Single cell analyses and machine learning define hematopoietic progenitor and HSC-like cells derived from human PSCs

Haematopoietic stem and progenitor cells (HSPCs) develop through distinct waves at various anatomical sites during embryonic development. The in vitro differentiation of human pluripotent stem cells (hPSCs) is able to recapitulate some of these processes, however, it has proven difficult to generate functional haematopoietic stem cells (HSCs). To define the dynamics and heterogeneity of HSPCs that can be generated in vitro from hPSCs, we exploited single cell RNA sequencing (scRNAseq) in combination with single cell protein expression analysis. Bioinformatics analyses and functional validation defined the transcriptomes of naïve progenitors as well as erythroid, megakaryocyte and leukocyte-committed progenitors and we identified CD44, CD326, ICAM2/CD9 and CD18 as markers of these progenitors, respectively. Using an artificial neural network (ANN), that we trained on a scRNAseq derived from human fetal liver, we were able to identify a wide range of hPSCs-derived HPSC phenotypes, including a small group classified as HSCs. This transient HSC-like population decreased as differentiation proceeded and was completely missing in the dataset that had been generated using cells selected on the basis of CD43expression. By comparing the single cell transcriptome of in vitro-generated HSC-like cells with those generated within the fetal liver we identified transcription factors and molecular pathways that can be exploited in the future to improve the in vitro production of HSCs

Aligning assessment with the needs of work-integrated learning: the challenges of authentic assessment in a complex context

Work-integrated learning (WIL) is a feature of university courses, both in professional areas, where it is commonplace, but also across many different disciplines. Assessment of WIL can be complex as it involves parties and settings external to the university, and it can be problematic because of difficulties in aligning learning activities during placements with what is or can be assessed by the university. This paper explores the relationship between students’ placement experiences and accompanying assessments in contexts where activities are tightly coupled with the curriculum, and in those where it is not. It draws on a qualitative analysis of student interviews and drawings by the interviewees of their WIL experiences, supplemented with analysis of unit guides. Our findings highlight that students’ perceptions of authenticity of assessment were undermined by misalignments between the student, university and industry. Assessment authenticity was perceived by students as based on alignment between their current and future selves in the assessment process, involvement of industry supervisors and relevance of placement activities to assessment activities. The paper discusses the complexity of coordination of educational activities with external partners, especially when one party drives assessment. It then suggests a reframing of WIL assessment to promote alignment and authenticity

Clinical course, therapeutic responses and outcomes in relapsing MOG antibody-associated demyelination.

Abstract OBJECTIVE: We characterised the clinical course, treatment and outcomes in 59 patients with relapsing myelin oligodendrocyte glycoprotein (MOG) antibody-associated demyelination. METHODS: We evaluated clinical phenotypes, annualised relapse rates (ARR) prior and on immunotherapy and Expanded Disability Status Scale (EDSS), in 218 demyelinating episodes from 33 paediatric and 26 adult patients. RESULTS: The most common initial presentation in the cohort was optic neuritis (ON) in 54% (bilateral (BON) 32%, unilateral (UON) 22%), followed by acute disseminated encephalomyelitis (ADEM) (20%), which occurred exclusively in children. ON was the dominant phenotype (UON 35%, BON 19%) of all clinical episodes. 109/226 (48%) MRIs had no brain lesions. Patients were steroid responsive, but 70% of episodes treated with oral prednisone relapsed, particularly at doses <10\u2009mg daily or within 2 months of cessation. Immunotherapy, including maintenance prednisone (P=0.0004), intravenous immunoglobulin, rituximab and mycophenolate, all reduced median ARRs on-treatment. Treatment failure rates were lower in patients on maintenance steroids (5%) compared with non-steroidal maintenance immunotherapy (38%) (P=0.016). 58% of patients experienced residual disability (average follow-up 61 months, visual loss in 24%). Patients with ON were less likely to have sustained disability defined by a final EDSS of 652 (OR 0.15, P=0.032), while those who had any myelitis were more likely to have sustained residual deficits (OR 3.56, P=0.077). CONCLUSION: Relapsing MOG antibody-associated demyelination is strongly associated with ON across all age groups and ADEM in children. Patients are highly responsive to steroids, but vulnerable to relapse on steroid reduction and cessation

Quasiparticle interfacial level alignment of highly hybridized frontier levels: H2_2O on TiO2_2(110)

