Kickin\u27 Sand and Tellin\u27 Lies

This document is the script of the two-act play, Kickin’ Sand and Tellin’ Lies, by Jackson B. Miller and Christopher Forrer. The Linfield College Theatre Program presented the world premieres of the play in November 2012 in McMinnville, Oregon and in Pacific City, Oregon. The play was created as part of the Launching through the Surf: The Dory Fleet of Pacific City project, which focuses on the historical and contemporary role of dory fishers and dories in the life of the coastal village of Pacific City, Oregon. Inspired by stories from the project, Kickin’ Sand and Tellin’ Lies is a fictional work. Inquiries concerning the professional or amateur rights to produce Kickin’ Sand and Tellin’ Lies, or any part thereof, should be addressed to Jackson B. Miller ([email protected]) or the Department of Theatre and Communication Arts, Linfield College, 900 SE Baker St., McMinnville, OR 97128 (503-883-2802).https://digitalcommons.linfield.edu/dory_kstl_play/1002/thumbnail.jp

Pax5 Haploinsufficiency Cooperates with BCR-ABL1 to Induce Acute Lymphoblastic Leukemia

Acute lymphoblastic leukemia (ALL) is the commonest pediatric malignancy and comprises several distinct subtypes each with its own unique pathogenesis, clinical behavior, and response to therapy. Chromosomal aberrations are a hallmark of ALL but alone fail to induce leukemia. Pediatric ALLs can be divided into several categories based on the expression of several genetically conserved chromosomal translocations including the t(9,22)[BCR-ABL1], t(1,19)[TCF3-PBX1], t(12,21)[ETV6-RUNX1], MLLrearranged leukemia’s, hyperdiploid and hypodiploid karyotypes, and T-lineage leukemia. Each translocation confers a characteristic transforming phenotype within the cell in which it originates but is alone insufficient to induce overt leukemia. In order to identify oncogenic lesions that cooperate with the aforementioned initiator lesions, we have performed genome-wide analysis of leukemia cells from 242 pediatric ALL patients using high resolution, single-nucleotide polymorphism microarrays. Our analysis revealed deletion, amplification, point mutation, and structural rearrangements in genes encoding principal regulators of B lymphocyte development and differentiation in 40% of B-progenitor ALL cases. The PAX5 gene was the most frequent target of somatic mutation, being altered in 31.7% of cases. The identified PAX5 mutations resulted in reduced levels of PAX5 protein or the generation of hypomorphic alleles. Deletions were also detected in TCF3 (also known as E2A), EBF1, LEF1, IKZF1 (IKAROS), and IKZF3(AIOLOS). These findings suggest that direct disruption of pathways controlling B-cell development and differentiation contributes to B-progenitor ALL pathogenesis. Moreover, these data demonstrate the power of high-resolution, genome-wide approaches to identify new molecular lesions in cancer. The Philadelphia chromosome, a chromosomal abnormality that encodes BCR-ABL1, is the defining lesion of chronic myelogenous leukemia (CML) and a subset of ALL. To specifically define oncogenic lesions that cooperate with BCR-ABL1 to induce ALL, we subsequently performed genome-wide analysis of diagnostic leukemia samples from 304 individuals with ALL, including 43 BCR-ABL1 B-progenitor ALLs and 23 CMLcases. IKZF1 (encoding the transcription factor Ikaros) was deleted in 83.7% of BCR-ABL1 ALL, but not chronic-phase CML. Deletion of IKZF1 was also identified as an acquired lesion at the time of transformation of CML to ALL (lymphoid blast crisis). The IKZF1 deletions resulted in haploinsufficiency, expression of a dominant-negative Ikaros isoform, or the complete loss of Ikaros expression. Sequencing of IKZF1deletion breakpoints suggested that aberrant RAG-mediated recombination is responsible for the deletions. These findings suggest that genetic lesions resulting in the loss of Ikaros function are an important event in the development of BCR-ABL1 ALL. In order to assess the contribution of the loss of B-cell developmental regulatory genes with BCR-ABL1 we performed bone marrow transplant assays. Pax5haploinsufficiency was shown to cooperate with BCR-ABL1 during leukemogenesis. Furthermore, as seen in human ALL, both Pax5 and p19Arf haploinsufficiency further cooperate during leukemogenesis. Pathological analysis of the leukemias revealed a B-lymphoid phenotype suggesting that this model results in the development of ALL. Secondary transplant studies confirmed that this was ALL and not a lymphoproliferative disorder. Immunophenotypic analysis confirmed the B-ALL phenotype and further revealed striking differences between Pax5+/+, Pax5+/-, and Pax5-/- leukemias. The leukemias that have lost either one or both Pax5 alleles revealed a more immature immunophenotype that was most pronounced in those with bi-allelic Pax5 loss. The wild-type leukemias were consistent with a Hardy fraction C immunophenotype while the Pax5 null leukemias were akin to Hardy fraction A with no expression of any definitive B-cell surface antigens except B220 and CD43. The Pax5+/+ and Pax5+/- leukemias were monoclonal while the Arf+/- and the compound heterozygous (Pax5+/- Arf+/-) leukemias were oligoclonal suggesting that the loss of p19Arf confers greater leukemogenic properties to a cell than does Pax5 loss. This is substantiated by the data that Arf heterozygous animals are tumor prone alone while Pax5 heterozygous animals live full normal lives. Genomic analysis of 50 murine leukemias (15 WT, 25 Pax5+/- and 10 Arf+/-) revealed that some of the same genomic abnormalities found in human ALL also develop in our murine ALL model. This finding suggests that our model is accurately recapitulating the development of human ALL. Furthermore, we have found through extensive gene expression studies that our mouse BCR-ABL1 leukemias share a gene expression profile similar to human BCR-ABL1 leukemias further supporting our murine model of ALL. The gene expression studies that we have performed have also given us insight into the role that Pax5 haploinsufficiency may be playing during leukemogenesis. Recently D.J Wong et al performed an exhaustive study of embryonic and adult stem cell gene expression profiling. He found that there are modules of genes that are common to either embryonic or adult stem cells. He went further to delineate a group of genes that are commonly expressed in both murine and human embryonic stem cells and call this the core ESC-like module. We performed gene set enrichment analysis (GSEA) using this core ESC-like module and found that this geneset is significantly enriched in our murine leukemias. In addition, we found that this core ESC-like module was significantly enriched in normal Hardy fraction B cells, but not in A, or C-F. We also found, using a principal component analysis method, that Pax5+/+ leukemias are most similar to Hardy fraction C while leukemias that have lost either one or both Pax5 alleles are most similar to Hardy fraction B suggesting that the loss of Pax5 blocks B-cell development and results in cells that are more similar to a stage that shares similar expression of embryonic stem cell genes. Taken together this data suggests that by losing Pax5 the leukemia becomes more stem cell like and may gain advantages that other B-cells do not because they continue down the road of differentiation

