937 research outputs found
BCG as a case study for precision vaccine development: lessons from vaccine heterogeneity, trained immunity, and immune ontogeny
Vaccines have been traditionally developed with the presumption that they exert identical immunogenicity regardless of target population and that they provide protection solely against their target pathogen. However, it is increasingly appreciated that vaccines can have off-target effects and that vaccine immunogenicity can vary substantially with demographic factors such as age and sex. Bacille Calmette-GuĂ©rin (BCG), the live attenuated Mycobacterium bovis vaccine against tuberculosis (TB), represents a key example of these concepts. BCG vaccines are manufactured under different conditions across the globe generating divergent formulations. Epidemiologic studies have linked early life immunization with certain BCG formulations to an unanticipated reduction (âŒ50%) in all-cause mortality, especially in low birthweight males, greatly exceeding that attributable to TB prevention. This mortality benefit has been related to prevention of sepsis and respiratory infections suggesting that BCG induces âheterologousâ protection against unrelated pathogens. Proposed mechanisms for heterologous protection include vaccine-induced immunometabolic shifts, epigenetic reprogramming of innate cell populations, and modulation of hematopoietic stem cell progenitors resulting in altered responses to subsequent stimuli, a phenomenon termed âtrained immunity.â In addition to genetic differences, licensed BCG formulations differ markedly in content of viable mycobacteria key for innate immune activation, potentially contributing to differences in the ability of these diverse formulations to induce TB-specific and heterologous protection. BCG immunomodulatory properties have also sparked interest in its potential use to prevent or alleviate autoimmune and inflammatory diseases, including type 1 diabetes mellitus and multiple sclerosis. BCG can also serve as a model: nanoparticle vaccine formulations incorporating Toll-like receptor 8 agonists can mimic some of BCGâs innate immune activation, suggesting that aspects of BCGâs effects can be induced with non-replicating stimuli. Overall, BCG represents a paradigm for precision vaccinology, lessons from which will help inform next generation vaccines
Dynamic Interactive Social Cognition Training in Virtual Reality (DiSCoVR) for adults with Autism Spectrum Disorder:A feasibility study
Background: Social cognitive difficulties in Autism Spectrum Disorder (ASD) can affect the daily lives of people with ASD profoundly, impacting the development and maintenance of meaningful social relations. Social cognition training (SCT) is commonly used for improving social functioning, but lacks ecological validity and the ability to effectively mimic social situations. Development of virtual reality (VR) interventions, focusing on enhancing social cognition, could add to the effectiveness of SCT within ASD care, by offering a safe, interactive and practical training setting, where generalization of knowledge and skills to the real-world are promoted. In this paper, our primary aim is to evaluate the feasibility and acceptance by participants and therapists of the Dynamic Interactive Social Cognition Method: Training in Virtual Reality (DiSCoVR) protocol as developed for adults with schizophrenic spectrum disorder (SSD), adapted for ASD (DiSCoVR-A). 26 participants, aged 18-63, took part in a pilot study. 22 participants completed baseline and post-assessment, including primary outcome evaluation assessment through a semi-structured interview. Secondary measures focused on social cognition, emotion recognition, mental flexibility, social anxiety, empathy and social responsiveness and were assessed at baseline (T0), post-treatment (T1), and at follow-up (T2) sixteen weeks after completion of the intervention. Results: Our results show that the majority of participant and therapists found the VR intervention acceptable and feasible, as reported in evaluation questionnaires and interviews. Conclusion: These preliminary findings are promising; however, controlled research is needed to further investigate the effectiveness of VR within social cognition training for adults with ASD
Lower fractional anisotropy without evidence for neuro-inflammation in patients with early-phase schizophrenia spectrum disorders
Various lines of research suggest immune dysregulation as a potential therapeutic target for negative and cognitive symptoms in schizophrenia spectrum disorders (SSD). Immune dysregulation would lead to higher extracellular free-water (EFW) in cerebral white matter (WM), which may partially underlie the frequently reported lower fractional anisotropy (FA) in SSD. We aim to investigate differences in EFW concentrations â a presumed proxy for neuro-inflammation â between early-phase SSD patients (n = 55) and healthy controls (HC; n = 37), and to explore immunological and cognitive correlates. To increase specificity for EFW, we study several complementary magnetic resonance imaging contrasts that are sensitive to EFW. FA, mean diffusivity (MD), magnetization transfer ratio (MTR), myelin water fraction (MWF) and quantitative T1 and T2 were calculated from diffusion-weighted imaging (DWI), magnetization transfer imaging (MTI) and multicomponent driven equilibrium single-pulse observation of T1/T2 (mcDESPOT). For each measure, WM skeletons were constructed with tract-based spatial statistics. Multivariate SSD-HC comparisons with WM skeletons and their average values (i.e. global WM) were not statistically significant. In voxel-wise analyses, FA was significantly lower in SSD in the genu of the corpus callosum and in the left superior longitudinal fasciculus (p < 0.04). Global WM measures did not correlate with immunological markers (i.e. IL1-RA, IL-6, IL-8, IL-10 and CRP) or cognition in HC and SSD after corrections for multiple comparisons. We confirmed lower FA in early-phase SSD patients. However, nonâFA measures did not provide additional evidence for immune dysregulation or for higher EFW as the primary mechanism underlying the reported lower FA values in SSD
Imaging Inter-Edge State Scattering Centers in the Quantum Hall Regime
