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Fetal magnetic resonance imaging (MRI) is increasingly utilized for prenatal diagnosis of agenesis of the corpus callosum (ACC). This study aimed to (1) describe cases of ACC diagnosed by fetal MRI, (2) determine the frequency of postnatal confirmation by MRI, and (3) understand postnatal outcomes of infants with ACC.Maternal records from Children's National Hospital between January 2012 and June 2019 with a prenatal neurological consultation, fetal MRI, and ACC on imaging were included. Maternal, prenatal, and postnatal infant data were collected. Each case was categorized as complete or partial ACC and isolated or complex ACC by fetal MRI and group comparisons of outcomes were analyzed.A total of 127 maternal-fetal dyads with ACC were categorized into 45 isolated-complete, 17 isolated-partial, 46 complex-complete, and 19 complex-partial ACC. Of 75 live births, 72 had postnatal evaluations. In 43 of 59 (73%) cases with postnatal neuroimaging, prenatal ACC subcategory was confirmed. Children with isolated or complex and with partial or complete ACC had similar rates of developmental delays and epilepsy. Complex ACC cases had worse outcomes than isolated ACC, with complex ACC having more postnatal dysmorphisms and abnormal feeding and vision compared with isolated ACC. Similar neurodevelopmental outcomes were seen for partial and complete ACC.Children with isolated or complex ACC and with partial or complete ACC have a range of neurodevelopmental outcomes. Fetal and postnatal brain MRI is a valuable tool to understand differences of the corpus callosum that can guide genetic testing, prenatal counseling, and postnatal care.

The perinucleolar compartment (PNC) is a dynamic subnuclear body found at the periphery of the nucleolus. The PNC is enriched with RNA transcripts and RNA-binding proteins, reflecting different states of genome organization. PNC prevalence positively correlates with cancer progression and metastatic capacity, making it a useful marker for metastatic cancer progression. A high-throughput, high-content assay was developed to identify novel small molecules that selectively reduce PNC prevalence in cancer cells. We identified and further optimized a pyrrolopyrimidine series able to reduce PNC prevalence in PC3M cancer cells at submicromolar concentrations without affecting cell viability. SAR exploration of the structural elements necessary for activity resulted in the discovery of several potent compounds. Analysis of in vitro drug-like properties led to the discovery of the bioavailable analogue, metarrestin, which has shown potent antimetastatic activity with improved survival in rodent models and is currently being evaluated in a first-in-human Phase 1 clinical trial.

O objetivo do estudo é analisar o papel facilitador do uso de informações gerenciais entre o mindfulness organizacional em direção à transformação digital e agilidade de mercado. Uma amostra de startups brasileiras foi investigada via survey. Os dados foram analisados via modelagem de equações estruturais e fuzzy-set qualitative comparative analysis. Os resultados revelam um efeito indireto do mindfulness organizacional em direção à transformação digital na agilidade de mercado, com mediação total do uso de informações gerenciais. Para alta (baixa) agilidade de mercado, a presença (ausência) de mindfulness organizacional em direção à transformação digital e uso de informações gerenciais é fundamental.

We present here an account of the way we employ the reading of poetry in engaging participants of an intensive four-week creative arts programme known as ARRTS (Arts for Recovery, Resilience, Teamw...

