Integrated Manipulation and Addressing of Spin Defect in Diamond.

Scalable and addressable integrated manipulation of qubits is crucial for practical quantum information applications. Different waveguides have been used to transport the optical and electrical driving pulses, which are usually required for qubit manipulation. However, the separated multifields may limit the compactness and efficiency of manipulation and introduce unwanted perturbation. Here, we develop a tapered fiber-nanowire-electrode hybrid structure to realize integrated optical and microwave manipulation of solid-state spins at nanoscale. Visible light and microwave driving pulses are simultaneously transported and concentrated along an Ag nanowire. Studied with spin defects in diamond, the results show that the different driving fields are aligned with high accuracy. The spatially selective spin manipulation is realized. And the frequency-scanning optically detected magnetic resonance (ODMR) of spin qubits is measured, illustrating the potential for portable quantum sensing. Our work provides a new scheme for developing compact, miniaturized quantum sensors and quantum information processing devices.

Trichinella spiralis Paramyosin Alleviates Collagen-Induced Arthritis in Mice by Modulating CD4+ T Cell Differentiation.

Rheumatoid arthritis (RA) is an autoimmune disease that significantly impacts quality of life by disrupting CD4+ T cell immune homeostasis. The identification of a low-side-effect drug for RA treatment is urgently needed. Our previous study suggests that Trichinella spiralis paramyosin (Ts-Pmy) has immunomodulatory effects, but its potential effect on CD4+ T cell response in RA remains unclear. In this study, we used a murine model to investigate the role of rTs-Pmy in regulating CD4+ T cell differentiation in collagen-induced arthritis (CIA). Additionally, we assessed the impact of rTs-Pmy on CD4+ T cell differentiation towards the Th1 and Th17 phenotypes, which are associated with inflammatory responses in arthritis, using in vitro assays. The results demonstrated that rTs-Pmy administration reduced arthritis severity by inhibiting Th1 and Th17 response while enhancing Treg response. Prophylactic administration of Ts-Pmy showed superior efficacy on CIA compared to therapeutic administration. Furthermore, in vitro assays demonstrated that rTs-Pmy could inhibit the differentiation of CD4+ T cells into Th1 and Th17 while inducing the production of Tregs, suggesting a potential mechanism underlying its therapeutic effects. This study suggests that Ts-Pmy may ameliorate CIA by restoring the immune balance of CD4+ T cells and provides new insights into the mechanism through which helminth-derived proteins exert their effects on autoimmune diseases.

Conditional knockout of ITGB4 in bronchial epithelial cells directs bronchopulmonary dysplasia.

Neonatal respiratory system disease is closely associated with embryonic lung development. Our group found that integrin ß4 (ITGB4) is downregulated in the airway epithelium of asthma patients. Asthma is the most common chronic respiratory illness in childhood. Therefore, we suspect whether the deletion of ITGB4 would affect fetal lung development. In this study, we characterized the role of ITGB4 deficiency in bronchopulmonary dysplasia (BPD). ITGB4 was conditionally knocked out in CCSP-rtTA, Tet-O-Cre and ITGB4f/f triple transgenic mice. Lung tissues at different developmental stages were collected for experimental detection and transcriptome sequencing. The effects of ITGB4 deficiency on lung branching morphogenesis were observed by fetal mouse lung explant culture. Deleting ITGB4 from the airway epithelial cells results in enlargement of alveolar airspaces, inhibition of branching, the abnormal structure of epithelium cells and the impairment of cilia growth during lung development. Scanning electron microscopy showed that the airway epithelial cilia of the ß4ccsp.cre group appear to be sparse, shortened and lodging. Lung-development-relevant factors such as SftpC and SOX2 significantly decreased both mRNA and protein levels. KEGG pathway analysis indicated that multiple ontogenesis-regulating-relevant pathways converge to FAK. Accordingly, ITGB4 deletion decreased phospho-FAK, phospho-GSK3ß and SOX2 levels, and the correspondingly contrary consequence was detected after treatment with GSK3ß agonist (wortmannin). Airway branching defect of ß4ccsp.cre mice lung explants was also partly recovered after wortmannin treatment. Airway epithelial-specific deletion of ITGB4 contributes to lung developmental defect, which could be achieved through the FAK/GSK3ß/SOX2 signal pathway.

