Toxoplasma effectors targeting host signaling and transcription

Early electron microscopy studies revealed the elaborate cellular features that define the unique adaptations of apicomplexan parasites. Among these were bulbous rhoptry (ROP) organelles and small, dense granules (GRAs), both of which are secreted during invasion of host cells. These early morphological studies were followed by the exploration of the cellular contents of these secretory organelles, revealing them to be comprised of highly divergent protein families with few conserved domains or predicted functions. In parallel, studies on host-pathogen interactions identified many host signaling pathways that were mysteriously altered by infection. It was only with the advent of forward and reverse genetic strategies that the connections between individual parasite effectors and the specific host pathways that they targeted finally became clear. The current repertoire of parasite effectors includes ROP kinases and pseudokinases that are secreted during invasion and that block host immune pathways. Similarly, many secretory GRA proteins alter host gene expression by activating host transcription factors, through modification of chromatin, or by inducing small noncoding RNAs. These effectors highlight novel mechanisms by whichhas learned to harness host signaling to favor intracellular survival and will guide future studies designed to uncover the additional complexity of this intricate host-pathogen interaction

Thin film refractive index and thickness

Integrated optics are a contemporaneous reality in which thin-film technology and methods utilized in the development of integrated circuitry, are applied to both optical circuits and devices. This provides systems that show improved characteristics when compared to their electronic counterparts. Optical systems enable wider bandwidth operation, less power consumption, more immunity to interference and higher cost-efficiency. These features definitely represent a huge improvement in our daily lives when completely embedded in Information and Communications Technologies, replacing a large percentage of contemporaneous electronic based systems. The building blocks of these optical systems consist on waveguides and structures formed by deposited thin films. Two characteristics of utmost importance for these structures are the height and refractive index of the deposited film. In this work and by using a prism coupler, we will be presenting an optical setup and the experimental method that is used to determine both refractive index and thickness of the wave guiding structure.info:eu-repo/semantics/publishedVersio

Connected pathway relative permeability from pore-scale imaging of imbibition

Pore-scale images obtained from a synchrotron-based X-ray computed micro-tomography (µCT) imbibition experiment in sandstone rock were used to conduct Navier–Stokes flow simulations on the connected pathways of water and oil phases. The resulting relative permeability was compared with steady-state Darcy-scale imbibition experiments on 5 cm large twin samples from the same outcrop sandstone material. While the relative permeability curves display a large degree of similarity, the endpoint saturations for the µCT data are 10% in saturation units higher than the experimental data. However, the two datasets match well when normalizing to the mobile saturation range. The agreement is particularly good at low water saturations, where the oil is predominantly connected. Apart from different saturation endpoints, in this particular experiment where connected pathway flow dominates, the discrepancies between pore-scale connected pathway flow simulations and Darcy-scale steady-state data are minor overall and have very little impact on fractional flow. The results also indicate that if the pore-scale fluid distributions are available and the amount of disconnected non-wetting phase is low, quasi-static flow simulations may be sufficient to compute relative permeability. When pore-scale fluid distributions are not available, fluid distributions can be obtained from a morphological approach, which approximates capillary-dominated displacement. The relative permeability obtained from the morphological approach compare well to drainage steady state whereas major discrepancies to the imbibition steady-state experimental data are observed. The morphological approach does not represent the imbibition process very well and experimental data for the spatial arrangement of the phases are required. Presumably for modeling imbibition relative permeability an approach is needed that captures moving liquid-liquid interfaces, which requires viscous and capillary forces simultaneously

The origin of non-thermal fluctuations in multiphase flow in porous media

Core flooding experiments to determine multiphase flow in properties of rock such as relative permeability can show significant fluctuations in terms of pressure, saturation, and electrical conductivity. That is typically not considered in the Darcy scale interpretation but treated as noise. However, in recent years, flow regimes that exhibit spatio-temporal variations in pore scale occupancy related to fluid phase pressure changes have been identified. They are associated with topological changes in the fluid configurations caused by pore-scale instabilities such as snap-off. The common understanding of Darcy-scale flow regimes is that pore-scale phenomena and their signature should have averaged out at the scale of representative elementary volumes (REV) and above. In this work, it is demonstrated that pressure fluctuations observed in centimeter-scale experiments commonly considered Darcy-scale at fractional flow conditions, where wetting and non-wetting phases are co-injected into porous rock at small (<10−6) capillary numbers are ultimately caused by pore-scale processes, but there is also a Darcy-scale fractional flow theory aspect. We compare fluctuations in fractional flow experiments conducted on samples of few centimeters size with respective experiments and in-situ micro-CT imaging at pore-scale resolution using synchrotron-based X-ray computed micro-tomography. On that basis we can establish a systematic causality from pore to Darcy scale. At the pore scale, dynamic imaging allows to directly observe the associated breakup and coalescence processes of non-wetting phase clusters, which follow “trajectories” in a “phase diagram” defined by fractional flow and capillary number and can be used to categorize flow regimes. Connected pathway flow would be represented by a fixed point, whereas processes such as ganglion dynamics follow trajectories but are still overall capillary-dominated. That suggests that the origin of the pressure fluctuations observed in centimeter-sized fractional flow experiments are capillary effects. The energy scale of the pressure fluctuations corresponds to 105-106 times the thermal energy scale. This means the fluctuations are non-thermal. At the centimeter scale, there are non-monotonic and even oscillatory solutions permissible by the fractional flow theory, which allow the fluctuations to be visible and—depending on exact conditions—significant at centimeter scale, within the viscous limit of classical (Darcy scale) fractional flow theory. That also means that the phenomenon involves both capillary aspects from the pore or cluster scale and viscous aspects of fractional flow and occurs right at the transition, where the physical description concept changes from pore to Darcy scale

