NPM1 is one of the most frequent acquired mutated genes in acute myeloid leukemia (AML). Previous studies have shown that NPM1 mutation (NPMc+) established the distinctive gene expression signatures, ...which were associated with mixed lineage leukemia (MLL)-target genes, like MEIS1 and HOXA cluster. In AML carrying MLL fusion-oncoproteins, DOT1L-mediated histone 3 lysine 79 (H3K79) methylation is implicated in the regulation of MLL-target genes. Compared with MLL abnormalities, NPM1 variants preserve the similar transcriptional characteristics. However, whether NPM1 mutation could affect the histone modification of H3K79 methylation is unknown. In this study, we showed that NPM1 mutation dysregulated the homeostasis of hematopoietic stem and progenitor cells and resulted in ageing-related myeloproliferation in NPMc+ transgenic mouse model. Interestingly, through scanning the chromatin modification related gene profiling, di- and tri- methylated H3K79 were significantly elevated in bone marrow (BM) Lin-Sca-1+c-Kit+ cells (LSKs) of NPMc+ mice comparing to wild type (WT). Meanwhile, in the leukemia cell lines and AML primary BM samples, we confirmed that NPM1 mutated cells expressed the higher level of H3K79 methylation. In vitro assays also indicated that the decrease or increase of methylated H3K79 could be regulated respectively by knockdown or overexpression of NPM1 mutant but not WT. Importantly, with DOT1L inhibitor treatment, reduced di- and tri- methylated H3K79 was observed in OCI-AML3 (NPMc+) strains but not OCI-AML2 (NPM1 WT) cells. In contrast with OCI-AML2, DOT1L inhibitor significantly promoted the cell apoptosis and restrained the cell cycle of OCI-AML3. Moreover, by the means of murine BM colony formation assay, DOT1L inhibitor obviously weakened myeloid cell proliferation in NPMc+ mice, while colony number in WT group did not change. Also, leukemia development was repressed in OCI-AML3-xenografted NOD/SCID mice with the treatment of DOT1L inhibitor. Taken together, NPM1 mutation contributes to hematological dysfunction by disrupting H3K79 methylation, which could be largely attenuated by DOT1L inhibitor.
No relevant conflicts of interest to declare.
A selenium–quercetin complex (SEQC) was synthesized and its structure was identified by IR, LC-MS and
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H-NMR. Its biochemical effects on bovine serum albumin (BSA) were studied by measuring its ...molecular spectra including three-dimensional fluorescence, ultraviolet and circular dichroism (CD) spectra. The interaction of SEQC and BSA is discussed in terns of fluorescence quenching and Förster’s non-radiation energy transfer theory. The thermodynamic parameters
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were calculated at different temperatures and the results indicate that the interaction is an endothermic as well as an entropy generating process. The binding site was explored by the fluorescence probe technique using warfarin and ibuprofen as markers. It was found that around body temperature hydrophobic forces maintained the average distance from the tryptophan residue in domain II of BSA (donor) to SEQC (acceptor) at 3.76 nm. The conformational changes of BSA were investigated by three-dimensional fluorescence and circular dichroism spectra.
Conventional fabrication methods lack the ability to control both macro- and micro-structures of generated scaffolds. Three-dimensional printing is a solid free-form fabrication method that provides ...novel ways to create customized scaffolds with high precision and accuracy. In this study, an electrically controlled cortical impactor was used to induce randomized brain tissue defects. The overall shape of scaffolds was designed using rat-specific anatomical data obtained from magnetic resonance imaging, and the internal structure was created by computer- aided design. As the result of limitations arising from insufficient resolution of the manufacturing process, we magnified the size of the cavity model prototype five-fold to successfully fabricate customized collagen-chitosan scaffolds using three-dimensional printing. Results demonstrated that scaffolds have three-dimensional porous structures, high porosity, highly specific surface areas, pore connectivity and good internal characteristics. Neural stem cells co-cultured with scaffolds showed good viability, indicating good biocompatibility and biodegradability. This technique may be a promising new strategy for regenerating complex damaged brain tissues, and helps pave the way toward personalized medicine.
