bluuebunny/crossref_metadata_2025_split huggingface dataset:
Comparison of Population Characteristics in Real-World Clinical Oncology Databases in the US: Flatiron Health, SEER, and NPCR
Authors: Ma Xinran , Long Lura , Moon Sharon , Adamson Blythe J.S. , Baxi Shrujal S. 
Published: March 2020

ABSTRACTBackground and ObjectiveThe Surveillance, Epidemiology, and End Results Program (SEER) program and the National Program of Cancer Registries (NPCR), are authoritative sources for population cancer surveillance and research in the US. An increasing number of recent oncology studies are based on the electronic health record (EHR)-derived de-identified databases created and maintained by Flatiron Health. This report describes the differences in the originating sources and data development processes, and compares baseline demographic characteristics in the cancer-specific databases from Flatiron Health, SEER, and NPCR, to facilitate interpretation of research findings based on these sources.MethodsPatients with documented care from January 1, 2011 through May 31, 2019 in a series of EHR-derived Flatiron Health de-identified databases covering multiple tumor types were included. SEER incidence data (obtained from the SEER 18 database) and NPCR incidence data (obtained from the US Cancer Statistics public use database) for malignant cases diagnosed from January 1, 2011 to December 31, 2016 were included. Comparisons of demographic variables were performed across all disease-specific databases, for all patients and for the subset diagnosed with advanced-stage disease.ResultsAs of May 2019, a total of 201,570 patients with 19 different cancer types were included in Flatiron Health datasets. In an overall comparison to national cancer registries, patients in the Flatiron Health databases had similar sex, age at initial diagnosis, and geographic distributions but appeared to be diagnosed with later stages of disease compared with patients in other datasets. For variables such as stage and race, Flatiron Health databases had a greater degree of incompleteness. There are variations in these trends by cancer types.ConclusionsThese three databases present general similarities in demographic and geographic distribution, but there are overarching differences across the populations they cover. Differences in data sourcing (medical oncology EHRs vs cancer registries), and disparities in sampling approaches and rules of data acquisition may explain some of these divergences. Furthermore, unlike the steady information flow entered into registries, the availability of medical oncology EHR-derived information reflects the extent of involvement of medical oncology clinics at different points in the specialty management of individual diseases, resulting in inter-disease variability. These differences should be considered when interpreting study results obtained with these databases.
Single-cell transcriptomic analysis of the adult mouse spinal cord
Authors: Blum Jacob A. , Klemm Sandy , Nakayama Lisa , Kathiria Arwa , Guttenplan Kevin A. , Hoang Phuong T. , Shadrach Jennifer L. , Kaltschmidt Julia A. , Greenleaf William J. , Gitler Aaron D. 
Published: March 2020

AbstractThe spinal cord is a fascinating structure responsible for coordinating all movement in vertebrates. Spinal motor neurons control the activity of virtually every organ and muscle throughout the body by transmitting signals that originate in the spinal cord. These neurons are remarkably heterogeneous in their activity and innervation targets. However, because motor neurons represent only a small fraction of cells within the spinal cord and are difficult to isolate, the full complement of motor neuron subtypes remains unknown. Here we comprehensively describe the molecular heterogeneity of motor neurons within the adult spinal cord. We profiled 43,890 single-nucleus transcriptomes using fluorescence-activated nuclei sorting to enrich for spinal motor neuron nuclei. These data reveal a transcriptional map of the adult mammalian spinal cord and the first unbiased characterization of all transcriptionally distinct autonomic and somatic spinal motor neuron subpopulations. We identify 16 sympathetic motor neuron subtypes that segregate spatially along the spinal cord. Many of these subtypes selectively express specific hormones and receptors, suggesting neuromodulatory signaling within the autonomic nervous system. We describe skeletal motor neuron heterogeneity in the adult spinal cord, revealing numerous novel markers that distinguish alpha and gamma motor neurons—cell populations that are specifically affected in neurodegenerative disease. We also provide evidence for a novel transcriptional subpopulation of skeletal motor neurons. Collectively, these data provide a single-cell transcriptional atlas for investigating motor neuron diversity as well as the cellular and molecular basis of motor neuron function in health and disease.
HARMONIES: A Hybrid Approach for Microbiome Networks Inference via Exploiting Sparsity
Authors: Jiang Shuang , Xiao Guanghua , Koh Andrew Young , Yao Bo , Li Qiwei , Zhan Xiaowei 
Published: March 2020

