Untersuchungen zur Didaktik des Gebrauchs des es-Korrelates im Deutschen

Diese Arbeit befasst sich mit den Auftretensbedingungen des Pronomens „es“, das im Deutschen als Korrelat (Platzhalter) zu Subjekt- und Akkusativobjektsätzen gebraucht wird. Für die aktive Kompetenz stellt das „es“-Korrelate in der DaF-Didaktik eine ausgesprochene Lernschwierigkeit dar, weil man eine Reihe linguistischer Faktoren mit einbeziehen muss, um festzustellen, ob ein „es“ als Korrelat im Matrixsatz auftreten muss, kann oder nicht darf. Wirft man einen Blick auf die vorhandenen Lernerkorpora, wird deutlich, dass die Probanden, selbst wenn sie seit einigen Jahren Deutsch lernen und daher als Fortgeschrittene gelten, beim Schreiben Korrelatfehler aller Art machen. Ziel der Arbeit ist es, ein Unterrichtskonzept in Bezug auf die „es“-Problematik zu erstellen, das im DaF-Unterricht für fortgeschrittene Lerner mit wenig linguistischem Vorwissen einsetzbar ist. Damit das Unterrichtskonzept über ein solides theoretisches Fundament verfügen kann, werden zunächst die Auftretensbedingungen von „es“ anhand einer korpuslinguistischen Untersuchung ermittelt. Des Weiteren wird eine Fehleranalyse aus Texten von fortgeschrittenen chinesischen DaF-Lernern vorgenommen, um herauszufinden, welche prädikativen Ausdrücke den Lernern wegen des „es“-Korrelates am meisten Schwierigkeiten bereiten und mit welchen die Lerner i. d. R. gut umgehen können. Ferner werden drei einschlägige Grammatiken in Bezug auf die „es“-Problematik kritisch betrachtet. Daran schließt das didaktische Konzept an, mit dem die Hoffnung verbunden ist, dass die DaF-Lerner mit nur geringem Zeitaufwand einen Überblick über diese Problematik erhalten und das „es“-Korrelat bei der schriftlichen Sprachproduktion richtig gebrauchen können

DNMT3A mutation promotes leukemia development through NAM-NAD metabolic reprogramming

Abstract Background DNA methyltransferase 3A (DNMT3A) is frequently mutated in acute myeloid leukemia (AML) with Arg882His (R882H) as the hotspot mutation. It has been reported that DNMT3A mutation plays a key role in leukemogenesis through hypomethylation of some target genes associated with cell growth and differentiation. In this study, we investigated the function of DNMT3A R882H in the malignant progression of AML by regulating metabolic reprogramming. Methods Ultra-High Performance Liquid Chromatography–High Resolution Tandem Mass Spectrometry (UHPLC-HRMS/MS) was used to detect metabolites in the serum of mice harboring Dnmt3a R878H mutation and the wild-type Dnmt3a. Methylated DNA Immunoprecipitation Sequencing (MeDIP-seq) and RNA sequencing (RNA-seq) were used to analyze the levels of DNA methylation and mRNA expression of genes in mouse Gr1+ bone marrow cells respectively. The TCGA and GO databases were used to analyze the differential genes between human samples carrying the DNMT3A R882 mutation and the wild-type DNMT3A. Co-immunoprecipitation and immunoblotting were used to illustrate the binding levels of Cyclins-CDKs and CDK inhibitors including CDKN1A and CDKN1B. Flow cytometry was used to analyze the cell differentiation, division, apoptosis and cell cycle. The effect of NAMPT inhibition on leukemia was evaluated by using in vivo fluorescence imaging in NOG mouse model bearing OCI-AML3 cells. Results DNMT3A mutation caused high expression of nicotinamide phosphoribosyltransferase (NAMPT), a key enzyme in the nicotinamide adenine dinucleotide (NAD) salvage synthetic pathway, through DNA hypomethylation, and finally led to abnormal nicotinamide (NAM) metabolism and NAD synthesis. The NAM-NAD metabolic abnormalities caused accelerated cell cycle progression. Inhibition of NAMPT can reduce the binding degree between Cyclins-CDKs, and increase the binding interaction of the CDK inhibitors with Cyclins-CDKs complexes. Moreover, cells with high expression of NAMPT were more sensitive to the NAMPT inhibitor FK866 with a lower IC50. The inhibition of NAMPT can remarkably extend the survival time of tumor-bearing mice and reduce the infiltration of tumor cells. Conclusions Taken together, our data showed that DNMT3A mutation caused NAMPT overexpression to induce the reprogramming of NAM-NAD metabolism and contribute to abnormal proliferation, which provided a potential direction for targeted therapy at the metabolic level in AML with DNMT3A mutation

