bluuebunny/crossref_metadata_2025 huggingface dataset:
Validation of T-MoCA in the Screening of Mild Cognitive Impairment in Chinese Patients With Atrial Fibrillation
Authors: Lai Yiwei , Zhao Manlin , Jiang Chao , Du Xin , Wang Zhiyan , Zhang Jingrui , Bai Yu , Xu Baolei , Zhang Weiwei , Tang Ribo , Sang Caihua , Long Deyong , Dong Jianzeng , Ma Changsheng
Published: June 2022

Background

Atrial fibrillation (AF) is associated with a high risk of mild cognitive impairment (MCI) and dementia. However, feasible and simple instruments that facilitate the regular assessment of cognitive status in patients with AF remain underdeveloped.

Methods

Cognitive function was first evaluated using telephone Montreal cognitive assessment (T-MoCA), and then patients were invited for an in-person interview for cognitive assessment using both Clinical Dementia Rating (CDR) and mini-mental status evaluation (MMSE). Using CDR = 0.5 as a reference standard, the ability of T-MoCA and MMSE to discriminate cognitive dysfunction, stratified by education level, was tested by receiver–operating curve (ROC) analysis. The net reclassification index was calculated for comparison between the performance of T-MoCA and MMSE.

Results

One hundred and one patients completed both telephone and in-person interview. Thirty-five MCI patients were identified as MCI using the criteria of CDR = 0.5. The areas under the ROC curve of T-MoCA were 0.80 (0.71–0.89), 0.83 (0.71–0.95), and 0.85 (0.64–0.92) for all patients, patients with high educational level, and patients with low education level, respectively. The optimal threshold was achieved at 16/17 with a sensitivity of 85.7% and a specificity of 69.7% in overall patients, 15/16 with a sensitivity of 88.2% and a specificity of 64.5% in the low educational level patients, and 16/17 with a sensitivity of 77.8% and a specificity of 87.9% in the high educational level patients. Compared to the criterion MMSE ≤ 27 and MMSE norms for the elderly Chinese community, the stratified T-MoCA threshold improves correct classification by 23.7% (p = 0.033) and 30.3% (p = 0.020), respectively.

Conclusion

T-MoCA is a feasible and effective instrument for MCI screening in patients with AF.
Incidence and Predictors of Cardiac Arrhythmias in Patients With COVID-19
Authors: Mouram Sahar , Pannone Luigi , Gauthey Anaïs , Sorgente Antonio , Vergara Pasquale , Bisignani Antonio , Monaco Cinzia , Mojica Joerelle , Al Housari Maysam , Miraglia Vincenzo , Del Monte Alvise , Paparella Gaetano , Ramak Robbert , Overeinder Ingrid , Bala Gezim , Almorad Alexandre , Ströker Erwin , Sieira Juan , Brugada Pedro , La Meir Mark , Chierchia Gian Battista , de Asmundis Carlo
Published: June 2022

Background

Coronavirus disease 2019 (COVID-19) is a systemic disease caused by severe acute respiratory syndrome coronavirus 2. Arrhythmias are frequently associated with COVID-19 and could be the result of inflammation or hypoxia. This study aimed to define the incidence of arrhythmias in patients with COVID-19 and to correlate arrhythmias with pulmonary damage assessed by computed tomography (CT).

Methods

All consecutive patients with a COVID-19 diagnosis hospitalized at Universitair Ziekenhuis Brussel, Belgium, between March 2020 and May 2020, were screened. All included patients underwent a thorax CT scan and a CT severity score, a semiquantitative scoring system of pulmonary damage, was calculated. The primary endpoint was the arrhythmia occurrence during follow-up.

Results

In this study, 100 patients were prospectively included. At a mean follow-up of 19.6 months, 25 patients with COVID-19 (25%) experienced 26 arrhythmic episodes, including atrial fibrillation in 17 patients, inappropriate sinus tachycardia in 7 patients, atrial flutter in 1 patient, and third-degree atrioventricular block in 1 patient. No ventricular arrhythmias were documented. Patients with COVID-19 with arrhythmias showed more often need for oxygen, higher oxygen maximum flow, longer QTc at admission, and worse damage at CT severity score. In univariate logistic regression analysis, significant predictors of the primary endpoint were: the need for oxygen therapy (odds ratio [OR] 4.59, 95% CI 1.44–14.67, p = 0.01) and CT severity score of pulmonary damage (OR per 1 point increase 1.25, 95% CI 1.11–1.4, p < 0.001).

Conclusions

In a consecutive cohort of patients with COVID-19 the incidence of cardiac arrhythmias was 25%. The need for oxygen therapy and CT severity score were predictors of arrhythmia occurrence during follow-up.
Depositional Controls on Detrital Zircon Provenance: An Example From Upper Cretaceous Strata, Southern Patagonia
Authors: Dobbs Stephen C. , Malkowski Matthew A. , Schwartz Theresa M. , Sickmann Zachary T. , Graham Stephan A.
Published: June 2022

