Depletion interaction in colloid/polymer mixtures: application of density functional theory

Insert-route density functional approach (IRDFT), modified fundamental measure theory (MFMT) and thermodynamic perturbation theory (TPT1 and TPT2) are combined to study the depletion force between colloidal particles in hard sphere/hard sphere chain mixtures which represent a model of systems containing colloids dispersed in an athermal polymer solution. The predicted results are compared to simulations showing the reliability of the method used which captures the main characteristics of depletion interaction between colloids induced by polymers. Results of TPT2 are slightly more repulsive and better than that of TPT1 especially when the inter-particle distance is small than the diameter of polymer segment indicating the essential influence of the three-body correlations. Effects of the polymer density, polymer chain length and size ratio of colloid to polymer segment on the depletion force are studied in detail. Due to a little deterioration of the prediction in the high density region, further improvement is anticipated to better balance the competition between the excluded-volume effect and the chain connectivity.     

GSK-3β Polymorphism Discriminates Bipolar Disorder and Schizophrenia: A Systematic Meta-Analysis

Glycogen synthase kinase 3 (GSK-3) is a well-known conserved and ubiquitous protein kinase and playing a pivotal role in neurodevelopment, neurogenesis, learning/memory, and neuronal cell death. Dysfunction of GSK-3 had been seen in multiple neurodegenerative and psychiatric diseases. Bipolar disorder and schizophrenia are two common psychiatric diseases first occur in adolescence or young adulthood. They share similar risk genes as well as clinical symptoms, which make it is difficult to be discriminated from each other. Here, by using meta-analysis we reported that glycogen synthase kinase 3β promoter inactive mutant rs334558 may contribute to the development of schizophrenia not bipolar disorder. This might be used to distinguish these two diseases.     

Molecular dynamics simulation of the Al2O3 film structure during atomic layer deposition

Based on an understanding of atomic layer deposition (ALD) from prior experimental and computational results, all-atom molecular dynamics (MD) simulations are used to model the Al₂O₃ film structure and composition during ALD processing. By separating the large time-scale surface reactions from the small time-scale structural relaxation, we have focused on the growth dynamics of amorphous Al₂O₃ films at the atomic scale. The simulations are able to reproduce some important properties and growth mechanisms of Al₂O₃ ALD films, and hence provide a bridge between atomic-level information and experimental measurements. Information about the evolution of the microscopic structures of the Al₂O₃ films is generated, and the influence of operation parameters on the Al₂O₃ ALD process. The simulations predict a strong influence of the initial surface composition and process temperature on the surface roughness, growth rate and growth mode of the deposited films.     

The regulation of the UCH-L1 gene by transcription factor NF-κB in podocytes

In kidney, the ubiquitin carboxy-terminal hydrolase 1 (UCH-L1) is involved in podocyte injury and proteinuria but details of the mechanism underlying its regulation are not known. Activation of NF-κB is thought to be the predominant risk factor for kidney disease; therefore, it is postulated that UCH-L1 may be one of the NF-κB target genes. In this study, we investigated the involvement of NF-κB activation in the regulation of UCH-L1 expression and the function of murine podocytes. Stimulation of podocytes with the cytokines TNF-α and IL-1β up-regulated UCH-L1 expression rapidly at the mRNA and protein levels and the NF-κB-specific inhibitor pyrrolidine dithiocarbamate resulted in down-regulation. NF-κB up-regulates UCH-L1 via binding the ? 300 bp and ? 109 bp sites of its promoter, which was confirmed by the electrophoretic mobility shift assay of DNA–nuclear protein binding. In the renal biopsy from lupus nephritis patients, the expressions of NF-κB and UCH-L1 increased in immunohistochestry staining and were positively correlated. Activation of NF-κB up-regulates UCH-L1 expression following changing of other podocytes molecules, such as nephrin and snail. These results suggest that activation of the NF-κB signaling pathway could be the major pathogenesis to up-regulate UCH-L1 in podocyte injury, followed by the turnover of other molecules, which might result in morphological changes and dysfunction of podocytes. This work help us to understand the effect of NF-κB on specific target molecules of podocytes, and suggest that targeting the NF-κB–UCH-L1 interaction could be a novel therapeutic strategy for the treatment of podocyte lesions and proteinuria.     

