'You speak a language that I understand not.' Hermione's words to Leontes in The Winter's Tale are likely to ring true with many people reading or watching Shakespeare's plays today. For decades, ...people have been studying Shakespeare's life and times, and in recent years there has been a renewed surge of interest into aspects of his language. So how can we better understand Shakespeare? How did he manipulate language to produce such an unrivalled body of work, which has enthralled generations both as theatre and as literature? David Crystal addresses these and many other questions in this lively and original introduction to Shakespeare's language. Covering in turn the five main dimensions of language structure - writing system, pronunciation, grammar, vocabulary, and conversational style - the book shows how examining these linguistic 'nuts and bolts' can help us achieve a greater appreciation of Shakespeare's linguistic creativity.
Centrioles are key structural elements of centrosomes and primary cilia. In mammals, only a few proteins including PLK4, CPAP (CENPJ), SAS6, CEP192, CEP152 and CEP135 have thus far been identified to ...be required for centriole duplication. STIL (SCL/TAL1 interrupting locus, also known as SIL) is a centrosomal protein that is essential for mouse and zebrafish embryonic development and mutated in primary microcephaly. Here, we show that STIL localizes to the pericentriolar material surrounding parental centrioles. Its overexpression results in excess centriole formation. siRNA-mediated depletion of STIL leads to loss of centrioles and abrogates PLK4-induced centriole overduplication. Additionally, we show that STIL is necessary for SAS6 recruitment to centrioles, suggesting that it is essential for daughter centriole formation, interacts with the centromere protein CPAP and rapidly shuttles between the cytoplasm and centrioles. Consistent with the requirement of centrioles for cilia formation, Stil(-/-) mouse embryonic fibroblasts lack primary cilia--a phenotype that can be reverted by restoration of STIL expression. These findings demonstrate that STIL is an essential component of the centriole replication machinery in mammalian cells.
The article presents an annotation system for narratological phenomena such as space, time, focalisation, reported speech, narrator's speech, the relationship between the speech of a character/of the ...narrator and that of a certain character, evaluative remarks, negation, figurative speech, and ambiguity. Guidelines for annotation are being developed in order to enable different people to achieve consistent results when working with the same text (inter-annotator agreement). In doing so, narratological models will be systematically reassessed and refined. The aim of this project is therefore to annotate approximately 100 short German-language narratives. The corpus will be reusable for a variety of purposes. It permits systematic access to corpus segments annotated in the same way and supports quantifiable contributions in the fields of historical narratology, cultural studies and the history of literary genres.
Beide Autoren hält man für ‘unlesbar’, beide trennen mehr als 300 Jahre. Von beiden Autoren sagt man sie hätten eine neue Sprache erfunden oder die alte Sprache verkünstelt. Dass Picasso wie viele ...seiner Zeitgenossen von Góngora fasziniert war und sich in der Kunst- wie in der Literaturgeschichte bediente, ist bekannt. Wie soll man aber auf Ebene des digitalisierten Werks beide Autoren vergleichen? Die Sprache des 16./17. Jahrhundert lässt sich nicht mit derjenigen des 20. Jahrhunderts vergleichen. Dennoch gibt es Mittel und Wege, neue Perspektiven auf das Thema Autor und Stil zu eröffnen. Hier werden exemplarisch verschiedene digitale Methoden vorgestellt und verwendet: Part of Speech Tagging, Stilometrie mit stylo für R und Topic Modeling. Außerdem wird die Verbindung zwischen Stilistik und Stilometrie diskutiert.
Die Besonderheiten der gongorinischen Syntax werden quantitativ im Vergleich zum poetischen Sprachgebrauch seiner Zeit untersucht. Dazu werden wiederkehrende grammatikalische Sequenzen (SGR, n-grams, ...POS-tags) mit einem ähnlichen zeitgenössischen Korpus verglichen. Nach einer theoretischen Betrachtung des Motivbegriffs, wird versucht, das Werk Góngoras stilistisch zu beschreiben, indem eine bestimmte überrepräsentierte Sequenz genauer betrachtet wird. Die zeitgleiche qualitative Analyse ermöglicht es, bestimmte wiederkehrende Sinneffekte zu erkennen, die diese Sequenz als Motiv gelten lassen. Es geht dabei um ein ausgesprochenes Annähern von heterogenen Entitäten, und um eine poetische Reflexion über die Intellektualisierung der Welt (in den Fällen, in denen die Sequenz ein vorangestelltes Komplement integriert), immer vom Besonderen auf das Allgemeine schließend.
Inflammatory breast cancer (IBC) is a rare and rapidly progressive form of invasive breast cancer. The aim of this study was to explore the clinical evolution, stromal tumour-infiltrating lymphocytes ...(sTIL) infiltration and programmed death-ligand 1 (PD-L1) expression in a large IBC cohort.
Data were collected prospectively from patients with IBC as part of an international collaborative effort since 1996. In total, 143 patients with IBC starting treatment between June 1996 and December 2016 were included. Clinicopathological variables were collected, and sTIL were scored by two pathologists on standard H&E stained sections. PD-L1 expression was assessed using a validated PD-L1 (SP142) assay. A validation cohort of 64 patients with IBC was used to test our findings.
Survival outcomes of IBC remained poor with a 5-year overall survival (OS) of 45.6%. OS was significantly better in patients with primary non-metastatic disease who received taxane-containing (neo)adjuvant therapy (P = 0.01), had a hormone receptor-positive tumour (P = 0.001) and had lower cN stage at diagnosis (P = 0.001). PD-L1 positivity on immune cells (42.9%) was higher in IBC than in non-IBC in both our patient samples and the validation cohort. Furthermore, PD-L1 expression predicted pCR (P = 0.002) and correlated with sTIL infiltration (P < 0.001). sTIL infiltration of more than 10% of the stroma was a significant predictor of improved OS (HR 0.47, 95% CI 0.27-0.81, P = 0.006) in a multivariate model.
