Cyclophilin A produced by thymocytes regulates the migration of murine bone marrow cells

Supernatant obtained from high dose hydrocortisone resistant thymocytes can induce migration of the bone marrow cell precursors to the periphery. This biological activity depends on the presence of the 18 kDa protein, whose amino acid sequence fits with the sequence of the secretory form of murine cyclophilin A (SP-18). Cyclophilin A isolated from the supernatant of the cortisone-resistant thymoma EL-4 shows its characteristic functional features as it demonstrates isomerase activity and binds with cyclosporine A. The cyclophilin A obtained manifests chemotactic activity that regulates migration of bone marrow cell precursors of neutrophils, T-, B- and dendritic cells.     

Pharmacologic modulation of RNA splicing enhances anti-tumor immunity

1. Download : Download high-res image (217KB)
2. Download : Download full-size image

     

Nitric oxide synthase 3 deficiency limits adverse ventricular remodeling after pressure overload in insulin resistance

Insulin resistance (IR) and systemic hypertension are independently associated with heart failure. We reported previously that nitric oxide synthase 3 (NOS3) has a beneficial effect on left ventricular (LV) remodeling and function after pressure-overload in mice. The aim of our study was to investigate the interaction of IR and NOS3 in pressure-overload-induced LV remodeling and dysfunction. Wild-type (WT) and NOS3-deficient (NOS3(-/-)) mice were fed either a standard diet (SD) or a high-fat diet (HFD) to induce IR. After 9 days of diet, mice underwent transverse aortic constriction (TAC). LV structure and function were assessed serially using echocardiography. Cardiomyocytes were isolated, and levels of oxidative stress were evaluated using 2',7'-dichlorodihydrofluorescein diacetate. Cardiac mitochondria were isolated, and mitochondrial respiration and ATP production were measured. TAC induced LV remodeling and dysfunction in all mice. The TAC-induced decrease in LV function was greater in SD-fed NOS3(-/-) mice than in SD-fed WT mice. In contrast, HFD-fed NOS3(-/-) developed less LV remodeling and dysfunction and had better survival than did HFD-fed WT mice. Seven days after TAC, oxidative stress levels were lower in cardiomyocytes from HFD-fed NOS3(-/-) than in those from HFD-fed WT. N(ω)-nitro-L-arginine methyl ester and mitochondrial inhibitors (rotenone and 2-thenoyltrifluoroacetone) decreased oxidative stress levels in cardiomyocytes from HFD-fed WT mice. Mitochondrial respiration was altered in NOS3(-/-) mice but did not worsen after HFD and TAC. In contrast with its protective role in SD, NOS3 increases LV adverse remodeling after pressure overload in HFD-fed, insulin resistant mice. Interactions between NOS3 and mitochondria may be responsible for increased oxidative stress levels in HFD-fed WT mice hearts.     

Morphological characterization and molecular phylogeny of Portunoidea Rafinesque, 1815 (Crustacea Brachyura): Implications for understanding evolution of swimming capacity and revision of the family-level classification

Cheliped construction, in particular the teeth pattern on chelae fingers is considered as most important character suit (along with burrowing/swimming apparatus) for the diagnosis of Portunoidea. Heterochelic and heterodontic chelipeds with the molariform tooth in the larger chela and multi-lobed serial teeth are presumably ancestral and most common pattern for the group. New material (mostly species of Thalamitinae Paulson, 1875, Lupocyclus Adamd and White, 1848 and Portunus Weber, 1795 sensu lato) have been combined with the existing sequences from the GenBank to produce molecular phylogenetic reconstructions based on the histone H3 gene fragment and a multi-gene tree (for smaller set of species) based on partial sequences of H3, D1 region of 28S gene and mitochondrial COI gene. These reconstructions have not provided necessary support to the monophyly of Portunoidea sensu lato but indicated the presence of several monophyletic lineages, i.e. Portunidae sensu stricto, Polybiidae + Thiidae + Carcinidae + Pirimelidae, Benthochascon + Geryonidae (to lesser extent), and Ovalipes. Monophyly of the Portunidae sensu stricto is supported by both the H3 and multigene trees and morphological evidence. Swimming capacity probably evolves as a result of parallel evolution in at least three different lineages of portunoids. A new version of the family level classification of Portunoidea and a key to their families are provided with the following taxa: Geryonidae (Geryoninae + Benthochasconinae subfam. nov.), Ovalipidae fam. nov., Brusiniidae Štev?i?, 1991, Thiidae, Pirimelidae, Carcinidae McLeay, 1838 (Carcininae + Portumninae Ortmann, 1893), Polybiidae Ortmann, 1893, and Portunidae Rafinesque, 1815 sensu stricto. The most radical change in the systematics of Portunidae sensu stricto is the final recognition of the polyphyly of Portunus sensu lato and the need for revalidization and re-diagnozing of several taxa that were synonymized by Stephenson and Campbell (1959) and Stephenson (1972) under Portunus. While some subfamilies of the Portunidae (Podophthalminae Dana, 1851, Thalamitinae, and Lupocyclinae Alcock, 1895) are well supported by molecular phylogenies and the presence of morphological synapomorphies, the others need re-assessment.     

Extracellular heat shock proteins and cancer: New perspectives

Heat shock proteins (HSPs) are a large family of molecular chaperones aberrantly expressed in cancer. The expression of HSPs in tumor cells has been shown to be implicated in the regulation of apoptosis, immune responses, angiogenesis and metastasis. Given that extracellular vesicles (EVs) can serve as potential source for the discovery of clinically useful biomarkers and therapeutic targets, it is of particular interest to study proteomic profiling of HSPs in EVs derived from various biological fluids of cancer patients. Furthermore, a divergent expression of circulating microRNAs (miRNAs) in patient samples has opened new opportunities in exploiting miRNAs as diagnostic tools. Herein, we address the current literature on the expression of extracellular HSPs with particular interest in HSPs in EVs derived from various biological fluids of cancer patients and different types of immune cells as promising targets for identification of clinical biomarkers of cancer. We also discuss the emerging role of miRNAs in HSP regulation for the discovery of blood-based biomarkers of cancer. We outline the importance of understanding relationships between various HSP networks and co-chaperones and propose the model for identification of HSP signatures in cancer. Elucidating the role of HSPs in EVs from the proteomic and miRNAs perspectives may provide new opportunities for the discovery of novel biomarkers of cancer.     

Influenza A virus PB1-F2 protein contributes to viral pathogenesis in mice

The influenza virus PB1-F2 protein is a novel protein previously shown to be involved in induction of cell death. Here we characterize the expression and the function of the protein within the context of influenza viral infection in tissue culture and a mouse model. We show that the C-terminal region of the protein can be expressed from a downstream initiation codon and is capable of interaction with the full-length protein. Using this knowledge, we generated influenza viruses knocked out for the expression of PB1-F2 protein and its downstream truncation products. Knocking out the PB1-F2 protein had no effect on viral replication in tissue culture but diminished virus pathogenicity and mortality in mice. The viruses replicated to similar levels in mouse lungs by day 3 postinfection, suggesting that the knockout did not impair viral replication. However, while the PB1-F2 knockout viruses were cleared after day 5, the wild-type viruses were detectable in mouse lungs until day 7, implying that expression of PB1-F2 resulted in delayed clearance of the viruses by the host immune system. Based on our findings and on the fact that the PB1 genomic segment was always newly introduced into some pandemic influenza viruses of the last century, we speculate that the PB1-F2 protein plays an important role in pathogenesis of influenza virus infection and may be an important contributor to pathogenicity of pandemic influenza viruses.