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Background While the role of high flow nasal cannulae (HFNC) in the management of respiratory failure continues to expand, few studies describe its use in acute hypercapnic respiratory failure. Aims In this retrospective study we assessed the safety and efficacy of HFNC for treatment of acute hypercapnic respiratory failure. Methods Admissions with acute hypercapnic respiratory failure to a thoracic medicine unit at a tertiary centre between January and August 2018 were included if treated with either HFNC or non-invasive ventilation (NIV). The primary outcome was post-treatment change in arterial pCO2 . Demographics, comorbidities, length of stay, readmission rate and mortality were also collected. Results 64 patients were identified, comprising 69 presentations grouped according to initial treatment: HFNC (n=24) or NIV (n=45). Patients in the NIV group had more severe blood gas derangement. In both groups, mean arterial pCO2 improved significantly (-10 (95% CI: -14 to -6) mmHg) from baseline with no evidence of a differential effect between groups. Six (25%) patients were transitioned from HFNC to NIV, of whom 3 had comorbid obesity and 2 had sleep disordered breathing. No significant differences in hospital length of stay, 30-day readmission rate or 90-day mortality were observed. Conclusions HFNC may be a reasonable initial treatment for patients with mild acute hypercapnic respiratory failure who do not have comorbid obesity or sleep disordered breathing. Prospective study may help identify clinical factors or phenotypes predictive of success with this treatment modality. This article is protected by copyright. All rights reserved.

Developing B cells generate DNA double-stranded breaks (DSBs) to assemble immunoglobulin receptor (Ig) genes necessary for the expression of a mature B cell receptor. These physiologic DSBs are made by the RAG endonuclease, which is comprised of the RAG1 and RAG2 proteins. In pre-B cells, RAG-mediated DSBs activate the ATM kinase to coordinate canonical and non-canonical DNA damage responses (DDR) that trigger DSB repair and B cell developmental signals, respectively. Whether this broad cellular response is distinctive to RAG DSBs is poorly understood. To delineate the factors that direct DDR signaling in B cells, we express a tetracycline-inducible Cas9 nuclease in Rag1-deficient pre-B cells. Both RAG- and Cas9-mediated DSBs at Ig genes activate canonical DDR. In contrast, RAG DSBs, but not Cas9 DSBs, induce the non-canonical DDR-dependent developmental program. This unique response to RAG DSBs is, in part, regulated by non-core regions of RAG1. Thus, B cells trigger distinct cellular responses to RAG DSBs through unique properties of the RAG endonuclease that promotes activation of B cell developmental programs.

Development of B cells requires the programmed generation and repair of double-stranded DNA breaks in antigen receptor genes. Investigation of the cellular responses to these DNA breaks has established important insights into B cell development and, more broadly, has provided fundamental advances into the molecular mechanisms of DNA damage response pathways. Abelson transformed pre-B cell lines and primary pre-B cell cultures are malleable experimental systems with diverse applications for studying DNA damage responses. This chapter describes methods for generating these cellular systems, inducing and quantifying DSBs, and assessing DNA damage programs.

SUMMARY Early B cell development is regulated by stage-specific transcription factors. PU.1, an ETS-family transcription factor, is essential for coordination of early B cell maturation and immunoglobulin gene (Ig) rearrangement. Here we show that RAG DNA double-strand breaks (DSBs) generated during Ig light chain gene (Igl) rearrangement in pre-B cells induce global changes in PU.1 chromatin binding. RAG DSBs activate a SPIC/BCLAF1 transcription factor complex that displaces PU.1 throughout the genome and regulates broad transcriptional changes. SPIC recruits BCLAF1 to gene-regulatory elements that control expression of key B cell developmental genes. The SPIC/BCLAF1 complex suppresses expression of the SYK tyrosine kinase and enforces the transition from large to small pre-B cells. These studies reveal that RAG DSBs direct genome-wide changes in ETS transcription factor activity to promote early B cell development., In Brief ETS-family transcription factors are key regulators of early B cell development. Soodgupta et al. show that RAG-induced DNA breaks generated during antigen receptor gene recombination activate a SPIC/BCLAF1 transcription factor complex that counters PU.1 activity and regulates gene expression changes to promote transition from large to small pre-B cells., Graphical Abstract