Understanding how depositional environments within a sedimentary system redistribute and sequester sediment is critical for interpreting basin-scale provenance trends. However, sedimentary source-to-sink models commonly examine temporal changes and do not consider how variation in sedimentation processes across a dispersal pathway may result in contrasting provenance signatures. In this paper, we demonstrate a down-paleoslope shift in detrital zircon provenance signatures correlated with shallow-marine lithofacies patterns from the Upper Cretaceous La Anita Formation and underlying continental slope lithofacies of the Alta Vista Formation (Magallanes-Austral Basin, southern Patagonia). New stratigraphic, sedimentologic, and lithofacies analysis results from the La Anita Formation suggest an upward shoaling succession, from a 1) storm-influenced shoreface, 2) fluvially dominated, wave-influenced delta, and a 3) high-energy, gravelly foreshore. Stratigraphic sections are paired with U-Pb detrital zircon sandstone samples (N = 20; n = 5,219), which provide both maximum depositional ages and provenance characteristics. While all samples contain abundant zircon derived from the Andean volcanic arc (ca. 145–75 Ma), the amount from both Jurassic distal volcanic massifs (ca. 188–162 Ma) and recycled orogenic sources exhumed during the advance of the Cretaceous fold-and-thrust belt (>200 Ma; 157–142 Ma) vary with changes in depositional environment. We argue that down-paleoslope, systematic enriching of local fold-and-thrust belt material within the La Anita Formation is reflective of progressive mixing of grains transported via shallow-marine processes, while distally enriched fluvio-deltaic transported zircons were sourced from large, regional catchments. This suggests that competition between transport processes across a shallow and marginal marine sequence of rocks affects the resulting provenance signatures recorded within a single stratigraphic succession. These data also detail the degree of sediment pathway connectivity between shallow-marine sources and deep-marine sinks. Detrital zircon results from muddy continental slope facies of the Alta Vista Formation are made up entirely locally derived material, while zircon results from deep-water, sand-rich channel facies of the Formation are indistinguishable from coeval fluvio-deltaic zircon signatures. This implies that continental shelf-to-slope connectivity in a sediment dispersal system, via submarine canyons or shelf-edge delta progradation, is necessary for detrital zircon distributions from the shallow-marine realm to propagate into the deeper marine.
Factors Influencing the Utilization of Diabetes Complication Tests Under the COVID-19 Pandemic: Machine Learning Approach
Authors: Byeon Haewon
Published: June 2022

Objective

There are still not enough studies on the prediction of non-utilization of a complication test or a glycated hemoglobin test for preventing diabetes complications by using large-scale community-based big data. This study identified the ratio of not taking a diabetes complication test (fundus examination and microprotein urination test) among adult diabetic patients over 19 years using a national survey conducted in South Korea and developed a model for predicting the probability of not taking a diabetes complication test based on it.

Methods

This study analyzed 25,811 subjects who responded that they had been diagnosed with diabetes by a doctor in the 2020 Community Health Survey. Outcome variables were defined as the utilization of the microprotein urination test and the fundus examination during the past year. This study developed a model for predicting the utilization of a diabetes complication test using logistic regression analysis and nomogram to understand the relationship of predictive factors on the utilization of a diabetes complication test.

Results

The results of this study confirmed that age, education level, the recognition of own blood glucose level, current diabetes treatment, diabetes management education, not conducting the glycated hemoglobin test in the past year, smoking, single-person household, subjectively good health, and living in the rural area were independently related to the non-utilization of diabetes complication test after the COVID-19 pandemic.

Conclusion

Additional longitudinal studies are required to confirm the causality of the non-utilization of diabetes complication screening tests.
Soil Moisture Affects the Rapid Response of Microbes to Labile Organic C Addition
Authors: Bian Hongfeng , Li Chao , Zhu Jianxing , Xu Li , Li Mingxu , Zheng Shuai , He Nianpeng
Published: June 2022

Pulsed inputs of labile organic carbon (LOC) are common in soils and significantly affect carbon cycling. However, it remains unclear how soil moisture content affects microbial responses to LOC inputs and the relative contributions of native soil organic matter (SOM) and LOC derived from CO2 emissions during this process. In this study, we aimed to elucidate how moisture content affects microbial response to LOC inputs and native SOM. Here, 13C-labeled glucose was added to soils under nine soil moisture treatments [ranging from 10 to 90% of the water holding capacity (WHC)], and the immediate utilization of LOC and native SOM by microbes was measured. We found that the response of soil microbes to LOC was rapid, and promoted native SOM decomposition. Soil moisture content influenced the microbial usage of LOC and native SOM. A soil water content of 60% WHC was the optimal threshold for changes in the proportion of LOC and native SOM utilized by the microbes. Specifically, we found that when the soil moisture content was below 60% WHC, the ratio between LOC and native SOM increased with increasing moisture content levels. It gradually decreased when the soil moisture content was above 60% WHC. Overall, these findings emphasize the important role of moisture and LOC inputs in soil C cycles.
A Comprehensive Analysis for Expression, Diagnosis, and Prognosis of m5C Regulator in Breast Cancer and Its ncRNA–mRNA Regulatory Mechanism
Authors: Liu Jingxing , Xiao Shuyuan , Chen Jing , Lou Weiyang , Chen Xu
Published: June 2022

Recent studies have well demonstrated that 5-methylcytosine (m5C) regulators play pivotal roles in pathological conditions, including cancer. This study first tried to identify potential 5-methylcytosine (m5C) regulators in breast cancer by combination of expression, diagnosis, and survival analyses, and then established an ncRNA–mRNA network accounting for m5C regulators’ roles in breast cancer. Among 13 m5C regulators, DNMT3B and ALYREF were significantly upregulated in breast cancer and their high expression indicated unfavorable prognosis. Both DNMT3B and ALYREF possessed the statistical abilities to distinguish breast cancer from normal breast samples. Moreover, five potential upstream miRNAs (let-7b-5p, miR-195-5p, miR-29a-3p, miR-26a-5p, and miR-26b-5p) of m5C regulators could not only serve as independent prognostic predictors but also together made up a promising miRNA prognostic signature in breast cancer. Next, upstream potential lncRNAs of the five miRNAs were predicted and analyzed. Pathway enrichment analysis revealed that the target genes of these miRNAs were markedly enriched in some cancer-related pathways, and further investigation indicated VEGFA and EZH2 were found to be the most potential target genes in the m5C regulators-related ncRNA–mRNA network in breast cancer. These findings comprehensively provided key clues for developing m5C regulators-related effective therapeutic targets and promising diagnostic biomarkers in breast cancer.
Multi-Trait Genomic Prediction Models Enhance the Predictive Ability of Grain Trace Elements in Rice
Authors: Muvunyi Blaise Pascal , Zou Wenli , Zhan Junhui , He Sang , Ye Guoyou
Published: June 2022

