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1.
J Neural Eng ; 2021 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-33524961

RESUMO

OBJECTIVE: Motor imagery (MI) is a mental representation of motor behavior and a widely used pattern in electroencephalogram (EEG) based brain-computer interface (BCI) systems. EEG is known for its non-stationary, non-linear features and sensitivity to artifacts from various sources. This study aimed to design a powerful classifier with a strong generalization capability for MI based BCIs. APPROACH: In this study, we proposed a cluster decomposing based ensemble learning framework (CDECL) for EEG classification of MI based BCIs. The EEG data was decomposed into sub-data sets with different distributions by clustering decomposition. Then a set of heterogeneous classifiers was trained on each sub-data set for generating a diversified classifier search space. To obtain the optimal classifier combination, the ensemble learning was formulated as a multi-objective optimization problem and a stochastic fractal based binary multi-objective fruit fly optimization algorithm was proposed for solving the ensemble learning problem. MAIN RESULTS: The proposed method was validated on two public EEG datasets (BCI Competition IV datasets IIb and BCI Competition IV dataset IIa) and compared with several other competing classification methods. Experimental results showed that the proposed CDECL based methods can effectively construct a diversity ensemble classifier and exhibits superior classification performance in comparison with several competing methods. SIGNIFICANCE: The proposed method is promising for improving the performance of MI-based BCIs.

2.
Int J Neural Syst ; : 2150004, 2021 Jan 12.
Artigo em Inglês | MEDLINE | ID: mdl-33438531

RESUMO

Tactile P300 brain-computer interface (BCI) generally has a worse accuracy and information transfer rate (ITR) than the visual-based BCI. It may be due to the fact that human beings have a relatively poor tactile perception. This study investigated the influence of visual attention on the performance of a tactile P300 BCI. We designed our paradigms based on a novel cheeks-stim paradigm which attached the stimulators on the subject's cheeks. Two paradigms were designed as follows: a paradigm with no visual attention and another paradigm with visual attention to the target position. Eleven subjects were invited to perform the two paradigms. We also recorded and analyzed the eyeball movement data during the paradigm with visual attention to explore whether the eyeball movement would have an effect on the BCI classification. The average online accuracy was 89.09% for the paradigm with visual attention, which was significantly higher than that of the paradigm with no visual attention (70.45%). Significant difference in ITR was also found between the two paradigms ([Formula: see text]). The results demonstrated that visual attention was an effective method to improve the performance of tactile P300 BCI. Our findings suggested that it may be feasible to complete an efficient tactile BCI system by adding visual attention.

3.
Mil Med Res ; 8(1): 5, 2021 01 21.
Artigo em Inglês | MEDLINE | ID: mdl-33472705

RESUMO

BACKGROUND: Heat stroke (HS) is an acute physical disorder that is associated with a high risk of organ dysfunction and even death. HS patients are usually treated symptomatically and conservatively; however, there remains a lack of specific and effective drugs in clinical practice. An analysis of publication contributions from institutions, journals and authors in different countries/regions was used to study research progress and trends regarding HS. METHODS: We extracted all relevant publications on HS between 1989 and 2019 from Web of Science. Using the Statistical Package for Social Science (SPSS, version 24) and the software GraphPad Prism 8, graphs were generated and statistical analyses were performed, while VOSviewer software was employed to visualize the research trends in HS from the perspectives of co-occurring keywords. RESULTS: As of April 14, 2020, we identified 1443 publications with a citation frequency of 5216. The United States accounted for the largest number of publications (36.2%) and the highest number of citations (14,410), as well as the highest H-index at 74. Although the sum of publications from China ranked second, there was a contradiction between the quantity and quality of publications. Furthermore, Medicine & Science in Sports & Exercise published the most papers related to HS, with Lin MT publishing the most papers in this field (112), while the review by Knochel JP received the highest citation frequency at 969. The keyword heat-stress appeared most recently, with an average appearing year of 2015.5. In the clinical research cluster, exertional heat-stroke was determined to be the hotspot, while ambient-temperature and heat waves were the new trends in the epidemiological research cluster. CONCLUSIONS: Corresponding to this important field, while the contributions of the publications from the United States were significant, the mismatch between the quantity and quality of publications from China must be examined. Moreover, it is hypothesized that clinical and epidemiological studies may become hotspots in the near future.

