bluuebunny/crossref_metadata_2025 huggingface dataset:
Genetic Profile of Epidermolysis Bullosa Cases in King Abdulaziz Medical City, Riyadh, Saudi Arabia
Authors: Alharthi Raghad , Alnahdi Muhannad A. , Alharthi Ahad , Almutairi Seba , Al-Khenaizan Sultan , AlBalwi Mohammed A.
Published: February 2022

Epidermolysis bullosa (EB) is a rare heterogeneous genetic mechanobullous skin disorder that is characterized by increased skin fragility leading to blistering following minor trauma. EB may be inherited as an autosomal dominant or an autosomal recessive disorder and can be classified into dystrophic EB (DEB), junctional EB (JEB), and EB simplex (EBS). A total of 28 Saudi patients with EB were included in this observational, retrospective chart-review study. A consecutive non-probability sampling technique was used to approach all affected patients. Molecular analysis was done to test the patients’ genomic DNA using a custom-designed AmpliSeq panel of suspected genes. All disease-causing variants were checked against available public databases. Twelve patients (42.9%) were found to have DEB, 6 patients (21.4%) with JEB, and 10 patients (35.7%) with EBS. The molecular genetic results revealed detections of 24 various homozygous genetic variations in the genes associated with EB, of which 14 were novel mutations. The most frequent variations were detected in COL7A1 in 12 cases (42.9%), followed by LAMB3 in 5 cases (17.9%), TGM5 in 4 cases (14.3%), and other genes. Furthermore, the majority (87.5%) of EB cases were confirmed to have homozygous mutations, and few were documented with positive consanguinity history. Only 3 cases (12.5%) were found to be autosomal dominant displaying heterozygous mutations. This is the first study to establish the EB genetic profile in Saudi Arabia where DEB is the most frequent type. A total of 14 novel mutations were identified that had not been previously reported. Consanguineous marriage is clearly recognized in the Saudi population; therefore, we propose a nationwide EB program that would help extend the spectrum of the genetic profile and help in the diagnosis and better understanding of this disease.
Generation of Realistic Gene Regulatory Networks by Enriching for Feed-Forward Loops
Authors: Zhivkoplias Erik K. , Vavulov Oleg , Hillerton Thomas , Sonnhammer Erik L. L.
Published: February 2022

The regulatory relationships between genes and proteins in a cell form a gene regulatory network (GRN) that controls the cellular response to changes in the environment. A number of inference methods to reverse engineer the original GRN from large-scale expression data have recently been developed. However, the absence of ground-truth GRNs when evaluating the performance makes realistic simulations of GRNs necessary. One aspect of this is that local network motif analysis of real GRNs indicates that the feed-forward loop (FFL) is significantly enriched. To simulate this properly, we developed a novel motif-based preferential attachment algorithm, FFLatt, which outperformed the popular GeneNetWeaver network generation tool in reproducing the FFL motif occurrence observed in literature-based biological GRNs. It also preserves important topological properties such as scale-free topology, sparsity, and average in/out-degree per node. We conclude that FFLatt is well-suited as a network generation module for a benchmarking framework with the aim to provide fair and robust performance evaluation of GRN inference methods.
AutoPlate: Rapid Dose-Response Curve Analysis for Biological Assays
Authors: Palmer Phil , Del Rosario Joanne Marie M. , da Costa Kelly A. S. , Carnell George W. , Huang Chloe Q. , Heeney Jonathan L. , Temperton Nigel J. , Wells David A.
Published: February 2022

The emergence of COVID-19 has emphasised that biological assay data must be analysed quickly to develop safe, effective and timely vaccines/therapeutics. For viruses such as SARS-CoV-2, the primary way of measuring immune correlates of protection is through assays such as the pseudotype microneutralisation (pMN) assay, thanks to its safety and versatility. However, despite the presence of existing tools for data analysis such as PRISM and R the analysis of these assays remains cumbersome and time-consuming. We introduce an open-source R Shiny web application and R library (AutoPlate) to accelerate data analysis of dose-response curve immunoassays. Using example data from influenza studies, we show that AutoPlate improves on available analysis software in terms of ease of use, flexibility and speed. AutoPlate (https://philpalmer.shinyapps.io/AutoPlate/) is a tool for the use of laboratories and wider scientific community to accelerate the analysis of biological assays in the development of viral vaccines and therapeutics.
MicroRNA-5112 Targets IKKγ to Dampen the Inflammatory Response and Improve Clinical Symptoms in Both Bacterial Infection and DSS-Induced Colitis
Authors: Kang Xilong , Jiao Yang , Zhou Yingying , Meng Chuang , Zhou Xiaohui , Song Li , Jiao Xinan , Pan Zhiming
Published: February 2022

Inflammation is a double-edged sword that can be induced by various PAMPs, resulting in the control of infection by invading pathogens or injuries. The inflammatory response requires strict and precise control and regulation. MicroRNAs (miRNAs) are small non-coding RNA molecules that regulate gene expression via translational inhibition or mRNA degradation. However, the role of miRNAs in inflammation induced by flagellin (ligand of TLR5) has yet to be fully determined. In this study, we identified differentially expressed miRNAs in murine bone marrow-derived dendritic cells (BMDCs) between flagellin treatment and medium alone using miRNA microarray. We found that flagellin stimulation downregulated miR-5112 expression in BMDCs and spleen DCs in vitro and in vivo. The overexpression of miR-5112 decreased inflammatory cytokine production, accompanied by a reduction of IKKγ in flagellin-stimulated BMDCs. We demonstrated that miR-5112 could directly target IKKγ to inhibit inflammatory cytokine production. Furthermore, miR-5112 inhibited the inflammatory response induced by flagellin or Salmonella infection in vivo. Interestingly, miR-5112 could also dampen the inflammatory response and alleviate dextran sulfate sodium (DSS)-induced colitis in C57BL/6 mice. These results suggest that miR-5112 could be a novel therapeutic target for both bacterial infection and DSS-induced colitis model.
Clinical Significance and Immunometabolism Landscapes of a Novel Recurrence-Associated Lipid Metabolism Signature In Early-Stage Lung Adenocarcinoma: A Comprehensive Analysis
Authors: Zhu Mingchuang , Zeng Qingpeng , Fan Tao , Lei Yuanyuan , Wang Feng , Zheng Sufei , Wang Xinfeng , Zeng Hui , Tan Fengwei , Sun Nan , Xue Qi , He Jie
Published: February 2022

