A Janus Adhesive Hydrogel with Integrated Attack and Defense for Bacteria Killing and Antifouling.

Objective: Skin wound exposed to complex external environment for a long time is highly susceptible to bacterial infection. Impact Statement: This work designs a Janus adhesive dual-layer hydrogel containing in situ silver nanoparticles (named PSAP/DXP@AgNPs) with integrated attack and defense to simultaneously kill the existing bacteria and prevent foreign bacterial contamination. Introduction: The current gauze dressing fixed by tape fails to well fit at skin wound and lacks intrinsic antibacterial property, making it highly prone to causing secondary infection. Moreover, foreign bacteria may contaminate the wound dressing during use, further increasing the risk of secondary infection. Methods: In this work, a Janus adhesive dual-layer PSAP/DXP@AgNPs hydrogel is prepared by sequentially building the PSAP gel layer containing zwitterionic poly(sulfobetaine methacrylamide) (PSBMA) on the DXP@AgNPs gel layer containing in situ catechol-reduced AgNPs. Results: The flexible PSAP/DXP@AgNPs can adapt shape change of skin and adhere to skin tissue with interfacial toughness of 153.38 J m-2 relying on its DXP@AgNPs layer, which is beneficial to build favorable fit. The in situ reduced AgNPs released from the DXP@AgNPs layer of PSAP/DXP@AgNPs exhibit obvious antibacterial effects against Escherichia coli and Staphylococcus aureus, with antibacterial rates of 99% and 88%, respectively. Meanwhile, the hydrated PSAP layer of PSAP/DXP@AgNPs containing PSBMA is able to prevent the bacterial contamination, decreasing the risk of secondary infection. Besides, cell experiments demonstrate that PSAP/DXP@AgNPs is biocompatible. Conclusion: The PSAP/DXP@AgNPs hydrogel with integrated attack and defense simultaneously possessing bacteria-killing and bacteria-antifouling properties is a potential alternative in treating infected skin wound.

Short- and mid-term outcomes of the aortic root repair versus root replacement in acute type A aortic dissection.

Background: In patients with acute acute type A aortic dissection (ATAAD) requiring emergency surgery, the use of aortic root repair or replacement remains a topic of controversy. The purpose of this study was to evaluate the early and mid-term clinical outcomes after aortic root repair or replacement, and to provide a theoretical basis for such patients. Methods: The study included 442 consecutive patients with ATAAD who underwent aortic root repair [n=227, repair group (RG)] or the Bentall procedure [n=215, Bentall group (BG)] at our hospital between December 2018 and December 2021. The indications for aortic root replacement were aortic root sinus diameter of ≥4.5 cm, severe sinotubular junction involvement, unrepairable aortic valvulopathy, severe coronary ostium involvement, connective tissue disease, intimal tear at the aortic root, or dissection involving three aortic sinuses. The primary outcome was the survival rate and incidence of reoperation between the two groups. Results: The in-hospital and 30-day mortality rates in the RG and BG were 10.1% and 11.6%, respectively. The two groups had no significant difference (P=0.613). Multivariate logistic analysis showed that aortic root surgery did not influence the in-hospital or 30-day mortality rates. The mean follow-up time was 36.8±11.6 months (median, 33.4 months; interquartile range, 27.0-45.2 months). The 5-year survival rates for the RG and BG were 88.1% and 85.9%, respectively (P=0.650). During the follow-up period, only one patient in the BG group underwent proximal aortic reoperation. Conclusions: Continuous improvement of aortic root repair technology and identification of its indications may help reduce reoperation rates. Aortic root repair can be considered safe and feasible.

Neuronal cathepsin S increases neuroinflammation and causes cognitive decline via CX3CL1-CX3CR1 axis and JAK2-STAT3 pathway in aging and Alzheimer's disease.