Subclinical mastitis, a common intramammary disease in sheep production, can be costly to producers due to compromised performance and decreased longevity. Our research focused on preventative and therapeutic measures on mammary health where the objectives were to identify (1) the impact of Zn supplementation on the milk microbiome and (2) the impact of management practices at lambing and weaning on prevalence and cure rate of subclinical mastitis, the milk microbiome, and levels of antimicrobial resistance in milk bacteria. In study 1, the milk microbiome was characterized during the first 3 wk of lactation and at weaning in ewes divergent in dietary Zn supplementation (1× = CON or 3× recommendations = ZnTRT). Mammary health was assessed using somatic cell count (SCC) class. Amplicon sequencing revealed the presence of Staphylococcus, Mannheimia, Corynebacterium, and Pseudomonas, all major mastitis pathogens. Effects of breed, dietary Zn concentration, and SCC class on diversity were limited to early lactation, where CON milk had greater composition stability than ZnTRT milk (P = 0.02). In study 2, milk bacteria were characterized by culture; Staphylococcus spp. and Streptococcus spp. were tested for antimicrobial susceptibility. Subclinical mastitis prevalence ranged from 22–66% where coagulase-negative staphylococci (CoNS; 59%), bacilli (35%), Mannheimia haemolytica (10%), S. aureus (8%), streptococci (5%), and Corynebacterium spp. (5%) were common. Milk samples were compared by jug bedding treatment: jugs were cleaned and dried with barn lime before adding fresh straw (CLEAN) or fresh straw was added atop soiled bedding (SOILED). Bedding had no effect on subclinical mastitis (P = 0.57), but CoNS had greater sulfadimethoxine resistance in SOILED isolates (P = 0.03). Additional mastitis control methods at weaning were evaluated: penicillin injection (PENN), restricted feed access (FAST), or their combination (COMBO). Weaning treatment did not affect cure rate from weaning to 3-d post- weaning (P = 0.21). Further characterization of these samples via microbial sequencing are underway with source tracking analyses to investigate an exogenous route via retrograde transfer and environmental bacteria or endogenous route via an entero-mammary pathway. Results support that breed, animal husbandry, and mammary health variably affect the milk microbiome and provide novel insight to the impact of management practices in a milk microbiome longitudinal study.

Dyslipidemia is a cardiovascular risk factor for coronary artery disease and atherosclerosis that is characterized by elevated serum cholesterol and lipid levels. Although high-density lipoprotein-associated cholesterol (HDL-C) is associated with reduced risk of cardiovascular events, targeted therapy to increase HDL-C levels have been unsuccessful in altering outcomes of associated atherosclerotic disease. Single nucleotide polymorphisms in SCARB1 , the gene that encodes HDL receptor Scavenger Receptor B1 (SR-BI), are associated with dyslipidemia and atherosclerotic cardiovascular disease. We were the first to identify inherited mutations in SCARB1 that segregate with disease in a family with severe coronary artery disease and dyslipidemia, including elevated HDL. Our findings suggest that HDL function (vs. HDL-C concentration) may be a promising target for cholesterol-based therapy. Here, we performed an unbiased high throughput drug screen with 788 FDA-approved compounds, using HepG2 cells to measure endogenous HDL binding. We identified five compounds that significantly increased endogenous HDL binding: imatinib, trimethoprim, eszopiclone, clemastine, and mepenzolate, of which, imatinib was the only compound to increase SR-BI expression. Imatinib is a tyrosine kinase inhibitor that is a chemotherapeutic agent designed to treat individuals with chronic myeloid leukemia. Limited clinical evidence suggests a reduction in total cholesterol with 400mg/day imatinib. Additionally, imatinib treatment (150mg/kg) in mouse models of atherosclerosis reduces total cholesterol. Yet, no data is available on the effects of imatinib on HDL and reverse cholesterol transport. We have found that imatinib promotes HDL binding and SR-BI expression in vitro . Furthermore, in wildtype C57Bl/6 mice on a high fat, high cholesterol diet, imatinib treatment (50mg/kg) was sufficient to decrease plasma total cholesterol, HDL-C and triglyceride levels and elevate hepatic SR-BI expression. In summary, our data supports the exploration of imatinib-mediated SR-BI regulation, HDL metabolism, and RCT pathway to identify new therapeutic targets for dyslipidemia.

Hepatic metabolic stability is a key pharmacokinetic parameter in drug discovery. Metabolic stability is usually assessed in microsomal fractions and only the best compounds progress in the drug discovery process. A high-throughput single time point substrate depletion assay in rat liver microsomes (RLM) is employed at the National Center for Advancing Translational Sciences. Between 2012 and 2020, RLM stability data was generated for ~ 24,000 compounds from more than 250 projects that cover a wide range of pharmacological targets and cellular pathways. Although a crucial endpoint, little or no data exists in the public domain. In this study, computational models were developed for predicting RLM stability using different machine learning methods. In addition, a retrospective time-split validation was performed, and local models were built for projects that performed poorly with global models. Further analysis revealed inherent medicinal chemistry knowledge potentially useful to chemists in the pursuit of synthesizing metabolically stable compounds. In addition, we deposited experimental data for ~ 2500 compounds in the PubChem bioassay database (AID: 1508591). The global prediction models are made publicly accessible (https://opendata.ncats.nih.gov/adme). This is to the best of our knowledge, the first publicly available RLM prediction model built using high-quality data generated at a single laboratory.

