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Browsing by Author "Yang, Yi"
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Item Effect of Esketamine Added to Propofol Sedation on Desaturation and Hypotension in Bidirectional Endoscopy: A Randomized Clinical Trial(American Medical Association, 2023-12-01) Song, Nan; Yang, Yi; Zheng, Zhong; Shi, Wen-Cheng; Tan, Ai-Ping; Shan, Xi-Sheng; Liu, Hong; Meng, Lingzhong; Peng, Ke; Ji, Fu-Hai; Anesthesia, School of MedicineImportance: Propofol sedation is widely used for endoscopic procedures, but it poses risks of hemodynamic and respiratory depression. The addition of esketamine as an adjuvant may reduce propofol requirements and associated adverse events. Objective: To evaluate the effects of low-dose esketamine added to propofol-based sedation on desaturation and hypotension during same-visit bidirectional endoscopy. Design, setting, and participants: This multicenter, double-blind, placebo-controlled randomized clinical trial assessed patients from 3 teaching hospitals in China who were scheduled for same-visit bidirectional endoscopy between February 8 and November 30, 2022, and randomly assigned to receive esketamine or normal saline (placebo). Interventions: After induction of sedation with 0.1 μg/kg of sufentanil and 0.5 mg/kg of propofol, patients in the esketamine group received 0.15 mg/kg of intravenous esketamine, whereas patients in the placebo group received an equivalent volume of saline. Sedation was achieved through propofol titration. Main outcomes and measures: The primary outcome was the composite of desaturation and hypotension during the procedures. Secondary outcomes included desaturation, hypotension, propofol requirements, postprocedure pain and fatigue, nausea or vomiting, dizziness or headache, hallucination or nightmare, endoscopist satisfaction, and patient satisfaction. Results: Among the 663 initially enrolled patients, 660 completed the study (median [IQR] age, 48 [36-57] years; 355 [53.8%] female), with 331 randomized to the esketamine group and 329 to the placebo group. The administration of esketamine compared with placebo significantly reduced the incidence of the composite outcome of desaturation and hypotension (8.2% vs 21.0%; difference, -12.8 percentage points; odds ratio [OR], 0.34; 95% CI, 0.21-0.54; P < .001). Additionally, esketamine led to significantly lower incidences of desaturation (OR, 0.36; 95% CI, 0.18-0.72; false discovery rate q = .01) and hypotension (OR, 0.33; 95% CI, 0.18-0.60; q < .001) and reduced propofol requirements (difference, -58.9 mg; 95% CI, -65.7 to -52.2 mg; q < .001), without significant effects on other secondary outcomes. Conclusions and relevance: In this randomized clinical trial of patients undergoing same-visit bidirectional endoscopy, the administration of low-dose esketamine resulted in an approximately 61% reduction in the incidence of desaturation and hypotension, accompanied by decreased propofol requirements. These findings support the use of esketamine as an adjuvant to propofol-based sedation in endoscopic procedures.Item Identification of TMEM230 mutations in familial Parkinson's disease(Nature Research, 2016-07) Deng, Han-Xiang; Shi, Yong; Yang, Yi; Ahmeti, Kreshnik B.; Miller, Nimrod; Huang, Cao; Cheng, Lijun; Zhai, Hong; Deng, Sheng; Nuytemans, Karen; Corbett, Nicola J.; Kim, Myung Jong; Deng, Hao; Tang, Baisha; Yang, Ziquang; Xu, Yanming; Chen, Piao; Huang, Bo; Gao, Xiao-Ping; Song, Zhi; Liu, Zhenhua; Fecto, Faisal; Siddique, Nailah; Foroud, Tatiana; Jankovic, Joseph; Ghetti, Bernardino; Nicholson, Daniel A.; Krainc, Dimitri; Melen, Onur; Vance, Jeffery M.; Pericak-Vance, Margaret A.; Ma, Yong-Chao; Rajput, Ali H.; Siddique, Teepu; Medical and Molecular Genetics, School of MedicineParkinson's disease is the second most common neurodegenerative disorder without effective