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Dysfunction of gamma-aminobutyric acid A (GABA(A)) receptors (GABA(A)Rs) is a prominent factor affecting intractable epilepsy. Plic-1, an ubiquitin-like protein enriched in the inhibitory synapses connecting GABA(A)Rs and the ubiq...
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Dysfunction of gamma-aminobutyric acid A (GABA(A)) receptors (GABA(A)Rs) is a prominent factor affecting intractable epilepsy. Plic-1, an ubiquitin-like protein enriched in the inhibitory synapses connecting GABA(A)Rs and the ubiquitin protease system (UPS), plays a key role in the modification of GABA(A)R functions. However, the relationship between Plic-1 and epileptogenesis is not known. In the present study, we aimed to investigate Plic-1 levels in patients with temporal lobe epilepsy, as well as the role of Plic-1 in regulating onset and progression of epilepsy in animal models. We found that Plic-1 expression was significantly decreased in patients with epilepsy as well as pilocarpine- and pentylenetetrazol (PTZ)-induced rat epileptic models. Intrahippocampal injection of the PeP alpha peptide, which disrupts Plic-1 binding to GABA(A)Rs, significantly shortened the latency of seizure onset, and increased the seizure severity and duration in these two epileptic models. Overexpressed Plic-1 through lentivirus transfection into a PTZ model resulted in a reduction in both seizure severity and generalized tonic-clonic seizure duration. Whole-cell clamp recordings revealed that the PeP alpha peptide decreased miniature inhibitory postsynaptic currents (mIPSCs) whereas overexpressed Plic-1 increased mIPSCs in the pyramidal neurons of the hippocampus. These effects can be blocked by picrotoxin, a GABA(A)R inhibitor. Our results indicate that Plic-1 plays an important role in managing epileptic seizures by enhancing seizure inhibition through regulation of GABA(A)Rs at synaptic sites.
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The embryology of the teeth was briefly covered in a previous review in this series. This present review addresses this embryology in more detail. The development of the teeth is a highly orchestrated, complex process that is the ...
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The embryology of the teeth was briefly covered in a previous review in this series. This present review addresses this embryology in more detail. The development of the teeth is a highly orchestrated, complex process that is the result of reciprocal inductions between the overlying first branchial arch oral cavity ectoderm, from which the cells that produce the enamel will develop, and the neural crest ectomesenchyme, from which the remaining tooth elements will arise. Early in development, the tooth germ grows and expands, and those cells that will form the mineralized components of the teeth differentiate. Once these formative cells differentiate, formation and mineralization of the dentin and enamel matrices occur. Eventually, the completed tooth will erupt into the oral cavity, and during eruption, the tooth roots become surrounded by the periodontal ligament, cementum, and supporting alveolar bone. There is also a discussion that notes some of the various abnormalities that can affect the teeth. Learning Objective: The reader will understand the current theory as to how the human tooth configuration arose, as well as the embryology and anatomy of the teeth, the process of tooth eruption, alterations in the number and morphology of the teeth, and inflammatory conditions.
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Diabetic nephropathy (DN) has been recognized as a severe complication of diabetes mellitus and a dominant pathogeny of end-stage kidney disease, which causes serious health problems and great financial burden to human society wor...
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Diabetic nephropathy (DN) has been recognized as a severe complication of diabetes mellitus and a dominant pathogeny of end-stage kidney disease, which causes serious health problems and great financial burden to human society worldwide. Conventional strategies, such as renin-angiotensin-aldosterone system blockade, blood glucose level control, and bodyweight reduction, may not achieve satisfactory outcomes in many clinical practices for DN management. Notably, due to the multi-target function, Chinese medicine possesses promising clinical benefits as primary or alternative therapies for DN treatment. Increasing studies have emphasized identifying bioactive compounds and molecular mechanisms of reno-protective effects of Chinese medicines. Signaling pathways involved in glucose/lipid metabolism regulation, antioxidation, anti-inflammation, anti-fibrosis, and podocyte protection have been identified as crucial mechanisms of action. Herein, we summarize the clinical efficacies of Chinese medicines and their bioactive components in treating and managing DN after reviewing the results demonstrated in clinical trials, systematic reviews, and meta-analyses, with a thorough discussion on the relative underlying mechanisms and molecular targets reported in animal and cellular experiments. We aim to provide comprehensive insights into the protective effects of Chinese medicines against DN.
