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Abstract Positron emission tomography/computed tomography (PET/CT) is a molecular imaging method commonly used to diagnose and differentiate Parkinson’s disease (PD). This study aimed to evaluate the performance of PET/CT with 11C-2β-Carbomethoxy-3β-(4-fluorophenyl) tropane (11C-CFT) and 18F-fluorodeoxyglucose (18F-FDG) tracers in the differential diagnosis between PD, multiple system atrophy parkinsonian type (MSA-P), progressive supranuclear palsy (PSP) and vascular parkinsonism (VP) using the data of 220 patients with clinical PD-like symptoms. Of the 220 enrolled patients, 166 (PD, n = 80; MSA-P, n = 54; PSP, n = 15; VP, n = 17) completed the motor, cognitive and PET/CT assessment and were included in this study. 11C-CFT and 18F-FDG PET/CT images were analyzed using the SNBPI toolbox and CortexID Suite software. The uptake values of 11C-CFT and 18F-FDG PET/CT were compared among the groups after controlling for covariates using generalized linear models. Receiver operating characteristic (ROC) curves were generated to estimate the diagnostic values. Patients with PSP showed the most significant reduction on 11C-CFT PET/CT, while patients with PD and MSA-P showed similar reductions, and patients with VP did not show any significant reduction in 11C-CFT uptake. The areas under the curve (AUCs) for 11C-CFT PET/CT for distinguishing PD from VP, PSP, and MSA-P were 0.902, 0.830, and 0.580, respectively, and 0.728 for distinguishing advanced-stage PD from PSP. On 18F-FDG PET/CT, the AUCs for distinguishing PD from PSP and MSA-P were 0.968 and 0.963, respectively. These results suggest that 11C-CFT and 18F-FDG PET/CT complement each other in improving the accuracy in differential diagnosis of PD.

Abstract 6-Gingerol, the main bioactive compound of ginger, has antioxidant, anti-inflammatory, anti-cancer and neuroprotective effects. However, it is unclear whether 6-Gingerol has protective effects against hepatic ischemia/reperfusion (I/R) injury. In this study, the mouse liver I/R injury model and the mouse AML12 cell hypoxia/reoxygenation (H/R) model were established by pretreatment with 6-Gingerol at different concentrations to explore the potential effects of 6-Gingerol. Serum transaminase levels, liver necrotic area, cell viability, inflammatory response, and cell apoptosis were used to assess the effect of 6-Gingerol on hepatic I/R or cell H/R injury. Quantitative polymerase chain reaction (qPCR) and Western blotting were used to detect the mRNA and protein expression. The results show that 6-Gingerol decreased serum alanine aminotransferase (ALT), aspartate aminotransferase (AST) levels, liver necrosis, inflammatory cytokines IL-1β, IL-6, MCP-1, TNF-α expression, Ly6g+ inflammatory cell infiltration, protein phosphorylation of NF-κB signaling pathway, Terminal deoxynucleotidyl transferase dUTP nick-end labeling (TUNEL) positive cells, cell apoptosis rate, the protein expression of pro-apoptotic protein BAX and C-Caspase3, increased cell viability, and expression of anti-apoptotic protein BCL-2. Moreover, 6-Gingerol could increase the mRNA and protein expression of mitogen activated protein kinase phosphatase 5 (MKP5) and inhibit the activation of P38/JNK signaling pathway. In MKP5 knockout (KO) mice, the protective effect of 6-gingerol and the inhibition of P38/JNK pathway were significantly weakened. Therefore, our results suggest that 6-Gingerol exerts anti-inflammatory and anti-apoptotic effects to attenuate hepatic I/R injury by regulating the MKP5-mediated P38/JNK signaling pathway.

