Cotton annexin proteins participate in the establishment of fiber cell elongation scaffold

Cotton plant is one of the most important economic crops in the world which supplies natural fiber for textile industry. The crucial traits of cotton fiber quality are fiber length and strength, which are mostly determined by the fiber elongation stage. Annexins are assumed to be involved in regulating fiber elongation, but direct evidences remain elusive. Recently, we have investigated the activities of fiber-specific expressed annexins AnGb5/6 and their interacted proteins in cotton. AnGb5 and 6 can interact reciprocally to generate a protein macro-raft in cell membrane. This macro-raft is probably a stabilized scaffold for Actin1 organization. The actin assembling direction and density are correlated with AnGb6 gene expression and fiber expanding rate among three fiber length genotypes. These results suggest that annexins may act as the adaptor that linked fiber cell membrane to actin assembling. Due to the strong Ca²⁺ and lipid binding ability of annexins, these results also indicate that annexins complex may function as an intermediate to receive Ca²⁺ or lipid signals during fiber elongation.     

Overcoming resistance to rapalogs in gliomas by combinatory therapies

Glioblastoma is the most common and aggressive brain tumor type, with a mean patient survival of approximately 1 year. Many previous analyses of the glioma kinome have identified key deregulated pathways that converge and activate mammalian target of rapamycin (mTOR). Following the identification and characterization of mTOR-promoting activity in gliomagenesis, data from preclinical studies suggested the targeting of mTOR by rapamycin or its analogs (rapalogs) as a promising therapeutic approach. However, clinical trials with rapalogs have shown very limited efficacy on glioma due to the development of resistance mechanisms. Analysis of rapalog-insensitive glioma cells has revealed increased activity of growth and survival pathways compensating for mTOR inhibition by rapalogs that are suitable for therapeutic intervention. In addition, recently developed mTOR inhibitors show high anti-glioma activity. In this review, we recapitulate the regulation of mTOR signaling and its involvement in gliomagenesis, discuss mechanisms resulting in resistance to rapalogs, and speculate on strategies to overcome resistance. This article is part of a Special Issue entitled: Inhibitors of Protein Kinases (2012).     

Conformational insights into the inhibitory mechanism of phyto-compounds against Src kinase family members implicated in psoriasis

Abstract

Psoriasis is a chronic immune mediated disorder of the skin. There is growing evidence that the Src family tyrosine kinases (SFK) are highly upregulated in psoriasis. The SFK are the key components of the signaling pathways triggering cell growth and differentiation in addition to the immune cascades. In the current work, the interactions between SFK and selective phyto-compounds were studied using molecular docking approach. Based on the results of docking and binding energy calculations quercetin was identified as potential lead compound. To get a deeper insight into the binding of quercetin with the SFK, a combined molecular dynamics and binding free energy calculations were performed. The binding of quercetin disrupted the intra-molecular contacts making the SFK compact except Src kinase. The MM/PBSA free energy decomposition analysis highlighted the significance of hydrophobic and polar residues which are involved in the binding of quercetin. An experimental validation was carried out against the activated forms of Fyn, Lyn and Src kinases, the top three proteins which showed high preference for quercetin. The flow cytometry analysis showed that the expression levels of Fyn, Lyn and Src kinases were dramatically increased in HaCaT cells. However, the treatment of quercetin at the concentration of 51.65 µM for 24?h markedly decreased their expression in HaCaT cells. Besides, similar results were also observed when the HaCaT cells were treated with the kinase inhibitor Ponitinib (1.43 µM) for 24?h.

Communicated by Ramaswamy H. Sarma     

A Bayesian nonparametric testing procedure for paired samples

We propose a Bayesian hypothesis testing procedure for comparing the distributions of paired samples. The procedure is based on a flexible model for the joint distribution of both samples. The flexibility is given by a mixture of Dirichlet processes. Our proposal uses a spike-slab prior specification for the base measure of the Dirichlet process and a particular parametrization for the kernel of the mixture in order to facilitate comparisons and posterior inference. The joint model allows us to derive the marginal distributions and test whether they differ or not. The procedure exploits the correlation between samples, relaxes the parametric assumptions, and detects possible differences throughout the entire distributions. A Monte Carlo simulation study comparing the performance of this strategy to other traditional alternatives is provided. Finally, we apply the proposed approach to spirometry data collected in the United States to investigate changes in pulmonary function in children and adolescents in response to air polluting factors.     