Knowledge of the frontier levels' alignment prior to photo-irradiation is necessary to achieve a complete quantitative description of H$_2$O photocatalysis on TiO$_2$(110). Although H$_2$O on rutile TiO$_2$(110) has been thoroughly studied both experimentally and theoretically, a quantitative value for the energy of the highest H$_2$O occupied levels is still lacking. For experiment, this is due to the H$_2$O levels being obscured by hybridization with TiO$_2$(110) levels in the difference spectra obtained via ultraviolet photoemission spectroscopy (UPS). For theory, this is due to inherent difficulties in properly describing many-body effects at the H$_2$O-TiO$_2$(110) interface. Using the projected density of states (DOS) from state-of-the-art quasiparticle (QP) $G_0W_0$, we disentangle the adsorbate and surface contributions to the complex UPS spectra of H$_2$O on TiO$_2$(110). We perform this separation as a function of H$_2$O coverage and dissociation on stoichiometric and reduced surfaces. Due to hybridization with the TiO$_2$(110) surface, the H$_2$O 3a$_1$ and 1b$_1$ levels are broadened into several peaks between 5 and 1 eV below the TiO$_2$(110) valence band maximum (VBM). These peaks have both intermolecular and interfacial bonding and antibonding character. We find the highest occupied levels of H$_2$O adsorbed intact and dissociated on stoichiometric TiO$_2$(110) are 1.1 and 0.9 eV below the VBM. We also find a similar energy of 1.1 eV for the highest occupied levels of H$_2$O when adsorbed dissociatively on a bridging O vacancy of the reduced surface. In both cases, these energies are significantly higher (by 0.6 to 2.6 eV) than those estimated from UPS difference spectra, which are inconclusive in this energy region. Finally, we apply self-consistent QP$GW$ (scQP$GW$1) to obtain the ionization potential of the H$_2$O-TiO$_2$(110) interface.Comment: 12 pages, 12 figures, 1 tabl

Cold season emissions dominate the Arctic tundra methane budget

Arctic terrestrial ecosystems are major global sources of methane (CH4); hence, it is important to understand the seasonal and climatic controls on CH4 emissions from these systems. Here, we report year-round CH4 emissions from Alaskan Arctic tundra eddy flux sites and regional fluxes derived from aircraft data. We find that emissions during the cold season (September to May) account for >= 50% of the annual CH4 flux, with the highest emissions from noninundated upland tundra. A major fraction of cold season emissions occur during the "zero curtain" period, when subsurface soil temperatures are poised near 0 degrees C. The zero curtain may persist longer than the growing season, and CH4 emissions are enhanced when the duration is extended by a deep thawed layer as can occur with thick snow cover. Regional scale fluxes of CH4 derived from aircraft data demonstrate the large spatial extent of late season CH4 emissions. Scaled to the circumpolar Arctic, cold season fluxes from tundra total 12 +/- 5 (95% confidence interval) Tg CH4 y(-1), similar to 25% of global emissions from extratropical wetlands, or similar to 6% of total global wetland methane emissions. The dominance of late-season emissions, sensitivity to soil environmental conditions, and importance of dry tundra are not currently simulated in most global climate models. Because Arctic warming disproportionally impacts the cold season, our results suggest that higher cold-season CH4 emissions will result from observed and predicted increases in snow thickness, active layer depth, and soil temperature, representing important positive feedbacks on climate warming.Peer reviewe

Use of Laboratory Markers in Addition to Symptoms for Diagnosis of Inflammatory Bowel Disease in Children:A Meta-analysis of Individual Patient Data

