bluuebunny/crossref_metadata_2025_split huggingface dataset:
Reconsidering macroeconomic policy prescriptions with meta-analysis
Authors: Gechert Sebastian 
Published: February 2022

AbstractThis paper investigates recent developments in meta-analysis, the tool to quantitatively synthesize research in a certain body of literature. After providing a brief overview on how to do a meta-analysis and discussing recent methodological advancements, I review applied contributions to the field of macroeconomics. It turns out that meta-analyses have often questioned the conventional wisdom and established new consensuses in fiscal, monetary, and labor market policies by uncovering substantial publication bias and unexpected determining factors in many bodies of literature—in particular those dominated by policy conclusions in the neoclassical tradition like minimum wages, central bank strategies, financial regulation and the relative effects of tax and spending policies.
Salvage debulking surgery and hyperthermic intrathoracic chemotherapy for massive recurrent mesothelioma in the mediastinum
Authors: Poon Shi Sum , Alberti Caterina , Nardini Marco , Migliore Marcello 
Published: February 2022

Abstract
Mediastinal malignant pleural mesothelioma with signs of tamponade is rare. Indication for reoperation for recurrent malignant pleural mesothelioma is a controversial but viable option in selected patients. We report a case of a 68-year-old man presenting with epithelioid malignant pleural mesothelioma who underwent a total of three debulking surgeries (pleurectomy/decortication) combined with hyperthermic intrathoracic chemotherapy. Five years after the first procedure, a third urgent operation was performed for recurrence of a large mediastinal mesothelioma causing acute symptoms of pericardial constriction and tamponade. The patient was alive for eight years since the first treatment and 36 months after the second reoperation.
Reduced cytotoxicity by mutation of lysine 590 of Pseudomonas exotoxin can be restored in an optimized, lysine-free immunotoxin
Authors: Ammon A , Mellenthin L , Emmerich C , Naschberger E , Stürzl M , Mackensen A , Müller F 
Published: February 2022

Abstract
Immunotoxins, which are fusion proteins of an antibody fragment and a fragment of a bacterial or a plant toxin, induce apoptosis in target cells by inhibition of protein synthesis. ADP-ribosylating toxins often have few lysine residues in their catalytic domain. As they are the target for ubiquitination, the low number of lysines possibly prevents ubiquitin-dependent degradation of the toxin in the cytosol. To reduce this potential degradation, we aimed to generate a lysine-free (noK), Pseudomonas exotoxin (PE)-based immunotoxin. The new generation 24 kDa PE, which lacks all but the furin-cleavage site of domain II, was mutated at lysine 590 (K590) and at K606 in a CD22-targeting immunotoxin and activity was determined against various B cell malignancies in vitro and in vivo. On average, K590 mutated to arginine (R) reduced cytotoxicity by 1.3-fold and K606R enhanced cytotoxicity by 1.3-fold compared to wild type (wt). Mutating K590 to histidine or deleting K590 did not prevent this loss in cytotoxicity. Neither stability nor internalization rate of K590R could explain reduced cytotoxicity. These results highlight the relevance of lysine 590 for PE intoxication. In line with in vitro results, the K606R mutant was more than 1.8-fold more active than the other variants in vivo suggesting that this single mutation may be beneficial when targeting CD22-positive malignancies. Finally, reduced cytotoxicity by K590R was compensated for by K606R and the resulting lysine-free variant achieved wt-like activity in vitro and in vivo. Thus, PE24-noK may represent a promising candidate for down-stream applications that would interfere with lysines.
Does the Pachytene Checkpoint, a Feature of Meiosis, Filter Out Mistakes in Double-Strand DNA Break Repair and as a side-Effect Strongly Promote Adaptive Speciation?
Authors: Foe Victoria E 
Published: February 2022

