MicroRNAs (miRNAs) play a key role in fine-tuning host immune homeostasis and responses through the negative regulation of mRNA stability and translation. The pathways regulated by miRNAs are well ...characterized, but the precise mechanisms that control the miRNA-mediated regulation of gene expression during immune cell-development and immune responses to invading pathogens are incompletely understood. Context-specific interactions of miRNAs with other RNA species or proteins may modulate the function of a given miRNA. Dysregulation of miRNA function is associated with various human diseases, such as cardiovascular diseases and cancers. Here, we review the potential modulators of miRNA function in the immune system, including the transcription regulators of miRNA genes, miRNA-processing enzymes, factors affecting miRNA targeting, and intercellular communication.
TAR-DNA-binding protein-43 (TDP-43) C-terminus encodes a prion-like domain widely presented in RNA-binding proteins, which functions to form dynamic oligomers and also, amazingly, hosts most ...amyotrophic lateral sclerosis (ALS)-causing mutations. Here, as facilitated by our previous discovery, by circular dichroism (CD), fluorescence and nuclear magnetic resonance (NMR) spectroscopy, we have successfully determined conformations, dynamics, and self-associations of the full-length prion-like domains of the wild type and three ALS-causing mutants (A315E, Q331K, and M337V) in both aqueous solutions and membrane environments. The study decodes the following: (1) The TDP-43 prion-like domain is intrinsically disordered only with some nascent secondary structures in aqueous solutions, but owns the capacity to assemble into dynamic oligomers rich in β-sheet structures. By contrast, despite having highly similar conformations, three mutants gained the ability to form amyloid oligomers. The wild type and three mutants all formed amyloid fibrils after incubation as imaged by electron microscopy. (2) The interaction with nucleic acid enhances the self-assembly for the wild type but triggers quick aggregation for three mutants. (3) A membrane-interacting subdomain has been identified over residues Met311-Gln343 indispensable for TDP-43 neurotoxicity, which transforms into a well-folded Ω-loop-helix structure in membrane environments. Furthermore, despite having very similar membrane-embedded conformations, three mutants will undergo further self-association in the membrane environment. Our study implies that the TDP-43 prion-like domain appears to have an energy landscape, which allows the assembly of the wild-type sequence into dynamic oligomers only under very limited condition sets, and ALS-causing point mutations are sufficient to remodel it to more favor the amyloid formation or irreversible aggregation, thus supporting the emerging view that the pathologic aggregation may occur via the exaggeration of functionally important assemblies. Furthermore, the coupled capacity of TDP-43 in aggregation and membrane interaction may critically account for its high neurotoxicity, and therefore its decoupling may represent a promising therapeutic strategy to treat TDP-43 causing neurodegenerative diseases.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Macrophages play a crucial role in the innate immune system and contribute to a broad spectrum of pathologies, like in the defence against infectious agents, in inflammation resolution, and wound ...repair. In the past several years, microRNAs (miRNAs) have been demonstrated to play important roles in immune diseases by regulating macrophage functions. In this review, we will summarize the role of miRNAs in the differentiation of monocytes into macrophages, in the classical and alternative activation of macrophages, and in the regulation of phagocytosis and apoptosis. Notably, miRNAs preferentially target genes related to the cellular cholesterol metabolism, which is of key importance for the inflammatory activation and phagocytic activity of macrophages. miRNAs functionally link various mechanisms involved in macrophage activation and contribute to initiation and resolution of inflammation. miRNAs represent promising diagnostic and therapeutic targets in different conditions, such as infectious diseases, atherosclerosis, and cancer.
