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"Curran, John"
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The Pleasing Analysis of The Faerie Queene
In his “Letter to Raleigh,” Edmund Spenser describes his project using the strange and provocative term analysis. This essay explores three ways in which the Ramist ideas closely associated with this term can inform our understanding of The Faerie Queene. First, since analysis recalls Ramism’s ideal of analytical method, organization of matter in a descent from the most general principles to the more special and obscure, the poem might be approached as an analysis of virtue ethics, with concepts sequenced and divided methodically. Second, the “Letter” excuses out-of-order poetry by the second or imperfect method, crypsis. Spenser’s disclaimer about his “method” as poet historical does not necessarily abnegate logic: we may consider that by puzzling, cryptical features we are alerted to a hidden order, so that an analysis of virtue becomes a pleasing analysis. Third, analysis might refer not just to the poet’s project but to readerly exercise. In analyzing the virtue-knights’ efforts at invention and judgment, we exercise our own. Ramist commentary on these senses of analysis is represented by William Temple, Abraham Fraunce, Gabriel Harvey, and Ramus himself. Readerly analytical exercise is illustrated by the parallel failures of logic of the Redcrosse Knight and Artegall.
Journal Article
Identification of new ALK and RET gene fusions from colorectal and lung cancer biopsies
Using high-coverage targeted next-generation sequencing, this report provides a catalog of genetic alterations in colorectal and lung cancers, identifying previously unknown alterations, such as JAK2 mutations and KIF5B-RET fusions, that may represent druggable targets.
Applying a next-generation sequencing assay targeting 145 cancer-relevant genes in 40 colorectal cancer and 24 non–small cell lung cancer formalin-fixed paraffin-embedded tissue specimens identified at least one clinically relevant genomic alteration in 59% of the samples and revealed two gene fusions,
C2orf44-ALK
in a colorectal cancer sample and
KIF5B-RET
in a lung adenocarcinoma. Further screening of 561 lung adenocarcinomas identified 11 additional tumors with
KIF5B-RET
gene fusions (2.0%; 95% CI 0.8–3.1%). Cells expressing oncogenic
KIF5B-RET
are sensitive to multi-kinase inhibitors that inhibit RET.
Journal Article
COVID-19 induces a hyperactive phenotype in circulating platelets
Coronavirus Disease 2019 (COVID-19), caused by the novel Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2), has affected over 30 million globally to date. Although high rates of venous thromboembolism and evidence of COVID-19-induced endothelial dysfunction have been reported, the precise aetiology of the increased thrombotic risk associated with COVID-19 infection remains to be fully elucidated. Therefore, we assessed clinical platelet parameters and circulating platelet activity in patients with severe and nonsevere COVID-19. An assessment of clinical blood parameters in patients with severe COVID-19 disease (requiring intensive care), patients with nonsevere disease (not requiring intensive care), general medical in-patients without COVID-19, and healthy donors was undertaken. Platelet function and activity were also assessed by secretion and specific marker analysis. We demonstrated that routine clinical blood parameters including increased mean platelet volume (MPV) and decreased platelet:neutrophil ratio are associated with disease severity in COVID-19 upon hospitalisation and intensive care unit (ICU) admission. Strikingly, agonist-induced ADP release was 30- to 90-fold higher in COVID-19 patients compared with hospitalised controls and circulating levels of platelet factor 4 (PF4), soluble P-selectin (sP-selectin), and thrombopoietin (TPO) were also significantly elevated in COVID-19. This study shows that distinct differences exist in routine full blood count and other clinical laboratory parameters between patients with severe and nonsevere COVID-19. Moreover, we have determined all COVID-19 patients possess hyperactive circulating platelets. These data suggest abnormal platelet reactivity may contribute to hypercoagulability in COVID-19 and confirms the role that platelets/clotting has in determining the severity of the disease and the complexity of the recovery path.
Journal Article
Inside Tracks : Robyn Davidson's solo journey across the Outback /
At once the story of a twenty-seven-year-old Australian woman who sets off to cross the desolute Western Australia desert with her camels and dog; a fascinating pictorial journal by photographer Rick Smolan, taken while photographing her journey; and an inside look at the images and screenplay of the extraordinary movie based on the now-famous trek.