Multi-trait (MT) genomic prediction models enable breeders to save phenotyping resources and increase the prediction accuracy of unobserved target traits by exploiting available information from non-target or auxiliary traits. Our study evaluated different MT models using 250 rice accessions from Asian countries genotyped and phenotyped for grain content of zinc (Zn), iron (Fe), copper (Cu), manganese (Mn), and cadmium (Cd). The predictive performance of MT models compared to a traditional single trait (ST) model was assessed by 1) applying different cross-validation strategies (CV1, CV2, and CV3) inferring varied phenotyping patterns and budgets; 2) accounting for local epistatic effects along with the main additive effect in MT models; and 3) using a selective marker panel composed of trait-associated SNPs in MT models. MT models were not statistically significantly (p < 0.05) superior to ST model under CV1, where no phenotypic information was available for the accessions in the test set. After including phenotypes from auxiliary traits in both training and test sets (MT-CV2) or simply in the test set (MT-CV3), MT models significantly (p < 0.05) outperformed ST model for all the traits. The highest increases in the predictive ability of MT models relative to ST models were 11.1% (Mn), 11.5 (Cd), 33.3% (Fe), 95.2% (Cu) and 126% (Zn). Accounting for the local epistatic effects using a haplotype-based model further improved the predictive ability of MT models by 4.6% (Cu), 3.8% (Zn), and 3.5% (Cd) relative to MT models with only additive effects. The predictive ability of the haplotype-based model was not improved after optimizing the marker panel by only considering the markers associated with the traits. This study first assessed the local epistatic effects and marker optimization strategies in the MT genomic prediction framework and then illustrated the power of the MT model in predicting trace element traits in rice for the effective use of genetic resources to improve the nutritional quality of rice grain.
An Immune-Related Long Noncoding RNA Pair as a New Biomarker to Predict the Prognosis of Patients in Breast Cancer
Authors: Jiang Hanwen , Sun Jingxian , Liu Fucong , Wu Xincai , Wen Zhaohui
Published: June 2022

Background: Immune-related long non-coding RNAs (irlncRNAs) might remodel the tumor immune microenvironment by changing the inherent properties of tumor cells and the expression of immune genes, which have been used to predict the efficacy of immunotherapy and the prognosis of various tumors. However, the value of irlncRNAs in breast cancer (BRCA) remains unclear.

Materials and Methods: Initially, transcriptome data and immune-related gene sets were downloaded from The Cancer Genome Atlas (TCGA) database. The irlncRNAs were extracted from the Immunology Database and Analysis Portal (ImmPort) database. Differently expressed irlncRNAs (DEirlncRNAs) were further identified by utilizing the limma R package. Then, univariate and multivariate Cox regression analyses were conducted to select the DEirlncRNAs associated with the prognosis of BRCA patients. In addition, the univariate and least absolute shrinkage and selection operator (LASSO) Cox regression analyses were performed to determine the DEirlncRNA pairs with the independent prediction capability of prognosis in BRCA patients. Finally, the chosen DEirlncRNA pair would be evaluated in terms of survival time, clinicopathological characteristics, tumor-infiltrating immune cells, immune checkpoints (ICs), signaling pathways, and potential small-molecule drugs.

Results: A total of 21 DEirlncRNA pairs were extracted, and among them, lncRNA MIR4435-2HG and lncRNA U62317.1 were chosen to establish a risk signature that served as an independent prognostic biomarker in BRCA patients. Patients in the high-risk group had a worse prognosis than those in the low-risk group, and they also had an abundance of infiltration of CD4+ T and CD8+ T cells to enhance the immune response to tumor cells. Furthermore, the risk signature showed a strong correlation with ICs, signaling pathways, and potential small-molecule drugs.

Conclusion: Our research revealed that the risk signature independent of specific DEirlncRNA pair expression was closely associated with the prognosis and tumor immune microenvironment in BRCA patients and had the potential to function as an independent prognostic biomarker and a predictor of immunotherapy for BRCA patients, which would provide new insights for BRCA accurate treatment.
The Immunological Effect of Oxygen Carriers on Normothermic Ex Vivo Liver Perfusion
Authors: Jennings Heather , Carlson Kristin N. , Little Chris , Verhagen Joshua C. , Nagendran Jeevan , Liu Yongjun , Verhoven Bret , Zeng Weifeng , McMorrow Stacey , Chlebeck Peter , Al-Adra David P.
Published: June 2022

Introduction

Normothermic ex vivo liver perfusion (NEVLP) is an organ preservation method that allows liver graft functional assessment prior to transplantation. One key component of normothermic perfusion solution is an oxygen carrier to provide oxygen to the liver to sustain metabolic activities. Oxygen carriers such as red blood cells (RBCs) or hemoglobin-based oxygen carriers have an unknown effect on the liver-resident immune cells during NEVLP. In this study, we assessed the effects of different oxygen carriers on the phenotype and function of liver-resident immune cells.

Methods

Adult Lewis rat livers underwent NEVLP using three different oxygen carriers: human packed RBCs (pRBCs), rat pRBCs, or Oxyglobin (a synthetic hemoglobin-based oxygen carrier). Hourly perfusate samples were collected for downstream analysis, and livers were digested to isolate immune cells. The concentration of common cytokines was measured in the perfusate, and the immune cells underwent phenotypic characterization with flow cytometry and quantitative reverse transcription polymerase chain reaction (qRT-PCR). The stimulatory function of the liver-resident immune cells was assessed using mixed lymphocyte reactions.

