scholarly journals Three types of HLA-G+ extravillous trophoblasts that have distinct immune regulatory properties

2020 ◽  
Vol 117 (27) ◽  
pp. 15772-15777 ◽  
Author(s):  
Henrieta Papuchova ◽  
Sarika Kshirsagar ◽  
Lily Xu ◽  
Hannah A. Bougleux Gomes ◽  
Qin Li ◽  
...  
Keyword(s):  
Pregnancy Complications ◽  
Inflammatory Responses ◽  
Expression Profiles ◽  
Gene Expression Profiles ◽  
First Trimester ◽  
Term Pregnancy ◽  
Placental Development ◽  
Underlying Mechanisms ◽  
And Function ◽  
Extravillous Trophoblasts

During pregnancy, invading HLA-G+ extravillous trophoblasts (EVT) play a key role in placental development, uterine spiral artery remodeling, and prevention of detrimental maternal immune responses to placental and fetal antigens. Failures of these processes are suggested to play a role in the development of pregnancy complications, but very little is known about the underlying mechanisms. Here we present validated methods to purify and culture primary HLA-G+ EVT from the placental disk and chorionic membrane from healthy term pregnancy. Characterization of HLA-G+ EVT from term pregnancy compared to first trimester revealed their unique phenotypes, gene expression profiles, and differing capacities to increase regulatory T cells (Treg) during coculture assays, features that cannot be captured by using surrogate cell lines or animal models. Furthermore, clinical variables including gestational age and fetal sex significantly influenced EVT biology and function. These methods and approaches form a solid basis for further investigation of the role of HLA-G+ EVT in the development of detrimental placental inflammatory responses associated with pregnancy complications, including spontaneous preterm delivery and preeclampsia.

scholarly journals Chamber-enriched gene expression profiles in failing human hearts with reduced ejection fraction

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Xin Luo ◽  
Jun Yin ◽  
Denise Dwyer ◽  
Tracy Yamawaki ◽  
Hong Zhou ◽  
...  
Keyword(s):  
Heart Failure ◽  
Ejection Fraction ◽  
Human Genetics ◽  
Expression Profiles ◽  
Gene Expression Profiles ◽  
Left Heart ◽  
Reduced Ejection Fraction ◽  
Cell Type Composition ◽  
Type Composition ◽  
Underlying Mechanisms

AbstractHeart failure with reduced ejection fraction (HFrEF) constitutes 50% of HF hospitalizations and is characterized by high rates of mortality. To explore the underlying mechanisms of HFrEF etiology and progression, we studied the molecular and cellular differences in four chambers of non-failing (NF, n = 10) and HFrEF (n = 12) human hearts. We identified 333 genes enriched within NF heart subregions and often associated with cardiovascular disease GWAS variants. Expression analysis of HFrEF tissues revealed extensive disease-associated transcriptional and signaling alterations in left atrium (LA) and left ventricle (LV). Common left heart HFrEF pathologies included mitochondrial dysfunction, cardiac hypertrophy and fibrosis. Oxidative stress and cardiac necrosis pathways were prominent within LV, whereas TGF-beta signaling was evident within LA. Cell type composition was estimated by deconvolution and revealed that HFrEF samples had smaller percentage of cardiomyocytes within the left heart, higher representation of fibroblasts within LA and perivascular cells within the left heart relative to NF samples. We identified essential modules associated with HFrEF pathology and linked transcriptome discoveries with human genetics findings. This study contributes to a growing body of knowledge describing chamber-specific transcriptomics and revealed genes and pathways that are associated with heart failure pathophysiology, which may aid in therapeutic target discovery.

scholarly journals FLAMs: A self-replicating ex vivo model of alveolar macrophages for functional genetic studies

2021 ◽  
Author(s):  
Sean Thomas ◽  
Kathryn Wierenga ◽  
James Pestka ◽  
Andrew Olive
Keyword(s):  
Alveolar Macrophages ◽  
Ex Vivo ◽  
Fetal Liver ◽  
Expression Profiles ◽  
Surface Expression ◽  
Specific Gene ◽  
Ex Vivo Model ◽  
A Genome ◽  
Underlying Mechanisms ◽  
And Function

