bluuebunny/crossref_metadata_2025 huggingface dataset:
Author Correction: Ultra-small microorganisms in the polyextreme conditions of the Dallol volcano, Northern Afar, Ethiopia
Authors: Gómez Felipe , Cavalazzi Barbara , Rodríguez Nuria , Amils Ricardo , Ori Gian Gabriele , Olsson-Francis Karen , Escudero Cristina , Martínez Jose M. , Miruts Hagos
Published: February 2020

An amendment to this paper has been published and can be accessed via a link at the top of the paper.
Effects of partial hydrolysis on the structural, functional and antioxidant properties of oat protein isolate
Authors: Zheng Zhaojun , Li Jiaxin , Liu Yuanfa
Published: February 2020

Partial hydrolysis plays an important role in the structural, functional and antioxidant properties of oat protein isolate.
Enhancement of the cancer inhibitory effect of the bioactive food component resveratrol by nanoparticle based delivery
Authors: Bano Sameena , Ahmed Faheem , Khan Farha , Chaudhary Sandeep Chand , Samim M.
Published: February 2020

Enhanced chemo-preventive effect of nanoresveratrol on skin tumorigenesis in mouse by suppressing inflammatory responses and oxidative stress and inducing apoptosis.
High-viscosity α-starch nanogel particles to enhance oil recovery
Authors: Liang Tuo , Hou Jirui , Qu Ming , Zhao Mengdan , Raj Infant
Published: February 2020

The formation of dominant water channels is a serious problem for most oilfields, which results in low sweep efficiency.
Self-assembly of glycerol monooleate with the antimicrobial peptide LL-37: a molecular dynamics study
Authors: Innocenti Malini R. , Zabara M. , Gontsarik M. , Maniura-Weber K. , Rossi R. M. , Spano F. , Salentinig S.
Published: February 2020

Molecular dynamics simulations of glycerol-monooleate (GMO)/LL-37 nanocarriers show that hydrophobic interactions among the molecules drive the formation of GMO/LL-37 micelles.
N- and C-terminal regions of the small heat shock protein IbpA from Acholeplasma laidlawii competitively govern its oligomerization pattern and chaperone-like activity
Authors: Chernova Liliya S. , Bogachev Mikhail I. , Chasov Vitaly V. , Vishnyakov Innokentii E. , Kayumov Airat R.
Published: February 2020

The CTD provides fibrils (active form) formation. The NTD leads to globules formation and behaves as an intramolecular inhibitor of CTD. Their competition governs the equilibrium between either fibrills or globules regulating the AlIbpA activity.
Selection and application of aptamers with high-affinity and high-specificity against dinophysistoxin-1
Authors: Li Zhen , Hu Bo , Zhou Rong , Zhang Xiaojuan , Wang Ruizhe , Gao Yun , Sun Mingjuan , Jiao Binghua , Wang Lianghua
Published: February 2020

For the first time, the aptamer of dinophysistoxin-1 was successfully obtained with high affinity and specificity by SELEX, and an aptasensor with a detection range from 40 to 600 nM was developed by biolayer interferometry.
Efficient and stable catalyst of α-FeOOH for NO oxidation from coke oven flue gas by the catalytic decomposition of gaseous H2O2
Authors: Meng Ziheng , Wang Chenye , Wang Xingrui , Li Huiquan
Published: February 2020

A catalyst α-FeOOH possesses excellent catalytic activity for NO oxidation, and N2O5 is first found in NO oxidation products.
Colloidal quantum dot light-emitting diodes employing solution-processable tin dioxide nanoparticles in an electron transport layer
Authors: Park Myeongjin , Song Jiyun , An Myungchan , Lim Jaehoon , Lee Changhee , Roh Jeongkyun , Lee Donggu
Published: February 2020

QD-LEDs have gained tremendous attention to potentially replace current emissive display technologies. Here, we explore solution-processable SnO2 nanoparticles (NPs) as alternatives to ZnO for the electron transporting layer in QD-LEDs.
Voice Onset Time in Individuals With Hyperfunctional Voice Disorders: Evidence for Disordered Vocal Motor Control
Authors: McKenna Victoria S. , Hylkema Jennifer A. , Tardif Monique C. , Stepp Cara E.
Published: February 2020

Purpose

This study examined vocal hyperfunction (VH) using voice onset time (VOT). We hypothesized that speakers with VH would produce shorter VOTs, indicating increased laryngeal tension, and more variable VOTs, indicating disordered vocal motor control.

