1,747,729 research outputs found
Exosomes derived from human umbilical cord blood mesenchymal stem cells improve hepatic ischemia reperfusion injury via delivering miR-1246
No full textThe purpose of this study was to explore the associated mechanism by which MSCs-derived exosomes exerted protective effect in hepatic ischemia/reperfusion injury (IRI). Human umbilical cord blood mesenchymal stem cells (hUCB-MSCs)-derived exosomes were administrated into LO2 cells exposed to hypoxia/reoxygenation (H/R) and mice subjected to IRI. Cell viability was assessed by CCK-8 assay. Apoptosis was analyzed by flow cytometry and TUNEL staining. The expression of miR-1246 and Wnt/β-catenin pathway-related proteins was detected by quantitative real-time PCR (qRT-PCR) and western blotting. The concentration of pro-inflammatory cytokines was determined by ELISA. Luciferase activity assay was performed to confirm the interaction between miR-1246 and glycogen synthase kinase 3β (GSK3β). Hepatic function was assessed by determining serum alanine amino transferase (ALT) and aspartate amino transferase (AST) levels. Histological changes were observed using hematoxylin-eosin (H&E) staining. MiR-1246 was significantly downregulated in H/R-treated LO2 cells. Treatment with exosomes derived from hUCB-MSCs led to miR-1246 upregulation. Furthermore, hUCB-MSCs-derived exosomes induced anti-apoptotic and pro-survival effects in LO2 cells and ameliorated IRI-induced hepatic dysfunction in mice, while treatment of exosomes from miR-1246 inhibitor-transfected hUCB-MSCs showed opposite effect, which was mediated by regulating GSK3β-Wnt/β-catenin pathway. Collectively, hUCB-MSCs-derived exosomes alleviated hepatic IRI by transporting miR-1246 via regulating GSK3β-mediated Wnt/β-catenin pathway.</p
Untersuchungen zur Maturierung der microRNA-1246
No full textDie microRNA-1246 (miR-1246) wird in der Literatur als potentieller Biomarker beschrieben. Im Widerspruch dazu stehen Daten, die die Klassifikation der miR-1246 als microRNA-Molekül anzweifeln. Es stellte sich die Frage, ob miR-1246 überhaupt existiert oder eine Kreuzreaktion mit der teilweise Sequenz-identischen U2 snRNA (RNU2-1) aus dem Spleißosom-Komplex für eine Fehldetektion verantwortlich ist. Es wurde eine Spezifitäts-Analyse der qRT-PCR-Methode zur miR-1246-Detektion durchgeführt, die nahe legt, dass das miR-1246-Signal wahrscheinlich ein U2 snRNA-Signal ist. Zudem wurde ein Modellsystem zur Überexpression des endogenen miR-1246-Vorläufers primary-miR-1246 in einer humanen Pankreaskarzinom-Zelllinie generiert, welches veranschaulicht, dass trotz erfolgreicher Expression des Vorläufer-Transgens keine reife (mature) miR-1246 in der Zelle hergestellt wird. Diese Daten legen nahe, dass miR-1246 eine Pseudo-microRNA ist und die miR-1246-Literatur neu bewertet werden muss
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No full textT-cell-mediated immunity is crucial in the immunopathology of periodontitis. The restoration of the homeostasis between the T helper cell 17 (Th17) and regulatory T cell (Treg) subsets by extracellular vesicles (EVs) obtained from human bone marrow stem cells (hBMSCs) promotes new bone formation and suppresses inflammation. Uncovering the functions of hBMSC-derived EVs in the immune microenvironment of periodontal tissue and their underlying regulatory mechanisms may shed new light on developing potential cell-free immunotherapies for periodontal regeneration. Here, we reported that the Th17/Treg ratio elevated in peripheral blood from periodontitis patients. Furthermore, we found that hBMSC-derived EVs could reduce the Th17/Treg ratio in CD4+ T cells from periodontitis patients in vitro and ameliorate conditions of experimental periodontitis in mice. Additionally, by investigating the differentially expressed miRNAs and target genes in EVs from hBMSCs stimulated with Porphyromonas gingivalis LPS using miRNA sequencing, we found that EV-miR-1246 is highly effective at downregulating the ratio of Th17/Treg in vitro. Mechanistically, EV-miR-1246 suppressed expression of its potential target angiotensin-converting enzyme 2 (ACE2) and increased the p-Yes-associated protein (YAP)1/YAP1 ratio in CD4+ T cells. Our results indicated that hBMSC-derived EVs improve periodontitis via miR-1246, consequently downregulating Th17/Treg ratio, and represented a promising therapeutic target for precision treatment in periodontitis.</p
The Process of Generating Single Large Combined Cloud for Grid-Free Solvers
Full text linkDealing with moving body problems, where one component moves relatively with respect to other, is a difficult task in CFD due to the efforts needed in grid handling for every delta change in position of the moving component. The inherent nature of mesh-free solvers reduces the efforts needed for these kinds of problems by operating on a cloud of points rather than a grid. A new method to handle moving body problems is proposed, where individual clouds are generated around each component and are combined into a single large combined cloud. The proposed method is applied to store separation problem and results generated using NAL-MCIR mesh-less solver is compared with experimental results
The origin of exosomal miR-1246 in human cancer cells