Aging is an intricate process involving interactions among multiple factors, which is one of the main risks for chronic diseases, including Alzheimer's disease (AD). As a member of cysteine protease, cathepsin S (CTSS) has been implicated in inflammation across various diseases. Here, we investigated the role of neuronal CTSS in aging and AD started by examining CTSS expression in hippocampus neurons of aging mice and identified a significant increase, which was negatively correlated with recognition abilities. Concurrently, we observed an elevation of CTSS concentration in the serum of elderly people. Transcriptome and fluorescence-activated cell sorting (FACS) results revealed that CTSS overexpression in neurons aggravated brain inflammatory milieu with microglia activation to M1 pro-inflammatory phenotype, activation of chemokine C-X3-C-motif ligand 1 (CX3CL1)-chemokine C-X3-C-motif receptor 1 (CX3CR1) axis and janus kinase 2 (JAK2)-signal transducer and activator of transcription 3 (STAT3) pathway. As CX3CL1 is secreted by neurons and acts on the CX3CR1 in microglia, our results revealed for the first time the role of neuron CTSS in neuron-microglia "crosstalk." Besides, we observed elevated CTSS expression in multiple brain regions of AD patients, including the hippocampus. Utilizing CTSS selective inhibitor, LY3000328, rescued AD-related pathological features in APP/PS1 mice. We further noticed that neuronal CTSS overexpression increased cathepsin B (CTSB) activity, but decreased cathepsin L (CTSL) activity in microglia. Overall, we provide evidence that CTSS can be used as an aging biomarker and plays regulatory roles through modulating neuroinflammation and recognition in aging and AD process.

ACE2 deficiency inhibits thoracic aortic dissection by enhancing SIRT3 mediated inhibition of inflammation and VSCMs phenotypic switch.

BACKGROUND: Thoracic aortic dissection (TAD) is an irreversible cardiovascular disorder with high mortality and morbidity. However, the molecular mechanisms remain elusive. Thus, identifying an effective therapeutic target to prevent TAD is especially critical. The purpose of this study is to elucidate the potential mechanism of inflammation and vascular smooth muscle cell (VSMCs) phenotypic switch in ß-aminopropionitrile fumarate (BAPN)-induced TAD. METHODS: A mouse model of TAD induced by BAPN and IL-1ß -stimulated HVSMCs in vivo and in vitro models, respectively. ACE2 Knockdown mice treated with BAPN or without, and the TAD mouse model was treated with or without AAV-ACE2. Transthoracic ultrasound was conducted for assessment the maximum internal diameter of the thoracic aorta arch. RNA sequencing analysis was performed to recapitulate transcriptome profile changes. Western blot were used to detect the expression of MMP2, MMP9, ACE2, SIRT3, OPN, SM22α and other inflammatory markers. The circulating levels of ACE2 was measured by ELISA assay. Histological changes of thoracic aorta tissues were assessed by H&E, EVG and IHC analysis. RESULTS: We found that circulating levels of and the protein levels of ACE2 were increased in the TAD mouse model and in patients with TAD. For further evidence, ACE2 deficiency decelerated the formation of TAD. However, overexpression of ACE2 aggravated BAPN-induced aortic injury and VSMCs phenotypic switch via lowered SIRT3 expression and elevated inflammatory cytokine expression. CONCLUSION: ACE2 deficiency prevented the development of TAD by inhibiting inflammation and VSMCs phenotypic switch in a SIRT3-dependent manner, suggesting that the ACE2/SIRT3 signaling pathway played a pivotal role in the pathological process of TAD and might be a potential therapeutical target.

Mechanical and Lattice Thermal Properties of Si-Ge Lateral Heterostructures.

Two-dimensional (2D) materials have drawn extensive attention due to their exceptional characteristics and potential uses in electronics and energy storage. This investigation employs simulations using molecular dynamics to examine the mechanical and thermal transport attributes of the 2D silicene-germanene (Si-Ge) lateral heterostructure. The pre-existing cracks of the Si-Ge lateral heterostructure are addressed with external strain. Then, the effect of vacancy defects and temperature on the mechanical attributes is also investigated. By manipulating temperature and incorporating vacancy defects and pre-fabricated cracks, the mechanical behaviors of the Si-Ge heterostructure can be significantly modulated. In order to investigate the heat transport performance of the Si-Ge lateral heterostructure, a non-equilibrium molecular dynamics approach is employed. The efficient phonon average free path is obtained as 136.09 nm and 194.34 nm, respectively, in the Si-Ge heterostructure with a zigzag and armchair interface. Our results present the design and application of thermal management devices based on the Si-Ge lateral heterostructure.