4.
Ecotoxicol Environ Saf ; 207: 111224, 2021 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-32890955

RESUMO

The roots of 4 japonica, 4 indica, and 7 hybrid rice varieties were obtained by hydroponic experiment and used to explore the relationship between charge characteristics and exchangeable manganese(II) (Mn(II)) on rice roots and Mn(II) absorption in roots and shoots of the rice. Results indicated Mn(II) adsorbed on rice roots mainly existed as exchangeable Mn(II) after 2 h. The roots of indica and hybrid rice carried more negative charges than the roots of japonica rice. Accordingly, this led to more exchangeable Mn(II) to be adsorbed on roots of indica and hybrid rice after 2 h and more Mn(II) absorbed in the roots of the same varieties after 48 h. However, this was contrary to the result of Mn(II) absorption in rice shoots after 48 h. Coexisting cations of K+, Na+, Ca2+, and Mg2+ reduced the exchangeable Mn(II) on rice roots through their competition with Mn(II) for sorption sites on rice roots, which led to the decrease in Mn(II) absorption in rice roots and shoots. Ca2+ and Mg2+ showed a greater decrease in the Mn(II) absorbed in roots and shoots than K+ and Na+. The reduction of Mn(II) absorption in the roots of indica rice and hybrid rice induced by Ca2+ and Mg2+ was more than that of japonica rice. This was attributed to more negative charges on the roots of the former than the latter. Therefore, the absorption of Mn(II) by rice roots was determined by surface charge properties and exchangeable Mn(II) on the rice roots. The results suggested that Ca2+ and Mg2+ have potential to alleviate Mn(II) toxicity to rice.


Assuntos
Manganês/toxicidade , Oryza/metabolismo , Poluentes do Solo/toxicidade , Adsorção , Manganês/metabolismo , Oryza/efeitos dos fármacos , Raízes de Plantas/efeitos dos fármacos , Poluentes do Solo/metabolismo
5.
Environ Pollut ; 267: 115590, 2020 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-33254607

RESUMO

The rapid increase in soil acidification rate has led to a decrease in global agricultural productivity owing to the debilitating effects of Al and Mn toxicities. In this study, we investigated the adaptation of plants to acidic conditions by examining the behavior of plant roots grown in hydroponic solution and pot experiments at different pHs. The Mn(II) sorption by the roots was investigated and the mechanisms involved were deduced by analyzing the changes in the zeta potential and functional groups on the root surface. The exchangeable, complexed, and precipitated Mn(II) on plant roots were extracted sequentially with 1 M KNO3, 0.05 M EDTA-2Na, and 0.01 M HCl. The results of hydroponic experiment indicated that plant roots subjected to NH4+ treatment carried lower negative charge and fewer functional groups owing to acidic pH condition induced by NH4+ uptake of roots, when compared with plant roots treated with NO3-. Similarly, in pot experiments, the surface negative charge and functional groups of plant roots cultured in soils with lower pH were fewer than those on plant roots cultured in soils with higher pH, with the former presenting less exchangeable and complexed Mn(II) sorption than the latter. Thus, alterations in the charge properties and number of functional groups on the surface of plant roots are some of the mechanisms used by plants to adapt to acidic soil condition.

