bluuebunny/crossref_metadata_2025_split huggingface dataset:
scRMD: imputation for single cell RNA-seq data via robust matrix decomposition
Authors: Chen Chong , Wu Changjing , Wu Linjie , Wang Xiaochen , Deng Minghua , Xi Ruibin 
Published: February 2020

AbstractMotivationSingle cell RNA-sequencing (scRNA-seq) technology enables whole transcriptome profiling at single cell resolution and holds great promises in many biological and medical applications. Nevertheless, scRNA-seq often fails to capture expressed genes, leading to the prominent dropout problem. These dropouts cause many problems in down-stream analysis, such as significant increase of noises, power loss in differential expression analysis and obscuring of gene-to-gene or cell-to-cell relationship. Imputation of these dropout values can be beneficial in scRNA-seq data analysis.ResultsIn this article, we model the dropout imputation problem as robust matrix decomposition. This model has minimal assumptions and allows us to develop a computational efficient imputation method called scRMD. Extensive data analysis shows that scRMD can accurately recover the dropout values and help to improve downstream analysis such as differential expression analysis and clustering analysis.Availability and implementationThe R package scRMD is available at https://github.com/XiDsLab/scRMD.Supplementary informationSupplementary data are available at Bioinformatics online.
Feature set optimization in biomarker discovery from genome-scale data
Authors: Fortino V , Scala G , Greco D 
Published: February 2020

Abstract

Motivation
Omics technologies have the potential to facilitate the discovery of new biomarkers. However, only few omics-derived biomarkers have been successfully translated into clinical applications to date. Feature selection is a crucial step in this process that identifies small sets of features with high predictive power. Models consisting of a limited number of features are not only more robust in analytical terms, but also ensure cost effectiveness and clinical translatability of new biomarker panels. Here we introduce GARBO, a novel multi-island adaptive genetic algorithm to simultaneously optimize accuracy and set size in omics-driven biomarker discovery problems.

Results
Compared to existing methods, GARBO enables the identification of biomarker sets that best optimize the trade-off between classification accuracy and number of biomarkers. We tested GARBO and six alternative selection methods with two high relevant topics in precision medicine: cancer patient stratification and drug sensitivity prediction. We found multivariate biomarker models from different omics data types such as mRNA, miRNA, copy number variation, mutation and DNA methylation. The top performing models were evaluated by using two different strategies: the Pareto-based selection, and the weighted sum between accuracy and set size (w = 0.5). Pareto-based preferences show the ability of the proposed algorithm to search minimal subsets of relevant features that can be used to model accurate random forest-based classification systems. Moreover, GARBO systematically identified, on larger omics data types, such as gene expression and DNA methylation, biomarker panels exhibiting higher classification accuracy or employing a number of features much lower than those discovered with other methods. These results were confirmed on independent datasets.

Availability and implementation
github.com/Greco-Lab/GARBO.

Contact
dario.greco@tuni.fi

Supplementary information
Supplementary data are available at Bioinformatics online.
ASPRAlign: a tool for the alignment of RNA secondary structures with arbitrary pseudoknots
Authors: Quadrini Michela , Tesei Luca , Merelli Emanuela 
Published: February 2020

Abstract

Summary
Current methods for comparing RNA secondary structures are based on tree representations and exploit edit distance or alignment algorithms. Most of them can only process structures without pseudoknots. To overcome this limitation, we introduce ASPRAlign, a Java tool that aligns particular algebraic tree representations of RNA. These trees neglect the primary sequence and can handle structures with arbitrary pseudoknots. A measure of comparison, called ASPRA distance, is computed with a worst-case time complexity of O(n2) where n is the number of nucleotides of the longer structure.

Availability and implementation
ASPRAlign is implemented in Java and source code is released under the GNU GPLv3 license. Code and documentation are freely available at https://github.com/bdslab/aspralign.

Contact
luca.tesei@unicam.it

Supplementary information
Supplementary data are available at Bioinformatics online.
CloudASM: an ultra-efficient cloud-based pipeline for mapping allele-specific DNA methylation
Authors: Dumont Emmanuel L P , Tycko Benjamin , Do Catherine 
Published: February 2020

Abstract

Summary
Methods for quantifying the imbalance in CpG methylation between alleles genome-wide have been described but their algorithmic time complexity is quadratic and their practical use requires painstaking attention to infrastructure choice, implementation and execution. To solve this problem, we developed CloudASM, a scalable, ultra-efficient, turn-key, portable pipeline on Google Cloud Platform (GCP) that uses a novel pipeline manager and GCP’s serverless enterprise data warehouse.