Early B cell development is regulated by stage-specific transcription factors. PU.1, an ETS family transcription factor, is essential for coordination of early B cell maturation and immunoglobulin gene (Ig) rearrangement. Here we show that RAG DNA double-strand breaks (DSBs) generated during Ig light chain gene (Igl) rearrangement in pre-B cells induce global changes in PU.1 chromatin binding. RAG DSBs activate a SPIC/BCLAF1 transcription factor complex that displaces PU.1 throughout the genome and regulates broad transcriptional changes. SPIC uniquely recruits BCLAF1 to gene regulatory elements that control expression of key B cell developmental genes. The SPIC/BCLAF1 complex suppresses expression of the SYK tyrosine kinase and enforces the transition from large to small pre-B cells. These studies reveal that RAG DSBs direct genome-wide changes in ETS transcription factor activity to promote early B cell development.

The Narrative Cloth project was a collaboration between Fine Art and History staff at the University of Chichester. The aim of the project was to make a series of material interpretations based on research by historian Dr Danae Tankard into the clothing of the 17th century rural poor and the Clothing Project based at the Weald and Downland Open Air Museum. \ud The practical and interpretative processes that were used to create a body of textile-based work are looked at in detail in this paper along with themes relating to value in making, craft, personal identity and social dynamics.

Dispersal from release areas is a critical problem for reintroductions. Reliable methods are therefore needed for analysing post-release monitoring data to guide further releases. Radio tracking can greatly improve data quality by distinguishing dispersal from mortality. However, fates of animals continue to be uncertain if transmitters have short battery life and detection range, as is typically the case with small animals. We present an approach for simultaneously modelling probabilities of fidelity (remaining in release area), survival, detection and transmitter failure from post-release monitoring data, and illustrate how it was applied to translocations of North Island robins ( Petroica longipes ) to 17 forest fragments (5–56 ha) over 5 years. The modelling showed that fidelity probability depended on the sex (higher in females) and translocation date (higher in winter than autumn), and that variation among fragments was well explained by the “cost distance to nearest neighbour” (an index reflecting the amount of pasture and shrubland needing to be crossed to reach another forest area) and the area of the release fragment (higher in larger fragments). Combined with survival, the estimated probability of a bird remaining in its release fragment the next breeding season ranged from 0.02 to 0.39. As these estimates were refined, they could be used to assess suitability of fragments for further releases and numbers of each sex needing to be released to compensate for dispersal. The Bayesian framework underlying the approach potentially allows application to any amount of data by using informative priors derived from previous translocations or expert opinion.

Hematopoietic stem cells (HSC) persist throughout life by undergoing extensive self-renewal divisions while maintaining an undifferentiated state. The mechanisms that support HSC self-renewal change throughout the course of development as temporal changes in transcriptional regulators coordinate distinct genetic programs in fetal, post-natal and adult HSCs. These self-renewal programs are often ectopically activated in leukemia cells to drive neoplastic proliferation and high expression of HSC-associated genes predicts a poor prognosis in acute myelogenous leukemia (AML). In this regard, it was recently shown that expression of the transcriptional regulator BCLAF1 (Bcl2 associated transcription factor 1) is increased in AML blasts relative to normal precursor populations and suppression of BCLAF1 causes reduced proliferation and induction of differentiation to a dendritic cell fate. These findings raise the question of whether BCLAF1 may regulate normal as well as neoplastic self-renewal programs. We find that Bclaf1 is highly expressed in HSCs versus committed bone marrow populations consistent with a potential role for this gene in HSC functions. To test whether BCLAF1 regulates HSC development and hematopoiesis, we used germline loss of function mice. Bclaf1-/- mice succumb to pulmonary failure shortly after birth due to poor lung development, so we assessed prenatal hematopoiesis. Bclaf1-deficient mice had significantly reduced HSC and hematopoietic progenitor cell (HPC) frequencies and numbers despite normal fetal liver cellularity. To determine if Bclaf1 is required for HSC function during fetal development, we performed competitive reconstitution assays. Fetal liver cells from Bclaf1+/+or Bclaf1-/-mice were transplanted along with wild-type competitor bone marrow cells into lethally irradiated recipient mice. Compared to recipients of Bclaf1+/+fetal liver cells, recipients of Bclaf1-/-cells had a significantly lower percentage of donor-derived leukocytes at all time points after transplantation as well as reduced percentage of donor HSCs at 16 weeks post-transplant. Notably, all leukocyte populations (B cells, T cells, granulocytes and macrophages) from Bclaf1-/-donors were reduced consistent with an abnormality in HSC repopulating activity rather than a defect in a specific differentiation pathway. Consistent with these findings, Bclaf-deficient cells did not engraft in competitive transplants with limiting numbers of sorted fetal liver HSCs whereas sorted wild-type Bclaf1+/+cells effectively reconstituted hematopoiesis in recipient mice. In addition, Vav-cre:Bclaf1flox/floxmice, which have selective deletion of Bclaf1 in hematopoietic cells, have reduced frequencies and numbers of fetal liver HSCs identical to the findings observed in germline Bclaf1-/-mice. These results show that loss of Bclaf1 leads to defective development and repopulating activity of fetal HSCs. Interestingly, when adult mice are successfully engrafted with Bclaf1-deficient HSCs, the donor HSCs suffer no additional functional impairment. Furthermore, in secondary transplant experiments Bclaf1-deficient HSCs maintain long-term repopulating activity. Thus, Bclaf1 may have distinct functions in fetal versus adult HSC self-renewal. Collectively, our findings reveal Bclaf1 is a novel regulator of fetal HSC function and suggest that it may have distinct functions in different developmental contexts. Disclosures No relevant conflicts of interest to declare.

