41 research outputs found

    Recovering the second moment of the strain distribution from neutron Bragg edge data

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    Point by point strain scanning is often used to map the residual stress (strain) in engineering materials and components. However, the gauge volume and hence spatial resolution is limited by the beam defining apertures and can be anisotropic for very low and high diffraction (scattering) angles. Alternatively, wavelength resolved neutron transmission imaging has a potential to retrieve information tomographically about residual strain induced within materials through measurement in transmission of Bragg edges - crystallographic fingerprints whose locations and shapes depend on microstructure and strain distribution. In such a case the spatial resolution is determined by the geometrical blurring of the measurement setup and the detector point spread function. Mathematically, reconstruction of strain tensor field is described by the longitudinal ray transform; this transform has a non-trivial null-space, making direct inversion impossible. A combination of the longitudinal ray transform with physical constraints was used to reconstruct strain tensor fields in convex objects. To relax physical constraints and generalise reconstruction, a recently introduced concept of histogram tomography can be employed. Histogram tomography relies on our ability to resolve the distribution of strain in the beam direction, as we discuss in the paper. More specifically, Bragg edge strain tomography requires extraction of the second moment (variance about zero) of the strain distribution which has not yet been demonstrated in practice. In this paper we verify experimentally that the second moment can be reliably measured for a previously well characterised aluminium ring and plug sample. We compare experimental measurements against numerical calculation and further support our conclusions by rigorous uncertainty quantification of the estimated mean and variance of the strain distribution

    Antigen presenting ILC3 regulate T cell-dependent IgA responses to colonic mucosal-associated bacteria

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    Intestinal immune homeostasis is dependent upon tightly regulated and dynamic host interactions with the commensal microbiota. Immunoglobulin A (IgA) produced by mucosal B cells dictates the composition of commensal bacteria residing within the intestine. While emerging evidence suggests the majority of IgA is produced innately and may be polyreactive, mucosal-dwelling species can also elicit IgA via T cell-dependent mechanisms. However, the mechanisms that modulate the magnitude and quality of T cell-dependent IgA responses remain incompletely understood. Here we demonstrate that group 3 innate lymphoid cells (ILC3) regulate steady state interactions between T follicular helper cells (TfH) and B cells to limit mucosal IgA responses. ILC3 used conserved migratory cues to establish residence within the interfollicular regions of the intestinal draining lymph nodes, where they act to limit TfH responses and B cell class switching through antigen presentation. The absence of ILC3-intrinsic antigen presentation resulted in increased and selective IgA coating of bacteria residing within the colonic mucosa. Together these findings implicate lymph node resident, antigen-presenting ILC3 as a critical regulatory checkpoint in the generation of T cell-dependent colonic IgA and suggest ILC3 act to maintain tissue homeostasis and mutualism with the mucosal-dwelling commensal microbiota

    31st Annual Meeting and Associated Programs of the Society for Immunotherapy of Cancer (SITC 2016) : part two

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    Background The immunological escape of tumors represents one of the main ob- stacles to the treatment of malignancies. The blockade of PD-1 or CTLA-4 receptors represented a milestone in the history of immunotherapy. However, immune checkpoint inhibitors seem to be effective in specific cohorts of patients. It has been proposed that their efficacy relies on the presence of an immunological response. Thus, we hypothesized that disruption of the PD-L1/PD-1 axis would synergize with our oncolytic vaccine platform PeptiCRAd. Methods We used murine B16OVA in vivo tumor models and flow cytometry analysis to investigate the immunological background. Results First, we found that high-burden B16OVA tumors were refractory to combination immunotherapy. However, with a more aggressive schedule, tumors with a lower burden were more susceptible to the combination of PeptiCRAd and PD-L1 blockade. The therapy signifi- cantly increased the median survival of mice (Fig. 7). Interestingly, the reduced growth of contralaterally injected B16F10 cells sug- gested the presence of a long lasting immunological memory also against non-targeted antigens. Concerning the functional state of tumor infiltrating lymphocytes (TILs), we found that all the immune therapies would enhance the percentage of activated (PD-1pos TIM- 3neg) T lymphocytes and reduce the amount of exhausted (PD-1pos TIM-3pos) cells compared to placebo. As expected, we found that PeptiCRAd monotherapy could increase the number of antigen spe- cific CD8+ T cells compared to other treatments. However, only the combination with PD-L1 blockade could significantly increase the ra- tio between activated and exhausted pentamer positive cells (p= 0.0058), suggesting that by disrupting the PD-1/PD-L1 axis we could decrease the amount of dysfunctional antigen specific T cells. We ob- served that the anatomical location deeply influenced the state of CD4+ and CD8+ T lymphocytes. In fact, TIM-3 expression was in- creased by 2 fold on TILs compared to splenic and lymphoid T cells. In the CD8+ compartment, the expression of PD-1 on the surface seemed to be restricted to the tumor micro-environment, while CD4 + T cells had a high expression of PD-1 also in lymphoid organs. Interestingly, we found that the levels of PD-1 were significantly higher on CD8+ T cells than on CD4+ T cells into the tumor micro- environment (p < 0.0001). Conclusions In conclusion, we demonstrated that the efficacy of immune check- point inhibitors might be strongly enhanced by their combination with cancer vaccines. PeptiCRAd was able to increase the number of antigen-specific T cells and PD-L1 blockade prevented their exhaus- tion, resulting in long-lasting immunological memory and increased median survival

    Ground Motion and Variability from 3-D Deterministic Broadband Simulations

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    The accuracy of earthquake source descriptions is a major limitation in high-frequency (>1 Hz) deterministic ground motion prediction, which is critical for performance-based design by building engineers. With the recent addition of realistic fault topography in 3D simulations of earthquake source models, ground motion can be deterministically calculated more realistically up to higher frequencies. We first introduce a technique to model frequency-dependent attenuation and compare its impact on strong ground motions recorded for the 2008 Chino Hills earthquake. Then, we model dynamic rupture propagation for both a generic strike-slip event and blind thrust scenario earthquakes matching the fault geometry of the 1994 Mw 6.7 Northridge earthquake along rough faults up to 8 Hz. We incorporate frequency-dependent attenuation via a power law above a reference frequency in the form Q0fnQ_0f^n ,with high accuracy down to Q values of 15, and include nonlinear effects via Drucker-Prager plasticity. We model the region surrounding the fault with and without small-scale medium complexity in both a 1D layered model characteristic of southern California rock and a 3D medium extracted from the SCEC CVMSi.426 including a near-surface geotechnical layer. We find that the spectral acceleration from our models are within 1-2 interevent standard deviations from recent ground motion prediction equations (GMPEs) and compare well with that of recordings from strong ground motion stations at both short and long periods. At periods shorter than 1 second, Q(f) is needed to match the decay of spectral acceleration seen in the GMPEs as a function of distance from the fault. We find that the similarity between the intraevent variability of our simulations and observations increases when small-scale heterogeneity and plasticity are included, extremely important as uncertainty in ground motion estimates dominates the overall uncertainty in seismic risk. In addition to GMPEs, we compare with simple proxy metrics to evaluate the performance of our deterministic models and to determine the importance of different complexities within our model. We find that 3D heterogeneity, at both the long and short scale-lengths, is necessary to agree with data, and should be included in future simulations to best model the ground motion from earthquakes
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