In public discourse, there is a tendency for arts and science – or, more broadly, academic research – to be cast as irreconcilable at best and oppositional at worst. However, the explication of trauma, resilience and wellbeing in creative writing is as much a matter of science communication as literary practice. It involves writing down the bones of the phenomena that researchers chart and treat, exploiting the narrative and poetic properties of such endeavours, and making explicit both cognition and affect, empirical evidence and felt experience. It is evident in fictional worldmaking, creative nonfiction, poetry, and in hybrid works such as narratives that combine memoir and scholarship. Such diverse approaches to literary expression do not necessarily aim to extend theory or present experimental data, but to provide opportunities for alternative ways to view and review such material content, and explicitly incorporate imaginative and evocative engagements. At their best, such writings enact a form of affective, micro-macro testimony that has the potential to demystify scholarly findings, personalise and humanise related issues, confront denial and minimisation, and build bridges between what C.P. Snow named the “two cultures”. This paper begins by considering Snow’s advice to rethink how science and literature operate, and moves on to discuss hybrid and multiple lines of knowledge and practice – in fiction, memoir and personal writing, and healing workshops – that can build bridges across knowledge domains and social cultures, and afford recovery from personal, community and environmental trauma.

Problems with drug ADME are responsible for many clinical failures. By understanding the ADME properties of marketed drugs and modeling how chemical structure contributes to these inherent properties, we can help new projects reduce their risk profiles. Kinetic aqueous solubility, the parallel artificial membrane permeability assay (PAMPA), and rat liver microsomal stability constitute the Tier I ADME assays at the National Center for Advancing Translational Sciences (NCATS). Using recent data generated from in-house lead optimization Tier I studies, we update quantitative structure-activity relationship (QSAR) models for these three endpoints and validate in silico performance against a set of marketed drugs (balanced accuracies range between 71% and 85%). Improved models and experimental datasets are of direct relevance to drug discovery projects and, together with the prediction services that have been made publicly available at the ADME@NCATS web portal (https://opendata.ncats.nih.gov/adme/), provide important tools for the drug discovery community. The results are discussed in light of our previously reported ADME models and state-of-the-art models from scientific literature.

Objectives To examine the impact of a nurse-led intervention on anxiety levels and perceived self-efficacy to cope in patients receiving first-time chemotherapy using a customized prechemotherapy educational virtual reality (VR) video. Sample & setting 35 patients with cancer receiving first-time chemotherapy participated in this study at a large suburban cancer center in Newark, Delaware. Methods & variables A single-group, quasi-experimental pilot study was conducted to examine the feasibility of a customized prechemotherapy educational VR video in patients receiving first-time chemotherapy. The State-Trait Anxiety Inventory, heart rate, and blood pressure were used to measure anxiety, and the Cancer Behavior Inventory-Brief Version measured perceived self-efficacy to cope with cancer. Measures were taken pre- and postintervention, and patient satisfaction was examined postintervention. Results Anxiety level, heart rate, and blood pressure significantly decreased from baseline to postintervention, and perceived self-efficacy to cope significantly increased from baseline to postintervention. Implications for nursing Personalized prechemotherapy educational VR videos could be further examined as an innovative nursing intervention to meet the health, emotional, and educational needs of diverse patient populations.

Specimen-based data are an invaluable resource for an increasing diversity of scientific fields, including global change biology, ecology, evolution, and genetics; however, certain analyses of these data may be limited by the non-random nature of collecting activity. Geographic, temporal, and trait-based collecting biases may consequently affect the understanding of species’ distributions, obviating the need to determine what biases exist and how they may impact further analyses. Trait-based biases were examined in herbarium specimen records of two abundant and diverse families (Asteraceae and Fabaceae) in a well-collected and digitized region (California) by comparing geographic-bias-adjusted simulations of random collections to actual collecting patterns. Collecting biases were fairly similar between families for a number of traits, such as a strong bias against collecting introduced species, while seasonal collecting biases showed a peak in activity in the Spring for both families. However, while there was only a dip in the fall for Asteraceae, Fabaceae were seriously under-collected for the majority of the year. These results demonstrate that significant collecting biases exist and may differ depending on the dataset, highlighting the importance of understanding the dataset and potentially accounting for its sampling limitations.

