Origin and functioning of circumstantial clause linkers: a cross-linguistic study

The thesis analyses a variety of clause linkers used in the world’s languages as dedicated markers of four circumstantial relations between states of affairs: anteriority (‘after’), causality (‘because’), purpose (‘in order to’) and conditionality (‘if’). Focusing primarily on the function of the linkers rather than on their formal properties the study scrutinizes the origin and functioning of free-word adverbial subordinators, converbal endings as well as other subordinating affixes and polymorphemic structures specialized for clause-linking functions. The database consist of nearly 700 items which come from a geographically and genetically balanced sample of 84 languages. In the first part of the thesis I discuss in detail the scope of the study, theoretical foundations (functional approach to language analysis) and methodology. In the second part I focus on the issues of grammaticalization and semantic scope of the linkers. The analysis of patterns of polysemy of the linkers, as well as the make-up of the polymorphemic items among them provide material for the reconstruction of the most common sources and pathways of grammaticalization. Looking closer at the patterns of semantic polyfunctionality (i.e. other circumstantial meanings that the clause linkers convey in addition to being markers of the four analysed relations) I reveal the architecture of the network of their cognitive affinities. The result of this investigation is a set of findings, which add to our understanding of the origin and functioning of the markers – a topic which has received little attention so far. The third part of the dissertation is dedicated to the analysis of the crosslinguistic variation in the degree of grammaticalization, lexicalization and explicitness of the linkers and discussion on the motivations behind their development. The main body of the analyses is focused on the investigation of the potential influence of a variety of socio-cultural factors on the variations observed. The factors include those most often mentioned in the context of the forces shaping language structure: presence and vitality of written form as well as other media of displaced communication, presence of the language in schooling, population size of the speech community, and type of society. The results obtained show that the degrees of grammaticalization, lexicalization and explicitness are much stronger correlated with socio-cultural factors for anteriority and conditionality than for causality and purpose. In order to account for the differences I evoke the concepts of cognitive salience and communicative pressure arguing that the influence of socio-cultural factors on language structure should always be considered in a broader context which includes also pragmatics and cognitive psychology

ON NONLOCAL MODELING IN CONTINUUM MECHANICS

The objective of the paper is to provide an overview of nonlocal formulations for models of elastic solids. The author presents the physical foundations for nonlocal theories of continuum mechanics, followed by various analytical and numerical techniques. The characteristics and range of practical applications for the presented approaches are discussed. The results of numerical simulations for the selected case studies are provided to demonstrate the properties of the described methods. The paper is illustrated with outcomes from peridynamic analyses. Fatigue and axial stretching were simulated to show the capabilities of the developed numerical tools

SHAPE-MEMORY MATERIALS AS CONTROL ELEMENTS USED IN DOT BRAILLE ACTUATOR

The objective of this paper is to show a designing process for actuators that utilizes shape-memory materials. Analytical studies are carried out to design a dot actuator to be used in an electronic Braille display. Shape-memory materials are a relatively new group of smart materials that exhibit the transformation of their internal structures in solid state phases resulting from external mechanical or thermal excitation. This unique property shows up as three phenomena: one- and two-way memory effects as well as superelasticity, which all significantly influence the change of both the material properties and geometry. Hence, shape-memory materials are used as actuators effectively controlled by the above-mentioned types of excitation.The work presents the design guidelines for a proposed technical solution as well as the phenomenon utilized in the elaborated model of the actuator. The authors derived the mathematical descriptions for the proposed design configuration and an example of the calculations is shown. Moreover, the characteristics of the elaborated configuration are also discussed, taking into account the range of application areas

Lamb wave transducers made of piezoelectric macro-fiber composite

During recent years, an intensive research activity concerning the application of Lamb waves (LWs) for SHM has been observed. LWs may be generated and sensed using different types of transducers, and their selection is essential for the SHM system’s performance. Results of the investigation of three types of transducers based on macro-fiber composite (MFC) are presented in this paper; two types of commercially available MFC actuators are compared with a novel type of custom-designed interdigital transducer also based on the MFC substrate. After a short presentation of the piezoelectric transducer designed for SHM applications, details concerning the proposed interdigital transducer design are provided. Beampatterns of the investigated transducers are first compared using numerical FEM simulations, and next, the numerically obtained beampatterns are verified experimentally using laser vibrometry. In the final part of this paper, advantages and disadvantages of the investigated transducers ar

A chemokine network of T cell exhaustion and metabolic reprogramming in renal cell carcinoma

