dataesr/scientific-paragraphs-categorization huggingface dataset:
Coupled decadal prediction systems often use atmospheric states sampled either from reanalyses or operational products to initialize the atmosphere. However, this practice may need to be revisited and potentially replaced with more sophisticated methods such as CDA. For example, comparison of these products with the sparsely available ocean surface meteorological flux buoys consistently show significant differences both globally and regionally, indicating imbalances in the surface energy and freshwater fluxes at the air-sea interface  (Yu, 2019). Maintaining and extending surface flux buoys is vital to understanding the source of these inconsistencies, to improving coupled models, and to evaluating decadal prediction systems. The heterogeneous nature of the in situ ocean-observing system requires comprehensive metadata, sophisticated data integration, and organized interpretation activity in order to realize the maximum benefit of the observations.
With upcoming satellite missions, the satellite-based ocean-observing system may at times evolve to support much higher resolutions of observed data products than a state-of-the-art operational forecast model can support. While a precise DA strategy should be developed for such scenarios, we also encourage coordination to take place between the modeling and prediction centers and the teams developing plans for future satellite observing missions in order to ensure prioritization of those missions that have maximum impact on prediction skill. To support CDA developments for operational applications, we recommend that a high priority be placed on ensuring consistency between atmosphere and ocean data governance bodies (e. g. , WMO and Copernicus Climate Change Service and Copernicus Marine Environment Monitoring Service).
At present, many ocean observations risk missing the cutoff times associated with the timelines of operational NWP. Improved infrastructure is needed to support research and operations, including real-time transmission of observed data and real-time feedback from users regarding the quality control of those data relative to other observing sources. For operational coupled Earth system approaches, used for reanalyses and prediction, it is crucial to enhance the consistency between the atmospheric and the ocean-observing systems, not only in terms of timeliness and infrastructure but also in terms of funding support and sustainability. The European Environment Agency State of Play Report (The European Environment Agency [EEA], 2017) pointed out that the oceanobserving system lacks prospects for long term funding.
About 70% of data in the GOOS is funded by time-limited research projects (in contrast to 25% for atmospheric observations). In situ ocean observations are based on infrastructures mainly supported by national agencies, and in recent years the number of observation sites and platforms have gone through periods of decline. They also emphasized that more coordination is needed between funding agencies, operators, and users of ocean observations internationally. In addition, the EEA State of Play report emphasized the lack of biogeochemical and deep (2000 m and deeper) ocean observations. Finally, the combination of increases in computing power and availability of observations has enabled the development of ensemble coupled DA systems. Ensemble-based approaches have the ability to identify and track the largest growing disturbances within the system.
Acknowledgments FUNDING SP was supported by the  National Oceanographic and Atmospheric Administration (NOAA)  via the National Environmental Satellite, Data, and  Information Service (NESDIS) , and the  Next Generation Global Prediction System (NGGPS) Research  to  Operations  ( R2O ) program, and the  Climate Prediction Office (CPO). BS, TO'K, PS, TM, and CC were supported by  CSIROs Decadal Climate Forecasting Project. PH is supported in part by  NASA  # NNH15ZDA001N-MAP  and  NSF-OPP #1750035. The Reviewer DM declares an ongoing collaboration on a project with the Author, PH, as a contribution to the collaboration on OceanObs19. The peer review was handled under the close supervision of the Chief Editors to ensure an objective process.
Research design In total, 43 patients were supported over the first four months of implementation, with individual interviews conducted with eight patients from across both sites. Demographic information collated included: age; sex; primary referral reason and referral source. Satisfaction questionnaires were also administered, assessing components including: promotion of independent living; choice of received support and perceived confidence in teams. These components were chosen to closely mirror the underpinning principles of Buurtzorg, such as self-management and enablement  [6]. As the data collection fell within the remit of service evaluation, ethical approval was not necessary to acquire.
A common endpoint in vaccine trials is measurement of the breadth and magnitude of vaccine-induced CD4 + and CD8 + Tcell responses. Identification and characterization of CD8 + and CD4 + T-cell epitopes, as well as the restricting HLA alleles can play a major role in elucidating the nature of protective cellular responses and mechanism of the immune evasion of HIV. CD8 + T-cell epitopes are typically 8-11-mer peptides restricted by HLA class I  [11]  and CD4 + T-cell epitopes are 12-20-mer peptides restricted by HLA class II  [12]. A large number of HIV epitopes have been identified and deposited into various databases. The growing amount of class-I and class-II HLA / peptide-binding data generated by experimental methods has supported the generation of more sophisticated, computational tools which can predict CD8 + and CD4 + T-cell epitopes within viral proteomes by using different data-driven bioinformatic approaches including Artificial Neural Network (ANN), Support Vector Machines, hidden Markov models, as well as other motif search algorithms.