While there are many factors that affect traffic accidents, safe road design plays a key role. It is critical to understand traffic flow and driver response to various scenarios. Furthermore, with the inclusion of new traffic trends such as bicycle friendly roads and autonomous vehicles, it is ever more important to study the complex relationships between traffic entities. However, controlled experiments can be difficult to implement in the real world. Traffic simulation has been researched for decades to understand the flow of traffic in a variety of environments and how users interact within it. However, these platforms are limited in simulation and authoring capabilities, do not allow for multiple human agents, or are not accessible by roadway designers. This research explores the technical development of a multi-user multi-modal traffic simulation platform that expands on the capabilities of traditional traffic simulators. Traffic simulation of virtual cars and pedestrian agents were generated through VISSIM and networked into a simulation platform. Multiple human agents can interface with the system through a physical car and bicycle rig featuring both a virtual reality head mounted display and a multi-monitor display. Furthermore, the multi-user nature of the platform allows for a variety of complex research applications including multi-user behavior. By utilizing low-cost commodity hardware and software, the accessibility of this platform is greatly increased. A testbed environment was created to evaluate the technical limitations of the platform and assess where further work is needed. Through this evaluation, the authoring process and networking capabilities were optimized. Additionally, the core functionality of the platform, including the various simulator modes and multi-user functionality, was found to be successful. Through this research, combining commodity hardware with traffic simulation will allow a larger number of researchers to better understand traffic environments and how humans may interact within them.

Obesity rates have been climbing steadily for the past hundred years, and in conjunction so have the rates of many metabolic disease. The reasons for this are both complex and multifaceted. Homecooked meals have been replaced by many highly processed foods, while lifestyles have become more sedentary. Throughout this time, as obesity rates have grown, the consumption of fructose has increased in parallel. In addition to the correlation between fructose consumption and obesity it has been linked to the development of multiple metabolic diseases, including hypertension, NAFLD, diabetes, and cancer. While great strides have been made to begin to understand these associations, more work is required to mechanistically link fructose-induced metabolism to the development of metabolic disease. More specifically, evidence is lacking for how fructose catabolism is altered after the continued ingestion of a high-fructose diet for long periods of time, and these specific changes to metabolic pathways are hypothesized to drive the development of many of these metabolic diseases which continue to plague society. In the following chapters we strove to answer some of these questions through investigating the effects of long-term high-fructose feeding in FVB/N mice. Overall, these mice were resistant to the development of fructose-driven obesity and glucose intolerance, while still showing evidence of metabolic disturbance in peripheral tissues. Furthermore, while short-term high-fructose feeding in these mice led to an increase in fructolytic and adipogenic genes, as expected, long-term high-fructose feeding caused these same metabolic pathways to no longer be elevated. These data provide evidence for a fructolytic pathway which cannot be maintained after excessive and prolonged high-fructose feeding.

Membrane permeability plays an important role in oral drug absorption. Caco-2 and Madin-Darby Canine Kidney (MDCK) cell culture systems have been widely used for assessing intestinal permeability. Since most drugs are absorbed passively, Parallel Artificial Membrane Permeability Assay (PAMPA) has gained popularity as a low-cost and high-throughput method in early drug discovery when compared to high-cost, labor intensive cell-based assays. At the National Center for Advancing Translational Sciences (NCATS), PAMPA pH 5 is employed as one of the Tier I absorption, distribution, metabolism, and elimination (ADME) assays. In this study, we have developed a quantitative structure activity relationship (QSAR) model using our ∼6500 compound PAMPA pH 5 permeability dataset. Along with ensemble decision tree-based methods such as Random Forest and eXtreme Gradient Boosting, we employed deep neural network and a graph convolutional neural network to model PAMPA pH 5 permeability. The classification models trained on a balanced training set provided accuracies ranging from 71% to 78% on the external set. Of the four classifiers, the graph convolutional neural network that directly operates on molecular graphs offered the best classification performance. Additionally, an ∼85% correlation was obtained between PAMPA pH 5 permeability and in vivo oral bioavailability in mice and rats. These results suggest that data from this assay (experimental or predicted) can be used to rank-order compounds for preclinical in vivo testing with a high degree of confidence, reducing cost and attrition as well as accelerating the drug discovery process. Additionally, experimental data for 486 compounds (PubChem AID: 1645871) and the best models have been made publicly available (https://opendata.ncats.nih.gov/adme/).