6.
Nat Commun ; 11(1): 5704, 2020 11 11.
Artigo em Inglês | MEDLINE | ID: mdl-33177525

RESUMO

Neurofibromatosis type I (NF1) is characterized by prominent skeletal manifestations caused by NF1 loss. While inhibitors of the ERK activating kinases MEK1/2 are promising as a means to treat NF1, the broad blockade of the ERK pathway produced by this strategy is potentially associated with therapy limiting toxicities. Here, we have sought targets offering a more narrow inhibition of ERK activation downstream of NF1 loss in the skeleton, finding that MEKK2 is a novel component of a noncanonical ERK pathway in osteoblasts that mediates aberrant ERK activation after NF1 loss. Accordingly, despite mice with conditional deletion of Nf1 in mature osteoblasts (Nf1fl/fl;Dmp1-Cre) and Mekk2-/- each displaying skeletal defects, Nf1fl/fl;Mekk2-/-;Dmp1-Cre mice show an amelioration of NF1-associated phenotypes. We also provide proof-of-principle that FDA-approved inhibitors with activity against MEKK2 can ameliorate NF1 skeletal pathology. Thus, MEKK2 functions as a MAP3K in the ERK pathway in osteoblasts, offering a potential new therapeutic strategy for the treatment of NF1.

8.
Huan Jing Ke Xue ; 41(9): 4197-4209, 2020 Sep 08.
Artigo em Chinês | MEDLINE | ID: mdl-33124301

RESUMO

Heavy metals (HMs) are naturally occurring elements that have high natural background levels in the environment. Therefore, it is important to conduct ecological risk assessment and identify potential sources of HMs. In the past, studies were conducted at the regional scale. The accuracy of those studies could not meet the needs of spatial planning and natural resource management. Therefore, it is necessary to conduct ecological risk assessment at the township scale. In this study, 1092 soil samples (from 0-20 cm depth) were collected in the town of Reshui, an area with high background levels of soil HMs with the parent material of carbonatite, which is commonly found in Southwest China. The town of Reshui is a multi-ecological risk superimposed area where the ecological risk is high. In this study, concentrations of HMs (Cd, Cr, As, Hg, Pb, Cu, Zn, and Ni) in the topsoil were analyzed, and statistical analysis (SA), geographic information system (GIS) modeling, and positive matrix factorization (PMF) analysis were performed. The geoaccumulation index (Igeo) and potential ecological risk index (PERI) were applied for the ecological risk assessment and quantification of the sources of the soil HMs. The mean values of HM concentrations in the topsoil were 18.1, 1.18, 174.1, 202.2, 0.09, 71.1, 34.9, and 167.2 mg ·kg-1for As, Cd, Cr, Cu, Hg, Ni, Pb, and Zn, respectively, which were considerably higher than the average background value (ABV) in soils in Yunnan Province except for As and Pb. The average concentrations of Cd, Cr, Cu, and Ni exceeded the screening values specified in the soil contamination risk in agricultural land (GB 15618-2018) by 5.82, 1.16, 4.04, and 1.02 times, respectively. The Igeo value shows that the major pollutant is Cu in the surface soil of the study area, followed by Cr, and Cd. Speciation analysis of HMs indicates that HMs (Cr, As, Pb, Cu, Zn, and Ni) mainly exist in the residual form, mostly from the geological background with low bioavailability. The potential effective components of Hg have higher levels, but the total amount of Hg and its pollution risk are lower. Cd has a high bioavailability ratio, is easy to enter the soil solution and be absorbed by crops, and is the HM with the highest pollution risk in the study area. The PERI shows that the proportions of low ecological risk, moderate risk, and high risk soil samples are 44.23%, 54.40%, and 1.37% of the total number of samples, respectively. Hg and Cd were the major sources of risk because of their high toxicity coefficient. The PMF analysis indicates that there are four major sources of HMs in the study area: human activity, natural sources, coal mining and traffic emissions, and agricultural sources with the risk contribution ratios of 9.29%, 53.67%, 11.23%, and 25.81%, respectively. The PMF analysis effectively quantified the ecological risk from these sources, providing a reference for further pollution control and prevention measures.