Method

We enrolled 32 adult women with VH (aged 20–74 years) and 32 age- and sex-matched controls. All were speakers of American English. Participants produced vowel–consonant–vowel combinations that varied by vowel (ɑ/u) and plosive (p/b, t/d, k/g). VOT—measured at the release of the plosive to the initiation of voicing—was averaged over three repetitions of each vowel–consonant–vowel combination. The coefficient of variation (CoV), a measure of VOT variability, was also computed for each combination.

Results

The mean VOTs were not significantly different between the two groups; however, the CoVs were significantly greater in speakers with VH compared to controls. Voiceless CoV values were moderately correlated with clinical ratings of dysphonia (
r
= .58) in speakers with VH.

Conclusion

Speakers with VH exhibited greater variability in phonemic voicing targets compared to vocally healthy speakers, supporting the hypothesis for disordered vocal motor control in VH. We suggest future work incorporate VOT measures when assessing auditory discrimination and auditory–motor integration deficits in VH.
Thoraxchirurgische Aspekte beim Polytrauma
Authors: Toffel Melanie , Pin Martin , Ludwig Corinna
Published: February 2020

Häufig sind thorakale Verletzungen Begleitverletzungen im Rahmen eines Polytraumas. Die Therapie polytraumatisierter Patienten ist anspruchsvoll und nur im interdisziplinären Kontext erfolgversprechend. Aus thoraxchirurgischer Sicht steht dabei das stumpfe Thoraxtrauma im Vordergrund.
Akute psychotische Störungsbilder
Authors: Englisch Susanne , Zink Mathias
Published: February 2020

Akute psychotische Störungsbilder sind nicht auf organische Ursachen oder Substanzeinfluss zurückzuführen. Sie zeichnen sich durch einen akuten Beginn sowie diverse Symptome aus, die sowohl affektiver als auch produktiv-psychotischer und psychomotorischer Art sein können. Die Beschwerden remittieren meist binnen kurzer Zeit vollständig ohne nennenswerte Residuen, neigen jedoch zu rezidivierenden Verläufen. Auch sind Übergänge in andere Krankheitsbilder möglich.
Wirkung der Kältekammer bei entzündlich-rheumatischen Erkrankungen
Authors: Dischereit Gabriel , Klemm Philipp , Lange Uwe
Published: February 2020

In der Behandlung entzündlich-rheumatischer Systemerkrankungen nehmen multimodale physikalische Therapiemaßnahmen eine zentrale Rolle ein. Kryotherapeutische Verfahren haben hierbei nicht nur eine lange Tradition, sondern, aufgrund ihrer guten Wirksamkeit, auch einen festen Stellenwert. Neben der lokalen Kälteapplikation, beispielsweise durch Coolpacks oder Kaltluft, kommt in Deutschland seit Mitte der 1980er-Jahre auch die Ganzkörperkältetherapie mittels Kältekammer bei der Behandlung unterschiedlicher Krankheitsbilder und Funktionsstörungen zur Anwendung, wobei verschiedene Kammersysteme und Temperaturbereiche verfügbar sind. Neben einer kurzen Einführung in die historischen und technischen Gegebenheiten fokussiert der vorliegende Artikel auf zentrale Wirkmechanismen der Ganzkörperkältetherapie und gibt einen Überblick über die aktuelle Evidenz in der Behandlung entzündlich-rheumatischer Erkrankungen.
Evaluation eines Laienhilfeprojekts zur psychischen Stabilisierung von Geflüchteten
Authors: Gutknecht Sarah , Kaiser Franziska , Leiding Delia Vanessa , Schneider Frank , Habel Ute , Schulte Holthausen Barbara
Published: February 2020

Ziel der Studie Der Artikel beschreibt Evaluationsergebnisse eines Modellprojekts zur Unterstützung psychisch belasteter Geflüchteter durch geschulte Laien. Ziel der Evaluation war eine Beurteilung hinsichtlich Notwendigkeit, Nützlichkeit und Effektivität des Projekts.