Background

The early-stage lung adenocarcinoma (LUAD) rate has increased with heightened public awareness and lung cancer screening implementation. Lipid metabolism abnormalities are associated with lung cancer initiation and progression. However, the comprehensive features and clinical significance of the immunometabolism landscape and lipid metabolism-related genes (LMRGs) in cancer recurrence for early-stage LUAD remain obscure.

Methods

LMRGs were extracted from Gene Set Enrichment Analysis (GSEA) and Kyoto Encyclopedia of Genes and Genomes (KEGG) databases. Samples from The Cancer Genome Atlas (TCGA) were used as training cohort, and samples from four Gene Expression Omnibus (GEO) datasets were used as validation cohorts. The LUAD recurrence-associated LMRG molecular pattern and signature was constructed through unsupervised consensus clustering, time-dependent receiver operating characteristic (ROC), and least absolute shrinkage and selection operator (LASSO) analyses. Kaplan-Meier, ROC, and multivariate Cox regression analyses and prognostic meta-analysis were used to test the suitability and stability of the signature. We used Gene Ontology (GO), KEGG pathway, immune cell infiltration, chemotherapy response analyses, gene set variation analysis (GSVA), and GSEA to explore molecular mechanisms and immune landscapes related to the signature and the potential of the signature to predict immunotherapy or chemotherapy response.

Results

First, two LMRG molecular patterns were established, which showed diverse prognoses and immune infiltration statuses. Then, a 12-gene signature was identified, and a risk model was built. The signature remained an independent prognostic parameter in multivariate Cox regression and prognostic meta-analysis. In addition, this signature stratified patients into high- and low-risk groups with significantly different recurrence rates and was well validated in different clinical subgroups and several independent validation cohorts. The results of GO and KEGG analyses and GSEA showed that there were differences in multiple lipid metabolism, immune response, and drug metabolism pathways between the high- and low-risk groups. Further analyses revealed that the signature-based risk model was related to distinct immune cell proportions, immune checkpoint parameters, and immunotherapy and chemotherapy response, consistent with the GO, KEGG, and GSEA results.

Conclusions

This is the first lipid metabolism-based signature for predicting recurrence, and it could provide vital guidance to achieve optimized antitumor for immunotherapy or chemotherapy for early-stage LUAD.
Combined Consideration of Tumor-Associated Immune Cell Density and Immune Checkpoint Expression in the Peritumoral Microenvironment for Prognostic Stratification of Non-Small-Cell Lung Cancer Patients
Authors: Yang Yong , Yang Xiaobao , Wang Yichao , Xu Jingsong , Shen Hanyu , Gou Hongquan , Qin Xiong , Jiang Gening
Published: February 2022

Given the complexity and highly heterogeneous nature of the microenvironment and its effects on antitumor immunity and cancer immune evasion, the prognostic value of a single immune marker is limited. Here, we show how the integration of immune checkpoint molecule expression and tumor-associated immune cell distribution patterns can influence prognosis prediction in non-small-cell lung cancer (NSCLC) patients. We analyzed tissue microarray (TMA) data derived from multiplex immunohistochemistry results and measured the densities of tumor-infiltrating CD8+ and FOXP3+ immune cells and tumor cells (PanCK+), as well as the densities of programmed cell death 1 (PD-1)+ and programmed cell death ligand 1 (PD-L1)+ cells in the peritumor and intratumor subregions. We found a higher density of infiltrating CD8+ and FOXP3+ immune cells in the peritumoral compartment than in the intratumoral compartment. In addition, unsupervised hierarchical clustering analysis of these markers revealed that the combination of high CD8/FOXP3 expression, low PD-1 and PD-L1 immune checkpoint expression, and lack of epidermal growth factor receptor (EGFR) mutation could be a favorable predictive marker. On the other hand, based on the clustering analysis, low CD8/FOXP3 and immune checkpoint (PD-1 and PD-L1) expression might be a marker for patients who are likely to respond to strategies targeting regulatory T (Treg) cells. Furthermore, an immune risk score model was established based on multivariate Cox regression, and the risk score was determined to be an independent prognostic factor for NSCLC patients. These results indicate that the immune context is heterogeneous because of the complex interactions of different components and that using multiple factors in combination might be promising for predicting the prognosis of and stratifying NSCLC patients.
Fibroblasts From Idiopathic Pulmonary Fibrosis Induce Apoptosis and Reduce the Migration Capacity of T Lymphocytes
Authors: Chavez-Galan Leslie , Becerril Carina , Ruiz Andy , Ramon-Luing Lucero A. , Cisneros José , Montaño Martha , Salgado Alfonso , Ramos Carlos , Buendía-Roldán Ivette , Pardo Annie , Selman Moisés
Published: February 2022