ObjectiveSeveral laboratory and imaging assays are required to diagnose multiple myeloma (MM). Serum and urine immunofixation electrophoresis are two key assays to diagnose MM, while they have not ...been extensively utilized in Chinese hospitals. Serum light chain (sLC), β2 microglobulin (β2-MG), lactic dehydrogenase (LDH), and immunoglobulin (Ig) are routinely measured in the majority of Chinese hospitals. Imbalance of sLC ratio (involved light chain/uninvolved light chain) is frequently observed in MM patients. This study aimed to evaluate the screening value of sLC ratio, β2-MG, LDH, and Ig in MM patients using receiver operating characteristic (ROC) curves.MethodsData of 303 suspected MM patients, who were admitted to the Taizhou Central Hospital between March 2015 and July 2021, were retrospectively analyzed. In total, 69 patients (MM arm) met the International Myeloma Working Group (IMWG) updated criteria for the diagnosis of MM, while 234 patients were non-MM (non-MM arm). All patients' sLC, β2-MG, LDH, and Ig were measured using commercially available kits according to the manufacturer's instructions. The ROC curve analysis was employed to assess the screening value of sLC ratio, β2-MG, LDH, creatinine (Cr) and Ig. The statistical analysis was carried out by SPSS 26.0 (IBM, Armonk, NY, USA) and MedCalc 19.0.4 (Ostend, Belgium) software.ResultsThere was no significant difference between the MM and non-MM arms in terms of gender, age and Cr. The median sLC ratio in the MM arm was 11.5333, which was significantly higher than that of 1.9293 in the non-MM arm (P<0.001). The area under the curve (AUC) of sLC ratio was 0.875, which indicated a robust screening value. The optimal sensitivity and specificity were 81.16% and 94.87% respectively, when the sLC ratio was set as 3.2121. The serum levels of β2-MG and Ig were higher in the MM arm than those in the non-MM arm (P<0.001). The AUC values of β2-MG, LDH, and Ig were 0.843 (P<0.001), 0.547 (P = 0.2627), and 0.723 (P<0.001), respectively. The optimal cutoff values of β2-MG, LDH, and Ig were 1.95 mg/L, 220 U/L, and 46.4 g/L respectively, in the context of screening value. The triple combination of sLC ratio (3.2121), β2-MG (1.95 mg/L), and Ig (46.4 g/L) yielded a higher screening value compared with that of sLC ratio alone (AUC, 0.952; P<0.0001). The triple combination had a sensitivity of 94.20% and a specificity of 86.75%. The addition of LDH to the triple combination and formation of quadruple combination did not optimize the screening value, with AUC, sensitivity, and specificity of 0.952, 94.20%, and 85.47%, respectively.ConclusionThe triple combination strategy (sLC ratio, 3.2121; β2-MG, 1.95 mg/L; Ig, 46.4 g/L) is accompanied by remarkable sensitivity and specificity for screening MM in Chinese hospitals.
Probiotics as antibiotic alternatives for preventing and controlling infectious diseases are a relatively eco-friendly strategy in aquaculture. The bacteriocin-producing probiotic Paenibacillus ...ehimensis NPUST1 was isolated from tilapia culture pond water in our previous study. The present study demonstrated that P. ehimensis NPUST1 produced hydrolytic enzymes, including protease, amylase, cellulase, xylanase and lipase. The effects of P. ehimensis NPUST1 on zebrafish nutrient metabolism, growth performance and innate immunity were evaluated by measuring the expression of indicator genes in zebrafish after feeding P. ehimensis NPUST1 at doses of 10sup.6 and 10sup.7 CFU/g for 8 weeks. There was an obvious increase in the hepatic mRNA expression of carbohydrate metabolism-related genes, including glucokinase, hexokinase 1, glucose-6-phosphatase, and pyruvate kinase, and growth-related genes, including the growth hormone receptor and insulin-like growth factor-1. The expression of the innate immune-related genes including interleukin (IL)-1β, IL-6, IL-15, tumor necrosis factor-α, toll-like receptor (TLR)-1, TLR-4, complement component C3b and lysozyme were significantly increased in P. ehimensis NPUST1-supplemented fish. A significant reduction in cumulative mortality was exhibited in P. ehimensis NPUST1-supplemented fish after infection with Aeromonas hydrophila and Streptococcus iniae. In conclusion, our data suggested that P. ehimensis NPUST1 supplementation in feed could potentially improve nutrient metabolism and growth in addition to enhancing innate immunity and disease resistance against A. hydrophila and S. iniae in zebrafish.