SynopsisThis essay aims to explain two biological puzzles: why eukaryotic transcription units are composed of short segments of coding DNA interspersed with long stretches of non-coding (intron) DNA, and the near ubiquity of sexual reproduction. As is well known, alternative splicing of its coding sequences enables one transcription unit to produce multiple variants of each encoded protein. Additionally, padding transcription units with non-coding DNA (often many thousands of base pairs long) provides a readily evolvable way to set how soon in a cell cycle the various mRNAs will begin being expressed and the total amount of mRNA that each transcription unit can make during a cell cycle. This regulation complements control via the transcriptional promoter and facilitates the creation of complex eukaryotic cell types, tissues, and organisms. However, it also makes eukaryotes exceedingly vulnerable to double-strand DNA breaks, which end-joining break repair pathways can repair incorrectly. Transcription units cover such a large fraction of the genome that any mis-repair producing a reorganized chromosome has a high probability of destroying a gene. During meiosis, the synaptonemal complex aligns homologous chromosome pairs and the pachytene checkpoint detects, selectively arrests, and in many organisms actively destroys gamete-producing cells with chromosomes that cannot adequately synapse; this creates a filter favoring transmission to the next generation of chromosomes that retain the parental organization, while selectively culling those with interrupted transcription units. This same meiotic checkpoint, reacting to accidental chromosomal reorganizations inflicted by error-prone break repair, can, as a side effect, provide a mechanism for the formation of new species in sympatry. It has been a long-standing puzzle how something as seemingly maladaptive as hybrid sterility between such new species can arise. I suggest that this paradox is resolved by understanding the adaptive importance of the pachytene checkpoint, as outlined above.
Dietary supplementation with lysine (protein) stimulates mammary development in late pregnant gilts
Authors: Farmer Chantal , Palin Marie-France , Hovey Russell C , Falt Tara D , Huber Lee-Anne 
Published: February 2022

AbstractThe goal of this project was to determine if standardized ileal digestible (SID) lysine provided at 40% above estimated requirements, with the concomitant increase in protein intake, from days 90 to 110 of gestation would stimulate mammary development in gilts. From day 90 of gestation, Yorkshire × Landrace gilts were fed 2.65 kg of either a conventional diet (CTL, control, n = 19) providing 18.6 g/d of SID Lys or a diet providing 26.0 g/d of SID Lys via additional soybean meal (HILYS, n = 19). Both diets were isoenergetic. Jugular blood samples obtained on days 90 and 110 of gestation were used to measure concentrations of insulin-like growth factor-1 (IGF-1), metabolites, and amino acids (AA). Gilts were necropsied on day 110 ± 1 of gestation to obtain mammary glands for compositional analyses, immunohistochemistry, and analysis of mRNA abundance for AA transporters and markers of cell proliferation and differentiation. The HILYS gilts gained more body weight (P &lt; 0.01) during the experimental period compared with CTL gilts, and had greater fetal weights (1.29 vs. 1.21 ± 0.03 kg, P &lt; 0.05). There was no difference in circulating IGF-1, glucose, or albumin (P &gt; 0.10) between HILYS and CTL gilts on day 110 of gestation, whereas concentrations of urea and free fatty acids were greater (P &lt; 0.01), and those of Trp and Ala were lower (P &lt; 0.05), in HILYS than CTL gilts. The provision of lysine at 40% above estimated requirements increased total mammary parenchymal mass by 44%, as well as total parenchymal fat, protein, DNA, and RNA (P &lt; 0.01). The mRNA abundance of ACACA was greater (P &lt; 0.05) in HILYS than CTL gilts, while only the AA transporter SLC6A14 tended (P &lt; 0.10) to be greater. Results demonstrate that providing dietary Lys above current National Research Council recommendations in late gestation increases mammary development in gilts. Results also indicate that Lys may have been limiting for protein retention. These data suggest that the use of a two-phase feeding strategy during gestation, whereby dietary Lys is increased from day 90, could benefit potential sow milk yield in the subsequent lactation.
A9 SIALIC ACID METABOLISM PLAYS A KEY ROLE IN INTESTINAL FITNESS AND VIRULENCE OF AN ATTACHING/ EFFACING BACTERIAL PATHOGEN
Authors: Liang Q , Allaire J M , Yu H , Crowley S M , Han X , Vallance B 
Published: February 2022

Abstract

Background
The gastrointestinal (GI) mucus barrier acts as an important interface between the host and luminal gut microbes, beyond its role in limiting direct contact between noxious luminal agents and the underlying intestinal epithelium. Mucus is comprised of highly glycosylated mucin proteins, modified by O-glycan side chains, formed by five sugar monomers, including sialic acid. Sialic acid frequently occupies the terminal position of O-glycans and can be cleaved by microbial sialidases. We hypothesize that upon entering their hosts, enteric pathogens, such as the attaching and effacing (A/E) family (EHEC, EPEC and Citrobacter rodentium) metabolically adapt to their intestinal environment, and express key virulence factors by sensing and metabolizing mucin sugars, such as sialic acid.