treatment. It is generally sporadic with unknown etiology. However, genetic studies of rare familial forms have led to the identification of mutations in several genes, which are linked to typical Parkinson's disease or parkinsonian disorders. The pathogenesis of Parkinson's disease remains largely elusive. Here we report a locus for autosomal dominant, clinically typical and Lewy body-confirmed Parkinson's disease on the short arm of chromosome 20 (20pter-p12) and identify TMEM230 as the disease-causing gene. We show that TMEM230 encodes a transmembrane protein of secretory/recycling vesicles, including synaptic vesicles in neurons. Disease-linked TMEM230 mutants impair synaptic vesicle trafficking. Our data provide genetic evidence that a mutant transmembrane protein of synaptic vesicles in neurons is etiologically linked to Parkinson's disease, with implications for understanding the pathogenic mechanism of Parkinson's disease and for developing rational therapies.Item Petrogenesis of Early Cretaceous intermediate-felsic dikes in the Jiaodong Peninsula, south-eastern North China Craton: Constraints from geochronology, geochemistry and Sr-Nd-Pb-Hf isotopes(Elsevier, 2018-08) Liu, Xuefei; Deng, Jun; Liang, Yayun; Wang, Qingfei; Pan, Ruiguang; Qin, Cheng; Yang, Yi; Earth Sciences, School of ScienceEarly Cretaceous dike swarms are widely developed in the Jiaodong Peninsula, NE China. In this study, we newly investigated the spatial-temporal distribution, petrography, geochronology and whole-rock geochemistry of the intermediate-felsic dikes from the Jiaobei terrane and the Sulu orogenic belt in the Jiadong Peninsula. The zircon U-Pb dating has constrained the timing of the emplacement of intermediate-felsic dikes to 128–108 Ma. The quartz diorite dikes in Jiaobei show adakitic geochemical features, including high SiO2 (66.3–67.5 wt%) contents and high Sr/Y (76–149) and La/Yb (41–91) ratios. The combination of a series of isotopic data, including initial 87Sr/86Sr ratios (0.7098–0.7104) and negative εNd(t) (−20.1 to −14.7) and zircon εHf(t) values (−19.9 to −9.5), indicates that these quartz diorite dikes were likely derived from partial melting of thickened ancient lower crust with involvement of underplated mafic magmas. Additionally, the diorite dikes in Jiaobei and those in Sulu show similar chemical compositions, as both yield the high-Mg andesite (or andesitic rocks) (HMAs) characteristics with a high Mg# value (60–72), high MgO, Cr, and Ni contents, and low Na2O (average = 3.25 wt%) contents. They also exhibit crustal geochemical signatures, such as depletion in Nb, Ta, and Ti, but enrichment in Th and U; high initial 87Sr/86Sr ratios (0.7063–0.7094), and low εNd(t) (−16.7 to −9.6) and εHf(t) values (−29.4 to −9.8). The entire geochemical evidences imply that they derived from the partial melting of mantle wedge peridotite metasomatized by hydrous fluids from the subduction of the oceanic slab with marine sediments. In combination with the Early Cretaceous intrusions and mafic dikes at Jiaodong, the intermediate-felsic dikes represent a magmatic response to lithospheric thinning resulted from the prolonged thermo-mechanical-chemical erosion processes caused by slab rollback of the Paleo-Pacific plate.Item Plasminogen deficiency suppresses pancreatic ductal adenocarcinoma disease progression(Wiley, 2024) Chowdhury, Nayela N.; Yang, Yi; Dutta, Ananya; Luo, Michelle; Wei, Zimu; Abrahams, Sara R.; Revenko, Alexey S.; Shah, Fenil; Miles, Lindsey A.; Parmer, Robert J.; de Laat, Bas; Wolberg, Alisa S.; Luyendyk, James P.; Fishel, Melissa L.; Flick, Matthew J.; Pediatrics, School of MedicinePancreatic ductal adenocarcinoma (PDAC) is a highly fatal metastatic disease associated with robust activation of the coagulation and fibrinolytic systems. However, the potential contribution of the primary fibrinolytic protease