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Hematopoietic stem cell (HSC) therapy for myocardial repair is limited by the number of stem cells that migrate to, engraft in, and proliferate at sites of injured myocardium. To alleviate this limitation, we studied whether a strategy using a bispecific antibody (BiAb) could target human stem cells specifically to injured myocardium and preserve myocardial function. Using a xenogeneic rat model whereby ischemic injury was induced by transient ligation of the left anterior descending artery (LAD), we determined the ability of a bispecific antibody to target human CD34+ cells to specific antigens expressed in ischemic injured myocardium. A bispecific antibody comprising an anti-CD45 antibody recognizing the common leukocyte antigen found on HSCs and an antibody recognizing myosin light chain, an organ-specific injury antigen expressed by infarcted myocardium, was prepared by chemical conjugation. CD34+ cells armed and unarmed with this BiAb were injected intravenously in rats 2 days postmyocardial injury. Immunohistochemistry studies showed that the armed CD34+ cells specifically localized to the infarcted region of the heart, colocalized with troponin T-stained cells, and colocalization with vascular structures. Compared to unarmed CD34+ cells, the bispecific antibody improved delivery of the stem cells to injured myocardium, and such targeted delivery was correlated with improved myocardial function 5 weeks after infarction (p < .01). Bispecific antibody targeting offers a unique means to improve the delivery of stem cells to facilitate organ repair and a tool to study stem cell biology. [ABSTRACT FROM AUTHOR]

In Steiner tree game associated with a graph G=(V,E), players consist of a subset N⊆V of nodes. The characteristic function value of a subset S⊆N of the players is the minimum weight of a Steiner tree that spans S. We show that it is NP-hard to determine whether a Steiner tree game is totally balanced, i.e., cores for all its subgames are non-empty. In addition, the NP-hardness result is also proven for deciding whether the core is non-empty, or whether an imputation is a member of the core. [Copyright &y& Elsevier]