Apolipoprotein A-1 protected hepatic ischaemia-reperfusion injury through suppressing macrophage pyroptosis via TLR4-NF-κB pathway.

BACKGROUND AND AIMS: Apolipoprotein A-1 (ApoA-1), the major apolipoprotein of high-density lipoprotein, plays anti-atherogenic role in cardiovascular diseases and exerts anti-inflammation effect in various inflammatory and infectious diseases. However, the role and mechanism of ApoA-1 in hepatic ischaemia-reperfusion (I/R) injury is unknown. METHODS: In this study, we measured ApoA-1 expression in human liver grafts after transplantation. Mice partial hepatic I/R injury model was made in ApoA-1 knockout mice, ApoA-1 mimetic peptide D-4F treatment mice and corresponding control mice to examine the effect of ApoA-1 on liver damage, inflammation response and cell death. Primary hepatocytes and macrophages were isolated for in vitro study. RESULTS: The results showed that ApoA-1 expression was down-regulated in human liver grafts after transplantation and mice livers subjected to hepatic I/R injury. ApoA-1 deficiency aggravated liver damage and inflammation response induced by hepatic I/R injury. Interestingly, we found that ApoA-1 deficiency increased pyroptosis instead of apoptosis during acute phase of hepatic I/R injury, which mainly occurred in macrophages rather than hepatocytes. The inhibition of pyroptosis compensated for the adverse impact of ApoA-1 deficiency. Furthermore, the up-regulated pyroptosis process was testified to be mediated by ApoA-1 through TLR4-NF-κB pathway and TLR4 inhibition significantly improved hepatic I/R injury. In addition, we confirmed that D-4F ameliorated hepatic I/R injury. CONCLUSIONS: Our study has identified the protective role of ApoA-1 in hepatic I/R injury through inhibiting pyroptosis in macrophages via TLR4-NF-κB pathway. The effect of ApoA-1 may provide a novel therapeutic approach for hepatic I/R injury.

Merging Visible Light Photocatalysis and P(III)-Directed C-H Activation by a Single Catalyst: Modular Assembly of P-Alkyne Hybrid Ligands.

Metal-catalyzed C-H activation strategies provide an efficient approach for synthesis by minimizing atom, step, and redox economy. Developing milder, greener, and more effective protocols for these strategies is always highly desirable to the scientific community. In this study, the utilization of a single rhodium complex enabled the visible-light-induced late-stage C-H activation of biaryl-type phosphines with alkynyl bromides, employing inherent phosphorus atoms as directing groups. This chemistry combines P(III)-directed C-H activation with visible light photocatalysis, under exogenous photosensitizer-free conditions, offering a unique platform for ligand design and preparation. Furthermore, this study also explores the asymmetric catalysis and coordination chemistry of the resulting P-alkyne hybrid ligands with specific transition metals. Experimental results and density functional theory calculations demonstrate the mechanistic intricacies of this transformation.

CTNNAL1 participates in the regulation of mucus overproduction in HDM-induced asthma mouse model through the YAP-ROCK2 pathway.

Our previous study indicated that adhesion molecule catenin alpha-like 1(CTNNAL1) is downregulated in airway epithelial cells of asthma patients and asthma animal model but little is known about how the CTNNAL1 affects asthma pathogenesis. To reveal the direct relationship between asthma and CTNNAL1, CTNNAL1-deficient mouse model in bronchopulmonary tissue was constructed by introducing CTNNAL1-siRNA sequence using adeno-associated virus (AAV) as vector. The mouse model of asthma was established by stimulation of house dust mite (HDM). After HDM-challenged, there was marked airway inflammation, especially mucus hypersecretion in the CTNNAL1-deficient mice. In addition, the CTNNAL1-deficient mice exhibited an increase of lung IL-4 and IL-13 levels, as well as a significant increase of goblet cell hyperplasia and MUC5AC after HDM exposure. The expression of Yes-associated protein (YAP), protein that interacted with α-catenin, was downregulated after CTNNAL1 silencing and was upregulated due to its overexpression. In addition, the interaction between CTNNAL1 and YAP was confirmed by CO-IP. Besides, inhibition of YAP could decrease the secretion of MUC5AC, IL-4 and IL-13 in CTNNAL1-deficient 16HBE14o-cells. Above results indicated us that CTNNAL1 regulated mucus hypersecretion through YAP pathway. In addition, the expression of ROCK2 increased when CTNNAL1 was silenced and decreased after YAP silencing, and inhibition of YAP decreased the expression of ROCK2 in CTNNAL1-deficient HBE cells. Inhibition of ROCK2 decreased MUC5AC expression and IL-13 secretion. In all, our study demonstrates that CTNNAL1 plays an important role in HDM-induced asthma, mediating mucus secretion through the YAP-ROCK2 pathway.