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The impact of perineural invasion and perineural spread on survival and the MR imaging of this tumor spread have been well documented in the literature. What has not been addressed in the radiology literature is the mechanics that...
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The impact of perineural invasion and perineural spread on survival and the MR imaging of this tumor spread have been well documented in the literature. What has not been addressed in the radiology literature is the mechanics that are behind perineural invasion. Perineural invasion is not the result of a passive invasion of a nerve by tumor, a common misconception. Because there are no lymphatics within a nerve, perineural invasion is not mediated by a direct lymphatic extension. Rather, perineural invasion is the result of complex molecular interactions between a nerve and an adjacent cancer. Once the cancer has entered a nerve, it can travel in the spaces between fascicles, which explains how such perineural invasion can appear at great distances from the primary tumor. This article reviews the current concepts regarding the mechanisms of perineural invasion and the relationship to peripheral nerve regeneration. Perineural invasion is diagnosed by histology, whereas perineural spread can be identified on imaging. Learning Objective: The reader will learn the intimate relationship between a tumor and its adjacent nerves that lead to perineural invasion. This process is the result of a series of molecular pathways, in part related to nerve regeneration.
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The relevance of protein-glycan interactions in immunity has long been underestimated. Yet, the immune system possesses numerous classes of glycan-binding proteins, so-called lectins. Of specific interest is the group of myeloid C...
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The relevance of protein-glycan interactions in immunity has long been underestimated. Yet, the immune system possesses numerous classes of glycan-binding proteins, so-called lectins. Of specific interest is the group of myeloid C-type lectin receptors (CLRs) as they are mainly expressed by myeloid cells and play an important role in the initiation of an immune response. Myeloid CLRs represent a major group amongst pattern recognition receptors (PRRs), placing them at the center of the rapidly growing field of glycoimmunology. CLRs have evolved to encompass a wide range of structures and functions and to recognize a large number of glycans and many other ligands from different classes of biopolymers. This review aims at providing the reader with an overview of myeloid CLRs and selected ligands, while highlighting recent insights into CLR-ligand interactions. Subsequently, methodological approaches in CLR-ligand research will be presented. Finally, this review will discuss how CLR-ligand interactions culminate in immunological functions, how glycan mimicry favors immune escape by pathogens, and in which way immune responses can be affected by CLR-ligand interactions in the long term.
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The immune checkpoint blockade (ICB) targeting on PD-1/PD-L1 has shown remarkable promise in treating cancers. However, the low response rate and frequently observed severe side effects limit its broad benefits. It is partially du...
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The immune checkpoint blockade (ICB) targeting on PD-1/PD-L1 has shown remarkable promise in treating cancers. However, the low response rate and frequently observed severe side effects limit its broad benefits. It is partially due to less understanding of the biological regulation of PD-L1. Here, we systematically and comprehensively summarized the regulation of PD-L1 from nuclear chromatin reorganization to extracellular presentation. In PD-L1 and PD-L2 highly expressed cancer cells, a new TAD (topologically associating domain) (chr9: 5,400,000–5,600,000) around CD274 and CD273 was discovered, which includes a reported super-enhancer to drive synchronous transcription of PD-L1 and PD-L2. The re-shaped TAD allows transcription factors such as STAT3 and IRF1 recruit to PD-L1 locus in order to guide the expression of PD-L1. After transcription, the PD-L1 is tightly regulated by miRNAs and RNA-binding proteins via the long 3′UTR. At translational level, PD-L1 protein and its membrane presentation are tightly regulated by post-translational modification such as glycosylation and ubiquitination. In addition, PD-L1 can be secreted via exosome to systematically inhibit immune response. Therefore, fully dissecting the regulation of PD-L1/PD-L2 and thoroughly detecting PD-L1/PD-L2 as well as their regulatory networks will bring more insights in ICB and ICB-based combinational therapy.
