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1.
Molecules ; 25(3)2020 Jan 28.
Artigo em Inglês | MEDLINE | ID: mdl-32013003

RESUMO

The crystal structure of the sorafenib and B-RAF complex indicates that the binding cavity occupied by the pyridine-2-carboxamide in sorafenib has a large variable space, making it a reasonable modification site. In order to identify novel compounds with anti-cancer activity, better safety and polar groups for further application, five sorafenib analogs with new pyridine-2-amide side chains were designed and synthesized. Preliminary pharmacologic studies showed that these compounds displayed much lower toxicities than that of sorafenib. Among them, compound 10b bearing mercaptoethyl group kept relevant antiproliferation potency compared to sorafenib in Huh7 and Hela cell lines with values of IC50 58.79 and 63.67 M, respectively. As a small molecule inhibitor targeting protein tyrosine kinases, thiol in compound 10b would be an active group to react with maleimide in a mild condition for forming nanoparticles Sorafenib-PEG-DGL, which could be developed as a delivery vehicle to improve the concentration of anti-tumor therapeutic agents in the target cancer tissue and reduce side effects in the next study.

2.
Nat Mater ; 2020 Feb 03.
Artigo em Inglês | MEDLINE | ID: mdl-32015537

RESUMO

The quantum anomalous Hall (QAH) effect is a consequence of non-zero Berry curvature in momentum space. The QAH insulator harbours dissipation-free chiral edge states in the absence of an external magnetic field. However, the topological Hall (TH) effect, a hallmark of chiral spin textures, is a consequence of real-space Berry curvature. Here, by inserting a topological insulator (TI) layer between two magnetic TI layers, we realized the concurrence of the TH effect and the QAH effect through electric-field gating. The TH effect is probed by bulk carriers, whereas the QAH effect is characterized by chiral edge states. The appearance of the TH effect in the QAH insulating regime is a consequence of chiral magnetic domain walls that result from the gate-induced Dzyaloshinskii-Moriya interaction and occurs during the magnetization reversal process in the magnetic TI sandwich samples. The coexistence of chiral edge states and chiral spin textures provides a platform for proof-of-concept dissipationless spin-textured spintronic applications.

3.
J Cell Physiol ; 2020 Feb 04.
Artigo em Inglês | MEDLINE | ID: mdl-32017073

RESUMO

Prostate cancer (PCa) is a common malignancy with a high tendency for metastasis. Epithelial-mesenchymal transition (EMT) plays a crucial role in PCa metastasis. Metabolic reprogramming offers metabolic advantages for cancer development and could result in the discovery of novel targets for cancer therapy. However, the metabolic features of PCa cells undergoing EMT remain unclear. We used metabolome and transcriptome analyses and found that PCa cells undergoing EMT showed impaired glucose utilization. In vitro studies demonstrated that PCa cells undergoing EMT were less addicted to glucose than epithelial-like PCa cells. However, cells that underwent EMT had higher levels of aspartate and its downstream metabolites, indicative of upregulated aspartate metabolism. As aspartate is a contributor for EMT and metastasis in human cancer cells, we conclude that this metabolic reprogramming may play a vital role in EMT and PCa progression.

4.
Mol Cell Endocrinol ; : 110742, 2020 Jan 29.
Artigo em Inglês | MEDLINE | ID: mdl-32006608

RESUMO

Epidemiological evidence suggests that the etiology and pathogenesis of rheumatoid arthritis (RA) are closely associated with estrogen metabolism and deficiency. Estrogen protects against articular damage. Estradiol replacement therapy ameliorates local inflammation and knee joint swelling in ovariectomized models of RA. The mechanistic basis for the protective role of 17ß-estradiol (17ß-E2) is poorly understood. Acid-sensing ion channel 1a (ASIC1a), a sodium-permeable channel, plays a pivotal role in acid-induced articular chondrocyte injury. The aims of this study were to evaluate the role of 17ß-E2 in acid-induced chondrocyte injury and to determine the effect of 17ß-E2 on the level and activity of ASIC1a protein. Results showed that pretreatment with 17ß-E2 attenuated acid-induced damage, suppressed apoptosis, and restored mitochondrial function. Further, 17ß-E2 was shown to reduce protein levels of ASIC1a through the autophagy-lysosomal pathway, to protect chondrocytes from acid-induced apoptosis, and to induce ASIC1a protein degradation through the ERα receptor. Taken together, these results show that the use of 17ß-E2 may be a novel strategy for the treatment of RA by reducing cartilage destruction through down-regulation of ASIC1a protein levels.

