Molecular mechanisms governing Fcgamma receptor mediated signal transduction

Receptors for the constant region of immunoglobulin G (FcgammaRs) expressed on myeloid cells play a pivotal role in the clearance of immune complexes and cell activation. In this thesis, the human monoblastic cell line, U937, has been used as a model system to study the coupling of Fcgamma receptors to specific signal transduction events. These cells are known to express both the high affinity receptor, FcgammaRI, and the low affinity activation receptor, FcgammaRIIa. Previous work has shown that the nature of the signalling cascades initiated by FcgammaRI fundamentally changes as U937 cells differentiate from a monocyte to a more macrophage phenotype. This thesis describes mechanisms that underlie this developmental switch. In IFNgamma primed U937 cells, FcgammaRI is coupled to the activation of phospholipase D (PLD). As the subsequent calcium mobilisation is independent of measurable inositol trisphophate production and is not coupled to calcium influx, we examined a potential role for the 5' inositol phosphatase, SHIP, which has been characterised to block both PLC? activation and calcium influx in mast and B-cells. Here, I demonstrate that following immune complex stimulation, SHIP is tyrosine phosphorylated and associates with the adapter protein. Shc, and immune complexes at the plasma membrane. In B-cells and mast cells, SHIP is recruited by the inhibitory Fc receptor, FcgammaRIIb. However, in IFNgamma primed U937 cells, no FcgammaRIIb could be found. Interestingly, FcgammaRIIb expression was induced following differentiation of U937 cells to a more macrophage phenotype using dibutyryl cyclic AMP (dbcAMP). This was surprising as here immune complexes activate PLCgamma and induce calcium influx. In these cells, FcgammaRIIb appears to modulate rather than inhibit immune complex activation. In IFNy primed U937 cells, activation of PLCgamma was coupled to FcgammaRIIa but not to FcgammaRI. The mechanism of this coupling was investigated. I demonstrate that FcgammaRIIa recruits preformed SLP76:PLCgamma complexes to the plasma membrane whereas FcgammaRI does not. I further show that FcgammaRI and FcgammaRIIa induce distinct activation patterns of the MAP kinase cascades. Finally I have demonstrated that the signalling pathway initiated by FcgammaRI depends entirely on the recruited accessory molecule. Thus, in IFNgamma primed cells, FcgammaRJ physically and functionally associates with the gamma-chain. Conversely, in dbcAMP differentiated cells, FcgammaRI no longer uses the gamma-chain but is coupled to PLC? activation by the recruitment of FcgammaRIIa. The gamma-chain in these differentiated cells is preferentially associated with the IgA receptor and appears to define receptor coupling to PLD

Functional network changes and cognitive control in schizophrenia

Cognitive control is a cognitive and neural mechanism that contributes to managing the complex demands of day-to-day life. Studies have suggested that functional impairments in cognitive control associated brain circuitry contribute to a broad range of higher cognitive deficits in schizophrenia. To examine this issue, we assessed functional connectivity networks in healthy adults and individuals with schizophrenia performing tasks from two distinct cognitive domains that varied in demands for cognitive control, the RiSE episodic memory task and DPX goal maintenance task. We characterized general and cognitive control-specific effects of schizophrenia on functional connectivity within an expanded frontal parietal network (FPN) and quantified network topology properties using graph analysis. Using the network based statistic (NBS), we observed greater network functional connectivity in cognitive control demanding conditions during both tasks in both groups in the FPN, and demonstrated cognitive control FPN specificity against a task independent auditory network. NBS analyses also revealed widespread connectivity deficits in schizophrenia patients across all tasks. Furthermore, quantitative changes in network topology associated with diagnostic status and task demand were observed. The present findings, in an analysis that was limited to correct trials only, ensuring that subjects are on task, provide critical insights into network connections crucial for cognitive control and the manner in which brain networks reorganize to support such control. Impairments in this mechanism are present in schizophrenia and these results highlight how cognitive control deficits contribute to the pathophysiology of this illness

Both unmedicated and medicated individuals with schizophrenia show impairments across a wide array of cognitive and reinforcement learning tasks