Availability and implementation
CloudASM is freely available in the GitHub repository https://github.com/TyckoLab/CloudASM and a sample dataset and its results are also freely available at https://console.cloud.google.com/storage/browser/cloudasm.

Contact
emmanuel.dumont@hmh-cdi.org
A Case of 2019 Novel Coronavirus in a Pregnant Woman With Preterm Delivery
Authors: Wang Xiaotong , Zhou Zhiqiang , Zhang Jianping , Zhu Fengfeng , Tang Yongyan , Shen Xinghua 
Published: February 2020

AbstractWe present a case of a 30-week pregnant woman with the 2019 novel coronavirus (COVID-19) delivering a healthy infant with no evidence of COVID-19.
A16 ROLE OF MYELOID CELLS IN THE INITIATION OF COLITIS-ASSOCIATED COLON CANCER
Authors: Shin A E , Good H J , Tesfagiorgis Y , Zhang L , Kerfoot S M , Sherman P M , Wang T C , Asfaha S 
Published: February 2020

Abstract

Background
Colorectal cancer (CRC) is the second leading cause of cancer death, with a major risk factor being chronic inflammation. Despite the clear association between inflammation and cancer, the mechanism by which colitis leads to CRC is not well understood. We recently showed that the presence of inflammation does not always correlate with colonic tumorigenesis, as the type of colitis (i.e. colitis-inducing agent) appears to be important for tumor initiation.

Aims
In this study, we aim to explore the mechanism by which inflammation contributes to the initiation of colitis-associated cancer. We hypothesized that dextran sodium sulfate (DSS)-induced colitis leads to the infiltration of a specific immune cell type that is associated with colonic tumorigenesis.

Methods
To generate tamoxifen-inducible Cre transgenic mice that allow for Dclk1+ cell lineage tracing and cell-specific knock-out of the tumor suppressor adenomatous polyposis coli (APC), we first crossed our transgenic Dclk1CreERT2 mice to both ROSA26tdTomato and APCfl/fl mice (Dclk1/APCfl/fl). Following Tamoxifen induction, mice were treated with the colitis-inducing agents DSS, trinitrobenzene sulfonic acid (TNBS), oxazolone, or Citrobacter rodentium. The tumor studies were repeated using azoxymethane (AOM)-DSS induced colitis-associated cancer model.

Results
Treatment with any of the four colitis-inducing agents (DSS, TNBS, oxazolone, or C. rodentium) induced colonic inflammation as detected by increased myeloperoxidase (MPO) activity and histologic analysis. Interestingly, DSS administration led to colonic tumors, whereas TNBS, oxazolone, or C. rodentium did not, even up to 52 weeks following colitis induction. FACS analysis of immune cells in the colon revealed no difference in the number of T or B cells in mice treated with any of the colitis-inducing agents. We did, however, detect significantly increased levels of Ly6G+ neutrophils and F4/80+ macrophages in DSS-treated mice compared to mice in any of the other three models of colitis. Consistent with this myeloid cell infiltration, significantly upregulated protein levels of G-CSF, IL-6, TNF-α, and CXCL1 were detected in DSS-treated mice compared to the other three models of colitis. IL-1α, IL-1β, IL-4, IL-10, and TGF-β levels were unchanged.

Conclusions
Our data suggest that infiltration of Ly6G+ neutrophils and pro-inflammatory F4/80+ macrophages, unique to DSS-induced colitis, contributes to colonic tumor formation. These data demonstrate that specific immune cell types, rather than the presence of colonic inflammation, play a critical role in the initiation of colitis-associated CRC.

Funding Agencies
CAG, CIHR
A18 BUILDING BETTER ENTEROIDS: A NOVEL STRATEGY FOR ENRICHING SECRETORY EPITHELIAL CELL SUBTYPES
Authors: Davies E E , Crowley S M , Tsai K , Diaz Gomez M , Han X , Vallance B 
Published: February 2020

Abstract

Background
Inflammatory bowel diseases (IBD) are chronic gastrointestinal disorders that affect more than 270,000 Canadians, including over 7,000 children. Inflammation arising from IBD severely damages intestinal epithelial cells (IECs), however their role in disease pathogenesis is not fully understood, in part due to a lack of in vitro systems that recapitulate the epithelium’s complex cellular composition.
Enteroids are an in vitro model where primary IECs are isolated and cultured as 3D ‘mini guts.’ They offer distinct advantages over cell lines, however current protocols generate enteroids primarily composed of enterocytes that seldom contain rarer IEC subtypes (goblet, enteroendocrine, tuft and Paneth cells). These cells are responsible for the gut’s mucus, antimicrobial and hormone secretory functions, yet their role in the pathophysiology of IBD is unclear.

