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Frontiers in Endocrinology 2018MicroRNAs (miRNAs) are a class of non-coding RNAs that play important roles in regulating gene expression. The majority of miRNAs are transcribed from DNA sequences into... (Review)
Review
MicroRNAs (miRNAs) are a class of non-coding RNAs that play important roles in regulating gene expression. The majority of miRNAs are transcribed from DNA sequences into primary miRNAs and processed into precursor miRNAs, and finally mature miRNAs. In most cases, miRNAs interact with the 3' untranslated region (3' UTR) of target mRNAs to induce mRNA degradation and translational repression. However, interaction of miRNAs with other regions, including the 5' UTR, coding sequence, and gene promoters, have also been reported. Under certain conditions, miRNAs can also activate translation or regulate transcription. The interaction of miRNAs with their target genes is dynamic and dependent on many factors, such as subcellular location of miRNAs, the abundancy of miRNAs and target mRNAs, and the affinity of miRNA-mRNA interactions. miRNAs can be secreted into extracellular fluids and transported to target cells via vesicles, such as exosomes, or by binding to proteins, including Argonautes. Extracellular miRNAs function as chemical messengers to mediate cell-cell communication. In this review, we provide an update on canonical and non-canonical miRNA biogenesis pathways and various mechanisms underlying miRNA-mediated gene regulations. We also summarize the current knowledge of the dynamics of miRNA action and of the secretion, transfer, and uptake of extracellular miRNAs.
PubMed: 30123182
DOI: 10.3389/fendo.2018.00402 -
Journal of Cardiovascular Magnetic... Oct 2017Parametric mapping techniques provide a non-invasive tool for quantifying tissue alterations in myocardial disease in those eligible for cardiovascular magnetic...
Clinical recommendations for cardiovascular magnetic resonance mapping of T1, T2, T2* and extracellular volume: A consensus statement by the Society for Cardiovascular Magnetic Resonance (SCMR) endorsed by the European Association for Cardiovascular Imaging (EACVI).
Parametric mapping techniques provide a non-invasive tool for quantifying tissue alterations in myocardial disease in those eligible for cardiovascular magnetic resonance (CMR). Parametric mapping with CMR now permits the routine spatial visualization and quantification of changes in myocardial composition based on changes in T1, T2, and T2*(star) relaxation times and extracellular volume (ECV). These changes include specific disease pathways related to mainly intracellular disturbances of the cardiomyocyte (e.g., iron overload, or glycosphingolipid accumulation in Anderson-Fabry disease); extracellular disturbances in the myocardial interstitium (e.g., myocardial fibrosis or cardiac amyloidosis from accumulation of collagen or amyloid proteins, respectively); or both (myocardial edema with increased intracellular and/or extracellular water). Parametric mapping promises improvements in patient care through advances in quantitative diagnostics, inter- and intra-patient comparability, and relatedly improvements in treatment. There is a multitude of technical approaches and potential applications. This document provides a summary of the existing evidence for the clinical value of parametric mapping in the heart as of mid 2017, and gives recommendations for practical use in different clinical scenarios for scientists, clinicians, and CMR manufacturers.
Topics: Consensus; Europe; Heart; Heart Diseases; Humans; Image Processing, Computer-Assisted; Magnetic Resonance Imaging; Societies, Medical
PubMed: 28992817
DOI: 10.1186/s12968-017-0389-8 -
Frontiers in Immunology 2022In recent years, the introduction of chimeric antigen receptor (CAR) T-cell therapies into clinics has been a breakthrough in treating relapsed or refractory... (Review)
Review
In recent years, the introduction of chimeric antigen receptor (CAR) T-cell therapies into clinics has been a breakthrough in treating relapsed or refractory malignancies in hematology and oncology. To date, Food and Drug Administration (FDA) has approved six CAR-T therapies for specific non-Hodgkin lymphomas, B-cell acute lymphoblastic leukemia, and multiple myeloma. All registered treatments and most clinical trials are based on so-called 2nd generation CARs, which consist of an extracellular antigen-binding region, one costimulatory domain, and a CD3z signaling domain. Unfortunately, despite remarkable overall treatment outcomes, a relatively high percentage of patients do not benefit from CAR-T therapy (overall response rate varies between 50 and 100%, with following relapse rates as high as 66% due to limited durability of the response). Moreover, it is associated with adverse effects such as cytokine release syndrome and neurotoxicity. Advances in immunology and molecular engineering have facilitated the construction of the next generation of CAR-T cells equipped with various molecular mechanisms. These include additional costimulatory domains (3rd generation), safety switches, immune-checkpoint modulation, cytokine expression, or knockout of therapy-interfering molecules, to name just a few. Implementation of next-generation CAR T-cells may allow overcoming current limitations of CAR-T therapies, decreasing unwanted side effects, and targeting other hematological malignancies. Accordingly, some clinical trials are currently evaluating the safety and efficacy of novel CAR-T therapies. This review describes the CAR-T cell constructs concerning the clinical application, summarizes completed and ongoing clinical trials of next-generation CAR-T therapies, and presents future perspectives.