Abstract Background Long noncoding RNAs (lncRNAs) have emerged as important regulators in a variety of human diseases. The dysregulation of liver sinusoidal endothelial cell (LSEC) phenotype is a critical early event in the fibrotic process. However, the biological function of lncRNAs in LSEC still remains unclear. Methods The expression level of lncRNA Airn was evaluated in both human fibrotic livers and serums, as well as mouse fibrotic livers. Gain- and loss-of-function experiments were performed to detect the effect of Airn on LSEC differentiation and hepatic stellate cell (HSC) activation in liver fibrosis. Furthermore, RIP, RNA pull-down-immunoblotting, and ChIP experiments were performed to explore the underlying mechanisms of Airn. Results We have identified Airn was significantly upregulated in liver tissues and LSEC of carbon tetrachloride (CCl4)-induced liver fibrosis mouse model. Moreover, the expression of AIRN in fibrotic human liver tissues and serums was remarkably increased compared with healthy controls. In vivo studies showed that Airn deficiency aggravated CCl4- and bile duct ligation (BDL)-induced liver fibrosis, while Airn over-expression by AAV8 alleviated CCl4-induced liver fibrosis. Furthermore, we revealed that Airn maintained LSEC differentiation in vivo and in vitro. Additionally, Airn inhibited HSC activation indirectly by regulating LSEC differentiation and promoted hepatocyte (HC) proliferation by increasing paracrine secretion of Wnt2a and HGF from LSEC. Mechanistically, Airn interacted with EZH2 to maintain LSEC differentiation through KLF2-eNOS-sGC pathway, thereby maintaining HSC quiescence and promoting HC proliferation. Conclusions Our work identified that Airn is beneficial to liver fibrosis by maintaining LSEC differentiation and might be a serum biomarker for liver fibrogenesis.

Abstract The excessive accumulation of extracellular matrix (ECM) is a key feature of liver fibrosis and the activated hepatic stellate cells (HSCs) are the major producer of ECM proteins. However, the precise mechanisms and target molecules that are involved in liver fibrosis remain unclear. In this study, we reported that activating transcription factor 3 (ATF3) was over-expressed in mice and human fibrotic livers, in activated HSCs and injured hepatocytes (HCs). Both in vivo and in vitro study have revealed that silencing ATF3 reduced the expression of pro-fibrotic genes and inhibited the activation of HSCs, thus alleviating the extent of liver fibrosis, indicating a potential protective role of ATF3 knockdown. However, ATF3 was not involved in either the apoptosis or proliferation of HCs. In addition, our data illustrated that increased nuclear localization of ATF3 promoted the transcription of fibrogenic genes and lnc-SCARNA10, which functioned as a novel positive regulator of TGF-β signaling in liver fibrogenesis by recruiting SMAD3 to the promoter of these genes. Interestingly, further study also demonstrated that lnc-SCARNA10 promoted the expression of ATF3 in a TGF-β/SMAD3-dependent manner, revealing a TGF-β/ATF3/lnc-SCARNA10 axis that contributed to liver fibrosis by activating HSCs. Taken together, our data provide a molecular mechanism implicating induced ATF3 in liver fibrosis, suggesting that ATF3 may represent a useful target in the development of therapeutic strategies for liver fibrosis.

In this paper, we develop a T-spline-based isogeometric method for the large deformation of Kirchhoff–Love shells considering highly nonlinear elastoplastic materials. The adaptive refinement is implemented, and some relatively complex models are considered by utilizing the superiorities of T-splines. A classical finite strain plastic model combining von Mises yield criteria and the principle of maximum plastic dissipation is carefully explored in the derivation of discrete isogeometric formulations under the total Lagrangian framework. The Bézier extraction scheme is embedded into a unified framework converting T-spline or NURBS models into Bézier meshes for isogeometric analysis. An a posteriori error estimator is established and used to guide the local refinement of T-spline models. Both standard T-splines with T-junctions and unstructured T-splines with extraordinary points are investigated in the examples. The obtained results are compared with existing solutions and those of ABAQUS. The numerical results confirm that the adaptive refinement strategy with T-splines could improve the convergence behaviors when compared with the uniform refinement strategy.

