CDC28 phosphorylates Cac1p and regulates the association of chromatin assembly factor i with chromatin

Chromatin Assembly Factor I (CAF-I) plays a key role in the replication-coupled assembly of nucleosomes. It is expected that its function is linked to the regulation of the cell cycle, but little detail is available. Current models suggest that CAF-I is recruited to replication forks and to chromatin via an interaction between its Cac1p subunit and the replication sliding clamp, PCNA, and that this interaction is stimulated by the kinase CDC7. Here we show that another kinase, CDC28, phosphorylates Cac1p on serines 94 and 515 in early S phase and regulates its association with chromatin, but not its association with PCNA. Mutations in the Cac1p-phosphorylation sites of CDC28 but not of CDC7 substantially reduce the in vivo phosphorylation of Cac1p. However, mutations in the putative CDC7 target sites on Cac1p reduce its stability. The association of CAF-I with chromatin is impaired in a cdc28–1 mutant and to a lesser extent in a cdc7–1 mutant. In addition, mutations in the Cac1p-phosphorylation sites by both CDC28 and CDC7 reduce gene silencing at the telomeres. We propose that this phosphorylation represents a regulatory step in the recruitment of CAF-I to chromatin in early S phase that is distinct from the association of CAF-I with PCNA. Hence, we implicate CDC28 in the regulation of chromatin reassembly during DNA replication. These findings provide novel mechanistic insights on the links between cell-cycle regulation, DNA replication and chromatin reassembly.     

The imbalanced supertree of flowering-plant phylogeny

Two contrasting approaches have been used to construct the overall tree of life from molecular data: one involves the analysis of single large datasets, while the other involves joining many independent smaller analyses into a supertree. A recent study uses the latter approach to produce the most complete phylogeny yet of flowering plant families.     

Cytotoxicity and hepatoprotective attributes of methanolic extract of Rumex vesicarius L.

Background

To evaluate the hepatoprotective potential and invitro cytotoxicity studies of whole plant methanol extract of Rumex vesicarius L. Methanol extract at a dose of 100 mg/kg bw and 200 mg/kg bw were assessed for its hepatoprotective potential against CCl₄-induced hepatotoxicity by monitoring activity levels of SGOT (Serum glutamic oxaloacetic transaminase), SGPT (Serum glutamic pyruvic transaminase), ALP (Alkaline phosphatase), TP (Total protein), TB (Total bilirubin) and SOD (Superoxide dismutase), CAT (Catalase), MDA (Malondialdehyde). The cytotoxicity of the same extract on HepG2 cell lines were also assessed using MTT assay method at the concentration of 62.5, 125, 250, 500 μg/ml.

Results

Pretreatment of animals with whole plant methanol extracts of Rumex vesicarius L. significantly reduced the liver damage and the symptoms of liver injury by restoration of architecture of liver. The biochemical parameters in serum also improved in treated groups compared to the control and standard (silymarin) groups. Histopathological investigation further corroborated these biochemical observations. The cytotoxicity results indicated that the plant extract which were inhibitory to the proliferation of HepG2 cell line with IC50 value of 563.33 ± 0.8 μg/ml were not cytotoxic and appears to be safe.

Conclusions

Rumex vesicarius L. whole plant methanol extract exhibit hepatoprotective activity. However the cytotoxicity in HepG2 is inexplicable and warrants further study.     

Glucocorticoids synergize with IL-1β to induce TLR2 expression via MAP Kinase Phosphatase-1-dependent dual Inhibition of MAPK JNK and p38 in epithelial cells

Background  

Despite the importance of glucocorticoids in suppressing immune and inflammatory responses, their role in enhancing host immune and defense response against invading bacteria is poorly understood. Toll-like receptor 2 (TLR2) has recently gained importance as one of the major host defense receptors. The increased expression of TLR2 in response to bacteria-induced cytokines has been thought to be crucial for the accelerated immune response and resensitization of epithelial cells to invading pathogens.     