Methodik Es wurden involvierte und außenstehende Akteure mittels validierter sowie selbst entworfener Instrumente befragt und die Ergebnisse durch statistische Datenanalyse ausgewertet. Bei den Stichproben handelte es sich um 197 in Sammelunterkünften lebende Geflüchtete, 18 im Projekt arbeitende Laienhelfer (LH) sowie 16 Sozialarbeiter und Verwalter aus zwölf Flüchtlingsunterkünften.

Ergebnisse Mehr als die Hälfte der befragten Geflüchteten gaben eine psychisch auffällige Belastung an. Die Laienhilfe, die primär aus individualisierten Einzelangeboten bestand, wurde von den Geflüchteten positiv bewertet. 58,5 % der Klienten der LH wurden in die Regelversorgung weitervermittelt. Schulung, Koordination und Supervision wurden von den LH als gut bewertet. Im Projektverlauf änderte sich die Belastung der LH nicht. Sozialarbeiter und Verwalter der Flüchtlingsunterkünfte sahen die Arbeit der LH als hilfreich an.

Schlussfolgerung Das Konzept des Modellprojekts erweist sich als notwendig und sinnvoll. Psychisch belastete Geflüchtete profitieren von dem niedrigschwelligen Angebot in den Flüchtlingsunterkünften, und die LH leisten eine wertvolle muttersprachliche Hilfestellung. Gute Schulung, Koordination und Supervision als Rahmenbedingungen ermöglichen den erfolgreichen Einsatz von Laien zur effektiven Unterstützung von psychisch belasteten Geflüchteten.
Improved Synthetic Method for 5-[(Phenylthio)methyl]oxazoline Derivatives: Electrophilic Cyclization of Allylic Amide Using a Brønsted Acid and Tetrabutylammonium Chloride under Mild Conditions
Authors: Nagao Yoshihiro , Hiroya Kou
Published: February 2020

The synthesis of oxazolines using electrophilic cyclization of allylic amide is a simple and powerful method. However, cyclization involving arylsulfenylation requires harsh reaction conditions. We found that the reaction proceeds under mild heating conditions with the combination of a Brønsted acid and tetrabutylammonium chloride. This method enabled the synthesis of 5-[(arylsulfenyl)methyl]oxazoline derivatives under mild conditions and demonstrated high tolerance for various functional groups.
Kommentar von Stefan Krojer: Was im Klinikeinkauf 2020 wichtig wird
Authors: Krojer Stefan
Published: February 2020

Stefan Krojer ist leidenschaftlicher Einkäufer und ehemaliger Leiter des Strategischen Einkaufs der Johanniter Competence Center GmbH (Berlin). Er ist der Meinung, dass sieben Aspekte in diesem Jahr besonderes Augenmerk der Klinikeinkäufer verdienen.
Compliance im Beschaffungsprozess: Korruptionsrisiko bei Rabatten? Was der Einkauf wissen sollte.
Authors: Orrù Martina
Published: February 2020

Schlägt man die strafrechtlichen Kommentare auf, die auch von Staatsanwälten und Richtern herangezogen werden, findet man die pauschale Aussage, die Einräumung eines Rabattes sei ein Vorteil im Sinne des Korruptionsstrafrechts. Rabatte, die ein grundlegendes Element des wirtschaftlich und politisch erwünschten Preiswettbewerbs sind, werden so zu Unrecht in die Nähe zum Strafrecht gerückt und mit einem Korruptionsvorwurf überschattet.
Factors influencing the soil-test calibration for Colwell P and wheat under winter-dominant rainfall
Authors: Conyers Mark , Bell Richard , Bell Michael
Published: February 2020