Aims
Manipulate cell differentiation pathways in mouse and human enteroids to increase the prevalence of secretory IECs, as well as determine if enteroids derived from pediatric IBD patients exhibit impaired responses to differentiation treatments.

Methods
Mouse enteroids were derived from ileal, cecal and colonic crypts of C57BL/6 mice while human enteroids were isolated from healthy or pediatric IBD patient intestinal biopsies. Enteroids were initially supplemented with Wnt signaling activators and the extracellular matrix modified to enhance enteroid culture “stemness”. Differentiation was induced by growth media modulation of the Notch and Wnt signaling pathways. Enteroids were analyzed via flow cytometry to quantify expression of secretory cell markers, while immunofluorescent and Peroidic acid Schiff/Alcian Blue staining was used to visualize goblet cells.

Results
“Stem” treatment potentiated Wnt signaling and enhanced enteroid “stemness” as measured by Lgr5 and CD44 expression. Comparatively, differentiation of these “stem” enteroids led to a larger relative increase in secretory markers. Differentiation treatment increased expression of goblet cell markers (Muc2 and lectin) in the “stem” treated mouse cecal and colonic enteroids, but not in ileal enteroids. Notch inhibition produced increased expression of lysozyme, a Paneth cell marker, in all enteroids.
A similar increase in secretory cell numbers was observed in control human enteroids following differentiation treatment. In contrast, enteroids derived from pediatric IBD patients displayed irregular differentation responses to treatment.

Conclusions
We demonstrate that manipulation of cell differentiation pathways increases the number of secretory IEC subtypes within enteroids. Furthermore, these pro-secretory cell responses differ in IBD patient enteroids, indicating that an alteration of the targeted cell signaling pathways may be linked to IBD pathogenesis.

Funding Agencies
CCC, CIHRBCCHRI Summer Studentship
A19 NOVEL HLA-DQ2 TRANSGENIC MICE DEVELOP GLUTEN-IMMUNOPATHOLOGY FOLLOWING GLUTEN SENSITIZATION
Authors: Clarizio A V , Galipeau H J , Jury J , Rondeau L , Godbout J , Williams L , Anderson B , Verdu E 
Published: February 2020

Abstract

Background
Celiac disease (CeD), an autoimmune and chronic inflammatory enteropathy triggered by the ingestion of gluten, is associated with HLA-DQ2 (~90%) and, to a lesser extent, HLA-DQ8. We previously characterized a humanized mouse model of gluten sensitivity that expresses the HLA-DQ8 allele, and that develops mild innate and adaptive immune pathways related to DQ8+ CeD patients. Gluten peptides recognized in the context of DQ2 differ from those bound to DQ8 molecules and homozygous carriage of HLA-DQ2 provides higher risk for CeD development. Thus, characterization of a transgenic HLA-DQ2 model would allow for the investigation of disease pathways that affect the majority of celiac patients.

Aims
Our aim was to determine gluten-immune responses and small intestinal pathology in C57BL/6 mice humanized with the HLA DR3-DQ2 gene.

Methods
To break oral tolerance to gluten, DR3-DQ2 mice were orally sensitized with gliadin (5mg/mL) and cholera toxin (CT; 2.5mg/mL) before being challenged with gluten (10mg/mL) for three weeks. Non-sensitized DR3-DQ2 controls mice received CT and a sham challenge. To determine the effects of long-term exposure to gluten, gliadin sensitized DR3-DQ2 mice were placed on a gluten-containing diet for twelve weeks. Controls were given CT and remained on a gluten-free diet. Pathology was evaluated by CD3+ intraepithelial lymphocytes (IELs) counts; villus-crypt (V/C) ratios. Gluten-induced immune responses were evaluated by anti-tissue transglutaminase-2 (tTG) and anti-gliadin antibodies, inflammatory gene expression by Nanostring Technology, and CD4+ T cell proliferation using flow cytometry. Intestinal permeability was measured in vitro by Ussing Chamber.

Results
DR3-DQ2 mice that were sensitized and challenged with gluten for three weeks had higher IEL counts, lower V/C ratios, higher anti-gliadin and tTG antibodies, which are used in the serological diagnosis of the disease. Gluten sensitized mice also has higher expression of pro-inflammatory genes, and an induction of gluten specific T cells, but no changes in permeability compared to control mice. DR3-DQ2 mice given a gluten-containing diet for 12 weeks also had higher IEL counts, lower V/C ratios, and higher anti-gliadin and tTG antibodies, but had no changes in permeability compared to controls.