5.
J Ethnopharmacol ; : 112614, 2020 Jan 30.
Artigo em Inglês | MEDLINE | ID: mdl-32007630

RESUMO

ETHNOPHARMACOLOGICAL RELEVANCE: Harpagide is the main ingredient in Scrophularia ningpoensis Hemsl which is used for the therapeutic purpose of treating encephalopathy. Harpagide has shown promise in the treatment of oxygen-glucose deprivation and reoxygenation (OGD/R)-induced brain injury. However, the underlying mechanisms remain unclear. AIM OF STUDY: In this study, we aimed to determine the neuroprotective effect of harpagide on rat cortical neurons under OGD/R conditions that induce the development of ischaemia-reperfusion (I/R). MATERIALS AND METHODS: To explore the biological function of harpagide in cerebral ischaemia-reperfusion injury (CIRI), The CIRI model was established by oxygen-glucose deprivation and reoxygenation (OGD/R) on rat cortical neurons. It tested cell survival rate by 3-(4,5-dimethylthiazol-2-thiazolyl)-2,5-diphenyl-2-H-tetrazolium bromide (MTT) assay, apoptosis by flow cytometry, intracellular Ca2+ concentration [Ca2+] i by cofocal laser, and expressions related to endoplasmic reticulum stress (ERS) by RT-PCR and Western blot. RESULTS: We found that pretreatment with harpagide (50 µM) prevented OGD/R-induced apoptotic cell death. Harpagide also significantly decreased the gene expression levels and protein production of ERS-related proteins. We found that harpagide also exerted a neuroprotective effect on TG-induced apoptosis in rat cortical neurons and decreased the gene expression levels and protein production of GRP78, caspase-12 and CHOP. We also measured the intracellular calcium ion concentration ([Ca2+]i) in neurons and found that harpagide significantly decreased the [Ca2+]i induced by OGD/R and TG. CONCLUSION: These results suggest that harpagide protects against OGD/R-induced cell apoptosis, likely by decreasing ERS. Collectively, harpagide was demonstrated to be a prominent suppressor of ERS and prevented the apoptosis of rat cortical neurons. Based on the results, harpagide could potentially serve as a therapeutic agent of ischaemia-like injury associated with excessive ERS and apoptosis.

6.
Bioresour Technol ; 302: 122883, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-32006923

RESUMO

The metabolic function and organic degradation behavior of bacterial and fungal communities were detected in 60 days composting of chicken manure and pumice by using Biolog tools, PICRUSt and FUNGuild. Fungal diversity increased from 57 OTUs in fresh chicken manure to 109 OTUs in high temperature stage, while bacterial diversity decreased from 86 OTUs to 44 OTUs after composting treatment. The carbohydrates degradation ability of bacterial community was enhanced in the high temperature stage. Fungal community had relatively higher degradation rates of carboxylic acids and amino acids in the maturation stage. Saprotroph was the main trophic mode of fungal community during the incubation process. The fungal animal pathogen decreased from 12.5% to 1.2% after composting treatment. Bacterial community composition and substrates degradation rate were mainly influenced by redox potential, pH and moisture, while temperature was the main environmental factor influencing on organic degradation of fungal community.

7.
Theriogenology ; 146: 20-25, 2020 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-32036056

RESUMO

The down syndrome cell adhesion molecule like 1 (DSCAML1), is associated with the development of the nervous system and neurologic diseases. Previous Genome-wide association studies have shown that it is associated with sperm morphology, suggesting it has a critical role in fecundity. In this study, expression profiles of goat DSCAML1 mRNA were analyzed. The results showed that its expression in the testis differ significantly between the mitotic stage and meiotic stage. Three insertion/deletion (indel) variants of goat DSCAML1 were determined in the Shaanbei White Cashmere Goat (SWCG, n = 2162). Based on the association analysis, two indels (P2-16bp, P14-15bp) were significantly related to sperm quality (sperm motility and sperm density) in male goat and three loci were markedly related to the first-birth litter size in female goat (P = 4.0 × 10-6; P = 1.0 × 10-6; P = 4.7 × 10-2). In male goats, the different genotypes of P2-16bp and P14-15bp revealed a noticeable effect on the expression of DSCAML1. Moreover, the effects observed in the first-birth litter followed a similar trend, which may provide the basis for further research of DSCAML1 gene function and marker assisted selection (MAS) programs to improve reproductive traits.