AbstractThe human microbiome is a collection of microorganisms. They form complex communities and collectively affect host health. Recently, the advances in next-generation sequencing technology enable the high-throughput profiling of the human microbiome. This calls for a statistical model to construct microbial networks from the microbiome sequencing count data. As microbiome count data are high-dimensional and suffer from uneven sampling depth, over-dispersion, and zero-inflation, these characteristics can bias the network estimation and require specialized analytical tools. Here we propose a general framework, HARMONIES, a Hybrid Approach foR MicrobiOme Network Inferences via Exploiting Sparsity, to infer a sparse microbiome network. HARMONIES first utilizes a zero-inflated negative binomial (ZINB) distribution to model the skewness and excess zeros in the microbiome data, as well as incorporates a stochastic process prior for sample-wise normalization. This approach infers a sparse and stable network by imposing non-trivial regularizations based on the Gaussian graphical model. In comprehensive simulation studies, HARMONIES outperformed four other commonly used methods. When using published microbiome data from a colorectal cancer study, it discovered a novel community with disease-enriched bacteria. In summary, HARMONIES is a novel and useful statistical framework for microbiome network inference, and it is available athttps://github.com/shuangj00/HARMONIES.
The vesicular trafficking system component MIN7 is required for minimizingFusarium graminearuminfection
Authors: Machado Wood Ana K. , Panwar Vinay , Grimwade-Mann Mike , Ashfield Tom , Hammond-Kosack Kim E. , Kanyuka Kostya 
Published: March 2020

ABSTRACTPlants have developed intricate defense mechanisms, referred to as innate immunity, to defend themselves against a wide range of pathogens. Plants often respond rapidly to pathogen attack by the synthesis and delivery of various antimicrobial compounds, proteins and small RNA in membrane vesicles to the primary infection sites. Much of the evidence regarding the importance of vesicular trafficking in plant-pathogen interactions comes from the studies involving model plants whereas this process is relatively understudied in crop plants. Here we assessed whether the vesicular trafficking system components previously implicated in immunity inArabidopsis thalianaplay a role in the interaction withFusarium graminearum, a fungal pathogen notoriously famous for its ability to cause Fusarium head blight (FHB) disease in wheat. Among the analyzed vesicular trafficking mutants, two independent T-DNA insertion mutants in theAtMin7gene displayed a markedly enhanced susceptibility toF. graminearum. Earlier studies identified this gene, encoding an ARF-GEF protein, as a target for the HopM1 effector of the bacterial pathogenPseudomonas syringaepv.tomato, which destabilizes AtMIN7 leading to its degradation and weakening host defenses. To test whether this key vesicular trafficking component may also contribute to defense in crop plants, we identified the candidateTaMin7genes in wheat and knocked-down their expression through Virus induced gene silencing. Wheat plants in whichTaMIN7were silenced displayed significantly more FHB disease. This suggests that disruption of MIN7 function in both model and crop plants compromises the trafficking of innate immunity signals or products resulting in hyper-susceptibility to various pathogens.One sentence summaryDisruption of an ARF-GEF protein encoding geneAtMin7inArabidopsis thalianaand silencing of the orthologous gene in wheat result in hyper susceptibility to the fungal pathogenFusarium graminearum.
Rational design and implementation of a chemically inducible hetero-trimerization system
Authors: Wu Helen D. , Kikuchi Masaki , Dagliyan Onur , Aragaki Adam K. , Nakamura Hideki , Dokholyan Nikolay V. , Umehara Takashi , Inoue Takanari 
Published: March 2020