Topics: United States; Humans; Receptors, Chimeric Antigen; Receptors, Antigen, T-Cell; T-Lymphocytes; Multiple Myeloma; Hematology
PubMed: 36389658
DOI: 10.3389/fimmu.2022.1034707 -
Frontiers in Immunology 2022Neutrophil extracellular traps (NETs) are specialized structures formed by neutrophils that were initially found to be important in killing pathogenic bacteria during...
BACKGROUND
Neutrophil extracellular traps (NETs) are specialized structures formed by neutrophils that were initially found to be important in killing pathogenic bacteria during infection. With the development of related research, the relationship between NETs and diseases such as sepsis, cancer, and systemic lupus erythematosus has received close attention. However, there is a lack of reports that comprehensively and objectively present the current status of NETs-related studies. Therefore, this study aims to visually analyze the current status and trends of NETs-related research by means of bibliometrics and knowledge mapping.
METHODS
NETs-related articles and reviews were retrieved using the Web of Science core collection subject search, and bibliometric analysis was performed in Excel 365, CiteSpace, VOSviewer, and Bibliometrix (R-Tool of R-Studio).
RESULTS
A total of 4866 publications from 2004 to 2022 were included in the bibliometric analysis. The number of publications shows an increasing trend from year to year. Collaborative network analysis shows that the United States and Germany are the most influential countries in this field, with the highest number of publications and citations. The journal with the most publications is Frontiers in Immunology. Brinkmann Volker is an authoritative author in this field, and his publication "Neutrophil extracellular traps kill bacteria" is the most frequently cited. The literature and keyword analysis shows that the relationship between NETs and diseases (hematological diseases, sepsis, cancer, etc.) and cell death (apoptosis, necroptosis, pyroptosis, etc.) is a popular research topic. Currently, NETs and SARS-CoV-2-related studies are at the forefront of the field.
CONCLUSION
This study is the first to visualize the research in NETs-related fields using bibliometric methods, revealing the trends and frontiers of NETs research. This study will provide valuable references for scholars to find research focus questions and partners.
Topics: Humans; United States; Extracellular Traps; SARS-CoV-2; COVID-19; Bibliometrics; Sepsis; Neoplasms
PubMed: 36341351
DOI: 10.3389/fimmu.2022.1025861 -
European Journal of Human Genetics :... Dec 2016Usher syndrome (USH), the most prevalent cause of hereditary deafness-blindness, is an autosomal recessive and genetically heterogeneous disorder. Three clinical...
Usher syndrome (USH), the most prevalent cause of hereditary deafness-blindness, is an autosomal recessive and genetically heterogeneous disorder. Three clinical subtypes (USH1-3) are distinguishable based on the severity of the sensorineural hearing impairment, the presence or absence of vestibular dysfunction, and the age of onset of the retinitis pigmentosa. A total of 10 causal genes, 6 for USH1, 3 for USH2, and 1 for USH3, and an USH2 modifier gene, have been identified. A robust molecular diagnosis is required not only to improve genetic counseling, but also to advance gene therapy in USH patients. Here, we present an improved diagnostic strategy that is both cost- and time-effective. It relies on the sequential use of three different techniques to analyze selected genomic regions: targeted exome sequencing, comparative genome hybridization, and quantitative exon amplification. We screened a large cohort of 427 patients (139 USH1, 282 USH2, and six of undefined clinical subtype) from various European medical centers for mutations in all USH genes and the modifier gene. We identified a total of 421 different sequence variants predicted to be pathogenic, about half of which had not been previously reported. Remarkably, we detected large genomic rearrangements, most of which were novel and unique, in 9% of the patients. Thus, our strategy led to the identification of biallelic and monoallelic mutations in 92.7% and 5.8% of the USH patients, respectively. With an overall 98.5% mutation characterization rate, the diagnosis efficiency was substantially improved compared with previously reported methods.