A novel thiolysis-high-performance liquid chromatography method for the determination of proanthocyanidins in grape seeds.

A novel thiolysis-high-performance liquid chromatography method for the quantitative determination of total proanthocyanidins and the mean degree of polymerization in grape seeds has been developed. Following thiolysis with formic acid and benzyl mercaptan, reaction products were separated and purified. Three proanthocyanidin monomers and three derivatives were obtained and their structures were identified by liquid chromatography-mass spectrometry, FTIR spectroscopy, and NMR spectroscopy. A decomposition model of the thiolysis products and a correction formula for proanthocyanidins concentration were established. This thiolysis-high-performance liquid chromatography method displayed good calibration linearity (R2  > 0.999 over the concentration range 0.01 to 10 mg/mL), excellent accuracy (recoveries of 97.9-99.6%), and precision (repeatability relative standard deviations of 0.45-0.75%). This method is suitable for the quantitative analysis of proanthocyanidins in grape seed products.

Airway epithelial integrin ß4-deficiency exacerbates lipopolysaccharide-induced acute lung injury.

Airway epithelial cells, the first barrier of the respiratory tract, play an indispensable role in innate immunity. Integrin ß4 (ITGB4) is a structural adhesion molecule that is involved in the pathological progression of acute inflammatory diseases and is downregulated in asthmatic patients. Research has shown that endothelial ITGB4 has proinflammatory properties in acute lung injury (ALI). However, the role of epithelial ITGB4 in a murine ALI model is still unknown. This study investigated the role of ITGB4 in lipopolysaccharide (LPS)-induced ALI. We found that ITGB4 in the airway epithelium had remarkably increased after the introduction of LPS in vivo and in vitro. Then, we constructed airway epithelial cell-specific ITGB4 knockout (ITGB4-/- ) mice to study its role in ALI. At a time point of 12 h after the tracheal injection of LPS, ITGB4-/- mice showed increased macrophages (mainly M1-type macrophages) and neutrophil infiltration into the lungs; inflammation-related proteins including interleukin (IL)-6, tumor necrosis factor, and IL-17A were significantly elevated compared to their levels in ITGB4+/+ mice. Furthermore, we investigated the role of ITGB4 in the anti-inflammatory response. Intriguingly, in the ITGB4-/- + LPS group, we found significantly reduced expression of anti-inflammatory factors, including IL-10 messenger RNA (mRNA) and ARG-1 mRNA. We also observed that monocyte chemotactic protein (MCP-1) increased significantly both in vivo and in vitro. Airway epithelium activates macrophages, most likely driven by MCP-1, which we confirmed in the coculture of epithelia and macrophages. These phenomena indicate that ITGB4 in airway epithelial cells plays an important role in the process of inflammation and activation of macrophages in ALI. Overall, these data demonstrated a novel link between airway epithelial ITGB4 and the inflammatory response in LPS-induced ALI.

Human splenic TER cells: A relevant prognostic factor acting via the artemin-GFRα3-ERK pathway in pancreatic ductal adenocarcinoma.