Purpose: Myocardial infarction (MI) with subsequent inflammation is one of the most common heart conditions leading to progressive tissue damage. A reliable imaging marker to assess tissue viability after MI would help determine the risks and benefits of any intervention. In this study, we investigate whether a new mitochondria-targeted imaging agent, 18F-labeled 2'-deoxy-2'-18F-fluoro-9-β-d-arabinofuranosylguanine ([18F]F-AraG), a positron emission tomography (PET) agent developed for imaging activated T cells, is suitable for cardiac imaging and to test the myocardial viability after MI.To test whether the myocardial [18F]-F-AraG signal is coming from cardiomyocytes or immune infiltrates, we compared cardiac signal in wild-type (WT) mice with that of T cell deficient Rag1 knockout (Rag1 KO) mice. We assessed the effect of dietary nucleotides on myocardial [18F]F-AraG uptake in normal heart by comparing [18F]F-AraG signals between mice fed with purified diet and those fed with purified diet supplemented with nucleotides. The myocardial viability was investigated in rodent model by imaging rat with [18F]F-AraG and 2-deoxy-2[18F]fluoro-D-glucose ([18F]FDG) before and after MI. All PET signals were quantified in terms of the percent injected dose per cc (%ID/cc). We also explored [18F]FDG signal variability and potential T cell infiltration into fibrotic area in the affected myocardium with H&E analysis.The difference in %ID/cc for Rag1 KO and WT mice was not significant (p = ns) indicating that the [18F]F-AraG signal in the myocardium was primarily coming from cardiomyocytes. No difference in myocardial uptake was observed between [18F]F-AraG signals in mice fed with purified diet and with purified diet supplemented with nucleotides (p = ns). The [18F]FDG signals showed wider variability at different time points. Noticeable [18F]F-AraG signals were observed in the affected MI regions. There were T cells in the fibrotic area in the H&E analysis, but they did not constitute the predominant infiltrates.Our preliminary preclinical data show that [18F]F-AraG accumulates in cardiomyocytes indicating that it may be suitable for cardiac imaging and to evaluate the myocardial viability after MI.Procedure: Myocardial infarction (MI) with subsequent inflammation is one of the most common heart conditions leading to progressive tissue damage. A reliable imaging marker to assess tissue viability after MI would help determine the risks and benefits of any intervention. In this study, we investigate whether a new mitochondria-targeted imaging agent, 18F-labeled 2'-deoxy-2'-18F-fluoro-9-β-d-arabinofuranosylguanine ([18F]F-AraG), a positron emission tomography (PET) agent developed for imaging activated T cells, is suitable for cardiac imaging and to test the myocardial viability after MI.To test whether the myocardial [18F]-F-AraG signal is coming from cardiomyocytes or immune infiltrates, we compared cardiac signal in wild-type (WT) mice with that of T cell deficient Rag1 knockout (Rag1 KO) mice. We assessed the effect of dietary nucleotides on myocardial [18F]F-AraG uptake in normal heart by comparing [18F]F-AraG signals between mice fed with purified diet and those fed with purified diet supplemented with nucleotides. The myocardial viability was investigated in rodent model by imaging rat with [18F]F-AraG and 2-deoxy-2[18F]fluoro-D-glucose ([18F]FDG) before and after MI. All PET signals were quantified in terms of the percent injected dose per cc (%ID/cc). We also explored [18F]FDG signal variability and potential T cell infiltration into fibrotic area in the affected myocardium with H&E analysis.The difference in %ID/cc for Rag1 KO and WT mice was not significant (p = ns) indicating that the [18F]F-AraG signal in the myocardium was primarily coming from cardiomyocytes. No difference in myocardial uptake was observed between [18F]F-AraG signals in mice fed with purified diet and with purified diet supplemented with nucleotides (p = ns). The [18F]FDG signals showed wider variability at different time points. Noticeable [18F]F-AraG signals were observed in the affected MI regions. There were T cells in the fibrotic area in the H&E analysis, but they did not constitute the predominant infiltrates.Our preliminary preclinical data show that [18F]F-AraG accumulates in cardiomyocytes indicating that it may be suitable for cardiac imaging and to evaluate the myocardial viability after MI.Results: Myocardial infarction (MI) with subsequent inflammation is one of the most common heart conditions leading to progressive tissue damage. A reliable imaging marker to assess tissue viability after MI would help determine the risks and benefits of any intervention. In this study, we investigate whether a new mitochondria-targeted imaging agent, 18F-labeled 2'-deoxy-2'-18F-fluoro-9-β-d-arabinofuranosylguanine ([18F]F-AraG), a positron emission tomography (PET) agent developed for imaging activated T cells, is suitable for cardiac imaging and to test the myocardial viability after MI.To test whether the myocardial [18F]-F-AraG signal is coming from cardiomyocytes or immune infiltrates, we compared cardiac signal in wild-type (WT) mice with that of T cell deficient Rag1 knockout (Rag1 KO) mice. We assessed the effect of dietary nucleotides on myocardial [18F]F-AraG uptake in normal heart by comparing [18F]F-AraG signals between mice fed with purified diet and those fed with purified diet supplemented with nucleotides. The myocardial viability was investigated in rodent model by imaging rat with [18F]F-AraG and 2-deoxy-2[18F]fluoro-D-glucose ([18F]FDG) before and after MI. All PET signals were quantified in terms of the percent injected dose per cc (%ID/cc). We also explored [18F]FDG signal variability and potential T cell infiltration into fibrotic area in the affected myocardium with H&E analysis.The difference in %ID/cc for Rag1 KO and WT mice was not significant (p = ns) indicating that the [18F]F-AraG signal in the myocardium was primarily coming from cardiomyocytes. No difference in myocardial uptake was observed between [18F]F-AraG signals in mice fed with purified diet and with purified diet supplemented with nucleotides (p = ns). The [18F]FDG signals showed wider variability at different time points. Noticeable [18F]F-AraG signals were observed in the affected MI regions. There were T cells in the fibrotic area in the H&E analysis, but they did not constitute the predominant infiltrates.Our preliminary preclinical data show that [18F]F-AraG accumulates in cardiomyocytes indicating that it may be suitable for cardiac imaging and to evaluate the myocardial viability after MI.Conclusions: Myocardial infarction (MI) with subsequent inflammation is one of the most common heart conditions leading to progressive tissue damage. A reliable imaging marker to assess tissue viability after MI would help determine the risks and benefits of any intervention. In this study, we investigate whether a new mitochondria-targeted imaging agent, 18F-labeled 2'-deoxy-2'-18F-fluoro-9-β-d-arabinofuranosylguanine ([18F]F-AraG), a positron emission tomography (PET) agent developed for imaging activated T cells, is suitable for cardiac imaging and to test the myocardial viability after MI.To test whether the myocardial [18F]-F-AraG signal is coming from cardiomyocytes or immune infiltrates, we compared cardiac signal in wild-type (WT) mice with that of T cell deficient Rag1 knockout (Rag1 KO) mice. We assessed the effect of dietary nucleotides on myocardial [18F]F-AraG uptake in normal heart by comparing [18F]F-AraG signals between mice fed with purified diet and those fed with purified diet supplemented with nucleotides. The myocardial viability was investigated in rodent model by imaging rat with [18F]F-AraG and 2-deoxy-2[18F]fluoro-D-glucose ([18F]FDG) before and after MI. All PET signals were quantified in terms of the percent injected dose per cc (%ID/cc). We also explored [18F]FDG signal variability and potential T cell infiltration into fibrotic area in the affected myocardium with H&E analysis.The difference in %ID/cc for Rag1 KO and WT mice was not significant (p = ns) indicating that the [18F]F-AraG signal in the myocardium was primarily coming from cardiomyocytes. No difference in myocardial uptake was observed between [18F]F-AraG signals in mice fed with purified diet and with purified diet supplemented with nucleotides (p = ns). The [18F]FDG signals showed wider variability at different time points. Noticeable [18F]F-AraG signals were observed in the affected MI regions. There were T cells in the fibrotic area in the H&E analysis, but they did not constitute the predominant infiltrates.Our preliminary preclinical data show that [18F]F-AraG accumulates in cardiomyocytes indicating that it may be suitable for cardiac imaging and to evaluate the myocardial viability after MI. [ABSTRACT FROM AUTHOR]