8.
Stem Cell Res Ther ; 11(1): 58, 2020 Feb 13.
Artigo em Inglês | MEDLINE | ID: mdl-32054528

RESUMO

BACKGROUND: Skeletal unloading can induce severe disuse osteopenia that often occurs in spaceflight astronauts or in patients subjected to prolonged bed-rest or immobility. Previously, we revealed a mechano-sensitive factor, miRNA-132-3p, that is closely related to the osteoblast function. The aim of this study was to investigate whether miRNA-132-3p could be an effective target for treating disuse osteopenia. METHODS: The 2D-clinostat device and the hindlimb-unloaded (HU) model were used to copy the mechanical unloading condition at the cellular and animal levels, respectively. Mimics or inhibitors of miRNA-132-3p were used to interfere with the expression of miRNA-132-3p in bone marrow-derived mesenchymal stem cells (BMSCs) in vitro for analyzing the effects on osteogenic differentiation. The special in vivo antagonists of miRNA-132-3p was delivered to the bone formation regions of HU mice for treating disuse osteopenia by a bone-targeted (AspSerSer)6-cationic liposome system. The bone mass, microstructure, and strength of the hindlimb bone tissue were analyzed for evaluating the therapeutic effect in vivo. RESULTS: miRNA-132-3p expression was declined under normal conditions and increased under gravitational mechanical unloading conditions during osteogenic differentiation of BMSCs in vitro. The upregulation of miRNA-132-3p expression resulted in the inhibition of osteogenic differentiation, whereas the downregulation of miRNA-132-3p expression enhanced osteogenic differentiation. The inhibition of miRNA-132-3p expression was able to attenuate the negative effects of mechanical unloading on BMSC osteogenic differentiation. Most importantly, the targeted silencing of miRNA-132-3p expression in the bone tissues could effectively preserve bone mass, microstructure, and strength by promoting osteogenic differentiation and osteogenesis in HU mice. CONCLUSION: The overexpression of miRNA-132-3p induced by mechanical unloading is disadvantageous for BMSC osteogenic differentiation and osteogenesis. Targeted silencing of miRNA-132-3p expression presents a potential therapeutic target for the prevention and treatment of disuse osteoporosis.

9.
Sensors (Basel) ; 20(3)2020 Feb 07.
Artigo em Inglês | MEDLINE | ID: mdl-32046078

RESUMO

Local patch-based methods of object detection and pose estimation are promising. However, to the best of the authors' knowledge, traditional red-green-blue and depth (RGB-D) patches contain scene interference (foreground occlusion and background clutter) and have little rotation invariance. To solve these problems, a new edge patch is proposed and experimented with in this study. The edge patch is a local sampling RGB-D patch centered at the edge pixel of the depth image. According to the normal direction of the depth edge, the edge patch is sampled along a canonical orientation, making it rotation invariant. Through a process of depth detection, scene interference is eliminated from the edge patch, which improves the robustness. The framework of the edge patch-based method is described, and the method was evaluated on three public datasets. Compared with existing methods, the proposed method achieved a higher average F1-score (0.956) on the Tejani dataset and a better average detection rate (62%) on the Occlusion dataset, even in situations of serious scene interference. These results showed that the proposed method has higher detection accuracy and stronger robustness.