BACKGROUND: Schizophrenia is a disorder characterized by pervasive deficits in cognitive functioning. However, few well-powered studies have examined the degree to which cognitive performance is impaired even among individuals with schizophrenia not currently on antipsychotic medications using a wide range of cognitive and reinforcement learning measures derived from cognitive neuroscience. Such research is particularly needed in the domain of reinforcement learning, given the central role of dopamine in reinforcement learning, and the potential impact of antipsychotic medications on dopamine function. METHODS: The present study sought to fill this gap by examining healthy controls (N = 75), unmedicated (N = 48) and medicated (N = 148) individuals with schizophrenia. Participants were recruited across five sites as part of the CNTRaCS Consortium to complete tasks assessing processing speed, cognitive control, working memory, verbal learning, relational encoding and retrieval, visual integration and reinforcement learning. RESULTS: Individuals with schizophrenia who were not taking antipsychotic medications, as well as those taking antipsychotic medications, showed pervasive deficits across cognitive domains including reinforcement learning, processing speed, cognitive control, working memory, verbal learning and relational encoding and retrieval. Further, we found that chlorpromazine equivalency rates were significantly related to processing speed and working memory, while there were no significant relationships between anticholinergic load and performance on other tasks. CONCLUSIONS: These findings add to a body of literature suggesting that cognitive deficits are an enduring aspect of schizophrenia, present in those off antipsychotic medications as well as those taking antipsychotic medications

The discovery of WASP-151b, WASP-153b, WASP-156b: Insights on giant planet migration and the upper boundary of the Neptunian desert

To investigate the origin of the features discovered in the exoplanet population, the knowledge of exoplanets’ mass and radius with a good precision (≲10%) is essential. To achieve this purpose the discovery of transiting exoplanets around bright stars is of prime interest. In this paper, we report the discovery of three transiting exoplanets by the SuperWASP survey and the SOPHIE spectrograph with mass and radius determined with a precision better than 15%. WASP-151b and WASP-153b are two hot Saturns with masses, radii, densities and equilibrium temperatures of 0.31−0.03+0.04 MJ, 1.13−0.03+0.03 RJ, 0.22−0.02+0.03 ρJ and 1290−10+20 K, and 0.39−0.02+0.02 MJ, 1.55−0.08+0.10 RJ, 0.11−0.02+0.02 ρJ and 1700−40+40 K, respectively. Their host stars are early G type stars (with mag V ~ 13) and their orbital periods are 4.53 and 3.33 days, respectively. WASP-156b is a super-Neptune orbiting a K type star (mag V = 11.6). It has a mass of 0.128−0.009+0.010 MJ, a radius of 0.51−0.02+0.02 RJ, a density of 1.0−0.1+0.1 ρJ, an equilibrium temperature of 970−20+30 K and an orbital period of 3.83 days. The radius of WASP-151b appears to be only slightly inflated, while WASP-153b presents a significant radius anomaly compared to a recently published model. WASP-156b, being one of the few well characterized super-Neptunes, will help to constrain the still debated formation of Neptune size planets and the transition between gas and ice giants. The estimates of the age of these three stars confirms an already observed tendency for some stars to have gyrochronological ages significantly lower than their isochronal ages. We propose that high eccentricity migration could partially explain this behavior for stars hosting a short period planet. Finally, these three planets also lie close to (WASP-151b and WASP-153b) or below (WASP-156b) the upper boundary of the Neptunian desert. Their characteristics support that the ultra-violet irradiation plays an important role in this depletion of planets observed in the exoplanet population

Characterizing K2 planet discoveries : a super-Earth transiting the bright K dwarf HIP 116454

We report the first planet discovery from the two-wheeled Kepler (K2) mission: HIP 116454 b. The host star HIP 116454 is a bright (V = 10.1, K = 8.0) K1 dwarf with high proper motion and a parallax-based distance of 55.2 ± 5.4 pc. Based on high-resolution optical spectroscopy, we find that the host star is metal-poor with [Fe/H] =–0.16 ± 0.08 and has a radius R = 0.716 ± 0.024 R ☉ and mass M = 0.775 ± 0.027 M ☉. The star was observed by the Kepler spacecraft during its Two-Wheeled Concept Engineering Test in 2014 February. During the 9 days of observations, K2 observed a single transit event. Using a new K2 photometric analysis technique, we are able to correct small telescope drifts and recover the observed transit at high confidence, corresponding to a planetary radius of pR = 2.53 ± 0.18 R ⊕. Radial velocity observations with the HARPS-N spectrograph reveal a 11.82 ± 1.33 M ⊕ planet in a 9.1 day orbit, consistent with the transit depth, duration, and ephemeris. Follow-up photometric measurements from the MOST satellite confirm the transit observed in the K2 photometry and provide a refined ephemeris, making HIP 116454 b amenable for future follow-up observations of this latest addition to the growing population of transiting super-Earths around nearby, bright stars.Publisher PDFPeer reviewe

