Systems Analysis of MVA-C Induced Immune Response Reveals Its Significance as a Vaccine Candidate against HIV/AIDS of Clade C

Based on the partial efficacy of the HIV/AIDS Thai trial (RV144) with a canarypox vector prime and protein boost, attenuated poxvirus recombinants expressing HIV-1 antigens are increasingly sought as vaccine candidates against HIV/AIDS. Here we describe using systems analysis the biological and immunological characteristics of the attenuated vaccinia virus Ankara strain expressing the HIV-1 antigens Env/Gag-Pol-Nef of HIV-1 of clade C (referred as MVA-C). MVA-C infection of human monocyte derived dendritic cells (moDCs) induced the expression of HIV-1 antigens at high levels from 2 to 8 hpi and triggered moDCs maturation as revealed by enhanced expression of HLA-DR, CD86, CD40, HLA-A2, and CD80 molecules. Infection ex vivo of purified mDC and pDC with MVA-C induced the expression of immunoregulatory pathways associated with antiviral responses, antigen presentation, T cell and B cell responses. Similarly, human whole blood or primary macrophages infected with MVA-C express high levels of proinflammatory cytokines and chemokines involved with T cell activation. The vector MVA-C has the ability to cross-present antigens to HIV-specific CD8 T cells in vitro and to increase CD8 T cell proliferation in a dose-dependent manner. The immunogenic profiling in mice after DNA-C prime/MVA-C boost combination revealed activation of HIV-1-specific CD4 and CD8 T cell memory responses that are polyfunctional and with effector memory phenotype. Env-specific IgG binding antibodies were also produced in animals receiving DNA-C prime/MVA-C boost. Our systems analysis of profiling immune response to MVA-C infection highlights the potential benefit of MVA-C as vaccine candidate against HIV/AIDS for clade C, the prevalent subtype virus in the most affected areas of the world

The Neuro-Glial Properties of Adipose-Derived Adult Stromal (ADAS) Cells Are Not Regulated by Notch 1 and Are Not Derived from Neural Crest Lineage

We investigated whether adipose-derived adult stromal (ADAS) are of neural crest origin and the extent to which Notch 1 regulates their growth and differentiation. Mouse ADAS cells cultured in media formulated for neural stem cells (NSC) displayed limited capacity for self-renewal, clonogenicity, and neurosphere formation compared to NSC from the subventricular zone in the hippocampus. Although ADAS cells expressed Nestin, GFAP, NSE and Tuj1 in vitro, exposure to NSC differentiation supplements did not induce mature neuronal marker expression. In contrast, in mesenchymal stem cell (MSC) media, ADAS cells retained their ability to proliferate and differentiate beyond 20 passages and expressed high levels of Nestin. In neuritizing cocktails, ADAS cells extended processes, downregulated Nestin expression, and displayed depolarization-induced Ca2+ transients but no spontaneous or evoked neural network activity on Multi-Electrode Arrays. Deletion of Notch 1 in ADAS cell cultures grown in NSC proliferation medium did not significantly alter their proliferative potential in vitro or the differentiation-induced downregulation of Nestin. Co-culture of ADAS cells with fibroblasts that stably expressed the Notch ligand Jagged 1 or overexpression of the Notch intracellular domain (NICD) did not alter ADAS cell growth, morphology, or cellular marker expression. ADAS cells did not display robust expression of neural crest transcription factors or genes (Sox, CRABP2, and TH); and lineage tracing analyses using Wnt1–Cre;Rosa26R-lacZ or -EYFP reporter mice confirmed that fewer than 2% of the ADAS cell population derived from a Wnt1-positive population during development. In summary, although media formulations optimized for MSCs or NSCs enable expansion of mouse ADAS cells in vitro, we find no evidence that these cells are of neural crest origin, that they can undergo robust terminal differentiation into functionally mature neurons, and that Notch 1 is likely to be a key regulator of their cellular and molecular characteristics

