PI3K signaling supports amphetamine-induced dopamine efflux

The dopamine (DA) transporter (DAT) is a major molecular target of the psychostimulant amphetamine (AMPH). AMPH, as a result of its ability to reverse DAT-mediated inward transport of DA, induces DA efflux thereby increasing extracellular DA levels. This increase is thought to underlie the behavioral effects of AMPH. We have demonstrated previously that insulin, through phosphatidylinositol 3-kinase (PI3K) signaling, regulates DA clearance by fine-tuning DAT plasma membrane expression. PI3K signaling may represent a novel mechanism for regulating DA efflux evoked by AMPH, since only active DAT at the plasma membrane can efflux DA. Here, we show in both a heterologous expression system and DA neurons that inhibition of PI3K decreases DAT cell surface expression and, as a consequence, AMPH-induced DA efflux.     

Chemokine gene expression during fatal murine cerebral malaria and protection due to CXCR3 deficiency

Cerebral malaria (CM) can be a fatal manifestation of Plasmodium falciparum infection. Using murine models of malaria, we found much greater up-regulation of a number of chemokine mRNAs, including those for CXCR3 and its ligands, in the brain during fatal murine CM (FMCM) than in a model of non-CM. Expression of CXCL9 and CXCL10 RNA was localized predominantly to the cerebral microvessels and in adjacent glial cells, while expression of CCL5 was restricted mainly to infiltrating lymphocytes. The majority of mice deficient in CXCR3 were found to be protected from FMCM, and this protection was associated with a reduction in the number of CD8+ T cells in brain vessels as well as reduced expression of perforin and FasL mRNA. Adoptive transfer of CD8+ cells from C57BL/6 mice with FMCM abrogated this protection in CXCR3-/- mice. Moreover, there were decreased mRNA levels for the proinflammatory cytokines IFN-gamma and lymphotoxin-alpha in the brains of mice protected from FMCM. These data suggest a role for CXCR3 in the pathogenesis of FMCM through the recruitment and activation of pathogenic CD8+ T cells.     

Genetic analysis of SH2D4A, a novel adapter protein related to T cell-specific adapter and adapter protein in lymphocytes of unknown function, reveals a redundant function in T cells

T cell-specific adapter (TSAd) protein and adapter protein in lymphocytes of unknown function (ALX) are two related Src homology 2 (SH2) domain-containing signaling adapter molecules that have both been shown to regulate TCR signal transduction in T cells. TSAd is required for normal TCR-induced synthesis of IL-2 and other cytokines in T cells and acts at least in part by promoting activation of the LCK protein tyrosine kinase at the outset of the TCR signaling cascade. By contrast, ALX functions as a negative-regulator of TCR-induced IL-2 synthesis through as yet undetermined mechanisms. In this study, we report a novel T cell-expressed adapter protein named SH2D4A that contains an SH2 domain that is highly homologous to the TSAd protein and ALX SH2 domains and that shares other structural features with these adapters. To examine the function of SH2D4A in T cells we produced SH2D4A-deficient mice by homologous recombination in embryonic stem cells. T cell development, homeostasis, proliferation, and function were all found to be normal in these mice. Furthermore, knockdown of SH2D4A expression in human T cells did not impact upon their function. We conclude that in contrast to TSAd and ALX proteins, SH2D4A is dispensable for TCR signal transduction in T cells.     

Changes in red fox habitat preference and rest site fidelity following a disease-induced population decline

Mammal Research - The habitat preferences of red foxesVulpes vulpes (Linnaeus, 1758) in Bristol, UK, were compared during periods of high and low population density following an outbreak of...     

Making more sense of the order: A review of Canoco for Windows 4.5, PC‐ORD version 4 and SYN‐TAX 2000

Abstract. Personal computers of ever‐increasing speed have motivated programmers of multivariate software to adapt their programs to be run in Microsoft Windows and Macintosh platforms. Updated versions of these multivariate programs appear more and more frequently and are marketed intensively. In this review we provide a comparative analysis of the most recent versions of three analytical software packages –Canoco for Windows 4.5, PC‐ORD version 4 and SYN‐TAX 2000. The three packages share two characteristics. First, the most recent versions are now compatible with the most recent Windows platforms and should therefore be accessible for use by virtually all vegetation scientists. Second, they have capabilities for numerous multivariate techniques, although each package has some unique techniques. Thus, any one of the packages will have much to offer the user.     

Heparan sulfate proteoglycans retain Noggin at the cell surface: a potential mechanism for shaping bone morphogenetic protein gradients.