Explainable spatio-temporal graph evolution learning with applications to dynamic brain network analysis during development.

Modeling dynamic interactions among network components is crucial to uncovering the evolution mechanisms of complex networks. Recently, spatio-temporal graph learning methods have achieved noteworthy results in characterizing the dynamic changes of inter-node relations (INRs). However, challenges remain: The spatial neighborhood of an INR is underexploited, and the spatio-temporal dependencies in INRs' dynamic changes are overlooked, ignoring the influence of historical states and local information. In addition, the model's explainability has been understudied. To address these issues, we propose an explainable spatio-temporal graph evolution learning (ESTGEL) model to model the dynamic evolution of INRs. Specifically, an edge attention module is proposed to utilize the spatial neighborhood of an INR at multi-level, i.e., a hierarchy of nested subgraphs derived from decomposing the initial node-relation graph. Subsequently, a dynamic relation learning module is proposed to capture the spatio-temporal dependencies of INRs. The INRs are then used as adjacent information to improve the node representation, resulting in comprehensive delineation of dynamic evolution of the network. Finally, the approach is validated with real data on brain development study. Experimental results on dynamic brain networks analysis reveal that brain functional networks transition from dispersed to more convergent and modular structures throughout development. Significant changes are observed in the dynamic functional connectivity (dFC) associated with functions including emotional control, decision-making, and language processing.

Broadening Horizons: Exploring the Cathepsin Family as Therapeutic Targets for Alzheimer's Disease.

Alzheimer's disease (AD) is an intricate neurodegenerative disorder characterized by the accumulation of misfolded proteins, including beta-amyloid (Aß) and tau, leading to cognitive decline. Despite decades of research, the precise mechanisms underlying its onset and progression remain elusive. Cathepsins are a family of lysosomal enzymes that play vital roles in cellular processes, including protein degradation and regulation of immune responses. Emerging evidence suggests that cathepsins may be involved in AD pathogenesis. Cathepsins can influence the activation of microglia and astrocytes, the resident immune cells in the brain. However, cathepsin dysfunction may lead to the accumulation of misfolded proteins, notably Aß and tau. In addition, dysregulated cathepsin activity may induce an exaggerated immune response, promoting chronic inflammation and neuronal dysfunction in patients with AD. By unraveling the classification, functions, and roles of cathepsins in AD's pathogenesis, this review sheds light on their intricate involvement in this devastating disease. Targeting cathepsin activity could be a promising and novel approach for mitigating the pathological processes that contribute to AD, providing new avenues for its treatment and prevention.

Stacking engineering induced Z-scheme MoSSe/WSSe heterostructure for photocatalytic water splitting.

Stacking engineering is a popular method to tune the performance of two-dimensional materials for advanced applications. In this work, Jansu MoSSe and WSSe monolayers are constructed as a van der Waals (vdWs) heterostructure by different stacking configurations. Using first-principle calculations, all the relaxed stacking configurations of the MoSSe/WSSe heterostructure present semiconductor properties while the direct type-II band structure can be obtained. Importantly, the Z-scheme charge transfer mode also can be addressed by band alignment, which shows the MoSSe/WSSe heterostructure is an efficient potential photocatalyst for water splitting. In addition, the built-in electric field of the MoSSe/WSSe vdWs heterostructure can be enhanced by the S-Se interface due to further asymmetric structures, which also results in considerable charge transfer comparing with the MoSSe/WSSe vdWs heterostructure built by the S-S interface. Furthermore, the excellent optical performances of the MoSSe/WSSe heterostructure with different stacking configurations are obtained. Our results provide a theoretical guidance for the design and control of the two-dimensional heterostructure as photocatalysts through structural stacking.

Fabrication of hollow fiber composite membranes via opposite transmission reaction method for dye/salt separation.