Critical ranges for soil tests are based on results that inevitably involve some broad variance around the fitted relationship. Some of the variation is related to field-based factors affecting crop response to nutrients in the soil and some to the efficiency of the soil-test extractant itself. Most attempts to improve soil tests focus on the extractant, whereas here, we explore the variation that could be accounted for by field-based factors in the soil-test calibration relationship between Colwell phosphorus (P) and wheat yield, using the Australian Better Fertiliser Decisions for Crops database—the biggest dataset available for this relationship. Calibrations developed from this dataset have been criticised, and so we aimed to explore factors accounting for more of the variation in the relationships for the dryland, winter-dominant rainfall region of southern New South Wales.
As reported previously, soil type was shown to influence the critical range and r-value for the Colwell P soil-test calibration for P responses by wheat. We also identified a tendency for dry conditions, at sowing or during the season, to lower relative yields for a given soil-test value, indicating increased reliance on fertiliser P over soil P. A similar trend was evident for later sowing date, again suggesting an increased probability of crop P requirements being met from the fertiliser P. However, additional records need to be generated to establish definitively that early sowing or subsurface P reserves minimise response to fertiliser P. In general, factors that influence crop access to soil P will have an impact on response to fertiliser P.
Although this analysis shows that it is possible to ‘tighten’ the response curve for Colwell P and wheat by restricting the data for a given soil type to ideal management and seasonal conditions, the ‘outliers’ that are excluded frequently reflect an important subset of environmental conditions encountered by wheat crops in dryland agriculture.
Yield reduction of direct-seeded rice under returned straw can be mitigated by appropriate water management improving soil phosphorus availability
Authors: Yang Haishui , Feng Jinxia , Weih Martin , Meng Yi , Li Yifan , Zhai Silong , Zhang Wuyi
Published: February 2020

The yield of direct-seeded rice has been shown to decrease after straw amendment. However, the reasons for the yield decrease, and any measures to alleviate it, are currently unknown. We hypothesised that straw return exerts negative effects on soil fertility and on root growth of direct-seeded rice, which subsequently reduces the remobilisation of reserves to grains under continuous flooding (CF); and that alternate wetting and drying (AWD) irrigation can alleviate these negative impacts. Field and greenhouse experiments were conducted to test the hypotheses, by comparing CF and AWD in combination with two wheat-straw treatments (incorporation and mulching). Under CF, wheat-straw incorporation decreased soil available phosphorus by 23–79%, root biomass by 10%, leaf biomass by 13%, and leaf area by 15% compared with the control with no straw incorporation; negative effects on these characteristics were lessened if the straw was mulched. The AWD treatment alleviated the negative effects of straw incorporation compared with CF, and straw mulching with AWD had no negative effects or resulted in positive effects. The results suggest that CF along with straw incorporation limits soil phosphorus availability, root growth and grain yield by affecting photosynthate accumulation and remobilisation. AWD irrigation mitigates these undesirable effects by decreasing soil total reductants, which subsequently increases soil pH and plant-available phosphorus. The proposed AWD treatment could be a promising strategy for the sustainable production of direct-seeded rice.
How do learners engage with oral corrective feedback on lexical stress errors?
Authors: Saeli Hooman , Dalman Mohammadreza , Rahmati Payam
Published: February 2020

This study explored the affective, behavioral, and cognitive engagement of 18 Iranian EFL learners with oral corrective
feedback on lexical stress errors. The data were collected using questionnaires, pretests, posttests, and interviews. The questionnaire
responses showed that the participants held various perceptions about direct feedback. Additionally, the pretest and posttest results
indicated that the learners with positive perceptions about direct feedback had significant lexical stress accuracy gains. Also, the
students who viewed direct feedback favorably showed positive affective, behavioral, and cognitive engagement with it. These learners, for
instance, frequently reviewed the provided feedback and used cognitive resources when utilizing it. In contrast, the students with negative
perceptions about direct feedback showed negative engagement with it. The findings suggest that learners’ affective, behavioral, and
cognitive engagement can determine the working of feedback. Also, students’ perceptions seem to filter the feedback they receive, thereby
helping shape how they engage with feedback.
印尼華裔中學生繼承語學習動機及其影響因素 [Motivational orientations of secondary school students of Mandarin Chinese as a heritage language in Indonesia]
Authors: Tam Hugo Wing-Yu
Published: February 2020