The role of endosomal signaling triggered by metastatic growth factors in tumor progression

Within tumor microenvironment, a lot of growth factors such as hepatocyte growth factor and epidermal growth factor may induce similar signal cascade downstream of receptor tyrosine kinase (RTK) and trigger tumor metastasis synergistically. In the past decades, the intimate relationship of RTK-mediated receptor endocytosis with signal transduction was well established. In general, most RTK undergoes clathrin-dependent endocytosis and/or clathrin-independent endocytosis. The internalized receptors may sustain the signaling within early endosome, recycling to plasma membrane for subsequent ligand engagement or sorting to late endosomes/lysosome for receptor degradation. Moreover, receptor endocytosis influences signal transduction in a temporal and spatial manner for periodical and polarized cellular processes such as cell migration. The endosomal signalings triggered by various metastatic factors are quite similar in some critical points, which are essential for triggering cell migration and tumor progression. There are common regulators for receptor endocytosis including dynamin, Rab4, Rab5, Rab11 and Cbl. Moreover, many critical regulators within the RTK signal pathway such as Grb2, p38, PKC and Src were also modulators of endocytosis. In the future, these may constitute a new category of targets for prevention of tumor metastasis.     

DNA methylation and MeCP2 regulation of PTCH1 expression during rats hepatic fibrosis

Hepatic stellate cell (HSC) activation plays an important role in liver fibrogenesis. Transdifferentiation of quiescent hepatic stellate cells into myofibroblastic-HSCs is a key event in liver fibrosis. The methyl-CpG-binding protein MeCP2 which promotes repressed chromatin structure is selectively detected in myofibroblasts of diseased liver. MeCP2 binds to methylated CpG dinucleotides, which are abundant in the promoters of many genes. Treatment of HSCs with DNA methylation inhibitor 5-aza-2′- deoxycytidine (5-azadC) prevented proliferation and activation. Treatment with 5-azadC prevented loss of Patched (PTCH1) expression that occurred during HSCs activation. In a search for underlying molecular medchanisms, we investigated whether the targeting of epigenetic silencing mechanisms could be useful in the treatment of PTCH1-associated fibrogenesis. It was indicated that hypermethylation of PTCH1 is associated with the perpetuation of fibroblast activation and fibrosis in the liver. siRNA knockdown of MeCP2 increased the expressions of PTCH1 mRNA and protein in hepatic myofibroblasts. These data suggest that DNA methylation and MeCP2 may provide molecular mechanisms for silencing of PTCH1.     

Comparative study of the binding mode between cytochrome P450 17A1 and prostate cancer drugs in the absence of haem iron

Abstract

According to the X-ray crystal structures of CYP17A1 (including its complexes with inhibitors), it is shown that a hydrogen bond exists between CYP17A1 and its inhibitors (such as abiraterone and TOK-001). Previous short MD simulations (50?ns) suggested that the binding of abiraterone to CYP17A1 is stronger than that of TOK-001. In this work, by carrying out long atomistic MD simulations (200?ns) of CYP17A1 and its complexes with abiraterone and TOK-001, we observed a binding mode between CYP17A1 and abiraterone, which is different from the binding mode between CYP17A1 and TOK-001. In the case of abiraterone binding, the unfilled volume in the active site cavity increases the freedom of movement of abiraterone within CYP17A1, leading to the collective motions of the helices G and B′ as well as the breaking of hydrogen bond existing between the 3β-OH group of abiraterone and N202 of CYP17A1. However, the unfilled volume in the active site cavity can be occupied by the benzimidazole ring of TOK-001, restraining the motion of TOK-001. By pulling the two inhibitors (abiraterone and TOK-001) out of the binding pocket in CYP17A1, we discovered that abiraterone and TOK-001 were moved from their binding sites to the surface of protein similarly through the channels formed by the helices G and B′. In addition, based on the free energy calculations, one can see that it is energetically favorable for the two inhibitors (abiraterone and TOK-001) to enter into the binding pocket in CYP17A1.