Non-insulin-based insulin resistance indexes in predicting atrial fibrillation recurrence following ablation: a retrospective study.

BACKGROUND: Insulin resistance (IR) is involved in the pathophysiological processes of arrhythmias. Increasing evidence suggests triglyceride and glucose (TyG) index, metabolic score for insulin resistance (METS-IR), triglyceride glucose-body mass index (TyG-BMI), and triglyceride to high-density lipoprotein cholesterol (TG/HDL-C) ratio are simple and reliable surrogates for IR. Although they have been associated with atrial fibrillation (AF), evidence supporting this is limited. Here, this is the first study to investigate the association between TyG-BMI index and AF recurrence following radiofrequency catheter ablation (RFCA). The performance of the four non-insulin-based IR indexes in predicting AF recurrence after ablation was explored. METHODS: A total of 2242 AF patients who underwent a de novo RFCA between June 2018 to January 2022 at two hospitals in China were included in this retrospective study. The predictive values of IR indexes for AF recurrence after ablation were assessed. RESULTS: During 1-year follow-up, 31.7% of patients experienced AF recurrence. The multivariable analysis revealed that TyG index, METS-IR, and TyG-BMI index were independent risk factors for AF recurrence. Restricted cubic spline analysis revealed a connection between METS-IR, TyG-BMI index, and AF recurrence (P < 0.001). Furthermore, incorporating the METS-IR or TyG-BMI index to the basic risk model with fully adjusted factors considerably enhanced the forecast of AF recurrence, as demonstrated by the C-statistic, continuous net reclassification improvement, and integrated discrimination improvement. CONCLUSIONS: TyG index, METS-IR, and TyG-BMI index were independently associated with AF recurrence following ablation. Among the four non-insulin-based IR indexes, TyG-BMI had the highest predictive value, followed by METS-IR.

Blood-brain barrier dysfunction mediated by the EZH2-Claudin-5 axis drives stress-induced TNF-α infiltration and depression-like behaviors.

Growing evidence suggests that neurovascular dysfunction characterized by blood-brain barrier (BBB) breakdown underlies the development of psychiatric disorders, such as major depressive disorder (MDD). Tight junction (TJ) proteins are critical modulators of homeostasis and BBB integrity. TJ protein Claudin-5 is the most dominant BBB component and is downregulated in numerous depression models; however, the underlying mechanisms remain elusive. Here, we demonstrate a molecular basis of BBB breakdown that links stress and depression. We implemented an animal model of depression, chronic unpredictable mild stress (CUMS) in male C57BL/6 mice, and showed that hippocampal BBB breakdown was closely associated with stress vulnerability. Concomitantly, we found that dysregulated Cldn5 level coupled with repression of the histone methylation signature at its promoter contributed to stress-induced BBB dysfunction and depression. Moreover, histone methyltransferase enhancer of zeste homolog 2 (EZH2) knockdown improved Cldn5 expression and alleviated depression-like behaviors by suppressing the tri-methylation of lysine 27 on histone 3 (H3K27me3) in chronically stressed mice. Furthermore, the stress-induced excessive transfer of peripheral cytokine tumor necrosis factor-α (TNF-α) into the hippocampus was prevented by Claudin-5 overexpression and EZH2 knockdown. Interestingly, antidepressant treatment could inhibit H3K27me3 deposition at the Cldn5 promoter, reversing the loss of the encoded protein and BBB damage. Considered together, these findings reveal the importance of the hippocampal EZH2-Claudin-5 axis in regulating neurovascular function and MDD development, providing potential therapeutic targets for this psychiatric illness.

ROR1-AS1 might promote in vivo and in vitro proliferation and invasion of cholangiocarcinoma cells.