The separation layer prepared by the conventional coating-crosslinking method is typically thick and prone to forming defective macropores, significantly affecting the water permeability and dye/salt separation performance of membranes. This work presented a novel method to prepare hollow fiber composite membranes for dye/salt separation based on the opposite transmission reaction of crosslinker. In this method, the macromolecule in situ reacted with a small-molecule crosslinker at the openings of membrane pore channels, forming a separation layer with discontinuous sheet-like and granular structure. Compared to the conventional forward coating-crosslinking method, the separation layer prepared by the opposite transmission reaction method exhibited an ultra-thin thickness of 29.1 nm. Consequently, the composite membrane exhibited a high water permeability of 72.7 L·m-2·h-1·bar-1, which was 2.3 times higher than that of conventional methods. Moreover, the prepared composite membrane presented a more uniformed pore structure, completely retaining the VBB (100%) with a low Na2SO4 rejection of 4.3%, demonstrating excellent dye/salt separation performance. Additionally, the prepared composite membrane exhibited superior anti-fouling properties compared to that prepared by the conventional method. Therefore, the opposite transmission reaction method proposed in this study held promising applications in the preparation of hollow fiber composite membranes for efficient dye/salt separation.

Electrical impedance tomography provides information of brain injury during total aortic arch replacement through its correlation with relative difference of neurological biomarkers.

Postoperative neurological dysfunction (PND) is one of the most common complications after a total aortic arch replacement (TAAR). Electrical impedance tomography (EIT) monitoring of cerebral hypoxia injury during TAAR is a promising technique for preventing the occurrence of PND. This study aimed to explore the feasibility of electrical impedance tomography (EIT) for warning of potential brain injury during total aortic arch replacement (TAAR) through building the correlation between EIT extracted parameters and variation of neurological biomarkers in serum. Patients with Stanford type A aortic dissection and requiring TAAR who were admitted between December 2021 to March 2022 were included. A 16-electrode EIT system was adopted to monitor each patient's cerebral impedance intraoperatively. Five parameters of EIT signals regarding to the hypothermic circulatory arrest (HCA) period were extracted. Meanwhile, concentration of four neurological biomarkers in serum were measured regarding to time before and right after surgery, 12 h, 24 h and 48 h after surgery. The correlation between EIT parameters and variation of serum biomarkers were analyzed. A total of 57 TAAR patients were recruited. The correlation between EIT parameters and variation of biomarkers were stronger for patients with postoperative neurological dysfunction (PND(+)) than those without postoperative neurological dysfunction (PND(-)) in general. Particularly, variation of S100B after surgery had significantly moderate correlation with two parameters regarding to the difference of impedance between left and right brain which were MRAIabs and TRAIabs (0.500 and 0.485 with p < 0.05, respectively). In addition, significantly strong correlations were seen between variation of S100B at 24 h and the difference of average resistivity value before and after HCA phase (ΔARVHCA), the slope of electrical impedance during HCA (kHCA) and MRAIabs (0.758, 0.758 and 0.743 with p < 0.05, respectively) for patients with abnormal S100B level before surgery. Strong correlations were seen between variation of TAU after surgery and ΔARVHCA, kHCA and the time integral of electrical impedance for half flow of perfusion (TARVHP) (0.770, 0.794 and 0.818 with p < 0.01, respectively) for patients with abnormal TAU level before surgery. Another two significantly moderate correlations were found between TRAIabs and variation of GFAP at 12 h and 24 h (0.521 and 0.521 with p < 0.05, respectively) for patients with a normal GFAP serum level before surgery. The correlations between EIT parameters and serum level of neurological biomarkers were significant in patients with PND, especially for MRAIabs and TRAIabs, indicating that EIT may become a powerful assistant for providing a real-time warning of brain injury during TAAR from physiological perspective and useful guidance for intensive care units.

Stepwise structural evolution toward robust carboranealkynyl-protected copper nanocluster catalysts for nitrate electroreduction.