Topics: Alleles; Comparative Genomic Hybridization; Europe; Exome; Extracellular Matrix Proteins; Genes, Modifier; Genetic Testing; Humans; Mutation; Sensitivity and Specificity; Sequence Analysis, DNA; Usher Syndromes
PubMed: 27460420
DOI: 10.1038/ejhg.2016.99 -
South African Medical Journal =... Mar 2023Since the identification of anti-N-methyl-D-aspartate (NMDA) receptor antibodies about 15 years ago, many patients with rapidly progressing psychiatric symptoms,... (Review)
Review
Since the identification of anti-N-methyl-D-aspartate (NMDA) receptor antibodies about 15 years ago, many patients with rapidly progressing psychiatric symptoms, abnormal movements, seizures or unexplained coma, have been diagnosed with autoimmune encephalitis (AE). The symptom onset is often unspecific and might mimic psychiatric disease, but the later course is frequently characterized by severe disease, often requiring intensive care. Clinical and immunological criteria are helpful in identifying the patients, but no biomarkers exist to guide the clinician in therapy or predict outcome. While persons of all ages can be affected by AE, some types of AE affect more children and young adults and are more prevalent in women. This review will focus on encephalitides associated with neuronal cell-surface or synaptic antibodies, which can result in characteristic syndromes, and are often recognizable on clinical grounds. AE subtypes associated with antibodies against extracellular epitopes can occur with or without tumours. Because the antibodies bind and alter the function of the antigen, the effects are often reversible if immunotherapy is initiated, and the prognosis is favourable in most instances. The first part of this series will introduce the topic, provide an overview of current neuronal surface antibodies and how they present, describe the most common subtype, anti-NMDA receptor encephalitis, and discuss the difficulties in recognizing patients with underlying AE amongst patients with new onset psychiatric disorders.
Topics: Child; Young Adult; Humans; Female; South Africa; Critical Care; Encephalitis; Hashimoto Disease
PubMed: 36876357
DOI: No ID Found -
Nature Communications Feb 2022During decidualization in rodents, uterine stroma undergoes extensive reprograming into distinct cells, forming the discrete regions defined as the primary decidual zone...
During decidualization in rodents, uterine stroma undergoes extensive reprograming into distinct cells, forming the discrete regions defined as the primary decidual zone (PDZ), the secondary decidual zone (SDZ) and the layer of undifferentiated stromal cells respectively. Here we show that uterine deletion of Men1, a member of the histone H3K4 methyltransferase complex, disrupts the terminal differentiation of stroma, resulting in chaotic decidualization and pregnancy failure. Genome-wide epigenetic profile reveals that Men1 binding in chromatin recapitulates H3K4me3 distribution. Further transcriptomic investigation demonstrates that Men1 directly regulates the expression of PTX3, an extra-cellular trap for FGF2 in decidual cells. Decreased Ptx3 upon Men1 ablation leads to aberrant activation of ERK1/2 in the SDZ due to the unrestrained FGF2 signal emanated from undifferentiated stromal cells, which blunt BMP2 induction and decidualization. In brief, our study provides genetic and molecular mechanisms for epigenetic rewiring mediated decidual regionalization by Men1 and sheds new light on pregnancy maintenance.
Topics: C-Reactive Protein; Decidua; Embryo Implantation; Female; Fibroblast Growth Factor 2; Humans; Pregnancy; Serum Amyloid P-Component; Signal Transduction; Stromal Cells; Transcription Factors; Uterus
PubMed: 35194044
DOI: 10.1038/s41467-022-28657-2 -
Clinical and Translational Medicine Feb 2022Vascular calcification is a prominent feature of late-stage diabetes, renal and cardiovascular disease (CVD), and has been linked to adverse events. Recent studies in... (Observational Study)
Observational Study
RATIONALE
Vascular calcification is a prominent feature of late-stage diabetes, renal and cardiovascular disease (CVD), and has been linked to adverse events. Recent studies in patients reported that plasma levels of osteomodulin (OMD), a proteoglycan involved in bone mineralisation, associate with diabetes and CVD. We hypothesised that OMD could be implicated in these diseases via vascular calcification as a common underlying factor and aimed to investigate its role in this context.
