and sense of control (F=5.78, p=0.017, η
2
p
=0.033), and significantly lower number ore readmission in one year (-0.278 (95%CI=-0.54, -0.008, p=0.043).

Conclusions:
The T-FamE is effective to improve the self-care, HRQL and readmission outcomes. Digitalized transitional care model with optimized family support play explain the therapeutic benefits. Autonomous response to health monitoring data may enhance self-care decision-making.
Abstract 19141: Carotid Artery Plaque Rim Sign on Computed Tomography Angiography is Associated With Intraplaque Hemorrhage and Inflammatory Microenvironment
Authors: Nardi Valentina , Rajotia Arush , Benson John C , Saba Luca , Lerman Lilach O , Lerman Amir
Published: November 2023

Introduction:
The carotid artery rim sign on CTA is characterized by soft-plaque components surrounded by a rind of thin, adventitial calcification and its role in plaque instability is not established yet. Intraplaque hemorrhage (IPH) and the inflammatory microenvironment in carotid atheroma are considered features of atherosclerotic plaque vulnerability leading to cerebrovascular events.

Hypothesis:
The association between rim sign on CTA and carotid IPH and inflammation remains scantly investigated. In this study, we aimed to determine whether rim sign is associated with IPH on MRA and with the extent of IPH and inflammation on histology. We hypothesized that rim sign may be a radiological predictor of carotid IPH and inflammation.

Methods:
We retrospectively enrolled 100 consecutive patients who underwent carotid endarterectomy (CEA) and neck CTA before CEA. On CTA, the ipsilateral rim sign was defined as the presence of adventitial calcifications with internal soft-tissue plaque of ≥2 mm in maximum thickness. Of the included patients, 25 had MRA with 3D magnetization-prepared rapid acquisition with gradient echo (MPRAGE) sequence. Carotid plaque specimens were collected and stained with H&E to quantify IPH (%). Histologically, we defined IPH as an area of carotid plaque with blood elements, and inflammatory microenvironment as the presence of lymphocytes and plasma cells (chronic inflammation) and foam cells.

Results:
The rim sign on CTA was present in 56 (56%) of patients. IPH on MRA was present in 11 (44%) patients. The rim sign was significantly associated with the presence of IPH on MRA [9 (81.8%) vs 2 (14.3%); p=0.003]. On histology, the rim sign was associated with a higher extent of IPH [5.0 % (IQR 2.0-25.0) vs 5.0% (IQR 0.0-10.0); p=0.017], with chronic inflammation [44 (78.6%) vs 12 (21.4%); p=0.003], and foam cells [51 (91.1%) vs 5 (8.9%); p<0.001].

Conclusions:
These findings suggest that rim sign on CTA may be proposed as a potential imaging marker of IPH as well as a histologic predictor of IPH extent and carotid plaque inflammatory microenvironment.