Idiopathic pulmonary fibrosis (IPF) is a progressive and irreversible lung disease of unknown etiology. Myofibroblasts are organized in peculiar subepithelial fibroblasts foci (FF), where they abnormally persist and exclude lymphocytes by unclear mechanisms. FF are the source of an excessive extracellular matrix, which results in progressive stiffening and destruction of the lung architecture. We hypothesized that the absence of T cells inside the FF could be related, at least partially, to an inefficient function of lymphocytes induced by IPF fibroblasts. Here, we evaluated the effect of a supernatant from IPF fibroblasts on T-cell apoptosis and migration capacity. Data showed that IPF fibroblasts secrete pro-apoptotic molecules (both from extrinsic and intrinsic pathways), generating a microenvironment that induces apoptosis of T cells at 3 h of culture, despite a weak anti-apoptotic profile exhibited by these T cells. At 24 h of culture, the supernatants from both IPF and control fibroblasts provoked T-cell death. However, at this time of culture, IPF fibroblasts caused a marked decrease in T-cell migration; in contrast, control lung fibroblasts induced an increase of T-cell migration. The reduction of T-cell migratory capacity provoked by IPF fibroblasts was associated with a negative regulation of RHOA and ROCK, two essential GTPases for migration, and was independent of the expression of chemokine receptors. In conclusion, our findings demonstrate that IPF fibroblasts/myofibroblasts induce apoptosis and affect T-cell migration, revealing a mechanism involved in the virtual absence of T lymphocytes inside the FF.
Thyroid Function and Low Free Triiodothyronine in Chinese Patients With Autoimmune Encephalitis
Authors: Qiao Shan , Zhang Shan-chao , Zhang Ran-ran , Wang Lei , Wang Zhi-hao , Jiang Jing , Wang Ai-hua , Liu Xue-wu
Published: February 2022

Background and Objectives

Low free triiodothyronine (FT3) is usually associated with worse functional outcome in critical illness; however, the information on thyroid dysfunction and autoimmune encephalitis (AE) is limited. This study aims to evaluate the clinical prognostic value of thyroid function and low-T3 syndrome in patients with multiple subtypes of AE.

Methods

In this retrospective study, we identified the hospital records of 319 candidate patients with AE admitted between January 2016 and December 2020. We then extracted the clinical features and outcomes. Modified Rankin scale (mRS) scores were used to evaluate the patients’ neurological function. The serum levels of FT3, free thyroxine (FT4), and thyroid-stimulating hormone (TSH) were measured upon admission. Normal thyroid stimulating hormone level with FT3 below the lower limit of the reference interval (2.63 nmol/L) was defined as low-T3 syndrome.

Results

A total of 237 AE cases remained after screening. Among these, 57.81% (137/237) were men and the average age at onset was 41 y (interquartile range, 12–61 y). We found that 83.54% (198/237) of the patients had a good prognosis, and 16.46% (39/237) had a poor prognosis. Abnormal thyroid function was observed in 30.80% of these patients, with a relatively greater prevalence in the group with a poor prognosis (p < 0.001). The serum FT3 levels in the poor-prognosis group were significantly lower than those in the good-prognosis group (p < 0.001). Low-T3 syndrome occurred in 15.19% of AE cases and was more frequent in patients with poor prognosis (p < 0.001).

Conclusions

Abnormal thyroid function in AE is frequent, and serum FT3 levels in patients with poor prognosis are significantly lower than in those with good prognosis. Low-T3 syndrome could be a potential candidate for predicting the prognosis of AE following future research.
SGK1, a Critical Regulator of Immune Modulation and Fibrosis and a Potential Therapeutic Target in Chronic Graft-Versus-Host Disease
Authors: Lu Run-qing , Zhang Yin-yin , Zhao Hai-qiu , Guo Rong-qun , Jiang Zhong-xing , Guo Rong
Published: February 2022

Patients with severe chronic graft-versus-host disease (cGVHD) always experience debilitating tissue injury and have poorer quality of life and shorter survival time. The early stage of cGVHD is characterized by inflammation, which eventually leads to extensive tissue fibrosis in various organs, such as skin and lung, eventually inducing scleroderma-like changes and bronchiolitis obliterans syndrome. Here we review the functions of serum/glucocorticoid regulated kinase 1 (SGK1), a hub molecule in multiple signal transduction pathways and cell phosphorylation cascades, which has important roles in cell proliferation and ion channel regulation, and its relevance in cGVHD. SGK1 phosphorylates the ubiquitin ligase, NEDD4, and induces Th cells to differentiate into Th17 and Th2 phenotypes, hinders Treg development, and promotes inflammatory fibrosis. Phosphorylation of NEDD4 by SGK1 also leads to up-regulation of the transcription factor SMAD2/3, thereby amplifying the fibrosis-promoting effect of TGF-β. SGK1 also up-regulates the inflammatory transcription factor, nuclear factor-κB (NF-κB), which in turn stimulates the expression of multiple inflammatory mediators, including connective tissue growth factor. Overexpression of SGK1 has been observed in various fibrotic diseases, including pulmonary fibrosis, diabetic renal fibrosis, liver cirrhosis, hypertensive cardiac fibrosis, peritoneal fibrosis, and Crohn’s disease. In addition, SGK1 inhibitors can attenuate, or even reverse, the effect of fibrosis, and may be used to treat inflammatory conditions and/or fibrotic diseases, such as cGVHD, in the future.
Glycoprotein 96 in Peritoneal Dialysis Effluent-Derived Extracellular Vesicles: A Tool for Evaluating Peritoneal Transport Properties and Inflammatory Status
Authors: Fang Junyan , Tong Yan , Ji Ouyang , Wei Shan , Chen Zhihao , Song Ahui , Li Pu , Zhang Yi , Zhang Huiping , Ruan Hongqiang , Ding Feng , Liu Yingli
Published: February 2022

Background

Extracellular vesicles (EVs) from peritoneal dialysis effluent (PDE), containing molecules such as proteins and microRNAs (miRNAs), may be potential biological markers to monitor peritoneal function or injury. Peritoneal inflammation is an important determinant of peritoneal solute transport rate (PSTR). Thus, the aim of this study is to determine whether the specific proteins capable of evaluating the PSTR could be found in PDE-EVs, and explore the underlying mechanism for the association between PSTR and peritoneal inflammation.