Assuntos
Metais Pesados , Poluentes do Solo , China , Cidades , Monitoramento Ambiental , Humanos , Metais Pesados/análise , Medição de Risco , Solo , Poluentes do Solo/análise
9.
Front Immunol ; 11: 570524, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33117360

RESUMO

Liver fibrosis can result from various causes and could progress to cirrhosis and cancer; however, there are no effective treatments due to that its molecular mechanism is unclear. liver fibrosis model made by Schistosoma japonicum (S. japonicum) infection or Carbon tetrachloride (CCl4) intraperitoneal injection is a conventional model used in liver fibrosis-related studies for mechanism or pharmaceutical research purposes. But the differences in the pathological progression, immune responses and the underlying mechanism between the two liver fibrosis model have not been carefully compared and characterized, which hinders us from correctly understanding and making better use of the two models. In the present study, the pathological changes to the liver, and the cytokines, inflammatory factors, macrophages, and lymphocytes subsets involved were analyzed in the liver fibrosis model of S. japonicum infection or CCl4 intraperitoneal injection. Additionally, the pathological progression, immune responses and the underlying injury mechanism in these two models were compared and characterized. The results showed that the changing trend of interleukin-13 (IL-13), transforming growth factor beta (TGF-ß), inflammatory factors, and M1, M2 macrophages, were consistent with the development trend of fibrosis regardless of whether liver fibrosis was caused by S. japonicum or CCl4. For lymphocyte subsets, the proportions of CD3+ T cells and CD4+ T cells decreased gradually, while proportion of CD8+ T cells peaked at 6 weeks in mice infected with S. japonicum and at 12 weeks in mice injected with CCl4. With prolonged S. japonicum infection time, Th1 (CD4+IFN-γ+) immunity converted to Th2 (CD4+IL-4+)/Th17 (CD4+IL-17+) with weaker regulatory T cell (Treg) (CD4+CD25+FOXP3+) immunity. However, in liver fibrosis caused by CCl4, Th1 cells occupied the dominant position, while proportions of Th2, Th17, and Treg cells decreased gradually. In conclusion, liver fibrosis was a complex pathological process that was regulated by a series of cytokines and immune cells. The pathological progressions and immune responses to S. japonicum or CCl4 induced liver fibrosis were different, possibly because of their different injury mechanisms. The appropriate animal model should be selected according to the needs of different experiments and the pathogenic factors of liver fibrosis in the study.

10.
Brain Sci ; 10(10)2020 Oct 17.
Artigo em Inglês | MEDLINE | ID: mdl-33080842

RESUMO

The evaluation of the level of consciousness in patients with disorders of consciousness (DOC) is primarily based on behavioural assessments. Patients with unresponsive wakefulness syndrome (UWS) do not show any sign of awareness of their environment, while minimally conscious state (MCS) patients show reproducible but fluctuating signs of awareness. Some patients, although with remaining cognitive abilities, are not able to exhibit overt voluntary responses at the bedside and may be misdiagnosed as UWS. Several studies investigated functional neuroimaging and neurophysiology as an additional tool to evaluate the level of consciousness and to detect covert command following in DOC. Most of these studies are based on auditory stimulation, neglecting patients suffering from decreased or absent hearing abilities. In the present study, we aim to assess the response to a P3-based paradigm in 40 patients with DOC and 12 healthy participants using auditory (AEP) and vibrotactile (VTP) stimulation. To this end, an EEG-based brain-computer interface was used at DOC patient's bedside. We compared the significance of the P3 performance (i.e., the interpretation of significance of the evoked P3 response) as obtained by 'direct processing' (i.e., theoretical-based significance threshold) and 'offline processing' (i.e., permutation-based single subject level threshold). We evaluated whether the P3 performances were dependent on clinical variables such as diagnosis (UWS and MCS), aetiology and time since injury. Last we tested the dependency of AEP and VTP performances at the single subject level. Direct processing tends to overestimate P3 performance. We did not find any difference in the presence of a P3 performance according to the level of consciousness (UWS vs. MCS) or the aetiology (traumatic vs. non-traumatic brain injury). The performance achieved at the AEP paradigm was independent from what was achieved at the VTP paradigm, indicating that some patients performed better on the AEP task while others performed better on the VTP task. Our results support the importance of using multimodal approaches in the assessment of DOC patients in order to optimise the evaluation of patient's abilities.

