Performance optimization and load-balancing modeling for superparametrization by 3D LES

In order to eliminate climate uncertainty w.r.t. cloud and convection parametrizations, superpramaterization (SP) [1] has emerged as one of the possible ways forward. We have implemented (regional) superparametrization of the ECMWF weather model OpenIFS [2] by cloud-resolving, three-dimensional large-eddy simulations. This setup, described in [3], contains a two-way coupling between a global meteorological model that resolves large-scale dynamics, with many local instances of the Dutch Atmospheric Large Eddy Simulation (DALES) [4], resolving cloud and boundary layer physics. The model is currently prohibitively expensive to run over climate or even seasonal time scales, and a global SP requires the allocation of millions of cores. In this paper, we study the performance and scaling behavior of the LES models and the coupling code and present our implemented optimizations. We mimic the observed load imbalance with a simple performance model and present strategies to improve hardware utilization in order to assess the feasibility of a world-covering superparametrization. We conclude that (quasi-)dynamical load-balancing can significantly reduce the runtime for such large-scale systems with wide variability in LES time-stepping speeds

Immunoliposome-mediated targeting of doxorubicin to human ovarian carcinoma in vitro and in vivo.

This paper deals with the utility of immunoliposomes for the delivery of doxorubicin (DXR) to human ovarian carcinoma cells in vitro and in vivo. We aimed to investigate whether immunoliposome-mediated targeting of DXR to ovarian cancer cells translates in an enhanced anti-tumour effect compared with that of non-targeted DXR liposomes (lacking the specific antibody). Target cell binding and anti-tumour activity of DXR immunoliposomes were studied in vitro and in vivo (xenograft model of ovarian carcinoma). In vitro we observed that target cell binding and cell growth inhibition of DXR immunoliposomes is superior to that of non-targeted DXR-liposomes. However, in vivo, despite the efficient target cell binding and good anti-tumour response of DXR-immunoliposomes, no difference in anti-tumour effect, compared with non-targeted DXR-liposomes, could be determined. The results indicate that premature DXR leakage from immunoliposomes occurring before the actual target cell binding and subsequent DXR association with the tumour cells, explains why no significant differences in anti-tumour activity between DXR-immunoliposomes and non-targeted DXR-liposomes were observed in vivo

Supported discharge service versus Inpatient care Evaluation (SITE): a randomised controlled trial comparing effectiveness of an intensive community care service versus inpatient treatment as usual for adolescents with severe psychiatric disorders: self-harm, functional impairment, and educational and clinical outcomes.

Background: Clinical guidelines recommend intensive community care service treatment (ICCS) to reduce adolescent psychiatric inpatient care. We have previously reported that the addition of ICCS led to a substantial decrease in hospital use and improved school re-integration. Aim: To undertake a randomised controlled trial (RCT) comparing an inpatient admission followed by an early discharge supported by ICCS with usual inpatient admission (treatment as usual; TAU). In this paper, we report the impact of ICCS on self-harm and other clinical and educational outcomes. Method: 106 patients aged 12-18 admitted for psychiatric inpatient care were randomised (1:1) to either ICCS or TAU. Six months after randomization, we compared the two treatment arms on the number and severity of self-harm episodes, the functional impairment, severity of psychiatric symptoms, clinical improvement, reading and mathematical ability, weight, height and the use of psychological therapy and medication. Results: At six-month follow-up, there were no differences between the two groups on most measures. Patients receiving ICCS were significantly less likely to report multiple episodes (5 or more) of self-harm (OR=0·18, 95% CI: 0·05 to 0·64). Patients admitted to private inpatient units spent on average 118.4 (95% CI: 28·2 to 208.6) fewer days in hospitals if they were in the ICCS group compared to TAU. Conclusion: The addition of ICCS to TAU may lower the risk of multiple self-harm and may reduce the duration of inpatient stay, especially in those patients admitted for private care. Early discharge with ICCS appears to be a viable alternative to standard inpatient treatment

Critical factors for liposome-incorporated tumour-associated antigens to induce protective tumour immunity to SL2 lymphoma cells in mice

