Co-expression Network Analysis Identifies Four Hub Genes Associated With Prognosis in Soft Tissue Sarcoma

Background: Soft tissue sarcomas (STS) are heterogeneous tumors derived from mesenchymal cells that differentiate into soft tissues. The prognosis of patients who present with an STS is influenced by the regulation of a complex gene network.Methods: Weighted gene co-expression network analysis (WGCNA) was performed to identify gene modules associated with STS (Samples = 156).Results: Among the 11 modules identified, the black and blue modules were highly correlated with STS. However, using preservation analysis, the black module demonstrated low preservation, therefore the blue module was chosen as the module of interest. Furthermore, a total of 20 network hub genes were identified in the blue module, 12 of which were also hub nodes in the protein-protein interaction network of the module genes. Following additional verification, 4 of 12 genes (RRM2, BUB1B, CENPF, and KIF20A) demonstrated poorer overall survival and disease-free survival rate in the test datasets. In addition, gene set enrichment analysis (GSEA) demonstrated that samples with a high level of blue module eigengene (ME) were enriched in cell cycle and metabolism associated signaling pathways.Conclusion: In summary, co-expression network analysis identified four hub genes associated with prognosis for STS, which may diminish the prognosis by influencing cell cycle and metabolism associated signaling pathways

CDK‐mediated activation of the SCFFBXO28 ubiquitin ligase promotes MYC‐driven transcription and tumourigenesis and predicts poor survival in breast cancer

SCF (Skp1/Cul1/F‐box) ubiquitin ligases act as master regulators of cellular homeostasis by targeting key proteins for ubiquitylation. Here, we identified a hitherto uncharacterized F‐box protein, FBXO28 that controls MYC‐dependent transcription by non‐proteolytic ubiquitylation. SCFFBXO28 activity and stability are regulated during the cell cycle by CDK1/2‐mediated phosphorylation of FBXO28, which is required for its efficient ubiquitylation of MYC and downsteam enhancement of the MYC pathway. Depletion of FBXO28 or overexpression of an F‐box mutant unable to support MYC ubiquitylation results in an impairment of MYC‐driven transcription, transformation and tumourigenesis. Finally, in human breast cancer, high FBXO28 expression and phosphorylation are strong and independent predictors of poor outcome. In conclusion, our data suggest that SCFFBXO28 plays an important role in transmitting CDK activity to MYC function during the cell cycle, emphasizing the CDK‐FBXO28‐MYC axis as a potential molecular drug target in MYC‐driven cancers, including breast cancer

25th annual computational neuroscience meeting: CNS-2016

The same neuron may play different functional roles in the neural circuits to which it belongs. For example, neurons in the Tritonia pedal ganglia may participate in variable phases of the swim motor rhythms [1]. While such neuronal functional variability is likely to play a major role the delivery of the functionality of neural systems, it is difficult to study it in most nervous systems. We work on the pyloric rhythm network of the crustacean stomatogastric ganglion (STG) [2]. Typically network models of the STG treat neurons of the same functional type as a single model neuron (e.g. PD neurons), assuming the same conductance parameters for these neurons and implying their synchronous firing [3, 4]. However, simultaneous recording of PD neurons shows differences between the timings of spikes of these neurons. This may indicate functional variability of these neurons. Here we modelled separately the two PD neurons of the STG in a multi-neuron model of the pyloric network. Our neuron models comply with known correlations between conductance parameters of ionic currents. Our results reproduce the experimental finding of increasing spike time distance between spikes originating from the two model PD neurons during their synchronised burst phase. The PD neuron with the larger calcium conductance generates its spikes before the other PD neuron. Larger potassium conductance values in the follower neuron imply longer delays between spikes, see Fig. 17.Neuromodulators change the conductance parameters of neurons and maintain the ratios of these parameters [5]. Our results show that such changes may shift the individual contribution of two PD neurons to the PD-phase of the pyloric rhythm altering their functionality within this rhythm. Our work paves the way towards an accessible experimental and computational framework for the analysis of the mechanisms and impact of functional variability of neurons within the neural circuits to which they belong