IBC is characterised by poor survival and high PD-L1 immunoreactivity on sTIL. This suggests a role for PD1/PD-L1 inhibitors in the treatment of IBC. Furthermore, we showed that PD-L1 expression predicts response to neo-adjuvant therapy and that sTIL have prognostic significance in IBC.
U radu se analizira djelatnost znamenitoga jugoslavenskog arhitekta Milana Zlokovića (1898.-1965.) na prostoru Hrvatske u razdoblju između svjetskih ratova (1918.-1941.). Inspiriran mediteranstvom i ...modernizmom, ostavio je nekoliko natječajnih i nerealiziranih projekata, kao i dvije izvedbe u Orebiću, od kojih svi zaslužuju podrobniji historiografski osvrt. Dokumentacija koja svjedoči o Zlokovićevu radu, odnedavno dostupna u digitaliziranom obliku, pomoći će u valorizaciji njegova djela i u drugim dijelovima bivše Jugoslavije.
This paper focuses on the architectural work of Milan Zloković, the renowned Yugoslav architect (1898-1965) who worked in Croatia between the two world wars (1918-1941). Inspired by the Mediterranean style and Modernism, he left a legacy of several competition and unbuilt projects as well as two realized projects in Orebić. They deserve to be thoroughly examined from a historiographical perspective. The archives about Zloković’s work, now available in digital format, will help to evaluate his work in other parts of former Yugoslavia as well.
The H&E stromal tumor-infiltrating lymphocyte (sTIL) score and programmed death ligand 1 (PD-L1) SP142 immunohistochemistry assay are prognostic and predictive in early-stage breast cancer, but are ...operator-dependent and may have insufficient precision to characterize dynamic changes in sTILs/PD-L1 in the context of clinical research. We illustrate how multiplex immunofluorescence (mIF) combined with statistical modeling can be used to precisely estimate dynamic changes in sTIL score, PD-L1 expression, and other immune variables from a single paraffin-embedded slide, thus enabling comprehensive characterization of activity of novel immunotherapy agents.
Serial tissue was obtained from a recent clinical trial evaluating loco-regional cytokine delivery as a strategy to promote immune cell infiltration and activation in breast tumors. Pre-treatment biopsies and post-treatment tumor resections were analyzed by mIF (PerkinElmer Vectra) using an antibody panel that characterized tumor cells (cytokeratin-positive), immune cells (CD3, CD8, CD163, FoxP3), and PD-L1 expression. mIF estimates of sTIL score and PD-L1 expression were compared to the H&E/SP142 clinical assays. Hierarchical linear modeling was utilized to compare pre- and post-treatment immune cell expression, account for correlation of time-dependent measurement, variation across high-powered magnification views within each subject, and variation between subjects. Simulation methods (Monte Carlo, bootstrapping) were used to evaluate the impact of model and tissue sample size on statistical power.
mIF estimates of sTIL and PD-L1 expression were strongly correlated with their respective clinical assays (p < .001). Hierarchical linear modeling resulted in more precise estimates of treatment-related increases in sTIL, PD-L1, and other metrics such as CD8+ tumor nest infiltration. Statistical precision was dependent on adequate tissue sampling, with at least 15 high-powered fields recommended per specimen. Compared to conventional t-testing of means, hierarchical linear modeling was associated with substantial reductions in enrollment size required (n = 25➔n = 13) to detect the observed increases in sTIL/PD-L1.
mIF is useful for quantifying treatment-related dynamic changes in sTILs/PD-L1 and is concordant with clinical assays, but with greater precision. Hierarchical linear modeling can mitigate the effects of intratumoral heterogeneity on immune cell count estimations, allowing for more efficient detection of treatment-related pharmocodynamic effects in the context of clinical trials.
NCT02950259 .
Intertemporal choice involves deciding between smaller, sooner and larger, later rewards. People tend to prefer smaller rewards that are available earlier to larger rewards available later, a ...phenomenon referred to as temporal or delay discounting. Despite its ubiquity in human and non-human animals, temporal discounting is subject to considerable individual differences. Here, we provide a critical narrative review of this literature and make suggestions for future work. We conclude that temporal discounting is associated with key socio-economic and health-related variables. Regarding personality, large-scale studies have found steeper temporal discounting to be associated with higher levels of self-reported impulsivity and extraversion; however, effect sizes are small. Temporal discounting correlates negatively with future-oriented cognitive styles and inhibitory control, again with small effect sizes. There are consistent associations between steeper temporal discounting and lower intelligence, with effect sizes exceeding those of personality or cognitive variables, although socio-demographic moderator variables may play a role. Neuroimaging evidence of brain structural and functional correlates is not yet consistent, neither with regard to areas nor directions of effects. Finally, following early candidate gene studies, recent Genome Wide Association Study (GWAS) approaches have revealed the molecular genetic architecture of temporal discounting to be more complex than initially thought. Overall, the study of individual differences in temporal discounting is a maturing field that has produced some replicable findings. Effect sizes are small-to-medium, necessitating future hypothesis-driven work that prioritizes large samples with adequate power calculations. More research is also needed regarding the neural origins of individual differences in temporal discounting as well as the mediating neural mechanisms of associations of temporal discounting with personality and cognitive variables.
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