11.
Bone Rep ; 13: 100713, 2020 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-32964075

RESUMO

Considering that stress condition associated with osteoporosis, the hypothalamic-pituitary-adrenal (HPA) axis, which is essential for central stress response system, is implicated in regulating bone mass accrual. Melanocortin 2 receptor (MC2R), the receptor of adrenocorticotropic hormone is expressed in both adrenal gland cells and bone cells. To elucidate the role of HPA axis in bone metabolism, we assessed the skeletal phenotype of MC2R deficient mice (MC2R -/- mice). We first examined bone mineral density and cortical thickness of femur using dual x-ray absorptiometry and micro-computed tomography. We then conducted histomorphometric analysis to calculate the static and dynamic parameters of vertebrae in MC2R -/- mice. The levels of osteoblastic marker genes were examined by quantitative PCR in primary osteoblasts derived from MC2R -/- mice. Based on these observations, bone mineral density of femur in MC2R -/- mice was increasing relative to litter controls. Meanwhile, the thickness of cortical bone of femur in MC2R -/- mice was remarkably elevated. Moreover, serum osteocalcin level was drastically raised in MC2R -/- mice. However, bone histomorphometry revealed that static and dynamic parameters reflecting bone formation and resorption were unchanged in vertebrae of MC2R -/- mice compared to the control, indicating that MC2R function may be specific to appendicular bone than axis bone. Taken together, the HPA axis due to deletion of MC2R is involved in bone metabolism.

12.
Int J Mol Sci ; 21(18)2020 Sep 10.
Artigo em Inglês | MEDLINE | ID: mdl-32927660

RESUMO

Collagen prolyl 4-hydroxylase 1 (C-P4H1) is an α-ketoglutarate (α-KG)-dependent dioxygenase that catalyzes 4-hydroxylation of proline on collagen. C-P4H1-induced prolyl hydroxylation is required for proper collagen deposition and cancer metastasis. Therefore, targeting C-P4H1 is considered a potential therapeutic strategy for collagen-related cancer progression and metastasis. However, no C-P4H1 inhibitors are available for clinical testing, and the high content assay is currently not available for C-P4H1 inhibitor screening. In the present study, we developed a high-throughput screening assay by quantifying succinate, a byproduct of C-P4H-catalyzed hydroxylation. C-P4H1 is the major isoform of collagen prolyl 4-hydroxylases (CP4Hs) that contributes the majority prolyl 4-hydroxylase activity. Using C-P4H1 tetramer purified from the eukaryotic expression system, we showed that the Succinate-GloTM Hydroxylase assay was more sensitive for measuring C-P4H1 activity compared with the hydroxyproline colorimetric assay. Next, we performed high-throughput screening with the FDA-approved drug library and identified several new C-P4H1 inhibitors, including Silodosin and Ticlopidine. Silodosin and Ticlopidine inhibited C-P4H1 activity in a dose-dependent manner and suppressed collagen secretion and tumor invasion in 3D tissue culture. These C-P4H1 inhibitors provide new agents to test clinical potential of targeting C-P4H1 in suppressing cancer progression and metastasis.