The first five were already described as CD4 + T-cell epitopes  [53]  and listed in the HIV molecular immunology database (http://www. hiv. lanl. gov/content/immunology/tables/helper_summary. html). Gag253-3, Gag253-4, Gag253-5 and Gag253-6 have been described as DRB1 � 04:01 restricted epitopes in a study using HLA DR4 transgenic mice  [54]. Gag253-4, Gag253-5 and Gag253-6 were also found to be promiscuous peptides, i. e. able to bind multiple HLA-DR alleles, using NetMH-CIIpan 3. 2, the server we used to predict binding of 15-mer peptides to HLA Class II DRB1 alleles. Pol325-5 was not listed in the HIV molecular immunology database, nonetheless it is nearly totally contained (93% overlap) in a Pol CD4 + T-cell promiscuous epitope identified by van der Burg and colleagues  [55]. Of note, in some studies where the breadth of Gag-specific CD4 + T-cell responses was shown to be associated with lower viral load in HIV-infected individuals  [56] [57] [58] , Gag17-4, Gag253-4, Gag253-5, Gag253-6 and Gag253-7 were the main targeted epitopes.
One hour later, BD GolgiPlug and GolgiStop (Becton Dickinson France) were added and the culture was continued for additional 5 hours. Cells were then washed and stained for surface antibodies and live/dead marker for 20 minutes. Following fixation and permeabilization, cells were stained with intracellular antibodies for 30 minutes. Cells were then washed and resuspended in 250 μl PBS 1% PFA. To determine optimal CD8 responses, predicted CD8 + T-cell epitopes (8-to 10-mers) were used in ICS assay. To Samples were analyzed with a BD LSRII and data were acquired with DIVA software. FlowJo 9. 9. 6 (TreeStar, Inc. , Ashland, OR), Pestle 1. 7 and Spice 5. 35 (M. Roederer, National Institute of Health) softwares were used for data analysis.
Acknowledgments The authors wish to thank all participants of the DALIA trial and the members of the trial committees and of the  ANRS/VRI  study team. DSMB members:  William Duncan ,  Roy M. Gulick ,  Daniel R. Kuritzkes ,  James Neaton ,  Richard Pollard  (Chair). Event Validation Committee members:  Joseph Fay ,  Ronald Mitsuyasu ,  Jean-Paul Viard. Trial management:  Derek Blankenship ,  Celine Boucherie ,  Carson Harrod ,  David Jutras ,  Bryan King ,  Christine Lacabaratz ,  Sophie Pe  ´rusat,  Elisa Priest ,  Charlie Quinn ,  Anna Laura Ross ,  Louis Sloan. Vaccine/GMP team:  Susan Burkeholder ,  Amanda Cobb ,  Charles McWilliams ,  Jennifer Finholt-Perry ,  Lee Roberts.
Funding: "This study was supported by the  Investissement d'Avenir program  managed by the  ANR  under reference  ANR-10-LABX-77  and by the  Agence Nationale pour la Recherche sur le SIDA et les hepatites virales (ANRS) , the  Vaccine Research Institute (VRI). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. ".
Thus, WGS data from nine Hmong donors with a history of treatment for blastomycosis were used in the subsequent disease mapping strategy. Operating under the hypothesis that susceptibility loci would be enriched in regions of autozygosity, we mapped runs of homozygosity (ROH). Consistent with other worldwide populations  (10) , the majority of ROH identified in Hmong cases are small (Ͻ49,277. 2 bp using 3 clusters; see Fig. S1  in the supplemental material). We identified 27,514 consensus ROH (defined as regions where at least seven of the nine donors have overlapping ROH segments), which comprised 638,091,042 bp of the autosomes (Fig. 1A ). The median consensus ROH was 8,773 bp in length, with the largest identified being 11,100,866 bp. ROH segments within 500 bp of another were merged prior to variant annotation and filtering (1,176 segments).
In support of this hypothesis, we found a strong correlation between the AS-IL6 expression and IL6 when we reanalyzed published transcriptomic data from monocytes stimulated with lipopolysaccharide (LPS) (R 2 ϭ 0. 91, P ϭ 0. 002)  (12) , which may reflect our hypothesis or a shared promoter (Fig. 2D ). Functional validation of ethnic difference in cytokine production. While IL-17 responses have been implicated in murine models of B. dermatitidis infection, they have not been studied in humans with blastomycosis. Recognizing a unique opportunity to study the role of IL-6 and related IL-17 responses in human populations with known susceptibility, we quantified cytokine responses by Hmong and European donors' cells. We were not able to reach Hmong blastomycosis patients for re-collection of primary cells; to circumvent this limitation, we created immortalized B-lymphoblastoid cells (B-LCLs) from Hmong and European subjects.