OBJECTIVE: To compare in-hospital outcomes after umbilical cord milking versus delayed cord clamping among infants

ObjectiveTo assess whether length of hospital stay is decreased among moderately preterm infants weaned from incubator to crib at a lower vs higher weight.Study designThis trial was conducted in the Eunice Kennedy Shriver National Institute of Child Health and Human Development Neonatal Research Network. Infants with gestational ages 29-33 weeks, birthweight

Canberra is now a century old, and locals are recovering from a year of centenary celebrations. One of the factors that emerged during this year was the gap between its two states of being: Canberra is both the national capit[al] – the ‘head’ of the nation; and at the same time a community's hometown. The centenary celebrations also generated discussion about its history, and the process of its development from territory, through ‘sheep paddock’, to at once a federal capital and a small regional city. To a large extent, this history is story: a set of possibilities and lines of thought that have coalesced in the idea of a capital. Expounding sometimes ideals and sometimes practicalities, and complying with policy, legislation and aesthetic theories, the initiators of Canberra established a way of living in, and thinking through, what it is to be within a landscape, within discourse and within particular ideas of history. We draw on insights from Jean Baudrillard, and Deleuze and Guattari, and reference th...

This article is co-authored by three writer-academics who have been collaborating as supervisors, doctoral candidates and co-authors over the past decade. Jen Webb supervised Jordan Williams during her creative PhD in digital poetry and Deleuze (awarded 2006); Jordan and Jen co-supervised Paul Collis’s creative PhD in fiction and Barkindji identity (awarded 2016); and he has long supervised both Jen and Jordan in their (informal) education in Indigenous epistemology. Over these years, the supervisor-candidate relationships have unfolded, developed, changed and folded back on themselves. We explore how this long-term relationship between three mature-aged writers and scholars, from three very different cultural backgrounds, has inflected our individual approaches to the preparation and writing of creative research, including the exegesis. We begin, therefore, with our own understandings of what the word ‘exegesis’ means to us, how it mobilised (or hindered) the generation of creative knowledge, what models are of value to us, and what we envisage as its possible future/s. We write this in the form of a three-way conversation, with scholarly annotations.

Lymph node (LN) lymphatic sinuses transport lymph, cells, and antigens from the periphery through the LN. The lymphatic endothelium lining these sinuses appears to be an important contributor to the lymph node immune response. It has been challenging to obtain sufficient LN lymphatic endothelial cells for investigation of their functions, as they are minor constituents of LNs.A procedure was developed to purify lymphatic endothelial cells (LEC) from murine LNs, which yields large numbers of primary LN LEC. Two-dimensional in vitro cultures of dissociated LN stromal cells initially consist of multiple cell types, and then rapidly evolve to produce pure cultures of lymphatic endothelium within a few passages. One million LEC can be harvested after 4 weeks of culture, and much larger cell numbers can be obtained by continued culturing over long periods. The LEC cultures maintain endothelial morphology and expression of LEC markers, and preserve the same slow growth characteristics over at least 20 passages. The LEC cultures readily form tubes in Matrigel at early and at late passages, resembling those formed by LEC lines.A simple and economical approach to obtain purified primary murine LN LEC was developed for in vitro studies of their function. The morphology, growth characteristics, and functional behavior of these cells in tube formation assays did not change between initial and long-term passages. Large numbers of these cells can be harvested after long-term passage, so that they can be studied in biochemical and biological assays.

Intensified warming in the Arctic and Subarctic is resulting in a wide range of changes in the extent, productivity, and composition of aquatic and terrestrial ecosystems. Analysis of remote sensing imagery has documented regional changes in the number and area of ponds and lakes as well as expanding cover of shrubs and small trees in uplands. To better understand long-term changes across the edaphic gradient, we compared the number and area of water bodies and dry barrens (>100 m2) between 1956 (aerial photographs) and 2008–2011 (high-resolution satellite images) for eight ∼25 km2 sites near Nejanilini Lake, Manitoba (59.559°N, 97.715°W). In the modern landscape, the number of water bodies and barrens were similar (1162 versus 1297, respectively), but water bodies were larger (mean 3.1 × 104 versus 681 m2, respectively) and represented 17% of surface area compared with 0.4% for barrens. Over the past 60 years, total surface area of water did not change significantly (16.7%–17.1%) despite a ∼30% decrease in numbers of small (2) water bodies. However, the number and area of barrens decreased (55% and 67%, respectively) across all size classes. These changes are consistent with Arctic greening in response to increasing temperature and precipitation. Loss of small water bodies suggests that wet tundra areas may be drying, which, if true, may have important implications for carbon balance. Our observations may be the result of changes in winter conditions in combination with low permafrost ice content in the region, in part explaining regional variations in responses to climate change.