13.
J Orthop Res ; 2020 Sep 11.
Artigo em Inglês | MEDLINE | ID: mdl-32915488

RESUMO

Administration of bisphosphonates following total joint arthroplasty might be beneficial to reduce aseptic loosening. However, their effects on peri-implant bone formation and bone-implant interface strength have not been investigated yet. We used a physiologically loaded mouse implant model to investigate the short-term effects of postoperative systemic alendronate on osseointegration. A titanium implant with a rough surface was inserted in the proximal tibiae of 17-week-old female C57BL/6 mice (n = 44). Postimplantation mice were given alendronate (73 µg/kg/days, n = 22) or vehicle (n = 22) 5 days/week. At 7- and 14-day postimplantation, histology and histomorphometry were conducted. At 28 days, microcomputed tomography and biomechanical testing were performed (n = 10/group). Postoperative alendronate treatment enhanced osseointegration, increasing maximum pullout load by 45% (p < .001) from 19.1 ± 4.5 N in the control mice to 27.6 ± 4.9 N in the treated mice, at day 28 postimplantation. Alendronate treatment increased the bone volume fraction by 139% (p < .001) in the region distal to the implant and 60% (p < .05) in the peri-implant region. At 14-day postimplantation, alendronate treatment decreased the number of osteoclasts per bone perimeter (p < .05) and increased bone volume fraction (p < .01) when compared with the control group. Postimplantation, short-term alendronate treatment enhanced osseointegration as demonstrated by increased bone mass, trabecular bone thickness, and maximum pullout load. Alendronate decreased peri-implant osteoclasts while preserving peri-implant osteoblasts and endothelial cells, in turn, increasing bone volume fraction. This data supports the postoperative clinical use of bisphosphonates, especially in patients with high risks of aseptic loosening.

14.
Artigo em Inglês | MEDLINE | ID: mdl-32955666

RESUMO

Variable charge soils have low agricultural productivity associated with low pH, low cation exchange capacity (CEC), and low pH buffering capacity (pHBC). As a result of rapid acidification rates, these soils are prone to infertility resulting from Al phytotoxicity and deficiency of P, Ca, Mg, and K, and thus require amendments that can ameliorate soil acidity and enhance soil CEC and pHBC. A 30-day pot experiment was carried out using a clay Ultisol and a sandy Ultisol amended with straw decayed products (SDPs) of peanut, pea, canola, and rice. The results showed that applying SDPs increased the soil CEC, organic matter content, and exchangeable base cations in the two Ultisols. The ameliorative effects of the SDPs were superior for the sandy Ultisol than for the clay Ultisol. The addition of SDPs significantly increased soil pH and pHBC of the two Ultisols, and simultaneously decreased soil exchangeable Al3+. Among them, the greatest effect was found in the treatment with pea straw decayed products (PeaSD). The soil pHs of clay Ultisol and sandy Ultisol treated with PeaSD were respectively 5.70 and 7.37 and were 1.26 and 2.63 pH units higher than those of control. Also, applying SDPs increased maize seedling biomass in both soils and the most significant effect was found in the treatment with PeaSD, which were 0.97 (clay Ultisol) and 2.5 (sandy Ultisol) times higher than in the respective controls. The results of this study demonstrated that carefully selected straws for SDP production can effectively improve soil chemical properties, enhanced soil pHBC, and thus promote agricultural sustainability.

15.
Pharmacol Ther ; : 107668, 2020 Aug 24.
Artigo em Inglês | MEDLINE | ID: mdl-32853629

RESUMO

Tumor development and progression require chemical and mechanical cues derived from cellular and non-cellular components in the tumor microenvironment, including the extracellular matrix (ECM), cancer-associated fibroblasts (CAFs), endothelial cells, and immune cells. Therefore, it is crucial to develop tissue culture models that can mimic in vivo cancer cell-ECM and cancer-stromal cell interactions. Three-dimensional (3D) tumor culture models have been widely utilized to study cancer development and progression. A recent advance in 3D culture is the development of patient-derived tumor organoid (PDO) models from primary human cancer tissue. PDOs maintain the heterogeneity of the primary tumor, which makes them more relevant for identifying therapeutic targets and verifying drug response. Other significant advances include development of 3D co-culture assays to investigate cell-cell interactions and tissue/organ morphogenesis, and microfluidic technology that can be integrated into 3D culture to mimic vasculature and blood flow. These advances offer spatial and temporal insights into cancer cell-stromal interactions and represent novel techniques to study tumor progression and drug response. Here, we summarize the recent progress in 3D culture and tumor organoid models, and discuss future directions and the potential of utilizing these models to study cancer-stromal interactions and direct personalized treatment.

