Cell-Mediated Immune Predictors of Vaccine Effect on Viral Load and CD4 Count in a Phase 2 Therapeutic HIV-1 Vaccine Clinical Trial.

In a placebo-controlled trial of the peptide-based therapeutic HIV-1 p24 <sup>Gag</sup> vaccine candidate Vacc-4x, participants on combination antiretroviral therapy (cART) received six immunizations over 18weeks, followed by analytical treatment interruption (ATI) between weeks 28 and 52. Cell-mediated immune responses were investigated as predictors of Vacc-4x effect (VE) on viral load (VL) and CD4 count during ATI. All analyses of week 28 responses and fold-changes relative to baseline considered per-protocol participants (Vacc-4x:placebo=72:32) resuming cART after week 40. Linear regression models with interaction tests were used. VE was estimated as the Vacc-4x-placebo difference in log <sub>10</sub> -transformed VL (VE <sup>VL</sup> ) or CD4 count (VE <sup>CD4</sup> ). A lower fold-change of CD4+ T-cell proliferation was associated with VE <sup>CD4</sup> at week 48 (p=0.036, multiplicity adjusted q=0.036) and week 52 (p=0.040, q=0.080). A higher fold-change of IFN-γ in proliferation supernatants was associated with VE <sup>VL</sup> at week 44 (p=0.047, q=0.07). A higher fold-change of TNF-α was associated with VE <sup>VL</sup> at week 44 (p=0.045, q=0.070), week 48 (p=0.028, q=0.070), and week 52 (p=0.037, q=0.074). A higher fold-change of IL-6 was associated with VE <sup>VL</sup> at week 48 (p=0.017, q=0.036). TNF-α levels (>median) were associated with VE <sup>CD4</sup> at week 48 (p=0.009, q=0.009). These exploratory analyses highlight the potential value of investigating biomarkers in T-cell proliferation supernatants for VE in clinical studies

Evolutionary Scheduler for the Deep Space Network

A computer program assists human schedulers in satisfying, to the maximum extent possible, competing demands from multiple spacecraft missions for utilization of the transmitting/receiving Earth stations of NASA s Deep Space Network. The program embodies a concept of optimal scheduling to attain multiple objectives in the presence of multiple constraints

Treatment-aware Diffusion Probabilistic Model for Longitudinal MRI Generation and Diffuse Glioma Growth Prediction

Diffuse gliomas are malignant brain tumors that grow widespread through the brain. The complex interactions between neoplastic cells and normal tissue, as well as the treatment-induced changes often encountered, make glioma tumor growth modeling challenging. In this paper, we present a novel end-to-end network capable of generating future tumor masks and realistic MRIs of how the tumor will look at any future time points for different treatment plans. Our approach is based on cutting-edge diffusion probabilistic models and deep-segmentation neural networks. We included sequential multi-parametric magnetic resonance images (MRI) and treatment information as conditioning inputs to guide the generative diffusion process. This allows for tumor growth estimates at any given time point. We trained the model using real-world postoperative longitudinal MRI data with glioma tumor growth trajectories represented as tumor segmentation maps over time. The model has demonstrated promising performance across a range of tasks, including the generation of high-quality synthetic MRIs with tumor masks, time-series tumor segmentations, and uncertainty estimates. Combined with the treatment-aware generated MRIs, the tumor growth predictions with uncertainty estimates can provide useful information for clinical decision-making.Comment: 13 pages, 10 figures, 2 tables, 2 agls, preprints in the IEEE trans. format for submission to IEEE-TM

Repeated glacial lake outburst flood threatening the oldest Buddhist monastery in north-western Nepal

Since 2004, Halji village, home of the oldest Buddhist Monastery in north-western Nepal, has suffered from recurrent glacial lake outburst floods (GLOFs). A sudden englacial drainage of a supraglacial lake, located at a distance of 6.5 km from the village, was identified as the source of the flood. The topography of the lake basin was mapped by combining differential Global Positioning System (DGPS) measurements with a structure-from-motion (SFM) approach using terrestrial photographs. From this model the maximum filling capacity of the lake has been estimated as 1.06 ×10^6 m³ with a maximum discharge of 77.8 m³ s⁻¹, calculated using the empiric Clague–Mathews formula. A simulation of the flooded area employing a raster-based hydraulic model considering six scenarios of discharge volume and surface roughness did not result in a flooding of the village. However, both the village and the monastery are threatened by undercutting of the river bank formed by unconsolidated sediments, as it already happened in 2011. Further, the comparison of the GLOF occurrences with temperature and precipitation from the High Asia Reanalysis (HAR) data set for the period 2001–2011 suggests that the GLOF is climate-driven rather than generated by an extreme precipitation event. The calculation of geodetic mass balance and the analysis of satellite images showed a rapid thinning and retreat of Halji Glacier which will eventually lead to a decline of the lake basin. As the basin will persist for at least several years, effective mitigation measures should be considered. A further reinforcement of the gabion walls was suggested as an artificial lake drainage is not feasible given the difficult accessibility of the glacier

