Probing UV-Sensitive Pathways for CN and HCN Formation in Protoplanetary Disks with the Hubble Space Telescope

The UV radiation field is a critical regulator of gas-phase chemistry in surface layers of disks around young stars. In an effort to understand the relationship between photocatalyzing UV radiation fields and gas emission observed at infrared and sub-mm wavelengths, we present an analysis of new and archival HST, Spitzer, ALMA, IRAM, and SMA data for five targets in the Lupus cloud complex and 14 systems in Taurus-Auriga. The HST spectra were used to measure LyA and FUV continuum fluxes reaching the disk surface, which are responsible for dissociating relevant molecular species (e.g. HCN, N2). Semi-forbidden C II] 2325 and UV-fluorescent H2 emission were also measured to constrain inner disk populations of C+ and vibrationally excited H2. We find a significant positive correlation between 14 micron HCN emission and fluxes from the FUV continuum and C II] 2325, consistent with model predictions requiring N2 photodissociation and carbon ionization to trigger the main CN/HCN formation pathways. We also report significant negative correlations between sub-mm CN emission and both C II] and FUV continuum fluxes, implying that CN is also more readily dissociated in disks with stronger FUV irradiation. No clear relationships are detected between either CN or HCN and LyA or UV-H2 emission. This is attributed to the spatial stratification of the various molecular species, which span several vertical layers and radii across the inner and outer disk. We expect that future observations with JWST will build on this work by enabling more sensitive IR surveys than were possible with Spitzer.Comment: Accepted for publication in A

FOXM1 Deubiquitination by USP21 Regulates Cell Cycle Progression and Paclitaxel Sensitivity in Basal-like Breast Cancer

The cell cycle transcription factor FOXM1 is activated in basal-like breast cancer (BLBC) and associated with therapeutic resistance and poor patient outcomes. Arceci et al. show USP21 antagonizes FOXM1 degradation, thereby promoting proliferation and paclitaxel resistance. USP21 is catalytically active and recurrently overexpressed in BLBC, representing a potential therapeutic target. © 2019 The Author(s)The transcription factor FOXM1 contributes to cell cycle progression and is significantly upregulated in basal-like breast cancer (BLBC). Despite its importance in normal and cancer cell cycles, we lack a complete understanding of mechanisms that regulate FOXM1. We identified USP21 in an RNAi-based screen for deubiquitinases that control FOXM1 abundance. USP21 increases the stability of FOXM1, and USP21 binds and deubiquitinates FOXM1 in vivo and in vitro, indicating a direct enzyme-substrate relationship. Depleting USP21 downregulates the FOXM1 transcriptional network and causes a significant delay in cell cycle progression. Significantly, USP21 depletion sensitized BLBC cell lines and mouse xenograft tumors to paclitaxel, an anti-mitotic, frontline therapy in BLBC treatment. USP21 is the most frequently amplified deubiquitinase in BLBC patient tumors, and its amplification co-occurs with the upregulation of FOXM1 protein. Altogether, these data suggest a role for USP21 in the proliferation and potentially treatment of FOXM1-high, USP21-high BLBC

Nuclear Localized LSR: A Novel Regulator of Breast Cancer Behavior and Tumorigenesis

Lipolysis Stimulated Lipoprotein Receptor (LSR) has been found in the plasma membrane and is believed to function in lipoprotein endocytosis and tight junctions. Given the impact of cellular metabolism and junction signaling pathways on tumor phenotypes and patient outcome, it is important to understand how LSR cellular localization mediates its functions. We conducted localization studies, evaluated DNA binding, and examined the effects of nuclear LSR in cells, xenografts, and clinical specimens. We found LSR within the membrane, cytoplasm, and the nucleus of breast cancer cells representing multiple intrinsic subtypes. Chromatin immunoprecipitation (ChIP) showed direct binding of LSR to DNA, and sequence analysis identified putative functional motifs and post-translational modifications of the LSR protein. While neither overexpression of transcript variants, nor pharmacological manipulation of post-translational modification significantly altered localization, inhibition of nuclear export enhanced nuclear localization, suggesting a mechanism for nuclear retention. Co-immunoprecipitation and proximal ligation assays indicated LSR-pericentrin interactions, presenting potential mechanisms for nuclear-localized LSR. The clinical significance of LSR was evaluated using data from over 1,100 primary breast tumors, which showed high LSR levels in basal-like tumors and tumors from African-Americans. In tumors histosections, nuclear localization was significantly associated with poor outcomes. Finally, in vivo xenograft studies revealed that basal-like breast cancer cells that over-express LSR exhibited both membrane and nuclear localization, and developed tumors with 100% penetrance, while control cells lacking LSR developed no tumors. These results show that nuclear LSR alters gene expression and may promote aggressive cancer phenotypes