The bias of the submillimetre galaxy population: SMGs are poor tracers of the most massive structures in the z ~ 2 Universe

It is often claimed that overdensities of (or even individual bright) submillimetre-selected galaxies (SMGs) trace the assembly of the most-massive dark matter structures in the Universe. We test this claim by performing a counts-in-cells analysis of mock SMG catalogues derived from the Bolshoi cosmological simulation to investigate how well SMG associations trace the underlying dark matter structure. We find that SMGs exhibit a relatively complex bias: some regions of high SMG overdensity are underdense in terms of dark matter mass, and some regions of high dark matter overdensity contain no SMGs. Because of their rarity, Poisson noise causes scatter in the SMG overdensity at fixed dark matter overdensity. Consequently, rich associations of less-luminous, more-abundant galaxies (i.e. Lyman-break galaxy analogues) trace the highest dark matter overdensities much better than SMGs. Even on average, SMG associations are relatively poor tracers of the most significant dark matter overdensities because of 'downsizing': at z < ~2.5, the most-massive galaxies that reside in the highest dark matter overdensities have already had their star formation quenched and are thus no longer SMGs. At a given redshift, of the 10 per cent most-massive overdensities, only ~25 per cent contain at least one SMG, and less than a few per cent contain more than one SMG.Comment: 6 pages, 3 figures, 1 table; accepted for publication in MNRAS; minor revisions from previous version, conclusions unchange

1999-00 Illinois Trapper Survey Report

Federal Aid Project Number W-112-R-9, Job Number 101.2, Wildlife Restoration FundReport issued on: January 5, 200

Memory B cells and CD8⁺ lymphocytes do not control seasonal influenza A virus replication after homologous re-challenge of rhesus macaques.

