bluuebunny/crossref_metadata_2025 huggingface dataset:
Comprehensive Analysis to Identify SPP1 as a Prognostic Biomarker in Cervical Cancer
Authors: Zhao Kaidi , Ma Zhou , Zhang Wei
Published: January 2022

Background:SPP1, secreted phosphoprotein 1, is a member of the small integrin-binding ligand N-linked glycoprotein (SIBLING) family. Previous studies have proven SPP1 overexpressed in a variety of cancers and can be identified as a prognostic factor, while no study has explored the function and carcinogenic mechanism of SPP1 in cervical cancer.

Methods: We aimed to demonstrate the relationship between SPP1 expression and pan-cancer using The Cancer Genome Atlas (TCGA) database. Next, we validated SPP1 expression of cervical cancer in the Gene Expression Omnibus (GEO) database, including GSE7803, GSE63514, and GSE9750. The receiver operating characteristic (ROC) curve was used to evaluate the feasibility of SPP1 as a differentiating factor by the area under curve (AUC) score. Cox regression and logistic regression were performed to evaluate factors associated with prognosis. The SPP1-binding protein network was built by the STRING tool. Enrichment analysis by the R package clusterProfiler was used to explore potential function of SPP1. The single-sample GSEA (ssGSEA) method from the R package GSVA and TIMER database were used to investigate the association between the immune infiltration level and SPP1 expression in cervical cancer.

Results: Pan-cancer data analysis showed that SPP1 expression was higher in most cancer types, including cervical cancer, and we got the same result in the GEO database. The ROC curve suggested that SPP1 could be a potential diagnostic biomarker (AUC = 0.877). High SPP1 expression was associated with poorer overall survival (OS) (P = 0.032). Further enrichment and immune infiltration analysis revealed that high SPP1 expression was correlated with regulating the infiltration level of neutrophil cells and some immune cell types, including macrophage and DC.

Conclusion:SPP1 expression was higher in cervical cancer tissues than in normal cervical epithelial tissues. It was significantly associated with poor prognosis and immune cell infiltration. Thus, SPP1 may become a promising prognostic biomarker for cervical cancer patients.
SERPINH1 is a Potential Prognostic Biomarker and Correlated With Immune Infiltration: A Pan-Cancer Analysis
Authors: Wang Yu , Gu Weigang , Wen Weiwei , Zhang Xiaofeng
Published: January 2022

Background: Serpin peptidase inhibitor clade H, member 1 (SERPINH1) is a gene encoding a member of the serpin superfamily of serine proteinase inhibitors. The upregulated of SERPINH1 was associated with poor prognosis in breast cancer, stomach adenocarcinoma, and esophageal carcinoma. However, the role of SERPINH1 in pan-cancer is largely unexplored.

Methods: SERPINH1 expression and the correlation with prognosis in human pan-cancer were analyzed by the Cancer Genome Atlas and the Genotype-Tissue Expression dataset. Pearson correlation analysis was applied to evaluate the role of SERPINH1 expression in tumor mutation burden (TMB), microsatellite instability (MSI), mismatch repair (MMR), DNA methyltransferase, and common immunoregulators. Spearman’s correlation test was used to analysis SERPINH1 expression in tumor immune infiltration and infiltrating immune cells via the Tumor Immune Evaluation Resource database. Furtherly, immunohistochemistry staining of SERPINH1 was acquired from the Human Protein Atlas database for validation.

Results: SERPINH1 was abnormally expressed in fourteen cancers. The high expression of SERPINH1 significantly reduced the overall survival (OS), disease-specific survival, and progression free interval in eleven cancers. Moreover, SERPINH1 expression was correlated with MMR, MSI, TMB, and DNA methylation in multiple types of cancer. Also, SERPINH1 expression showed strong association with immunoregulators and immune checkpoint markers in testicular germ cell tumors, brain lower grade glioma (LGG), pheochromocytoma and paraganglioma. In addition, SERPINH1 expression was related to immune cell infiltration in multiple cancers, particularly in breast invasive carcinoma, LGG, and liver hepatocellular carcinoma. The result of immunohistochemistry verification shown that SERPINH1 staining was higher in tumor samples than in normal tissue in colon adenocarcinoma, head and neck squamous cell carcinoma, kidney renal papillary cell carcinoma and cervical squamous cell carcinoma, which was consistent with the result of OS.

Conclusion: Overall, these results indicate that SERPINH1 may serve as an important prognostic biomarker and correlate with tumor immunity in human pan-cancer.
Selection of Cashmere Fineness Functional Genes by Translatomics
Authors: Zhang Yu , Zhang Dongyun , Xu Yanan , Qin Yuting , Gu Ming , Cai Weidong , Bai Zhixian , Zhang Xinjiang , Chen Rui , Sun Yingang , Wu Yanzhi , Wang Zeying
Published: January 2022