Submodular optimization not only covers some classical combinatorial optimization problems, but also has a wide range of applications in fields such as machine learning and artificial intelligence. For submodular maximization problems with constraints, some work has been done including the design of approximation algorithms, the measurement of approximation algorithms in terms of quality and efficiency, etc. In this paper, we consider the problem of maximizing a non-negative monotone submodular function minus a non-negative modular function with the cardinality constraint. This model has been applied to many scenarios, such as team formation problem, influence maximization problem, recommender systems problem, etc. We propose a threshold algorithm that achieve a (1 / 2 − O (ε) , 2) -bicriteria approximation ratio and query complexity O (n log ⁡ n). Our algorithm makes a small sacrifice in the approximation ratio but improves the best query complexity result of existing deterministic algorithms from O (n 2) to O (n log ⁡ n) in the worst case. [ABSTRACT FROM AUTHOR]

Supplemental Digital Content is available in the text. Background: The left atrial end-systolic volume index (LAESVI) is a predictor of cardiovascular outcomes and is the recommended measurement of left atrial size. The left atrial end-diastolic volume index (LAEDVI), representing the minimum or residual left atrial volume, has not been fully evaluated as a predictor of cardiovascular events. This study evaluated the predictive power of LAEDVI compared with LAESVI for heart failure (HF) hospitalizations, a composite of HF hospitalizations, myocardial infarction, stroke, and heart disease death, and all-cause mortality. Methods: We measured LAESVI and LAEDVI in subjects without atrial fibrillation or flutter or significant mitral valve disease. Using Cox proportional-hazard models, the association of LAESVI and LAEDVI with the stated outcomes was examined. Results: After a mean of 7.3±2.6 years of follow-up, there were 147 HF hospitalizations, 118 myocardial infarctions, 45 strokes, 96 heart disease deaths, and 351 deaths from all causes in 938 subjects. When comparing the highest and the lowest quartiles of LAEDVI, there was a near 6-fold increase in the hazard ratio (HR) for HF hospitalization (HR, 5.96; P <0.001). This was higher than what was seen with LAESVI (HR, 4.85; P <0.001). Similar associations were noted for the composite cardiovascular outcome (HR for LAEDVI, 2.97; P <0.001) and for all-cause mortality (HR for LAEDVI, 2.08; P <0.001). In adjusted models, LAEDVI demonstrated equal or better predictive power than LAESVI for HF hospitalization and the composite cardiovascular outcome. Conclusions: LAEDVI is a strong predictor of cardiovascular events in ambulatory patients with stable coronary heart disease and may merit routine use. [ABSTRACT FROM AUTHOR]

Edge cover games are cooperative cost games arising from edge cover problems. In an edge cover game, each player controls a vertex and the cost of a coalition is the minimum weight of edge covers in the subgraph induced by the coalition. The approximate core is a relaxation of the core which is one of the most important concepts in cooperative game theory. A vector belongs to the α -core (0 ≤ α ≤ 1) if it recovers at least α -fraction of the total cost of the game when no deviating coalition is better off. In this paper, we show that the 3 4 -core of edge cover games is always non-empty and a vector in the 3 4 -core can be computed efficiently. We also show that 3 4 is the best constant ratio for the approximate core of edge cover games, as it is the reciprocal of the integrality gap for edge cover problems. [ABSTRACT FROM AUTHOR]