Splenectomy is routinely performed during distal or total pancreatectomy (DP or TP) for pancreatic ductal adenocarcinoma (PDAC), but information about its oncological value is limited. TER cells, nonimmune cells discovered in the spleens of tumour-bearing mice, are elicited by tumours and promote tumour progression, while their role in the clinical outcomes of patients with PDAC remains unclear. In our study, postoperative specimens from 622 patients who underwent DP or TP with splenectomy were analysed by flow cytometry or immunofluorescence, and the relationship between splenic TER cell count and clinical parameters was calculated. We also purified human TER cells for functional experiments and mechanistic studies. We found that TER cell numbers were increased only in the spleens of patients with PDAC but not in PDAC tissue and adjacent pancreatic tissue. High splenic TER cell counts independently predicted poor prognosis (P < .001) and indicated large tumour size, lymph node metastasis, advanced 8th AJCC/mAJCC stage and high CA19-9 classification (all P < .050) in patients with PDAC. Mechanistic analysis showed that TER cells express artemin, which facilitates the proliferation and invasion of PDAC cells by activating GFRα3-ERK signalling. Our study reveals that TER cell count is an indicator of poor prognosis of PDAC, while splenectomy during pancreatic surgery might provide oncological benefits in addition to ensuring the radical resection of PDAC.

NR2E3 is a key component in p53 activation by regulating a long noncoding RNA DINO in acute liver injuries.

Damage-induced long noncoding RNA (DINO) is a long noncoding RNA that directly interacts with p53 and thereby enhances p53 stability and activity in response to various cellular stresses. Here, we demonstrate that nuclear receptor subfamily 2 group E member 3 (NR2E3) plays a crucial role in maintaining active DINO epigenetic status for its proper induction and subsequent p53 activation. In acetaminophen (APAP)- or carbon tetrachloride-induced acute liver injuries, NR2E3 knockout (KO) mice exhibited far more severe liver injuries due to impaired DINO induction and p53 activation. Mechanistically, NR2E3 loss both in vivo and in vitro induced epigenetic DINO repression accompanied by reduced DINO chromatin accessibility. Furthermore, compared with the efficient reversal by a typical antidote N-acetylcysteine (NAC) treatment of APAP-induced liver injury in wild-type mice, the liver injury of NR2E3 KO mice was not effectively reversed, indicating that an intact NR2E3-DINO-p53-signaling axis is essential for NAC-mediated recovery against APAP-induced hepatotoxicity. These findings establish that NR2E3 is a critical component in p53 activation and a novel susceptibility factor to drug- or toxicant-induced acute liver injuries.-Khanal, T., Leung, Y.-K., Jiang, W., Timchenko, N., Ho, S.-M., Kim, K. NR2E3 is a key component in p53 activation by regulating a long noncoding RNA DINO in acute liver injuries.

[Progress of epithelial-mesenchymal transition in respiratory system and the modulatory mechanism of cell adhesion].

Epithelial-mesenchymal transition (EMT) plays an important role in the development and pathogenesis of respiratory system. Epithelial cells are characterized by well-developed, intercellular contacts, whereas EMT triggers the sequential destabilization of cell-cell adhesive junctions. The dynamic remodeling of the epithelial cell adhesion molecules is important for maintaining the integrity and normal function of epithelium. This paper reviews the research progress of EMT in lung development, lung injury repair and chronic lung diseases, and summarizes the effect of cell junctions and cell adhesion molecules on EMT molecular events.

Syntenin regulates hepatitis C virus sensitivity to neutralizing antibody by promoting E2 secretion through exosomes.

BACKGROUND & AIMS: Assembly of infectious hepatitis C virus (HCV) particles is known to involve host lipoproteins, giving rise to unique lipo-viro-particles (LVPs), but proteome studies now suggest that additional cellular proteins are associated with HCV virions or other particles containing the viral envelope glycoprotein E2. Many of these host cell proteins are common markers of exosomes, most notably the intracellular adaptor protein syntenin, which is required for exosome biogenesis. We aimed to elucidate the role of syntenin/E2 in HCV infection. METHODS: Using cell culture-derived HCV, we studied the biogenesis and function of E2-coated exosomes in both hepatoma cells and primary human hepatocytes (PHHs). RESULTS: Knockout of syntenin had a negligible impact on HCV replication and virus production, whereas ectopic expression of syntenin at physiological levels reduced intracellular E2 abundance, while concomitantly increasing the secretion of E2-coated exosomes. Importantly, cells expressing syntenin and HCV structural proteins efficiently released exosomes containing E2 but lacking the core protein. Furthermore, infectivity of HCV released from syntenin-expressing hepatoma cells and PHHs was more resistant to neutralization by E2-specific antibodies and chronic-phase patient serum. We also found that high E2/syntenin levels in sera correlate with lower serum neutralization capability. CONCLUSIONS: E2- and syntenin-containing exosomes are a major type of particle released from cells expressing high levels of syntenin. Efficient production of E2-coated exosomes renders HCV infectivity less susceptible to antibody neutralization in hepatoma cells and PHHs. LAY SUMMARY: This study identifies a key role for syntenin in the regulation of E2 secretion via exosomes. Efficient production of E2-coated exosomes was shown to make hepatitis C virus less sensitive to antibody neutralization. These results may have implications for the development of a hepatitis C virus vaccine.