11.
Medicine (Baltimore) ; 99(6): e18776, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-32028390

RESUMO

Liangshan Yi Autonomous Prefecture in Southwest China has a high human immunodeficiency virus (HIV) prevalence rate. This study examined the changing modes of HIV transmission among women with new HIV infections and explored the spatial heterogeneities in the factors associated with heterosexual transmission in this minority region.The data consisting of women with new HIV infections from 2011 to 2014 were collected from multiple sources. New infections were identified by BED capture enzyme immunoassay. The Bayesian hierarchical model was used to estimate the proportion of women with new HIV infections via heterosexual transmission across all townships in the Prefecture. A geographically weighted regression (GWR) model was utilized to investigate spatial variations in the sociodemographic characteristics associated with the changing modes of HIV transmission.An analytical sample of 927 women with new HIV infections was constructed and utilized to investigate the changing mode of HIV transmission. The rate of heterosexual transmission among women with new HIV infections in 2011 was below 20%. However, by 2014 this rate dramatically increased to nearly 80%. Among sociodemographic characteristics, GWR results revealed significant ethnic differences in heterosexual HIV transmission between Yi women and women in other ethnic groups, with Yi women demonstrating a lower risk of infection through heterosexual transmission. However, such ethnic differences were observed only in 30% of the townships in the Prefecture. Moreover, having a primary education decreased the odds of heterosexual transmission, which was observed in about 56% of the townships. Also, being involved in occupations other than agriculture or animal husbandry and being single or married decreased the odds of HIV infection through heterosexual contact among women, which did not significantly vary across the Prefecture.Heterosexual transmission was the predominant mode of HIV transmission among women in the Prefecture, and this transformation was clearly marked by a fast-growing trend and a spatial diffusion pattern. Spatial variations also existed in sociodemographic factors that were associated with the changing modes of HIV transmission.

12.
Breast Cancer ; 2020 Jan 03.
Artigo em Inglês | MEDLINE | ID: mdl-32030658

RESUMO

BACKGROUND: To date, anatomic tumor length is a key criterion for cancer staging and can be used to evaluate the effectiveness of therapies. This article describes growth pattern that can be used as a new characteristic to represent disease burden and tumor features and predict lymphatic metastasis. METHODS: Patients with breast cancer were included in this 10-year (1999-2008) hospital-based multicenter retrospective study. The pathologic length/height ratio was used to illustrate the correlation between tumor features, behaviors and treatments in breast malignancies. The most appropriate ratio was chosen based on the comprehensive evaluation of p value and changing trend of each characteristic. RESULTS: The sample consisted of 4211 women diagnosed with breast cancer. Among them, 2037 patients with complete pathologic length, width and height information were included in the final analysis. There were 2.34 ± 4.77 metastatic lymph nodes for spheroid tumors and 3.21 ± 5.82 for ellipsoid tumors when the cutoff point was 2. In addition, the proportion of ellipsoidal tumors gradually increased from 54.36 to 56.67% in the upper outer quadrant (UOQ) and from 6.7 to 9.03% in the central region with an increase in the cutoff point. The proportion of ER + PR + ellipsoid tumors significantly decreased from 50.1 to 45.35% and that of ER-PR ellipsoid tumors significantly increased from 32.73 to 36.24% with an increase in the cutoff point. Additionally, the best length/weight ratio to distinguish spheroid and ellipsoid tumors was 2. CONCLUSION: This study described for the first time how growth pattern is correlated with tumor malignancy and how it influences the selection of therapeutic strategies for patients.

13.
Histol Histopathol ; : 18198, 2020 Jan 09.
Artigo em Inglês | MEDLINE | ID: mdl-31916583

RESUMO

BACKGROUND: Studies have shown that estrogen can protect the function of the sublingual gland, but the specific mechanism is still unclear. Besides, the STIM1/Orai1 pathway is important to secretion in the salivary gland. Here, we explore the possible effects of estrogen on sublingual gland function by observing changes of STIM1 and Orai1 levels in the sublingual glands of ovariectomized rats. METHODS: 42 adult female Sprague-Dawley rats were randomly divided into three groups: SHAM, OVX, and OVX+E (n = 14 per group). Two weeks after ovariectomy, rats were treated with estrogen (ß-estradiol). The expression of STIM1 and Orai1 in the sublingual gland were observed by double label-immunohistochemistry and immunofluorescence. Calcium imaging was conducted to observe changes in cellular Ca²âº levels. RESULTS: IHC and IF showed that the levels of both STIM1 and Orai1 decreased following ovariectomy, but increased to SHAM levels after estrogen treatment. By IF, STIM1 and Orai1 exhibited perfect co-localization. Calcium imaging results showed that the Ca²âº in the cells decreased after ovariectomy. Estrogen intervention returned levels of these proteins and Ca²âº to the same as those in the control group. CONCLUSION: This study demonstrates that low estrogen status significantly reduced the expression of STIM1 and Orai1 in the sublingual gland of rats, along with cellular Ca²âº levels. These data provide insight into the likely mechanisms underlying sublingual gland secretion dysfunction during menopause.