16.
J Biomed Mater Res A ; 2020 Aug 17.
Artigo em Inglês | MEDLINE | ID: mdl-32803914

RESUMO

OBJECTIVE: After bone prosthesis replacement, M1-type macrophage polarization can be induced by titanium (Ti) particles and produce inflammatory, leading to osteolysis. Adipocyte-derived exosomes (ADEs) exert immune-modulatory impact on the macrophage, while whether it can inhibit the macrophage polarization induced by Ti is unclear. This study focuses on the M1-type macrophage and aims to determine the effect of ADEs on Ti-induced M1-type macrophage polarization in osteolytic mice and the involved mechanism. METHODS: Ti particle-induced osteolysis mouse model was established and macrophages were isolated from the osteolysis site. The levels of NLRP3 and specific markers for M1-type macrophage were determined. ADEs isolated from adipocyte cell line 3T3-L1, or conditioned ADEs with low-expressed miR-34a isolated from 3T3-L1 transfected with miR-34a inhibitor were co-cultured with RAW 264.7 to determine their impact on the polarization of macrophage. RESULTS: ADEs reduced the M1-type macrophage polarization and caused the upregulation of miR-34a in macrophage of the osteolysis site of the osteolysis mouse model. Also, the level of miR-34a in ADEs was higher than that in the adipocyte. The conditioned ADEs expressed a low level of miR-34a and boosted the Ti-induced M1-type polarization. MiR-34a could target NLRP3 and negatively regulated its expression. Moreover, NLRP3 knockdown in macrophage restricted the conditioned ADEs to promote macrophage towards to Ti-induced M1-type polarization. The inhibitory function of ADEs on M1-type macrophage polarization was abolished by miR-34a silencing in the mouse osteolysis model. CONCLUSION: The miR-34a carried by ADEs reduced the polarization of M1-type macrophages by targeting macrophage NLRP3 during Ti particle-induced osteolysis.

17.
J Clin Pathol ; 2020 Aug 17.
Artigo em Inglês | MEDLINE | ID: mdl-32817175

RESUMO

BACKGROUND: The absence of high-quality next-generation sequencing (NGS) reference material (RM) has impeded the clinical use of liquid biopsies with plasma cell-free DNA (cfDNA) in China. OBJECTIVE: This study aimed to develop a national RM panel for external quality assessment and performance evaluation during kit registration of non-small-cell lung cancer (NSCLC)-related Kirsten rat sarcoma viral oncogene (KRAS)/neuroblastoma ras oncogene (NRAS)/epidermal growth factor receptor (EGFR)/B-type Raf kinase (BRAF)/mesenchymal-epithelial transition factor (MET) genetic assays using plasma circulating tumor DNA (ctDNA). METHODS: Mutation cell lines detected by NGS and validated by Sanger sequencing were selected to establish the RM. Cell line genomic DNA was sheared and used to spike basal plasma cfDNA at 10% concentration. Then, the calibration accuracy was determined by four sequencing platforms. Average values were adopted and diluted to 0.1%, 0.3%, 1% and 3% concentrations with basal plasma as the RM panel. Then, five manufacturers were invited to evaluate the performance of the RM panel. RESULTS: 20 cell lines with 23 clinically important mutations were selected, including six mutations in KRAS, two mutations in NRAS, three in BRAF, four in phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha (PIK3CA), six in EGFR, one EGFR Gain (4-5 copy) and one MET Gain (2-5 copy). The RM panel consisted of 87 samples, including these 21 mutations at four concentrations (0.1%, 0.3%, 1% and 3%), one MET gain, one EGFR gain and one wild type. The detection rate was 100% for the 3%, 1% and 0.3% samples at all five companies. For the 0.1% concentration, 15 samples had inconsistent results, but at least three companies had correct results for each mutation. CONCLUSION: RM for a KRAS/NRAS/EGFR/BRAF/MET mutation panel for plasma ctDNA was developed, which will be essential for quality control of the performance of independent laboratories.