Cashmere fineness is an important index to evaluate cashmere quality. Liaoning Cashmere Goat (LCG) has a large cashmere production and long cashmere fiber, but its fineness is not ideal. Therefore, it is important to find genes involved in cashmere fineness that can be used in future endeavors aiming to improve this phenotype. With the continuous advancement of research, the regulation of cashmere fineness has made new developments through high-throughput sequencing and genome-wide association analysis. It has been found that translatomics can identify genes associated with phenotypic traits. Through translatomic analysis, the skin tissue of LCG sample groups differing in cashmere fineness was sequenced by Ribo-seq. With these data, we identified 529 differentially expressed genes between the sample groups among the 27197 expressed genes. From these, 343 genes were upregulated in the fine LCG group in relation to the coarse LCG group, and 186 were downregulated in the same relationship. Through GO enrichment analysis and KEGG enrichment analysis of differential genes, the biological functions and pathways of differential genes can be found. In the GO enrichment analysis, 491 genes were significantly enriched, and the functional region was mainly in the extracellular region. In the KEGG enrichment analysis, the enrichment of the human papillomavirus infection pathway was seen the most. We found that the COL6A5 gene may affect cashmere fineness.
Gene Co-Expression Network Analysis Identifies Vitamin D-Associated Gene Modules in Adult Normal Rectal Epithelium Following Supplementation
Authors: Blackmur James P. , Vaughan-Shaw Peter G. , Donnelly Kevin , Harris Bradley T. , Svinti Victoria , Ochocka-Fox Anna-Maria , Freile Paz , Walker Marion , Gurran Toby , Reid Stuart , Semple Colin A. , Din Farhat V. N. , Timofeeva Maria , Dunlop Malcolm G. , Farrington Susan M.
Published: January 2022

Colorectal cancer (CRC) is a common, multifactorial disease. While observational studies have identified an association between lower vitamin D and higher CRC risk, supplementation trials have been inconclusive and the mechanisms by which vitamin D may modulate CRC risk are not well understood. We sought to perform a weighted gene co-expression network analysis (WGCNA) to identify modules present after vitamin D supplementation (when plasma vitamin D level was sufficient) which were absent before supplementation, and then to identify influential genes in those modules. The transcriptome from normal rectal mucosa biopsies of 49 individuals free from CRC were assessed before and after 12 weeks of 3200IU/day vitamin D (Fultium-D3) supplementation using paired-end total RNAseq. While the effects on expression patterns following vitamin D supplementation were subtle, WGCNA identified highly correlated genes forming gene modules. Four of the 17 modules identified in the post-vitamin D network were not preserved in the pre-vitamin D network, shedding new light on the biochemical impact of supplementation. These modules were enriched for GO terms related to the immune system, hormone metabolism, cell growth and RNA metabolism. Across the four treatment-associated modules, 51 hub genes were identified, with enrichment of 40 different transcription factor motifs in promoter regions of those genes, including VDR:RXR. Six of the hub genes were nominally differentially expressed in studies of vitamin D effects on adult normal mucosa organoids: LCN2, HLA-C, AIF1L, PTPRU, PDE4B and IFI6. By taking a gene-correlation network approach, we have described vitamin D induced changes to gene modules in normal human rectal epithelium in vivo, the target tissue from which CRC develops.
EasyMicroPlot: An Efficient and Convenient R Package in Microbiome Downstream Analysis and Visualization for Clinical Study
Authors: Liu Bingdong , Huang Liujing , Liu Zhihong , Pan Xiaohan , Cui Zongbing , Pan Jiyang , Xie Liwei
Published: January 2022

Advances in next-generation sequencing (NGS) have revolutionized microbial studies in many fields, especially in clinical investigation. As the second human genome, microbiota has been recognized as a new approach and perspective to understand the biological and pathologic basis of various diseases. However, massive amounts of sequencing data remain a huge challenge to researchers, especially those who are unfamiliar with microbial data analysis. The mathematic algorithm and approaches introduced from another scientific field will bring a bewildering array of computational tools and acquire higher quality of script experience. Moreover, a large cohort research together with extensive meta-data including age, body mass index (BMI), gender, medical results, and others related to subjects also aggravate this situation. Thus, it is necessary to develop an efficient and convenient software for clinical microbiome data analysis. EasyMicroPlot (EMP) package aims to provide an easy-to-use microbial analysis tool based on R platform that accomplishes the core tasks of metagenomic downstream analysis, specially designed by incorporation of popular microbial analysis and visualization used in clinical microbial studies. To illustrate how EMP works, 694 bio-samples from Guangdong Gut Microbiome Project (GGMP) were selected and analyzed with EMP package. Our analysis demonstrated the influence of dietary style on gut microbiota and proved EMP package's powerful ability and excellent convenience to address problems for this field.
New Approaches to Dendritic Cell-Based Therapeutic Vaccines Against HIV-1 Infection
Authors: Espinar-Buitrago Marisierra , Muñoz-Fernández Ma Angeles
Published: January 2022

Due to the success of combined antiretroviral therapy (cART) in recent years, the pathological outcome of Human Immunodeficiency Virus type 1 (HIV-1) infection has improved substantially, achieving undetectable viral loads in most cases. Nevertheless, the presence of a viral reservoir formed by latently infected cells results in patients having to maintain treatment for life. In the absence of effective eradication strategies against HIV-1, research efforts are focused on obtaining a cure. One of these approaches is the creation of therapeutic vaccines. In this sense, the most promising one up to now is based on the establishing of the immunological synapse between dendritic cells (DCs) and T lymphocytes (TL). DCs are one of the first cells of the immune system to encounter HIV-1 by acting as antigen presenting cells, bringing about the interaction between innate and adaptive immune responses mediated by TL. Furthermore, TL are the end effector, and their response capacity is essential in the adaptive elimination of cells infected by pathogens. In this review, we summarize the knowledge of the interaction between DCs with TL, as well as the characterization of the specific T-cell response against HIV-1 infection. The use of nanotechnology in the design and improvement of vaccines based on DCs has been researched and presented here with a special emphasis.
Autoimmune Cytopenias and Dysregulated Immunophenotype Act as Warning Signs of Inborn Errors of Immunity: Results From a Prospective Study
Authors: Schiavo Ebe , Martini Beatrice , Attardi Enrico , Consonni Filippo , Ciullini Mannurita Sara , Coniglio Maria Luisa , Tellini Marco , Chiocca Elena , Fotzi Ilaria , Luti Laura , D’Alba Irene , Veltroni Marinella , Favre Claudio , Gambineri Eleonora
Published: January 2022