Long non-coding RNAs (lncRNAs) play important roles in many pathophysiological processes, including cancer progression. Namely, lncRNA Receptor-tyrosine-kinase-like orphan receptor-1 antisense 1 (ROR1-AS1) is crucial for cancer occurrence and progression in organs such as the liver or bladder. However, its expression and role in cholangiocarcinoma (CCA) have not been thoroughly explored.Firstly, we assessed cell viability, proliferation, invasion, and migration using three cell lines (HuCCT-1, QBC399, and RBE) to explore the biological characteristics of ROR1-AS1 in CCA. Secondly, to determine the in vivo effect of ROR1-AS1 on tumor growth, ROR1-AS1 knockdown (KD) HuCCT-1 cells were subcutaneously injected into nude mice to evaluate tumor growth. Finally, we conducted a bioinformatic analysis to confirm the role of ROR1-AS1 in the prognosis and immunity of CCA.In this study, we found that lncRNA ROR1-AS1 was increased in CCA samples and patients with higher ROR1-AS1 expression had a shorter overall survival period. siRNA-mediated KD of ROR1-AS1 significantly reduced cell proliferation and inhibited the migration of CCA cells. In addition, ROR1-AS1 KD HuCCT-1 cells injected into nude mice grew slower than normal CCA cells.In summary, our results show that ROR1-AS1 can promote CCA progression and might serve as a new target for diagnosis and treatment of CCA.

Norepinephrine promotes neuronal apoptosis of hippocampal HT22 cells by up-regulating the expression of long non-coding RNA MALAT1.

Stress is ever present in our modern, performance-oriented and demanding society, which causes adverse stress reactions of the body and affects health seriously. Chronic stress has been recognized as a significant risk factor leading to cognitive impairment, but the underlying mechanism is far from fully understood. Norepinephrine (NE), a pivotal stress-induced hormone, has been found to induce cell apoptosis. However, the function and the key downstream mediator of NE on the regulation of hippocampal neurons still need further exploration. In this study, we explored the role of NE in neuronal apoptosis and its association with MALAT1. Flow cytometry assay and automated western bot assay were carried out to evaluate the cell apoptosis. The data showed that the rate of apoptosis rate and the levels of apoptotic proteins (cleaved-Caspase3 and cleaved-PARP) were significantly increased in HT22 cells after a high dose of NE treatment, suggesting a facilitative role of NE on hippocampal neuronal apoptosis. Besides, a high level of NE up-regulated the expression of MALAT1 in HT22 cells. Then, a lentivirus expressing MALAT1 shRNA was constructed to investigate the role of MALAT1 in cell apoptosis and the results revealed that MALAT1 depletion decreased the cell apoptosis. Moreover, the knockdown of MALAT1 abolished the discrepancy in apoptosis between NE-treated cells and control cells. In conclusion, a high level of the stress-induced hormone NE promoted apoptosis of hippocampal neurons by elevating the expression of MALAT1. Our findings provide new experimental data supporting the epigenetic mechanisms in the regulation of stress response and may provide a potential therapeutic target for stress-related cognition dysfunction.

COL17A1 facilitates tumor growth and predicts poor prognosis in pancreatic cancer.

OBJECTIVE: This study aimed to determine the role of COL17A1 in tumor progression and predict the prognosis of pancreatic cancer (PC). METHODS: RNA-seq data from The Cancer Genome Atlas and Genotype-Tissue Expression were analyzed using bioinformatics methods. "Limma" package was used to screen differentially expressed genes (DEGs). Prognostic-associated data were further analyzed using univariate Cox regression and verified using the GSE28375 and GSE62452 datasets. Protein-protein interaction (PPI) network analysis was integrated to screen for hub genes. In vitro quantitative real-time PCR (qPCR) and western blotting were used to detect gene expression. The functional attributes of PC cells were verified by wound healing assays, migration and invasion assays, Cell Counting Kit 8 (CCK8), and 5-ethynyl-2'-deoxyuridine (EdU) assay. RESULTS: On analyzing PC data, 4637 DEGs were identified. Of these, 2399 genes were upregulated and 2238 were downregulated. Through PPI network analysis, we identified that COL17A1 expression was highly correlated with poor prognosis of patients with PC. Functional attribute assays in the in vitro study showed that COL17A1 knockdown inhibited PC cell proliferation, migration, and invasion. CONCLUSIONS: According to our results, COL17A1 promotes PC cell proliferation, migration, and invasion mediated by the epithelial-mesenchymal transition (EMT) pathway. Thus, COL17A1 could be used as a prognostic marker in PC.