This study sought to define the role of memory lymphocytes in the protection from homologous influenza A virus re-challenge in rhesus macaques. Depleting monoclonal antibodies (mAb) were administered to the animals prior to their second experimental inoculation with a human seasonal influenza A virus strain. Treatment with either anti-CD8α or anti-CD20 mAbs prior to re-challenge had minimal effect on influenza A virus replication. Thus, in non-human primates with pre-existing anti-influenza A antibodies, memory B cells and CD8α⁺ T cells do not contribute to the control of virus replication after re-challenge with a homologous strain of influenza A virus

Infection with host-range mutant adenovirus 5 suppresses innate immunity and induces systemic CD4+ T cell activation in rhesus macaques.

Ad5 is a common cause of respiratory disease and an occasional cause of gastroenteritis and conjunctivitis, and seroconversion before adolescence is common in humans. To gain some insight into how Ad5 infection affects the immune system of rhesus macaques (RM) 18 RM were infected with a host-range mutant Ad5 (Ad5hr) by 3 mucosal inoculations. There was a delay of 2 to 6 weeks after the first inoculation before plasmacytoid dendritic cell (pDC) frequency and function increased in peripheral blood. Primary Ad5hr infection suppressed IFN-γ mRNA expression, but the second Ad5hr exposure induced a rapid increase in IFN-gamma mRNA in peripheral blood mononuclear cells (PBMC). Primary Ad5hr infection suppressed CCL20, TNF and IL-1 mRNA expression in PBMC, and subsequent virus exposures further dampened expression of these pro-inflammatory cytokines. Primary, but not secondary, Ad5hr inoculation increased the frequency of CXCR3+ CD4+ T cells in blood, while secondary, but not primary, Ad5hr infection transiently increased the frequencies of Ki67+, HLADR+ and CD95+/CCR5+ CD4+ T cells in blood. Ad5hr infection induced polyfunctional CD4 and CD8+ T cells specific for the Ad5 hexon protein in all of the animals. Thus, infection with Ad5hr induced a complex pattern of innate and adaptive immunity in RM that included transient systemic CD4+ T cell activation and suppressed innate immunity on re-exposure to the virus. The complex effects of adenovirus infection on the immune system may help to explain the unexpected results of testing Ad5 vector expressing HIV antigens in Ad5 seropositive people

Probing the distance and morphology of the Large Magellanic Cloud with RR Lyrae stars

We present a Bayesian analysis of the distances to 15,040 Large Magellanic Cloud (LMC) RR Lyrae stars using $V$- and $I$-band light curves from the Optical Gravitational Lensing Experiment, in combination with new $z$-band observations from the Dark Energy Camera. Our median individual RR Lyrae distance statistical error is 1.89 kpc (fractional distance error of 3.76 per cent). We present three-dimensional contour plots of the number density of LMC RR Lyrae stars and measure a distance to the core LMC RR Lyrae centre of ${50.2482\pm0.0546 {\rm(statistical)} \pm0.4628 {\rm(systematic)} {\rm kpc}}$, equivalently ${\mu_{\rm LMC}=18.5056\pm0.0024 {\rm(statistical)} \pm0.02 {\rm(systematic)}}$. This finding is statistically consistent with and four times more precise than the canonical value determined by a recent meta-analysis of 233 separate LMC distance determinations. We also measure a maximum tilt angle of $11.84^{\circ}\pm0.80^{\circ}$ at a position angle of $62^\circ$, and report highly precise constraints on the $V$, $I$, and $z$ RR Lyrae period--magnitude relations. The full dataset of observed mean-flux magnitudes, derived colour excess ${E(V-I)}$ values, and fitted distances for the 15,040 RR Lyrae stars produced through this work is made available through the publication's associated online data.Comment: 7 pages, 8 figure