Inborn errors of immunity (IEI) are genetic disorders characterized by a wide spectrum of clinical manifestations, ranging from increased susceptibility to infections to significant immune dysregulation. Among these, primary immune regulatory disorders (PIRDs) are mainly presenting with autoimmune manifestations, and autoimmune cytopenias (AICs) can be the first clinical sign. Significantly, AICs in patients with IEI often fail to respond to first-line therapy. In pediatric patients, autoimmune cytopenias can be red flags for IEI. However, for these cases precise indicators or parameters useful to suspect and screen for a hidden congenital immune defect are lacking. Therefore, we focused on chronic/refractory AIC patients to perform an extensive clinical evaluation and multiparametric flow cytometry analysis to select patients in whom PIRD was strongly suspected as candidates for genetic analysis. Key IEI-associated alterations causative of STAT3 GOF disease, IKAROS haploinsufficiency, activated PI3Kδ syndrome (APDS), Kabuki syndrome and autoimmune lymphoproliferative syndrome (ALPS) were identified. In this scenario, a dysregulated immunophenotype acted as a potential screening tool for an early IEI diagnosis, pivotal for appropriate clinical management and for the identification of new therapeutic targets.
Emerging Role of Cancer-Associated Fibroblasts-Derived Exosomes in Tumorigenesis
Authors: Peng Lushan , Wang Dan , Han Yingying , Huang Tao , He Xiaoyun , Wang Junpu , Ou Chunlin
Published: January 2022

Cancer-associated fibroblasts (CAFs) are the most important component of the stromal cell population in the tumor microenvironment and play an irreplaceable role in oncogenesis and cancer progression. Exosomes, a class of small extracellular vesicles, can transfer biological information (e.g., proteins, nucleic acids, and metabolites as messengers) from secreting cells to target recipient cells, thereby affecting the progression of human diseases, including cancers. Recent studies revealed that CAF-derived exosomes play a crucial part in tumorigenesis, tumor cell proliferation, metastasis, drug resistance, and the immune response. Moreover, aberrant expression of CAF-derived exosomal noncoding RNAs and proteins strongly correlates with clinical pathological characterizations of cancer patients. Gaining deeper insight into the participation of CAF-derived exosomes in tumorigenesis may lead to novel diagnostic biomarkers and therapeutic targets in human cancers.
Anti-Thymocyte Globulin Treatment Augments 1,25-Dihydroxyvitamin D3 Serum Levels in Patients Undergoing Hematopoietic Stem Cell Transplantation
Authors: Matos Carina , Peter Katrin , Weich Laura , Peuker Alice , Schoenhammer Gabriele , Roider Tobias , Ghimire Sakhila , Babl Nathalie , Decking Sonja , Güllstorf Martina , Kröger Nicolaus , Hammon Kathrin , Herr Wolfgang , Stark Klaus , Heid Iris M. , Renner Kathrin , Holler Ernst , Kreutz Marina
Published: January 2022

Application of anti-thymocyte globulin (ATG) is a widely used strategy for the prevention of graft-versus-host disease (GvHD). As vitamin D3 serum levels are also discussed to affect hematopoietic stem cell transplantation (HSCT) outcome and GvHD development, we analysed a possible interplay between ATG treatment and serum levels of 25-hydroxyvitamin D3 and 1,25-dihydroxyvitamin D3 in 4 HSCT cohorts with different vitamin D3 supplementation. ATG is significantly associated with higher serum level of 1,25-dihydroxyvitamin D3 around HSCT (day -2 to 7, peri-transplant), however only in patients with adequate levels of its precursor 25-hydroxyvitamin D3. ATG exposure had no impact on overall survival in patients supplemented with high dose vitamin D3, but was associated with higher risk of one-year treatment-related mortality (log rank test p=0.041) in patients with no/low vitamin D3 supplementation. However, the difference failed to reach significance applying a Cox-model regression without and with adjustment for baseline risk factors (unadjusted P=0,058, adjusted p=0,139). To shed some light on underlying mechanisms, we investigated the impact of ATG on 1,25-Dihydroxyvitamin D3 production by human dendritic cells (DCs) in vitro. ATG increased gene expression of CYP27B1, the enzyme responsible for the conversion of 25-hydroxyvitamin D3 into 1,25-dihydroxyvitamin D3, which was accompanied by higher 1,25-dihydroxyvitamin D3 levels in ATG-treated DC culture supernatants. Our data demonstrate a cooperative effect of 25-hydroxyvitamin D3 and ATG in the regulation of 1,25-dihydroxyvitamin D3 production. This finding may be of importance in the context of HSCT, where early high levels of 1,25-dihydroxyvitamin D3 levels have been shown to be predictive for lower transplant related mortality and suggest that vitamin D3 supplementation may especially be important in patients receiving ATG for GvHD prophylaxis.
Immunoprofiling Reveals Novel Mast Cell Receptors and the Continuous Nature of Human Lung Mast Cell Heterogeneity
Authors: Rönnberg Elin , Boey Daryl Zhong Hao , Ravindran Avinash , Säfholm Jesper , Orre Ann-Charlotte , Al-Ameri Mamdoh , Adner Mikael , Dahlén Sven-Erik , Dahlin Joakim S. , Nilsson Gunnar
Published: January 2022

Background

Immunohistochemical analysis of granule-associated proteases has revealed that human lung mast cells constitute a heterogeneous population of cells, with distinct subpopulations identified. However, a systematic and comprehensive analysis of cell-surface markers to study human lung mast cell heterogeneity has yet to be performed.