Aims
Investigate the role of sialic acid in regulating the fitness and virulence strategies of the A/E pathogen C. rodentium within the GI environment.

Methods
C57Bl/6 mice were orally infected with either wildtype (WT) or mutant strains of C. rodentium to study bacterial pathogenicity in vivo. Sialic acid was localized in mouse colonic tissue sections through lectin staining, and quantified in mouse feces and mucus scrapings using a commercial kit. Protein secretion by C. rodentium, in the presence or absence of sialic acid was analyzed by SDS-PAGE and mass spectrometry. Intestinal epithelial cell lines were infected with enteropathogenic E. coli (EPEC) or C. rodentium to examine bacterial adherence.

Results
Sialic acid was expressed widely in the GI tracts of mice, primarily in the colonic mucus layer and by intestinal goblet cells. Both EPEC and C. rodentium were found to take up and metabolize sialic acid through the transporter NanT. A C. rodentium strain deficient in sialic acid uptake ( ΔnanT) was dramatically impaired in colonizing the intestines of mice and was rapidly cleared. Sialic acid also impacted C. rodentium’s virulence by inducing the secretion of two key virulence factors, which significantly enhanced the pathogen’s adhesion to intestinal epithelial cells. Moreover, sialic acid increased C. rodentium’s ability to degrade mucus, due to the increased production of these two secreted virulence factors.

Conclusions
We demonstrate that sialic acid, a mucin-derived sugar, is an essential nutrient for A/E pathogens to thrive and expand within their host’s intestines. Moreover, sialic acid enhances pathogen virulence by inducing secretion of two important virulence factors, which increase adhesion to the epithelium and promote the degradation of mucus.

Funding Agencies
CCC, CIHRCH.I.L.D. Fdn
A19 PROTEOMICS FOR PREDICTING NECROTIZING ENTEROCOLITIS IN THE PREMATURE NEONATE
Authors: Shajari E , Gagné D , Thibault M , Tremblay É , Gryspan D , Ferretti E , Bertelle V , Beaulieu J 
Published: February 2022

Abstract

Background
Necrotizing enterocolitis (NEC) represents a major challenge in neonatal intensive care units (NICU). The search for indicators that could be used to predict the development of NEC, which would provide more time to apply targeted interventions in the NICU before the appearance of the symptoms is required.

Aims
The aim of the present work was to investigate the potential of fecal proteomics signatures for NEC prediction

Methods
In the present study, stools from 132 very low birth weight infants (less than 1500 g and born younger than 30 weeks) were collected daily in the context of a multi-center prospective study. Seven of the infants received a stage 3 NEC diagnosis. Stools collected up to 10 days before diagnosis were included and each NEC was matched with 2 non-NEC controls. These samples had been used to evaluate various biomarkers by ELISA in a previous study, which revealed that lipocalin-2 and calprotectin used in conjunction can allow the prediction of half of very low birth weight infants 7 days before their NEC diagnosis (Thibault et al., Ped Res 2021). Herein, we explore a proteomics approach to investigate whether this predictability can be improved. The same stool samples were thus prepared and processed for liquid chromatography-tandem mass spectrometer analysis (TripleTOF 5600) coupled with SWATH acquisition software.

Results
Data were analyzed by Skyline using the peptide transition list of a spectral library leading to the identification of 1374 proteins with a minimum of two peptides. From these, 192 proteins (1061 peptides) were detected at strong levels in a majority of the samples while 37 of them (2–4 peptides/protein, 102 peptides) were found to display significantly altered levels between NEC and non-NEC samples (17 up; 20 down) based on statistical analyzes and displaying an AUC ≥ 0.7 (ROC curve). Interestingly, both sets of peptides for the NEC samples were significantly different from controls for all three tested periods (group 1: -10 to -7, group 2: -6 to -3, and group 3: -2 to +1 days before diagnosis) using One-way ANOVA Dunnett’s multiple comparison test, p &lt; 0.001. Furthermore, analyzing the data for each infant confirmed the usefulness of the peptide signature for predicting NEC development in 6 of the 7 available cases one week in advance of the diagnosis.

Conclusions
Taken together, these results indicate that stool proteomics represents a promising potential approach for predicting NEC in very low-weight infants.