Background The presence of frailty or prefrailty in older adults is a risk factor for postsurgical complications. The frailty phenotype can be improved through long-term resistance and aerobic training. It is unknown whether short-term preoperative interventions targeting frailty will help to mitigate surgical risk. The purpose of this study was to determine the proportion of frail and prefrail patients presenting to a thoracic surgical clinic who could benefit from a frailty reduction intervention. Methods A prospective cohort study was performed at a single-site thoracic surgical clinic. Starting October 1, 2014, surgical candidates 60 years of age or older who consented to be screened were included. Patients were screened using an adapted version of Fried's phenotypic frailty criteria: weakness (grip strength), slow gait (15-foot walk), unintentional weight loss, self-reported exhaustion, and low self-reported physical activity (Physical Activity Scale for the Elderly). Prefrailty was identified when participants demonstrated one to two frailty characteristics; frailty was identified when participants demonstrated three to five frailty characteristics. Results Of 180 eligible patients, 126 consented, and 125 completed screening. Thirty-nine participants (31%) were not frail, 71 (57%) were prefrail, and 15 (12%) were frail. Exhaustion was the most common frailty symptom (34%). Frailty prevalence did not significantly differ among men and women (men: 10%, women: 14%; p = 0.75). Conclusions We found a high proportion of prefrail and frail patients among patients deemed candidates for thoracic surgical procedures. This finding indicates that frailty may be underrecognized. Substantial numbers of patients may be considered for a presurgical frailty reduction intervention.

INTRODUCTION: Progression from precursor states, MGUS and smoldering multiple myeloma (SMM), to multiple myeloma (MM) is dependent upon adaptive and innate immune contexture shaped by cross-talk between malignant plasma cells and bone marrow (BM) milieu. The complexity and heterogeneity of interactions between the immune system and plasma cells in BM triggers alterations in peripheral blood (PB) immune cell subsets. The advantage of using PB as a surrogate is that dynamic changes in the immune cells can be measured at various time points during disease progression or therapeutic intervention. Here, we performed a comprehensive analysis of immune repertoire to identify immune signatures in PB and BM associated with MM or its precursor states. We also performed T cell receptor (TCR) clonotyping to quantify clonal expansion specific to each immunotype. METHODS: Paired PB and BM specimens were collected from patients with MGUS/SMM (n=12) and MM (n=16) through an IRB-approved biospecimen protocol. PB mononuclear cells and BM mononuclear cells were isolated for immune profiling. A total of 59 immune variables were analyzed by flow cytometry surveying 6 cell lineages' [NK, NK-T, Th, CTL, Treg and ɣδ T cells] distribution and functional status [activation, differentiation and anergy]. In addition, ArcherDx Immunoverse TCR αδ-βɣ CDR3 targeted NGS assay was performed to study clonal distributions of Vα24Jα18 NK-T, βα and ɣδ T cell. Univariate analyses (ANOVA) were performed using p RESULTS: PB immunotyping identified 1 marker of innate inflammation and 9 markers of adaptive T mobilization that differentiated precursor states and MM (p=0.005). This model generated 3 PB immune clusters (Figure): cluster #1 [8 precursor states, 1 MM] showed a lack of innate inflammation and low Th/CTL mobilization, cluster #2 [2MGUS, 5MM] showed low innate inflammation and, cluster #3 [2SMM, 10MM] showed strong innate inflammation (Vɣ9-Vδ2-NKG2D+), Th terminal differentiation (central memory phenotype) and CTL anergy (Tim3+). TCR clonotyping confirmed increased innate inflammation (TCRδ SI 3.99±0.3 vs 4.75±0.15, p BM immunotyping identified 3 markers of innate inflammation and 2 markers of adaptive T mobilization (p=0.0274) distinguishing precursor states from MM. This model generated 3 BM immune clusters: cluster #1 [6 precursor states, 6 MM] showed innate inflammation (ɣδ T) and CTL terminal differentiation (central memory phenotype); cluster #2 [4 SMM, 8 MM] showed innate inflammation (NK-T, ɣδ T) and CTL effector anergy; and cluster #3 [2 MGUS, 2 MM] showed low NK cell cytotoxicity (KIR3DL1+) and CTL terminal differentiation. TCR clonotyping confirmed qualitative differences in innate inflammation between BM cluster #1 and #2 with higher NK-T (%Vα24Jα18 p Comparisons showed associations between PB and BM ɣδ T cell involvement in 13/13 patients. High PB Th/CTL mobilization (terminal differentiation) was associated with high T cell anergy in BM in 9/12 patients; conversely low PB Th/CTL mobilization was associated with low BM T cell involvement in 6/7 patients. CONCLUSION: This pilot study shows immune clustering of MGUS, SMM and MM patients based on BM and PB immunotypes. This is the first study to demonstrate two very distinct MM immunotypes based on low vs. high inflammatory states. We also show a high correlation between innate immune inflammation status in both PB and BM, specifically pertaining to ɣδ T cell, conventional T cell mobilization or lack thereof. Additional studies including a larger cohort for validation and longer follow up to establish correlation with clinical outcomes are currently underway. Figure. Figure. Disclosures Foureau: Teneobio Inc.: Research Funding. Berlin:ArcherDx: Employment. Johnson:ArcherDx: Employment. Williams:ArcherDx: Employment. Voorhees:Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; BMS: Consultancy, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Other: served on an IRC; Amgen Inc.: Speakers Bureau; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: served on an IRC; Oncopeptides: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: served on an IRC; TeneoBio: Consultancy, Membership on an entity's Board of Directors or advisory committees. Usmani:Amgen, BMS, Celgene, Janssen, Merck, Pharmacyclics,Sanofi, Seattle Genetics, Takeda: Research Funding; Abbvie, Amgen, Celgene, Genmab, Merck, MundiPharma, Janssen, Seattle Genetics: Consultancy.