Methods

Human lung mast cells were obtained from lung lobectomies, and the expression of 332 cell-surface markers was analyzed using flow cytometry and the LEGENDScreen™ kit. Markers that exhibited high variance were selected for additional analyses to reveal whether they were correlated and whether discrete mast cell subpopulations were discernable.

Results

We identified the expression of 102 surface markers on human lung mast cells, 23 previously not described on mast cells, of which several showed high continuous variation in their expression. Six of these markers were correlated: SUSD2, CD49a, CD326, CD34, CD66 and HLA-DR. The expression of these markers was also correlated with the size and granularity of mast cells. However, no marker produced an expression profile consistent with a bi- or multimodal distribution.

Conclusions

LEGENDScreen analysis identified more than 100 cell-surface markers on mast cells, including 23 that, to the best of our knowledge, have not been previously described on human mast cells. The comprehensive expression profiling of the 332 surface markers did not identify distinct mast cell subpopulations. Instead, we demonstrate the continuous nature of human lung mast cell heterogeneity.
A Deep Learning Approach to Design and Discover Sustainable Cementitious Binders: Strategies to Learn From Small Databases and Develop Closed-form Analytical Models
Authors: Han Taihao , Ponduru Sai Akshay , Cook Rachel , Huang Jie , Sant Gaurav , Kumar Aditya
Published: January 2022

To reduce the energy-intensity and carbon footprint of Portland cement (PC), the prevailing practice embraced by concrete technologists is to partially replace the PC in concrete with supplementary cementitious materials [SCMs: geological materials (e.g., limestone); industrial by-products (e.g., fly ash); and processed materials (e.g., calcined clay)]. Chemistry and content of the SCM profoundly affect PC hydration kinetics; which, in turn, dictates the evolutions of microstructure and properties of the [PC + SCM] binder. Owing to the substantial diversity in SCMs’ compositions–plus the massive combinatorial spaces, and the highly nonlinear and mutually-interacting processes that arise from SCM-PC interactions–state-of-the-art computational models are unable to produce a priori predictions of hydration kinetics or properties of [PC + SCM] binders. In the past 2 decades, the combination of Big data and machine learning (ML)—commonly referred to as the fourth paradigm of science–has emerged as a promising approach to learn composition-property correlations in materials (e.g., concrete), and capitalize on such learnings to produce a priori predictions of properties of materials with new compositions. Notwithstanding these merits, widespread use of ML models is hindered because they: 1) Require Big data to learn composition-property correlations, and, in general, large databases for concrete are not publicly available; and 2) Function as black-boxes, thus providing little-to-no insights into the materials laws like theory-based analytical models do. This study presents a deep learning (DL) model capable of producing a priori, high-fidelity predictions of composition- and time-dependent hydration kinetics and phase assemblage development in [PC + SCM] pastes. The DL is coupled with: 1) A fast Fourier transformation algorithm that reduces the dimensionality of training datasets (e.g., kinetic datasets), thus allowing the model to learn intrinsic composition-property correlations from a small database; and 2) A thermodynamic model that constrains the model, thus ensuring that predictions do not violate fundamental materials laws. The training and outcomes of the DL are ultimately leveraged to develop a simple, easy-to-use, closed-form analytical model capable of predicting hydration kinetics and phase assemblage development in [PC + SCM] pastes, using their initial composition and mixture design as inputs.
Non-invasive Respiratory Support in COVID-19: A Narrative Review
Authors: Luján Manel , Sayas Javier , Mediano Olga , Egea Carlos
Published: January 2022

Acute respiratory failure secondary to COVID-19 pneumonia may require a variety of non-pharmacological strategies in addition to oxygen therapy to avoid endotracheal intubation. The response to all these strategies, which include high nasal flow, continuous positive pressure, non-invasive ventilation, or even prone positioning in awake patients, can be highly variable depending on the predominant phenotypic involvement. Deciding when to replace conventional oxygen therapy with non-invasive respiratory support, which to choose, the role of combined methods, definitions, and attitudes toward treatment failure, and improved case improvement procedures are directly relevant clinical questions for the daily care of critically ill COVID-19 patients. The experience accumulated after more than a year of the pandemic should lead to developing recommendations that give answers to all these questions.
The Association of an Alpha-2 Adrenergic Receptor Agonist and Mortality in Patients With COVID-19
Authors: Hamilton John L. , Vashi Mona , Kishen Ekta B. , Fogg Louis F. , Wimmer Markus A. , Balk Robert A.
Published: January 2022

There is a need for treatments to reduce coronavirus disease 2019 (COVID-19) mortality. Alpha-2 adrenergic receptor (α2 AR) agonists can dampen immune cell and inflammatory responses as well as improve oxygenation through physiologic respiratory parameters. Therefore, α2 AR agonists may be effective in reducing mortality related to hyperinflammation and acute respiratory failure in COVID-19. Dexmedetomidine (DEX) is an α2 AR agonist used for sedation. We performed a retrospective analysis of adults at Rush University System for Health hospitals between March 1, 2020 and July 30, 2020 with COVID-19 requiring invasive mechanical ventilation and sedation (n = 214). We evaluated the association of DEX use and 28-day mortality from time of intubation. Overall, 28-day mortality in the cohort receiving DEX was 27.0% as compared to 64.5% in the cohort that did not receive DEX (relative risk reduction 58.2%; 95% CI 42.4–69.6). Use of DEX was associated with reduced 28-day mortality on multivariable Cox regression analysis (aHR 0.19; 95% CI 0.10–0.33; p < 0.001). Adjusting for time-varying exposure to DEX also demonstrated that DEX was associated with reduced 28-day mortality (aHR 0.51; 95% CI 0.28–0.95; p = 0.03). Earlier DEX use, initiated <3.4 days from intubation, was associated with reduced 28-day mortality (aHR 0.25; 95% CI 0.13–0.50; p < 0.001) while later DEX use was not (aHR 0.64; 95% CI 0.27–1.50; p = 0.30). These results suggest an α2 AR agonist might reduce mortality in patients with COVID-19. Randomized controlled trials are needed to confirm this observation.
Identification and Validation of Novel Serum Autoantibodies Biomarkers for Staging Liver Fibrosis in Patients With Chronic Hepatitis B
Authors: Qi Saiping , Li Jing , He Xiaomin , Zhou Jialing , Chen Zhibin , Li Xiaojin , Zhang Bei , Ma Hong , You Hong , Huang Jian
Published: January 2022

