This dissertation advances a new interpretation on the national formation of modern China through the lens of Chinese cinema. Primarily, this project explores how cinema—a modern invention imported... Show moreThis dissertation advances a new interpretation on the national formation of modern China through the lens of Chinese cinema. Primarily, this project explores how cinema—a modern invention imported from the West—has shaped China’s sociopolitical transition from a dynastic empire to a nation-state. It is argued that, the concurrence of motion picture’s arrival and nation-state’s advent in China at the turn of the twentieth century, is not to be considered as isolated events, but rather as a dialectical dynamism in which the imagined community of modern China has largely relied on cinema for its symbolic construction, and yet encountered constant resistance from cinematic representation. Viewing the formation of the Chinese nation-state from a cinematic perspective, this study centers on the conflicts between marginal figures and central categories in Chinese films. In approaching this unresolved dilemma, Jiyu Zhang dedicates his study to mapping out a dialectical relationship between China’s internal and external tensions. Through an extensive investigation of cinematic embodiment, Zhang hones in on four groups of characters that he terms the “central frontiers” of modern China’s cultural imaginary: children, women, ethnic minorities, and diaspora. Show less
Zhang, T.; Madunic, K.; Holst, S.; Zhang, J.; Jin, C.S.; Dijke, P. ten; ... ; Wuhrer, M. 2020
Changes in glycosylation signatures of cells have been associated with pathological processes in cancer as well as infectious and autoimmune diseases. The current protocols for comprehensive... Show moreChanges in glycosylation signatures of cells have been associated with pathological processes in cancer as well as infectious and autoimmune diseases. The current protocols for comprehensive analysis ofN-glycomics andO-glycomics derived from cells and tissues often require a large amount of biological material. They also only allow the processing of very limited numbers of samples at a time. Here we established a workflow for sequential release ofN-glycans andO-glycans based on PVDF membrane immobilization in 96-well format from 5 x 10(5)cells. Released glycans are reduced, desalted, purified, and reconstituted, all in 96-well format plates, without additional staining or derivatization. Glycans are then analyzed with porous graphitized carbon nano-liquid chromatography coupled to tandem mass spectrometry using negative-mode electrospray ionization, enabling the chromatographic resolution and structural elucidation of glycan species including many compositional isomers. The approach was demonstrated using glycoprotein standards and further applied to analyze the glycosylation of the murine mammary gland NMuMG cell line. The developed protocol allows the analysis ofN- andO-glycans from relatively large numbers of samples in a less time consuming way with high repeatability. Inter- and intraday repeatability of the fetuinN-glycan analysis showed two median intraday coefficients of variations (CVs) of 7.6% and 8.0%, and a median interday CV of 9.8%. Median CVs of 7.9% and 8.7% for the main peaks ofN- andO-glycans released from the NMuMG cell line indicate a very good repeatability. The method is applicable to purified glycoproteins as well as to biofluids and cell- or tissue-based samples. Show less
Ouwerkerk, A.F. van; Bosada, F.M.; Liu, J.; Zhang, J.; Duijvenboden, K. van; Chaffin, M.; ... ; Christoffels, V.M. 2020
Rationale: Genome-wide association studies have identified a large number of common variants (single-nucleotide polymorphisms) associated with atrial fibrillation (AF). These variants are located... Show moreRationale: Genome-wide association studies have identified a large number of common variants (single-nucleotide polymorphisms) associated with atrial fibrillation (AF). These variants are located mainly in noncoding regions of the genome and likely include variants that modulate the function of transcriptional regulatory elements (REs) such as enhancers. However, the actual REs modulated by variants and the target genes of such REs remain to be identified. Thus, the biological mechanisms by which genetic variation promotes AF has thus far remained largely unexplored. Objective: To identify REs in genome-wide association study loci that are influenced by AF-associated variants. Methods and Results: We screened 2.45 Mbp of human genomic DNA containing 12 strongly AF-associated loci for RE activity using self-transcribing active regulatory region sequencing and a recently generated monoclonal line of conditionally immortalized rat atrial myocytes. We identified 444 potential REs, 55 of which contain AF-associated variants (P<10(-8)). Subsequently, using an adaptation of the self-transcribing active regulatory region sequencing approach, we identified 24 variant REs with allele-specific regulatory activity. By mining available chromatin conformation data, the possible target genes of these REs were mapped. To define the physiological function and target genes of such REs, we deleted the orthologue of an RE containing noncoding variants in theHcn4(potassium/sodium hyperpolarization-activated cyclic nucleotide-gated channel 4) locus of the mouse genome. Mice heterozygous for the RE deletion showed bradycardia, sinus node dysfunction, and selective loss ofHcn4expression. Conclusions: We have identified REs at multiple genetic loci for AF and found that loss of an RE at theHCN4locus results in sinus node dysfunction and reduced gene expression. Our approach can be broadly applied to facilitate the identification of human disease-relevant REs and target genes at cardiovascular genome-wide association studies loci. Show less