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Background Bone marrow stem cell clonal dysfunction by somatic mutation is suspected to affect post-infarction myocardial regeneration after coronary bypass surgery (CABG). Methods Transcriptome and variant expression analysis was...
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Background Bone marrow stem cell clonal dysfunction by somatic mutation is suspected to affect post-infarction myocardial regeneration after coronary bypass surgery (CABG). Methods Transcriptome and variant expression analysis was studied in the phase 3 PERFECT trial post myocardial infarction CABG and CD133<sup>+</sup> bone marrow derived hematopoetic stem cells showing difference in left ventricular ejection fraction (?LVEF) myocardial regeneration Responders ( n= 14; ?LVEF +16% day 180/0) and Non-responders ( n= 9; ?LVEF -1.1% day 180/0). Subsequently, the findings have been validated in an independent patient cohort ( n= 14) as well as in two preclinical mouse models investigating SH2B3 /LNK antisense or knockout deficient conditions. Findings 1. Clinical: R differed from NR in a total of 161 genes in differential expression ( n= 23, q <0?05) and 872 genes in coexpression analysis ( n= 23, q<0?05). Machine Learning clustering analysis revealed distinct R vs NR preoperative gene-expression signatures in peripheral blood acorrelated to SH2B3 ( p< 0.05). Mutation analysis revealed increased specific variants in R vsN R. (R: 48 genes; NR: 224 genes). 2. Preclinical: SH2B3 /LNK-silenced hematopoietic stem cell (HSC) clones displayed significant overgrowth of myeloid and immune cells in bone marrow, peripheral blood, and tissue at day 160 after competitive bone-marrow transplantation into mice. SH2B3 /LNK<sup>?/?</sup> mice demonstrated enhanced cardiac repair through augmenting the kinetics of bone marrow-derived endothelial progenitor cells, increased capillary density in ischemic myocardium, and reduced left ventricular fibrosis with preserved cardiac function. 3. Validation: Evaluation analysis in 14 additional patients revealed 85% R vs NR (12/14 patients) prediction accuracy for the identified biomarker signature. Interpretation Myocardial repair is affected by HSC gene response and somatic mutation. Machine Learning can be utilized to identify and predict pathological HSC response. Funding German Ministry of Research and Education (BMBF): Reference and Translation Center for Cardiac Stem Cell Therapy - FKZ0312138A and FKZ031L0106C, German Ministry of Research and Education (BMBF): Collaborative research center - DFG:SFB738 and Center of Excellence - DFG:EC-REBIRTH), European Social Fonds: ESF/IV-WM-B34-0011/08, ESF/IV-WM-B34-0030/10, and Miltenyi Biotec GmbH, Bergisch-Gladbach, Germany.
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Rheumatoid arthritis (RA) is a chronic systemic autoimmune disease characterized by synovial inflammation and progressive joint destruction and is a primary cause of disability worldwide. Despite the existence of numerous anti-rhe...
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Rheumatoid arthritis (RA) is a chronic systemic autoimmune disease characterized by synovial inflammation and progressive joint destruction and is a primary cause of disability worldwide. Despite the existence of numerous anti-rheumatic drugs, a significant number of patients with RA do not respond or are intolerant to current treatments. Mesenchymal stem/stromal cell (MSCs) therapy represents a promising therapeutic tool to treat RA, mainly attributable to the immunomodulatory effects of these cells. This review comprises a comprehensive analysis of the scientific literature related to preclinical studies of MSC-based therapy in RA to analyse key aspects of current protocols as well as novel approaches which aim to improve the efficacy of MSC-based therapy.
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