A number of studies have investigated phrasal verbs from various aspects (Liu, 2006; Yu, 2011; Liao & Fukuya, 2004). However, those studies lack generality, because only a couple of phrasal verbs ...were chosen as examples, or too much content prompt was offered in task response of L2 learners. The current study applies a corpus-based approach to investigate English phrasal verbs in free conversations from a Chinese learner corpus, SWECCL (Wen & Wang, 2008), which demonstrates Chinese students actual use of phrasal verbs. This study focuses on analysis of two phenomena: development of phrasal verb uses and avoidance of phrasal verbs across different proficiency levels in Chinese students oral English conversations. Results showed that students at higher proficiency level used more phrasal verbs in oral communication, and the progress of phrasal verb use was evident from middle proficiency level to advanced proficiency level. The study also found that phrasal verbs occurred less frequently overall in L2 learners oral conversations compared with frequency of their single-word synonyms. Keywords English phrasal verbs, Chinese learner corpus, proficiency level, single-word synonyms
Long non-coding RNAs (lncRNAs) represent crucial transcriptional and post-transcriptional gene regulators during antimicrobial responses in the host innate immune system. Studies have shown that ...lncRNAs are expressed in a highly tissue- and cell-specific- manner and are involved in the differentiation and function of innate immune cells, as well as inflammatory and antiviral processes, through versatile molecular mechanisms. These lncRNAs function via the interactions with DNA, RNA, or protein in either cis or trans pattern, relying on their specific sequences or their transcriptions and processing. The dysregulation of lncRNA function is associated with various human non-infectious diseases, such as inflammatory bowel disease, cardiovascular diseases, and diabetes mellitus. Here, we provide an overview of the regulation and mechanisms of lncRNA function in the development and differentiation of innate immune cells, and during the activation or repression of innate immune responses. These elucidations might be beneficial for the development of therapeutic strategies targeting inflammatory and innate immune-mediated diseases.
Before anti-EGFR therapy is given to patients with colorectal cancer, it is required to determine KRAS mutation status in tumor. When tumor tissue is not available, cell-free DNA (liquid biopsy) is ...commonly used as an alternative. Due to the low abundance of tumor-derived DNA in cell-free DNA samples, methods with high sensitivity were preferred, including digital polymerase chain reaction, amplification refractory mutation system and next-generation sequencing. The aim of this systemic review and meta-analysis was to investigate the accuracy of those methods in detecting KRAS mutation in cell-free DNA sample from patients with colorectal cancer.
Literature search was performed in Pubmed, Embase, and Cochrane Library. After removing duplicates from the 170 publications found by literature search, eligible studies were identified using pre-defined criteria. Quality of the publications and relevant data were assessed and extracted thereafter. Meta-DiSc and STATA softwares were used to pool the accuracy parameters from the extracted data.
A total of 33 eligible studies were identified for this systemic review and meta-analysis. After pooling, the overall sensitivity, specificity, and diagnostic odds ratio were 0.77 (95%CI: 0.74-0.79), 0.87 (95%CI: 0.85-0.89), and 23.96 (95%CI: 13.72-41.84), respectively. The overall positive and negative likelihood ratios were 5.55 (95%CI: 3.76-8.19) and 0.29 (95%CI: 0.21-0.38), respectively. Area under curve of the summarized ROC curve was 0.8992.
Digital polymerase chain reaction, amplification refractory mutation system, and next-generation sequencing had overall high accuracy in detecting KRAS mutation in cell-free DNA sample. Large prospective randomized clinical trials are needed to further convince the accuracy and usefulness of KRAS mutation detection using cfDNA/liquid biopsy samples in clinical practice.
PROSPERO CRD42020176682; https://www.crd.york.ac.uk/prospero/display_record.php?RecordID=176682.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Rheumatoid arthritis (RA) is a chronic autoimmune disease that primarily affects the joints. Microbial infection is considered a crucial inducer of RA. Alterations in the composition of intestinal ...bacteria in individuals with preclinical and established RA suggest a vital role of the gut microbiota in immune dysfunction characteristic of RA. However, the mechanisms by which gut dysbiosis contributes to RA are not fully understood. Furthermore, multiple therapies commonly used to treat RA may alter gut microbiota diversity, suggesting that modulating the gut microbiota may help prevent or treat RA. Hence, a better understanding of the changes in the gut microbiota that accompany RA should aid the development of novel therapeutic approaches. This mini-review discusses the impact of gut dysbiosis in the pathogenesis of RA, the selection of gut microbiota-related biomarkers for diagnosing RA, and provides examples of cross-modulation between the gut microbiota and some drugs commonly used to treat RA. Some suggestions and outlooks are also raised, which may help guide future research efforts.