Stress distribution in cylindrical and conical implants under rotational micromovement with different boundary conditions and bone properties: 3-D FEA

Factors related to micromovements at bone-implant interface have been studied because they are considered adverse to osseointegration. Simplifications are commonly observed in these FEA evaluations. The aim of this study was to clarify the influence of FEA parameters (boundary conditions and bone properties) on the stress distribution in peri-implant bone tissue when micromovements are simulated in implants with different geometries. Three-dimensional models of an anterior section of the jaw with cylindrical or conical titanium implants (4.1 mm in width and 11 mm in length) were created. Micromovement (50, 150, or 250 μm) was applied to the implant. The FEA parameters studied were linear vs. non-linear analyses, isotropic vs. orthogonal anisotropic bone, friction coefficient (0.3) vs. frictionless bone-implant contact. Data from von Mises, shear, maximum, and minimum principal stresses in the peri-implant bone tissue were compared. Linear analyses presented a relevant increase of the stress values, regardless of the bone properties. Frictionless contact reduced the stress values in non-linear analysis. Isotropic bone presented lower stress than orthogonal anisotropic. Conical implants behave better, in regard to compressive stresses (minimum principal), than cylindrical ones, except for nonlinear analyses when micromovement of 150 and 250 μm were simulated. The stress values raised as the micromovement amplitude increased. Non-linear analysis, presence of frictional contact and orthogonal anisotropic bone, evaluated through maximum and minimum principal stress should be used as FEA parameters for implant-micromovement studies.     

Effect of double flasking and investing methods on artificial teeth movement in complete dentures processing

doi: 10.1111/j.1741‐2358.2011.00494.x
Effect of double flasking and investing methods on artificial teeth movement in complete dentures processing Purpose: The aim of this study was to evaluate linear dimensional alterations of artificial teeth for complete dentures when using different investment and flasking techniques. Background: Dimensional changes in the vertical dimension may occur owing to changes in artificial teeth positioning caused by different investing and flasking techniques. Materials and methods: Thirty pairs of the complete dentures were manufactured and randomly divided into three groups (n = 10): (1) invested with type III stone in monomaxillary PVC flask; (2) invested with type III stone in bimaxillary PVC flask; and (3) invested with laboratory silicone in bimaxillary PVC flask. Dentures were polymerised by microwave, and 12 linear distances were measured before and after denture processing. Data were analysed by one‐way anova , considering manufacturing technique as the study factor. Tukey’s HSD was used as post hocanova (p = 0.05). Results: Most of the linear distances were comparable for all groups. All transversal maxillary and mandibular distances were higher for group 1 compared with groups 2 and 3 (p < 0.05), except the distance 3–6 for mandibular arch, in which no difference was found between groups (p < 0.05). Both maxillary diagonal distances were higher in group 1 (p < 0.05), and no differences were found among all groups for mandibular measurements. Conclusions: Double flasking technique independent on the investment material is shown to be the most effective method to reduce changes in artificial teeth positioning.     

Breaking androgen receptor addiction of prostate cancer by targeting different functional domains in the treatment of advanced disease

In the last decade, treatment for castration-resistant prostate cancer has changed markedly, impacting symptom control and longevity for patients. However, a large proportion of cases progress despite androgen deprivation therapy and chemotherapy, while still being fit enough for several more lines of treatment. Overstimulation of the androgen receptor (AR) activity is the main driver of this cancer. Targeting biological functions of the AR or its co-regulators has proven very effective in this disease and led to the development of several highly effective drugs targeting the AR signalling axis. Drugs such as enzalutamide demonstrated that the improvement in anti-tumour efficacy is closely correlated with an affinity for the AR and its activity and have established the paradigm that AR remains activity in aggressive disease. However, as importantly, key insights into mechanisms of resistance are guiding the development of the next generation of AR-targeted drugs. This review outlines the historical development of these highly specific agents, their mechanism of action in the context of defective AR activity, and explores the potential for the upcoming next-generation AR inhibitors (ARI) for prostate cancer by targeting the alternative domains of AR, rather than by the conventional ligand-binding domain approach. There is huge potential in these approaches to develop new drugs with high clinical activity and further improve the outlook for patients.