Methods

Sixty patients undergoing peritoneal dialysis (PD) were divided into two groups: high/high average transport (H/A) group (PET >0.65) and low/low average transport (L/A) group (PET <0.65). EVs derived from PDE (PDE-EVs) were isolated by ultracentrifugation. Proteomic analysis was performed to explore the differentially expressed proteins and identify the potential biomarkers in PDE-EVs from the two groups, and we focused on glycoprotein 96 (GP96) as it could be involved in the inflammatory process. The expression of GP96 in PDE-EVs and inflammatory cytokines was quantified by real-time PCR and enzyme-linked immunosorbent assay. The infiltration of macrophages and neutrophils into the peritoneum was detected using immunohistochemistry in a PD rat model.

Results

The expression of PDE-EVs-GP96 was significantly higher in the H/A group, and was positively correlated with the PSTR and the level of the inflammatory factor interleukin (IL)-6. GP96-enriched EVs enhanced the secretion of proinflammatory cytokines IL-1β, IL-6, tumor necrosis factor (TNF)-α, and IL-8 in macrophages, which was reversed by a pharmacological GP96-specific inhibitor (PU-WS13). The GP96 inhibitor also reduced local peritoneal inflammation by decreasing the infiltration of inflammatory cells and levels of proinflammatory cytokines (IL-6 and TNF-α) and chemokines (CCL2, CXCL1, and CXCL2) in a PD rat model.

Conclusions

PDE-EVs-GP96 is a new promising tool to evaluate the status of peritoneal inflammation and PSTR, and the mechanism may be related to affecting the inflammatory properties of macrophages.
mTOR Signaling in the Regulation of CD4+ T Cell Subsets in Periodontal Diseases
Authors: Jiang Qian , Huang Xiaobin , Yu Wenjing , Huang Ranran , Zhao Xuefeng , Chen Chider
Published: February 2022

Periodontal disease results from the inflammatory infiltration by the microbial community which is marked through tooth mobility and alveolar bone resorption. The inflammation in periodontal disease is mediated by CD4+ T cells through cytokine secretion and osteoclastogenetic activity. Historically, the inflammatory model in periodontal disease is described through disruption of the balance between two subsets of T helper cells which are T-helper type 1 (Th1) and T-helper type 2 (Th2). However, more and more studies have found that apart from subsets of helper T cells, regulatory T-cells and Th17 cells are also involved in the pathogenesis of periodontal diseases. Growing evidence proves that helper T cells differentiation, activation, and subset determination are under the strong impact of mTOR signaling. mTOR signaling could promote Th1 and Th17 cell differentiation and inhibit Treg commitment through different mTOR complexes, therefore we anticipate a regulation effect of mTOR signaling on periodontal diseases by regulating CD4+ T cell subsets. This review aims to integrate the topical researches about the role of different types of Th cells in the pathogenesis of periodontal diseases, as well as the regulation of mTOR signaling in the specification and selection of Th cell commitment.
Pregnant Women Develop a Specific Immunological Long-Lived Memory Against SARS-COV-2
Authors: Fenizia Claudio , Cetin Irene , Mileto Davide , Vanetti Claudia , Saulle Irma , Di Giminiani Maria , Saresella Marina , Parisi Francesca , Trabattoni Daria , Clerici Mario , Biasin Mara , Savasi Valeria
Published: February 2022

It is well established that pregnancy induces deep changes in the immune system. This is part of the physiological adaptation of the female organism to the pregnancy and the immunological tolerance toward the fetus. Indeed, over the three trimesters, the suppressive T regulatory lymphocytes are progressively more represented, while the expression of co-stimulatory molecules decreases overtime. Such adaptations relate to an increased risk of infections and progression to severe disease in pregnant women, potentially resulting in an altered generation of long-lived specific immunological memory of infection contracted during pregnancy. How potent is the immune response against SARS-CoV-2 in infected pregnant women and how long the specific SARS-CoV-2 immunity might last need to be urgently addressed, especially considering the current vaccinal campaign. To address these questions, we analyzed the long-term immunological response upon SARS-CoV-2 infection in pregnant women from delivery to a six-months follow-up. In particular, we investigated the specific antibody production, T cell memory subsets, and inflammation profile. Results show that 80% developed an anti-SARS-CoV-2-specific IgG response, comparable with the general population. While IgG were present only in 50% of the asymptomatic subjects, the antibody production was elicited by infection in all the mild-to-critical patients. The specific T-cell memory subsets rebalanced over-time, and the pro-inflammatory profile triggered by specific SARS-CoV-2 stimulation faded away. These results shed light on SARS-CoV-2-specific immunity in pregnant women; understanding the immunological dynamics of the immune system in response to SARS-CoV-2 is essential for defining proper obstetric management of pregnant women and fine tune gender-specific vaccinal plans.
Modulation of mRNA 3′-End Processing and Transcription Termination in Virus-Infected Cells
Authors: Vijayakumar Aarthi , Park Annsea , Steitz Joan A.
Published: February 2022

