Conditional Astroglial Rictor Overexpression Induces Malignant Glioma in Mice

Background

Hyperactivation of the mTORC2 signaling pathway has been shown to contribute to the oncogenic properties of gliomas. Moreover, overexpression of the mTORC2 regulatory subunit Rictor has been associated with increased proliferation and invasive character of these tumor cells.

Methodology/Principal Findings

To determine whether Rictor overexpression was sufficient to induce glioma formation in mice, we inserted a Cre-lox-regulated human Rictor transgene into the murine ROSA26 locus. This floxed Rictor strain was crossed with mice expressing the Cre recombinase driven from the glial fibrillary acidic protein (GFAP) promoter whose expression is limited to the glial cell compartment. Double transgenic GFAP-Cre/Rictor^loxP/loxP mice developed multifocal infiltrating glioma containing elevated mTORC2 activity and typically involved the subventricular zone (SVZ) and lateral ventricle. Analysis of Rictor-dependent signaling in these tumors demonstrated that in addition to elevated mTORC2 activity, an mTORC2-independent marker of cortical actin network function, was also elevated. Upon histological examination of the neoplasms, many displayed oligodendroglioma-like phenotypes and expressed markers associated with oligodendroglial lineage tumors. To determine whether upstream oncogenic EGFRvIII signaling would alter tumor phenotypes observed in the GFAP-Cre/Rictor^loxP/loxP mice, transgenic GFAP-EGFRvIII; GFAP-Cre/Rictor^loxP/loxP mice were generated. These mice developed mixed astrocytic-oligodendroglial tumors, however glioma formation was accelerated and correlated with increased mTORC2 activity. Additionally, the subventricular zone within the GFAP-Cre/Rictor^loxP/loxP mouse brain was markedly expanded, and a further proliferation within this compartment of the brain was observed in transgenic GFAP-EGFRvIII; GFAP-Cre/Rictor^loxP/loxP mice.

Conclusion/Significance

These data collectively establish Rictor as a novel oncoprotein and support the role of dysregulated Rictor expression in gliomagenesis via mTOR-dependent and mTOR-independent mechanisms. Furthermore, oncogenic EGFRvIII signaling appears to potentiate the in vivo proliferative capacity of GFAP-Cre/Rictor^loxP/loxP gliomas.     

Functional genomics based prioritization of potential nsSNPs in EPHX1, GSTT1, GSTM1 and GSTP1 genes for breast cancer susceptibility studies

In the present study, nsSNPs in EPHX1, GSTT1, GSTM1 and GSTP1 genes were screened for their functional impact on concerned proteins and their plausible role in breast cancer susceptibility. Initially, SNPs were retrieved from dbSNP, followed by identification of potentially deleterious nsSNPs using PolyPhen and SIFT. Functional analysis was done with SNPs3D, SNPs&GO and MutPred methods. Prediction and evaluation of the functional impact on the 3D structure of proteins were performed with Swiss PDB viewer and NOMAD-Ref servers. On analysis, 13 nsSNPs were found to be highly deleterious and damaging to the protein structure, of which 6 nsSNPs, rs45549733, rs45506591 and rs4986949 of GSTP1, rs72549341 and rs148240980 of EPHX1 and rs17856199 of GSTT1 were predicted to be potentially polymorphic. It is therefore hypothesized that the 6 identified nsSNPs may alter the detoxification process and elevate carcinogenic metabolite accumulation thus modifies the risk of breast cancer susceptibility in a group of women.     

Molecular identification and characterization of a new type of bovine enterovirus

Bovine enteroviruses belong to the family Picornaviridae. Little is known about their pathogenic potential; however, they cause asymptomatic infections in cattle and are excreted in feces. In the present study, viruses isolated from environmental samples were sequenced. According to phylogenetic analyses and standard picornavirus nomenclature, these isolates constitute a new type of bovine enterovirus serogroup A.     

Accelerated decolorization of reactive azo dyes under saline conditions by bacteria isolated from Arabian seawater sediment

Presence of huge amount of salts in the wastewater of textile dyeing industry is one of the major limiting factors in the development of an effective biotreatment system for the removal of azo dyes from textile effluents. Bacterial spp. capable of thriving under high salt conditions could be employed for the treatment of saline dye-contaminated textile wastewaters. The present study was aimed at isolating the most efficient bacterial strains capable of decolorizing azo dyes under high saline conditions. Fifty-eight bacterial strains were isolated from seawater, seawater sediment, and saline soil, using mineral salt medium enriched with 100?mg?l^?1 Reactive Black-5 azo dye and 50?g NaCl l^?1 salt concentration. Bacterial strains KS23 (Psychrobacter alimentarius) and KS26 (Staphylococcus equorum) isolated from seawater sediment were able to decolorize three reactive dyes including Reactive Black 5, Reactive Golden Ovifix, and Reactive Blue BRS very efficiently in liquid medium over a wide range of salt concentration (0–100?g NaCl l^?1). Time required for complete decolorization of 100?mg dye l^?1 varied with the type of dye and salt concentration. In general, there was an inverse linear relationship between the velocity of the decolorization reaction (V) and salt concentration. This study suggested that bacteria isolated from saline conditions such as seawater sediment could be used in designing a bioreactor for the treatment of textile effluent containing high concentration of salts.     