plasminogen to PDAC disease progression has remained largely undefined. Mice bearing C57Bl/6-derived KPC (KRasG12D , TRP53R172H ) tumors displayed evidence of plasmin activity in the form of high plasmin-antiplasmin complexes and high plasmin generation potential relative to mice without tumors. Notably, plasminogen-deficient mice (Plg- ) had significantly diminished KPC tumor growth in subcutaneous and orthotopic implantation models. Moreover, the metastatic potential of KPC cells was significantly diminished in Plg- mice, which was linked to reduced early adhesion and/or survival of KPC tumor cells. The reduction in primary orthotopic KPC tumor growth in Plg- mice was associated with increased apoptosis, reduced accumulation of pro-tumor immune cells, and increased local proinflammatory cytokine production. Elimination of fibrin(ogen), the primary proteolytic target of plasmin, did not alter KPC primary tumor growth and resulted in only a modest reduction in metastatic potential. In contrast, deficiencies in the plasminogen receptors Plg-RKT or S100A10 in tumor cells significantly reduced tumor growth. Plg-RKT reduction in tumor cells, but not reduced S100A10, suppressed metastatic potential in a manner that mimicked plasminogen deficiency. Finally, tumor growth was also reduced in NSG mice subcutaneously or orthotopically implanted with patient-derived PDAC tumor cells in which circulating plasminogen was pharmacologically reduced. Collectively, these studies suggest that plasminogen promotes PDAC tumor growth and metastatic potential, in part through engaging plasminogen receptors on tumor cells.Item STAT4 Regulates the CD8+ Regulatory T Cell/T Follicular Helper Cell Axis and Promotes Atherogenesis in Insulin-Resistant Ldlr-/- Mice(American Association of Immunologists, 2017-11-15) Taghavie-Moghadam, Parésa L; Wassem, Tayab C.; Hattler, Julian; Glenn, Lindsey M.; Dobrian, Anca D.; Kaplan, Mark H.; Yang, Yi; Nurieva, Roza; Nadler, Jerry L.; Galkina, Elena V.; Pediatrics, School of MedicineThe metabolic syndrome and diabetic conditions support atherosclerosis, but the exact mechanisms for accelerated atherogenesis remain unclear. Although the proinflammatory role of STAT4 in atherosclerosis and diet-induced insulin resistance (IR) was recently established, the impact of STAT4 on atherogenesis in conditions of IR is not known. In this study, we generated Stat4-/-Ldlr-/- mice that were fed a diabetogenic diet with added cholesterol (DDC). DDC-fed Stat4-/-Ldlr-/- mice demonstrated improved glucose tolerance, insulin sensitivity, and a 36% reduction in atherosclerosis compared with Ldlr-/- controls. Interestingly, we detected a reduction in T follicular helper (Tfh) cells and plasma B cells but a sharp elevation in CD8+ regulatory T cells (Tregs) in spleens and aortas of Stat4-/-Ldlr-/- mice compared with Ldlr-/- mice. Similarly, STAT4 deficiency supported CD8+ Treg differentiation in vitro. STAT4-deficient CD8+ Tregs suppressed Tfh cell and germinal center B cell development upon immunization with keyhole limpet hemocyanin, indicating an important role for STAT4 in CD8+ Treg functions in vivo. Furthermore, adoptive transfer of Stat4-/-Ldlr-/- CD8+ Tregs versus Ldlr-/- CD8+ Tregs resulted in a significant reduction in plaque burden and suppression of Tfh cell and germinal center B cells in DDC-fed Ldlr-/- recipients. STAT4 expression in macrophages (MΦs) also affected the Tfh/CD8+ Treg axis, because conditioned media from Stat4-/-Ldlr-/- MΦs supported CD8+ Treg differentiation, but not Tfh cell differentiation, in a TGF-β-dependent manner. These findings suggest a novel mechanism by which STAT4 supports atherosclerosis in IR Ldlr-/- mice via STAT4-dependent MΦs, as well as cell-intrinsic suppression of CD8+ Treg generation and functions and maintenance of Tfh cell generation and the accompanying humoral immune response.