Abstract Background Exosomes are nanometer-sized vesicles that are released by normal and neoplastic cells. Previous studies have focused on the interaction between tumour-derived exosomes and the ...immune system, as a consequence of immune suppression or enhancement. However, the effects of tumour-derived exosomes on tumour cells themselves have not been well studied. Aims To investigate the effects of gastric cancer exosomes on tumour cell proliferation and the possible mechanisms. Methods By serial centrifugation and sucrose gradient ultracentrifugation, we isolated and purified the exosomes from gastric cancer SGC7901 cells, then viewed them by electron microscopy. Cell proliferation was measured by 3-(4,5-dimethylthiazol)-2,5-diphenyltetrazolium bromide assay. Protein expression was assayed by Western blotting. Results SGC7901-cell-derived exosomes promoted the proliferation of SGC7901 and BGC823 cells. The increase in proliferation induced by exosomes was accompanied by activation of Akt and extracellular-regulated protein kinase, and phosphoinositide 3-kinase or extracellular-regulated protein kinase inhibitor partially reversed the proliferative effect of exosomes. Moreover, the exosome-induced increase in activity of Akt and extracellular-regulated protein kinase coincided with decreased expression of the Casitas B-lineage lymphoma family of ubiquitin ligases. Conclusion Gastric cancer exosomes promoted tumour cell proliferation, at least in part, by activation of PI3K/Akt and mitogen-activated protein kinase/extracellular-regulated protein kinase pathways. The decreased expression of Casitas B-lineage lymphoma proteins might have contributed to the activation of Akt and extracellular-regulated protein kinase.
To better direct repair following spinal cord injury (SCI), we designed an implant modeled after the intact spinal cord consisting of a multicomponent polymer scaffold seeded with neural stem cells. ...Implantation of the scaffold-neural stem cells unit into an adult rat hemisection model of SCI promoted long-term improvement in function (persistent for 1 year in some animals) relative to a lesion-control group. At 70 days postinjury, animals implanted with scaffold-plus-cells exhibited coordinated, weight-bearing hindlimb stepping. Histology and immunocytochemical analysis suggested that this recovery might be attributable partly to a reduction in tissue loss from secondary injury processes as well as in diminished glial scarring. Tract tracing demonstrated corticospinal tract fibers passing through the injury epicenter to the caudal cord, a phenomenon not present in untreated groups. Together with evidence of enhanced local GAP-43 expression not seen in controls, these findings suggest a possible regeneration component. These results may suggest a new approach to SCI and, more broadly, may serve as a prototype for multidisciplinary strategies against complex neurological problems.
Hypoxic-ischemic injury is a prototype for insults characterized by extensive tissue loss. Seeding neural stem cells (NSCs) onto a polymer scaffold that was subsequently implanted into the infarction ...cavities of mouse brains injured by hypoxia-ischemia allowed us to observe the multiple reciprocal interactions that spontaneously ensue between NSCs and the extensively damaged brain: parenchymal loss was dramatically reduced, an intricate meshwork of many highly arborized neurites of both host- and donor-derived neurons emerged, and some anatomical connections appeared to be reconstituted. The NSC-scaffold complex altered the trajectory and complexity of host cortical neurites. Reciprocally, donor-derived neurons were seemingly capable of directed, target-appropriate neurite outgrowth (extending axons to the opposite hemisphere) without specific external instruction, induction, or genetic manipulation of host brain or donor cells. These "biobridges" appeared to unveil or augment a constitutive reparative response by facilitating a series of reciprocal interactions between NSC and host, including promoting neuronal differentiation, enhancing the elaboration of neural processes, fostering the re-formation of cortical tissue, and promoting connectivity. Inflammation and scarring were also reduced, facilitating reconstitution.