The Bacterial Preparation OK432 Induces IL-12p70 Secretion in Human Dendritic Cells in a TLR3 Dependent Manner

Dendritic cells (DC) used in therapeutic cancer immunotherapy have to be able to stimulate T cells resulting in an immune response that can efficiently target the cancer cells. One of the critical hurdles has been the lack of IL-12p70 production when maturating the DC, which is rectified by using the bacterial preparation OK432 (trade name Picibanil) to mature the cells. In order to identify the mechanism behind OK432 stimulation of DC, we investigated the contribution of different TLR to examine their involvement in IL-12p70 production. By combining different inhibitors of TLR signaling, we demonstrate here that TLR3 is responsible for the IL-12p70 production of DC induced by OK432. Moreover, our data suggest that the ligand triggering IL-12p70 secretion upon TLR3 stimulation is sensitive to proteinase and partly also RNAse treatment. The fact that a bacterial compound like OK432 can activate the TLR3 pathway in human DC is a novel finding. OK432 demonstrates a critical ability to induce IL-12p70 production, which is of great relevance in DC based cancer immunotherapy

Enhancing the immunogenicity of tumour lysate-loaded dendritic cell vaccines by conjugation to virus-like particles

BACKGROUND: Tumour cell lysates are an excellent source of many defined and undefined tumour antigens and have been used clinically in immunotherapeutic regimes but with limited success. METHODS: We conjugated Mel888 melanoma lysates to rabbit haemorrhagic disease virus virus-like particles (VLP), which can act as vehicles to deliver multiple tumour epitopes to dendritic cells (DC) to effectively activate antitumour responses. RESULTS: Virus-like particles did not stimulate the phenotypic maturation of DC although, the conjugation of lysates to VLP (VLP-lysate) did overcome lysate-induced suppression of DC activation. Lysate-conjugated VLP enhanced delivery of antigenic proteins to DC, while the co-delivery of VLP-lysates with OK432 resulted in cross-priming of naïve T cells, with expansion of a MART1(+) population of CD8(+) T cells and generation of a specific cytotoxic response against Mel888 tumour cell targets. The responses generated with VLP-lysate and OK432 were superior to those stimulated by unconjugated lysate with OK432. CONCLUSION: Collectively, these results show that the combination of VLP-lysate with OK432 delivered to DC overcomes the suppressive effects of lysates, and enables priming of naïve T cells with superior ability to specifically kill their target tumour cells

Gender Diversity in Sport Leadership: A Review of United States of America National Governing Bodies of Sport

This article examines the gender diversity within the governance structures of the National Governing Bodies of Sport (NGBs) that fall under the remit of the United States Olympic Committee. This article employs Kanter’s (1977) theory of Critical Mass to examine female representation within leadership positions held in NGBs. By categorising female representation into one of Kanter’s four groups; Uniformed, Skewed, Tilted and Balanced, the article examines whether female inclusion in leadership has any impact on the NGB achieving gender membership benchmarks. Data were obtained from the USOC’s Diversity and Inclusion Scorecard. The results indicate that females are largely under-represented in leadership roles within NGBs. However, the data indicates a positive correlation between female representation in the leadership structure of NGBs, and the ability of the NGB to achieve female membership benchmarks. The study concludes that as well as supporting the ethical case for female representation, the findings highlight a clear business performance case for greater gender diversity

Atomic-resolution spectroscopic imaging of ensembles of nanocatalyst particles across the life of a fuel cell

The thousandfold increase in data-collection speed enabled by aberration-corrected optics allows us to overcome an electron microscopy paradox - how to obtain atomic-resolution chemical structure in individual nanoparticles, yet record a statistically significant sample from an inhomogeneous population. This allowed us to map hundreds of Pt-Co nanoparticles to show atomic-scale elemental distributions across different stages of the catalyst aging in a proton-exchange-membrane fuel cell, and relate Pt-shell thickness to treatment, particle size, surface orientation, and ordering.Comment: 28 pages, 5 figures, accepted, nano letter