Despite catalyzed by fusion proteins of quite different molecular architectures, intracellular, viral, and cell-to-cell fusions are found to have the essential common features and the nearly same nature of transition states. The similarity inspires us to find a more general catalysis mechanism for membrane fusion that minimally depends on the specific structures of fusion proteins. In this work, we built a minimal model for membrane fusion, and by using dissipative particle dynamics simulations, we propose a mechanism that the pulling force generated by fusion proteins initiates the fusion process and the membrane tension regulates the subsequent fusion stages. The model shows different features compared to previous computer simulation studies: the pulling force catalyzes membrane fusion through lipid head overcrowding in the contacting region, leading to an increase in the head-head repulsion and/or the unfavorable head-tail contacts from opposing membranes, both of which destabilize the contacting leaflets and thus promote membrane fusion or vesicle rupture. Our simulations produce a variety of shapes and intermediates, closely resembling cases seen experimentally. Our work strongly supports the view that the tight pulling mechanism is a conserved feature of fusion protein-mediated fusion and that the membrane tension plays an essential role in fusion.
HES6 is a member of the hairy-enhancer of the split homolog family, which has been implicated in oncogenesis and cancer progression in a variety of human cancers, including prostate and breast cancer. However, its clinical significance and biological role in colorectal cancer (CRC) remain unclear. In the present study, the expression of HES6 was significantly upregulated in CRC cell lines and CRC tissues at both the mRNA and protein levels. The present study also reported high expression of HES6 in 138/213 (64.8%) paraffin-embedded archived CRC specimens. HES6 expression was significantly correlated with T classification (P<0.001), N classification (P=0.020), and distant metastasis (P<0.001). Patients with higher HES6 expression levels exhibited a reduced overall survival (P<0.001). In addition, a multivariate analysis revealed that the expression of HES6 may be a novel prognostic marker for the survival of patients with CRC. Furthermore, the present study demonstrated that ectopic expression of HES6 enhanced the migration and invasive abilities of CRC cells. These abilities were significantly inhibited upon knockdown of endogenous HES6 expression by specific short hairpin RNAs. Additionally, the present study reported that the effects of HES6 on metastasis may be associated with the activation of the Wnt/β-catenin signaling pathway. Collectively, the findings of the present study revealed that overexpression of HES6 played a key role in the progression of CRC, leading to a poor prognosis and clinical outcome.
Abstract Background Previous studies have indicated a potential relationship between zinc and epilepsy. The aim of this study is to investigate the causal relationship between zinc, zinc-dependent carbonic anhydrase, and gray matter volume in brain regions enriched with zinc, in relation to epileptic seizures, as well as explore the possible mechanisms by which zinc contributes to epilepsy. Methods First, this study assessed the risk causality between zinc, carbonic anhydrase, and gray matter volume alterations in zinc-enriched brain regions and various subtypes of epilepsy based on two-sample Mendelian randomization analysis. And then, Then, this study conducted GO/KEGG analysis based on colocalization analysis, MAGMA analysis, lasso regression, random forest model and xgboot model. Results 1. There was a causal relationship between zinc, carbonic anhydrase-4, and generalized epilepsy (p = 0.044, p = 0.010). Additionally, carbonic anhydrase-1 and gray matter volume of the caudate nucleus were found to be associated with epilepsy and focal epilepsy (p = 0.014, p = 0.003, p = 0.022, p = 0.009).2. A colocalization relationship was found between epilepsy and focal epilepsy (PP.H4.abf = 97.7e-2). MAGMA analysis indicated that SNPs associated with epilepsy and focal epilepsy were functionally localized to zinc-finger-protein-related genes (p < 1.0e-5).3. The genes associated with focal epilepsy were found to have a molecular function of zinc ion binding (FDR = 1.9e-4). Within 4 to 24 hours after experiencing epilepsy, the function of the gene whose expression changed in the rats with focal epilepsy was enriched in the biological process of vascular response (FDR = 4.0e-5), compared to the rats without seizure. Conclusion The mechanism of the increased risk of epilepsy caused by zinc may be related to the increase of zinc ion-dependent carbonic anhydrase or the increase of the volume of zinc-rich caudate gray matter.
// Wen Li 1, 2, * , Guangzhi Ma 2, * , Qiang Wu 2, * , Ya Liu 1 , Xuejuan Liu 1 and Jing Wang 1 1 Department of Thyroid and Breast Surgery, West China Hospital of Sichuan University, Chengdu, Sichuan 610041, P. R. China 2 Lung Cancer Center, West China Hospital of Sichuan University, Chengdu, Sichuan 610041, P. R. China * These authors contributed equally to this work Correspondence to: Jing Wang, email: wangj889@163.com Keywords: young age; breast cancer; prognosis; molecular subtypes; survival Received: July 05, 2017 Accepted: December 30, 2017 Published: January 06, 2018 ABSTRACT Objective: This study aims to analyze the relationship between clinicopathological characteristics and survival in young patients (≤ 35 years old) with breast cancer. Results: Compared with patients aged 30 to 35 years, age of younger patients (≤ 30 years) was an independent predictor for poor disease-free survival (DFS) and overall survival (OS). PR negative status ( p = 0.042), high tumor grade ( p = 0.012), and advanced lymph nodes post-surgery ( p < 0.001) were independent prognostic factors of DFS, while PR negative status ( p = 0.003) and advanced lymph nodes post-surgery ( p = 0.002) were both independent prognostic factors of OS. For patients with hormone receptor-positive breast cancer, people with ER+ or PR+ and HER2−/+ status showed poorer prognosis than the other two levels. Risk factor grouping based on the ER, PR, HER2, Ki-67 status, tumor grade, and lymph nodes post-surgery showed that patients in highest score group received the poorest prognosis. Materials and Methods: A total of 173 cases of young breast cancer patients were included in this study. The clinicopathological factors potentially associated with prognosis were evaluated by univariate and multivariate analyses. Furthermore, we categorized patients into different groups to evaluate the prognosis according to hormone receptor status or important risk factors. Conclusions: Patient age, PR status, tumor grade, and lymph nodes post-surgery had clinical value as predictive factors of prognosis. Grading system based on the hormone status or the risk factor grouping may offer a useful approach to assess which subgroups of young breast cancer patients present poorer prognosis.