Conclusions
These results indicate that mice humanized with the HLA DR3-DQ2 gene show innate and gluten-specific immune responses following sensitization. Thus, mice expressing HLA-DQ2 represents a novel model of gluten sensitivity that can be used to investigate celiac disease pathways related to gluten peptide repertoire that binds to DQ2 MHC class II, encoded by the HLA gene expressed by the majority of celiac patients.
Supported by CIHR to EFV and OGS to AVC

Funding Agencies
CIHROGS
A38 SUBOPTIMAL VACCINATION ADHERENCE IN MOTHERS WITH INFLAMMATORY BOWEL DISEASE AND THEIR BIOLOGIC-EXPOSED INFANTS
Authors: Chiarella-Redfern H , Jubran B , Constantinescu C , Favela L , Seow C 
Published: February 2020

Abstract

Background
Data suggests that postpartum IBD patients have low self-reported vaccine rates despite being exposed to multiple care providers. To date, there is limited data on vaccine safety in infants exposed to biologic therapies in utero for the treatment of maternal IBD, with only questionnaire style studies and one case report of a fatal outcome post BCG vaccine. This has led to guidelines recommending against live vaccines under 6 months, such as the rotavirus vaccine, in biologic exposed infants.

Aims
To assess vaccine compliance in mothers with IBD and their infants and evaluate rotavirus safety to help optimize preventative medicine and guide future vaccine recommendations.

Methods
We obtained data from the University of Calgary’s Pregnancy in IBD Registry from 2012 to 2018 and from provincial vaccination and personal health records. Vaccine rates for Hep-A, Hep-B, Pneu-C-13, Pneu-C-23 and DTap were obtained for 117 mothers who received biologic therapy during pregnancy. Rotavirus (n=74 as it was introduced in ‘14) and DTap-IPV-Hib, Men-C, Pneu-C-13 and MMR (n=117) rates were obtained for infants exposed to biologics in utero. Rotavirus (n=92) and non-rotavirus (n=142) rates for non-biologic exposed infants were also collected. Rotavirus complications, characterized by related emergency room visits, were obtained. Descriptive statistics were performed with chi-square tests.

Results
We found the following rates of vaccine uptake in the biologic treated mothers: Hep-A (47%), Pneu-C-13 (32%), Pneu-C-23 (36%), Hep-B (75%) and DTap (79%). When comparing biologic and non-biologic exposed infants there were high rates of compliance for recommended vaccines with no differences in DTap-IPV-Hib (91% vs. 89%, p=0.11), Men-C (96% vs. 92%, p=0.80), Pneu-C-13 (95% vs. 93%, p=0.14) and MMR (96% vs. 92%, p=0.80). There was a significant difference in rotavirus rates (20% vs. 87%, n &lt; 0.0001) given the recommendation against vaccination in biologic exposed infants. There was a significant difference in vaccination guideline adherence within the biologic group when comparing inappropriately administered rotavirus vaccines with inappropriately missed recommended vaccines (20% vs. 6%, p=0.02). No infants who received the rotavirus vaccine suffered from intussusception or death nor was there a significant difference in adverse events between the two groups (20% vs 9%; p=0.71).

Conclusions
The study highlights the need for improved vaccination education and implementation given suboptimal vaccine adherence in biologic treated mothers and the inadvertent administration of the live rotavirus vaccine in their biologic exposed infants. The lack of rotavirus vaccine adverse events shows potential vaccine safety in biologic exposed infants and requires further study.

Funding Agencies
None
A48 COLITIS FAVORS THE EXPANSION OF BACTERIA THAT ACTIVATE PAR2 AMPLIFYING INFLAMMATORY RESPONSE
Authors: Caminero Fernandez A , Rondeau L , Galipeau H J , Jury J , Bermudez-Brito M , Constante M , Clarizio A V , Deraison C , Ruf W , Vergnolle N , Verdu E 
Published: February 2020

Abstract

Background
Proteolytic imbalance has been described in patients with inflammatory bowel disease (IBD) and in different models of experimental colitis. Although the proteases reported to be increased are mainly from the host, the role of bacterial proteases has recently emerged, as they can promote inflammation, in part, through activation of Protease-activated receptors (PARs). PAR2 deficient mice are resistant to inflammation and PAR2 activation affects multiple aspects of the tissue response to injury. However, PAR2 communicates with other receptors such as toll-like and other PARs, which are important in multiple immune signaling pathways. Thus, the direct implication of PAR2 in colitis, and specifically the activation of the external domain by microbial proteases, remains unclear.

Aims
To study the role of PAR2 and bacterial proteases in experimental colitis.