Knowledge graph completion focuses on how to improve the missing information in knowledge graph. Knowledge graph completion task has many applications, for example, it can be applied to the knowledge ...graph of rail transit system to support the system design and maintenance optimization. The existing algorithm has high time com-plexity for the real knowledge graph, and it does not make good use of the data out of the knowledge graph. In view of the above two limitations, this paper proposes a knowledge graph completion framework based on active learning. Combined with the idea of active learning, this framework uses link prediction to predict the top-k pairs of entities which are most likely to generate links in the missing knowledge graph. The framework fully considers the internal and external information, and uses the combination of the internal data of the knowledge graph and the external data to realize the missing completion of the knowledge graph. Based on Freebase and DBpedia datasets, a comparative ex
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Inhibition of β-site amyloid precursor protein cleaving enzyme 1 (BACE1) to prevent brain β-amyloid (Aβ) peptide’s formation is a potential effective approach to treat Alzheimer’s ...disease. In this report we described a structure-based optimization of a series of BACE1 inhibitors derived from an iminopyrimidinone scaffold W-41 (IC50 = 7.1 μM) by Wyeth, which had good selectivity and brain permeability but low activity. The results showed that occupying the S3 cavity of BACE1 enzyme could be an effective strategy to increase the biological activity, and five compounds exhibited stronger inhibitory activity and higher liposolubility than W-41, with L-5 was the most potent inhibitor against BACE1 (IC50 = 0.12 μM, logP = 2.49).
We have theoretically investigated the control of wave-vector filtering (WVF) by introducing δ-doping into a magnetically modulated nanostructure fabricated by depositing ferromagnetic stripes on top ...and bottom of a GaAs/AlxGa1 -xAs heterostructure. With the help of an improved transfer matrix method, the Schrödinger equation for electrons in this semiconductor nanostructure is solved exactly and the transmission efficient calculated numerically. We demonstrate that the WVF efficiency is associated closely with the weight and position of the δ-doping, which may be helpful for designing a controllable electron-momentum filter based on such a magnetically modulated semiconductor nanostructure.
•E2C16-g-GO was successfully fabricated as a novel FSPCM.•It was the first time that E2C16 was grafted onto GO nanosheets, the reaction parameters were explored and determined.•E2C16-g-GO has ...excellent thermal properties for thermal energy storage and long-term application.
A novel form-stable phase change material (FSPCM), namely, diethylene glycol hexadecyl ether-grafted graphene oxide (E2C16-g-GO), was fabricated by an esterification reaction. As E2C16 was modified with GO for the first time, the optimal E2C16 and GO reactant ratio and reaction time were determined to be 6:1 and 6 h, respectively. The successful synthesis and chemical structure of E2C16-g-GO were confirmed by various spectroscopy and microscopy techniques. The thermal properties and stability of E2C16-g-GO were characterized by DSC and TGA. The melting and crystallization points of E2C16-g-GO are 43.3 °C and 29.4 °C, respectively. The latent heats of melting and crystallization are 70 and 72 J/g, respectively. The degradation temperature of E2C16-g-GO is approximately 20 °C higher than that of E2C16, indicating that it has good thermal stability. Furthermore, E2C16-g-GO exhibits good shape-stability and excellent thermal reliability and structural stability, indicating that it is a promising FSPCM for energy storage applications.
In a cell line (NB4) derived from a patient with acute promyelocytic leukemia, all-trans-retinoic acid (ATRA) and interferon (IFN) induce the expression of a novel gene we call RIG-G (for retinoic ...acid-induced gene G). This gene codes for a 58-kDa protein containing 490 amino acids with several potential sites for post-translational modification. In untreated NB4 cells, the expression of RIG-G is undetectable. ATRA treatment induces the transcriptional expression of RIG-G relatively late (12-24 hr) in a protein synthesis-dependent manner, whereas IFN-α induces its expression early (30 min to 3 hr). Database search has revealed a high-level homology between RIG-G and several IFN-stimulated genes in human (ISG54K, ISG56K, and IFN-inducible and retinoic acid-inducible 58K gene) and some other species, defining a well conserved gene family. The gene is composed of two exons and has been mapped by fluorescence in situ hybridization to chromosome 10q24, where two other human IFN-stimulated gene members are localized. A synergistic induction of RIG-G expression in NB4 cells by combined treatment with ATRA and IFNs suggests that a collaboration exists between their respective signaling pathways.
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