Atomically precise metal nanoclusters (NCs) are emerging as idealized model catalysts for imprecise metal nanoparticles to unveil their structure-activity relationship. However, the directional synthesis of robust metal NCs with accessible catalytic active sites remains a great challenge. In this work, we achieved bulky carboranealkynyl-protected copper NCs, the monomer Cu13·3PF6 and nido-carboranealkynyl bridged dimer Cu26·4PF6, with fair stability as well as accessible open metal sites step by step through external ligand shell modification and metal-core evolution. Both Cu13·3PF6 and Cu26·4PF6 demonstrate remarkable catalytic activity and selectivity in electrocatalytic nitrate (NO3-) reduction to NH3 reaction, with the dimer Cu26·4PF6 displaying superior performance. The mechanism of this catalytic reaction was elucidated through theoretical computations in conjunction with in situ FTIR spectra. This study not only provides strategies for accessing desired copper NC catalysts but also establishes a platform to uncover the structure-activity relationship of copper NCs.

Chemoradiotherapy versus surgery after neoadjuvant chemoimmunotherapy in patients with stage III NSCLC: a real-world multicenter retrospective study.

PURPOSE: The optimal treatment after neoadjuvant chemoimmunotherapy for patients with stage III non-small cell lung cancer (NSCLC) is unclear. This study aimed at comparing the efficacy and safety of chemoradiotherapy and surgery after neoadjuvant chemoimmunotherapy in stage III NSCLC. MATERIALS AND METHODS: We conducted a real-world multicenter retrospective study on patients with stage III NSCLC who received surgery or chemoradiotherapy after neoadjuvant chemoimmunotherapy between October 2018 and December 2022. Progression-free survival (PFS) and overall survival (OS) were assessed from the initiation of neoadjuvant treatment and estimated by the Kaplan‒Meier method. Univariate and multivariate Cox regression models were used to examine potential prognostic factors. One-to-one propensity score matching (PSM) was used to further minimize confounding. RESULTS: A total of 239 eligible patients were enrolled, with 104 (43.5%) receiving surgery and 135 (56.5%) receiving CRT. After 1:1 PSM, 1- and 2-year PFS rates in patients receiving radical surgery (rSurgery group) vs. patients receiving definitive cCRT (dCCRT group) were 80.0% vs. 79.2% and 67.2% vs. 53.1%, respectively (P = 0.774). One- and 2-year OS rates were 97.5% vs. 97.4% and 87.3% vs. 89.9%, respectively (P = 0.558). Patients in the dCCRT group had a numerically lower incidence of distant metastases compared to those in the rSurgery group (42.9% vs. 70.6%, P = 0.119). The incidence of treatment-related adverse events was similar in both groups, except that the incidence of grade 3/4 hematological toxicity was significantly higher in the dCCRT group (30.0% vs. 10.0%, P = 0.025). CONCLUSION: Following neoadjuvant chemoimmunotherapy, definitive concurrent chemoradiotherapy may achieve noninferior outcomes to radical surgery in stage III NSCLC.

Proteostatic reactivation of the developmental transcription factor TBX3 drives BRAF/MAPK-mediated tumorigenesis.

MAPK pathway-driven tumorigenesis, often induced by BRAFV600E, relies on epithelial dedifferentiation. However, how lineage differentiation events are reprogrammed remains unexplored. Here, we demonstrate that proteostatic reactivation of developmental factor, TBX3, accounts for BRAF/MAPK-mediated dedifferentiation and tumorigenesis. During embryonic development, BRAF/MAPK upregulates USP15 to stabilize TBX3, which orchestrates organogenesis by restraining differentiation. The USP15-TBX3 axis is reactivated during tumorigenesis, and Usp15 knockout prohibits BRAFV600E-driven tumor development in a Tbx3-dependent manner. Deleting Tbx3 or Usp15 leads to tumor redifferentiation, which parallels their overdifferentiation tendency during development, exemplified by disrupted thyroid folliculogenesis and elevated differentiation factors such as Tpo, Nis, Tg. The clinical relevance is highlighted in that both USP15 and TBX3 highly correlates with BRAFV600E signature and poor tumor prognosis. Thus, USP15 stabilized TBX3 represents a critical proteostatic mechanism downstream of BRAF/MAPK-directed developmental homeostasis and pathological transformation, supporting that tumorigenesis largely relies on epithelial dedifferentiation achieved via embryonic regulatory program reinitiation.

Exploring the mechanism of action of the combination of cinnamon and motherwort in the treatment of benign prostatic hyperplasia: A network pharmacology study.