Eukaryotic mRNA 3´-end processing is a multi-step process beginning with pre-mRNA transcript cleavage followed by poly(A) tail addition. Closely coupled to transcription termination, 3´-end processing is a critical step in the regulation of gene expression, and disruption of 3´-end processing is known to affect mature mRNA levels. Various viral proteins interfere with the 3´-end processing machinery, causing read-through transcription and altered levels of mature transcripts through inhibition of cleavage and polyadenylation. Thus, disruption of 3´-end processing contributes to widespread host shutoff, including suppression of the antiviral response. Additionally, observed features of read-through transcripts such as decreased polyadenylation, nuclear retention, and decreased translation suggest that viruses may utilize these mechanisms to modulate host protein production and dominate cellular machinery. The degree to which the effects of read-through transcript production are harnessed by viruses and host cells remains unclear, but existing research highlights the importance of host 3´-end processing modulation during viral infection.
Notch1 Modulation of Cellular Calcium Regulates Mitochondrial Metabolism and Anti-Apoptotic Activity in T-Regulatory Cells
Authors: Saini Neetu , Lakshminarayanan Sowmya , Kundu Priyanka , Sarin Apurva
Published: February 2022

As the major hub of metabolic activity and an organelle sequestering pro-apoptogenic intermediates, mitochondria lie at the crossroads of cellular decisions of death and survival. Intracellular calcium is a key regulator of these outcomes with rapid, uncontrolled uptake into mitochondria, activating pro-apoptotic cascades that trigger cell death. Here, we show that calcium uptake and mitochondrial metabolism in murine T-regulatory cells (Tregs) is tuned by Notch1 activity. Based on analysis of Tregs and the HEK cell line, we present evidence that modulation of cellular calcium dynamics underpins Notch1 regulation of mitochondrial homeostasis and consequently anti-apoptotic activity. Targeted siRNA-mediated ablations reveal dependency on molecules controlling calcium release from the endoplasmic reticulum (ER) and the chaperone, glucose-regulated protein 75 (Grp75), the associated protein Voltage Dependent Anion Channel (VDAC)1 and the Mitochondrial Calcium Uniporter (MCU), which together facilitate ER calcium transfer and uptake into the mitochondria. Endogenous Notch1 is detected in immune-complexes with Grp75 and VDAC1. Deficits in mitochondrial oxidative and survival in Notch1 deficient Tregs, were corrected by the expression of recombinant Notch1 intracellular domain, and in part by recombinant Grp75. Thus, the modulation of calcium dynamics and consequently mitochondrial metabolism underlies Treg survival in conditions of nutrient stress. This work positions a key role for Notch1 activity in these outcomes.
Single-Cell RNA Sequencing Identifies Intra-Graft Population Heterogeneity in Acute Heart Allograft Rejection in Mouse
Authors: Tang Yunhua , Wang Jiali , Zhang Yixi , Li Jun , Chen Maogen , Gao Yifang , Dai Meiqin , Lin Shengjie , He Xiaoshun , Wu Chenglin , Shi Xiaomin
Published: February 2022

Transplant rejection remains a major barrier to graft survival and involves a diversity of cell types. However, the heterogeneity of each cell type in the allograft remains poorly defined. In the present study, we used single-cell RNA sequencing technology to analyze graft-infiltrating cells to describe cell types and states associated with acute rejection in a mouse heart transplant model. Unsupervised clustering analysis revealed 21 distinct cell populations. Macrophages formed five cell clusters: two resident macrophage groups, two infiltrating macrophage groups and one dendritic cell-like monocyte group. Infiltrating macrophages were predominantly from allogeneic grafts. Nevertheless, only one infiltrating macrophage cluster was in an active state with the upregulation of CD40, Fam26f and Pira2, while the other was metabolically silent. Re-clustering of endothelial cells identified five subclusters. Interestingly, one of the endothelial cell populations was almost exclusively from allogeneic grafts. Further analysis of this population showed activation of antigen processing and presentation pathway and upregulation of MHC class II molecules. In addition, Ubiquitin D was specifically expressed in such endothelial cell population. The upregulation of Ubiquitin D in rejection was validated by staining of mouse heart grafts and human kidney biopsy specimens. Our findings present a comprehensive analysis of intra-graft cell heterogeneity, describe specific macrophage and endothelial cell populations which mediate rejection, and provide a potential predictive biomarker for rejection in the clinic.
Helicobacter Pylori and Autoimmune Diseases: Involving Multiple Systems
Authors: Wang Li , Cao Zheng-Min , Zhang Li-Li , Dai Xin-can , Liu Zhen-ju , Zeng Yi-xian , Li Xin-Ye , Wu Qing-Juan , Lv Wen-liang
Published: February 2022

The modern Gastroenterology have witnessed an essential stride since Helicobacter pylori was first found in the stomach and then its pathogenic effect was discovered. According to the researches conducted during the nearly 40 years, it has been found that this bacterium is associated with a natural history of many upper gastrointestinal diseases. Epidemiological data show an increased incidence of autoimmune disorders with or after infection with specific microorganisms. The researches have revealed that H. pylori is a potential trigger of gastric autoimmunity, and it may be associated with other autoimmune diseases, both innate and acquired. This paper reviews the current support or opposition about H. pylori as the role of potential triggers of autoimmune diseases, including inflammatory bowel disease, autoimmune thyroiditis, type 1 diabetes mellitus, autoimmune liver diseases, rheumatoid arthritis, idiopathic thrombocytopenic purpura, systemic lupus erythematosus, as well as Sjogren’s syndrome, chronic urticaria and psoriasis, and tried to explain the possible mechanisms.
The Combined Model of CX3CR1-Related Immune Infiltration Genes to Evaluate the Prognosis of Idiopathic Pulmonary Fibrosis
Authors: Cai Haozheng , Chen Shijie , Li Xinyu , Liu Hanying , Zhang Ying , Zhuang Quan
Published: February 2022

Background

High expression of chemokine (C-X3-C motif) receptor 1 (CX3CR1) was shown to contribute to the progression of many fibrotic diseases. However, there is still no study for the role of CX3CR1 in idiopathic pulmonary fibrosis (IPF). Therefore, we aimed to identify CX3CR1-related immune infiltration genes (IIGs) in IPF and establish a combined risk model to evaluate the prognosis of IPF.