Funding Agencies
CIHR
A20 INTESTINAL SMOOTH MUSCLE AND FIBROSTENOSIS: TARGETING NR4A1 TO MODULATE PROLIFERATIVE SIGNALLING
Authors: Lee J , Szczepanski H E , Flannigan K L , Hirota S A 
Published: February 2022

Abstract

Background
Fibrostenotic Crohn’s Disease (CD), presenting with intestinal fibrosis and stricture formation, has a substantial impact on patient quality of life. Given our poor understanding of its etiology, we lack viable preventative and therapeutic methods. While much focus has been on the fibrotic component, recent studies have implicated the role of intestinal smooth muscle cell (SMC) hyperplasia/hypertrophy in stricture formation. These data suggest targeting SMC proliferation may provide benefit for fibrostenotic CD patients. NR4A1 (nuclear receptor subfamily 4 group A member 1) is an orphan nuclear receptor that has shown to regulate inflammation in experimental models of colitis and dampen SMC proliferation and fibrotic signalling in intestinal and non-intestinal systems. Thus, we sought to characterize the role of NR4A1 in regulating proliferative signalling in intestinal SMCs to determine whether it could be a therapeutic target for fibrostenotic CD.

Aims
To determine how NR4A1 regulates intestinal SMC proliferative responses to mitogenic signalling.

Methods
Primary intestinal SMCs were isolated from the colonic tissue of Nr4a1+/+ and Nr4a1-/- mice. A commercially available human colonic SMC line was also used. EdU incorporation assays were used to quantify the relative proliferation of Nr4a1+/+ and Nr4a1-/- SMCs in their basal or stimulated state (with platelet-derived growth factor (PDGF)-BB). In addition, NR4A1 was activated using selective agonists, cytosporone-B (Csn-B) and 6-mercaptopurine (6-MP). Differences in PDGF-BB-induced intracellular signalling was determined using western blotting of phosphorylated proteins after stimulation. Quantification of PDGF receptor transcript expression in Nr4a1+/+ and Nr4a1-/- SMCs was done using qPCR. Finally, immunofluorescence was used to determine the localization of NR4A1 when stimulated with Csn-B, 6-MP, and/or PDGF-BB.

Results
The proliferation assays showed that Nr4a1-/- SMCs exhibit greater proliferation at baseline and when stimulated with PDGF-BB, compared to Nr4a1+/+ SMCs. However, this was not associated with any differences in the intracellular signalling directly downstream of PDGF receptor activation. Specifically, there were no differences in the intensity and temporal characteristics of Akt- and Erk1/2-phosphorylation between Nr4a1+/+ and Nr4a1-/- SMCs. Interestingly, Nr4a1-/- SMCs had less expression of Pdgfrb, the gene encoding PDGF receptor beta, when compared to Nr4a1+/+ SMCs. However, no changes in receptor expression were observed when SMCs were stimulated with Csn-B and 6-MP.

Conclusions
We show that NR4A1 regulates basal and PDGF-BB-induced SMC proliferation, without directly altering the intracellular signalling cascades induced by receptor activation. Our data supports NR4A1 as a target to control the aberrant SMC proliferation that contributes to fibrostenosis.

Funding Agencies
CIHR
A22 IMPACT OF COVID-19 PANDEMIC ON FOREIGN BODY INGESTION IN CHILDREN AND ADOLESCENTS: A CROSS-SECTIONAL STUDY
Authors: Zhao Y , Dehbidi Assadzadeh L , Gallant A , Gorenko-Lévêque S , Chekkal A , Djoukam Mbuko B , Pierre N , Dirks M , Groleau V , Lapointe A , Ngwanou D , Piché N , Deslandres C , Gravel J , Jantchou P 
Published: February 2022

Abstract

Background
Foreign Body Ingestions (FBI), sometimes associated with severe complications, are a common reason for emergency unit visits in children. In Quebec, since March 2020, the restrictions in response to the COVID-19 pandemic have increased the time children spend at home. We hypothesized that this could contribute to a rise in FBI incidence and severity.

Aims
The primary objective of our study was to evaluate the incidence as well as the clinical presentation of FBI cases seen at CHU Sainte-Justine Children’s Hospital in Montreal (CHUSJ) during the COVID-19 pandemic as compared to the two previous years. Our secondary objectives were to estimate the rate of severe FBI (involving hospitalisations and/or complications) and to evaluate the nature of the foreign bodies that were ingested.