A many-analysts approach to the relation between religiosity and well-being

The relation between religiosity and well-being is one of the most researched topics in the psychology of religion, yet the directionality and robustness of the effect remains debated. Here, we adopted a many-analysts approach to assess the robustness of this relation based on a new cross-cultural dataset (N=10,535 participants from 24 countries). We recruited 120 analysis teams to investigate (1) whether religious people self-report higher well-being, and (2) whether the relation between religiosity and self-reported well-being depends on perceived cultural norms of religion (i.e., whether it is considered normal and desirable to be religious in a given country). In a two-stage procedure, the teams first created an analysis plan and then executed their planned analysis on the data. For the first research question, all but 3 teams reported positive effect sizes with credible/confidence intervals excluding zero (median reported β=0.120). For the second research question, this was the case for 65% of the teams (median reported β=0.039). While most teams applied (multilevel) linear regression models, there was considerable variability in the choice of items used to construct the independent variables, the dependent variable, and the included covariates

A new classification of earthquake-induced landslide event sizes based on seismotectonic, topographic, climatic and geologic factors

Background This paper reviews the classical and some particular factors contributing to earthquake-triggered landslide activity. This analysis should help predict more accurately landslide event sizes, both in terms of potential numbers and affected area. It also highlights that some occurrences, especially those very far from the hypocentre/activated fault, cannot be predicted by state-of-the-art methods. Particular attention will be paid to the effects of deep focal earthquakes in Central Asia and to other extremely distant landslide activations in other regions of the world (e.g. Saguenay earthquake 1988, Canada). Results The classification of seismically induced landslides and the related ‘event sizes’ is based on five main factors: ‘Intensity’, ‘Fault factor’, ‘Topographic energy’, ‘Climatic background conditions’, ‘Lithological factor’. Most of these data were extracted from papers, but topographic inputs were checked by analyzing the affected region in Google Earth. The combination and relative weight of the factors was tested through comparison with well documented events and complemented by our studies of earthquake-triggered landslides in Central Asia. The highest relative weight (6) was attributed to the ‘Fault factor’; the other factors all received a smaller relative weight (2–4). The high weight of the ‘Fault factor’ (based on the location in/outside the mountain range, the fault type and length) is strongly constrained by the importance of the Wenchuan earthquake that, for example, triggered far more landslides in 2008 than the Nepal earthquake in 2015: the main difference is that the fault activated by the Wenchuan earthquake created an extensive surface rupture within the Longmenshan Range marked by a very high topographic energy while the one activated by the Nepal earthquake ruptured the surface in the frontal part of the Himalayas where the slopes are less steep and high. Finally, the calibrated factor combination was applied to almost 100 other earthquake events for which some landslide information was available. This comparison revealed the ability of the classification to provide a reasonable estimate of the number of triggered landslides and of the size of the affected area. According to this prediction, the most severe earthquake-triggered landslide event of the last one hundred years would actually be the Wenchuan earthquake in 2008 followed by the 1950 Assam earthquake in India – considering that the dominating role of the Wenchuan earthquake data (including the availability of a complete landslide inventory) for the weighting of the factors strongly influences and may even bias this result. The strongest landslide impacts on human life in recent history were caused by the Haiyuan-Gansu earthquake in 1920 – ranked as third most severe event according to our classification: its size is due to a combination of high shaking intensity, an important ‘Fault factor’ and the extreme susceptibility of the regional loess cover to slope failure, while the surface morphology of the affected area is much smoother than the one affected by the Wenchuan 2008 or the Nepal 2015 earthquakes. Conclusions The main goal of the classification of earthquake-triggered landslide events is to help improve total seismic hazard assessment over short and longer terms. Considering the general performance of the classification-prediction, it can be seen that the prediction either fits or overestimates the known/observed number of triggered landslides for a series of earthquakes, while it often underestimates the size of the affected area. For several events (especially the older ones), the overestimation of the number of landslides can be partly explained by the incompleteness of the published catalogues. The underestimation of the extension of the area, however, is real – as some particularities cannot be taken into account by such a general approach: notably, we used the same seismic intensity attenuation for all events, while attenuation laws are dependent on regional tectonic and geological conditions. In this regard, it is likely that the far-distant triggering of landslides, e.g., by the 1988 Saguenay earthquake (and the related extreme extension of affected area) is due to a very low attenuation of seismic energy within the North American plate. Far-distant triggering of landslides in Central Asia can be explained by the susceptibility of slopes covered by thick soft soils to failure under the effect of low-frequency shaking induced by distant earthquakes, especially by the deep focal earthquakes in the Pamir – Hindukush seismic region. Such deep focal and high magnitude (> > 7) earthquakes are also found in Europe, first of all in the Vrancea region (Romania). For this area as well as for the South Tien Shan we computed possible landslide event sizes related to some future earthquake scenarios