ObjectiveHepatocellular carcinoma (HCC) is one of the most common and malignant tumors with an insidious onset, difficult early diagnosis, and limited therapy options, resulting in a poor prognosis. Cell division cycle associated 2 (CDCA2), also known as Repo-Man, plays an important role in regulating mitosis and DNA repair, but the involvement of CDCA2 in HCC remains unclear.MethodsThe differentially expressed genes that were significantly upregulated in multiple RNA sequencing datasets of HCC were screened. Receiver operating characteristic (ROC) curve analysis was performed to identify diagnostic markers for HCC. Least absolute shrinkage and selection operator Cox regression analysis was performed to screen the prognosis-related genes. The screening and analyses identified CDCA2 as the target gene in this study. The expression of CDCA2 was analyzed in public databases and clinical specimens, and CDCA2 involvement in HCC was explored by both bioinformatic analysis and in vitro experiments.ResultsThe level of CDCA2 was enhanced in HCC compared with healthy livers. Overexpression of CDCA2 positively correlated with the pathological grade and TNM stage of the diseases. Furthermore, CDCA2 was found to be an independent prognostic predictor. An excellent prognostic model of HCC was successfully constructed with CDCA2 in combination with TNM stage. Bioinformatic analysis revealed that CDCA2 was closely associated with the cell cycle, apoptosis, and p53 signaling pathway. Silencing CDCA2 in Huh7 cells resulted in significant upregulation of p53 and the downstream PUMA and NOXA and a subsequently increased apoptosis. Inhibition of p53 signaling and apoptosis was found after overexpression of CDCA2 in L02 cells. Strikingly, the proliferation of cells was not affected by CDCA2.ConclusionsCDCA2 was a novel diagnostic marker for HCC, and overexpression of this gene reflected poor pathological grade, stage, and clinical prognosis. CDCA2 promoted the pathogenesis of HCC by suppressing the p53-PUMA/NOXA signaling and the subsequent apoptosis.

BackgroundOridonin (Ori), the main bioactive ingredient of the natural anti-inflammatory herb Rabdosia rubescens, could be a covalent inhibitor of the NLRP3 inflammasome. Solid organ transplantation provides a life-saving optional therapy for patients with end-stage organ dysfunction. The long-term survival of solid organ transplantation remains restricted because of the possibility of rejection and the toxicity, infection, cardiovascular disease, and malignancy related to immunosuppressive (IS) drugs. However, the pathogenic mechanisms involved remain unclear. The ideal IS drugs to prevent allograft rejection have not been identified. Here, we investigated whether Ori could prolong the in vivo survival of completely mismatched cardiac allografts.MethodsThe cardiac transplantation models were conducted among three groups of mice from C57BL/6NCrSlc (B6/N) or C3H/HeNSlc (C3H) to C3H: the syngeneic and the allogeneic group, whose recipients were treated with vehicle of Ori, and the Ori treatment group, in which the recipients were transplanted hearts from MHC-I mismatched donors and treated with different dosages of Ori from post-operative day (POD) 0 to 7. Then, we investigated the effect of Ori on bone marrow-derived dendritic cell (BMDC) and allogeneic mixed lymphocyte reaction in vitro.ResultsOri with 3, 10, and 15 mg/kg Ori could prolong the survival (MST = 22.8, 49.2, and 65.3 days, respectively). We found that infiltrating CD8+ T cells and macrophages were decreased, and regulatory T cells (Tregs) were expanded in allografts on POD7. The mRNA level of IL-1β and IFN-γ of allografts was downregulated. Mechanistically, Ori-treated BMDCs suppressed T-cell proliferation and IFN-γ+CD4+ T-cell differentiation, along with the expansion of Tregs and IL-10+CD4+ T cells. Ori inhibited NOD, LRR-, and pyrin domain-containing protein 3 (NLRP3) expression; attenuated NF-κB and IκBα phosphorylation in LPS-activated BMDCs; downregulated NLRP3, Caspase-1, IL-1β, IL-18, and IFN-γ; and upregulated IL-10 expression.ConclusionsOur findings highlight the potential of Ori as a novel and natural IS agent to improve transplant tolerance. Ori could exert IS activity through decreasing IL-1β and IL-18 production and Th1 differentiation and proliferation and expanding Tregs via inhibiting the NF-κB/NLRP3 signaling pathway.

Abstract To overcome the topological constraints of non-uniform rational B-splines, T-splines have been proposed to define the freeform surfaces. The introduction of T-junctions and extraordinary points makes it possible to represent arbitrarily shaped models by a single T-spline surface. Whereas, the complexity and flexibility of topology structure bring difficulty in programming, which have caused a great obstacle for the development and application of T-spline technologies. So far, research literatures concerning T-spline data structures compatible with extraordinary points are very scarce. In this paper, an efficient data structure for calculation of unstructured T-spline surfaces is developed, by which any complex T-spline surface models can be easily and efficiently computed. Several unstructured T-spline surface models are calculated and visualized in our prototype system to verify the validity of the proposed method.