Background: C-reactive protein (CRP) is an inflammatory marker that is associated with an increased risk of major adverse cardiovascular events (MACE) in ambulatory coronary artery disease (CAD). However, the association of longitudinal trends of CRP with subsequent MACE in ambulatory CAD is unknown. Hypothesis: We tested the hypothesis that an increase in CRP level over time is associated with an increased risk of subsequent MACE among patients with ambulatory CAD. Methods: We measured CRP levels at baseline and at 5-year follow-up in 629 participants enrolled in the Heart and Soul Study, a prospective cohort study of patients with ambulatory CAD. The outcomes evaluated were heart failure (HF) hospitalization, non-fatal myocardial infarction (MI), cardiovascular (CV) death and the combined outcome (MACE) occurring after the 5-year visit. We evaluated the association between change in CRP and outcomes using unadjusted and multivariable-adjusted Cox proportional hazards models. Results: The mean age of the participants was 71±10 years and 18% were female. Most of the participants (77%) had a fall in CRP over 5 years (median change -2.2 pg/ml, interquartile range (IQR) -6.4, -0.9), while 23% had a rise in CRP (median change +1.6 pg/ml, IQR +0.4, +5.4). During a mean follow-up of 4.2±1.4 years, 134 participants (21%) developed MACE. After full adjustment for demographic, clinical and laboratory variables, including year-1 CRP and year-5 N-terminal pro-brain natriuretic peptide (NT-proBNP) and high sensitivity troponin T levels, a rise in CRP was associated with an increased risk of developing HF (HR 3.3 [95% CI 1.3-8.0], p=0.01) and MI (HR 3.8 [95% CI 1.2-12.8], p=0.03). It was also associated with a two-fold risk of CV death (HR 2.2 [95% CI 1.0-4.7], p=0.05), and combined MACE (HR 2.0 [95% CI 1.2-3.5], p=0.01), although the risks of CV death and combined MACE were not significant after adjusting for year-5 NT-proBNP and troponin T levels. Conclusion: In patients with ambulatory CAD, a 5-year increase in CRP levels is independently associated with an elevated risk of non-fatal MI and HF hospitalization. An increase in CRP in this population identifies those who are at an increased risk of MACE and may therefore benefit most from aggressive preventive interventions. [ABSTRACT FROM AUTHOR]

Independent set games are cooperative games defined on graphs, where players are edges and the value of a coalition is the maximum cardinality of independent sets in the subgraph defined by the coalition. In this paper, we investigate the convexity of independent set games, as convex games possess many nice properties both economically and computationally. For independent set games introduced by Deng et al. [5] , we provide a necessary and sufficient characterization for the convexity, i.e., every non-pendant edge is incident to a pendant edge in the underlying graph. Our characterization implies that convex instances of independent set games can be recognized efficiently. Besides, we introduce a new class of independent set games and provide a necessary and sufficient characterization for the convexity. [ABSTRACT FROM AUTHOR]

Intramyocardial injection of hydrogels offers great potential for treating myocardial infarction (MI) in a minimally invasive manner. However, traditional bulk hydrogels generally lack microporous structures to support rapid tissue ingrowth and biochemical signals to prevent fibrotic remodeling toward heart failure. To address such challenges, a novel drug‐releasing microporous annealed particle (drugMAP) system is developed by encapsulating hydrophobic drug‐loaded nanoparticles into microgel building blocks via microfluidic manufacturing. By modulating nanoparticle hydrophilicity and pregel solution viscosity, drugMAP building blocks are generated with consistent and homogeneous encapsulation of nanoparticles. In addition, the complementary effects of forskolin (F) and Repsox (R) on the functional modulations of cardiomyocytes, fibroblasts, and endothelial cells in vitro are demonstrated. After that, both hydrophobic drugs (F and R) are loaded into drugMAP to generate FR/drugMAP for MI therapy in a rat model. The intramyocardial injection of MAP gel improves left ventricular functions, which are further enhanced by FR/drugMAP treatment with increased angiogenesis and reduced fibrosis and inflammatory response. This drugMAP platform represents a new generation of microgel particles for MI therapy and will have broad applications in regenerative medicine and disease therapy. [ABSTRACT FROM AUTHOR]