Cinnamon and motherwort are traditional Chinese medicines and are often combined to treat benign prostatic hyperplasia; however, the specific therapeutic mechanisms involved remain unclear. Therefore, in this study, we applied a network pharmacology approach to investigate the potential mechanisms of action of the drug pair cinnamon and motherwort (PCM) for the treatment of benign prostatic hyperplasia. Relevant targets for the use of PCM to treat benign prostatic hyperplasia were obtained through databases. Protein-protein interactions were then identified by the STRING database and core targets were screened. Enrichment analysis was conducted through the Metascape platform. Finally, molecular docking experiments were carried out to evaluate the affinity between the target proteins and ligands of PCM. We identified 22 active ingredients in PCM, 315 corresponding targets and 130 effective targets of PCM for the treatment of benign prostatic hyperplasia. These targets were related to the PI3K-Akt, MAPK, FoxO, TNF, and IL-17 signaling pathways. Network pharmacology was used to identify the effective components and action targets of PCM. We also identified potential mechanisms of action for PCM in the treatment of benign prostatic hyperplasia. Our results provide a foundation for expanding the clinical application of PCM and provide new ideas and directions for further research on the mechanisms of action of PCM and its components for the treatment of benign prostatic hyperplasia.

Gene expression profiling of peripheral blood in patients with steroid-induced osteonecrosis of the femoral head.

Aim: Steroid-induced osteonecrosis of the femoral head (SONFH) is a severe complication following glucocorticoid therapy. This study aimed to identify the differential mRNA expression and investigate the molecular mechanisms of SONFH. Materials & methods: RNA sequencing was performed in eight SONFH patients, five non-SONFH patients and five healthy individuals. Results: A total of 1555, 3997 and 5276 differentially expressed mRNAs existed between the following combinations: SONFH versus non-SONFH, SONFH versus healthy subjects and non-SONFH versus healthy subjects. Increased ISM1 expression might contribute to a high risk of SONFH through antiangiogenesis. Decreased FOLR3 expression might affect the metabolism of homocysteine, leading to avascular necrosis of the femoral head. KCNJ2, which plays a pivotal role in regulating bone development, was also deregulated. Conclusion: ISM1, FOLR3 and KCNJ2 might be related to the occurrence of SONFH.

[Box: see text].

Nanotexture and crystal phase regulation for synergistic enhancement in re-endothelialization on medical pure titanium surface.

Re-endothelialization has been recognized as a promising strategy to address the tissue hyperplasia and subsequent restenosis which are major complications associated with vascular implant/interventional titanium devices. However, the uncontrollable over-proliferation of smooth muscle cells (SMCs) limits the clinical application of numerous modified strategies. Herein, a novel modified strategy involving with a two-step anodic oxidation and annealing treatment was proposed to achieve rapid re-endothelialization function regulated by regular honeycomb nanotexture and specific anatase phase on the titanium surface. Theoretical calculation revealed that the presence of nanotexture reduced the polar component of surface energy, while the generation of anatase significantly enhanced the polar component and total surface energy. Meanwhile, the modified surface with regular nanotexture and anatase phase produced positive effect on the expression of CD31, VE-Cadherin and down-regulated α-SMA proteins expression, indicating excellent capacity of pro-endothelial regeneration and inhibition of SMCs proliferation and migration. One-month in vivo implantation in rabbit carotid arteries further confirmed that modified tube implant surface effectively accelerated confluent endothelial monolayer formation and promoted native-like endothelium tissue regeneration. By contrast, original titanium tube implant induced a disorganized tissue proliferation in the lumen with a high risk of restenosis. Collectively, this study opens us an alternative route to achieve the function that selectively promotes endothelial cells (ECs) growth and suppresses SMCs on the medical titanium surface, which has a great potential in facilitating re-endothelialization on the surface of blood-contacting titanium implant.

Administration of USP7 inhibitor p22077 alleviates Angiotensin II (Ang II)-induced atrial fibrillation in Mice.