Allograft rejection has been an obstacle for the long-term survival of patients. CD70, a tumor necrosis factor (TNF) family member critically expressed on antigen-presenting cells and strongly but transiently up-regulated during lymphocyte activation, represents an important co-stimulatory molecule that induces effective T cell responses. We used a mouse heterotopic cardiac transplantation model to evaluate the effects of monotherapy with the antibody targeting mouse CD70 (FR70) on transplantation tolerance and its immunoregulatory activity. FR70-treated C3H recipient mice permanently accepted B6 fully mismatched cardiac allografts. Consistent with the graft survival, the infiltration of CD8+ T cells in the graft was reduced, dendritic cells were differentiated into a tolerogenic status, and the number of regulatory T cells was elevated both in the graft and the recipient’s spleen. In addition, naïve C3H given an adoptive transfer of spleen cells from the primary recipients with FR70 treatment accepted a heart graft from a matching B6 donor but not third-party BALB/c mice. Our findings show that treatment with FR70 induced regulatory cells and inhibited cytotoxic T cell proliferation, which led to long-term acceptance of mouse cardiac allografts. These findings highlight the potential role of anti-CD70 antibodies as a clinically effective treatment for allograft rejection.

Liver transplantation is currently the most effective method for treating end-stage liver disease. However, recipients still need long-term immunosuppressive drug treatment to control allogeneic immune rejection, which may cause various complications and affect the long-term survival of the recipient. Many liver transplant researchers constantly pursue the induction of immune tolerance in liver transplant recipients, immunosuppression withdrawal, and the maintenance of good and stable graft function. Although allogeneic liver transplantation is more tolerated than transplantation of other solid organs, and it shows a certain incidence of spontaneous tolerance, there is still great risk for general recipients. With the gradual progress in our understanding of immune regulatory mechanisms, a variety of immune regulatory cells have been discovered, and good results have been obtained in rodent and non-human primate transplant models. As immune cell therapies can induce long-term stable tolerance, they provide a good prospect for the induction of tolerance in clinical liver transplantation. At present, many transplant centers have carried out tolerance-inducing clinical trials in liver transplant recipients, and some have achieved gratifying results. This article will review the current status of liver transplant tolerance and the research progress of different cellular immunotherapies to induce this tolerance, which can provide more support for future clinical applications.

The matrix pores of a coalbed methane (CBM) reservoir are mostly nanoscale pores, with tiny pore throats and poor connectivity, which belong to the category of low–permeability gas reservoirs. The matrix particles and organic pore surfaces adsorb a large amount of CBM. These problems are the main reasons that limit the increase in CBM production. At present, the primary measure to increase CBM production is hydraulic fracturing. However, due to the technical characteristics and geological conditions of CBM reservoirs, applying this technology to CBM exploitation still has some key issues that need to be resolved. Therefore, it is essential to develop a new technology that can effectively increase the production of CBM. This paper proposed a method that uses ultrasonic waves to improve the seepage characteristics of CBM reservoir and theoretically verifies the feasibility of this idea using numerical simulation. In this paper, we firstly coupled the temperature, pressure, and seepage parameters of the CBM reservoir and built a CBM seepage model under the action of ultrasonic waves. Secondly, by comparing the numerical simulation results with the experiment, we verified the accuracy of the model. Finally, on the basis of the mathematical model, we simulated the change characteristics of pore pressure, reservoir temperature, permeability, and porosity under the action of ultrasonic waves. Research results show that under the action of ultrasonic waves, the pressure-drop funnel of CBM reservoir becomes more apparent. The boundary affected by the pressure drop also increases. With the increase of the action time of ultrasonic waves, the temperature of CBM reservoir also increases, and the action distance is about 4 m. With decreased pore pressure, the permeability and porosity of CBM reservoir significantly increase under the action of ultrasonic waves. With increased ultrasonic power, its effect on reservoir permeability and porosity becomes more significant.