AbstractChemically inducible dimerization (CID) uses a small molecule to induce binding of two different proteins. CID tools exemplified by the FKBP/FRB/rapamycin system have been widely employed to probe molecular events inside and outside cells. While various CID tools are available, chemically inducible trimerization (CIT) has not been developed, due to inherent challenges in designing or identifying a chemical that simultaneously binds three proteins with high affinity and target specificity. Nevertheless, by introducing a third recruitable component, CIT could enable versatile applications. Here, we devised the CIT by rationally splitting FRB and FKBP. Based on cellular and structural datasets, select split pairs of FRB or FKBP underwent efficient trimerization with full length FKBP or FRB, respectively, upon addition of rapamycin. We also demonstrated its potential for cellular applications by rapidly inducing tri-organellar plasma membrane-ER-mitochondria junctions, and by perturbing intended membrane lipids exclusively at the plasma membrane-ER membrane contact sites. By conferring one additional condition to what is achievable with CID, CIT expands the types of manipulation in single live cells, to address cell biology questions otherwise intractable, and engineer cell functions for future synthetic biology applications.
A CTGF-YAP regulatory pathway is essential for angiogenesis and barriergenesis in the retina
Authors: Moon Sohyun , Lee Sangmi , Caesar JoyAnn , Pruchenko Sarah , Leask Andew , Knowles James A. , Sinon Jose , Chaqour Brahim 
Published: March 2020

ABSTRACTConnective tissue growth factor (CTGF) or CCN2 is a matricellular protein essential for normal embryonic development and tissue repair. CTGF exhibits cell- and context-dependent activities, but the CTGF function in vascular development and permeability barrier is not known. Here we show that endothelial cells (ECs) are one of the major cellular sources of CTGF in the developing and adult retinal vasculature. Mice lacking CTGF expression either globally or specifically in ECs exhibit impaired vascular cell growth and morphogenesis, and blood barrier breakdown. The global molecular signature of CTGF includes cytoskeletal and extracellular matrix protein, growth factor, and transcriptional co-regulator genes such as yes-associated protein (YAP). YAP, itself a transcriptional activator of the CTGF gene, mediates several CTGF-controlled angiogenic and barriergenic transcriptional programs. Re-expression of YAP rescues, at least partially, angiogenesis and barriergenesis in CTGF mutant mouse retinas. Thus, the CTGF-YAP angiomodulatory pathway is critical for vascular development and barrier function.
In vitroevolution and whole genome analysis to study chemotherapy drug resistance in haploid human cells
Authors: Jado Juan Carlos , Dow Michelle , Carolino Krypton , Klie Adam , Fonseca Gregory J. , Ideker Trey , Carter Hannah , Winzeler Elizabeth A. 
Published: March 2020

ABSTRACTBackgroundIn vitroevolution and whole genome analysis has proven to be a powerful method for studying the mechanism of action of small molecules in many haploid microbes but has generally not been applied to human cell lines in part because their diploid state complicates the identification of variants that confer drug resistance. To determine if haploid human cell could be used in MOA studies, we evolved resistance to five different anticancer drugs (doxorubicin, gemcitabine, etoposide, topotecan, and paclitaxel) using a near-haploid cell line (HAP1) and then analyzed the genomes of the drug resistant clones, developing a bioinformatic pipeline that involved filtering for high frequency alleles predicted to change protein sequence, or alleles which appeared in the same gene for multiple independent selections with the same compound. Applying the filter to sequences from 28 drug resistant clones identified a set of 21 genes which was strongly enriched for known resistance genes or known drug targets (TOP1, TOP2A, DCK, WDR33, SLCO3A1). In addition, some lines carried structural variants that encompassed additional known resistance genes (ABCB1, WWOX and RRM1). Gene expression knockdown and knockout experiments of 10 validation targets showed a high degree of specificity and accuracy in our calls and demonstrates that the same drug resistance mechanisms found in diverse clinical samples can be evolved, discovered and studied in an isogenic background.
Patient-derived xenografts and organoids model therapy response in prostate cancer
Authors: Karkampouna Sofia , La Manna Federico , De Filippo Maria R. , Kiener Mirjam , De Menna Marta , Zoni Eugenio , Grosjean Joël , Klima Irena , Garofoli Andrea , Bolis Marco , Theurillat Jean-Philippe , Genitsch Vera , Keller David , Booij Tijmen H. , Stirnimann Christian U. , Eng Kenneth , Sboner Andrea , Ng Charlotte K. Y. , Piscuoglio Salvatore , PC Gray , Spahn Martin , Rubin Mark A. , Thalmann George N. , Julio Marianna Kruithof-de 
Published: March 2020

