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-Guérin (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 (∼50%) 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 “heterologous” 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 “trained immunity.” 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 BCG’s innate immune activation, suggesting that aspects of BCG’s 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 – a presumed proxy for neuro-inflammation – 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, non–FA 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