Heavy metal phyto-accumulation in leafy vegetables irrigated with municipal wastewater and human health risk repercussions

In this study, heavy metal phyto-accumulation potential of selected cultivars of two leafy vegetables on irrigation with municipal wastewater and human health risks were investigated. Municipal wastewater chemistry was recorded significantly different from groundwater control and led to the two-fold high enrichment of soil heavy metal contents (Ni, 19.46; Pb, 23.94; Co, 4.68; Cd, 1.4 in mg/kg, respectively). Interactive effects for phyto-accumulation of most heavy metals were also recorded significant at p?相似文献   

Proteomic analysis of jasmonic acid-regulated proteins in rice leaf blades

Jasmonates play a critical role in plant defense against pathogens through regulation of the expression of defense-related genes. To study the role of jasmonic acid (JA) in the rice self-defense mechanism, a proteomic approach was applied. When 3-week-old rice cv. Java 14 was treated with 100 microM JA for 3 days, numerous necrotic brown spots were observed on the leaf blade. Three-week-old rice was treated with JA and proteins from cytosolic and membrane fractions of leaf blade were separated by two-dimensional polyacrylamide gel electrophoresis. A total of 305 proteins were detected in both cytosolic and membrane fractions. When rice plant was treated with 100 microM JA for 2 days, 12 proteins were up-regulated and 2 proteins were down-regulated. Out of them, 8 proteins were changed in dose dependence manner, while 4 proteins were changed in a time course manner. Among them, pathogenesis-related protein 5 (PR5) and probenazole inducible protein 1 (PBZ1) were significantly induced by 100 microM JA for 2 days. These results suggest that PR5 and PBZ1 are important proteins expressed down-stream of JA signals in rice cv. Java 14.     

Individuals co-exposed to sand fly saliva and filarial parasites exhibit altered monocyte function

BackgroundIn Mali, cutaneous leishmaniasis (CL) and filariasis are co-endemic. Previous studies in animal models of infection have shown that sand fly saliva enhance infectivity of Leishmania parasites in naïve hosts while saliva-specific adaptive immune responses may protect against cutaneous and visceral leishmaniasis. In contrast, the human immune response to Phlebotomus duboscqi (Pd) saliva, the principal sand fly vector in Mali, was found to be dichotomously polarized with some individuals having a Th1-dominated response and others having a Th2-biased response. We hypothesized that co-infection with filarial parasites may be an underlying factor that modulates the immune response to Pd saliva in endemic regions.Methodology/Principal findingsTo understand which cell types may be responsible for polarizing human responses to sand fly saliva, we investigated the effect of salivary glands (SG) of Pd on human monocytes. To this end, elutriated monocytes were cultured in vitro, alone, or with SG, microfilariae antigen (MF ag) of Brugia malayi, or LPS, a positive control. The mRNA expression of genes involved in inflammatory or regulatory responses was then measured as were cytokines and chemokines associated with these responses. Monocytes of individuals who were not exposed to sand fly bites (mainly North American controls) significantly upregulated the production of IL-6 and CCL4; cytokines that enhance leishmania parasite establishment, in response to SG from Pd or other vector species. This selective inflammatory response was lost in individuals that were exposed to sand fly bites which was not changed by co-infection with filarial parasites. Furthermore, infection with filarial parasites resulted in upregulation of CCL22, a type-2 associated chemokine, both at the mRNA levels and by its observed effect on the frequency of recruited monocytes.Conclusions/SignificanceTogether, our data suggest that SG or recombinant salivary proteins from Pd alter human monocyte function by upregulating selective inflammatory cytokines.     

Roles of Nitric Oxide in Conferring Multiple Abiotic Stress Tolerance in Plants and Crosstalk with Other Plant Growth Regulators

Journal of Plant Growth Regulation - Nitric oxide (NO) is a free-radical gasotransmitter signaling molecule associated with a varied spectrum of signal transduction pathways linked to inducing...     

Hydrogen Sulfide: A Novel Gaseous Molecule for Plant Adaptation to Stress

Hydrogen sulfide (H₂S) has emerged as a novel gaseous signal molecule with multifarious effects on seed germination, plant growth, development, and physiological processes. Due to its dominant role in plant stress tolerance and cross-adaptation, it is getting more attention nowadays, although it has been largely referred as toxic and environmental hazardous gas. In this review work, we are highlighting the importance of H₂S as an essential gaseous molecule to help in signaling, metabolism, and stress tolerance in plants. Firstly, production of H₂S from different natural and artificial sources were discussed with its transformation from sulfur (S) to sulfate (SO₄²⁻) and then to sulfite (SO₃²⁻). The importance of different kinds of transporters that helps to take SO₄²⁻ from the soil solution was presented. Mainly, these transporters are SULTRs (H⁺/SO₄²⁻ cotransporters) and multigene family encodes them. Furthermore, these SULTRs have LAST (Low affinity transport proteins), HAST (High affinity transport proteins), vacuole transporters, and plastid transporters. Since it is well known that there is strong relationship between SO₄²⁻ and synthesis of hydrogen sulfide or dihydrogen sulfide or sulfane in plant cells. Thus, cysteine (Cys) metabolism through which H₂S could be generated in plant cell with the role of different enzymes has been presented. Furthermore, H₂S in interaction with other molecules could help to mitigate biotic and abiotic stress. Based on this review work, it can be concluded that H₂S has potential to induce cross-adaptation to biotic and abiotic stress; thus, it is recommended that it should be considered in future studies to answer the questions like what are the receptors of H₂S in plant cell, where in plants the physiological concentration of H₂S is high in response to multiple stress and how it induces cross-adaptation by interaction with other signal molecules.