Book
Advanced urothelial carcinoma: next-generation sequencing reveals diverse genomic alterations and targets of therapy
Although urothelial carcinoma (UC) of the urinary bladder generally portends a favorable prognosis, metastatic tumors often follow an aggressive clinical course. DNA was extracted from 40 μm of formalin-fixed, paraffin-embedded (FFPE) sections from 35 stage IV UCs that had relapsed and progressed after primary surgery and conventional chemotherapy. Next-generation sequencing (NGS) was performed on hybridization-captured, adaptor ligation-based libraries for 3320 exons of 182 cancer-related genes plus 37 introns from 14 genes frequently rearranged in cancer to at an average sequencing depth of 1164 × and evaluated for all classes of genomic alterations (GAs). Actionable GAs were defined as those impacting the selection of targeted anticancer therapies on the market or in registered clinical trials. A total of 139 GAs were identified, with an average of 4.0 GAs per tumor (range 0–10), of which 78 (56%) were considered actionable, with an average of 2.2 per tumor (range 0–7). Twenty-nine (83%) cases harbored at least one actionable GA including: PIK3CA (9 cases; 26%); CDKN2A/B (8 cases; 23%); CCND1 (5 cases; 14%); FGFR1 (5 cases; 14%); CCND3 (4 cases; 11%); FGFR3 (4 cases; 11%); MCL1 (4 cases; 11%); MDM2 (4 cases; 11%); EGFR (2 cases, 6%); ERBB2 (HER2/neu) (2 cases, 6%); NF1 (2 cases, 6%) and TSC1 (2 cases, 6%). Notable additional alterations included TP53 (19 cases, 54%) and RB1 (6 cases; 17%). Genes involved in chromatin modification were altered by nonsense mutation, splice site mutation or frameshift indel in a mutually exclusive manner in nearly half of all cases including KDM6A (10 cases; 29%) and ARID1A (7 cases; 20%). Comprehensive NGS of 35 UCs of the bladder revealed a diverse spectrum of actionable GAs in 83% of cases, which has the potential to inform treatment decisions for patients with relapsed and metastatic disease.
Journal Article
CTCF couples long-range loop extrusion and diffusion to mediate a diverse Igκ repertoire
Dynamic genome folding is important for V(D)J recombination at the immunoglobulin kappa (
Igκ
) locus, which recombines Jκ and Vκ gene segments across a 3.2 Mb region in both deletional and inversional orientations. Chromatin loop extrusion and diffusion are considered two key mechanisms underlying
Igκ
locus folding, but how they coordinate remains unclear. Here we show that CTCF is a key regulator coupling loop extrusion and diffusion during
Igκ
V-J rearrangement, promoting recombination in both orientations across long genomic distances. Mechanistically, the CTCF N-terminus promotes long-range loop extrusion that facilitates distal Vκ usage by stabilizing cohesin against WAPL release, and also forms loop barriers enabling chromatin diffusion for inversional Vκ joining. In CTCF N-terminal-deficient B cells, defects in inversional Vκ joining are not restored by WAPL depletion but are instead largely rescued by a dCas9-blockade targeted to the Vκ-Jκ intergenic region, mimicking the CTCF barrier. Our findings thus highlight how CTCF coordinates distinct genome-folding mechanisms through its dual roles in cohesin stabilization and extrusion barrier formation to ensure the generation of a diverse
Igκ
repertoire.
Coordinated gene segment rearrangement across a long genomic distance is essential for antibody gene production, but how this is regulated at the chromatin level is still unclear. Here the authors show that an architectural protein, CTCF, modulates both chromatin loop extrusion and diffusion to enforce diverse Vκ gene segment utilization for a diverse Igκ repertoire.
Journal Article
That Suggestion: Catholic Casuistry, Complexity, and Macbeth
In a keeping with the view that Shakespeare harbored a sympathetic attitude to Catholic ways of seeing, this essay argues that Macbeth is a study in the dangers of oversimplification and certainty. In contradistinction to how Spenser’s Redcrosse Knight escapes the Cave of Despaire, Macbeth would benefit greatly from probing, questioning, nuancing, and sifting through ambiguity. He needs to examine the particular attenuation of his own moral thinking, and needs to engage equivocation, in the forms of both amphibology and mental reservation.
Journal Article