Results

There were no differences in liver function, liver damage, or histology between the three oxygen carriers. qRT-PCR revealed that the gene expression of nuclear factor κ light chain enhancer of activated B cells (NF-kB), Interleukin (IL-1β), C-C motif chemokine ligand 2 (CCL2), C-C motif chemokine ligand 7 (CCL7), and CD14 was significantly upregulated in the human pRBC group compared with that in the naive, whereas the rat pRBC and Oxyglobin groups were not different from that of naive. Flow cytometry demonstrated that the cell surface expression of the immune co-stimulatory protein, CD86, was significantly higher on liver-resident macrophages and plasmacytoid dendritic cells perfused with human pRBC compared to Oxyglobin. Mixed lymphocyte reactions revealed increased allogeneic T-cell proliferation in the human and rat pRBC groups compared to that in the Oxyglobin group.

Conclusions

Liver-resident immune cells are important mediators of rejection after transplantation. In this study, we show that the oxygen carrier used in NEVLP solutions can affect the phenotype of these liver-resident immune cells. The synthetic hemoglobin-based oxygen carrier, Oxyglobin, showed the least amount of liver-resident immune cell activation and the least amount of allogeneic proliferation when compared to human or rat pRBCs. To mitigate liver-resident immune cell activation during NEVLP (and subsequent transplantation), Oxyglobin may be an optimal oxygen carrier.
Schistosoma mansoni Fibroblast Growth Factor Receptor A Orchestrates Multiple Functions in Schistosome Biology and in the Host-Parasite Interplay
Authors: Du Xiaofeng , McManus Donald P. , Fogarty Conor E. , Jones Malcolm K. , You Hong
Published: June 2022

Stem cells play significant roles in driving the complex life cycle of Schistosoma mansoni. Fibroblast growth factor (FGF) receptor A (SmFGFRA) is essential for maintaining the integrity of schistosome stem cells. Using immunolocalization, we demonstrated that SmFGFRA was distributed abundantly in germinal/stem cells of different S. mansoni life stages including eggs, miracidia, cercariae, schistosomula and adult worms. Indeed, SmFGFRA was also localized amply in embryonic cells and in the perinuclear region of immature eggs; von Lichtenberg’s layer and the neural mass of mature eggs; the ciliated surface and neural mass of miracidia; the tegument cytosol of cercariae, schistosomula and adult worms; and was present in abundance in the testis and vitellaria of adult worms of S. mansoni. The distribution pattern of SmFGFRA illustrates the importance of this molecule in maintaining stem cells, development of the nervous and reproductive system of schistosomes, and in the host-parasite interplay. We showed SmFGFRA can bind human FGFs, activating the mitogen activated protein kinase (MAPK) pathway of adult worms in vitro. Inhibition of FGF signaling by the specific tyrosine kinase inhibitor BIBF 1120 significantly reduced egg hatching ability and affected the behavior of miracidia hatched from the treated eggs, emphasizing the importance of FGF signaling in driving the life cycle of S. mansoni. Our findings provide increased understanding of the complex schistosome life cycle and host-parasite interactions, indicating components of the FGF signaling pathway may represent promising targets for developing new interventions against schistosomiasis.
Identification of CFHR4 as a Potential Prognosis Biomarker Associated With lmmune Infiltrates in Hepatocellular Carcinoma
Authors: Yu Hongjun , Wang Chaoqun , Ke Shanjia , Bai Miaoyu , Xu Yanan , Lu Shounan , Feng Zhigang , Qian Baolin , Xu Yue , Zhou Menghua , Li Zihao , Yin Bing , Li Xinglong , Hua Yongliang , Zhou Yongzhi , Pan Shangha , Fu Yao , Ma Yong
Published: June 2022

Background

Complement factor H-related 4 (CFHR4) is a protein-coding gene that plays an essential role in multiple diseases. However, the prognostic value of CFHR4 in hepatocellular carcinoma (HCC) is unknown.

Methods

Using multiple databases, we investigated CFHR4 expression levels in HCC and multiple cancers. The relationship between CFHR4 expression levels and clinicopathological variables was further analyzed. Various potential biological functions and regulatory pathways of CFHR4 in HCC were identified by performing a Gene Ontology (GO) analysis, Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis and Gene Set Enrichment Analysis (GSEA). Single-sample gene set enrichment analysis (ssGSEA) was performed to confirm the correlation between CFHR4 expression and immune cell infiltration. The correlations between CFHR4 expression levels in HCC and N6-methyladenosine (m6A) modifications and the competing endogenous RNA (ceRNA) regulatory networks were confirmed in TCGA cohort.

Results

CFHR4 expression levels were significantly decreased in HCC tissues. Low CFHR4 expression in HCC tissues was significantly correlated with the patients’ sex, race, age, TNM stage, pathological stage, tumor status, residual tumor, histologic grade and alpha fetal protein (AFP) level. GO and KEGG analyses revealed that differentially expressed genes related to CFHR4 may be involved in the synaptic membrane, transmembrane transporter complex, gated channel activity, chemical carcinogenesis, retinol metabolism, calcium signaling pathway, PPAR signaling pathway, insulin and gastric acid secretion. GSEA revealed that the FCGR-activated reaction, PLK1 pathway, ATR pathway, MCM pathway, cascade reactions of PI3K and FGFR1, reactant-mediated MAPK activation and FOXM1 pathway were significantly enriched in HCC with low CFHR4 expression. Moreover, CFHR4 expression was inversely correlated the levels of infiltrating Th2 cells, NK CD56bright cells and Tfh cells. In contrast, we observed positive correlations with the levels of infiltrating DCs, neutrophils, Th17 cells and mast cells. CFHR4 expression showed a strong correlation with various immunomarker groups in HCC. In addition, high CFHR4 expression significantly prolonged the overall survival (OS), disease-specific survival (DSS) and progression-free interval (PFI). We observed a substantial correlation between the expression of CFHR4 and multiple N6-methyladenosine genes in HCC and constructed potential CFHR4-related ceRNA regulatory networks.