14.
Phys Chem Chem Phys ; 22(5): 2938-2948, 2020 Feb 07.
Artigo em Inglês | MEDLINE | ID: mdl-31951234

RESUMO

Eukaryotic translation initiation factor 4E binding protein 2 (4E-BP2) is an inhibitor of mRNA cap-dependent translations. Wild-type (WT) 4E-BP2 is intrinsically disordered under physiological conditions, while phosphorylation converts the disordered fragments 18-62 into a four-stranded ß-sheet structure. The regulation mechanism of phosphorylation on 4E-BP2 still remains ambiguous. In this study, replica-exchange molecular dynamics (REMD) simulations were utilized to sample the conformation spaces of WT, phosphorylated WT (pWT), and phosphorylated mutated (pMT) 4E-BP2. Starting from extended structures, the folded structures were only observed in pWT simulations. The folding pathway shows that the folded structures of pWT are formed in the order of ß1/ß4, ß3, and ß2. The formation of ß-turns on pWT, which are driven by hydrogen bonds between the phosphorylated residues and adjacent residues, are the rate-limiting steps in the folding process. The long-range electrostatic interactions contribute toward the stabilization of the folded structures. Moreover, the disruption of ß-turn structures induced by mutations would prevent the folding of pMT 4E-BP2. Our finding is helpful in understanding the regulation of the structural ensembles of intrinsically disordered proteins.

15.
J Phys Chem A ; 124(4): 721-730, 2020 Jan 30.
Artigo em Inglês | MEDLINE | ID: mdl-31917920

RESUMO

The reaction of ethyl propyl ether (EnPE) with OH radicals was studied using proton-transfer-reaction mass spectrum (PTR-MS), and the rate constant was measured at 298 K and atmospheric pressure using the relative rate method: kexp(OH+EnPE) = (1.13 ± 0.09) × 10-11 cm3 molecules-1 s-1. In addition, a parallel theoretical study was performed using the traditional transition state theory (TST) with a tunnelling effect correction in combination at M05-2X method with two basis sets, 6-311++G(d,p) and aug-cc-pVTZ. According to these calculations, H atom abstraction occurs more favorably from the methylene group adjacent to the -O- bond than from the other groups. The theoretical calculation of the total rate constant of the reaction of EnPE with OH radicals was consistent with the experimental values. The gas-phase products indicated that the major products observed were ethyl formate, ethyl propionate, propionic acid. Combined with the experimental and theoretical results, the possible reaction mechanisms were proposed and discussed. The atmospheric implications of the studied reaction are presented, and the lifetime of EnPE in the presence of OH radicals was evaluated to be approximately 1 day.

16.
World Neurosurg ; 2020 Jan 09.
Artigo em Inglês | MEDLINE | ID: mdl-31926359

RESUMO

OBJECTIVE: To study the natural growth dynamics of skull base chordomas. METHODS: A retrospective study of skull base chordomas was performed. Patients with ≥2 preoperative magnetic resonance (MR) images and with pathologically confirmed chordomas were enrolled. All clinical data and MR images were studied. RESULTS: Twenty-one patients with pathologically confirmed skull base chordomas were enrolled. The mean volume of the tumors at diagnosis was 19.9 ± 17.0 cm3, with a mean interval examination period of 22.4 ± 26.1 (range, 3-113) months. The mean tumor volume change was approximately 15.4 ± 16.3 cm3. The mean specific growth rate was 8% ± 9% per month, and the mean specific growth volume was 0.8 ± 0.7 cm3 per month. The tumor MR signal index grade, female gender, no dura mater breakthrough, endophytic type, small tumors, and soft tumor texture were related to a higher tumor growth rate (P < 0.05), and small tumors showed the greatest growth rate compared with the middle-sized and large tumors. Curve estimation was performed using a power function (R2 = 0.545). CONCLUSIONS: The skull base chordoma is a slow-growing tumor. The cases involving characteristics of female gender, endophytic type, small tumor size, and MR grade 3 showed a higher growth rate.