Pyroptosis, a type of Gasdermin-mediated cell death, contributes to an exacerbation of inflammation. To test the hypothesis that GSDME-mediated pyroptosis aggravates the progression of ...atherosclerosis, we generate ApoE and GSDME dual deficiency mice. As compared with the control mice, GSDME
/ApoE
mice show a reduction of atherosclerotic lesion area and inflammatory response when induced with a high-fat diet. Human atherosclerosis single-cell transcriptome analysis demonstrates that GSDME is mainly expressed in macrophages. In vitro, oxidized low-density lipoprotein (ox-LDL) induces GSDME expression and pyroptosis in macrophages. Mechanistically, ablation of GSDME in macrophages represses ox-LDL-induced inflammation and macrophage pyroptosis. Moreover, the signal transducer and activator of transcription 3 (STAT3) directly correlates with and positively regulates GSDME expression. This study explores the transcriptional mechanisms of GSDME during atherosclerosis development and indicates that GSDME-mediated pyroptosis in the progression of atherosclerosis could be a potential therapeutic approach for atherosclerosis.
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•The failure behavior of 3D-printed lattice-reinforced cement-based materials is found to change from brittle fracture to ductile failure.•3D-printed PA6 lattice-reinforced ...cementitious composite cannot significantly improve the cracking load of the cementitious matrix.•3D-printed graded lattice is used to strengthen the cement mortar, thus realizing the multiple cracking of the cementitious matrix.•The preparation method of the functionally graded lattice structure uses fewer materials and can improve the flexural bearing capacity and ductility of the cementitious matrix.•The weak interfacial adhesion between the 3D-printed polymer and cement-based materials is a problem that must be solved in subsequent research.
Three-dimensional (3D) printed polymer-reinforced cementitious composites are expected to be used to improve the ductility of cement-based materials. However, research on the maximum flexural capacity and failure mode of lattice-reinforced cementitious composites remains insufficient. In this study, six types of cells with different volume fractions are designed, and mainly undergo bending and tensile deformation. According to the load characteristics during a three-point bending test, five kinds of graded lattice structures are designed. Moreover, a skin-lattice structure and uniform lattice structure are designed, and plain cement mortar is set to comprehensively evaluate the bending mechanical properties of graded lattice-reinforced cementitious composites. The crack evolution and failure mode of these composites under three-point bending load are studied using digital image correlation (DIC). The results show that compared with the uniform lattice, the graded lattice can improve the maximum bending capacity of cement-based materials, improve their cracking characteristics and failure modes during the bending process, and enhance their toughness while reducing the amount of required material. Compared with the plain cement mortar specimen, the graded lattice-reinforced specimen with the largest bending peak load is found to have a 175% increase in the bending peak load and a significant increase in the bending bearing capacity.
A number of cardiovascular diseases, such as restenosis, aneurysm, and atherosclerosis, lead to vascular remodeling associated with complex adaptive reactions of different cell populations. These ...reactions include growth of smooth muscle cells, proliferation of endothelial cells, and the inflammatory response of macrophages. MicroRNAs (miRNAs), a class of short RNAs, play key roles in various biological processes and in the development of human disease by post-transcriptional regulation of gene expression. Here, we review the molecular mechanisms of a subset of miRNAs involved in vascular remodeling, including miR-143/145, miR-221/222, miR-126, miR-21, and miR-155. Some of these miRNAs, such as miR-143/145 and miR-126, have been shown to be protective during vascular remodeling, whereas others, such as miR-21, may promote the cellular response that leads to neointima formation. The increasing knowledge regarding the roles of miRNAs in vascular remodeling opens novel avenues for the treatment of various cardiovascular diseases. However, more in vivo studies on the functional roles of these miRNAs are required in the future.
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