Batf belongs to the activator protein 1 superfamily of basic leucine zipper transcription factors that includes Fos, Jun, and Atf proteins. Batf is expressed in mouse T and B lymphocytes, although the importance of Batf to the function of these lineages has not been fully investigated. We generated mice (Batf(DeltaZ/DeltaZ)) in which Batf protein is not produced. Batf(DeltaZ/DeltaZ) mice contain normal numbers of B cells but show reduced numbers of peripheral CD4(+) T cells. Analysis of CD4(+) T helper (Th) cell subsets in Batf(DeltaZ/DeltaZ) mice demonstrated that Batf is required for the development of functional Th type 17 (Th17), Th2, and follicular Th (Tfh) cells. In response to antigen immunization, germinal centers were absent in Batf(DeltaZ/DeltaZ) mice and the maturation of Ig-secreting B cells was impaired. Although adoptive transfer experiments confirmed that this B cell phenotype can be driven by defects in the Batf(DeltaZ/DeltaZ) CD4(+) T cell compartment, stimulation of Batf(DeltaZ/DeltaZ) B cells in vitro, or by a T cell-independent antigen in vivo, resulted in proliferation but not class-switch recombination. We conclude that loss of Batf disrupts multiple components of the lymphocyte communication network that are required for a robust immune response.

One way that higher education institutions attempt to promulgate and standardise practices around practice-based learning is through the use of artifacts: forms, workbooks, documented practices, narratives and the like. This chapter examines the functioning of practice-based learning artifacts. In particular, the chapter is concerned with understanding how artifacts, whose official purpose is to educate about and standardise practice-based learning, are used in positive ways to promote best practice while at the same time they may work against development and implementation of best practice. We employ Pierre Bourdieu’s concepts of habitus, field and cultural capital to theorise the reasons for variations in the effectiveness of artifacts in standardizing practice-based learning activities. We bring Michel de Certeau’s concepts of strategy and tactic to bear on understanding ways in which academics use artifacts to inform their implementation of practice-based learning.

The paper draws upon recent research investigating news frames, and risk theory to analyse Australian national news coverage of illegal drugs. Recent research has elaborated how risks are socially defined and acted upon, especially given changing media representations of risks. Public understandings of the risks associated with illegal drug use, policing and policies develop through the continuing and often changing representations of these risks in the media, as well as through other social practices. This paper questions the role of some prominent newspapers in setting alarmist and sensational frames to define risk in this context, and demonstrates how journalism can heighten community fear.