Aspirin inhibits osteoclast formation and wear-debris-induced bone destruction by suppressing mitogen-activated protein kinases

Excessive osteoclast recruitment and activation is the chief cause of periprosthetic osteolysis and subsequent aseptic loosening, so blocking osteolysis may be useful for protecting against osteoclastic bone resorption. We studied the effect of aspirin on titanium (Ti)-particle-induced osteolysis in vivo and in vitro using male C57BL/6J mice randomized to sham (sham surgery), Ti (Ti particles), low-dose aspirin (Ti/5 mg·kg⁻¹·d⁻¹ aspirin), and high-dose aspirin (Ti/30 mg·kg⁻¹·d⁻¹ aspirin). After 2 weeks, a three-dimensional reconstruction evaluation using micro-computed tomography and histomorphology assessment were performed on murine calvariae. Murine hematopoietic macrophages and RAW264.7 lineage cells were studied to investigate osteoclast formation and function. Aspirin attenuated Ti-particle-induced bone erosion and reduced osteoclasts. In vitro, aspirin suppressed osteoclast formation, osteoclastic-related gene expression, and osteoclastic bone erosion in a dose-dependent manner. Mechanically, aspirin reduced osteoclast formation by suppressing receptor activator of nuclear factor kappa-B ligand-induced activation of extracellular signal-related kinase, p-38 mitogen-activated protein kinase, and c-Jun N-terminal kinase. Thus, aspirin may be a promising option for preventing and curing osteoclastic bone destruction, including peri-implant osteolysis.     

Identification of a novel mutation in ZAP70 and prenatal diagnosis in a Turkish family with severe combined immunodeficiency disorder

Protein tyrosine kinases (PTKs) play an important role in T cell development and activation. In vitro and in vivo defects, resulting in variable deficiencies in thymic development and in T cell antigen receptor (TCR) signal transduction, in PTKs have been shown. ZAP70, one of those PTKs, is a 70-kDa tyrosine phosphoprotein and associates with the ζ chain and undergoes tyrosine phosphorylation following TCR stimulation. It is expressed in T and natural killer (NK) cells. Several mutations were shown to lead to an autosomal recessive form of severe combined immunodeficiency disease (SCID).     

Dehydration mediated microRNA response in the African clawed frog Xenopus laevis

Exposure to various environmental stresses induces metabolic rate depression in many animal species, an adaptation that conserves energy until the environment is again conducive to normal life. The African clawed frog, Xenopus laevis, is periodically subjected to arid summers in South Africa, and utilizes entry into the hypometabolic state of estivation as a mechanism of long term survival. During estivation, frogs must typically deal with substantial dehydration as their ponds dry out and X. laevis can endure > 30% loss of its body water. We hypothesize that microRNAs play a vital role in establishing a reversible hypometabolic state and responding to dehydration stress that is associated with amphibian estivation. The present study analyzes the effects of whole body dehydration on microRNA expression in three tissues of X. laevis. Compared to controls, levels of miR-1, miR-125b, and miR-16-1 decreased to 37 ± 6, 64 ± 8, and 80 ± 4% of control levels during dehydration in liver. By contrast, miR-210, miR-34a and miR-21 were significantly elevated by 3.05 ± 0.45, 2.11 ± 0.08, and 1.36 ± 0.05-fold, respectively, in the liver. In kidney tissue, miR-29b, miR-21, and miR-203 were elevated by 1.40 ± 0.09, 1.31 ± 0.05, and 2.17 ± 0.31-fold, respectively, in response to dehydration whereas miR-203 and miR-34a were elevated in ventral skin by 1.35 ± 0.05 and 1.74 ± 0.12-fold, respectively. Bioinformatic analysis of the differentially expressed microRNAs suggests that these are mainly involved in two processes: (1) expression of solute carrier proteins, and (2) regulation of mitogen-activated protein kinase signaling. This study is the first report that shows a tissue specific mode of microRNA expression during amphibian dehydration, providing evidence for microRNAs as crucial regulators of metabolic depression.