Renal cell carcinoma (RCC) is frequently infiltrated by immune cells, a process which is governed by chemokines. CD8+ T cells in the RCC tumor microenvironment (TME) may be exhausted which most likely influence therapy response and survival. The aim of this study was to evaluate chemokine-driven T cell recruitment, T cell exhaustion in the RCC TME, as well as metabolic processes leading to their functional anergy in RCC. Eight publicly available bulk RCC transcriptome collectives (n=1819) and a single cell RNAseq dataset (n=12) were analyzed. Immunodeconvolution, semi-supervised clustering, gene set variation analysis and Monte Carlo-based modeling of metabolic reaction activity were employed. Among 28 chemokine genes available, CXCL9/10/11/CXCR3, CXCL13/CXCR5 and XCL1/XCR1 mRNA expression were significantly increased in RCC compared to normal kidney tissue and also strongly associated with tumor-infiltrating effector memory and central memory CD8+ T cells in all investigated collectives. M1 TAMs, T cells, NK cells as well as tumor cells were identified as the major sources of these chemokines, whereas T cells, B cells and dendritic cells were found to predominantly express the cognate receptors. The cluster of RCCs characterized by high chemokine expression and high CD8+ T cell infiltration displayed a strong activation of IFN/JAK/STAT signaling with elevated expression of multiple T cell exhaustion-associated transcripts. Chemokinehigh RCCs were characterized by metabolic reprogramming, in particular by downregulated OXPHOS and increased IDO1-mediated tryptophan degradation. None of the investigated chemokine genes was significantly associated with survival or response to immunotherapy. We propose a chemokine network that mediates CD8+ T cell recruitment and identify T cell exhaustion, altered energy metabolism and high IDO1 activity as key mechanisms of their suppression. Concomitant targeting of exhaustion pathways and metabolism may pose an effective approach to RCC therapy

A Single cis Element Maintains Repression of the Key Developmental Regulator Gata2

In development, lineage-restricted transcription factors simultaneously promote differentiation while repressing alternative fates. Molecular dissection of this process has been challenging as transcription factor loci are regulated by many trans-acting factors functioning through dispersed cis elements. It is not understood whether these elements function collectively to confer transcriptional regulation, or individually to control specific aspects of activation or repression, such as initiation versus maintenance. Here, we have analyzed cis element regulation of the critical hematopoietic factor Gata2, which is expressed in early precursors and repressed as GATA-1 levels rise during terminal differentiation. We engineered mice lacking a single cis element −1.8 kb upstream of the Gata2 transcriptional start site. Although Gata2 is normally repressed in late-stage erythroblasts, the −1.8 kb mutation unexpectedly resulted in reactivated Gata2 transcription, blocked differentiation, and an aberrant lineage-specific gene expression pattern. Our findings demonstrate that the −1.8 kb site selectively maintains repression, confers a specific histone modification pattern and expels RNA Polymerase II from the locus. These studies reveal how an individual cis element establishes a normal developmental program via regulating specific steps in the mechanism by which a critical transcription factor is repressed

EpCAM expression varies significantly and is differentially associated with prognosis in the luminal B HER2+, basal-like, and HER2 intrinsic subtypes of breast cancer

BACKGROUND: Epithelial cell adhesion molecule (EpCAM) is frequently expressed in breast cancer, and its expression has been associated with poor prognosis. Breast cancer can be subdivided into intrinsic subtypes, differing in prognosis and response to therapy. METHODS: To investigate the association between EpCAM expression and prognosis in the intrinsic subtypes of breast cancer, we performed immunohistochemical studies on a tissue microarray encompassing a total of 1365 breast cancers with detailed clinicopathological annotation and outcomes data. RESULTS: We observed EpCAM expression in 660 out of 1365 (48%) cases. EpCAM expression varied significantly in the different intrinsic subtypes. In univariate analyses of all cases, EpCAM expression was associated with a significantly worse overall survival. In the intrinsic subtypes, EpCAM expression was associated with an unfavourable prognosis in the basal-like and luminal B HER2(+) subtypes but associated with a favourable prognosis in the HER2 subtype. Consistently, specific ablation of EpCAM resulted in increased cell viability in the breast cancer cell line SKBR3 (ER(−), PR(−), and HER2(+)) but decreased viability in the breast cancer cell line MDA-MB-231 (ER(−), PR(−), and HER2(−) ). CONCLUSION: The differential association of EpCAM expression with prognosis in intrinsic subtypes has important implications for the development of EpCAM-targeted therapies in breast cancer