Methods

A discovery cohort of IPF patients (GSE70867) was downloaded from the Gene Expression Omnibus dataset. We identified the composition of 22 kinds of immune cells infiltration by CIBERSORT. The Cox regression model with the LASSO method was used for identifying prognostic genes and developing CX3CR1-related IIGs. Kaplan–Meier was applied to plot the survival curve of prognosis model. Peripheral blood mononuclear cell (PBMC) and bronchoalveolar lavage fluid (BALF) were collected to be tested by quantitative reverse transcriptase-PCR (qRT-PCR) from 15 clinical samples, including 8 healthy controls (HC), 4 patients with usual interstitial pneumonia (UIP) and 3 patients with pulmonary fibrosis (FIB).

Results

We found that high expression of CX3CR1 in BALF contributed to the poor prognosis in IPF patients. ALR4C, RAB37, GPR56, MARCKS, PXN and RASSF2 were identified as CX3CR1-related IIGs, which were highly expressed in PBMC of UIP/FIB patients than that of HC. Moreover, the expression of PXN was higher in FIB patients’ PBMC than that of UIP ones. In the cohort of IPF patients, high infiltration of activated NK cells in BALF caused poor survival compared to low infiltration group. The infiltration of activated NK was regulated by CX3CR1-related IIGs. The combined risk model predicted that high expression of CX3CR1-related IIGs and high infiltrated activated NK cells caused poor prognosis in IPF patients.

Conclusion

We identified a group of CX3CR1-related IIGs in IPF patients. This combined risk model provided new insights in the prognosis and therapy of IPF.
Metabolomics Signature and Potential Application of Serum Polyunsaturated Fatty Acids Metabolism in Patients With Vitiligo
Authors: Ye Zhubiao , Chen Jianru , Du Pengran , Ni Qingrong , Li Baizhang , Zhang Zhe , Wang Qi , Cui Tingting , Yi Xiuli , Li Chunying , Li Shuli
Published: February 2022

Vitiligo is a depigmented skin disorder caused by a variety of factors, including autoimmune, metabolic disturbance or their combined effect, etc. Non-targeted metabolomic analyses have denoted that dysregulated fatty acids metabolic pathways are involved in the pathogenesis of vitiligo. However, the exact category of fatty acids that participate in vitiligo development and how they functionally affect CD8+ T cells remain undefined. We aimed to determine the difference in specific fatty acids among vitiligo patients and healthy individuals and to investigate their association with clinical features in patients with vitiligo. Serum levels of fatty acids in 48 vitiligo patients and 28 healthy individuals were quantified by performing ultra-performance liquid chromatography-tandem mass spectrometry. Univariate and multivariate analyses were carried out to evaluate the significance of differences. Moreover, flow cytometry was used to explore the effect of indicated fatty acids on the function of CD8+ T cells derived from patients with vitiligo. We demonstrated that serological level of alpha-linolenic acid (ALA) was markedly upregulated, while that of arachidonic acid (ARA), arachidic acid (AA) and behenic acid were significantly downregulated in patients with vitiligo. Moreover, ALA levels were positively associated with vitiligo area scoring index (VASI) and ARA was a probable biomarker for vitiligo. We also revealed that supplementation with ARA or nordihydroguaiaretic acid (NDGA) could suppress the function of CD8+ T cells. Our results showed that vitiligo serum has disorder-specific phenotype profiles of fatty acids described by dysregulated metabolism of polyunsaturated fatty acids. Supplementation with ARA or NDGA might promote vitiligo treatment. These findings provide novel insights into vitiligo pathogenesis that might add to therapeutic options.
Human Herpesvirus 6A Is a Risk Factor for Multiple Sclerosis
Authors: Lundström Wangko , Gustafsson Rasmus
Published: February 2022

The role for human herpesvirus (HHV)-6A or HHV-6B in multiple sclerosis (MS) pathogenesis has been controversial. Possibly because the damage of the virus infection may occur before onset of clinical symptoms and because it has been difficult to detect active infection and separate serological responses to HHV-6A or 6B. Recent studies report that in MS patients the serological response against HHV-6A is increased whereas it is decreased against HHV-6B. This effect seems to be even more pronounced in MS patients prior to diagnosis and supports previous studies postulating a predomination for HHV-6A in MS disease and suggests that the infection is important at early stages of the disease. Furthermore, HHV-6A infection interacts with other factors suspected of modulating MS susceptibility and progression such as infection with Epstein-Barr virus (EBV) and Cytomegalovirus (CMV), tobacco smoking, HLA alleles, UV irradiation and vitamin D levels. The multifactorial nature of MS and pathophysiological role for HHV-6A in inflammation and autoimmunity are discussed.
Angiogenesis as Therapeutic Target in Metastatic Prostate Cancer – Narrowing the Gap Between Bench and Bedside
Authors: Solimando Antonio Giovanni , Kalogirou Charis , Krebs Markus
Published: February 2022