Regulating Sodium Deposition through Gradiently-Graphitized Framework for Dendrite-Free Na Metal Anode.

Na metal anode (NMA) is one of the most promising candidate materials for next-generation low-cost sodium metal batteries. However, the preferred deposition of Na metal at the anode/separator interface increases the risk of dendrite penetration of the separator, consequently, reduces safety and life of batteries with NMA. In this study, a Na deposition-regulating strategy is shown by designing a gradiently graphitized 3D carbon fiber (CF) framework as host (grad-CF), whereby Na is guided to deposit preferentially at the bottom of the anode, safely away from the separator. The obtained Na anode significantly reduces the probability of dendrite-induced short circuits. The grad-CF host enables NMA stable cycling at a high current density of 6 mA cm-2 . When the Na@grad-CF is applied as anode in full cells pared with Na3 V2 (PO4 )3 (NVP) cathode, it exhibits a reversible capacity of 73 mA h g-1 after 500 cycles with a low decay rate of 0.13%.

Bacteria-derived outer membrane vesicles engineered with over-expressed pre-miRNA as delivery nanocarriers for cancer therapy.

Outer membrane vesicles (OMVs) of Escherichia coli as nanoscale spherical vesicles have been recently used in cancer therapy as drug carriers. However, most of them need complicated methods to load cargos. Herein, we proposed an inexpensive and potentially mass-produced method for the preparation of OMV engineered with over-expressed pre-miRNA. In this work, we found that OMV can be released and inherit over-expressed tRNALys-pre-miRNA from mother E. coli that directly used for the tumor therapy. The eukaryotic cells infection experiments revealed that the over-expressed pre-miRNA inside OMV could be released and processed into mature miRNAs with the aid of the camouflage of "tRNA scaffold". Moreover, the group in vivo treated with targeted OMVtRNA-pre-miR-126 obviously inhibited the expression of target oncogenic CXCR4, and significantly restrain the proliferation of breast cancer tissues. Together, these findings indicated that the OMV-based platform is a versatile and powerful strategy for personalized tumor therapy directly and specificity.

Visual naked-eye detection of SARS-CoV-2 RNA based on covalent organic framework capsules.

The ongoing outbreak of coronavirus disease 2019 (COVID-19) caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has highlighted that new diagnosis technologies are crucial for controlling the spread of the disease. Especially in the resources-limit region, conveniently operated detection methods such as "naked-eye" detection are urgently required that no instrument is needed. Herein, we have designed a novel and facile strategy to fabricate covalent organic framework (COF) capsules, which can be utilized to establish a new colorimetric assay for naked-eye detection of SARS-CoV-2 RNA. Specifically, we employ the digestible ZIF-90 as the sacrificial template to prepare the hollow COF capsules for horseradish peroxidase (HRP) encapsulation. The fabricated COF capsules can provide an appropriate microenvironment for the enzyme molecules, which may improve the conformational freedom of enzymes, enhance the mass transfer, and endow the enzyme with high environmental resistance. With such design, the proposed assay exhibits outstanding analytical performance for the detection of SARS-CoV-2 RNA in the linear range from 5 pM to 50 nM with a detection limit of 0.28 pM which can go parallel to qTR-PCR analysis. Our method also possesses excellent selectivity and reproducibility. Moreover, this method can also be served to analyze the clinical samples, and can successfully differentiate COVID-19 patients from healthy people, suggesting the promising potential in clinical diagnosis.

Electrochemical Deposition of Cu Metal-Organic Framework Films for the Dual Analysis of Pathogens.