Aim: Liver fibrosis monitoring is essential in patients with chronic hepatitis B (CHB). However, less robust, noninvasive diagnostic methods for staging liver fibrosis, other than liver biopsy, are available. Our previous study demonstrated a panel of cellular proteins recognized by autoantibodies that may have potential value in discrimination of CHB and liver cirrhosis. We aim to assess the diagnostic value of these serum autoantibodies for staging liver fibrosis.

Methods: Candidate autoantigens were screened and assessed by microarray analysis in 96 healthy controls and 227 CHB patients with pre-treatment biopsy-proven METAVIR fibrosis score, comprising 69, 115, and 43 cases with S0-1, S2-3, and S4 stages, respectively. Autoantibodies with potential diagnostic value for staging liver fibrosis were verified by enzyme-linked immunosorbent assays (ELISA). Receiver operating characteristic curve was conducted to evaluate autoantibody performance.

Results: Microarray analysis identified autoantigens CENPF, ACY1, HSPA6, and ENO1 with potential diagnostic value for liver fibrosis staging, among which CENPF and ACY1 were validated using ELISA. CENPF and ACY1 autoantibodies had area under the curve values of 0.746 and 0.685, 58.14 and 74.42% sensitivity, and 88.41 and 60.87% specificity, respectively, for discriminating liver fibrosis stages S4 and S0-1. The prevalence of CENPF and ACY1 autoantibodies was not correlated with age, sex or level of inflammation.

Conclusions: Autoimmune responses may be elicited during progression of liver fibrosis, and serum autoantibodies may be a valuable biomarker for staging liver fibrosis deserving of further study.
Formation, Development, and Cross-Species Interactions in Biofilms
Authors: Luo Aihua , Wang Fang , Sun Degang , Liu Xueyu , Xin Bingchang
Published: January 2022

Biofilms, which are essential vectors of bacterial survival, protect microbes from antibiotics and host immune attack and are one of the leading causes that maintain drug-resistant chronic infections. In nature, compared with monomicrobial biofilms, polymicrobial biofilms composed of multispecies bacteria predominate, which means that it is significant to explore the interactions between microorganisms from different kingdoms, species, and strains. Cross-microbial interactions exist during biofilm development, either synergistically or antagonistically. Although research into cross-species biofilms remains at an early stage, in this review, the important mechanisms that are involved in biofilm formation are delineated. Then, recent studies that investigated cross-species cooperation or synergy, competition or antagonism in biofilms, and various components that mediate those interactions will be elaborated. To determine approaches that minimize the harmful effects of biofilms, it is important to understand the interactions between microbial species. The knowledge gained from these investigations has the potential to guide studies into microbial sociality in natural settings and to help in the design of new medicines and therapies to treat bacterial infections.
In vitro Models of the Small Intestine for Studying Intestinal Diseases
Authors: Jung Sang-Myung , Kim Seonghun
Published: January 2022

The small intestine is a digestive organ that has a complex and dynamic ecosystem, which is vulnerable to the risk of pathogen infections and disorders or imbalances. Many studies have focused attention on intestinal mechanisms, such as host–microbiome interactions and pathways, which are associated with its healthy and diseased conditions. This review highlights the intestine models currently used for simulating such normal and diseased states. We introduce the typical models used to simulate the intestine along with its cell composition, structure, cellular functions, and external environment and review the current state of the art for in vitro cell-based models of the small intestine system to replace animal models, including ex vivo, 2D culture, organoid, lab-on-a-chip, and 3D culture models. These models are described in terms of their structure, composition, and co-culture availability with microbiomes. Furthermore, we discuss the potential application for the aforementioned techniques to these in vitro models. The review concludes with a summary of intestine models from the viewpoint of current techniques as well as their main features, highlighting potential future developments and applications.
Bacteroides Microbial Source Tracking Markers Perform Poorly in Predicting Enterobacteriaceae and Enteric Pathogen Contamination of Cow Milk Products and Milk-Containing Infant Food
Authors: Tsai Kevin , Hoffmann Vivian , Simiyu Sheillah , Cumming Oliver , Borsay Glorie , Baker Kelly K.
Published: January 2022