Linear independence of the blending functions is a necessary requirement for T-spline in isogeometric analysis. The main work in this paper focuses on the analysis about T-splines of degree one, we demonstrate that all the blending functions of such T-spline of degree one are linearly independent. The advantage owned by one degree T-spline is that it can avoid the problem of judging whether the model is analysis-suitable or not, especially for occasions that need a quick response from the analysis results. This may provide a new way of using T-spline for a CAD and CAE integrating scenario, since one degree T-spline still guarantees the topology flexibility and is compatible with the spline-based modeling system. In addition, we compare the numerical approximations of isogeometric analysis and finite element analysis, and the experiment indicates that isogeometric analysis using T-spline of degree one can reach a comparable result with classical method.

On-going knowledge mobilization and migration take place on a daily basis in the globalized world. Canada is a multilingual and multicultural country with a large number of visitors and immigrants. One in five Canadian speaks a foreign language other than English and French (Postmedia News, 2012). This case study examined six-year-old Chinese children’s heritage language learning in a community school from multiliteracies perspective using observations, interviews, and artefacts to understand children’s literacy learning. The findings indicated that Chinese children’s literacy learning was not in the traditional repetitive way but involved multimodal communication at school. Useful implications are made for heritage language educators regarding ways to support meaningful heritage language teaching and learning.

It is crucial to improve poorly water-soluble orally administered drugs through both preclinical and therapeutic drug discovery. A co-amorphous formulation consisting of two low molecular weight (MW) molecules offers a solubility/dissolubility advantage over its crystalline form by maintaining their amorphous status. Here, we report on a co-amorphous solid dispersion (SD) system that includes inert carriers (lactose monohydrate or microcrystalline cellulose) and co-amorphous sacubitril (SAC)-valsartan (VAL) using the spray drying process. The strong molecular interactions between drugs were the driving force for forming robust co-amorphous SDs. Our system provided the highest solubility with more than ~11.5- and 3.12-times solubility increases when compared with the physical mixtures. Co-amorphous lactose monohydrate (LM) SDs showed better bioavailability of APIs (~356.27.8% and 154.01% for the relative bioavailability of LBQ 657 and valsartan, respectively). Co-amorphous inert carrier SDs possessed an excellent compressibility for the production of a direct compression pharmaceutical product. In conclusion, these brand-new co-amorphous SDs could reduce the number of unit processes to produce a final pharmaceutical product for downstream manufacturability.

Canada is a multicultural and multilingual country with a large number of immigrants. It is therefore not unusual to see a highly diverse student population in Canadian elementary schools. This study examined primary grade Chinese immigrant children’s biliteracy learning at home using a qualitative case study approach. Data collection included home visits, interviews with parents, and conversations with children. Interpretational analysis was used when analyzing data (observational notes, interview transcriptions, and research journals) in order to identify emerging themes of biliteracy learning at home. The findings of my study indicate that several factors might affect children’s biliteracy learning at home including parents’ education background, attitudes, motivations, expectation level, degree of support toward biliteracy, as well as literacy resources and language environment. This study may help educators further understand Chinese children’s literacy learning at home and could encourage parents to more actively support their children’s biliteracy learning.

This study explores the implementation of computed tomography (CT) reconstruction and simulation techniques for patient-specific valves, aiming to dissect the mechanical attributes of calcified valves within transcatheter heart valve replacement (TAVR) procedures. In order to facilitate this exploration, it derives pertinent formulas for 3D multi-material isogeometric hyperelastic analysis based on Hounsfield unit (HU) values, thereby unlocking foundational capabilities for isogeometric analysis in calcified aortic valves. A series of uniaxial and biaxial tensile tests is executed to obtain an accurate constitutive model for calcified active valves. To mitigate discretization errors, methodologies for reconstructing volumetric parametric models, integrating both geometric and material attributes, are introduced. Applying these analytical formulas, constitutive models, and precise analytical models to isogeometric analyses of calcified valves, the research ascertains their close alignment with experimental results through the close fit in displacement-stress curves, compellingly validating the accuracy and reliability of the method. This study presents a step-by-step approach to analyzing themechanical characteristics of patient-specific valves obtained fromCT images, holding significant clinical implications and assisting in the selection of treatment strategies and surgical intervention approaches in TAVR procedures. [ABSTRACT FROM AUTHOR]