A Comprehensive and System Review for the Pharmacological Mechanism of Action of Rhein, an Active Anthraquinone Ingredient

AbstractRhein is a major medicinal ingredient isolated from several traditional Chinese medicines, including Rheum palmatum L., Aloe barbadensis Miller, Cassia angustifolia Vahl., and Polygonum multiflorum Thunb. Rhein has various pharmacological activities, such as anti-inflammatory, antitumor, antioxidant, antifibrosis, hepatoprotective, and nephroprotective activities. Although more than 100 articles in PubMed are involved in the pharmacological mechanism of action of rhein, only a few focus on the relationship of crosstalk among multiple pharmacological mechanisms. The mechanism of rhein involves multiple pathways which contain close interactions. From the overall perspective, the pathways which are related to the targets of rhein, are initiated by the membrane receptor. Then, MAPK and PI3K-AKT parallel signaling pathways are activated, and several downstream pathways are affected, thereby eventually regulating cell cycle and apoptosis. The therapeutic effect of rhein, as a multitarget molecule, is the synergistic and comprehensive result of the involvement of multiple pathways rather than the blocking or activation of a single signaling pathway. We review the pharmacological mechanisms of action of rhein by consulting literature published in the last 100 years in PubMed. We then summarize these pharmacological mechanisms from a comprehensive, interactive, and crosstalk perspective. In general, the molecular mechanism of action of drug must be understood from a systematic and holistic perspective, which can provide a theoretical basis for precise treatment and rational drug use

Research on the maximum fire smoke temperature beneath tunnel ceilings using longitudinal ventilation

The maximum fire smoke temperature beneath tunnel ceilings using longitudinal ventilation was studied by both small-scale experiments and numerical simulations for a small heat release rate (HRR) fire. And then, the accuracy of the numerical simulation is verified. A numerical simulation is subsequently employed to modify the Kurioka model for cases in large HRR. Then, the modified Kurioka model is verified by various on-site high HRR fire experimental results conducted by other authors

Research on the maximum fire smoke temperature beneath tunnel ceilings using longitudinal ventilation

The maximum fire smoke temperature beneath tunnel ceilings using longitudinal ventilation was studied by both small-scale experiments and numerical simulations for a small heat release rate (HRR) fire. And then, the accuracy of the numerical simulation is verified. A numerical simulation is subsequently employed to modify the Kurioka model for cases in large HRR. Then, the modified Kurioka model is verified by various on-site high HRR fire experimental results conducted by other authors

Clostridium butyricum improves cognitive dysfunction in ICV-STZ-induced Alzheimer's disease mice via suppressing TLR4 signaling pathway through the gut-brain axis.

In recent years, the relationship between gut-brain axis and Alzheimer's disease (AD) attracted increasing attention. The aim of this study is to investigate the therapeutic effect of Clostridium butyricum (CB) on intraventricular injection of streptozotocin (ICV-STZ)-induced mice and the potential mechanisms. ICV-STZ mice were treated with CB by gavage for 21 consecutive days. The pharmacological effect of CB was assessed by behavior test, brain tissue H&E staining and tau protein phosphorylation levels of hippocampus tissues. The expression levels of TLR4, MYD88, NF-κB p65, TNF-α, iNOS, Occludin and ZO-1 in hippocampal and colonic tissues were detected by Western-blot method. 16S rRNA gene sequencing analysis was used to analyze the intestinal microbiota of mice. The results showed that CB improved the cognitive dysfunction of ICV-STZ mice, restored the structure and cell number of hippocampal and cortical neurons, decreased the protein levels of pSer404-tau protein in hippocampal tissues and TLR4, MYD88, NF-κB p65 and iNOS in hippocampal and colonic tissues, and increased the protein levels of Occludin and ZO-1 in colonic tissues. Meanwhile, CB reversed the changes of intestinal microbiota in AD mice. Therefore, the mechanisms of cognitive function and brain pathological changes in AD mice improved by CB may be related to the regulation of TLR4 signaling pathway and intestinal microbiota. This study supports the potential anti-AD effect of CB and initially revealed its pharmacological mechanism of CB, providing a theoretical basis for further clinical application of CB

