Familiarity accentuates gaze cuing in women but not men

Gaze cuing, the tendency to shift attention in the direction other individuals are looking, is hypothesized to depend on a distinct neural module. One expectation of such a module is that information processing should be encapsulated within it. Here, we tested whether familiarity, a type of social knowledge, penetrates the neural circuits governing gaze cuing. Male and female subjects viewed the face of an adult male looking left or right and then pressed a keypad to indicate the location of a target appearing randomly left or right. Responses were faster for targets congruent with gaze direction. Moreover, gaze cuing was stronger in females than males. Contrary to the modularity hypothesis, familiarity enhanced gaze cuing, but only in females. Sex differences in the effects of familiarity on gaze cuing may reflect greater adaptive significance of social information for females than males.     

Cheilolejeunea morganii Bever. & Glenny (Lejeuneaceae,Marchantiopsida), a newly described species from lowland indigenous forest sites in New Zealand

Introduction. Cheilolejeunea morganii Bever. & Glenny, a new species of Cheilolejeunea from a lowland forest habitat in eastern Taranaki in the North Island of New Zealand, is described and illustrated.

Methods. DNA sequences were extracted from recently collected material at two locations and compared with those for species in a published phylogeny of the genus to establish the position of C. morganii. Photographic images were obtained of key features of the species for the preparation of illustrations for publication.

Key results. Cheilolejeunea morganii does not match any species described for New Zealand or Australia. The sequencing results indicate its position in the phylogeny is close to Section Paroicae. A key to the New Zealand species of Cheilolejeunea is provided.

Conclusions. In the Australasian flora, C. morganii is distinguished from other species by its combination of monoicy, pycnolejeuneoid gynoecial innovations, lobule length less than 50% lobe length and a multicellular second lobule tooth with 3–4 cells uniseriate. A case is presented for the recognition of the species as a New Zealand endemic.     

Interaction of gamma 1-syntrophin with diacylglycerol kinase-zeta. Regulation of nuclear localization by PDZ interactions

Syntrophins are modular adapter proteins that link ion channels and signaling proteins to dystrophin and its homologues. A yeast two-hybrid screen of a human brain cDNA library using the PDZ domain of gamma 1- syntrophin, a recently identified brain-specific isoform, yielded overlapping clones encoding the C terminus of diacylglycerol kinase-zeta (DGK-zeta), an enzyme that converts diacylglycerol into phosphatidic acid. In biochemical assays, the C terminus of DGK-zeta, which contains a consensus PDZ-binding motif, was found to be necessary and sufficient for association with gamma 1-syntrophin. When coexpressed in HeLa cells, DGK-zeta and gamma 1-syntrophin formed a stable complex that partitioned between the cytoplasm and nucleus. DGK-zeta translocates from the cytosol to the nucleus, a process negatively regulated by protein kinase C phosphorylation. We found that DGK-zeta recruits gamma 1-syntrophin into the nucleus and that the PDZ-binding motif is required. Disrupting the interaction altered the intracellular localization of both proteins; DGK-zeta accumulated in the nucleus, whereas gamma 1-syntrophin remained in the cytoplasm. The level of endogenous syntrophins in the nucleus of HeLa cells also reflected the amount of nuclear DGK-zeta. In the brain, DGK-zeta and gamma 1-syntrophin were colocalized in cell bodies and dendrites of cerebellar Purkinjie neurons and other neuronal cell types, suggesting that their interaction is physiologically relevant. Moreover, coimmunoprecipitation and pull-down experiments from brain extracts and cells suggest that DGK-zeta, gamma 1-syntrophin, and dystrophin form a ternary complex. Collectively, our results suggest that gamma 1-syntrophin participates in regulating the subcellular localization of DGK-zeta to ensure correct termination of diacylglycerol signaling.     

Induction of spine growth and synapse formation by regulation of the spine actin cytoskeleton

We explored the relationship between regulation of the spine actin cytoskeleton, spine morphogenesis, and synapse formation by manipulating expression of the actin binding protein NrbI and its deletion mutants. In pyramidal neurons of cultured rat hippocampal slices, NrbI is concentrated in dendritic spines by binding to the actin cytoskeleton. Expression of one NrbI deletion mutant, containing the actin binding domain, dramatically increased the density and length of dendritic spines with synapses. This hyperspinogenesis was accompanied by enhanced actin polymerization and spine motility. Synaptic strengths were reduced to compensate for extra synapses, keeping total synaptic input per neuron constant. Our data support a model in which synapse formation is promoted by actin-powered motility.     

Immune activation and CD8+ T-cell differentiation towards senescence in HIV-1 infection

Progress in the fight against the HIV/AIDS epidemic is hindered by our failure to elucidate the precise reasons for the onset of immunodeficiency in HIV-1 infection. Increasing evidence suggests that elevated immune activation is associated with poor outcome in HIV-1 pathogenesis. However, the basis of this association remains unclear. Through ex vivo analysis of virus-specific CD8⁺ T-cells and the use of an in vitro model of naïve CD8⁺ T-cell priming, we show that the activation level and the differentiation state of T-cells are closely related. Acute HIV-1 infection induces massive activation of CD8⁺ T-cells, affecting many cell populations, not only those specific for HIV-1, which results in further differentiation of these cells. HIV disease progression correlates with increased proportions of highly differentiated CD8⁺ T-cells, which exhibit characteristics of replicative senescence and probably indicate a decline in T-cell competence of the infected person. The differentiation of CD8⁺ and CD4⁺ T-cells towards a state of replicative senescence is a natural process. It can be driven by excessive levels of immune stimulation. This may be part of the mechanism through which HIV-1-mediated immune activation exhausts the capacity of the immune system.     