975) and is common in East Asian populations (AF EAS , 0. 783). CATT is rare in European populations (AF EUR , 0. 048). (D) AS-IL6 and IL6 expression in monocytes left unstimulated (NS) or stimulated with LPS; reanalysis of RNA-sequencing data (EMTAB2399). Our findings of an ethnic difference in IL-6 production, when correlated with genotype at the IL6 locus, fit with past reports of human genetic differences in IL-6 production. Indeed, one candidate SNP (rs1800796) has been repeatedly associated with serum levels of IL-6  (13) (14) (15) (16). These studies involve donors from different ethnicities and report contradicting relationships between genotype and IL-6 levels, perhaps indicating epistatic effects of these SNPs. We also sought to measure antifungal immune responses in our donors downstream of IL-6.
Starting from a list of genes in an antifungal immunity array and adding genes based on the literature, we interrogated 108 genes known or suspected to be involved in human immune responses to fungi (Table  S2 ). We flagged SNPs occurring within 100 kb on either side of the transcriptional start site of these genes. SNPs within consensus ROH were annotated using the Ensembl Variant Effector Predictor  (31)  and cross-referenced with the 1000 Genomes and Genotype-Tissue Expression (GTEx; https://gtexportal. org/home/) projects to identify variants with predicted or demonstrated effects on function. RNA-sequencing analysis. RNA-sequencing reads (FASTQs) for 8 samples from a previous study  (12) , accession number EMTAB2399, were mapped to the human genome (hg19) with the STAR aligner v. 2. 5.
0a  (32). We used Qualimap 'bamqc' and 'rnaseq' for quality control assessment  (33, 34). StringTie v. 1. 3. 3 and Ballgown (35)  were used to identify and quantify expression levels in fragments per kilobase of transcript per million mapped reads (FPKM) for each annotated transcript (GENCODE release 27). Gene expression matrices were correcting for GC percentage and 5=¡3= bias. B-Lymphoblastoid cells. Donors were selected by ancestry (self-reported), and to the best of our knowledge, no donors are first-degree relatives. Peripheral blood mononuclear cells (PBMCs) were isolated from blood of donors using Ficoll-Paque Plus (GE Healthcare). B-LCLs were generated by treating PBMCs with Epstein-Barr virus and then maintained in Iscove's modified Dulbecco's medium supplemented with 16% fetal bovine serum.
The data were analyzed either based on ancestry alone (including all donors) or including only donors who were homozygotic at 3 SNPs of interest (rs1800796, rs1524107, and rs2066992) following a priori expectations based on ancestry. Human CD4 ؉ T cell stimulation. Studies of immunologic memory were patterned after previously reported studies of primary CD4 ϩ T cell responses to C. albicans, among other stimuli  (36). Magnetic beads were used to isolate monocytes (CD14 ϩ ) and memory CD4 ϩ T cells (CD45RO ϩ ) from donor PBMCs (CD14 MicroBeads, Miltenyi; and MojoSort human memory CD4 ϩ T cell isolation kit; BioLegend). Cells were plated (3 ϫ 10 5 /well) in 24-well plates and maintained in RPMI supplemented with 10% autologous serum, sodium pyruvate, nonessential amino acids, and glutamine. Treatments included a ratio of 1:1 CD14 ϩ and CD45RO ϩ cells, except the positive control, which included only CD45RO ϩ cells.
Cells were separated by Percoll gradient. Mouse cells were stained for surface CD4, CD8, CD11b, CD11c, CD44, CD90. 2, NK1. 1, B220, Blastomyces endoglucanase 2 (Bl-Eng2)-specific tetramer (H. Dobson, L. Dias, L. Kohn, S. Fites, D. Wiesner, T. Dileepan, G. Kujoth, G. Ostroff, B. Klein, M. Wüthrich, unpublished data), and intracellular IFN-␥ and IL-17A (Fig. S3B  and C ). Dead cells were labeled with LIVE/DEAD fixable near-IR (Invitrogen). Surface markers were stained on ice for up to 60 min. Intracellular markers were analyzed using BD Cytofix/Cytoperm. After cell permeabilization at 4°C overnight, intracellular markers were stained on ice for up to 60 min. Count beads (UltraComp eBeads; Invitrogen) were included with each sample to calculate absolute cell numbers. All samples were run through a five-laser BD LSRFortessa, and data were analyzed with the FlowJo software v.