Alveolar macrophages (AMs) are tissue resident cells in the lungs derived from the fetal liver that maintain lung homeostasis and respond to inhaled stimuli. While the importance of AMs is undisputed, they remain refractory to standard experimental approaches and high-throughput functional genetics as they are challenging to isolate and rapidly lose AM properties in standard culture. This limitation hinders our understanding of key regulatory mechanisms that control AM maintenance and function. Here, we describe the development of a new model, fetal liver-derived alveolar-like macrophages (FLAMs), which maintains cellular morphologies, expression profiles, and functional mechanisms similar to murine AMs. FLAMs combine treatment with two key cytokines for AM maintenance, GM-CSF and TGFβ. We leveraged the long-term stability of FLAMs to develop functional genetic tools using CRISPR-Cas9-mediated gene editing. Targeted editing confirmed the role of AM-specific gene Marco and the IL-1 receptor Il1r1 in modulating the AM response to crystalline silica. Furthermore, a genome-wide knockout library using FLAMs identified novel genes required for surface expression of the AM marker Siglec-F, most notably those related to the peroxisome. Taken together, our results suggest that FLAMs are a stable, self-replicating model of AM function that enables previously impossible global genetic approaches to define the underlying mechanisms of AM maintenance and function.

High-throughput single-cell RNA-seq data imputation and characterization with surrogate-assisted automated deep learning

2021 ◽  
Author(s):  
Xiangtao Li ◽  
Shaochuan Li ◽  
Lei Huang ◽  
Shixiong Zhang ◽  
Ka-chun Wong
Keyword(s):  
Gene Expression ◽  
Neural Networks ◽  
Single Cell ◽  
Deep Neural Networks ◽  
Expression Profiles ◽  
Marker Gene ◽  
Gene Expression Profiles ◽  
Underlying Mechanisms ◽  
Cell Data ◽  
Gene Expression Levels

Abstract Single-cell RNA sequencing (scRNA-seq) technologies have been heavily developed to probe gene expression profiles at single-cell resolution. Deep imputation methods have been proposed to address the related computational challenges (e.g. the gene sparsity in single-cell data). In particular, the neural architectures of those deep imputation models have been proven to be critical for performance. However, deep imputation architectures are difficult to design and tune for those without rich knowledge of deep neural networks and scRNA-seq. Therefore, Surrogate-assisted Evolutionary Deep Imputation Model (SEDIM) is proposed to automatically design the architectures of deep neural networks for imputing gene expression levels in scRNA-seq data without any manual tuning. Moreover, the proposed SEDIM constructs an offline surrogate model, which can accelerate the computational efficiency of the architectural search. Comprehensive studies show that SEDIM significantly improves the imputation and clustering performance compared with other benchmark methods. In addition, we also extensively explore the performance of SEDIM in other contexts and platforms including mass cytometry and metabolic profiling in a comprehensive manner. Marker gene detection, gene ontology enrichment and pathological analysis are conducted to provide novel insights into cell-type identification and the underlying mechanisms. The source code is available at https://github.com/li-shaochuan/SEDIM.

scholarly journals n-3 Fatty acids, inflammation and immunity: new mechanisms to explain old actions

2013 ◽  
Vol 72 (3) ◽  
pp. 326-336 ◽  
Author(s):  
Philip C. Calder
Keyword(s):  
Fatty Acids ◽  
Inflammatory Responses ◽  
Expression Profiles ◽  
Gene Expression Profiles ◽  
Mechanisms Of Action ◽  
Lipid Mediators ◽  
Functional Responses ◽  
New Family ◽  
Epa And Dha ◽  
Novel Interactions

Numerous effects of n-3 fatty acids EPA and DHA on functional responses of cells involved in inflammation and immunity have been described. Fatty acid-induced modifications in membrane order and in the availability of substrates for eicosanoid synthesis are long-standing mechanisms that are considered important in explaining the effects observed. More recently, effects on signal transduction pathways and on gene expression profiles have been identified. Over the last 10 years or so, significant advances in understanding the mechanisms of action of n-3 fatty acids have been made. These include the identification of new actions of lipid mediators that were already described and of novel interactions among those mediators and the description of an entirely new family of lipid mediators, resolvins and protectins that have anti-inflammatory actions and are critical to the resolution of inflammation. It is also recognised that EPA and DHA can inhibit activation of the prototypical inflammatory transcription factor NF-κB. Recent studies suggest three alternative mechanisms by which n-3 fatty acids might have this effect. Within T-cells, as well as other cells of relevance to immune and inflammatory responses, EPA and DHA act to disrupt very early events involving formation of the structures termed lipid rafts which bring together various proteins to form an effective signalling platform. In summary, recent research has identified a number of new mechanisms of action that help to explain previously identified effects of n-3 fatty acids on inflammation and immunity.