Subsequently to the publication of the above article, an interested reader drew to the authors' attention that Fig. 2 on p. 1266 and Fig. 5 on p. 1269 contained some apparent errors in terms of the assembly of the various data panels. Specifically, Fig. 2D appeared to contain a pair of overlapping images, and Figs. 5D and 8A also appeared to include overlapping images. However, the authors were able to consult their original data, and assess where the errors had been made during the compilation of these figures. The corrected versions of Figs. 2 (showing the correct data for the '5T' panel in Fig. 2D) and 5 (showing alternative data) are shown on the subsequent pages. The authors regret the errors that were made during the preparation of the published figures, and confirm that these errors did not grossly affect the conclusions reported in the study. The authors are grateful to the Editor of Oncology Reports for allowing them the opportunity to publish a Corrigendum, and all the authors agree to this Corrigendum. Furthermore, they apologize to the readership for any inconvenience caused. [the original article was published in Oncology Reports 40: 1261‑1274, 2018; DOI: 10.3892/or.2018.6539].
We demonstrate an effective strategy for brightness modulation via the surface charge treatment of electrodes. The brightness can be raised by 110% due to the growth of a colloidal lattice.
The shape deformation of membrane nanotubes is studied by a combination of theoretical analysis and molecular simulation. First we perform free energy analysis to demonstrate the effects of various factors on two ideal states for the pearling transition, and then we carry out dissipative particle dynamics simulations, through which various types of membrane tube deformation are found, including membrane pearling, buckling, and bulging. Different models for inducing tube deformation, including the osmotic pressure, area difference and spontaneous curvature models, are considered to investigate tubular instabilities. Combined with free energy analysis, our simulations show that the origin of the deformation of membrane tubes in different models can be classified into two categories: effective spontaneous curvature and membrane tension. We further demonstrate that for different models, a positive membrane tension is required for the pearling transition. Finally we show that different models can be coupled to effectively deform the membrane tube.
The delay-time concept has been extensively applied in the field of maintenance, especially for determining the optimal inspection or maintenance interval. It defines a two-stage system failure process: the time from new to an initial defect, known as the normal stage, and the time from this defective point to failure, known as the delay-time stage. Previous works using the delay-time concept have mainly focused on single-component systems and multi-component systems with a series configuration. However, parallel systems also exist in reality, but most existing models for parallel systems use either a single-stage time-to-failure process or a Markov chain to describe the failure mechanism. In this article, we propose a new delay-time-based inspection model for a n-component parallel system and study the optimal inspection interval that minimizes the long-term expected cost per unit time. Two maintenance policies are considered, depending on whether the defective/failed components identified are replaced immediately or not. Numerical examples are presented to show the applicability of the model.
Iron tailings powder (ITP) is a kind of solid waste, which pollutes the environment, without any treatment. The application of ITP in cement concrete is a good choice. In this study, the influence of ITP on the flowability, compressive strength, chloride ion permeability and the attenuation of the performance of cement concrete during freeze–thaw cycle (F-T) damage are investigated. An X-ray diffraction, an analysis of the pores and a scanning electron microscope (SEM) are obtained to analyze the mechanism of cement concrete’s performance. The results show that the addition of ITP can decrease the flowability of fresh cement concrete. Cement concrete with a 7% ITP to mass ratio of the total aggregate shows the highest compressive strength and the minimum chloride ion permeability. The relative dynamic modulus of the elasticity of the specimens with 7% ITP during the F-T is the highest. The corresponding mass loss rate is the lowest. The mercury intrusion analysis results show that the pore volume of the specimens with 7% ITP is the lowest. The SEM results confirm that the specimens with 7% ITP show the densest microstructures.
Design of nanoparticles (NPs) for biomedical applications requires a thorough understanding of cascades of nano-bio interactions at different interfaces. Here, we take into account the cascading effect of NP functionalization on interactions with target cell membranes by determining coatings of biomolecules in biological media. Cell culture experiments show that NPs with more hydrophobic surfaces are heavily ingested by cells in both the A549 and HEK293 cell lines. However, before reaching the target cell, both the identity and amount of recruited biomolecules can be influenced by the pristine NPs' hydrophobicity. Dissipative particle dynamics (DPD) simulations show that hydrophobic NPs acquire coatings of more biomolecules, which may conceal the properties of the as-engineered NPs and impact the targeting specificity. Based on these results, we propose an amphiphilic ligand coating on NPs. DPD simulations reveal the design principle, following which the amphiphilic ligands first curl in solvent to reduce the surface hydrophobicity, thus suppressing the assemblage of biomolecules. Upon attaching to the membrane, the curled ligands extend and rearrange to gain contacts with lipid tails, thus dragging NPs into the membrane for translocation. Three NP-membrane interaction states are identified that are found to depend on the NP size and membrane surface tension. These results can provide useful guidelines to fabricate ligand-coated NPs for practical use in targeted drug delivery, and motivate further studies of nano-bio-interactions with more consideration of cascading effects.
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