No full textmiR-1246 is considered an oncomiR in various cancer types. However, the origin and biogenesis of miR-1246 remain controversial which often leads to misinterpretation of its detection and biological function, and inevitably masking its mechanisms of action. Using next generation small RNA sequencing, CRISPR-Cas9 knockout, siRNA knockdown and the poly-A tailing SYBR qRT-PCR, we examined the biogenesis of exosomal miR-1246 in human cancer cell model systems. We found that miR-1246 is highly enriched in exosomes derived from human cancer cells and that it originates from RNU2-1, a small nuclear RNA and essential component of the U2 complex of the spliceosome. Knockdown of Drosha and Dicer did not reduce exosomal miR-1246 levels, indicating that exosomal miR-1246 is generated in a Drosha- and Dicer-independent manner. Direct digestion of cellular lysate by RNase A and knockdown of the RNU2-1 binding protein SmB/B’ demonstrated that exosomal miR-1246 is a RNU2-1 degradation product. Furthermore, the GCAG motif present in the RUN2-1 transcript was shown to mediate miR-1246 enrichment in cancer exosomes. We conclude that exosome miR-1246 is derived from RNU2-1 degradation through a non-canonical microRNA biogenesis process. These findings reveal the origin of an oncomiR in human cancer cells, providing guidance in understanding miR-1246 detection and biological function. Abbreviations: CRISPR, Clustered Regularly Interspaced Short Palindromic Repeats; miRNA, microRNA; PDAC, pancreatic ductal adenocarcinoma; RNU2-1, U2 small nuclear RNA; RT-PCR, Reverse transcription polymerase chain reaction; sgRNA, single-guide RNA.</p
The TESS-Keck Survey. XI. Mass Measurements for Four Transiting sub-Neptunes orbiting K dwarf TOI-1246
Full text linkMulti-planet systems are valuable arenas for investigating exoplanet architectures and comparing planetary siblings. TOI-1246 is one such system, with a moderately bright K dwarf (V=11.6, K=9.9) and four transiting sub-Neptunes identified by TESS with orbital periods of 4.31 d, 5.90 d, 18.66 d, and 37.92 d. We collected 130 radial velocity observations with Keck/HIRES and TNG/HARPS-N to measure planet masses. We refit the 14 sectors of TESS photometry to refine planet radii (2.97±0.06 R⊕,2.47±0.08 R⊕,3.46±0.09 R⊕, 3.72±0.16 R⊕), and confirm the four planets. We find that TOI-1246 e is substantially more massive than the three inner planets (8.1±1.1M⊕, 8.8±1.2M⊕, 5.3±1.7M⊕, 14.8±2.3M⊕). The two outer planets, TOI-1246 d and TOI-1246 e, lie near to the 2:1 resonance (Pe/Pd=2.03) and exhibit transit timing variations. TOI-1246 is one of the brightest four-planet systems, making it amenable for continued observations. It is one of only six systems with measured masses and radii for all four transiting planets. The planet densities range from 0.70±0.24 to 3.21±0.44g/cm3, implying a range of bulk and atmospheric compositions. We also report a fifth planet candidate found in the RV data with a minimum mass of 25.6 ± 3.6 M⊕. This planet candidate is exterior to TOI-1246 e with a candidate period of 93.8 d, and we discuss the implications if it is confirmed to be planetary in nature
Pharmacological Characterization of KUR-1246, a Selective Uterine Relaxant
No full textABSTRACT The aim of the present study was to evaluate the efficacy and 2-adrenoceptor (AR) selectivity of KUR-1246, a new uterine relaxant. Inhibition of spontaneous or drug-induced uterine contractions by KUR-1246 was evaluated in pregnant rats and rabbits by an organ bath method or by a balloon method. The selectivity of KUR-1246 was assessed simultaneously in organs isolated from late-pregnant rats. The affinity of KUR-1246 for human 1-, 2-, and 3-ARs was determined using two radioligands. KUR-1246 suppressed both spontaneous and druginduced contractions in isolated uteri, the rank order of potency being isoproterenol Ͼ KUR-1246 Ͼ terbutaline Ͼ ritodrine. ICI-118551 (selective 2-AR antagonist) competitively antagonized the KUR-1246-induced inhibition of spontaneous uterine contractions, but CGP-20712A (selective 1-AR antagonist) and SR-58894A (selective 3-AR antagonist) did not. All -AR agonists tested produced significant inhibition of spontaneous uterine contractions in vivo: ED 30 value for KUR-1246 was 0.13 g/kg/min, a potency about 6 times and 400 times greater than that of terbutaline and ritodrine, respectively. In contrast, the positive chronotropic effect was minimal in KUR-1246-treated rats. KUR-1246 displaced radioligand binding to 1-, 2-, and 3-ARs, the pK i values being 5.75 Ϯ 0.03, 7.59 Ϯ 0.08, and 4.75 Ϯ 0.03 for 1-, 2-, and 3-ARs, respectively. , indicating an apparently higher affinity for human 2-AR than for other -AR subtypes. The present study clearly demonstrated that KUR-1246 is a more selective 2-AR agonist than the drugs presently used for relaxing uterine muscle
Going Beyond Counting First Authors in Author Co-citation Analysis
Full text linkThe present study examines one of the fundamental aspects of author co-citation analysis (ACA) - the way co-citation
counts are defined. Co-citation counting provides the data on which all subsequent statistical analyses and mappings
are based, and we compare ACA results based on two different types of co-citation counting - the traditional type that
only counts the first one among a cited work's authors on the one hand and a non-traditional type that takes into
account the first 5 authors of a cited work on the other hand. Results indicate that the picture produced through this non-traditional author co-citation counting contains more coherent author groups and is therefore considerably clearer. However, this picture represents fewer specialties in the research field being studied than that produced through the traditional first-author co-citation counting when the same number of top-ranked authors is selected and analyzed. Reasons for these effects are discussed
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