Biliary Tract Cancer at CT: A Radiomics-based Model to Predict Lymph Node Metastasis and Survival Outcomes.

Purpose To evaluate a radiomics model for predicting lymph node (LN) metastasis in biliary tract cancers (BTCs) and to determine its prognostic value for disease-specific and recurrence-free survival. Materials and Methods For this retrospective study, a radiomics model was developed on the basis of a primary cohort of 177 patients with BTC who underwent resection and LN dissection between June 2010 and December 2016. Radiomic features were extracted from portal venous CT scans. A radiomics signature was built on the basis of reproducible features by using the least absolute shrinkage and selection operator method. Multivariable logistic regression model was adopted to establish a radiomics nomogram. Nomogram performance was determined by its discrimination, calibration, and clinical usefulness. The model was internally validated in 70 consecutive patients with BTC between January 2017 and February 2018. Results The radiomics signature, composed of three LN-status-related features, was associated with LN metastasis in primary and validation cohorts (P < .001). The radiomics nomogram that incorporated radiomics signature and CT-reported LN status showed good calibration and discrimination in primary cohort (area under the curve, 0.81) and validation cohort (area under the curve, 0.80). Patients at high risk of LN metastasis portended lower disease-specific and recurrence-free survival than did those at low risk after surgery (both P < .001). High-risk LN metastasis was an independent preoperative predictor of disease-specific survival (hazard ratio, 3.37; P < .001) and recurrence-free survival (hazard ratio, 1.98; P = .003). Conclusion A radiomics model derived from portal phase CT of the liver has good performance for predicting lymph node metastasis in biliary tract cancer and may help to improve clinical decision making. © RSNA, 2018 Online supplemental material is available for this article. See also the editorial by Laghi and Voena in this issue.

A radiomics approach to predict lymph node metastasis and clinical outcome of intrahepatic cholangiocarcinoma.

OBJECTIVES: This study was conducted in order to establish and validate a radiomics model for predicting lymph node (LN) metastasis of intrahepatic cholangiocarcinoma (IHC) and to determine its prognostic value. METHODS: For this retrospective study, a radiomics model was developed in a primary cohort of 103 IHC patients who underwent curative-intent resection and lymphadenectomy. Radiomics features were extracted from arterial phase computed tomography (CT) scans. A radiomics signature was built based on highly reproducible features using the least absolute shrinkage and selection operator (LASSO) method. Multivariate logistic regression analysis was adopted to establish a radiomics model incorporating radiomics signature and other independent predictors. Model performance was determined by its discrimination, calibration, and clinical usefulness. The model was internally validated in 52 consecutive patients. RESULTS: The radiomics signature comprised eight LN-status-related features and showed significant association with LN metastasis in both cohorts (p < 0.001). A radiomics nomogram that incorporates radiomics signature and CA 19-9 level showed good calibration and discrimination in the primary cohort (AUC 0.8462) and validation cohort (AUC 0.8921). Promisingly, the radiomics nomogram yielded an AUC of 0.9224 in the CT-reported LN-negative subgroup. Decision curve analysis confirmed the clinical utility of this nomogram. High risk for metastasis portended significantly lower overall and recurrence-free survival than low risk for metastasis (both p < 0.001). The radiomics nomogram was an independent preoperative predictor of overall and recurrence-free survival. CONCLUSIONS: Our radiomics model provided a robust diagnostic tool for prediction of LN metastasis, especially in CT-reported LN-negative IHC patients, that may facilitate clinical decision-making. KEY POINTS: • The radiomics nomogram showed good performance for prediction of LN metastasis in IHC patients, particularly in the CT-reported LN-negative subgroup. • Prognosis of high-risk patients remains dismal after curative-intent resection. • The radiomics model may facilitate clinical decision-making and define patient subsets benefiting most from surgery.