Zhang, J.; Dijke, P. ten; Wuhrer, M.; Zhang, T. 2020
Glycosylation is a common posttranslational modification on membrane-associated and secreted proteins that is of pivotal importance for regulating cell functions. Aberrant glycosylation can lead to... Show moreGlycosylation is a common posttranslational modification on membrane-associated and secreted proteins that is of pivotal importance for regulating cell functions. Aberrant glycosylation can lead to uncontrolled cell proliferation, cell-matrix interactions, migration and differentiation, and has been shown to be involved in cancer and other diseases. The epithelial-to-mesenchymal transition is a key step in the metastatic process by which cancer cells gain the ability to invade tissues and extravasate into the bloodstream. This cellular transformation process, which is associated by morphological change, loss of epithelial traits and gain of mesenchymal markers, is triggered by the secreted cytokine transforming growth factor-beta (TGF-beta). TGF-beta bioactivity is carefully regulated, and its effects on cells are mediated by its receptors on the cell surface. In this review, we first provide a brief overview of major types of glycans, namely,N-glycans,O-glycans, glycosphingolipids and glycosaminoglycans that are involved in cancer progression. Thereafter, we summarize studies on how the glycosylation of TGF-beta signaling components regulates TGF-beta secretion, bioavailability and TGF-beta receptor function. Then, we review glycosylation changes associated with TGF-beta-induced epithelial-to-mesenchymal transition in cancer. Identifying and understanding the mechanisms by which glycosylation affects TGF-beta signaling and downstream biological responses will facilitate the identification of glycans as biomarkers and enable novel therapeutic approaches. Show less
Zhang, T.; I. van die; Tefsen, B.; Vliet, S.J. van; Laan, L.C.; Zhang, J.; ... ; Belo, A.I. 2020
Changes in the glycosylation profile of cancer cells have been strongly associated with cancer progression. To increase our insights into the role of glycosylation in human pancreatic ductal... Show moreChanges in the glycosylation profile of cancer cells have been strongly associated with cancer progression. To increase our insights into the role of glycosylation in human pancreatic ductal adenocarcinoma (PDAC), we performed a study onO-glycans and glycosphingolipid (GSL) glycans of the PDAC cell lines Pa-Tu-8988T (PaTu-T) and Pa-Tu-8988S (PaTu-S). These cell lines are derived from the same patient, but show an almost opposite phenotype, morphology and capacity to metastasize, and may thus provide an attractive model to study the role of glycosylation in progression of PDAC. Gene-array analysis revealed that 24% of the glycosylation-related genes showed a >= 1.5-fold difference in expression level between the two cell lines. Subsequent validation of the data by porous graphitized carbon nano-liquid chromatography coupled to a tandem ion trap mass spectrometry and flow cytometry established major differences inO-glycans and GSL-glycans between the cell lines, including lower levels of T and sialylated Tn (sTn) antigens, neoexpression of globosides (Gb3 and Gb4), and higher levels of gangliosides in the mesenchymal-like PaTu-T cells compared to the epithelial-like PaTu-S. In addition, PaTu-S cells demonstrated a significantly higher binding of the immune-lectins macrophage galactose-type lectin and galectin-4 compared to PaTu-T. In summary, our data provide a comprehensive and differential glycan profile of two PDAC cell lines with disparate phenotypes and metastatic behavior. This will allow approaches to modulate and monitor the glycosylation of these PDAC cell lines, which opens up avenues to study the biology and metastatic behavior of PDAC. Show less