Angiogenesis in metastatic castration-resistant prostate cancer (mCRPC) has been extensively investigated as a promising druggable biological process. Nonetheless, targeting angiogenesis has failed to impact overall survival (OS) in patients with mCRPC despite promising preclinical and early clinical data. This discrepancy prompted a literature review highlighting the tumor heterogeneity and biological context of Prostate Cancer (PCa). Narrowing the gap between the bench and bedside appears critical for developing novel therapeutic strategies. Searching clinicaltrials.gov for studies examining angiogenesis inhibition in patients with PCa resulted in n=20 trials with specific angiogenesis inhibitors currently recruiting (as of September 2021). Moreover, several other compounds with known anti-angiogenic properties – such as Metformin or Curcumin – are currently investigated. In general, angiogenesis-targeting strategies in PCa include biomarker-guided treatment stratification – as well as combinatorial approaches. Beyond established angiogenesis inhibitors, PCa therapies aiming at PSMA (Prostate Specific Membrane Antigen) hold the promise to have a substantial anti-angiogenic effect – due to PSMA´s abundant expression in tumor vasculature.
Association Between Perceived Medical Errors and Suicidal Ideation Among Chinese Medical Staff: The Mediating Effect of Depressive Symptoms
Authors: Wei Zhen , Wang Yifan , Yang Shijun , Sun Long
Published: February 2022

Both medical errors and suicidal behaviors are important problems for medical staff. Although the association between them was implied in previous studies, their association has not been built until now. In this study, the first aim was to build the association between perceived medical errors and suicidal ideation, and we also want to explore the mediating role of depression in the association between perceived medical errors and suicidal ideation among Chinese medical staff. In this study, we interviewed 3,338 medical staff in Chinese general hospitals. Questions about suicidal ideation (SI) and perceived medical errors were interviewed for medical staff. Depressive symptoms were evaluated by the Chinese version of Center for Epidemiologic Studies Depression Scale (CES-D). Social-demographic and occupation-related variables were also assessed in the data collection. This study found that the prevalence of suicidal ideation among medical staff was 9%. After the adjustment for controlling variables, suicidal ideation was significantly associated with a higher level of depression (OR = 1.10, p < 0.001) and perceived medical errors (OR = 2.41, p < 0.001). The other associated factors were female (OR = 2.21, p < 0.001), religious belief (OR = 2.66, p < 0.001), and weekly work hours (OR = 1.02 p < 0.001). The mediating effect of depressive symptoms on the association between perceived medical errors and suicidal ideation was also supported in this study, and it can explain the 38.73% of the total effects of the perceived medical errors on suicidal ideation. The medical staff, with perceived medical errors, were in higher risk of suicidal ideation, and depressive symptoms can partially mediate the association between perceived medical errors and suicidal ideation. For the medical staff who are experiencing medical errors, some scanning on their suicidal ideation and depressive symptoms are necessary to promote their mental health.
Dynamic Responses of Endosymbiotic Microbial Communities Within Microcystis Colonies in North American Lakes to Altered Nitrogen, Phosphorus, and Temperature Levels
Authors: Gobler Christopher J. , Jankowiak Jennifer G.
Published: February 2022

The toxic cyanobacterium, Microcystis, is a pervasive cyanobacterial harmful algal bloom (CHAB) - forming genus that naturally occurs in colonies that harbor diverse microbiomes of heterotrophic bacteria. While the effects of nutrient loading and climatic warming on CHABs are well-known, little is known regarding how these environmental drivers alter the structural and functional potential of the microbial assemblages associated with blooms that, in turn, may impact cyanobacterial growth. Here, we used next-generation sequencing of 16S ribosomal rRNA genes to characterize the dynamics of the bacterial assemblages within Microcystis colonies in two temperate North American lakes: Lake Erie and Lake Agawam (NY, United States) and quantified their responses to experimentally increased levels of nitrogen (N), phosphorus (P) and temperature. Across experiments, Microcystis populations were consistently and significantly promoted by N and, to a lesser extent, elevated temperature (p < 0.05). In contrast, bacterial assemblages within Microcystis colonies were more resilient to environmental perturbations, with the relative abundance of 7–16% of amplicon sequence variants changing and several individual taxa displaying significant (p < 0.05) increases and decreases in relative abundance, primarily in response to elevated temperature and to a lesser extent, N. In contrast to individual taxa, community diversity was not significantly altered by individual treatments during experiments but rather was inversely correlated with the intensity of Microcystis blooms (p < 0.001). While predicted metabolic function was even less impacted by environmental drivers than microbial diversity, the predicted abundance of nitrogenase (nifH), alkaline phosphatase (phoX), and urease (ure) genes significantly increased in response to N but decreased in response to increased temperature (p < 0.05). Collectively, the resilience of microbial community structure and function within colonies suggests they may support the ability of Microcystis to persist through short-term fluctuations in environmental conditions by supplying essential nutrients.
Genetic Structure of Cucumber Mosaic Virus From Natural Hosts in Nigeria Reveals High Diversity and Occurrence of Putative Novel Recombinant Strains
Authors: Apalowo Oluropo A. , Adediji Adedapo O. , Balogun Olusegun S. , Fakolujo Temitope I. , Archibong Joy M. , Izuogu Nkechi B. , Abdelgawad Mohamed A. , Ghoneim Mohammed M. , Mustapha Suleiman , Qashqari Fadi S. I. , Batiha Gaber E. , Atiri Gabriel I.
Published: February 2022