Metal-organic framework (MOF) thin films with flexible nature and prominent qualities have opened doors to new technological applications in different fields. Herein, we propose an electrochemical biosensor for the dual detection of Staphylococcus aureus based on the electrodeposition of Cu metal-organic framework (Cu-MOF) thin films. The promising sensing layer with features of good electronic conductivity and enhanced electron-transfer property can not only identify S. aureus through specific micrococcal nucleases in the supernatant but also detect the pathogen directly via aptamer recognition. The dual analysis design ensures the accuracy of this method for S. aureus detection in the range of 7-7 × 106 cfu/mL with the limits of detection of 1.9 and 5.2 cfu/mL. Moreover, the analytical method validation confirmed that the biosensor could efficiently work in complex biological samples, showing good selectivity and specificity and great potential for clinical diagnosis. More importantly, the current proposed strategy is simple and easy to implement without the need for extra signaling elements, which is convenient for timely clinical detection.

Solid-Solution-Based Metal Alloy Phase for Highly Reversible Lithium Metal Anode.

Lithium metal batteries are vital devices for high-energy-density energy storage, but the Li metal anode is highly reactive with electrolyte and forms uncontrolled dendrite that can cause undesirable parasitic reactions and, thus, poor cycling stability and raise safety concerns. Despite remarkable progress to partially solve these issues, the Li metal still plates at the electrode/electrolyte interface where the parasitic reactions and dendrite formation invariably occur. Here, we demonstrate the inward-growth plating of Li atoms into a metal foil of thickness of tens of micrometers while avoiding surface deposition, which is driven by the reversible solid-solution-based alloy phase change. Lithiation of the solid-solution alloy phase allows the freshly generated Li atoms at the surface to sink into the metal foil, while the reversible alloy phase change is companied by the dealloying reaction during delithiation, which extracts Li atoms from inside of the metal foil. The yielded dendrite free Li anode produces an enhanced Coulombic efficiency of 99.5 ± 0.2% with a reversible capacity of 1660 mA h g-1 (3.3 mA h cm-2).

Correction to: Exosome-transmitted miR-128-3p increase chemosensitivity of oxaliplatin-resistant colorectal cancer.

An amendment to this paper has been published and can be accessed via the original article.

Direct Analysis of Rare Circulating Tumor Cells in Whole Blood Based on Their Controlled Capture and Release on Electrode Surface.

The development of a simple, sensitive, and effective method for the analysis of circulating tumor cells (CTCs) is essential for cancer diagnosis and metastasis prediction. In this work, we have proposed an enzyme-free electrochemical method for specific capture, sensitive quantification, and efficient release of CTCs. To achieve this, the specific interaction between CTCs and the corresponding aptamer designed to be located in the identification probe (IP) will unfold the hairpin structure of IP. Consequently, IP will initiate a hybridization reaction to produce a duplex, which will further trigger the hybridization chain reaction (HCR) process to form a composite product of CTCs and double-stranded DNA polymers. Therefore, a significantly amplified signal readout can be obtained. Moreover, the composite product can be brought to the electrode surface by tetrahedral DNA nanostructures to achieve the purpose of capturing and quantifying CTCs. More significantly, these captured CTCs can be controlled released without compromising cell viability via a simple strand displacement reaction. Taking the breast cancer cell MCF-7 as a representative, the newly developed approach led to an ultralow detection limit of 3 cells mL-1, which is superior to several studies previously reported. The current method has also been demonstrated to analyze CTCs in human whole blood and hence revealed a great potential in the future.

An Electrochemical Biosensor Designed by Using Zr-Based Metal-Organic Frameworks for the Detection of Glioblastoma-Derived Exosomes with Practical Application.