Studies investigating different food processing techniques have shed light on the dietary habits and subsistence strategies adopted by prehistoric populations. They have shown that grinding cereals... Show moreStudies investigating different food processing techniques have shed light on the dietary habits and subsistence strategies adopted by prehistoric populations. They have shown that grinding cereals into flour has taken place since the Palaeolithic period, yet the grinding method employed has often not been investigated. The analysis presented here identified different types of use-wear traces associated with the dry-grinding and wet-grinding of cereals, which can be used to infer prehistoric grinding techniques. Applying this reference baseline to Jiahu, an early Neolithic site known for the earliest findings of domesticated rice in the central plain of China, reveals that dry-grinding rather than wet-grinding was employed for cereal (including rice) processing 9000 years ago. This grinding method could have been inherited from the earlier hunter-gatherers, but could also result from a broad-spectrum subsistence strategy adopted at Jiahu. By comparing the properties and ethnographic uses of different plant species, it is also suggested that cereals such as rice were a more sensible choice for the dry-grinding process. Show less
Purpose: The purpose of this study was to assess the association of baseline tumor size (BTS) with other baseline clinical factors and outcomes in pembrolizumab-treated patients with advanced... Show morePurpose: The purpose of this study was to assess the association of baseline tumor size (BTS) with other baseline clinical factors and outcomes in pembrolizumab-treated patients with advanced melanoma in KEYNOTE-001 (NCT01295827). Experimental Design: BTS was quantified by adding the sum of the longest dimensions of all measurable baseline target lesions. BTS as a dichotomous and continuous variable was evaluated with other baseline factors using logistic regression for objective response rate (ORR) and Cox regression for overall survival (OS). Nominal P values with no multiplicity adjustment describe the strength of observed associations. Results: Per central review by RECIST v1.1, 583 of 655 patients had baseline measurable disease and were included in this post hoc analysis. Median BTS was 10.2 cm (range, 1–89.5). Larger median BTS was associated with Eastern Cooperative Oncology Group performance status 1, elevated lactate dehydrogenase (LDH), stage M1c disease, and liver metastases (with or without any other sites; all P ≤ 0.001). In univariate analyses, BTS below the median was associated with higher ORR (44% vs. 23%; P < 0.001) and improved OS (HR, 0.38; P < 0.001). In multivariate analyses, BTS below the median remained an independent prognostic marker of OS (P < 0.001) but not ORR. In 459 patients with available tumor programmed death ligand 1 (PD-L1) expression, BTS below the median and PD-L1–positive tumors were independently associated with higher ORR and longer OS. Conclusions: BTS is associated with many other baseline clinical factors but is also independently prognostic of survival in pembrolizumab-treated patients with advanced melanoma. Show less
he site of Jiahu in the central plain of China is known for its early rice cultivation 9000 years ago. The preliminary starch analysis implies that the Jiahu grinding tools were used for processing... Show morehe site of Jiahu in the central plain of China is known for its early rice cultivation 9000 years ago. The preliminary starch analysis implies that the Jiahu grinding tools were used for processing various plants, including rice. This paper presents the use-wear analysis carried out on a sample of seventeen grinding tools from Jiahu, nine of which were previously analyzed for the presence of starch. Use-wear traces associated with processing cereal and wood-like material were identified. This result confirms important evidence of cereal processing in the early Neolithic period. It also reveals the diversity of functions in the grinding tool assemblage. Furthermore, the use-wear distribution indicates that grinding slabs without feet and cylindrical rollers were mainly associated with the processing of cereals while grinding slabs with feet were mainly related to the processing of wood-like material. Quantitative analysis of the starch data also indicates that grinding slabs without feet possess more starch grains than the grinding slabs with feet. Therefore, it is argued that specific types of grinding tools were used for processing specific kinds of material. This study highlights the different roles grinding tools may have played in early farming societies. Show less
We used the virtual hand illusion paradigm to study how sense of agency and sense of (body) ownership can interact with different emotional events on stress feelings. Converging evidence for at... Show moreWe used the virtual hand illusion paradigm to study how sense of agency and sense of (body) ownership can interact with different emotional events on stress feelings. Converging evidence for at least the partial independence of agency and ownership was found. For instance, sense of agency was a better predictor of individual anxiety levels than sense of ownership and males showed stronger effects related to agency—presumably due to gender-specific attribution styles and empathy skills. Moreover, agency and ownership also interacted with emotional events and led to different anxiety levels. Taken together, our findings suggest that the disentangled sense of agency and sense of ownership can interact with different emotional events and influenced stress feelings more in threatening situations than awarding ones. Show less