We investigated whether permeability transition-mediated release of mitochondrial cytochrome c is a potential therapeutic target for treating acute spinal cord injury (SCI). Based on previous ...reports, minocycline, a second-generation tetracycline, exerts neuroprotection partially by inhibiting mitochondrial cytochrome c release and reactive microgliosis. We first evaluated cytochrome c release at the injury epicenter after a T10 contusive SCI in rats. Cytochrome c release peaked at ≈4-8 h postinjury. A dose-response study generated a safe pharmacological regimen that enabled i.p. minocycline to significantly lower cytosolic cytochrome c at the epicenter 4 h after SCI. In the long-term study, i.p. minocycline (90 mg/kg administered 1 h after SCI followed by 45 mg/kg administered every 12 h for 5 days) markedly enhanced long-term hind limb locomotion relative to that of controls. Coordinated motor function and hind limb reflex recoveries also were improved significantly. Histopathology suggested that minocycline treatment alleviated later-phase tissue loss, with significant sparing of white matter and ventral horn motoneurons at levels adjacent to the epicenter. Furthermore, glial fibrillary acidic protein and 2′,3′ cyclic nucleotide 3′ phosphodiesterase immunocytochemistry showed an evident reduction in astrogliosis and enhanced survival of oligodendrocytes. Therefore, release of mitochondrial cytochrome c is an important secondary injury mechanism in SCI. Drugs with multifaceted effects in antagonizing this process and microgliosis may protect a proportion of spinal cord tissue that is clinically significant for functional recovery. Minocycline, with its proven clinical safety, capability to cross the blood-brain barrier, and demonstrated efficacy during a clinically relevant therapeutic window, may become an effective therapy for acute SCI.
Single-step genomic best linear unbiased prediction (ssGBLUP) is now intensively investigated and widely used in livestock breeding due to its beneficial feature of combining information from both ...genotyped and ungenotyped individuals in the single model. With the increasing accessibility of whole-genome sequence (WGS) data at the population level, more attention is being paid to the usage of WGS data in ssGBLUP. The predictive ability of ssGBLUP using WGS data might be improved by incorporating biological knowledge from public databases. Thus, we extended ssGBLUP, incorporated genomic annotation information into the model, and evaluated them using a yellow-feathered chicken population as the examples. The chicken population consisted of 1 338 birds with 23 traits, where imputed WGS data including 5 127 612 single nucleotide polymorphisms (SNPs) are available for 895 birds. Considering different combinations of annotation information and models, original ssGBLUP, haplotype-based ssGHBLUP, and four extended ssGBLUP incorporating genomic annotation models were evaluated. Based on the genomic annotation (GRCg6a) of chickens, 3 155 524 and 94 837 SNPs were mapped to genic and exonic regions, respectively. Extended ssGBLUP using genic/exonic SNPs outperformed other models with respect to predictive ability in 15 out of 23 traits, and their advantages ranged from 2.5 to 6.1% compared with original ssGBLUP. In addition, to further enhance the performance of genomic prediction with imputed WGS data, we investigated the genotyping strategies of reference population on ssGBLUP in the chicken population. Comparing two strategies of individual selection for genotyping in the reference population, the strategy of evenly selection by family (SBF) performed slightly better than random selection in most situations. Overall, we extended genomic prediction models that can comprehensively utilize WGS data and genomic annotation information in the framework of ssGBLUP, and validated the idea that properly handling the genomic annotation information and WGS data increased the predictive ability of ssGBLUP. Moreover, while using WGS data, the genotyping strategy of maximizing the expected genetic relationship between the reference and candidate population could further improve the predictive ability of ssGBLUP. The results from this study shed light on the comprehensive usage of genomic annotation information in WGS-based single-step genomic prediction.
Blade-health monitoring is intensely required for turbomachinery because of the high failure risk of rotating blades. Blade-Tip Timing (BTT) is considered as the most promising technique for ...operational blade-vibration monitoring, which obtains the parameters that characterize the blade condition from recorded signals. However, its application is hindered by severe undersampling and stringent probe layouts. An inappropriate probe layout can make most of the existing methods invalid or inaccurate. Additionally, a general conflict arises between the allowed and required layouts because of arrangement restrictions. For the sake of economy and safety, parameter identification based on fewer probes has been preferred by users. In this work, a spatial-transformation-based method for parameter identification is proposed based on a single-probe BTT measurement. To present the general Sampling-Aliasing Frequency (SAFE) map definition, the traditional time–frequency analysis methods are extended to a time-sampling frequency. Then, a SAFE map is projected onto a parameter space using spatial transformation to extract the slope and intercept parameters, which can be physically interpreted as an engine order and a natural frequency using coordinate transformation. Finally, the effectiveness and robustness of the proposed method are verified by simulations and experiments under uniformly and nonuniformly variable speed conditions.