Negative Pressure Wound Therapy in Necrotizing Fasciitis of the Head and Neck.

PURPOSE: Necrotizing fasciitis is a severe soft tissue infection that is uncommon in the head and neck region. Despite the advancement of care over the past few decades, the mortality rate remains high. Negative pressure wound therapy (NPWT), an advanced wound-healing technique, has become increasingly popular for a wide variety of complicated wounds. Since December 2015, we have used this technique in the management of necrotizing fasciitis of the head and neck. We report a consecutive case series treated with NPWT as the initial surgical procedure. MATERIALS AND METHODS: Seven patients who received a surgical diagnosis of necrotizing fasciitis of the head and neck underwent surgery under general anesthesia. After complete debridement, an NPWT device was applied for positive drainage of the involved areas. The drainage tube was connected to a central negative pressure system. The device was not replaced or removed until the infection was controlled. Then, a conventional drainage approach was used. RESULTS: Of the 7 patients, 6 underwent the surgical procedure and NPWT once; the remaining patient underwent these procedures twice. The infectious cavities showed a clean wound covered with healthy granulation formation during the removal of the NPWT device. The following course was uneventful. The mean time for wound healing was 17.3 ± 6.1 days. CONCLUSIONS: NPWT provides various advantages compared with conventional debridement and drainage, resulting in excellent clinical outcomes. This method could be recommended as an alternative approach in the management of necrotizing fasciitis in the head and neck region.

Short- and long-term outcomes of middle hepatic vein-oriented hepatectomy for advanced perihilar cholangiocarcinoma.

BACKGROUND: This study aimed to compare clinical outcomes of the middle hepatic vein (MHV)-oriented versus conventional hemihepatectomy for perihilar cholangiocarcinoma (PHC). METHODS: From 2008 to 2017, medical records of patients undergoing hemihepatectomy with caudate lobectomy for advanced PHC were reviewed retrospectively. MHV-oriented hepatectomy was defined as full exposure of the MHV on the dissection plane. Predictors of morbidity and survival were identified. RESULTS: A total of 125 patients were enrolled. MHV-oriented and conventional hepatectomies were performed in 44 and 81 patients, respectively. The curative resection rate, blood loss, transfusion, and survival were comparable between two groups; however, severe morbidity rate was significantly lower in the MHV-oriented group (9.1% vs 38.3%, P < 0.001). MHV-oriented approach was an independent predictor of severe morbidity, as were the age, bilirubin level, and blood transfusion. Severe morbidity was associated with significantly decreased overall survival and recurrence-free survival (RFS) (median 29.0 vs 46.9 months, P = 0.011 and 20.3 vs 31.1 months, P = 0.003, respectively). Multivariate analysis revealed that severe morbidity independently predicted shorter RFS (P = 0.025). CONCLUSIONS: MHV-oriented approach for advanced PHC is safe and associated with a significant decrease in severe morbidity. Severe morbidity adversely affects survival after surgery; therefore, optimal preoperative preparation and MHV-oriented hepatectomy with meticulous dissection remain of critical importance.

Molecular diversity of the domino annulation reaction of 2-aryl-3-nitrochromenes with pivaloylacetonitriles.

In the presence of triethylamine, the domino annulation reaction of two molecules of pivaloylacetonitrile with one molecule of 2-aryl-3-nitrochromene in tetrahydrofuran resulted in the unprecedented imino-substituted dihydrofuro[2,3-c]chromene derivatives in high yields. More importantly, the above domino reaction in refluxing methanol or ethanol afforded alkoxy-substituted chromeno[3,4-b]pyridines in satisfactory yields. However, a similar reaction of benzoylacetonitrile with 2-aryl-3-nitrochromenes in basic medium gave the expected furo[2,3-c]chromene derivatives in moderate yields.

Predictive Factors for the Spontaneous Recanalization of Large and Middle Cerebral Arteries after Acute Occlusion.