Quietly sharing the load? The role of school psychologists in enabling teacher resilience

Teacher resilience is associated with positive student outcomes and plays an important role in teacher retention and well-being. School ecologies can enable the resilience of teachers, with prior research illustrating the importance of supportive colleagues, strong leadership, and positive school culture. There is limited research, however, exploring the role of school psychologists in supporting or enabling teacher resilience. Using data from experienced Australian school psychologists and teachers, this exploratory qualitative study examines the role of school psychologists in enabling teacher resilience. Findings show that school psychologists directly and indirectly support teacher resilience, although teachers perceive school psychologists’ main role as work with individual students. Issues pertaining to variations in access and particular roles of school psychologists are discussed. Although further research is needed to clarify and promote the role of school psychologists, this study points to them potentially playing an important role in school ecologies that enable teacher resilience

Dislocation interactions during low-temperature plasticity of olivine and their impact on the evolution of lithospheric strength

The strength of the lithosphere is typically modelled based on constitutive equations for steady-state flow. However, strain hardening may cause significant evolution of strength in the colder load-bearing portion of the lithosphere. Recent rheological data from low-temperature deformation experiments on olivine suggest that strain hardening occurs due to the presence of temperature-independent back stresses generated by long-range elastic interactions among dislocations. These interpretations provided the basis for a flow law that incorporates hardening by the development of back stress. Here, we test this dislocation-interaction hypothesis by examining the microstructures of olivine samples deformed plastically at room temperature either in a deformation-DIA apparatus at differential stresses of ≤4.3GPa or in a nanoindenter at applied contact stresses of ≥10.2GPa. High-angular resolution electron backscatter diffraction maps reveal the presence of geometrically necessary dislocations with densities commonly above 1014m−2 and intragranular heterogeneities in residual stress on the order of 1 GPa in both sets of samples. Scanning transmission electron micrographs reveal straight dislocations aligned in slip bands and interacting with dislocations of other types that act as obstacles. The resulting accumulations of dislocations in their slip planes, and associated stress heterogeneities, are consistent with strain hardening resulting from long-range back-stresses acting among dislocations and thereby support the form of the flow law for low-temperature plasticity. Based on these observations, we predict that back stresses among dislocations will impart significant mechanical anisotropy to deformed lithosphere by enhancing or reducing the effective stress. Therefore, strain history, with associated microstructural and micromechanical evolution, is an important consideration for models of lithospheric strength. The microstructural observations also provide new criteria for identifying the operation of back-stress induced strain hardening in natural samples and therefore provide a means to test the applicability of the flow law for low-temperature plasticity.This research was supported by Natural Environment Research Council grants NE/M000966/1 to LNH, AJW, and DW and 1710DG008/JC4 to LNH and AJW; European Plate Observing System Transnational Access grant EPOS-TNA-MSL 2018-022 to LNH; Advanced Photon Source General User Proposal 55176 to LNH, DLG, and WBD; and National Science Foundation Awards EAR-1361319 to WBD, EAR-1625032 to JMW, and EAR-1806791 to KMK

Rotation of planet-harbouring stars

The rotation rate of a star has important implications for the detectability, characterisation and stability of any planets that may be orbiting it. This chapter gives a brief overview of stellar rotation before describing the methods used to measure the rotation periods of planet host stars, the factors affecting the evolution of a star's rotation rate, stellar age estimates based on rotation, and an overview of the observed trends in the rotation properties of stars with planets.Comment: 16 pages, 4 figures: Invited review to appear in 'Handbook of Exoplanets', Springer Reference Works, edited by Hans J. Deeg and Juan Antonio Belmont