METHODS AND RESULTS
In patients with chronic kidney disease, plasma OMD levels correlated with markers of inflammation and bone turnover, with the protein present in calcified arterial media. Plasma OMD also associated with cardiac calcification and the protein was detected in calcified valve leaflets by immunohistochemistry. In patients with carotid atherosclerosis, circulating OMD was increased in association with plaque calcification as assessed by computed tomography. Transcriptomic and proteomic data showed that OMD was upregulated in atherosclerotic compared to control arteries, particularly in calcified plaques, where OMD expression correlated positively with markers of smooth muscle cells (SMCs), osteoblasts and glycoproteins. Immunostaining confirmed that OMD was abundantly present in calcified plaques, localised to extracellular matrix and regions rich in α-SMA cells. In vivo, OMD was enriched in SMCs around calcified nodules in aortic media of nephrectomised rats and in plaques from ApoE mice on warfarin. In vitro experiments revealed that OMD mRNA was upregulated in SMCs stimulated with IFNγ, BMP2, TGFβ1, phosphate and β-glycerophosphate, and by administration of recombinant human OMD protein (rhOMD). Mechanistically, addition of rhOMD repressed the calcification process of SMCs treated with phosphate by maintaining their contractile phenotype along with enriched matrix organisation, thereby attenuating SMC osteoblastic transformation. Mechanistically, the role of OMD is exerted likely through its link with SMAD3 and TGFB1 signalling, and interplay with BMP2 in vascular tissues.
CONCLUSION
We report a consistent association of both circulating and tissue OMD levels with cardiovascular calcification, highlighting the potential of OMD as a clinical biomarker. OMD was localised in medial and intimal α-SMA regions of calcified cardiovascular tissues, induced by pro-inflammatory and pro-osteogenic stimuli, while the presence of OMD in extracellular environment attenuated SMC calcification.
Topics: Analysis of Variance; Cohort Studies; Cross-Sectional Studies; Extracellular Matrix Proteins; Humans; Linear Models; Muscle, Smooth; Netherlands; Osteogenesis; Prospective Studies; Proteoglycans; Statistics, Nonparametric; Sweden; Vascular Calcification
PubMed: 35184400
DOI: 10.1002/ctm2.682 -
The Journal of Neuroscience : the... Jun 2018Transporter-mediated glutamate uptake plays an essential role in shaping synaptic neurotransmission. The rapid removal of synaptically released glutamate ensures the...
Transporter-mediated glutamate uptake plays an essential role in shaping synaptic neurotransmission. The rapid removal of synaptically released glutamate ensures the high temporal dynamics characteristic of fast excitatory chemical neurotransmission and prevents the overexcitation of extrasynaptic NMDA receptors that have been implicated in synaptic plasticity impairments and cell death. Despite clear regional differences in plasticity and excitotoxic thresholds, few studies have compared extracellular glutamate dynamics across different brain regions and in response to a range of neural activity including plasticity-inducing stimuli. Here, we used the rapid extracellular fluorescent glutamate sensor iGluSnFR (intensity-based glutamate-sensing fluorescent reporter) and high-speed imaging (205 frames per second) to quantify relative differences in glutamate clearance rates over a wide range of presynaptic activity in the hippocampus, cortex, and striatum of male C57/BL6NCrl mice. We found that the hippocampus was significantly more efficient than the cortex and striatum at clearing synaptically released glutamate and that this efficiency could be attributed, at least in part, to faster glutamate diffusion away from the release site. In addition, we found that pharmacological inhibition of GLT-1, the brain's most abundant glutamate transporter, slowed clearance rates to only a fraction (∼20-25%) of the effect induced by nonselective transporter blockade, regardless of the brain region and the duration of presynaptic activity. In all, our data reveal clear regional differences in glutamate dynamics after neural activity and suggest that non-GLT-1 transporters can make a large contribution to the rate of glutamate clearance in the hippocampus, cortex, and striatum. Glutamate is the brain's most abundant neurotransmitter, and although essential for rapid cell-cell communication, too much glutamate can negatively impact cellular health. Extracellular glutamate levels are tightly regulated by membrane-bound transporters that rapidly remove the glutamate that is released during neural activity, thereby shaping both the spatial and temporal dynamics of excitatory neurotransmission. Using high-speed imaging of an optical sensor of extracellular glutamate, we show that glutamate dynamics vary widely from one brain region to the next and are highly dependent on the duration of synaptic activity. Our data demonstrate the heterogeneous nature of glutamate regulation in the brain and suggest that such regional differences can dramatically affect both the localization and duration of postsynaptic receptor activation during synaptic neurotransmission.
Topics: Amino Acid Transport System X-AG; Animals; Brain; Glutamic Acid; Male; Mice; Mice, Inbred C57BL; Synaptic Transmission
PubMed: 29760178
DOI: 10.1523/JNEUROSCI.3213-17.2018