Consumption of microbiologically contaminated food is one of the leading causes of diarrheal diseases. Understanding the source of enteric pathogens in food is important to guide effective interventions. Enterobacteriaceae bacterial assays typically used to assess food safety do not shed light on the source. Source-specific Bacteroides microbial source tracking (MST) markers have been proposed as alternative indicators for water fecal contamination assessment but have not been evaluated as an alternative fecal indicator in animal-derived foods. This study tested various milk products collected from vendors in urban Kenyan communities and infant foods made with the milk (n = 394 pairs) using conventional culture methods and TaqMan qPCR for enteric pathogens and human and bovine-sourced MST markers. Detection profiles of various enteric pathogens and Bacteroides MST markers in milk products differed from that of milk-containing infant foods. MST markers were more frequently detected in infant food prepared by caregivers, indicating recent contamination events were more likely to occur during food preparation at home. However, Bacteroides MST markers had lower sensitivity in detecting enteric pathogens in food than traditional Enterobacteriaceae indicators. Bacteroides MST markers tested in this study were not associated with the detection of culturable Salmonella enterica and Shigella sonnei in milk products or milk-containing infant food. The findings show that while Bacteroides MST markers could provide valuable information about how foods become contaminated, they may not be suitable for predicting the origin of the enteric pathogen contamination sources.
Development and Validation of a Novel Microbiome-Based Biomarker of Post-antibiotic Dysbiosis and Subsequent Restoration
Authors: Blount Ken , Jones Courtney , Walsh Dana , Gonzalez Carlos , Shannon William D.
Published: January 2022

Background: The human gut microbiota are important to health and wellness, and disrupted microbiota homeostasis, or “dysbiosis,” can cause or contribute to many gastrointestinal disease states. Dysbiosis can be caused by many factors, most notably antibiotic treatment. To correct dysbiosis and restore healthier microbiota, several investigational microbiota-based live biotherapeutic products (LBPs) are in formal clinical development. To better guide and refine LBP development and to better understand and manage the risks of antibiotic administration, biomarkers that distinguish post-antibiotic dysbiosis from healthy microbiota are needed. Here we report the development of a prototype Microbiome Health Index for post-Antibiotic dysbiosis (MHI-A).

Methods: MHI-A was developed and validated using longitudinal gut microbiome data from participants in clinical trials of RBX2660 and RBX7455 – investigational LBPs in development for reducing recurrent Clostridioides difficile infections (rCDI). The MHI-A algorithm relates the relative abundances of microbiome taxonomic classes that changed the most after RBX2660 or RBX7455 treatment, that strongly correlated with clinical response, and that reflect biological mechanisms believed important to rCDI. The diagnostic utility of MHI-A was reinforced using publicly available microbiome data from healthy or antibiotic-treated populations.

Results: MHI-A has high accuracy to distinguish post-antibiotic dysbiosis from healthy microbiota. MHI-A values were consistent across multiple healthy populations and were significantly shifted by antibiotic treatments known to alter microbiota compositions, shifted less by microbiota-sparing antibiotics. Clinical response to RBX2660 and RBX7455 correlated with a shift of MHI-A from dysbiotic to healthy values.

Conclusion: MHI-A is a promising biomarker of post-antibiotic dysbiosis and subsequent restoration. MHI-A may be useful for rank-ordering the microbiota-disrupting effects of antibiotics and as a pharmacodynamic measure of microbiota restoration.
Whole-Genome Sequencing of Extended-Spectrum Beta-Lactamase-Producing Escherichia coli From Human Infections in Finland Revealed Isolates Belonging to Internationally Successful ST131-C1-M27 Subclade but Distinct From Non-human Sources
Authors: Kurittu Paula , Khakipoor Banafsheh , Jalava Jari , Karhukorpi Jari , Heikinheimo Annamari
Published: January 2022

Antimicrobial resistance (AMR) is a growing concern in public health, particularly for the clinically relevant extended-spectrum beta-lactamase (ESBL) and AmpC-producing Enterobacteriaceae. Studies describing ESBL-producing Escherichia coli clinical samples from Finland to the genomic level and investigation of possible zoonotic transmission routes are scarce. This study characterizes ESBL-producing E. coli from clinical samples in Finland using whole genome sequencing (WGS). Comparison is made between animal, food, and environmental sources in Finland to gain insight into potential zoonotic transmission routes and to recognize successful AMR genes, bacterial sequence types (STs), and plasmids. ESBL-producing E. coli isolates (n = 30) obtained from the Eastern Finland healthcare district between 2018 and 2020 underwent WGS and were compared to sequences from non-human and healthy human sources (n = 67) isolated in Finland between 2012 and 2018. A majority of the clinical isolates belonged to ST131 (n = 21; 70%), of which 19 represented O25:H4 and fimH30 allele, and 2 O16:H5 and fimH41 allele. Multidrug resistance was common, and the most common bla gene identified was blaCTX–M–27 (n = 14; 47%) followed by blaCTX–M–15 (n = 10; 33%). blaCTX–M–27 was identified in 13 out of 21 isolates representing ST131, with 12 isolates belonging to a recently discovered international E. coli ST131 C1-M27 subclade. Isolates were found to be genetically distinct from non-human sources with core genome multilocus sequence typing based analysis. Most isolates (n = 26; 87%) possessed multiple replicons, with IncF family plasmids appearing in 27 (90%) and IncI1 in 5 (17%) isolates. IncF[F1:A2:B20] replicon was identified in 11, and IncF[F-:A2:B20] in 4 isolates. The results indicate the ST131-C1-M27 clade gaining prevalence in Europe and provide further evidence of the concerning spread of this globally successful pathogenic clonal group. This study is the first to describe ESBL-producing E. coli in human infections with WGS in Finland and provides important information on global level of the spread of ESBL-producing E. coli belonging to the C1-M27 subclade. The results will help guide public health actions and guide future research.
Epichloë Fungal Endophytes Influence Seed-Associated Bacterial Communities
Authors: Bastías Daniel A. , Bustos Ludmila Bubica , Jáuregui Ruy , Barrera Andrea , Acuña-Rodríguez Ian S. , Molina-Montenegro Marco A. , Gundel Pedro E.
Published: January 2022