學生學習動機的研究是當前華語第二語言教學的重要課題。華裔學生的繼承語言學習動機更是華語學習成效的重要關鍵。本研究通過問卷調查了印尼華裔中學生繼承語學習動機的類型，並檢視了不同背景變項對印尼華裔中學生繼承語學習動機類型的影響。研究者親自赴印尼中爪哇省進行華語教學與研究，以前導訪談和繼承語學習動機文獻為基礎，經專家進行題項審閱後，編製了印華雙語版本的「繼承語學習動機量表」。研究以分層叢集比例取樣的方式，向兩所初中和一所高中每級各兩班發出共 310 份問卷，共收回有效問卷174份。透過因素分析歸納出6種動機類型：學習情境、族裔傳承、學習期望、學習情感、綜合型、工具型。總量表Cronbachα = .85，六個分量表的α = .695~.884，顯示此量表的信度品質頗佳。研究分析顯示華裔印尼中學生的繼承語學習動機因性別、學校階段別、族裔語言背景和家族語言背景而有顯著差異。最後，文章結合研究結果提出教學應用與未來研究的具體建議，以期供繼承語教師作參考。
Levitated cavity optomechanics in high vacuum
Authors: Delić Uroš , Grass David , Reisenbauer Manuel , Damm Tobias , Weitz Martin , Kiesel Nikolai , Aspelmeyer Markus
Published: February 2020

We report dispersive coupling of an optically trapped nanoparticle to the field of a Fabry–Perot cavity in high vacuum. We demonstrate nanometer-level control in positioning the particle with respect to the cavity field, which allows access to linear, quadratic, and tertiary optomechanical interactions in the resolved sideband regime. We determine all relevant coupling rates of the system, i.e. mechanical and optical losses as well as optomechanical interaction, and obtain a quantum cooperativity of C
Q = 0.01. Based on the presented performance, the regime of strong cooperativity (C
Q > 1) is clearly within reach by further decreasing the mode volume of the cavity.
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

Motivation

Single 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.

Results

In 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 implementation

The R package scRMD is available at https://github.com/XiDsLab/scRMD.

Supplementary information

Supplementary 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

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

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

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

We 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

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

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

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

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 < 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

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

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
A84 LINITIS PLASTICA FROM A NON-GASTROINTESTINAL PRIMARY TUMOR: A CASE REPORT
Authors: Ghaith J , Alhafid I , Habal F
Published: February 2020

Background

Infiltrative malignancies to the stomach are unusual and are difficult to detect. Linitis Plastic is a syndrome caused by submucosal invasion of the gastric wall. It represents Bormann type III or IV of gastric adenocarcinoma. Uncommonly, the latter can be a manifestation of lobular breast cancer.

Aims

To present a case report of lobular breast cancer that manifested primarily as Linitis Plastica (LP). We review the literature of LP as a clinical syndrome and the diagnostic challenges associated with this condition. We aim to increase the awareness of LP as a non-gastric tumor and its endoscopic features.

Methods

-

Results

A seventy-two-year-old female patient, previously healthy, presented with general deconditioning and distended abdomen. Basic laboratory testing such as complete blood count, electrolytes and kidney function were normal. Computed tomography of the abdomen and pelvis revealed moderately sized peritoneal carcinomatosis deposits on the abdominal wall. Her family history was non-contributary for any gastrointestinal or gynecological malignancies. On review of system, the patient noted a history of successful eradication of Helicobacter pylori infection remotely. Additionally, no preceding age-appropriate malignancy screening tests were reported. A gastroscopy was done looking for a primary gastrointestinal tumor exhibited abnormally stiff gastric wall, erythematous thickened mucosal folds, and non-distensible stomach. No clear lesions, submucosal masses or ulcers were visualized. The duodenal mucosa was noted to be normal. Twelve deep random biopsies were retrieved from the mucosal body and fundus. Following immunohistochemistry, the histological diagnosis revealed lobular adenocarcinoma of the breast.