Ceramide is composed of sphingosine and a fatty acid found in large concentration within the cell membrane and often acts as a signaling molecule for various functions including programmed cell death. In the present investigation, we observed that C6-ceramide induces p53-dependent apoptosis and effectively killed the Astrocytoma grade4 (Glioblastoma Multiforme) HTB12 cell lines. Ceramide-induced cell death was confirmed by Trypan blue assay which showed about 65% cells dying from ceramide treatment. Apoptosis was confirmed by Caspase3 ELISA assay and DNA fragmentation assay. The p53 induction was confirmed by immunoblot studies. Since C6 Ceramide induces apoptosis in Glioblastoma cells, it may be employed in chemotherapeutic strategy to treat this highly malignant brain cancer.

Advancements in medical image visualization in recent years have enabled three-dimensional (3D) medical images to be volume-rendered from magnetic resonance imaging (MRI) and computed tomography (CT) scans. Medical data is crucial for patient diagnosis and medical education, and analyzing these three-dimensional models rather than two-dimensional (2D) slices would enable more efficient analysis by surgeons and physicians, especially non-radiologists. An interaction device that is intuitive, robust, and easily learned is necessary to integrate 3D modeling software into the medical community. The keyboard and mouse configuration does not readily manipulate 3D models because these traditional interface devices function within two degrees of freedom, not the six degrees of freedom presented in three dimensions. Using a familiar, commercial-off-the-shelf (COTS) device for interaction would minimize training time and enable maximum usability with 3D medical images. Multiple techniques are available to manipulate 3D medical images and provide doctors more innovative ways of visualizing patient data. One such example is windowing. Windowing is used to adjust the viewed tissue density of digital medical data. A software platform available at the Virtual Reality Applications Center (VRAC), named Isis, was used to visualize and interact with the 3D representations of medical data. In this paper, we present the methodology and results of a user study that examined the usability of windowing 3D medical imaging using a Kinect™ device compared to a traditional mouse.

Lymphocyte- and leukocyte-mediated lymph node (LN) lymphatic sinus growth (lymphangiogenesis) is involved in immune responses and in diseases including cancer and arthritis. We previously discovered a 10.1.1 Ab that recognizes the lymphatic endothelial cell (LEC) surface protein mCLCA1, which is an interacting partner for LFA1 and Mac-1 that mediates lymphocyte adhesion to LECs. Here, we show that 10.1.1 Ab treatment specifically induces LEC proliferation, and influences migration and adhesion in vitro. Functional testing by injection of mice with 10.1.1 Ab but not control hamster Abs identified rapid induction of LN LEC proliferation and extensive lymphangiogenesis within 23 h. BrdU pulse-chase analysis demonstrated incorporation of proliferating LYVE-1-positive LEC into the growing medullary lymphatic sinuses. The 10.1.1 Ab-induced LN remodeling involved coordinate increases in LECs and also blood endothelial cells, fibroblastic reticular cells, and double negative stroma, as is observed during the LN response to inflammation. 10.1.1 Ab-induced lymphangiogenesis was restricted to LNs, as mCLCA1-expressing lymphatic vessels of the jejunum and dermis were unaffected by 23 h 10.1.1 Ab treatment. These findings demonstrate that 10.1.1 Ab rapidly and specifically induces proliferation and growth of LN lymphatic sinuses and stroma, suggesting a key role of mCLCA1 in coordinating LN remodeling during immune responses.

Activator protein-1 (AP-1) is a dimeric transcription factor composed of the Jun, Fos and Atf families of proteins. Batf is expressed in the immune system and participates in AP-1 dimers that modulate gene expression in response to a variety of stimuli. Transgenic (Tg) mice overexpressing human BATF in T cells were generated using the human CD2 promoter (CD2-HA (hemagglutinin antigen) - BATF). By 1 year of age, over 90% of the mice developed a lymphoproliferative disorder (LPD). The enlarged lymph nodes characteristic of this LPD contain a polyclonal accumulation of T cells with a CD4(+) bias, yet efforts to propagate these tumor cells in vitro demonstrate that they do not proliferate as well as wild-type CD4(+) T cells. Instead, the accumulation of these cells is likely due to an apoptotic defect as CD2-HA-BATF Tg T cells challenged by trophic factor withdrawal in vitro resist apoptosis and display a pro-survival pattern of Bcl-2 family protein expression. As elevated levels of Batf expression are a feature of lymphoid tumors in both humans and mice, these observations support the use of CD2-HA-BATF mice as a model for investigating the molecular details of apoptotic dysregulation in LPD.