Whole blood genome-wide gene expression profile in males after prolonged wakefulness and sleep recovery

2012 ◽  
Vol 44 (21) ◽  
pp. 1003-1012 ◽  
Author(s):  
R. Pellegrino ◽  
D. Y. Sunaga ◽  
C. Guindalini ◽  
R. C. S. Martins ◽  
D. R. Mazzotti ◽  
...  
Keyword(s):  
Gene Expression ◽  
Whole Blood ◽  
Inflammatory Responses ◽  
Expression Profiles ◽  
Killer Cell ◽  
Gene Expression Profiles ◽  
Sleep Loss ◽  
The Body ◽  
Dna Damage And Repair ◽  
Peripheral Tissues

Although the specific functions of sleep have not been completely elucidated, the literature has suggested that sleep is essential for proper homeostasis. Sleep loss is associated with changes in behavioral, neurochemical, cellular, and metabolic function as well as impaired immune response. Using high-resolution microarrays we evaluated the gene expression profiles of healthy male volunteers who underwent 60 h of prolonged wakefulness (PW) followed by 12 h of sleep recovery (SR). Peripheral whole blood was collected at 8 am in the morning before the initiation of PW (Baseline), after the second night of PW, and one night after SR. We identified over 500 genes that were differentially expressed. Notably, these genes were related to DNA damage and repair and stress response, as well as diverse immune system responses, such as natural killer pathways including killer cell lectin-like receptors family, as well as granzymes and T-cell receptors, which play important roles in host defense. These results support the idea that sleep loss can lead to alterations in molecular processes that result in perturbation of cellular immunity, induction of inflammatory responses, and homeostatic imbalance. Moreover, expression of multiple genes was downregulated following PW and upregulated after SR compared with PW, suggesting an attempt of the body to re-establish internal homeostasis. In silico validation of alterations in the expression of CETN3, DNAJC, and CEACAM genes confirmed previous findings related to the molecular effects of sleep deprivation. Thus, the present findings confirm that the effects of sleep loss are not restricted to the brain and can occur intensely in peripheral tissues.

scholarly journals The origin, fate and function of macrophages in the peripheral nervous system—an update

2020 ◽  
Vol 32 (11) ◽  
pp. 709-717 ◽  
Author(s):  
Lukas Amann ◽  
Marco Prinz
Keyword(s):  
Gene Expression ◽  
Nervous System ◽  
Rna Sequencing ◽  
Peripheral Nervous System ◽  
Expression Profiles ◽  
Gene Expression Profiles ◽  
New Techniques ◽  
Macrophage Populations ◽  
And Function ◽  
First Time

Abstract The field of macrophage biology has made enormous progress over recent years. This was triggered by the advent of several new techniques such as the establishment of Cre/loxP-based transgenic mouse models that allowed for the first time delineation of the ontogeny and function of specific macrophage populations across many tissues. In addition, the introduction of new high-throughput technologies like bulk RNA sequencing and later single-cell RNA sequencing as well as advances in epigenetic analysis have helped to establish gene expression profiles, enhancer landscapes and local signaling cues that define and shape the identity of diverse macrophage populations. Nonetheless, some macrophage populations, like the ones residing in the peripheral nervous system (PNS), have not been studied in such detail yet. Here, we discuss recent studies that shed new light on the ontogeny, heterogeneity and gene expression profiles of resident macrophages in peripheral nerves and described differential activation of macrophage subsets during and after acute sciatic nerve injury.

scholarly journals Involvement of nephrin in human placental trophoblast syncytialization

Reproduction ◽  
2015 ◽  
Vol 149 (4) ◽  
pp. 339-346 ◽  
Author(s):  
Yue Li ◽  
Ru Zheng ◽  
Rui Wang ◽  
Xiaoyin Lu ◽  
Cheng Zhu ◽  
...  
Keyword(s):  
Cell Fusion ◽  
Connexin 43 ◽  
Transmembrane Protein ◽  
First Trimester ◽  
Trophoblast Cell ◽  
Term Pregnancy ◽  
Fusion Model ◽  
Placental Development ◽  
Functional Conservation ◽  
Ig Superfamily