Combination of Expanded Allogeneic NK Cells and T Cell-Based Immunotherapy Exert Enhanced Antitumor Effects

Immunotherapies based on immune checkpoint blockade, neoantigen-reactive tumor-infiltrating lymphocytes and T cell receptor-engineered T cells (TCR-T) have achieved favorable clinical outcomes in tumor treatment. However, sustained immune response and tumor regression have been observed only in a few patients due to immune escape. Natural killer (NK) cells can mediate direct tumor lysis and target cancer cells with low or no expression of human leukocyte antigen class I (HLA-I) that are no longer recognized by T cells during immune escape. Therefore, the combination of T cell-based immunotherapy and NK cell therapy is a promising strategy for improving antitumor response and response rate. However, allogeneic NK cells for adoptive cell therapy have been limited by both the required cell number and quality. Here, we developed an efficient manufacturing system that relies on genetically modified K562 cells for the expansion of high-quality NK cells derived from peripheral blood mononuclear cells. NK cells with the optimal expansion and activity were identified by comparing the different culture systems. Furthermore, we demonstrated that the cooperation of NK cells with tumor-reactive T cells or with NY-ESO-1-specific TCR-T cells further enhanced tumors lysis, especially against tumors with downregulated HLA-I expression. The advantages of HLA-mismatch and non-rejection by other allogeneic immune cells demonstrated the potential of “off-the-shelf” NK cells with the capacity to target tumors for immunotherapy. Our results indicate that the combination strategy based on T cell and allogeneic NK cell immunotherapy might have potential for overcoming the barrier of immune incompetence caused by HLA-I downregulation

Combination of Expanded Allogeneic NK Cells and T Cell-Based Immunotherapy Exert Enhanced Antitumor Effects

Immunotherapies based on immune checkpoint blockade, neoantigen-reactive tumor-infiltrating lymphocytes and T cell receptor-engineered T cells (TCR-T) have achieved favorable clinical outcomes in tumor treatment. However, sustained immune response and tumor regression have been observed only in a few patients due to immune escape. Natural killer (NK) cells can mediate direct tumor lysis and target cancer cells with low or no expression of human leukocyte antigen class I (HLA-I) that are no longer recognized by T cells during immune escape. Therefore, the combination of T cell-based immunotherapy and NK cell therapy is a promising strategy for improving antitumor response and response rate. However, allogeneic NK cells for adoptive cell therapy have been limited by both the required cell number and quality. Here, we developed an efficient manufacturing system that relies on genetically modified K562 cells for the expansion of high-quality NK cells derived from peripheral blood mononuclear cells. NK cells with the optimal expansion and activity were identified by comparing the different culture systems. Furthermore, we demonstrated that the cooperation of NK cells with tumor-reactive T cells or with NY-ESO-1-specific TCR-T cells further enhanced tumors lysis, especially against tumors with downregulated HLA-I expression. The advantages of HLA-mismatch and non-rejection by other allogeneic immune cells demonstrated the potential of “off-the-shelf” NK cells with the capacity to target tumors for immunotherapy. Our results indicate that the combination strategy based on T cell and allogeneic NK cell immunotherapy might have potential for overcoming the barrier of immune incompetence caused by HLA-I downregulation

Examining the Influence of Using First-Person View Drones as Auxiliary Devices in Matte Painting Courses on College Students’ Continuous Learning Intention

In terms of the teaching process of matte painting, it is essential for students to develop a sound understanding of the relationship between virtual and physical environments. In this study, first-person view (FPV) drones are applied to matte painting courses to evaluate the effectiveness of the teaching, and to propose more effective design suggestions for FPV drones that are more suitable for teaching. This provides students with a better learning environment using a digital education system. The results of the study indicate that the flow experience, learning interest, and continuous learning intention of students who use FPV drones in matte painting are significantly greater than those of students who only utilize traditional teaching methods. Furthermore, the technology incentive model (TIM) was developed in this study after being verified by the structural equation model. The results demonstrate that the second-order construct ‘technology incentive’ comprising perceived interactivity, perceived vividness, and novel experience positively influence students’ learning interest and continuous learning intentions under the mediation of flow experience

Modeling and analysis for group delay mismatch effect on wideband adaptive spatial interference cancellation