Physical and immunogenic properties of re- constituted membranes designed for the presentation of tumour-associated antigens (TAA) to the immune system are described. Proteins and lipids of crude membranes of SL2 routine lymphosarcoma cells were partially solubi- lized with octylglucoside. Reconstituted membranes, con- sisting mainly of unilamellar vesicles with a diameter of 0.03-0.15 gm, were formed by detergent removal and were purified by floatation in a discontinuous sucrose gra- dient to remove non-lipid-bound protein. Subcutaneous immunization of syngeneic mice with reconstituted mem- branes or with purified reconstituted membranes induced protection against an intraperitoneal challenge with 103 viable SL2 cells. Reconstituted membranes were more im- munogenic than crude membranes in immunoprotection experiments when compared on the basis of protein dose. Detergent removal was required to obtain an immunogenic presentation form of SL2 membrane antigens and to avoid toxicity associated with the detergent. Reconstitution of SL2 membranes in the presence of exogenous phos- pholipid slightly increased the fraction of protein that as- sociated with the reconstituted membranes. However, the immunogenicity of the solubilized membrane TAA was not significantly affected by the presence of exogenous phospholipid. The reconstitution procedure described may be useful in identifying membrane factors required for the induction of immune responses against TAA. The versatil- ity of the system may be employed to develop safe alterna- tives for whole-cell vaccines

Structural characterization and immunogenicity in wild-type and immune tolerant mice of degraded recombinant human interferon Alpha2b

Purpose: This study was conducted to study the influence of protein structure on the immunogenicity in wild-type and immune tolerant mice of well-characterized degradation products of recombinant human interferon alpha2b (rhIFNα2b). Methods: RhIFNα2b was degraded by metal-catalyzed oxidation (M), cross-linking with glutaraldehyde (G), oxidation with hydrogen peroxide (H), and incubation in a boiling water bath (B). The products were characterized with UV absorption, circular dichroism and fluorescence spectroscopy, gel permeation chromatography, reverse-phase high-pressure liquid chromatography, sodium dodecyl sulfate polyacrylamide gel electrophoresis, Western blotting, and mass spectrometry. The immunogenicity of the products was evaluated in wild-type mice and in transgenic mice immune tolerant for hIFNα2. Serum antibodies were detected by enzyme-linked immunosorbent assay or surface plasmon resonance. Results: M-rhIFNα2b contained covalently aggregated rhIFNα2b with three methionines partly oxidized to methionine sulfoxides. G-rhIFNα2b contained covalent aggregates and did not show changes in secondary structure. H-rhIFNα2b was only chemically changed with four partly oxidized methionines. B-rhIFNα2b was largely unfolded and heavily aggregated. Nontreated (N) rhIFNα2b was immunogenic in the wild-type mice but not in the transgenic mice, showing that the latter were immune tolerant for rhIFNα2b. The anti-rhIFNα2b antibody levels in the wild-type mice depended on the degradation product: M-rhIFNα2b > H-rhIFNα2b ∼ N-rhIFNα2b ≫ B-rhIFNα2b; G-rhIFNα2b did not induce anti-rhIFNα2b antibodies. In the transgenic mice, only M-rhIFNα2b could break the immune tolerance. Conclusions: RhIFNα2b immunogenicity is related to its structural integrity. Moreover, the immunogenicity of aggregated rhIFNα2b depends on the structure and orientation of the constituent protein molecules and/or on the aggregate size

Tutorial applications for Verification, Validation and Uncertainty Quantification using VECMA toolkit

The VECMA toolkit enables automated Verification, Validation and Uncertainty Quantification (VVUQ) for complex applications that can be deployed on emerging exascale platforms and provides support for software applications for any domain of interest. The toolkit has four main components including EasyVVUQ for VVUQ workflows, FabSim3 for automation and tool integration, MUSCLE3 for coupling multiscale models and QCG tools to execute application workflows on high performance computing (HPC). A more recent addition to the VECMAtk is EasySurrogate for various types of surrogate methods. In this paper, we present five tutorials from different application domains that apply these VECMAtk components to perform uncertainty quantification analysis, use surrogate models, couple multiscale models and execute sensitivity analysis on HPC. This paper aims to provide hands-on experience for practitioners aiming to test and contrast with their own applications