Methods
All children referred to or who presented at CHUSJ for FBI between March 2018 and February 2020 (pre-pandemic) as well as between March 2020 and February 2021 (pandemic) were included (n=690). Cases of food impaction were excluded (n=78). Incidence of FBI was calculated by dividing the number of FBI cases by the total number of emergency department visits per period. Differences between the two groups were analyzed by Student T test or Chi-square test.

Results
Between March 2018 and February 2021, 612 patients (median age 3.5 years (1.6–5.9); 54% male) were eligible. The mean monthly number of FBI cases (min-max) in 2020–2021 was 18.6 (9–28), significantly higher than the year 2018 [16.6 (8–22)] and the year 2019 [15.5 (9–24)]; p=0.04. The incidence rate of FBI doubled during the pandemic as compared to the prepandemic group: respectively 57.5/10,000 emergency department visits and 23.2/10,000 visits (p=0.002). Almost one fourth of the cohort was hospitalized. The hospitalization rate (&gt;1 day) was similar between the 2 periods: 8.8% before the pandemic and 7.1% during the pandemic. Digestive endoscopy was performed in 21.5% of cases, a rate similar before and during the pandemic. A total of 3.3% of the children developed complications related to FBI. This rate remained stable between the two periods. The most frequently ingested objects were coins (25.0%), toys (10.8%), button batteries (10.6%), magnets (6.2%), and jewellery (6.2%). There was no significant difference in the nature of FB ingested between the 2 periods although the number of magnet ingestions increased during the pandemic (18 per year vs 10 per year).

Conclusions
The incidence of FBI increased significantly during the pandemic in comparison with the two previous years. The high hospitalization and complications rates, although stable during the pandemic, underline the significant impact of pediatric FBI.

Funding Agencies
None
A32 DEVELOPMENT AND VALIDATION OF THE TORONTO UPPER GASTROINTESTINAL CLEANING SCORE
Authors: Seleq S , Khan R , Gimpaya N , Vargas J I , Amin S , Bilal M , Bollipo S , Charabaty A , de-Madaria E , Hashim A , Kral J , Pawlak K M , Sandhu D S , Lui R N , Sanchez-Luna S , Siau K , Mosko J , Grover S 
Published: February 2022

Abstract

Background
High quality esophagogastroduodenoscopy (EGD) depends on the ability to appropriately visualize upper gastrointestinal (GI) mucosa pathology. Evaluation can be limited by the presence of mucus, foam, bubbles and solid materials. Currently, there is no standardized method to assess mucosal visualization for use in clinical or research settings.

Aims
To develop and establish the content validity of the Toronto Upper Gastrointestinal Cleaning Score (TUGCS) and evaluate its interrater reliability.

Methods
An international panel of endoscopy experts rated potential items and their associated anchors for importance as indicators of adequacy of mucosal visualization during EGD. The survey utilized a Likert scale (1 (strongly disagree) to 5 (strongly agree)). The Delphi process was repeated until consensus was reached. Consensus was defined priori as ≥80% of experts in a given round scoring ≥4 on all survey items. To assess content validity, 48 EGD procedures were evaluated in real-time by two endoscopist reviewers using the TUGCS at a single institution. The interrater agreement between assessments was calculated for TUGCS total scores using intraclass correlation coefficient, one-way random effects model (ICC 1,1).

Results
Fourteen experts agreed to be part of the Delphi panel. An anatomical framework representing the upper GI mucosa and anchors for each mucosal portion representing various levels of visibility was generated through systematic review. Three survey rounds, with response rates of 100%, 100% and 71% respectively, achieved consensus. The final TUGCS includes four anatomical areas (fundus, body, antrum, duodenum) and mucosal visualization anchors ranging from 0 to 3 (Figure 1). TUGCS was used to assess foregut cleaning in 48 procedures (Table 1). The mean TUGCS for staff and trainee were 8.1 (±2.4) and 8.1 (±2.6), respectively. The ICC was 0.78 (95% confidence interval 0.62–0.88) indicating good reliability.

Conclusions
We developed and generated content validity evidence for the TUGCS through rigorous Delphi methodology, reflective of practice across different centres. Planned as future research is a video survey distributed to endoscopists internationally to further validate the TUGCS to create a tool that may be used to judge mucosal visualization for EGD in research and clinical settings.

Funding Agencies
None