AbstractTherapy resistance and metastatic processes in prostate cancer (PCa) remain undefined, due to lack of experimental models that mimic different disease stages. We describe a novel androgen-dependent PCa patient-derived xenograft (PDX) model from treatment-naïve, soft tissue metastasis (PNPCa). RNA and whole-exome sequencing of the PDX tissue and organoids confirmed transcriptomic and genomic similarity to primary tumor. PNPCa harboursBRCA2 and CHD1somatic mutations, shows anSPOP/FOXA1-like transcriptomic signature and microsatellite instability, which occurs in 3% of advanced PCa and has never been modelledin vivo. Comparison of the treatment-naïve PNPCa with additional metastatic PDXs (BM18, LAPC9), in a medium-throughput organoid screen of FDA-approved compounds, revealed differential drug sensitivities. Multikinase inhibitors (ponatinib, sunitinib, sorafenib) were broadly effective on all PDX- and patient-derived organoids from advanced cases with acquired resistance to standard-of-care compounds. This proof-of-principle study may provide a preclinical tool to screen drug responses to standard-of-care and newly identified, repurposed compounds.
Robustness of epithelial sealing is an emerging property of local ERK feedbacks driven by cell elimination
Authors: Valon Léo , Davidović Anđela , Levillayer Florence , Chouly Mathilde , Cerqueira-Campos Fabiana , Levayer Romain 
Published: March 2020

AbstractWhile the pathways regulating apoptosis and cell extrusion are rather well described1,2, what regulates the precise spatio-temporal distribution of cell elimination in tissues remains largely unknown. This is particularly relevant for epithelia with high rates of cell elimination, a widespread situation during embryogenesis3–6and epithelial homeostasis7, where concomitant death of neighbours could impair the maintenance of epithelial sealing. However, the extent to which epithelial tissues can cope with concomitant cell death, and whether any mechanism regulates such occurrence have never been explored so far. Here, using theDrosophilapupal notum (a single layer epithelium) and a new optogenetic tool to trigger caspase activation and cell extrusion, we first show that concomitant death of clusters of at least three cells is sufficient to transiently impair epithelial sealing. Such clustered extrusion was almost never observedin vivo, suggesting the existence of a mechanism preventing concomitant elimination of neighbours. Statistical analysis and simulations of cell death distribution in the notum highlighted a transient and local protective phase occurring near every dying cell. This protection is driven by a transient activation of ERK in the direct neighbours of extruding cells which reverts caspase activation and prevents elimination of cells in clusters. Altogether, this study demonstrates that the distribution of cell elimination in epithelia is an emerging property of transient and local feedbacks through ERK activation which is required to maintain epithelial sealing in conditions of high rate of cell elimination.
DNA methylation is indispensable for leukemia inhibitory factor dependent embryonic stem cells reprogramming
Authors: Wu Baojiang , Li Yunxia , Li Bojiang , Zhang Baojing , Wang Yanqiu , Li Lin , Gao Junpeng , Fu Yuting , Li Shudong , Chen Chen , Surani M. Azim , Tang Fuchou , Li Xihe , Bao Siqin 
Published: March 2020