As early as 1979, Frances Smith Foster was writing about the potential cultural power of collaborative humanities pedagogy. In an article written long before the slew of new anthologies that took hold in classrooms in the 1990s (several of which would be coedited by Foster herself), she reported on an innovative curriculum project to bring "previously unheard voices and stories" of women writers into classrooms ("Voices" 22). Foster chronicled not only the development of a new course for her own institution, then San Diego State University, but also how that process grew through collaboration. Opening the curriculum to little-studied women's texts, teachers from a range of college and university settings developed new courses. Foster's account rings with the energy of early canon interventions. It chronicles "interdisciplinary approaches to [asking] literary questions" and to enabling students' own primary research (19). It also urges readers to tell more stories about aspirational humanities education. Here, we seek to follow that forward-looking vision while also paying tribute to Foster. In a spirit we hope she would endorse, this essay emerged from conversations linking scholarship and teaching. Legacy had invited Sarah to submit a tribute, probably because of her involvement in nominating Foster for SSAWW'S lifetime achievement award. However, building on exchanges during Rachel's doctoral exams, we realized we should coauthor this essay. The impact Rachel's reading of Foster's writing is having on an emerging scholar-teacher demonstrates the enduring reach of Foster's influence. We hope, too, that emulating Foster's model of collaboration will reaffirm principles for feminist academic work that she promotes. Writing for Legacy, Foster celebrated her multiple collaborations with Nellie McKay ("Continuities" 12). Following Foster's lead, we collaborate here. With you, our readers, we will share several of our readings of Foster's texts and of her professional practice. This story culls only a few highlights of how Foster has guided our work. We begin by revisiting Foster's contributions to an NEH-sponsored institute from early in Sarah's university career. Then, Rachel describes how her current reading of Foster's writings is supporting a young academic's development. SARAH'S FIRST COLLABORATIVE STUDY WITH FRANCES My first personal experience reading Frances Smith Foster came through a curriculum project she generously joined in the 1990s. At Kennesaw State, one of my responsibilities was leading outreach to area educators. After one NEH-funded project had demonstrated a high interest level in curricular innovation among area teachers, we sought a larger grant for a three-year partnership with the University of California and the University of Michigan. "Making American Literatures" promoted canon changes in secondary school teaching. In the first year, team leaders convened in Berkeley for a two-week institute. In succeeding years, each region ran its own institute and school-year collaborative study. Frances, then housed at nearby Emory, joined our teaching team at Kennesaw State. During a project I had previously directed, "Domesticating the Canon," our NEH program officer Janet Edwards described the crucial role scholars leading the program can play. "The most important texts to read: Janet said, "are the scholars who come to the institute" to collaborate with participants. In the "Making American Literatures" initiative, Frances embodied that assessment. She spent several days with the secondary teachers exploring Minnie's Sacrifice, Sowing and Reaping, Trial and Triumph: Three Rediscovered Novels, an edition based on recovering Frances Harper's long-lost serialized texts. Of all the primary materials studied that summer, Harper's narratives easily became the favorite. When the teachers divvied up our budget for purchasing class sets that could rotate around classrooms throughout metro Atlanta, this text won hands down. …