Cucumber mosaic virus (CMV, Bromoviridae: Cucummovirus), one of the most widespread plant viruses with several hosts, causes huge losses in yield quality and quantity. The occurrence of various CMV strains and high genetic diversity within the virus complicate its management. We describe the population structure of CMV in Nigeria using partial RNA1 and RNA3 gene sequences from three natural hosts: pepper (Capsicum annuum), tomato (Solanum lycopersicum), and watermelon (Citrullus lanatus). One hundred and six leaf samples were obtained from 16 locations across Nigeria, and specific primers were used to amplify the two gene fragments using PCR. Twenty-four samples tested positive for CMV using RNA1 primers, and amplicons were sequenced from 12 isolates, revealing 82.94–99.80% nucleotide and 85.42–100% amino acid sequence similarities within the population. The partial RNA3 fragment, corresponding to the complete coat protein (CP) gene, was sequenced from seven isolates, with 95.79–97.90% and 98.62–100% nucleotide and amino acid intrapopulation similarities, respectively. The isolates belonged to subgroup IB and formed distinct phylogenetic clusters in both gene sets, indicating putative novel strains. Recombination signals, supported by phylogenetic inferences, were detected within the RNA1 dataset (P ≤ 0.05) and identified a recombinant isolate within the Nigerian sequences. No recombination was detected within the CP genes. Population genetics parameters established high diversity within the Nigerian population compared to other isolates worldwide, while selection pressure estimates revealed the existence of negative selection in both gene sets. Although CMV subgroup IB strains were postulated to originate from Asia, this study reveals their prevalence across several hosts from different locations in Nigeria. To our knowledge, this is the first comprehensive description of a recombinant CMV subgroup IB isolate from West Africa, which has implications for its robust detection and overall management.
The Role of the Two-Component System PhoP/PhoQ in Intrinsic Resistance of Yersinia enterocolitica to Polymyxin
Authors: Guo Haoran , Zhao Tong , Huang Can , Chen Jingyu
Published: February 2022

Polymyxin is the “last resort” of antibiotics. The self-induced resistance to polymyxin in Gram-negative bacteria could be mediated by lipopolysaccharide (LPS) modification, which is regulated by the two-component system, PhoP/PhoQ. Yersinia enterocolitica is a common foodborne pathogen. However, PhoP/PhoQ has not been thoroughly studied in Y. enterocolitica. In this study, the functions of PhoP/PhoQ in Y. enterocolitica intrinsic resistance were investigated. The resistance of Y. enterocolitica was found to decrease with the deletion of PhoP/PhoQ. Further, PhoP/PhoQ was found to play an important role in maintaining membrane permeability, intercellular metabolism, and reducing membrane depolarization. Based on subsequent studies, the binding ability of polymyxin to Y. enterocolitica was decreased by the modification of LPS with structures, such as L-Ara4N and palmitate. Analysis of the gene transcription levels revealed that the LPS modification genes, pagP and arn operon, were downregulated with the deletion of PhoP/PhoQ in Y. enterocolitica during exposure to polymyxin. In addition, pmrA, pmrB, and eptA were downregulated in the mutants compared with the wild-type strain. Such findings demonstrate that PhoP/PhoQ contributes to the intrinsic resistance of Y. enterocolitica toward polymyxins. LPS modification with L-Ara4N or palmitate is mainly responsible for the resistance of Y. enterocolitica to polymyxins. The transcription of genes related to LPS modification and PmrA/PmrB can be both affected by PhoP/PhoQ in Y. enterocolitica. This study adds to current knowledge regarding the role of PhoP/PhoQ in intrinsic resistance of Y. enterocolitica to polymyxin.
Identification of Type VI Secretion Systems Effector Proteins That Contribute to Interbacterial Competition in Salmonella Dublin
Authors: Amaya Fernando A. , Blondel Carlos J. , Barros-Infante María F. , Rivera Dácil , Moreno-Switt Andrea I. , Santiviago Carlos A. , Pezoa David
Published: February 2022

The Type VI Secretion System (T6SS) is a multiprotein device that has emerged as an important fitness and virulence factor for many Gram-negative bacteria through the injection of effector proteins into prokaryotic or eukaryotic cells via a contractile mechanism. While some effector proteins specifically target bacterial or eukaryotic cells, others can target both types of cells (trans-kingdom effectors). In Salmonella, five T6SS gene clusters have been identified within pathogenicity islands SPI-6, SPI-19, SPI-20, SPI-21, and SPI-22, which are differentially distributed among serotypes. Salmonella enterica serotype Dublin (S. Dublin) is a cattle-adapted pathogen that harbors both T6SSSPI-6 and T6SSSPI-19. Interestingly, while both systems have been linked to virulence and host colonization in S. Dublin, an antibacterial activity has not been detected for T6SSSPI-6 in this serotype. In addition, there is limited information regarding the repertoire of effector proteins encoded within T6SSSPI-6 and T6SSSPI-19 gene clusters in S. Dublin. In the present study, we demonstrate that T6SSSPI-6 and T6SSSPI-19 of S. Dublin CT_02021853 contribute to interbacterial competition. Bioinformatic and comparative genomic analyses allowed us to identify genes encoding three candidate antibacterial effectors located within SPI-6 and two candidate effectors located within SPI-19. Each antibacterial effector gene is located upstream of a gene encoding a hypothetic immunity protein, thus conforming an effector/immunity (E/I) module. Of note, the genes encoding these effectors and immunity proteins are widely distributed in Salmonella genomes, suggesting a relevant role in interbacterial competition and virulence. Finally, we demonstrate that E/I modules SED_RS01930/SED_RS01935 (encoded in SPI-6), SED_RS06235/SED_RS06230, and SED_RS06335/SED_RS06340 (both encoded in SPI-19) contribute to interbacterial competition in S. Dublin CT_02021853.