ACKNOWLEDGMENTS We thank  Jennifer Meece  and  Terrie Kitchner  from the  Marshfield Clinic Research Foundation  and the participants who made this study possible. We also acknowledge  Laura Felley ,  Elaine Kohn , and  Nicholas Hess  for support with experiments involving human donors. This work was supported by a pilot grant from the  UW-Madison Department of Medicine  (to C. S. P. ), a  Partnership Education and Research Committee grant  from the  Wisconsin Partnership Program  (to C. S. P. and B. S. K. ), and the  National Institutes of Health  (grants  AI035681  to B. S. K. and  AI093553  to M. W. ). M. B. O. was supported by the  National Science Foundation Graduate Research Fellowship Program  (grant  DGE-1255259 ). R. M. M. was supported by the  Ruth L. Kirschstein National Research Service Award , through the  National Institute for Minority Health and Health Disparities  (grant  F30 MD011547 ).
Loss of connexin-mediated cell-cell communication is a hallmark of breast cancer progression. Pannexin1 (PANX1), a glycoprotein that shares structural and functional features with connexins and engages in cell communication with its environment, is highly expressed in breast cancer metastatic foci; however, PANX1 contribution to metastatic progression is still obscure. Here we report elevated expression of PANX1 in different breast cancer (BRCA) subtypes using RNA-seq data from The Cancer Genome Atlas (TCGA). The elevated PANX1 expression correlated with poorer outcomes in TCGA BRCA patients. In addition, gene set enrichment analysis (GSEA) revealed that epithelial-to-mesenchymal transition (EMT) pathway genes correlated positively with PANX1 expression. Pharmacological inhibition of PANX1, in MDA-MB-231 and MCF-7 breast cancer cells, or genetic ablation of PANX1, in MDA-MB-231 cells, reverted the EMT phenotype, as evidenced by decreased expression of EMT markers.
Snail1 and Zeb1 act as transcriptional repressors of E-cadherin, leading to down-regulation of E-cadherin expression during EMT  [46, 47]. We have evaluated the contribution of PANX1 expression in a collection of breast cancer (BRCA) RNA-seq dataset available in The Cancer Genome Atlas (TCGA) database and correlated PANX1 expression with overall survival (OS). In addition, gene set enrichment analysis (GSEA) was performed to find pathways enriched in breast cancer, based on PANX1 expression. To support in silico data, breast cancer cell lines MDA-MB-231 and MCF-7 were used. Pharmacological inhibition by probenecid  [48]  or CRISPR/Cas9 gene knock-out of PANX1 channels were performed and their effects on EMT regulation were evaluated in both cell lines. This report provides evidence that upregulated PANX1 expression, in different breast cancer subtypes, enhances EMT phenotype in silico and in vitro and is associated with poorer breast cancer prognosis.
PANX1 Over-Expression Is Correlated With Poorer OS in Breast Cancer Patients To investigate the role that PANX1 plays during cancer progression, we compared PANX1 expression between primary breast carcinoma (BRCA) using the RNA-seq dataset obtained from The Cancer Genome Atlas (TCGA). The TCGA data set contained 1180 breast tissue samples in total; 1170 breast cancer samples and 109 samples from breast tissue adjacent to the primary tumor that were considered normal in this study. PANX1 mRNA levels are significantly higher in breast cancer patient tissues than in the normal non-cancerous adjacent tissues (Figure  1A ). Significantly higher PANX1 mRNA levels were seen in all of the intrinsic breast cancer subtypes when compared to normal breast cancer tissues of the TCGA data set (Figure  1B ).
Using qRT-PCR, we also investigated the expression of PANX1 in primary breast cancer tissues from a local cohort of archived breast cancer patients' samples. PANX1 mRNA levels were up-regulated in basal-like TNBC tissues (N = 11) and in HER2 -(N = 15) and HER2 + (N = 11) breast cancer subtypes, as compared to normal breast tissue obtained from subjects who underwent reduction mammoplasty; though statistical significance was only reached in the HER2 -subtype with p < 0. 05 (Figure  1D ). These data indicate that PANX1 is upregulated, yet differentially in the different subtypes of breast cancer. The elevated PANX1 expression in TCGA breast cancer tissues is correlated with clinical outcomes. In the TCGA dataset, BRCA patients with high or intermediate PANX1 expression had worse overall survival (OS) compared to patients with low expression (intermediate vs.