Seeds commonly harbour diverse bacterial communities that can enhance the fitness of future plants. The bacterial microbiota associated with mother plant’s foliar tissues is one of the main sources of bacteria for seeds. Therefore, any ecological factor influencing the mother plant’s microbiota may also affect the diversity of the seed’s bacterial community. Grasses form associations with beneficial vertically transmitted fungal endophytes of genusEpichloë. The interaction of plants withEpichloëendophytes and insect herbivores can influence the plant foliar microbiota. However, it is unknown whether these interactions (alone or in concert) can affect the assembly of bacterial communities in the produced seed. We subjectedLolium multiflorumplants with and without its common endophyteEpichloë occultans(E+, E-, respectively) to an herbivory treatment withRhopalosiphum padiaphids and assessed the diversity and composition of the bacterial communities in the produced seed. The presence ofEpichloëendophytes influenced the seed bacterial microbiota by increasing the diversity and affecting the composition of the communities. The relative abundances of the bacterial taxa were more similarly distributed in communities associated with E+ than E- seeds with the latter being dominated by just a few bacterial groups. Contrary to our expectations, seed bacterial communities were not affected by the aphid herbivory experienced by mother plants. We speculate that the enhanced seed/seedling performance documented forEpichloë-host associations may be explained, at least in part, by theEpichloë-mediated increment in the seed-bacterial diversity, and that this phenomenon may be applicable to other plant-endophyte associations.
Exosome-Transmitted miR-128 Targets CCL18 to Inhibit the Proliferation and Metastasis of Urothelial Carcinoma
Authors: Shang Donghao , Liu Yuting , Chen Zhenghao
Published: January 2022

Objective:To investigate the regulatory function of exosome-transmittedmiR-128and chemokine (C-C motif) ligand 18 (CCL18) on urothelial carcinomas (UCs).

Methods:Tumor tissues, paracancerous tissues, and serum were collected from 20 patients with UCs (diagnosed at Beijing Friendship Hospital, Capital Medical University). CCL18 was detected by immunohistochemistry and ELISA. PCR was used to measure the expression levels of CCL18 andmir-183,miR-128,mir-33ain UCs. We acquired exosomes from mesenchymal stem cells and synthesized exosomes overexpressingmiR-128(HMSC-128-EV). The effects ofmiR-128on the migration and invasion abilities, apoptosis and epithelial-mesenchymal transition of BUC T24 cells were investigated by co-culturing HMSC-128-EV. The therapeutic potential ofmiR-128on disease models was explored by injecting HMSC-128-EV into nude mice.

Results:The expression of CCL18 in UCs was significantly higher than that in normal tissues (p< 0.05), and the serum level of CCL18 in patients with UC was significantly increased compared with those in healthy controls (p< 0.05). CCL18 overexpression or downregulation enhanced or suppressed the proliferation, migration and invasion of BUC T24 cells, resectively (p< 0.05). The exosome-transmitted miR-128 can inhibit cell proliferation (p< 0.05), invasion (p< 0.05), and migration (p< 0.05) in UCs, and these effects can be reversed by CCL18. In terms of apoptosis,miR-128was able to promote the occurrence of BUC T24 apoptosis (p< 0.05), which can also be reversed by CCL18. In addition,miR-128can inhibit the proliferation (p< 0.05) and metastasis (p< 0.05) of UCs in nude mice.

Conclusion:ThemiR-128inhibits the proliferation, invasion, migration of UCs, and promotes its apoptosis by regulating CCL18 secretion.
Secoisolariciresinol Diglucoside Improves Ovarian Reserve in Aging Mouse by Inhibiting Oxidative Stress
Authors: He XueLai , Wang Yong , Wu MeiQi , Wei JiangChun , Sun XianDuo , Wang AnHua , Hu GaoSheng , Jia JingMing
Published: January 2022

Ovarian reserve is a key factor in the reproductive function of the ovaries. Ovarian aging is characterized by a gradual decline in the quantity and quality of follicles. The underlying mechanism of ovarian aging is complex and age-related oxidative stress is considered one of the most likely factors. Secoisolariciresinol diglucoside (SDG) has been shown to have good scavenging ability against reactive oxygen species (ROS) which slowly accumulates in ovarian tissues. However, it is unknown whether SDG had beneficial effects on aging ovaries. In this study, we used 37-week-old female C57BL/6J mouse as a natural reproductive aging model to evaluate the role of SDG in ovarian aging. SDG (7 and 70 mg/kg) intragastric administration was performed in the mice daily. After 8 weeks, the effects of SDG on aging ovaries were evaluated by counting the number of follicles and the expression of follicle-stimulating hormone receptors (FSHR) in the ovary. The mechanism of SDG on the aging ovaries was further explored through ovarian metabolomics. It was found that SDG can effectively increase the number of growing follicles and increase the expression of the FSHR protein. The metabolomics results showed that the ovaries in the SDG intervention group achieved better uptake and transport of nutrients, including amino acids and glucose that are necessary for the development of oocytes. At the same time, the ovaries of the SDG intervention group showed that the drug reduced ROS generation. Additionally, we found that ovarian telomere length and ovarian mitochondrial DNA copy number that are highly susceptible to ROS damage and are also related to aging. The results showed that SDG can significantly increase mitochondrial DNA copy number and slow down the process of telomere shortening. These data indicate that SDG improves ovarian reserve by inhibiting oxidative stress.
Rehabilitation Care at the Time of Coronavirus Disease-19 (COVID-19) Pandemic: A Scoping Review of Health System Recommendations
Authors: Negm Ahmed M. , Salopek Adrian , Zaide Mashal , Meng Victoria J. , Prada Carlos , Chang Yaping , Zanwar Preeti , Santos Flavia H. , Philippou Elena , Rosario Emily R. , Faieta Julie , Falvey Jason R. , Kumar Amit , Reistetter Timothy A. , Dal Bello-Haas Vanina , Bean Jonathan F. , Bhandari Mohit , Heyn Patricia C.
Published: January 2022

Purpose: The coronavirus disease-19 (COVID-19) was declared a pandemic by the World Health Organization in March 2020. COVID-19, caused by SARS-CoV-2 has imposed a significant burden on health care systems, economies, and social systems in many countries around the world. The provision of rehabilitation services for persons with active COVID-19 infection poses challenges to maintaining a safe environment for patients and treating providers.