Conclusions

Linitis Plastica (leather bottle stomach) or Brinton disease is a rare entity of diffuse gastric mucosa infiltrating tumor. LP depicts 3–10% of primary gastric carcinoma, whilst less than 10% are secondary breast cancer. Endoscopically, breast cancer-related LP can be divided into two morphologies: nodular pattern with ulceration, which is the typical presentation of ductal breast carcinoma and diffuse mural pattern in lobular breast carcinoma. LP is a unique condition with challenging diagnostic features. Many biopsies can result in negative histopathological diagnoses. This can be explained partially by 1. The scirrhous and fibrous stroma that forms LP tumors. 2. The deep location in the submucosa and muscular layer of the gastric wall. 3. Inability to identify this entity endoscopically. In one case report, Endoscopic Ultrasound-Fine Needle Aspirate (EUS-FNA) was incorporated after negative obtained biopsies. There are no standardized diagnostic approaches for LP. Further studies inquiring rates of missed malignant diagnoses and optimum diagnostic assessments in the setting of LP are needed.

Funding Agencies

None
A95 DO BENIGN LIVER TUMOURS ALWAYS STAY BENIGN? A CASE REPORT OF HEPATIC INFLAMMATORY PSEUDOTUMOR AND SUBSEQUENT CHOLANGIOCARCINOMA
Authors: Onizuka K , Schell M , Tsoi K
Published: February 2020

Background

Hepatic inflammatory pseudotumors (HIPTs) are rare, benign lesions of unclear etiology which can be challenging to diagnose and differentiate from malignant processes. The optimal treatment and follow up of these lesions is controversial, and literature exists to support both surgical resection as well as conservative medical management. The natural history of HIPTs is generally benign, however there are some reports of disease recurrence, and two reports of malignant transformation to lymphoma.

Aims

To describe a case of HIPT with progression to malignancy.

Methods

Case report and review of the literature.

Results

A 53-year-old male presented to St. Joseph’s Healthcare Hamilton in August 2019 with a three-week history of abdominal pain and distention. He had a previous diagnosis of HIPT, incidentally found on ultrasound four years earlier. CT in January 2016 reported two well-marginated focal liver masses with peripheral rim enhancement and central hypodensity, 3.9 x 3.9cm in segment 2, and a 6 x 4.6cm central lesion, as well as diffuse fatty infiltration of the liver. Bloodwork showed a mildly elevated Ca19-9 626 kU/L, and normal CEA and AFP.

Two biopsies were performed in 2016, both demonstrating dense fibrous tissue and abundant chronic inflammatory cell infiltrate composed of lymphocytes, histiocytes, eosinophils, and plasma cells, with some areas of bland spindle cell proliferation. No malignant cells, and histology was felt to be consistent with HIPT.

MRI in September 2017 showed progression of disease, prompting Rheumatology to initiate immunosuppressive medications, however serial imaging continued to show increase in the size and number of lesions.

Upon presentation to hospital in August 2019 ultrasound showed new ascites, with ascitic fluid analysis reporting highly atypical cells with prominent nucleoli of uncertain origin. CT showed extensive intrahepatic lesions throughout both lobes of the liver, and tumor markers were elevated with Ca19-9 16,581 kU/L, CEA 10 ug/L, Ca125 511 kU/L, and normal AFP.

Repeat liver biopsy reported adenocarcinoma, likely cholangiocarcinoma, with background cirrhosis. Medical oncology did not feel he would tolerate chemotherapy, and he was thus discharged home with palliative supports.

Conclusions

HIPTs are benign lesions that are often initially misdiagnosed as malignancy, however this is the first case reporting progression of HIPT to cholangiocarcinoma. It is unclear if HIPT itself has premalignant potential, or whether its presence delays diagnosis of subsequent de novo malignancies. Given these uncertainties, as well as the lack of clarity on optimal management of HIPT, this case illustrates the importance of long-term clinical and radiographic follow up of these uncommon lesions, with consideration of repeat biopsy if the disease is not following the expected clinical course.

Funding Agencies

None