Repairing cardiac tissue after myocardial infarction (MI) is one of the most challenging goals in tissue engineering. Following ischemic injury, significant matrix remodeling and the formation of avascular scar tissue significantly impairs cell engraftment and survival in the damaged myocardium. This limits the efficacy of cell replacement therapies, demanding strategies that reduce pathological scarring to create a suitable microenvironment for healthy tissue regeneration. Here, we demonstrate the successful fabrication of discrete hyaluronic acid (HA)-based microrods to provide local biochemical and biomechanical signals to reprogram cells and attenuate cardiac fibrosis. HA microrods were produced in a range of physiological stiffness and shown to degrade in the presence of hyaluronidase. Additionally, we show that fibroblasts interact with these microrods in vitro , leading to significant changes in proliferation, collagen expression and other markers of a myofibroblast phenotype. When injected into the myocardium of an adult rat MI model, HA microrods prevented left ventricular wall thinning and improved cardiac function at 6 weeks post infarct. [ABSTRACT FROM AUTHOR]

The cohesive subgraph k-core is a maximal connected subgraph with the minimum degree δ ≥ k of a simple graph, where integer k ≥ 0. Define the core number of a vertex w as the maximum k such that w is contained in a k -core. The core decomposition problem which is calculating the core numbers of all vertices in static graphs, and the core maintenance problem which is updating the core numbers in dynamic graphs are our main concern. Although, core numbers can be updated by the core decomposition algorithms, only a small part of vertices' core numbers have changed after the change of a graph. Thus, it is necessary to update core numbers locally to reduce the cost. In this paper, we study the core maintenance problem on edge-weighted graphs by using the vertex sequence k-order which is ordered by the order that the core decomposition algorithm removes vertices. We design the core maintenance algorithms for inserting one edge at a time and the method of updating the k -order, which reduce the searching range and the time cost evidently. For the removing case, we use the existing subcore algorithm to do the core maintenance and modify it with the method of updating k -order we design. Finally, we do extensive experiments to evaluate the effectiveness and the efficiency of our algorithms, which shows that the order based algorithm has a better performance than the existing for the core maintenance on edge-weighted graphs. • We solve the core maintenance problem on edge-weighted graphs with a tool named weighted k -order. • The weighted k -order, a vertex sequence, is defined on edge-weighted graphs for the first time. • We give the properties of vertices whose core numbers increase on the k-order for inserting case on edge-weighted graphs. • The order based core maintenance algorithm for inserting case on edge-weighted graphs is given, which is the best. • We give the methods to update the k-order after inserting or removing one edge for the next core maintenance. [ABSTRACT FROM AUTHOR]

Background: The pathophysiology of cardiomyopathy associated with premature ventricular contractions (PVCs) remains unclear.Objectives: This study prospectively explored cardiomyopathy development in a swine model of paced ectopic beats.Methods: A total of 35 swine underwent pacemaker implantation. A group exposed to paced bigeminy from the right ventricular apex (RVA) for 14 weeks (RVA PVC) (n = 10) were compared with a group exposed to regular pacing from the RVA at 140 beats/min (RV-140) (n = 5) and a control group (n = 5). To test the role of ectopic beat dyssynchrony, further groups were exposed for 12 weeks to bigeminy from the right ventricular free wall (RVFW PVC) (n = 5), the left ventricular epicardium (LV Epi PVC) (n = 5) or the right atrium (premature atrial complex) (n = 5).Results: After 14 weeks, the mean left ventricular ejection fraction (LVEF) was significantly lower in the RVA PVC group than in the RV-140 or control groups (p < 0.05). LVEF declined significantly in the LV Epi PVC (65.2 ± 2.4% to 39.7 ± 3.0%; p < 0.01) and RVFW PVC (66.1 ± 2.6% to 48.6 ± 2.7%; p < 0.01) groups, with final LVEF significantly lower and ventricular fibrosis significantly higher in the LV Epi PVC group compared with all others (p < 0.05). Protein levels of pRyR2, NCX-1, CaMKII-α, and PLN were up-regulated and levels of SERCA2a were down-regulated in the LV Epi PVC group compared with the control group (p < 0.05). Longer ectopic beat QRS duration and greater LV dyssynchrony were significantly associated with larger declines in LV systolic function.Conclusions: In a swine model of paced ectopic beats, PVC-induced cardiomyopathy is phenotypically distinct from a tachycardia-induced cardiomyopathy. Cardiomyopathy severity is strongly associated with severity of the hemodynamic derangement associated with the paced ectopic beats, particularly the extent of LV dyssynchrony. [ABSTRACT FROM AUTHOR]