Conclusions

CFHR4 might be a potential therapeutic target for improving the HCC prognosis and is closely related to immune cell infiltration.
Investigation of Antibody Levels During Three Doses of Sinopharm/BBIBP Vaccine Inoculation
Authors: Ma Jing , Cheng Zhangkai J. , Xue Mingshan , Huang Huimin , Li Shiyun , Fang Yanting , Zeng Yifeng , Lin Runpei , Liang Zhiman , Liang Huan , Deng Yijun , Cheng Yuanyi , Huang Shuangshuang , Wang Qian , Niu Xuefeng , Li Siping , Zheng Peiyan , Sun Baoqing
Published: June 2022

Levels of neutralizing antibodies (NAb) after vaccine against coronavirus disease 2019 (COVID-19) can be detected using a variety of methods. A critical challenge is how to apply simple and accurate methods to assess vaccine effect. In a population inoculated with three doses of the inactivated Sinopharm/BBIBP vaccine, we assessed the performance of chemiluminescent immunoassay (CLIA) in its implementation to detect severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) specific antibodies, as well as the antibody kinetics of healthcare workers throughout the course of vaccination. The antibody levels of NAb, the receptor-binding-domain (RBD) antibodies and IgG peaked one month after the second and remained at a relatively high level for over three months after the booster injection, while IgM and IgA levels remained consistently low throughout the course of vaccination. The production of high-level neutralizing antibodies is more likely when the inoculation interval between the first two doses is within the range of one to two months, and that between the first and booster dose is within 230 days. CLIA showed excellent consistency and correlation between NAb, RBD, and IgG antibodies with the cytopathic effect (CPE) conventional virus neutralization test (VNT). Receiver operating characteristic (ROC) analysis revealed that the optimal cut-off levels of NAb, RBD and IgG were 61.77 AU/ml, 37.86 AU/ml and 4.64 AU/ml, with sensitivity of 0.833, 0.796 and 0.944, and specificity of 0.768, 0.750 and 0.625, respectively, which can be utilized as reliable indicators of COVID-19 vaccination immunity detection.
Fibrin(ogen) Is Constitutively Expressed by Differentiated Intestinal Epithelial Cells and Mediates Wound Healing
Authors: Seltana Amira , Cloutier Gabriel , Reyes Nicolas Vilcy , Khalfaoui Taoufik , Teller Inga C. , Perreault Nathalie , Beaulieu Jean-François
Published: June 2022

Fibrinogen is a large molecule synthesized in the liver and released in the blood. Circulating levels of fibrinogen are upregulated after bleeding or clotting events and support wound healing. In the context of an injury, thrombin activation drives conversion of fibrinogen to fibrin. Fibrin deposition contains tissue damage, stops blood loss, and prevents microbial infection. In most circumstances, fibrin needs to be removed to allow the resolution of inflammation and tissue repair, whereas failure of this may lead to the development of various disorders. However, the contribution of fibrinogen to tissue inflammation and repair is likely to be context-dependent. In this study, the concept that fibrin needs to be removed to allow tissue repair and to reduce inflammation is challenged by our observations that, in the intestine, fibrinogen is constitutively produced by a subset of intestinal epithelial cells and deposited at the basement membrane as fibrin where it serves as a substrate for wound healing under physiological conditions such as epithelial shedding at the tip of the small intestinal villus and surface epithelium of the colon as well as under pathological conditions that require rapid epithelial repair. The functional integrity of the intestine is ensured by the constant renewal of its simple epithelium. Superficial denuding of the epithelial cell layer occurs regularly and is rapidly corrected by a process called restitution that can be influenced by various soluble and insoluble factors. Epithelial cell interaction with the extracellular matrix greatly influences the healing process by acting on cell morphology, adhesion, and migration. The functional contribution of a fibrin(ogen) matrix in the intestine was studied under physiological and pathological contexts. Our results (immunofluorescence, immunoelectron microscopy, and quantitative PCR) show that fibrin(ogen) is a novel component of the basement membrane associated with the differentiated epithelial cell population in both the small intestine and colon. Fibrin(ogen) alone is a weak ligand for epithelial cells and behaves as an anti-adhesive molecule in the presence of type I collagen. Furthermore, the presence of fibrin(ogen) significantly shortens the time required to achieve closure of wounded epithelial cell monolayers and co-cultures in a PI3K-dependent manner. In human specimens with Crohn’s disease, we observed a major accumulation of fibrin(ogen) throughout the tissue and at denuded sites. In mice in which fibrin formation was inhibited with dabigatran treatment, dextran sulfate sodium administration provoked a significant increase in the disease activity index and pathological features such as mucosal ulceration and crypt abscess formation. Taken together, these results suggest that fibrin(ogen) contributes to epithelial healing under both normal and pathological conditions.
Antibodies to Citrullinated Protein Antigens, Rheumatoid Factor Isotypes and the Shared Epitope and the Near-Term Development of Clinically-Apparent Rheumatoid Arthritis
Authors: Bergstedt Dylan T. , Tarter Wyatt J. , Peterson Ryan A. , Feser Marie L. , Parish Mark C. , Striebich Christopher C. , Demoruelle M. Kristen , Moss LauraKay , Bemis Elizabeth A. , Norris Jill M. , Holers V. Michael , Edison Jess D. , Thiele Geoffrey M. , Mikuls Ted R. , Deane Kevin D.
Published: June 2022

Background/Purpose

In rheumatoid arthritis (RA) autoantibodies including antibodies to citrullinated protein antigens (ACPA) and rheumatoid factor (RF) can be predictive of incident clinical RA. However, there is limited understanding of how antibody changes over time impact prediction of the likelihood and timing of future clinical RA.