Switching Virally Suppressed, Treatment-Experienced Patients to a Raltegravir-Containing Regimen Does Not Alter Levels of HIV-1 DNA

Background: Current HIV-1 antiretroviral therapy (ART) greatly reduces virus replication but does not significantly affect the viral reservoir. Raltegravir, a recently introduced integrase inhibitor, could, at least theoretically, reduce residual viremia in patients on ART and affect the viral reservoir size. The aim of this study was to assess whether switching therapy in treatment-experienced patients that were virally suppressed to a raltegravir-containing regimen reduces the size of the viral reservoir, and if such treatment leads to a change in levels of HIV 2-LTR circles in this patient group. Methods: 14 ART experienced individuals with a suppressed viral load (,50 HIV-1 RNA copies/mL plasma) at baseline (for at least 2 months) were switched to a raltegravir-containing regimen. Blood samples were taken at baseline and at $2 timepoints up to 4866 weeks. Levels of total HIV-1 DNA and 2-LTR circles in peripheral blood mononuclear cells (PBMCs) were measured using real-time PCR assays. Results: There was no significant change in HIV-1 total DNA levels over the study duration (p = 0.808), median slope 0.24 (conservative nonparametric 95 % CI: 211.78, 26.23). Low levels of 2-LTR circles were detected in 2 patients. One had 16 copies/10 6 PBMCs at baseline and the other had 34 copies/10 6 PBMCs at week 51. Conclusions: The switch to a raltegravir containing regimen was not associated with a significant change in HIV-1 total DNA levels in this cohort. There were no observed changes in the levels of HIV-1 2-LTR circles associated with raltegravi

The effects of equine-assisted activities on the social functioning in children and adolescents with autism spectrum disorder

Equine-assisted activities and therapies are increasing in popularity for treatment of ASD symptoms. This research evaluated effects of a 5-week programme of therapeutic riding on social functioning of children/adolescents (N = 15) with ASD. The effectiveness of the programme was evaluated using the autism spectrum quotient, the Vineland Adaptive Behaviour Scale and the empathising and systemising quotient. Results established that the TR intervention increased empathising and reduced maladaptive behaviours. The findings also indicated that specific adaptive behaviours like socialization and communication were not affected by the intervention. Thus, a complex picture of the effects of this intervention emerges: while TR does not change all of the child’s behaviour, it can improve specific aspects of social functioning and also reduce maladaptive ASD traits

CD40, autophagy and Toxoplasma gondii

Toxoplasmagondii represents a pathogen that survives within host cells by preventing the endosomal-lysosomal compartments from fusing with the parasitophorous vacuoles. The dogma had been that the non-fusogenic nature of these vacuoles is irreversible. Recent studies revealed that this dogma is not correct. Cell-mediated immunity through CD40 re-routes the parasitophorous vacuoles to the lysosomal compartment by a process called autophagy. Autophagosome formation around the parasitophorous vacuole results in killing of the T. gondii. CD40-induced autophagy likely contributes to resistance against T. gondii particularly in neural tissue

Structural Insights into Human Peroxisome Proliferator Activated Receptor Delta (PPAR-Delta) Selective Ligand Binding

Peroxisome proliferator activated receptors (PPARs δ, α and γ) are closely related transcription factors that exert distinct effects on fatty acid and glucose metabolism, cardiac disease, inflammatory response and other processes. Several groups developed PPAR subtype specific modulators to trigger desirable effects of particular PPARs without harmful side effects associated with activation of other subtypes. Presently, however, many compounds that bind to one of the PPARs cross-react with others and rational strategies to obtain highly selective PPAR modulators are far from clear. GW0742 is a synthetic ligand that binds PPARδ more than 300-fold more tightly than PPARα or PPARγ but the structural basis of PPARδ:GW0742 interactions and reasons for strong selectivity are not clear. Here we report the crystal structure of the PPARδ:GW0742 complex. Comparisons of the PPARδ:GW0742 complex with published structures of PPARs in complex with α and γ selective agonists and pan agonists suggests that two residues (Val312 and Ile328) in the buried hormone binding pocket play special roles in PPARδ selective binding and experimental and computational analysis of effects of mutations in these residues confirms this and suggests that bulky substituents that line the PPARα and γ ligand binding pockets as structural barriers for GW0742 binding. This analysis suggests general strategies for selective PPARδ ligand design

Search for new phenomena in final states with an energetic jet and large missing transverse momentum in pp collisions at √ s = 8 TeV with the ATLAS detector

Results of a search for new phenomena in final states with an energetic jet and large missing transverse momentum are reported. The search uses 20.3 fb−1 of √ s = 8 TeV data collected in 2012 with the ATLAS detector at the LHC. Events are required to have at least one jet with pT > 120 GeV and no leptons. Nine signal regions are considered with increasing missing transverse momentum requirements between Emiss T > 150 GeV and Emiss T > 700 GeV. Good agreement is observed between the number of events in data and Standard Model expectations. The results are translated into exclusion limits on models with either large extra spatial dimensions, pair production of weakly interacting dark matter candidates, or production of very light gravitinos in a gauge-mediated supersymmetric model. In addition, limits on the production of an invisibly decaying Higgs-like boson leading to similar topologies in the final state are presente