Bone morphogenetic proteins (BMPs) are expressed broadly and regulate a diverse array of developmental events in vivo. Essential to many of these functions is the establishment of activity gradients of BMP, which provide positional information that influences cell fates. Secreted polypeptides, such as Noggin, bind BMPs and inhibit their function by preventing interaction with receptors on the cell surface. These BMP antagonists are assumed to be diffusible and therefore potentially important in the establishment of BMP activity gradients in vivo. Nothing is known, however, about the potential interactions between Noggin and components of the cell surface or extracellular matrix that might limit its diffusion. We have found that Noggin binds strongly to heparin in vitro, and to heparan sulfate proteoglycans on the surface of cultured cells. Noggin is detected only on the surface of cells that express heparan sulfate, can be specifically displaced from cells by heparin, and can be directly cross-linked to a cell surface proteoglycan in culture. Heparan sulfate-bound Noggin remains functional and can bind BMP4 at the plasma membrane. A Noggin mutant with a deletion in a putative heparin binding domain has reduced binding to heparin and does not bind to the cell surface but has preserved BMP binding and antagonist functions. Our results imply that interactions between Noggin and heparan sulfate proteoglycans in vivo regulate diffusion and therefore the formation of gradients of BMP activity.     

Geology and geochronology of the middle Miocene Kipsaramon site complex, Muruyur Beds, Tugen Hills, Kenya.

The Muruyur Beds are a substantial sedimentary deposit within a middle Miocene sequence of mafic volcanic flows associated with early stages of rifting in the central Kenyan Rift Valley. They are best represented in the Muruyur region, near Bartabwa, north of Kipsaramon, where dates range from 16.0 to 13.4 Ma. At Kipsaramon, located about 10 km south of Muruyur along the crest of the Tugen Hills, the upper Muruyur Beds are absent and the lower part can be divided into three members. Important fossil sites within Member 1 are dated between 15.8 and 15.6 Ma, and within Member 3 between 15.6 and 15.4 Ma. BPRP#89, in Member 1, is a bonebed at least 2500 m(2)in areal extent and up to 30 cm thick, which constitutes one of the richest concentrations of in situ fossil vertebrate bones in eastern Africa. BPRP#91, at approximately the same level at BPRP#89, is the source of a hominoid talus and other mammal and bird fossils. In Member 3, BPRP#122 has produced specimens of at least five individuals of the hominoid Equatorius, including a partial skeleton. The Muyuyur Beds were deposited near the western margin of a lake that was formed during the early stages of faulting and volcanism in the African Rift system. The bonebed in Member 1 appears to represent the influx of fluvially transported vertebrate and plant remains into a shallow portion of the lake. Elements of the fauna as well as stable isotopes that indicate both forest and more open environments occurred in proximity to the lake during the time of deposition of Member 1.     

Survival in Nuclear Waste,Extreme Resistance,and Potential Applications Gleaned from the Genome Sequence of Kineococcus radiotolerans SRS30216

Kineococcus radiotolerans {"type":"entrez-protein","attrs":{"text":"SRS30216","term_id":"1414251709","term_text":"SRS30216"}}SRS30216 was isolated from a high-level radioactive environment at the Savannah River Site (SRS) and exhibits γ-radiation resistance approaching that of Deinococcus radiodurans. The genome was sequenced by the U.S. Department of Energy''s Joint Genome Institute which suggested the existence of three replicons, a 4.76 Mb linear chromosome, a 0.18 Mb linear plasmid, and a 12.92 Kb circular plasmid. Southern hybridization confirmed that the chromosome is linear. The K. radiotolerans genome sequence was examined to learn about the physiology of the organism with regard to ionizing radiation resistance, the potential for bioremediation of nuclear waste, and the dimorphic life cycle. K. radiotolerans may have a unique genetic toolbox for radiation protection as it lacks many of the genes known to confer radiation resistance in D. radiodurans. Additionally, genes involved in the detoxification of reactive oxygen species and the excision repair pathway are overrepresented. K. radiotolerans appears to lack degradation pathways for pervasive soil and groundwater pollutants. However, it can respire on two organic acids found in SRS high-level nuclear waste, formate and oxalate, which promote the survival of cells during prolonged periods of starvation. The dimorphic life cycle involves the production of motile zoospores. The flagellar biosynthesis genes are located on a motility island, though its regulation could not be fully discerned. These results highlight the remarkable ability of K radiotolerans to withstand environmental extremes and suggest that in situ bioremediation of organic complexants from high level radioactive waste may be feasible.