Atrial fibrillation (AF), the most common cardiac arrhythmia, is an important contributor to mortality and morbidity. Ubquitin-specific protease 7 (USP7), one of the most abundant ubiquitin-specific proteases (USP), participated in many cellular events, such as cell proliferation, apoptosis, and tumourigenesis. However, its role in AF remains unknown. Here, the mice were treated with Ang II infusion to induce the AF model. Echocardiography was used to measure the atrial diameter. Electrical stimulation was programmed to measure the induction and duration of AF. The changes in atrial remodeling were measured using routine histologic analysis. Here, a significant increase in USP7 expression was observed in Ang II-stimulated atrial cardiomyocytes and atrial tissues, as well as in atrial tissues from patients with AF. The administration of p22077, the inhibitor of USP7, attenuated Ang II-induced inducibility and duration of AF, atrial dilatation, connexin dysfunction, atrial fibrosis, atrial inflammation, and atrial oxidase stress, and then inhibited the progression of AF. Mechanistically, the administration of p22077 alleviated Ang II-induced activation of TGF-ß/Smad2, NF-κB/NLRP3, NADPH oxidases (NOX2 and NOX4) signals, the up-regulation of CX43, ox-CaMKII, CaMKII, Kir2.1, and down-regulation of SERCA2a. Together, this study, for the first time, suggests that USP7 is a critical driver of AF and revealing USP7 may present a new target for atrial fibrillation therapeutic strategies.

Integrative analysis reveals chemokines CCL2 and CXCL5 mediated shear stress-induced aortic dissection formation.

Background: Aortic dissection (AD) is a critical emergency in cardiovascular disease. AD occurs only in specific sites of the aorta, and the variation of shear stress in different aortic segments is a possible cause not reported. This study investigated the key molecules involved in shear stress-induced AD through quantitative bioinformatic analysis of a public RNA sequencing database and clinical tissue sample validation. Methods: Gene expression data from the GSE153434, GSE147026, and GSE52093 datasets were downloaded from the Gene Expression Omnibus. Next, differently expressed genes (DEGs) in each dataset were identified and integrated to identify common AD DEGs. STRING, Cytoscape, and MCODE were used to identify hub genes and crucial clustering modules, and Connectivity Map (CMap) was used to identify positive and negative agents. The same procedure was performed for the GSE160611 dataset to obtain shear stress-induced human aortic endothelial cell (HAEC) DEGs. After the integration of these two DEGs sets to identify shear stress-associated hub DEGs in AD, Gene Ontology Enrichment Analysis was performed. The common chemokine receptors and ligands in AD were identified by analyzing AD's three RNA sequencing datasets. Their origin was verified by analyzing AD single-cell sequencing data and validated by immunoblotting and immunofluorescence. Results: We identified 100 down-regulated and 50 up-regulated AD common DEGs. Enrichment results showed that common DEGs were closely related to blood vessel morphogenesis, muscle structure development, muscle tissue development, and chemotaxis. Among those DEGs, MYC, CCL2, and SPP1 are the three molecules with the highest degree. A crucial cluster of 15 genes was identified using MCODE, which contained inflammation-related genes with elevated expression and muscle cell-related genes with decreased expression, and CCL2 is central to immune-related genes. CMap confirmed MEK inhibitors and ALK inhibitors as possible therapeutic agents for AD. Moreover, 366 shear stress-associated DEGs in HAEC were identified in the GSE160611 dataset. After taking the intersection, we identified five shear stress-associated hub DEGs in AD (ANGPTL4, SNAI2, CCL2, GADD45B, and PROM1), and the enrichment analysis indicated they were related to the endothelial cell apoptotic process. Chemokine CCL2 was the molecule with a high degree in both DEG sets. Besides CCL2, CXCL5 was the only chemokine ligand differentially expressed in the three datasets. Additionally, immunoblotting confirmed the increased expression of CCL2 and CXCL5 in clinical tissue samples. Further research at the single-cell level revealed that CCL2 has multiple origins, and CXCL5 is macrophage-derived. Conclusion: Through integrative analysis, we identified core common AD DEGs and possible therapeutic agents based on these DEGs. We elucidated that the chemokine CCL2 and CXCL5-mediated "Endothelial-Monocyte-Neutrophil" axis may contribute to the development of shear stress-induced AD. These findings provide possible therapeutic targets for the prevention and treatment of AD.