We use an atomic force microscope tip as a local gate to study the scattering
between edge channels in a 2D electron gas in the quantum Hall regime. The
scattering is dominated by individual, microscopic scattering centers, which we
directly image here for the first time. The tip voltage dependence of the
scattering indicates that tunneling occurs through weak links and localized
states.Comment: 4 pages, 5 figure
Acoustic and optical variations during rapid downward motion episodes in the deep north-western Mediterranean Sea
An Acoustic Doppler Current Profiler (ADCP) was moored at the deep-sea site
of the ANTARES neutrino telescope near Toulon, France, thus providing a unique
opportunity to compare high-resolution acoustic and optical observations
between 70 and 170 m above the sea bed at 2475 m. The ADCP measured downward
vertical currents of magnitudes up to 0.03 m s-1 in late winter and early
spring 2006. In the same period, observations were made of enhanced levels of
acoustic reflection, interpreted as suspended particles including zooplankton,
by a factor of about 10 and of horizontal currents reaching 0.35 m s-1. These
observations coincided with high light levels detected by the telescope,
interpreted as increased bioluminescence. During winter 2006 deep dense-water
formation occurred in the Ligurian subbasin, thus providing a possible
explanation for these observations. However, the 10-20 days quasi-periodic
episodes of high levels of acoustic reflection, light and large vertical
currents continuing into the summer are not direct evidence of this process. It
is hypothesized that the main process allowing for suspended material to be
moved vertically later in the year is local advection, linked with topographic
boundary current instabilities along the rim of the 'Northern Current'.Comment: 30 pages, 7 figure
Electron transport in a quasi-one dimensional channel on suspended helium films
Quasi-one dimensional electron systems have been created using a suspended
helium film on a structured substrate. The electron mobility along the channel
is calculated by taking into account the essential scattering processes of
electrons by helium atoms in the vapor phase, ripplons, and surface defects of
the film substrate. It is shown that the last scattering mechanism may dominate
the electron mobility in the low temperature limit changing drastically the
temperature dependence of the mobility in comparison with that controlled by
the electron-ripplon scattering.Comment: 4 pages, 1 figur
Quantum Hall fluctuations and evidence for charging in the quantum Hall effect
We find that mesoscopic conductance fluctuations in the quantum Hall regime
in silicon MOSFETs display simple and striking patterns. The fluctuations fall
into distinct groups which move along lines parallel to loci of integer filling
factor in the gate voltage-magnetic field plane. Also, a relationship appears
between the fluctuations on quantum Hall transitions and those found at low
densities in zero magnetic field. These phenomena are most naturally attributed
to charging effects. We argue that they are the first unambiguous manifestation
of interactions in dc transport in the integer quantum Hall effect.Comment: 4 pages RevTeX including 4 postscript bitmapped figure
The Peroxisomal Targeting Signal 1 in sterol carrier protein 2 is autonomous and essential for receptor recognition
<p>Abstract</p> <p>Background</p> <p>The majority of peroxisomal matrix proteins destined for translocation into the peroxisomal lumen are recognised <it>via </it>a C-terminal Peroxisomal Target Signal type 1 by the cycling receptor Pex5p. The only structure to date of Pex5p in complex with a cargo protein is that of the C-terminal cargo-binding domain of the receptor with sterol carrier protein 2, a small, model peroxisomal protein. In this study, we have tested the contribution of a second, ancillary receptor-cargo binding site, which was found in addition to the characterised Peroxisomal Target Signal type 1.</p> <p>Results</p> <p>To investigate the function of this secondary interface we have mutated two key residues from the ancillary binding site and analyzed the level of binding first by a yeast-two-hybrid assay, followed by quantitative measurement of the binding affinity and kinetics of purified protein components and finally, by <it>in vivo </it>measurements, to determine translocation capability. While a moderate but significant reduction of the interaction was found in binding assays, we were not able to measure any significant defects <it>in vivo</it>.</p> <p>Conclusions</p> <p>Our data therefore suggest that at least in the case of sterol carrier protein 2 the contribution of the second binding site is not essential for peroxisomal import. At this stage, however, we cannot rule out that other cargo proteins may require this ancillary binding site.</p
Scanned Potential Microscopy of Edge and Bulk Currents in the Quantum Hall Regime
Using an atomic force microscope as a local voltmeter, we measure the Hall
voltage profile in a 2D electron gas in the quantum Hall (QH) regime. We
observe a linear profile in the bulk of the sample in the transition regions
between QH plateaus and a distinctly nonlinear profile on the plateaus. In
addition, localized voltage drops are observed at the sample edges in the
transition regions. We interpret these results in terms of theories of edge and
bulk currents in the QH regime.Comment: 4 pages, 5 figure
Individual scatterers as microscopic origin of equilibration between spin- polarized edge channels in the quantum Hall regime
The equilibration length between spin-polarized edge states in the Quantum
Hall regime is measured as a function of a gate voltage applied to an electrode
on top of the edge channels. Reproducible fluctuations in the coupling are
observed and interpreted as a mesoscopic fingerprint of single spin-flip
scatterers which are turned on and off. A model to analyze macroscopic edge
state coupling in terms of individual scatterers is developed, and
characteristic values for these scatterers in our samples are extracted. For
all samples investigated, the distance between spin-flip scatterers lies
between the Drude and the quantum scattering length.Comment: 4 pages, 2 figure
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