Glioblastoma (GBM) is one of the most fatal tumors in the brain, and its early diagnosis remains technically challenging due to the complex repertoires of oncogenic alterations and blood-brain barrier (BBB). GBM-derived specific exosomes can cross the BBB and circulate in body fluids, so they can be noninvasive biomarkers for the early diagnosis of GBM. Herein, we propose a sensitive and label-free electrochemical biosensor designed by using Zr-based metal-organic frameworks (Zr-MOFs) for the detection of GBM-derived exosomes with practical application. In the design, a peptide ligand can specifically bind with human epidermal growth factor receptor (EGFR) and EGFR variant (v) III mutation (EGFRvIII), which are overexpressed on the GBM-derived exosomes. Meanwhile, Zr-MOFs encapsulated with methylene blue can absorb on the surface of the exosomes due to the interaction between Zr4+ and the intrinsic phosphate groups outside of exosomes. Consequently, the concentration of exosomes can be directly quantified by monitoring the electroactive molecules inside MOFs, ranging from 9.5 × 103 to 1.9 × 107 particles/µL with the detection of limit of 7.83 × 103 particles/µL. Furthermore, this proposed biosensor can distinguish GBM patients from healthy groups, demonstrating the great prospect for early clinical diagnosis.

Exosome-transmitted miR-128-3p increase chemosensitivity of oxaliplatin-resistant colorectal cancer.

BACKGROUND: Oxaliplatin resistance is a major challenge for treatment of advanced colorectal cancer (CRC). Both acquisition of epithelial-mesenchymal transition (EMT) and suppressed drug accumulation in cancer cells contributes to development of oxaliplatin resistance. Aberrant expression of small noncoding RNA, miR-128-3p, has been shown to be a key regulator in tumorigenesis and cancer development. However, its roles in the progression of CRC and oxaliplatin-resistance are largely unknown. METHODS: Oxaliplatin-resistant CRC and normal intestinal FHC cells were transfected with a miR-128-3p expression lentivirus. After transfection, FHC-derived exosomes were isolated and co-cultured with CRC cells. miR-128-3p expression in resistant CRC cells, FHC cells, and exosomes was quantified by quantitative real-time PCR (RT-qPCR). The mRNA and protein levels of miR-128-3p target genes in resistant CRC cells were quantified by RT-qPCR and western blot, respectively. The effects of miR-128-3p on CRC cell viability, apoptosis, EMT, motility and drug efflux were evaluated by CCK8, flow cytometry, Transwell and wound healing assays, immunofluorescence, and atomic absorption spectrophotometry. Xenograft models were used to determine whether miR-128-3p loaded exosomes can re-sensitize CRC cells to oxaliplatin in vivo. RESULTS: In our established stable oxaliplatin-resistant CRC cell lines, in vitro and vivo studies revealed miR-128-3p suppressed EMT and increased intracellular oxaliplatin accumulation. Importantly, our results indicated that lower miR-128-3p expression was associated with poor oxaliplatin response in advanced human CRC patients. Moreover, data showed that miR-128-3p-transfected FHC cells effectively packaged miR-128-3p into secreted exosomes and mediated miR-128-3p delivery to oxaliplatin-resistant cells, improving oxaliplatin response in CRC cells both in vitro and in vivo. In addition, miR-128-3p overexpression up-regulated E-cadherin levels and inhibited oxaliplatin-induced EMT by suppressing Bmi1 expression in resistant cells. Meanwhile, it also decreased oxaliplatin efflux through suppressed expression of the drug transporter MRP5. CONCLUSION: Our results demonstrate that miR-128-3p delivery via exosomes represents a novel strategy enhancing chemosensitivity in CRC through negative regulation of Bmi1 and MRP5. Moreover, miR-128-3p may be a promising diagnostic and prognostic marker for oxaliplatin-based chemotherapy.

Sensor Array Fabricated with Nanoscale Metal-Organic Frameworks for the Histopathological Examination of Colon Cancer.

There is still no good method for the diagnosis of colon cancer, so in this work we have presented a nanoscale metal-organic framework (NMOF)-based sensor array to effectively identify normal and pathological tissues. Moreover, this method can enable a rapid and accurate histopathological examination of colon cancer with simple and easy operation. The method is designed by making use of the different interactions between the overall intracellular proteome signatures of colonic tissues and three structurally stable NMOFs featuring characteristic surface chemistry. We have demonstrated that this sensor array can exhibit excellent performance to detect unknown specimens from low-dose tissue samples with clinically relevant specificity and accuracy. Collectively, the versatile detector array based on NMOFs offers a highly discerning and adaptive alternative for identifying colon cancer tissues, which exhibits wide-ranging prospects in medical diagnosis.