Abstract The adaptive interference cancellation technique has been widely utilized in radar, GPS, data link, etc., systems to address challenges from external interference, such as co-site and hostile interference. Since the anti-jamming performance of the adaptive interference cancellation technique is sensitive to group delay mismatch between channels, the group delay mismatch becomes one of the main factors that limit the system’s anti-jamming capability. However, the traditional adaptive interference cancellation system’s mathematical model cannot quantitatively characterize the group delay mismatch effect on the wideband interference cancellation performance. In this paper, the mathematical model of the wideband adaptive spatial interference cancellation (ASIC) system is established, which considers the group delay mismatch, to quantitatively analyze the impact of group delay mismatch on the hostile interference cancellation. The mathematical model utilizes the weighted multi-tone signals to fit the wideband interference, and then, delay differences are attached to each tone signal to simulate the group delay mismatch. Then, the analytic expressions of weight and interference cancellation ratio are derived, which consider the interference bandwidth and group delay mismatch, to quantitatively analyze the group delay mismatch effect on the anti-jamming performance of the wideband ASIC system. Simulation results indicate that the theoretical analysis based on the mathematical model of wideband ASIC system are accurate, which can achieve the quantitative analysis of the group delay mismatch effect on the WIC performance

Additional file 2 of DNMT3A mutation promotes leukemia development through NAM-NAD metabolic reprogramming

Additional file 2: Table S2. The mRNA expression level of NAMPT in AML obtained from the Oncomine database

Additional file 1 of DNMT3A mutation promotes leukemia development through NAM-NAD metabolic reprogramming

Additional file 1: Table S1. Primer sequences used in Q-RT-PCR

Connexin 43-modified bone marrow stromal cells reverse the imatinib resistance of K562 cells via Ca2+-dependent gap junction intercellular communication

Abstract. Background:. Imatinib mesylate (IM) resistance is an emerging problem for chronic myeloid leukemia (CML). Previous studies found that connexin 43 (Cx43) deficiency in the hematopoietic microenvironment (HM) protects minimal residual disease (MRD), but the mechanism remains unknown. Methods:. Immunohistochemistry assays were employed to compare the expression of Cx43 and hypoxia-inducible factor 1α (HIF-1α) in bone marrow (BM) biopsies of CML patients and healthy donors. A coculture system of K562 cells and several Cx43-modified bone marrow stromal cells (BMSCs) was established under IM treatment. Proliferation, cell cycle, apoptosis, and other indicators of K562 cells in different groups were detected to investigate the function and possible mechanism of Cx43. We assessed the Ca2+-related pathway by Western blotting. Tumor-bearing models were also established to validate the causal role of Cx43 in reversing IM resistance. Results:. Low levels of Cx43 in BMs were observed in CML patients, and Cx43 expression was negatively correlated with HIF-1α. We also observed that K562 cells cocultured with BMSCs transfected with adenovirus-short hairpin RNA of Cx43 (BMSCs-shCx43) had a lower apoptosis rate and that their cell cycle was blocked in G0/G1 phase, while the result was the opposite in the Cx43-overexpression setting. Cx43 mediates gap junction intercellular communication (GJIC) through direct contact, and Ca2+ is the key factor mediating the downstream apoptotic pathway. In animal experiments, mice bearing K562, and BMSCs-Cx43 had the smallest tumor volume and spleen, which was consistent with the in vitro experiments. Conclusions:. Cx43 deficiency exists in CML patients, promoting the generation of MRD and inducing drug resistance. Enhancing Cx43 expression and GJIC function in the HM may be a novel strategy to reverse drug resistance and promote IM efficacy

Photoelectrochemical C-H Activation Through a Quinacridone Dye Enabling Proton-Coupled Electron Transfer

Dye-sensitized photoanodes for C-H activation in organic substrates are assembled by vacuum sublimation of a commercially available quinacridone (QNC) dye in the form of nanosized rods onto fluorine-doped tin oxide (FTO), TiO2, and SnO2 slides. The photoanodes display extended absorption in the visible range (450-600 nm) and ultrafast photoinduced electron injection (<1 ps, as revealed by transient absorption spectroscopy) of the QNC dye into the semiconductor. The proton-coupled electron-transfer reactivity of QNC is exploited for generating a nitrogen-based radical as its oxidized form, which is competent in C-H bond activation. The key reactivity parameter is the bond-dissociation free energy (BDFE) associated with the N center dot/N-H couple in QNC of 80.5 +/- 2.3 kcal mol(-1), which enables hydrogen atom abstraction from allylic or benzylic C-H moieties. A photoelectrochemical response is indeed observed for organic substrates characterized by C-H bonds with BDFE below the 80.5 kcal mol(-1) threshold, such as gamma-terpinene, xanthene, or dihydroanthracene. This work provides a rational, mechanistically oriented route to the design of dye-sensitized photoelectrodes for selective organic transformations