A Global Community of Courts? Modelling the Use of Persuasive Authority as a Complex Network

There is a growing discussion in the legal literature of an emerging global community of courts composed of a network of increasing judicial dialogue across national borders. We investigate the use of foreign persuasive authority in common law countries by analyzing the network of citations to case law in a corpus of over 1.5 million judgments given by the senior courts of twenty-six common law countries. Our corpus of judgments is derived from data available in the vLex Justis database. In this paper we aim to quantify the flow of jurisprudence across the countries in our corpus and to explore the factors that may influence a judge’s selection of foreign jurisprudence. Utilization of foreign case law varies across the countries in our data, with the courts of some countries presenting higher engagement with foreign jurisprudence than others. Our analysis shows that there has been an upward trend in the use of foreign case law over time, with a marked increase in citations across national borders from the 1990s onward, potentially indicating that increased digital access to foreign judgments has served to facilitate and promote comparative analysis. Not only has the use of foreign case law generally increased over time, the factors that may influence the selection of case law have also evolved, with judges gradually casting their research beyond the most influential and well-known foreign authorities. Notwithstanding that judgments emanating from the United Kingdom (chiefly from the courts of England and Wales) constitute the most frequently consulted body of jurisprudence, we find evidence that domestic courts favor citing the case law of countries that are geographically proximal

In vitro and in vivo analysis of B-Myb in basal-like breast cancer

A defining feature of basal-like breast cancer, a breast cancer subtype with poor clinical prognosis, is the high expression of “proliferation signature” genes. We identified B-Myb, a MYB family transcription factor that is often amplified and overexpressed in many tumor types, as being highly expressed in the proliferation signature. However, the roles of B-Myb in disease progression, and its mammary-specific transcriptional targets, are poorly understood. Here, we demonstrated that B-Myb expression is a significant predictor of survival and pathological complete response to neoadjuvant chemotherapy in breast cancer patients. We also identified a significant association between the G/G genotype of a nonsynonymous B-Myb germline variant (rs2070235, S427G) and an increased risk of basal-like breast cancer [OR 2.0, 95% CI (1.1-3.8)]. In immortalized, human mammary epithelial cell lines, but not basal-like tumor lines, cells ectopically expressing wild-type B-Myb or the S427G variant showed increased sensitivity to two DNA topoisomerase IIα inhibitors, but not to other chemotherapeutics. In addition, microarray analyses identified many G2/M genes as being induced in B-Myb overexpressing cells. These results confirm that B-Myb is involved in cell cycle control, and that dysregulation of B-Myb may contribute to increased sensitivity to a specific class of chemotherapeutic agents. These data provide insight into the influence of B-Myb in human breast cancer, which is of potential clinical importance for determining disease risk and for guiding treatment

Intratumor Heterogeneity of the Estrogen Receptor and the Long-term Risk of Fatal Breast Cancer.

Background:Breast cancer patients with estrogen receptor (ER)-positive disease have a continuous long-term risk for fatal breast cancer, but the biological factors influencing this risk are unknown. We aimed to determine whether high intratumor heterogeneity of ER predicts an increased long-term risk (25 years) of fatal breast cancer. Methods:The STO-3 trial enrolled 1780 postmenopausal lymph node-negative breast cancer patients randomly assigned to receive adjuvant tamoxifen vs not. The fraction of cancer cells for each ER intensity level was scored by breast cancer pathologists, and intratumor heterogeneity of ER was calculated using Rao's quadratic entropy and categorized into high and low heterogeneity using a predefined cutoff at the second tertile (67%). Long-term breast cancer-specific survival analyses by intra-tumor heterogeneity of ER were performed using Kaplan-Meier and multivariable Cox proportional hazard modeling adjusting for patient and tumor characteristics. Results:A statistically significant difference in long-term survival by high vs low intratumor heterogeneity of ER was seen for all ER-positive patients (P < .001) and for patients with luminal A subtype tumors (P = .01). In multivariable analyses, patients with high intratumor heterogeneity of ER had a twofold increased long-term risk as compared with patients with low intratumor heterogeneity (ER-positive: hazard ratio [HR] = 1.98, 95% confidence interval [CI] = 1.31 to 3.00; luminal A subtype tumors: HR = 2.43, 95% CI = 1.18 to 4.99). Conclusions:Patients with high intratumor heterogeneity of ER had an increased long-term risk of fatal breast cancer. Interestingly, a similar long-term risk increase was seen in patients with luminal A subtype tumors. Our findings suggest that intratumor heterogeneity of ER is an independent long-term prognosticator with potential to change clinical management, especially for patients with luminal A tumors