Materials and Methods

We evaluated relationships between ACPA, the shared epitope (SE), RF isotypes and incident RA in a prospective cohort of 90 ACPA(+) individuals without baseline arthritis identified through health-fair testing (i.e. Healthfair). We also evaluated ACPA and RF isotypes and time-to-diagnosis of RA in a retrospective cohort of 215 individuals with RA from the Department of Defense Serum Repository (DoDSR).

Results

Twenty-six of 90 (29%) of ACPA(+) Healthfair participants developed incident RA. Baseline or incident dual RF-IgA and RF-IgM positivity was associated with increased risk for incident RA (HR 3.09; 95% CI 1.15 to 8.29) although RFs were negative in ~50% of individuals with incident RA. SE was associated with increased risk of RA (HR 2.87, 95% CI 1.22-6.76). In the DoDSR cohort, triple positivity for ACPA, RF-IgA and RF-IgM was present a median of 1-2 years prior to RA diagnosis, with some sex-specific differences.

Conclusion

These findings can be used to counsel individuals at-risk for future RA and to design clinical trials for RA prevention. The findings also suggest that RF could be a surrogate outcome as a success of an immunologic intervention in RA prevention. Additional studies are needed to understand the biologic of different patterns of autoantibody elevations in RA evolution.
Subsurface Water Property Structures Along 80°E Under the Positive Indian Ocean Dipole Mode in December 2019
Authors: Kouketsu Shinya , Murata Akihiko , Arulananthan Kanapathipillai
Published: June 2022

High-accuracy ship-based observations were conducted at 80°E in the Indian Ocean. Salinity below the mixed layer in 2019 was observed to be lower than that in 1995. This decrease in salinity was mainly attributed to anomalous advection associated with one of the strongest positive Indian Ocean dipole (pIOD) events in 2019 through analysis of the gridded time series of the salinity distributions based on the Argo float array. Increases and decreases in nitrate and dissolved inorganic carbon (DIC) and dissolved oxygen (DO), respectively, were also detected on the isopycnal surfaces where decreases in salinity were observed, suggesting that the anomalous upwelling and westward advection associated with the pIOD in the eastern part of the equatorial region resulted in low-salinity, low-oxygen, and nutrient-rich waters in the central off-equatorial region of the Indian Ocean. However, downward isopycnal heaving, which was also associated with the pIOD, was too strong to have increased nitrate below the mixed layers, and thus might have suppressed biological activity. The heaving also affected the DIC and DO distributions, and the effect of interannual changes such as those associated with the Indian Ocean dipole is essential to estimating changes in anthropogenic carbon storage. This research represents a case study, based on only two occupations; therefore, an assessment utilizing more intensive observations and more realistic numerical simulations is necessary in the future.
Distribution of Dinoflagellate Cysts in Surface Sediments From the Qingdao Coast, the Yellow Sea, China: The Potential Risk of Harmful Algal Blooms
Authors: Wang Zhaohui , Zhang Yuning , Lei Mingdan , Ji Shuanghui , Chen Jiazhuo , Zheng Hu , Tang Yali , Hu Ren
Published: June 2022

Surface sediments were collected from three sea areas of the Qingdao coast, the Yellow Sea, China, namely, the inner Jiaozhou Bay, the Laoshan coast, and the Amphioxus Reserve area in November to December 2017. Dinoflagellate cysts were observed in the sediments, focusing on the distribution of toxic and harmful species. Contents of biogenic elements were analyzed to reveal their relationships to cysts. A total of 32 cyst taxa were identified, including 23 autotrophic and 9 heterotrophic taxa. Cyst concentrations ranged from 83.3 to 346.5 cysts/g D Wt with an average of 210.7 cysts/g D Wt. Generally, cysts of autotrophic dinoflagellates dominated in sediments from the Qingdao coast with proportions of 41.05%–90.25%. There were no dominant group in cyst assemblages; cysts of Protoperidiniaceae, Suessiales, and Calciodinelloideae showed similar contributions. Cyst assemblages were quite different in the inner Jiaozhou Bay reflected by the lower species richness, diversity, and cyst concentration. Results from the redundancy analysis (RDA) demonstrated the influence of biogenic elements on cyst assemblages, which explained well why the three sea areas with different degrees of human activities showed different dinocyst storages. Notably, 17 harmful algal bloom (HAB) dinoflagellate cysts were identified in this study, including cysts of those producing toxins that may damage human health and marine animals. Some of these cysts occurred widely and dominantly in this study, such as cysts of Gonyaulax spinifera, Azadinium trinitatum, Scrippsiella acuminata, and Biecheleria halophila, suggesting the potential risk of HABs in the Qingdao coastal area.
Long Term Time-Lapse Imaging of Geographic Atrophy: A Pilot Study
Authors: Paques Michel , Norberg Nathaniel , Chaumette Céline , Sennlaub Florian , Rossi Ethan , Borella Ysé , Grieve Kate
Published: June 2022