17.
Radiology ; : 191470, 2020 Jan 14.
Artigo em Inglês | MEDLINE | ID: mdl-31934830

RESUMO

Background Early stage hepatocellular carcinoma (HCC) is the ideal candidate for resection in patients with preserved liver function; however, cancer will recur in half of these patients and no reliable prognostic tool has been established. Purpose To investigate the effectiveness of radiomic features in predicting tumor recurrence after resection of early stage HCC. Materials and Methods In total, 295 patients (median age, 58 years; interquartile range, 50-65 years; 221 men) who underwent contrast material-enhanced CT and curative resection for early stage HCC that met the Milan criteria between February 2009 and December 2016 were retrospectively recruited from three independent institutions. Follow-up consisted of serum α-fetoprotein level, liver function tests, and dynamic imaging examinations every 3 months during the first 2 years and then every 6 months thereafter. In the development cohort of 177 patients from institution 1, recurrence-related radiomic features were computationally extracted from the tumor and its periphery and a radiomics signature was built with least absolute shrinkage and selection operator regression. Two models, one integrating preoperative and one integrating pre- and postoperative variables, were created by using multivariable Cox regression analysis. An independent external cohort of 118 patients from institutions 2 and 3 was used to validate the proposed models. Results The preoperative model integrated radiomics signature with serum α-fetoprotein level and tumor number; the postoperative model incorporated microvascular invasion and satellite nodules into the above-mentioned predictors. In both study cohorts, two radiomics-based models provided better predictive performance (concordance index ≥0.77, P < .05 for all), lower prediction error (integrated Brier score ≤0.14), and larger net benefits, as determined by means of decision curve analysis, than rival models without radiomics and widely adopted staging systems. The radiomics-based models gave three risk strata with high, intermediate, or low risk of recurrence and distinct profiles of recurrent tumor number. Conclusion The proposed radiomics models with pre- and postresection features helped predict tumor recurrence for early stage hepatocellular carcinoma. © RSNA, 2020 Online supplemental material is available for this article.

18.
Methods Mol Biol ; 2090: 147-166, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-31975167

RESUMO

The Multiple Sequentially Markovian Coalescent (MSMC) is a population genetic method and software for inferring demographic history and population structure through time from genome sequences. Here we describe the main program MSMC and its successor MSMC2. We go through all the necessary steps of processing genomic data from BAM files all the way to generating plots of inferred population size and separation histories. Some background on the methodology itself is provided, as well as bash scripts and python source code to run the necessary programs. The reader is also referred to community resources such as a mailing list and github repositories for further advice.

19.
Plant J ; 2020 Jan 10.
Artigo em Inglês | MEDLINE | ID: mdl-31923329

RESUMO

Anthocyanin biosynthesis is induced by low temperatures in a number of plants. However, in peach (cv Zhonghuashoutao), anthocyanin accumulation was observed in fruit stored at 16°C but not at or below 12°C. Fruit stored at 16°C showed elevated transcript levels of genes encoding anthocyanin biosynthetic enzymes, the transport protein glutathione S-transferase and key transcription factors. Higher transcript levels of PpPAL1/2, PpC4H, Pp4CL4/5/8, PpF3H, PpF3'H, PpDFR1/2/3 and PpANS, as well as transcription factor gene PpbHLH3, were associated with lower methylation levels in the promoter of these genes. The DNA methylation level was further highly correlated with the expression of the DNA methyltransferase genes and DNA demethylase genes. The application of DNA methylation inhibitor 5-azacytidine induced anthocyanin accumulation in peach flesh, further implicating a critical role for DNA demethylation in regulating anthocyanin accumulation in peach flesh. Our data reveal that temperature-dependent DNA demethylation is a key factor to the post-harvest temperature-dependent anthocyanin accumulation in peach flesh.

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