Preparation and Characterization of Vancomycin-Loaded Electrospun Rana chensinensis

Collagen was extracted from abandoned Rana chensinensis skin in northeastern China via an acid enzymatic extraction method for the use of drug carriers. In this paper we demonstrated two different nanofiber-vancomycin (VCM) systems, that is, VCM blended nanofibers and core-shell nanofibers with VCM in the core. Rana chensinensis skin collagen (RCSC) and poly(L-lactide) (PLLA) (3 : 7) were blended in 1,1,1,3,3,3-hexafluoroisopropanol (HFIP) at a concentration of 10% (g/mL) to fabricate coaxial and blend nanofibers, respectively. Coaxial and blend electrospun RCSC/PLLA nanofibers containing VCM (5 wt%) were evaluated for the local and temporal delivery of VCM. The nanofiber scaffolds were characterized by environmental scanning electron microscope (ESEM), transmission electron microscopy (TEM), Fourier transform infrared spectra (FTIR), differential scanning calorimeter (DSC), water contact angle (WCA), and mechanical tests. The drug release of VCM in these two systems was compared by using UV spectrophotometer. The empirical result indicated that both the blend and coaxial RCSC/PLLA scaffolds followed sustained control release for a period of 80 hours, but the coaxial nanofiber might be a potential drug delivery material for its better mechanical properties and sustained release effect

Isolation of stem-like cells from human MG-63 osteosarcoma cells using limiting dilution in combination with vincristine selection

340-347To isolate stem-like cells from the human MG-63 osteosarcoma cell line, different subpopulations of MG-63 cells were cloned by limiting dilution and passaged to obtain different sublines. The subline with highest clonogenicity was identified using a proliferation assay, cell-cycle analysis, and soft-agar colony-forming assay. The sublines were further selected in serum-free medium containing 20 ng/ml vincristine to identify cells that could form suspended sarcospheres. Identified cells were then characterized based on morphology, cell surface markers, adipogenic and osteogenic differentiation, and tumorigenicity in nude mice. A total of 19 holoclones that could be stably passaged were obtained. Sublines A1, A3, and D1 were markedly different from other sublines and the parental cell line. Subline D1 not only had a higher colony-forming efficiency and formed larger colonies, but also possessed a shorter latency of tumorigenesis in vivo. After subline D1 was cultured in suspension in medium containing vincristine, a highly enriched subpopulation of cells that could form sarcospheres and be stably passaged were obtained. These cells, designated as MG-63-M expressed multiple markers of multipotent or embryonic stem cells and possessed the capacity for self-renewal, multilineage differentiation, and significant multi-drug resistance. Thus, our results suggest that a subpopulation of stem-like cells can be isolated from human MG-63 osteosarcoma cell line

Preparation and Characterization of Vancomycin-Loaded Electrospun Rana chensinensis Skin Collagen/Poly(L-lactide) Nanofibers for Drug Delivery

Collagen was extracted from abandoned Rana chensinensis skin in northeastern China via an acid enzymatic extraction method for the use of drug carriers. In this paper we demonstrated two different nanofiber-vancomycin (VCM) systems, that is, VCM blended nanofibers and core-shell nanofibers with VCM in the core. Rana chensinensis skin collagen (RCSC) and poly(L-lactide) (PLLA) (3 : 7) were blended in 1,1,1,3,3,3-hexafluoroisopropanol (HFIP) at a concentration of 10% (g/mL) to fabricate coaxial and blend nanofibers, respectively. Coaxial and blend electrospun RCSC/PLLA nanofibers containing VCM (5 wt%) were evaluated for the local and temporal delivery of VCM. The nanofiber scaffolds were characterized by environmental scanning electron microscope (ESEM), transmission electron microscopy (TEM), Fourier transform infrared spectra (FTIR), differential scanning calorimeter (DSC), water contact angle (WCA), and mechanical tests. The drug release of VCM in these two systems was compared by using UV spectrophotometer. The empirical result indicated that both the blend and coaxial RCSC/PLLA scaffolds followed sustained control release for a period of 80 hours, but the coaxial nanofiber might be a potential drug delivery material for its better mechanical properties and sustained release effect