Materials and Methods: Established frameworks were used to guide the scoping review methodology. Medline, Embase, Pubmed, CINAHL databases from inception to August 1, 2020, and prominent rehabilitation organizations’ websites were searched.

Study Selection: We included articles and reports if they were focused on rehabilitation related recommendations for COVID-19 patients, treating providers, or the general population.

Data Extraction: Pairs of team members used a pre-tested data abstraction form to extract data from included full-text articles. The strength and the quality of the extracted recommendations were evaluated by two reviewers using the Grading of Recommendations, Assessment, Development and Evaluation (GRADE) approach.

Results: We retrieved 6,468 citations, of which 2,086 were eligible for review, after duplicates were removed. We excluded 1,980 citations based on title and abstract screening. Of the screened full-text articles, we included all 106 studies. A summary of recommendations is presented. We assessed the overall evidence to be strong and of fair quality.

Conclusion: The rehabilitation setting, and processes, logistics, and patient and healthcare provider precaution recommendations identified aim to reduce the spread of SARS-CoV-2 infection and ensure adequate and safe rehabilitation services, whether face-to-face or through teleservices. The COVID-19 pandemic is rapidly changing. Further updates will be needed over time in order to incorporate emerging best evidence into rehabilitation guidelines.
Sonic Hedgehog Pathway Modulation Normalizes Expression of Olig2 in Rostrally Patterned NPCs With Trisomy 21
Authors: Klein Jenny A. , Li Zhen , Rampam Sanjeev , Cardini Jack , Ayoub Amara , Shaw Patricia , Rachubinski Angela L. , Espinosa Joaquin M. , Zeldich Ella , Haydar Tarik F.
Published: January 2022

The intellectual disability found in people with Down syndrome is associated with numerous changes in early brain development, including the proliferation and differentiation of neural progenitor cells (NPCs) and the formation and maintenance of myelin in the brain. To study how early neural precursors are affected by trisomy 21, we differentiated two isogenic lines of induced pluripotent stem cells derived from people with Down syndrome into brain-like and spinal cord-like NPCs and promoted a transition towards oligodendroglial fate by activating the Sonic hedgehog (SHH) pathway. In the spinal cord-like trisomic cells, we found no difference in expression of OLIG2 or NKX2.2, two transcription factors essential for commitment to the oligodendrocyte lineage. However, in the brain-like trisomic NPCs, OLIG2 is significantly upregulated and is associated with reduced expression of NKX2.2. We found that this gene dysregulation and block in NPC transition can be normalized by increasing the concentration of a SHH pathway agonist (SAG) during differentiation. These results underscore the importance of regional and cell type differences in gene expression in Down syndrome and demonstrate that modulation of SHH signaling in trisomic cells can rescue an early perturbed step in neural lineage specification.
Associations Among Diffusion Tensor Image Along the Perivascular Space (DTI-ALPS), Enlarged Perivascular Space (ePVS), and Cognitive Functions in Asymptomatic Patients With Carotid Plaque
Authors: Liu Hui , Yang Shuai , He Wei , Liu Xiaojuan , Sun Shanyi , Wang Song , Wang Yang , Zhou Xiaoliang , Tang Tao , Xia Jian , Liu Yunhai , Huang Qing
Published: January 2022

Background and Aim: Carotid atherosclerosis (CAS) is a common pathogenesis of cerebrovascular disease closely related to stroke and silent cerebrovascular disease (SCD), while the insufficient brain perfusion mechanism cannot quite explain the mechanism. The purpose of this study was to utilize diffusion tensor image analysis along the perivascular space (DTI-ALPS) to evaluate the glymphatic system activity and correlated DTI-ALPS with enlarged perivascular spaces (ePVS), carotid intima-media thickening (CIMT), mini-mental state examination (MMSE), and serological indicator in individuals with carotid plaque.

Methods: Routine MRI and diffusion tensor images scan of the brain, carotid ultrasound, and blood examination were conducted on 74 individuals (52 carotid plaque subjects, 22 non-carotid plaque subjects), whose demographic and clinical characteristics were also recorded. DTI-ALPS index between patients with carotid plaque and normal controls were acquired and the correlations with other variables were analyzed.

Results: The values of ALPS-index in the carotid plaque group was significantly lower compared to normal controls (2.12 ± 0.39, 1.95 ± 0.28, respectively, p = 0.034). The ALPS-index was negatively correlated with the basal ganglia (BG)-ePVS score (r = −0.242, p = 0.038) while there was no significant difference in the centrum semiovale (CSO)-ePVS score. Further analysis showed that there are more high-grade ePVS in the BG compared to the carotid plaque group than in the non-carotid plaque group (84.6% vs. 40.9%, p = 0.001).

Conclusions: ALPS-index reflects the glymphatic system of the brain, which is associated with early high-risk cerebrovascular diseases. There may be damage in the function of the glymphatic system which induces the expansion of the perivascular space (PVS) in the BG in individuals with carotid plaque.