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The overproduction of reactive oxygen species (ROS) and burst of inflammation following cardiac ischemia–reperfusion (I/R) are the leading causes of cardiomyocyte injury. Monotherapeutic strategies designed to enhance anti-inflammatory or anti-ROS activity explicitly for treating I/R injury have demonstrated limited success because of the complex mechanisms of ROS production and induction of inflammation. Intense oxidative stress leads to sustained injury, necrosis, and apoptosis of cardiomyocytes. The damaged and necrotic cells can release danger-associated molecular patterns (DAMPs) that can cause the aggregation of immune cells by activating Toll-like receptor 4 (TLR4). These immune cells also promote ROS production by expressing NADPH oxidase. Finally, ROS production and inflammation form a vicious cycle, and ROS and TLR4 are critical nodes of this cycle. In the present study, we designed and prepared an injectable hydrogel system of EGCG@Rh-gel by co-assembling epigallocatechin-3-gallate (EGCG) and the rhein-peptide hydrogel (Rh-gel). The co-assembled hydrogel efficiently blocked the ROS–inflammation cycle by ROS scavenging and TLR4 inhibition. Benefited by the abundant noncovalent interactions of π–π stacking and hydrogen bonding between EGCG and Rh-gel, the co-assembled hydrogel had good mechanical strength and injectable property. Following the injection EGCG@Rh-gel into the damaged region of the mice's heart after I/R, the hydrogel enabled to achieve long-term sustained release and treatment, improve cardiac function, and significantly reduce the formation of scarring. Further studies demonstrated that these beneficial outcomes arise from the reduction of ROS production, inhibition of inflammation, and induction of anti-apoptosis in cardiomyocytes. Therefore, EGCG@Rh-gel is a promising drug delivery system to block the ROS-inflammation cycle for resisting myocardial I/R injury. 1. Monotherapeutic strategies designed to enhance anti-inflammatory or anti-ROS effects for treating I/R injury have demonstrated limited success because of the complex mechanisms of ROS and inflammation. 2. ROS production and inflammation form a vicious cycle, and ROS and TLR4 are critical nodes of this cycle. 3. Here, we designed an injectable hydrogel system of EGCG@Rh-gel by co-assembling epigallocatechin-3-gallate (EGCG) and a rhein-peptide hydrogel (Rh-gel). EGCG@Rh-gel efficiently blocked the ROS–inflammation cycle by ROS scavenging and TLR4 inhibition. 4. EGCG@Rh-gel achieved long-term sustained release and treatment, improved cardiac function, and significantly reduced the formation of scarring after I/R. 5. The beneficial outcomes arise from reducing ROS production, inhibiting inflammation, and inducing anti-apoptosis in cardiomyocytes. [Display omitted] [ABSTRACT FROM AUTHOR]

Bayesian network (BN) structure learning is the basis of BN applications and plays a pivotal role in many machine learning tasks. Whereas remarkable progress in structure learning has been achieved in the past, making further improvements in the efficiency and accuracy of structure learning is a significant challenge. In this paper, we propose an efficient skeleton learning approach-based hybrid algorithm (ESLH), which consists of two phases. In the constraint-based phase, a dynamic threshold (DTH) strategy and a skeleton learning method based on triangle breaking (SLTB) are proposed to learn the skeleton of a BN structure efficiently. DTH designs a dynamic threshold to remove redundant edges in the initial skeleton with little time overhead. By the result of DTH, SLTB first finds, tests and breaks triangles in the initial skeleton to efficiently remove redundant edges and then removes the remaining redundant edges to discover the final skeleton. In the score-and-search phase, ESLH employs the hill-climbing algorithm to find the highest-scored structure. We propose a novel strategy to divide this phase into three steps, both utilizing the learned skeleton to constrain the search space and preventing the errors of the learned skeleton from reducing the quality of the final learned structure. Extensive experiments on benchmark BNs validate the effectiveness of DTH and SLTB and demonstrate that ESLH is more than five times faster than the state-of-the-art structure learning algorithms while maintaining the highest average accuracy. [ABSTRACT FROM AUTHOR]