low: HR = 2, p = 0. 025; High vs. Low: HR = 2. 26, p = 0. 013) (Figure  1E , left panel). Remarkably, PANX1 was of prognostic value in a microarray dataset from the Molecular Taxonomy of Breast Cancer International Consortium (METABRIC) (intermediate vs. low: HR = 1. 4, p = 0. 012; high vs. low: HR = 1. 89, p < 0. 001) (Figure  1E , right panel). Analysis showed that PANX1 gene expression levels were not age-dependent in breast cancer tissue (p = 0. 904, Figure  S1 ) or in adjacent non-cancer breast tissue (p = 0. 892, Figure  S1 ). were not age-dependent in breast cancer tissue (p = 0. 904, Figure  S1 ) or in adjacent non-cancer breast tissue (p = 0. 892, Figure  S1 ).
EMT Pathway Correlates Positively with PANX1 Expression To gain a mechanistic insight into the effect of PANX1 overexpression in BRCA tissues, GSEA based on PANX1 expression in BRCA patients was run on the KEGG database and the gene ontology (GO) database. Three cell adhesion-related pathways, including adhaerens junction, focal adhesion, and gap junctions gene set, were among the highly enriched pathways in the KEGG database analysis (data not shown). GSEA analysis of the GO database revealed that the EMT pathway was one of the top enriched GO pathways, based on PANX1 expression (Figure  2A ). Figure 2A also shows 16 highly enriched EMT genes that form the leading edge of the enrichment plot. In addition to their high.
EMT Pathway Correlates Positively with PANX1 Expression To gain a mechanistic insight into the effect of PANX1 overexpression in BRCA tissues, GSEA based on PANX1 expression in BRCA patients was run on the KEGG database and the gene ontology (GO) database. Three cell adhesion-related pathways, including adhaerens junction, focal adhesion, and gap junctions gene set, were among the highly enriched pathways in the KEGG database analysis (data not shown). GSEA analysis of the GO database revealed that the EMT pathway was one of the top enriched GO pathways, based on PANX1 expression (Figure  2A ). Figure 2A also shows 16 highly enriched EMT genes that form the leading edge of the enrichment plot. In addition to their high correlation with PANX1 expression, the 16 EMT genes of the leading edge are also highly inter-correlated (Figure  2B ).
The probenecid mode of action is thought to be mediated at least in part through the inhibition of PANX1 channels  [48]. The dye uptake assay was performed to evaluate the ability of cells to uptake EtBr through PANX1 channels. PBN-treated and control MDA-MB-231 cells were incubated with EtBr. Control cells were able to uptake EtBr, while PBN-treated MDA-MB-231 cells displayed a significant reduction of EtBr uptake as determined by lower EtBr mean fluorescence intensity (MFI; Figure  4D ). These data confirm effective inhibition of EtBr dye uptake. The knocked-out PANX1 expression was further confirmed by the lack of EtBr uptake in MDA-PANX1 -cells as revealed by dye uptake assay (Figure  4D ). The decrease in PANX1 channel activity in MDA-PANX1 -cells was similar to that exhibited by PBN-treated MDA-MB-231 cells (Figure  4D ).
The EtBr dye uptake was also evaluated in the presence of normal divalent ion solution (2 mM CaCl2 and 1 mM MgCl2), at room temperature and in the presence of 1 mM ATP to activate EtBr uptake by PANX1  [49]. PBN effectively inhibited ATP-induced EtBr dye uptake (Figure  S2 ). The probenecid mode of action is thought to be mediated at least in part through the inhibition of PANX1 channels  [48]. The dye uptake assay was performed to evaluate the ability of cells to uptake EtBr through PANX1 channels. PBN-treated and control MDA-MB-231 cells were incubated with EtBr. Control cells were able to uptake EtBr, while PBN-treated MDA-MB-231 cells displayed a significant reduction of EtBr uptake as determined by lower EtBr mean fluorescence intensity (MFI; Figure  4D ). These data confirm effective inhibition of EtBr dye uptake.
We provide evidence that PANX1 upregulation is correlated with poor prognosis in breast cancer patients and that it is differentially expressed in the different "intrinsic" human breast cancer subtypes. This observation is supported in a previous report by Stewart et al. who correlated PANX1 with negative clinical outcomes leading to poor overall survival and distant metastasis free survival in patients with breast cancer using in silico arrays  [31]. Furthermore, Furlow et al. have shown that PANX1 is enriched at metastatic breast cancer foci without any elucidation into the underlying mechanism  [30]. Here, we have provided data on pathways and biological processes that are enriched upon PANX1 increased expression. EMT pathway genes, were among the highly enriched gene ontology (GO) pathways following GSEA.