Generation of CD1 tetramers as a tool to monitor glycolipid-specific T cells

CD1 molecules are beta(2)m-associated HLA class-I-like glycoproteins which have the unique ability to present glycolipid and phospholipid antigens to specific T lymphocytes. To study the biology of CD1 and its role in human disease we developed novel techniques for generation of recombinant CD1/lipid complexes by in vitro refolding. Fluorescent tetrameric complexes made from soluble recombinant CD1d/alpha-galactosylceramide complexes allowed highly sensitive and specific ex vivo and in vitro detection and functional characterization of novel human T-lymphocyte populations. Furthermore, protein crystals were obtained from soluble recombinant CD1b/beta(2)m-proteins loaded either with phosphatidylinositol or ganglioside GM2, which led to the first atomic structure determination of a CD1/lipid complex. The analysis of these crystal structures clarified how CD1b molecules can bind lipid ligands of different size, and revealed a broader spectrum of potential CD1b ligands than previously predicted.     

TNF-alpha and leptin activate the alpha-isoform of class II phosphoinositide 3-kinase

The class II PI 3-kinases are known to be activated by growth factors and chemokines but to date there are no reports of cytokine mediated regulation. Further, the intracellular signalling mechanisms regulating the class-II PI 3-kinases are poorly understood. We investigated the effects of the cytokines TNFalpha and leptin on the activity of the alpha isoform of the class II PI 3-kinase (PI3K-C2alpha) and find that these stimulate the enzyme 2-fold and 3-fold, in CHO cells and J774.2 macrophages, respectively. The stimulation by leptin was not accompanied by recruitment of any tyrosine phosphorylated proteins to PI3K-C2alpha and no shift in electrophoretic mobility was noted. Furthermore, we demonstrate that the actions of both cytokines are blocked by the MEK inhibitor PD98059. These findings indicate that the cytokines activate PI3K-C2alpha and do so by a mechanism that requires activation of the ERK pathway and thus differs from the mechanism used by insulin to activate the enzyme.     

The p38 MAPK inhibitor, PD169316, inhibits transforming growth factor beta-induced Smad signaling in human ovarian cancer cells

Transforming growth factor beta (TGFbeta) can signal through a variety of Smad-independent pathways, including the p38 MAPK pathway. Recent work has shown that inhibitors of p38 MAPK, such as SB203580 and SB202190, can inhibit signaling induced by TGFbeta. Here we show that another p38 MAPK inhibitor, PD169316, abrogates signaling initiated by both TGFbeta and Activin A, but not bone morphogenetic protein (BMP) 4. Inhibition of TGFbeta signaling is dose dependent and results in reduced Smad2 and Smad3 phosphorylation, nuclear translocation, and up-regulation of the TGFbeta target gene Smad7. Reduced TGFbeta signaling is not due to abrogation of p38 MAPK activity, since blocking p38 MAPK activity with a dominant negative form of p38 MAPK has no effect on TGFbeta/Smad signaling. Our results show that use of PD169316 at 5 MICROM or higher can block TGFbeta signaling activity and thus caution must be used when attributing cellular activities exclusively to p38 MAPK signaling when these inhibitors are used experimentally.     

Progress in the development of a recombinant vaccine for human hookworm disease: the Human Hookworm Vaccine Initiative

Hookworm infection is one of the most important parasitic infections of humans, possibly outranked only by malaria as a cause of misery and suffering. An estimated 1.2 billion people are infected with hookworm in areas of rural poverty in the tropics and subtropics. Epidemiological data collected in China, Southeast Asia and Brazil indicate that, unlike other soil-transmitted helminth infections, the highest hookworm burdens typically occur in adult populations, including the elderly. Emerging data on the host cellular immune responses of chronically infected populations suggest that hookworms induce a state of host anergy and immune hyporesponsiveness. These features account for the high rates of hookworm reinfection following treatment with anthelminthic drugs and therefore, the failure of anthelminthics to control hookworm. Despite the inability of the human host to develop naturally acquired immune responses to hookworm, there is evidence for the feasibility of developing a vaccine based on the successes of immunising laboratory animals with either attenuated larval vaccines or antigens extracted from the alimentary canal of adult blood-feeding stages. The major antigens associated with each of these larval and adult hookworm vaccines have been cloned and expressed in prokaryotic and eukaryotic systems. However, only eukaryotic expression systems (e.g., yeast, baculovirus, and insect cells) produce recombinant proteins that immunologically resemble the corresponding native antigens. A challenge for vaccinologists is to formulate selected eukaryotic antigens with appropriate adjuvants in order to elicit high antibody titres. In some cases, antigen-specific IgE responses are required to mediate protection. Another challenge will be to produce anti-hookworm vaccine antigens at high yield low cost suitable for immunising large impoverished populations living in the developing nations of the tropics.