IMPORTANCE: Blood markers and fecal calprotectin are used in the diagnostic workup for inflammatory bowel disease (IBD) in pediatric patients. Any added diagnostic value of these laboratory markers remains unclear.OBJECTIVE: To determine whether adding laboratory markers to evaluation of signs and symptoms improves accuracy when diagnosing pediatric IBD.DATA SOURCES: A literature search of MEDLINE and EMBASE from inception through September 26, 2016. Studies were identified using indexing terms and free-text words related to child, target condition IBD, and diagnostic accuracy.STUDY SELECTION: Two reviewers independently selected studies evaluating the diagnostic accuracy of more than 1 blood marker or fecal calprotectin for IBD, confirmed by endoscopy and histopathology or clinical follow-up, in pediatric patients with chronic gastrointestinal symptoms. Studies that included healthy controls and/or patients with known IBD were excluded.DATA EXTRACTION AND SYNTHESIS: Individual patient data from each eligible study were requested from the authors. In addition, 2 reviewers independently assessed quality with Quality Assessment of Diagnostic Accuracy Studies-2.MEAN OUTCOMES AND MEASURES: Laboratory markers were added as a single test to a basic prediction model based on symptoms. Outcome measures were improvement of discrimination by adding markers as a single test and improvement of risk classification of pediatric patients by adding the best marker.RESULTS: Of the 16 eligible studies, authors of 8 studies (n = 1120 patients) provided their data sets. All blood markers and fecal calprotectin individually significantly improved the discrimination between pediatric patients with and those without IBD, when added to evaluation of symptoms. The best marker-fecal calprotectin-improved the area under the curve of symptoms by 0.26 (95% CI, 0.21-0.31). The second best marker-erythrocyte sedimentation rate-improved the area under the curve of symptoms by 0.16 (95% CI, 0.11-0.21). When fecal calprotectin was added to the model, the proportion of patients without IBD correctly classified as low risk of IBD increased from 33% to 91%. The proportion of patients with IBD incorrectly classified as low risk of IBD decreased from 16% to 9%. The proportion of the total number of patients assigned to the intermediate-risk category decreased from 55% to 6%.CONCLUSIONS AND RELEVANCE: In a hospital setting, fecal calprotectin added the most diagnostic value to symptoms compared with blood markers. Adding fecal calprotectin to the diagnostic workup of pediatric patients with symptoms suggestive of IBD considerably decreased the number of patients in the group in whom challenges in clinical decision making are most prevalent.</p

Human Resources and the Resource Based View of the Firm

The resource-based view (RBV) of the firm has influenced the field of strategic human resource management (SHRM) in a number of ways. This paper explores the impact of the RBV on the theoretical and empirical development of SHRM. It explores how the fields of strategy and SHRM are beginning to converge around a number of issues, and proposes a number of implications of this convergence

Genotoxic agents promote the nuclear accumulation of annexin A2: role of annexin A2 in mitigating DNA damage

Annexin A2 is an abundant cellular protein that is mainly localized in the cytoplasm and plasma membrane, however a small population has been found in the nucleus, suggesting a nuclear function for the protein. Annexin A2 possesses a nuclear export sequence (NES) and inhibition of the NES is sufficient to cause nuclear accumulation. Here we show that annexin A2 accumulates in the nucleus in response to genotoxic agents including gamma-radiation, UV radiation, etoposide and chromium VI and that this event is mediated by the nuclear export sequence of annexin A2. Nuclear accumulation of annexin A2 is blocked by the antioxidant agent N-acetyl cysteine (NAC) and stimulated by hydrogen peroxide (H2O2), suggesting that this is a reactive oxygen species dependent event. In response to genotoxic agents, cells depleted of annexin A2 show enhanced phospho-histone H2AX and p53 levels, increased numbers of p53-binding protein 1 nuclear foci and increased levels of nuclear 8-oxo-2'-deoxyguanine, suggesting that annexin A2 plays a role in protecting DNA from damage. This is the first report showing the nuclear translocation of annexin A2 in response to genotoxic agents and its role in mitigating DNA damage.Natural Sciences and Engineering Research Council of Canada (NSERC); European Union [PCOFUND-GA-2009-246542]; Foundation for Science and Technology of Portugal; Beatrice Hunter Cancer Research Institute; Terry Fox Foundationinfo:eu-repo/semantics/publishedVersio

Genome-wide association and HLA fine-mapping studies identify risk loci and genetic pathways underlying allergic rhinitis

Allergic rhinitis is the most common clinical presentation of allergy, affecting 400 million people worldwide, with increasing incidence in westernized countries1,2. To elucidate the genetic architecture and understand the underlying disease mechanisms, we carried out a meta-analysis of allergic rhinitis in 59,762 cases and 152,358 controls of European ancestry and identified a total of 41 risk loci for allergic rhinitis, including 20 loci not previously associated with allergic rhinitis, which were confirmed in a replication phase of 60,720 cases and 618,527 controls. Functional annotation implicated genes involved in various immune pathways, and fine mapping of the HLA region suggested amino acid variants important for antigen binding. We further performed genome-wide association study (GWAS) analyses of allergic sensitization against inhalant allergens and nonallergic rhinitis, which suggested shared genetic mechanisms across rhinitis-related traits. Future studies of the identified loci and genes might identify novel targets for treatment and prevention of allergic rhinitis