The placenta has numerous functions, such as transporting oxygen and nutrients and building the immune tolerance of the fetus. Cell fusion is an essential process for placental development and maturation. In human placental development, mononucleated cytotrophoblast (CTB) cells can fuse to form a multinucleated syncytiotrophoblast (STB), which is the outermost layer of the placenta. Nephrin is a transmembrane protein that belongs to the Ig superfamily. Previous studies have shown that nephrin contributes to the fusion of myoblasts into myotubes in zebrafish and mice, presenting a functional conservation with its Drosophila ortholog sticks and stones. However, whether nephrin is involved in trophoblast syncytialization remains unclear. In this study, we report that nephrin was localized predominantly in the CTB cells and STB of human placenta villi from first trimester to term pregnancy. Using a spontaneous fusion model of primary CTB cells, the expression of nephrin was found to be increased during trophoblast cell fusion. Moreover, the spontaneous syncytialization and the expression of syncytin 2, connexin 43, and human chorionic gonadotropin beta were significantly inhibited by nephrin-specific siRNAs. The above results demonstrate that nephrin plays an important role in trophoblast syncytialization.

Distinct gene expression profiles provoked by polyacrylamide beads (Biogel) during chronic and acute inflammation in mice selected for maximal and minimal inflammatory responses

2016 ◽  
Vol 65 (4) ◽  
pp. 313-323 ◽  
Author(s):  
Jussara Gonçalves Fernandes ◽  
Tatiane Canhamero ◽  
Andrea Borrego ◽  
José Ricardo Jensen ◽  
Wafa Hanna Cabrera ◽  
...  
Keyword(s):  
Gene Expression ◽  
Acute Inflammation ◽  
Inflammatory Responses ◽  
Expression Profiles ◽  
Gene Expression Profiles ◽  
Distinct Gene

scholarly journals Identification of significant genes with invasive promotion in non-functional pituitary adenoma via bioinformatical analysis

2021 ◽  
Author(s):  
An Shuo Wang ◽  
Hao Xu ◽  
Ming Hui Zeng ◽  
Fei Wang
Keyword(s):  
Pituitary Adenoma ◽  
Expression Profiles ◽  
Gene Expression Profiles ◽  
Pituitary Tumors ◽  
Receptor Interaction ◽  
Protein Protein Interaction ◽  
Normal Tissues ◽  
Non Invasive ◽  
Pathway Gene ◽  
Underlying Mechanisms

Abstract Background Non-functional pituitary adenoma (NFPA) is a disease with a high incidence, which accounts for a large part of pituitary tumors and plays a pivotal role. While invasive NFPAs which have not any endocrinology manifestations and space-occupying symptoms at early stages account for about 30 percent of NFPAs. The purpose of the present academic work was to identify significant genes with invasive promotion and their underlying mechanisms. Methods Gene expression profiles of GSE51618 was available from GEO database. There are 4 non-invasive NFPA tissues, 3 invasive NFPA tissues and 3 normal tissues in the profile datasets. Differentially expressed genes (DEGs) between non-invasive NFPA tissues and invasive NFPA tissues were picked out by GEO2R online tool. There were total of 226 up-regulated genes and 298 down-regulated genes. Next, we made use of the Database for Annotation, Visualization and Integrated Discovery (DAVID) to analyze Kyoto Encyclopedia of Gene and Genome (KEGG) pathway, gene ontology (GO) and Kaplan Meier Plotter. Then protein-protein interaction (PPI) of these DEGs was visualized by Cytoscape with Search Tool for the Retrieval of Interacting Genes (STRING). There were total of 141 up-regulated genes and 171 down-regulated genes. Of PPI network analyzed by Molecular Complex Detection (MCODE) plug-in, all 141 up-regulated genes were selected. Results After reanalysis of GO, five genes (ATP2B3, ADCYAP1R1, PTGER2, FSHβ, HTR4) were found to significantly enrich in the cAMP signaling pathway, Neuroactive ligand-receptor interaction and Renin secretion via reanalysis of DAVID. Conclusions We have identified five significant up-regulated DEGs with invasive promotion in invasive NFPAs on the basis of integrated bioinformatical methods, which could be potential therapeutic targets for invasive NFPAs patients.

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