18.
J Pharm Biomed Anal ; 190: 113496, 2020 Oct 25.
Artigo em Inglês | MEDLINE | ID: mdl-32768890

RESUMO

In the present study, an accurate, simple and fast bioanalytical method based on ultra performance liquid chromatography tandem mass spectrometry (UPLC-MS/MS) technique for simultaneous quantification of plasma selexipag and its main metabolite ACT-333679 concentrations in rats was optimized and established. The purpose of chromatographic separation of selexipag, ACT-333679 and the internal standard (IS, diazepam) was accomplished using an Acquity BEH C18 (2.1 mm × 50 mm, 1.7 µm) column. The mobile phase was consisted of acetonitrile (solution A) and 0.1 % formic acid in water (solution B) in a linear gradient elution procedure with a flow rate of 0.40 mL/min. The measurement of the analytes and IS was explored using a XEVO TQ-S triple quadrupole tandem mass spectrometer, which was comprised with electrospray ionization (ESI) source in positive ion mode. Selected multiple reaction monitoring (MRM) mode was employed to detect the parent-to-daughter ion transitions as follows: m/z 497.4 → 302.2 for selexipag, m/z 420.1 → 378.2 for ACT-333679, and m/z 285.0 → 154.0 for diazepam (IS), respectively. The new UPLC-MS/MS method showed good linearity respectively at the calibration curve range of 0.05-50 ng/mL for selexipag, and 0.05-250 ng/mL for ACT-333679. The intra- and inter-day of accuracy and precision were all within the acceptable limits in the bioanalytical method, and the results of recovery and matrix effect were also met the requirements. The newly developed UPLC-MS/MS assay was forward successfully used to describe the pharmacokinetic profiles of selexipag and ACT-333679 in rats after oral treatment with 6.0 mg/kg selexipag.

19.
Stem Cells ; 38(10): 1229-1240, 2020 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-32627865

RESUMO

The differentiation and maturation of mesenchymal stem cells (MSCs) to mesodermal and other lineages are known to be controlled by various extrinsic and intrinsic signals. The dysregulation of the MSC differentiation balance has been linked to several pathophysiological conditions, including obesity and osteoporosis. Previous research of the molecular mechanisms governing MSC differentiation has mostly focused on transcriptional regulation. However, recent findings are revealing the underrated role of alternative splicing (AS) in MSC differentiation and functions. In this review, we discuss recent progress in elucidating the regulatory roles of AS in MSC differentiation. We catalogue and highlight the key AS events that modulate MSC differentiation to major osteocytes, chondrocytes, and adipocytes, and discuss the regulatory mechanisms by which AS is regulated.

20.
J Pharm Biomed Anal ; 188: 113386, 2020 Sep 05.
Artigo em Inglês | MEDLINE | ID: mdl-32502954

RESUMO

Pexidartinib was approved in the USA for targeted therapy of adult patients with symptomatic tenosynovial giant cell tumour (TGCT) by the FDA. The purpose of our study was to develop and establish a quick assay based on ultra performance liquid chromatography tandem mass spectrometry (UPLC-MS/MS) for the measurement of pexidartinib concentrations in plasma and to survey whether antifungal drugs (isavuconazole, posaconazole, fluconazole and itraconazole) could change the pharmacokinetic parameters of pexidartinib in rats. After the quick protein crash with acetonitrile, the chromatographic separation of pexidartinib and upadacitinib (used as the internal standard in this study, IS) were conducted on an Acquity BEH C18 (2.1 × 50 mm, 1.7 µm) column, and the detection of the analyte was also accomplished with a Xevo TQ-S triple quadrupole tandem mass spectrometer in the positive ion electro-spray ionization (ESI) interface. The assay showed good linearity in the range of 1-7000 ng/mL. The accuracy and precision were all within the acceptable limits in the bioanalytical method, and the results of recovery, matrix effect, stability, and carry-over were also met the requirements. The application of the validated UPLC-MS/MS bioanalytical method was further successfully involved in the drug-drug interactions study from rats. It was found that fluconazole and itraconazole significantly increased the concentration of pexidartinib and had the inhibitory effect on the metabolism of pexidartinib, while not isavuconazole and posaconazole. Thus, more attention should be paid to the concurrent use of pexidartinib with fluconazole or itraconazole to reduce the risk of unexpected clinical outcomes.

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