AbstractNaïve pluripotency can be maintained by the 2i/LIF supplements (CHIR99021, PD0325901 and LIF), which primarily affect canonical WNT, FGF/ERK, and JAK/STAT3 signaling. However, whether one of these tripartite supplements alone is sufficient to maintain naïve self-renewal remain unclear. Here we show that LIF alone is sufficient to induce reprogramming of 2i/LIF cultured ESCs (2i/L-ESCs) to ESCs with hypermethylated state (L-ESCs).In vitro, upon withdrawal of 2i, 2i/L-ESCs overcome the epigenetic barrier and DNA hypermethylated, which accompanies transcriptional changes and subsequent establishment of epigenetic memory. Global transcriptome features also show that L-ESCs are close to 2i/L-ESCs and in a stable state between naïve and primed pluripotency. Notably, our results demonstrate that DNA methylation was indispensable for LIF-dependent mouse ESCs reprogramming and self-renew. LIF-dependent ESCs reprogramming efficiency is significantly increased in serum treatment and reduced inDnmt3aorDnmt3lknockout ESCs. Importantly, unlike epiblast and EpiSCs, L-ESCs contribute to somatic tissues and germ cells in chimaeras. Such simple culture system of ESCs is more conducive to clarify the molecular mechanism of ESCsin vitroculture.SignificanceEmbryonic stem cell (ESCs) exhibit naïve pluripotency which reflects their ability to contribute to all embryonic lineages upon injection into blastocyst. ESCs were originally derived by co-culture with feeder cells and fetal calf serum. In this manuscript, we took a detailed approach to dissect the roles of LIF alone in ESC reprogramming of 2i/LIF cultured ESCs (2i/L-ESCs). Here, for the first time, we derived stable hypermethylated pluripotent ESCs under culture of LIF alone (L-ESCs). We further assessed L-ESCs properties both in vitro and in vivo, and provide molecular insights to the mechanism which allows LIF alone to maintain pluripotency and a hypermethylated state. We believe these findings are novel and valuable for future ESCs study.
Boron induces osteogenesis by stimulating NaBC1 in cooperation with BMPR1A
Authors: Rico Patricia , Rodrigo-Navarro Aleixandre , Sánchez Pérez Laura , Salmeron-Sanchez Manuel 
Published: March 2020

AbstractThe intrinsic properties of Mesenchymal Stem Cells (MSCs) make them ideal candidates for tissue engineering applications as they are regulated by the different signals present in the stem cell niche. Considerable efforts have been made to control stem cell behavior by designing material system approaches to engineer synthetic extracellular matrices and/or include soluble factors in the media. This work proposes a novel and simple approach based on ion-channel stimulation to determine stem cell fate that avoids the use of growth factors (GFs). We used boron ion - essential item in cell metabolism - transported inside cells by the NaBC1-channel. Addition of boron alone enhanced MSC adhesion and contractility, promoted osteogenesis and inhibited adipogenesis. The stimulated NaBC1 promoted osteogenesis via activation of the BMP canonical pathway (comprising Smad1 and YAP nucleus translocation and osteopontin expression) through a mechanism that involves simultaneous NaBC1/BMPR1A and NaBC1/α5β1/αvβ3co-localization,. We describe a novel function for NaBC1 as a mechanosensitive ion-channel capable of interacting and stimulating GF receptors and fibronectin-binding integrins. Our results open up new biomaterial engineering approaches for biomedical applications by a cost-effective strategy that avoids the use of soluble GFs.
Identification of key candidate genes and pathways in axial Spondyloarthritis through integrated bioinformatics analysis
Authors: Zhang Zhen-zhen , Zeng Jing , Li Hai-hong , Zou Yu-cong , Liang Shuang , Liu Gang 
Published: March 2020

AbstractBackgroundRadiographic axial Spondyloarthritis (r-axSpA) is the prototypic form of seronegative spondyloarthritis (SpA). In the present study, we evaluated the key genes related with r-axSpA, and then elucidated the possible molecular mechanisms of r-axSpA.Material/MethodsThe gene expression GSE13782 was downloaded from the GEO database contained five proteoglycan-induced spondylitis mice and three naïve controls. The differentially expressed genes (DEGs) were identified with the Bioconductor affy package in R. Gene Ontology (GO) enrichment and the Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis were built with the DAVID program followed by construction of a protein-protein interaction (PPI) network performed with Cytoscape. WebGestalt was performed to construct transcriptional regulatory network and microRNAs-target regulatory networks. RT-PCR and immunohistochemical staining were performed to testify the expression of hub genes, transcription factors (TFs) and microRNAs.ResultsA total of 230 DEGs were identified. PPI networks were constructed by mapping DEGs into STRING, in which 20 hub proteins were identified. KEGG pathway analyses revealed that the chemokine, NOD-like receptor, IL-17, and TNF signalling pathways were altered. GO analyses revealed that DEGs were extensively involved in the regulation of cytokine production, the immune response, the external side of the plasma membrane, and G-protein coupled chemoattractant receptor activity. The results of RT-PCR and immunohistochemical staining demonstrated that the expression of DEGs, TFs and microRNAs in our experiment were basically consistent with the predictions.ConclusionsThe results of this study offer insight into the pathomechanisms of r-axSpA and provide potential research directions.