In pancreatic cancer (PC), surgical resection remains the sole curative option, albeit patients undergoing resection are susceptible to postoperative pancreatic fistula (PF) formation and tumor recurrence. An unmet need exists for a unified strategy capable of concomitantly averting PF and tumor relapse to mitigate morbidity in PC patients after surgery. Herein, an original dual crosslinked biological sealant hydrogel (methacrylate-hyaluronic acid-dopamine (MA-HA-DA) and sulfhydryl-hyaluronic acid-dopamine (SH-HA-DA)) was engineered as a drug depot and loaded with polydopamine-cloaked cytokine interleukin-15 and platelets conjugated with anti-TIGIT. In vitro analyses validated favorable tissue adhesion, cytocompatibility, and stability of the hydrogels. In a PF rodent model, the hydrogel effectively adhered to the pancreatic stump, sealing the severed pancreatic end and impeding post-operative elevations in amylase and lipase. In PC murine models, hydrogels potently stimulated CD8+ T and NK cells to deter residual tumor re-growth and distant metastasis. This innovative hydrogel strategy establishes a new framework for concomitant prevention of PF and PC recurrence. [ABSTRACT FROM AUTHOR]

A cell-implantation strategy offers a promising paradigm for cardiac repair after myocardial infarction (MI). However, the hostile reactive oxygen species (ROS) microenvironment in infarcted zone hinders the survival and maturation of implanted cells and affects the ultimate therapeutic outcome. Besides, the generation of fibrosis scarring deprives the myocardium of electrical communications and induces cardiac dysfunction, eventually resulting in heart failure. Herein, an injectable ROS-scavenging/conductive composite hydrogel (R&C-Gel) was constructed via specific binding between conductive polypyrrole (PPy) and multi-component co-assembly peptides. Integrating antioxidant TEMPOL into the peptide endows it with strong ROS-eliminating ability, and the nanoengineering of polypyrrole (PPy) by wet milling facilitates PPy uniformly binding to the target T59 peptide in nanofibers. The thixotropy of co-assembly hydrogels confirmed by rheology and the macroporous structure of the R&C-Gel surface observed by SEM together suggest that the R&C-Gel could be an ideal vehicle for cell engraftment. The antioxidant ability and electroconductivity of the R&C-Gel were verified. In vitro experiments demonstrated that the R&C-Gel could efficiently remove ROS in cardiomyocytes and reduce apoptosis under oxygen-glucose deprivation (OGD) conditions. The rhythmic intracellular Ca2+ puffs and expression of Cx-43 protein further proved the R&C-Gel could enhance the electrical and contractile performance of cardiomyocytes. Echocardiography and histological analysis convincingly revealed that the R&C-Gel-combined cardiomyocytes significantly promoted cardiac repair and rebuilt cardiac function, such as reducing apoptosis, accelerating gap junction formation, increasing ejection fraction, and decreasing the fibrosis area. This study provides new insight into the design and construction of multifunctional conductive hydrogels for cardiac tissue engineering. • An injectable composite hydrogel (R&C-Gel) is prepared via specific binding between conductive PPy and multi-component peptides. • Integrating the TEMPOL endows the R&C-Gel with strong ROS-eliminating ability to reduce the apoptosis of CMs under hypoxia. • Nanoengineering of vapor-polymerized PPy membrane to conductive NanoClusters facilitates PPy uniformly binding to nanofibers of R&C-gel. • R&C-Gel promotes rhythmic intracellular Ca2+ puffs and the expression of Cx-43 protein in the maturation of CMs. • Injection of CMs@R&C-Gel is capable of restoring cardiac function post-MI. [ABSTRACT FROM AUTHOR]

Cell therapy offers a promising paradigm for heart tissue regeneration. Human induced pluripotent stem cells (hiPS) and their cardiac derivatives are emerging as a novel treatment for post-myocardial infarction repair. However, the immature phenotype and function of hiPS-derived cardiomyocytes (hiPS-CMs), particularly poor electrical coupling, limit their potential as a therapy. Herein, we developed a hybrid gold nanoparticle (AuNP)-hyaluronic acid (HA) hydrogel matrix encapsulating hiPS-CMs to overcome this limitation. Methacrylate-modified-HA was used as the backbone and crosslinked with a matrix metalloproteinase-2 (MMP-2) degradable peptide to obtain a MMP-2-responsive hydrogel; RGD peptide was introduced as an adhesion point to enhance biocompatibility; AuNPs were incorporated to regulate the mechanical and topological properties of the matrix by significantly increasing its stiffness and surface roughness, thereby accelerating gap junction formation in hiPS-CMs and orchestrating calcium handling via the α n β1integrin-mediated ILK-1/p-AKT/GATA4 pathway. Transplanted AuNP-HA-hydrogel-encapsulated-hiPS-CMs developed more robust gap junctions in the infarcted mice heart and resynchronized electrical conduction of the ventricle post-myocardial infarction. The hiPS-CMs delivered by the hydrogels exerted stronger angiogenic effects, which also contributed to the recovery process. This study provides insight into constructing an injectable biomimetic for structural and functional renovation of the injured heart. [ABSTRACT FROM AUTHOR]