Methods
C57BL/6 and protease-resistant PAR2 (R38E-PAR2) mice, in which activation site of PAR2 is missing, were given 3.5% dextran sodium sulfate (DSS) in drinking water for 5 days followed by 2 days of water. Control C57BL/6 (wild-type) and R38E-PAR2 mice received only water. Percent weight change was evaluated along the study. Fecal microbiota (16S Ilumina), expression of proinflammatory genes (Nanostring), gut permeability (Ussing chamber), proteolytic activities (colorimetric assay) and bacterial translocation (plating) were measured in all mice at sacrifice. Inflammation was determined by analyzing stool consistency, fecal blood and by microscopic scores (Cooper score). Bacteria with proteolytic activity were isolated using agar-media with protein as main nutrient and bacterial capacity to release the external domain of PAR2 was tested in cells harbouring luciferase at the PAR2 N terminus.

Results
Wild-type, but not R38E-PAR2 mice, had increased expression of several pro-inflammatory genes, such as tnf, map3k and tlr, gut dysfunction and increased intestinal permeability, increased bacterial translocation into spleen and altered microbiota profiles following DSS treatment. DSS induced colitis in both mouse strains, but clinical and microscopic scores were significantly lower in R38E-PAR2 compared with wild-type mice. DSS increased the abundance of opportunistic pathogens such as Enterococcus and Staphylococcus only in wild-type mice. Proteolytic phenotype of these bacteria, and their capacity to cleave the external domain of PAR2, was confirmed.

Conclusions
Mice lacking the activation site of PAR2 are protected from DSS-induced colitis. DSS treatment leads to expansion of bacteria releasing active proteases, which may mediate injury through PAR2. These results suggest that intestinal injury promotes microbial proteolytic imbalance which in turn, exacerbates inflammation.

Funding Agencies
CAG, CCC, CIHR
A50 TRANSFER OF DEPRESSIVE-LIKE PHENOTYPE TO GNOTOBIOTIC MICE DEPENDS ON MICROBIAL FEATURES SPECIFIC TO INDIVIDUAL PATIENTS
Authors: Hanuschak J , Louis-Auguste M P , De Palma G , Verdu E , Anglin R , Surette M , Collins S M , Bercik P 
Published: February 2020

Abstract

Background
Major depressive disorder (MDD) affects approximately 4.4% of the global population. Despite its high prevalence, little is known about the mechanisms underlying this disorder. Recent studies in both humans and rodents have suggested that the intestinal microbiota may play a role in depression. Altered microbiota composition has been found in a subset of MDD patients. Preclinical studies have suggested that fecal microbiota transplant using pooled MDD patient samples can induce depressive-like behaviour in rodents. We have previously shown that the use of different microbiota donors with irritable bowel syndrome results in the induction of different phenotypes in recipient mice. Thus, we have hypothesized that pooling microbiota samples abrogates features that are unique to individual donors.

Aims
(1) Investigate whether the transfer of individual MDD patient microbiota can induce depressive-like behaviour in germ-free (GF) mice
(2) Identify features of individual MDD patient microbiota that are associated with the depressive-like phenotype

Methods
GF NIH Swiss mice of both sexes (min. n=10 per group, total n=110) were colonized with either fecal microbiota from a single donor, MDD patient (MDD1-4) or matched healthy control (HC1-4), or pooled fecal microbiota from MDD1-4 or HC1-4. Mouse behaviour was assessed, using the open field test, three chamber sociability assay, tail suspension test, and sucrose preference test. Stool samples were collected throughout the experiment for 16S rRNA gene sequencing.

Results
Mice colonized with microbiota from patient MDD1 exhibited depressive-like behaviour, as assessed by the sucrose preference test and sociability assay, when compared to mice colonized with HC1 microbiota. This was not true for mice colonized with individual microbiota from the other three patients (MDD2-4) or with pooled MDD microbiota. Comparative analysis of the 16S data revealed a significant difference in Faith’s Phylogenetic Diversity between MDD1 microbiota and pooled MDD microbiota. Four bacterial species were found to be significantly associated with the depressive-like phenotype in mice: Bacteroides acidifaciens, Bacteroides ovatus, unclassified species of Phascolarctobacterium (Veillonellacae family), and Eggerthella lenta. The relative abundances of these species did not differ significantly between the two pooled groups.

Conclusions
Microbiota from some, but not all, MDD patients can induce a depressive-like phenotype in GF mice. The ability to induce depressive-like behaviour in GF mice is lost when microbiota from multiple patients is pooled. Specific bacterial species may be responsible for the successful transfer of the depressive-like phenotype to mice.

Funding Agencies
NIH