OBJECTIVE: This study aims to investigate the predictive factors for the spontaneous recanalization of occluded arteries in patients with acute ischemic stroke. METHODS: A total of 139 patients with consecutive acute ischemic stroke were enrolled from June 2010 to June 2013. The clinical and biochemical parameters were measured in each participant. Occlusion and recanalization of the carotid artery, the middle cerebral artery, and the vertebral and basilar arteries were identified by using computed tomographic angiography or digital subtraction angiography. RESULTS: Among the 139 patients, 23 showed spontaneous recanalization, whereas 116 did not. In the patients with spontaneous recanalization, the proportion of atrial fibrillation was significantly lower (0% versus 29.31%, P= .01), whereas the proportion of stage 3 hypertension was significantly higher (60.87% versus 32.76%, P= .01) than that of those without recanalization. Logistic regression analysis showed that the proportion of atrial fibrillation was negatively (odds ratio [OR]: .117, 95% confidence interval [CI]: .015-.918, P= .04) associated with spontaneous recanalization, whereas the proportion of stage 3 hypertension was positively (OR: 4.316, 95% CI: 1.533-12.154, P= .01) associated with it. CONCLUSIONS: Atrial fibrillation is associated with reduced spontaneous recanalization of the large and middle cerebral arteries in patients after acute ischemic stroke-induced occlusion, whereas stage 3 hypertension may contribute to the promotion of the recanalization.

NEDD4 and NEDD4L: Ubiquitin Ligases Closely Related to Digestive Diseases.

Protein ubiquitination is an enzymatic cascade reaction and serves as an important protein post-translational modification (PTM) that is involved in the vast majority of cellular life activities. The key enzyme in the ubiquitination process is E3 ubiquitin ligase (E3), which catalyzes the binding of ubiquitin (Ub) to the protein substrate and influences substrate specificity. In recent years, the relationship between the subfamily of neuron-expressed developmental downregulation 4 (NEDD4), which belongs to the E3 ligase system, and digestive diseases has drawn widespread attention. Numerous studies have shown that NEDD4 and NEDD4L of the NEDD4 family can regulate the digestive function, as well as a series of related physiological and pathological processes, by controlling the subsequent degradation of proteins such as PTEN, c-Myc, and P21, along with substrate ubiquitination. In this article, we reviewed the appropriate functions of NEDD4 and NEDD4L in digestive diseases including cell proliferation, invasion, metastasis, chemotherapeutic drug resistance, and multiple signaling pathways, based on the currently available research evidence for the purpose of providing new ideas for the prevention and treatment of digestive diseases.

Unveiling potential therapeutic targets for diabetes-induced frozen shoulder through Mendelian randomization analysis of the human plasma proteome.

INTRODUCTION: This study aimed to assess the causal relationship between diabetes and frozen shoulder by investigating the target proteins associated with diabetes and frozen shoulder in the human plasma proteome through Mendelian randomization (MR) and to reveal the corresponding pathological mechanisms. RESEARCH DESIGN AND METHODS: We employed the MR approach for the purposes of establishing: (1) the causal link between diabetes and frozen shoulder; (2) the plasma causal proteins associated with frozen shoulder; (3) the plasma target proteins associated with diabetes; and (4) the causal relationship between diabetes target proteins and frozen shoulder causal proteins. The MR results were validated and consolidated through colocalization analysis and protein-protein interaction network. RESULTS: Our MR analysis demonstrated a significant causal relationship between diabetes and frozen shoulder. We found that the plasma levels of four proteins were correlated with frozen shoulder at the Bonferroni significance level (p<3.03E-5). According to colocalization analysis, parathyroid hormone-related protein (PTHLH) was moderately correlated with the genetic variance of frozen shoulder (posterior probability=0.68), while secreted frizzled-related protein 4 was highly correlated with the genetic variance of frozen shoulder (posterior probability=0.97). Additionally, nine plasma proteins were activated during diabetes-associated pathologies. Subsequent MR analysis of nine diabetic target proteins with four frozen shoulder causal proteins indicated that insulin receptor subunit alpha, interleukin-6 receptor subunit alpha, interleukin-1 receptor accessory protein, glutathione peroxidase 7, and PTHLH might contribute to the onset and progression of frozen shoulder induced by diabetes. CONCLUSIONS: Our study identified a causal relationship between diabetes and frozen shoulder, highlighting the pathological pathways through which diabetes influences frozen shoulder.