Combined Orthodontic-Surgical Sequential Treatment of Cleidocranial Dysplasia: A Case Report With 7-Year Follow-up and Review of the Literature.

Cleidocranial dysplasia (CCD) is a rare hereditary disorder characterized by skeletal malformations and dental abnormalities. Mutations of the transcription factor RUNX2 are responsible for the pathogenesis of CCD. We present a case of a 10-year-old boy with CCD, presenting with hypoplastic clavicles, delayed closure of the fontanelles, retarded exfoliation of the deciduous teeth, retarded eruption of the permanent teeth, and multiple impacted supernumerary teeth. Based on the clinical and radiographic examination results showing abnormalities of the bones and teeth, a diagnosis was reached easily, but it was difficult to achieve a complete curative effect. We carried out a highly organized schedule of treatment, including extraction of the deciduous and supernumerary teeth, partial resection of alveolar bone, distraction of impacted teeth, and orthodontic surgery. After 7-year follow-up, the patient has achieved acceptable occlusion and midfacial appearance. The main objectives of this study were to present the diagnosis and treatment of CCD and to emphasize the benefits of combined orthodontic-surgical sequential treatment.

Finite-Time Attitude Stabilization Adaptive Control for Spacecraft with Actuator Dynamics.

For the attitude stabilization of spacecraft with actuator dynamics, this paper proposed a finite-time control law. Firstly, the dynamic property of the actuator is analyzed by an example. Then, a basic control law is derived to achieve the finite-time stability using the double fast terminal sliding mode manifold. When there is no prior knowledge of time matrix of the actuator, an adaptive law is proposed to estimate the unknown information. An adaptive control law is derived to guarantee the finite-time convergence of the attitude, and a Lyapunov-based analysis is provided. Finally, simulations are carried out to demonstrate the effectiveness of the proposed control law to the attitude stabilization with the actuator dynamics. The results show that the high-precision attitude control performance can be achieved by the proposed scheme.

A Novel Autonomous Celestial Integrated Navigation for Deep Space Exploration Based on Angle and Stellar Spectra Shift Velocity Measurement.

Traditional autonomous celestial navigation usually uses astronomical angle as measurement, which is a function of spacecraft's position and can't resolve the spacecraft's velocity directly. To solve this problem, velocity measurement by stellar spectra shift is proposed in this paper. The autonomous celestial integrated navigation method is derived by combining velocity measurement with angle measurement, which can ensure the long-term high accuracy, real-time and continuous navigation performance for deep space exploration (DSE) missions. The observability of the integrated navigation system is analyzed. Moreover, the design of doppler navigator and hardware in-the-loop simulation system are described. Finally, a simulation example is employed to demonstration the feasibility and effectiveness of the proposed navigation algorithm.

Extending the linker region increases the activity of the Bacillus subtilis cellulase CelI15.

OBJECTIVES: To investigate the effect of the linker region (LR) on the enzymatic activity, stability, and flexibility of Bacillus subtilis cellulase CelI15, six mutants were constructed that contained increasing numbers of the LR. RESULTS: The CelI15 mutant with three copies of the LR (approx. 57 amino acids) showed the highest activity, which was almost 20 % greater than that of wild type CelI15. The stability of the mutant enzymes increased as the copy number of the LR decreased. However, the substrate affinity of the mutant enzymes increased as the LR copy number increased, and the mutant with four copies of the LR exhibited the highest substrate affinity. Additionally, the flexibility of the CelI15 mutants increased as the LR copy number increased from zero to four copies, although it decreased sharply for the mutant with five copies of the LR. CONCLUSION: The activity of CelI15 was increased by increasing the LR copy number, which could be a potential way to improve its enzymatic properties.