Geographic atrophy (GA), the late stage of age-related macular degeneration, is a major cause of visual disability whose pathophysiology remains largely unknown. Modern fundus imaging and histology revealed the complexity of the cellular changes that accompanies atrophy. Documenting the activity of the disease in the margins of atrophy, where the transition from health to disease occurs, would contribute to a better understanding of the progression of GA. Time-lapse imaging facilitates the identification of structural continuities in changing environments. In this retrospective pilot study, we documented the long-term changes in atrophy margins by time-lapse imaging of infrared scanning laser ophthalmoscopy (SLO) and optical coherence tomography (OCT) images in 6 cases of GA covering a mean period of 32.8 months (range, 18–72). The mean interval between imaging sessions was 2.4 months (range, 1.4–3.8). By viewing time-lapse sequences we observed extensive changes in the pattern of marginal hyperreflective spots, which associated fragmentation, increase and/or disappearance. Over the entire span of the follow-up, the most striking changes were those affecting hyperreflective spots closest to margins of atrophy, on the non-atrophic side of the retina; a continuum between the successive positions of some of the hyperreflective spots was detected, both by SLO and OCT. This continuum in their successive positions resulted in a subjective impression of a centrifugal motion of hyperreflective spots ahead of atrophy progression. Such mobilization of hyperreflective spots was detected up to several hundred microns away from atrophic borders. Such process is likely to reflect the inflammatory and degenerative process underlying GA progression and hence deserves further investigations. These results highlight the interest of multimodal time-lapse imaging to document cell-scale dynamics during progression of GA.

Clinical Trial Registration

clinicaltrials.gov, identifier: NCT04128150 and NCT04129021.
Altered Pattern of Immunoglobulin A-Targeted Microbiota in Inflammatory Bowel Disease After Fecal Transplantation
Authors: Huang Wen-qi , Huang Hong-Li , Peng Wu , Liu Yan-Di , Zhou You-Lian , Xu Hao-Ming , Zhang Liang-jie , Zhao Chong , Nie Yu-Qiang
Published: June 2022

Adaptive immune response to the gut microbiota is one of the main drivers of inflammatory bowel disease (IBD). Under inflammatory conditions, immunoglobulin (Ig)-targeted bacteria are altered. However, changes in Ig-targeted bacteria in Asian patients with IBD with ulcerative colitis (UC) remain unclear. Furthermore, changes in IgA-targeted bacteria in patients with UC treated with fecal microbiota transplantation (FMT) are unclear. Here, we analyzed fecal samples of patients with IBD and patients with UC before and after FMT by flow cytometry. We found that the percentage of IgA/G-coated bacteria can be used to assess the severity of IBD. Besides oral pharyngeal bacteria such as Streptococcus, we hypothesized that Megamonas, Acinetobacter, and, especially, Staphylococcus might play an important role in IBD pathogenesis. Moreover, we evaluated the influence of FMT on IgA-coated bacteria in patients with UC. We found that IgA-bacterial interactions were re-established in human FMT recipients and resembled those in the healthy fecal donors. Additionally, the IgA targeting was not influenced by delivery methods: gastroscopy spraying and colonic transendoscopic enteral tubing (TET). Then, we established an acute dextran sulfate sodium (DSS)-induced mouse model to explore whether FMT intervention would impact IgA/G memory B cell in the intestine. We found that after FMT, both IgA/G memory B cell and the percentage of IgA/G-targeted bacteria were restored to normal levels in DSS mice.
Characterization and Functional Studies of a Novel Depolymerase Against K19-Type Klebsiella pneumoniae
Authors: Hua Yunfen , Wu Yongqin , Guo Minjie , Ma Ruijing , Li Qingchuan , Hu Zheyuan , Chen Hongrui , Zhang Xingyu , Li Hui , Li Qingtian , He Ping
Published: June 2022

Carbapenem-resistant Klebsiella pneumoniae (CRKP), a pathogen that causes severe nosocomial infections and yields a high mortality rate, poses a serious threat to global public health due to its high antimicrobial resistance. Bacteriophages encode polysaccharide-degrading enzymes referred to as depolymerases that cleave the capsular polysaccharide (CPS), one of the main virulence factors of K. pneumoniae. In this study, we identified and characterized a new capsule depolymerase K19-Dpo41 from K. pneumoniae bacteriophage SH-KP156570. Our characterization of K19-Dpo41 demonstrated that this depolymerase showed specific activities against K19-type K. pneumoniae. K19-Dpo41-mediated treatments promoted the sensitivity of a multidrug-resistant K19-type K. pneumoniae strain to the bactericidal effect of human serum and significantly increased the survival rate of Galleria mellonella infected with K19-type K. pneumoniae. Our results provided strong primary evidence that K19-Dpo41 was not only effective in capsular typing of K19-type K. pneumoniae but promising in terms of developing new alternative therapeutic strategies against K19-type CRKP infections in the future.
Using Targeted Liquid Chromatography-Tandem Mass Spectrometry to Rapidly Detect β-Lactam, Aminoglycoside, and Fluoroquinolone Resistance Mechanisms in Blood Cultures Growing E. coli or K. pneumoniae
Authors: Foudraine Dimard E. , Dekker Lennard J. M. , Strepis Nikolaos , Nispeling Stan J. , Raaphorst Merel N. , Kloezen Wendy , Colle Piet , Verbon Annelies , Klaassen Corné H. W. , Luider Theo M. , Goessens Wil H. F.
Published: June 2022