Live Coding, Live Notation, Live Performance

This paper/demonstration explores relationships between code, notation including representation, visualisation and performance. Performative aspects of live coding activities are increasingly being investigated as the live coding movement continues to grow and develop. Although live instrumental performance is sometimes included as an accompaniment to live coding, it is often not a fully integrated part of the performance, relying on improvisation and/or basic indicative forms of notation with varying levels of sophistication and universality. Technologies are developing which enable the use of fully explicit music notations as well as more graphic ones, allowing more fully integrated systems of code in and as performance which can also include notations of arbitrary complexity. This itself allows the full skills of instrumental musicians to be utilised and synchronised in the process. This presentation/demonstration presents work and performances already undertaken with these technologies, including technologies for body sensing and data acquisition in the translation of the movements of dancers and musicians into synchronously performable notation, integrated by live and prepared coding. The author together with clarinetist Ian Mitchell present a short live performance utilising these techniques, discuss methods for the dissemination and interpretation of live generated notations and investigate how they take advantage of instrumental musicians’ training-related neuroplasticity skills

What do we teach when we teach the Learning Sciences? A document analysis of 75 graduate programs

The learning sciences, as an academic community investigating human learning, emerged more than 30 years ago. Since then, graduate learning sciences programs have been established worldwide. Little is currently known, however, about their disciplinary backgrounds and the topics and research methods they address. In this document analysis of the websites of 75 international graduate learning sciences programs, we examine central concepts and research methods across institutions, compare the programs, and assess the homogeneity of different subgroups. Results reveal that the concepts addressed most frequently were real-world learning in formal and informal contexts, designing learning environments, cognition and metacognition, and using technology to support learning. Among research methods, design-based research (DBR), discourse and dialog analyses, and basic statistics stand out. Results show substantial differences between programs, yet programs focusing on DBR show the greatest similarity regarding the other concepts and methods they teach. Interpreting the similarity of the graduate programs using a community of practice perspective, there is a set of relatively coherent programs at the core of the learning sciences, pointing to the emergence of a discipline, and a variety of multidisciplinary and more heterogeneous programs “orbiting” the core in the periphery, shaping and innovating the field

BreakTrans: Uncovering the genomic architecture of gene fusions

Producing gene fusions through genomic structural rearrangements is a major mechanism for tumor evolution. Therefore, accurately detecting gene fusions and the originating rearrangements is of great importance for personalized cancer diagnosis and targeted therapy. We present a tool, BreakTrans, that systematically maps predicted gene fusions to structural rearrangements. Thus, BreakTrans not only validates both types of predictions, but also provides mechanistic interpretations. BreakTrans effectively validates known fusions and discovers novel events in a breast cancer cell line. Applying BreakTrans to 43 breast cancer samples in The Cancer Genome Atlas identifies 90 genomically validated gene fusions. BreakTrans is available at http://bioinformatics.mdanderson.org/main/BreakTran

Tumor Evolution in Two Patients with Basal-like Breast Cancer: A Retrospective Genomics Study of Multiple Metastases

Metastasis is the main cause of cancer patient deaths and remains a poorly characterized process. It is still unclear when in tumor progression the ability to metastasize arises and whether this ability is inherent to the primary tumor or is acquired well after primary tumor formation. Next-generation sequencing and analytical methods to define clonal heterogeneity provide a means for identifying genetic events and the temporal relationships between these events in the primary and metastatic tumors within an individual