To explore the genetic features and signatures of selection in indigenous pigs from South China and Duroc pigs, 259 pigs from six populations were genotyped using single-nucleotide polymorphism (SNP) ...BeadChips. Principal component analysis (PCA), effective population size (Ne), linkage disequilibrium (LD), and signatures of selection were explored and investigated among the six pig populations. The results showed the Ne of five South China indigenous pig populations has been decreasing rapidly since 100 generations ago. The LD between pairwise SNP distance at 100 kb ranged from 0.16 to 0.20 for the five indigenous pig populations, while it was 0.32 for the Duroc population. However, the LD of all six pig populations showed the opposite order at long distances (>5 Mb). Furthermore, 15 potential signatures of selection associated with meat quality and age at puberty were exclusively detected in South China indigenous pigs, while eight potential signatures of selection associated with growth traits were detected in Duroc pigs. Our work provides valuable insights for the utilization and conservation of South China indigenous pigs.
N-Heterocyclic carbenes (NHCs) prove to be efficient catalysts for the aza-Morita−Baylis−Hillman (aza-MBH) reaction of cyclopent-2-en-1-one or cyclohex-2-en-1-one with a variety of N-tosylarylimines ...to give the aza-MBH adduct in high yields. Crossover experiments show NHC can add to N-tosylarylimines in a reversible manner, which allows the addition of NHC to cyclic enones and thus catalyzes the aza-Mortia−Baylis−Hillman reaction.
Human non-small cell lung carcinoma (NSCLC) is one of the most common cancer worldwide. In previous studies, lovastatin, acting as an inhibitor of 3-hydroxy-3-methylglutaryl Co A (HMG-CoA) reductase, ...exhibited significant antitumor activity during tumorigenesis. However, whether or not this effect is mediated through changes in minichromosome maintenance (MCM) 2 expression remains unclear. The present study investigated whether lovastatin inhibits proliferation due to MCM2 in NSCLCs. We first assessed the effects of lovastatin on cell anti-proliferation, cell cycle progression and apoptosis in NSCLC cells. We found, by quantitative RT-PCR and western blot analysis, that lovastatin treatment markedly and consistently inhibited the expression of MCM2. Then, to further explore the anticancer mechanism of lovastatin involving MCM2, we silenced MCM2 by siRNA in two cell lines (A549 and GLC-82). Silencing of MCM2 triggered G1/S arrest. Following further examination of cell cycle-related factors, MCM2 knockdown inhibited protein retinoblastoma (Rb), cyclin D1 and CDK4 expression, but increased p21 and p53 expression, suggesting that siMCM2 indeed triggered cell cycle arrest. In addition, siMCM2 induced apoptosis. Finally, lovastatin treatment increased p-JNK, which is involved in the downregulation of MCM2. In conclusion, our data suggest that MCM2 may be a novel therapeutic target of lovastatin treatment in NSCLCs.
An accurate local bond–slip model is of fundamental importance in the modelling of FRP-strengthened RC structures. In this paper, a review of existing bond strength models and bond–slip models is ...first presented. These models are then assessed using the results of 253 pull tests on simple FRP-to-concrete bonded joints, leading to the conclusion that a more accurate model is required. In the second half of the paper, a set of three new bond–slip models of different levels of sophistication is proposed. A unique feature of the present work is that the new bond–slip models are not based on axial strain measurements on the FRP plate; instead, they are based on the predictions of a meso-scale finite element model, with appropriate adjustment to match their predictions with the experimental results for a few key parameters. Through comparisons with the large test database, all three bond–slip models are shown to provide accurate predictions of both the bond strength (i.e. ultimate load) and the strain distribution in the FRP plate.
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