New and rapid antimicrobial susceptibility/resistance testing methods are required for bacteria from positive blood cultures. In this study, a multiplex-targeted liquid chromatography-tandem mass spectrometry (LC-MS/MS) assay was developed and validated for the detection of β-lactam, aminoglycoside, and fluoroquinolone resistance mechanisms in blood cultures growing Escherichia coli or Klebsiella pneumoniae complex. Selected targets were the β-lactamases SHV, TEM, OXA-1-like, CTX-M-1-like, CMY-2-like, chromosomal E. coli AmpC (cAmpC), OXA-48-like, NDM, VIM, and KPC; the aminoglycoside-modifying enzymes AAC(3)-Ia, AAC(3)-II, AAC(3)-IV, AAC(3)-VI, AAC(6′)-Ib, ANT(2′′)-I, and APH(3′)-VI; the 16S-RMTases ArmA, RmtB, RmtC, and RmtF; the quinolone resistance mechanisms QnrA, QnrB, AAC(6′)-Ib-cr; the wildtype quinolone resistance determining region of GyrA; and the E. coli porins OmpC and OmpF. The developed assay was evaluated using 100 prospectively collected positive blood cultures, and 148 negative blood culture samples spiked with isolates previously collected from blood cultures or isolates carrying less prevalent resistance mechanisms. The time to result was approximately 3 h. LC-MS/MS results were compared with whole-genome sequencing and antimicrobial susceptibility testing results. Overall, there was a high agreement between LC-MS/MS results and whole-genome sequencing results. In addition, the majority of susceptible and non-susceptible phenotypes were correctly predicted based on LC-MS/MS results. Exceptions were the predictions for ciprofloxacin and amoxicillin/clavulanic acid that matched with the phenotype in 85.9 and 63.7% of the isolates, respectively. Targeted LC-MS/MS based on parallel reaction monitoring can be applied for the rapid and accurate detection of various resistance mechanisms in blood cultures growing E. coli or K. pneumoniae complex.
Prediction of Antibiotic Susceptibility Profiles of Vibrio cholerae Isolates From Whole Genome Illumina and Nanopore Sequencing Data: CholerAegon
Authors: Fuesslin Valeria , Krautwurst Sebastian , Srivastava Akash , Winter Doris , Liedigk Britta , Thye Thorsten , Herrera-León Silvia , Wohl Shirlee , May Jürgen , Fobil Julius N. , Eibach Daniel , Marz Manja , Schuldt Kathrin
Published: June 2022

During the last decades, antimicrobial resistance (AMR) has become a global public health concern. Nowadays multi-drug resistance is commonly observed in strains of Vibrio cholerae, the etiological agent of cholera. In order to limit the spread of pathogenic drug-resistant bacteria and to maintain treatment options the analysis of clinical samples and their AMR profiles are essential. Particularly, in low-resource settings a timely analysis of AMR profiles is often impaired due to lengthy culturing procedures for antibiotic susceptibility testing or lack of laboratory capacity. In this study, we explore the applicability of whole genome sequencing for the prediction of AMR profiles of V. cholerae. We developed the pipeline CholerAegon for the in silico prediction of AMR profiles of 82 V. cholerae genomes assembled from long and short sequencing reads. By correlating the predicted profiles with results from phenotypic antibiotic susceptibility testing we show that the prediction can replace in vitro susceptibility testing for five of seven antibiotics. Because of the relatively low costs, possibility for real-time data analyses, and portability, the Oxford Nanopore Technologies MinION sequencing platform—especially in light of an upcoming less error-prone technology for the platform—appears to be well suited for pathogen genomic analyses such as the one described here. Together with CholerAegon, it can leverage pathogen genomics to improve disease surveillance and to control further spread of antimicrobial resistance.
Changes in Serum Fatty Acid Composition and Metabolome-Microbiome Responses of Heigai Pigs Induced by Dietary N-6/n-3 Polyunsaturated Fatty Acid Ratio
Authors: Wang Liyi , Nong Qiuyun , Zhou Yanbing , Sun Ye , Chen Wentao , Xie Jintang , Zhu Xiaodong , Shan Tizhong
Published: June 2022

Changing fatty acid composition is a potential nutritional strategy to shape microbial communities in pigs. However, the effect of different n-6/n-3 polyunsaturated fatty acid (PUFA) ratios on serum fatty acid composition, microbiota, and their metabolites in the intestine of pigs remains unclear. Our study investigated the changes in serum fatty acid composition and metabolome–microbiome responses induced by dietary n-6/n-3 PUFA ratio based on a Heigai-pig model. A total of 54 Heigai finishing pigs (body weight: 71.59 ± 2.16 kg) fed with 3 types of diets (n-6/n-3 PUFA ratios are 8:1, 5:1, and 3:1) were randomly divided into 3 treatments with 6 replications (3 pigs per replication) for 75 days. Results showed that dietary n-6/n-3 PUFA ratio significantly affected biochemical immune indexes including glucose (Glu), triglycerides (TG), total cholesterol (TChol), non-esterified fatty acid (NEFA), high-density lipoprotein (HDL), low-density lipoprotein (LDL), and total thyroxine (TT4), and medium- and long-chain fatty acid composition, especially n-3 PUFA and n-6/n-3 PUFA ratio in the serum. However, no significant effects were found in the SCFAs composition and overall composition of the gut microbiota community. In the low dietary n-6/n-3 PUFA ratio group, the relative abundance of Cellulosilyticum, Bacteroides, and Alloprevotella decreased, Slackia and Sporobacter increased. Based on the metabolomic analysis, dietary n-6/n-3 PUFA ratio altered the metabolome profiles in the colon. Moreover, Pearson’s correlation analysis indicated that differential microbial genera and metabolites induced by different n-6/n-3 PUFA ratio had tight correlations and were correlated with the n-6 PUFA and n-3 PUFA content in longissimus dorsi muscle (LDM) and subcutaneous adipose tissue (SAT). Taken together, these results showed that lower dietary n-6/n-3 PUFA ratio improved serum fatty acid composition and metabolome–microbiome responses of Heigai pigs and may provide a new insight into regulating the metabolism of pigs and further better understanding the crosstalk with host and microbes in pigs.