Attenuating Mutations in nsP1 Reveal Tissue-Specific Mechanisms for Control of Ross River Virus Infection

Ross River virus (RRV) is one of a group of mosquito-transmitted alphaviruses that cause debilitating, and often chronic, musculoskeletal disease in humans. Previously, we reported that replacement of the nonstructural protein 1 (nsP1) gene of the mouse-virulent RRV strain T48 with that from the mouse-avirulent strain DC5692 generated a virus that was attenuated in a mouse model of disease. Here we find that the six nsP1 nonsynonymous nucleotide differences between strains T48 and DC5692 are determinants of RRV virulence, and we identify two nonsynonymous nucleotide changes as sufficient for the attenuated phenotype. RRV T48 carrying the six nonsynonymous DC5692 nucleotide differences (RRV-T48-nsP16M) was attenuated in both wild-type and Rag1−/− mice. Despite the attenuated phenotype, RRV T48 and RRV-T48-nsP16M loads in tissues of wild-type and Rag1−/− mice were indistinguishable from 1 to 3 days postinoculation. RRV-T48-nsP16M loads in skeletal muscle tissue, but not in other tissues, decreased dramatically by 5 days postinoculation in both wild-type and Rag1−/− mice, suggesting that the RRV-T48-nsP16M mutant is more sensitive to innate antiviral effectors than RRV T48 in a tissue-specific manner. In vitro, we found that the attenuating mutations in nsP1 conferred enhanced sensitivity to type I interferon. In agreement with these findings, RRV T48 and RRV-T48-nsP16M loads were similar in mice deficient in the type I interferon receptor. Our findings suggest that the type I IFN response controls RRV infection in a tissue-specific manner and that specific amino acid changes in nsP1 are determinants of RRV virulence by regulating the sensitivity of RRV to interferon

Clinical effectiveness of Enneking appropriate versus Enneking inappropriate procedure in patients with primary osteosarcoma of the spine: a systematic review with meta-analysis

Purpose Primary osteosarcoma of the spine is a rare osseous tumour. En bloc resection, in contrast to intralesional resection, is the only procedure able to provide Enneking appropriate (EA) margins, which has improved local control and survival of patients with primary osteosarcoma of the spine. The objective of this study is to compare the risk of local recurrence, metastases development and survival in patients with primary osteosarcoma of the spine submitted to Enneking appropriate (EA) and Enneking inappropriate (EI) procedures. Methods A systematic search was performed on EBSCO, PubMed and Web of Science, between 1966 and 2018, to identify studies evaluating patients submitted to resection of primary osteosarcoma of the spine. Two reviewers independently assessed all reports. The outcomes were local recurrence, metastases development and survival at 12, 24 and 60 months. Results Five studies (108 patients) were included for systematic review. These studies support the conclusion that EA procedure has a lower local recurrence rate (RR 0.33, 95% CI 0.17-0.66), a lower metastases development rate (RR 0.39, 95% CI 0.17-0.89) and a higher survival rate at 24 months (RR 1.78, 95% CI 1.24-2.55) and 60 months (RR 1.97, 95% CI 1.14-3.42) of follow-up; however, at 12 months, there is a non-significant difference. Conclusions EA procedure increases the ratio of remission and survival after 24 months of follow-up. Multidisciplinary oncologic groups should weigh the morbidity of an en bloc resection, knowing that in the first year the probability of survival is the same for EA and EI procedures. Graphic abstract These slides can be retrieved under Electronic Supplementary Material

NBS Building Science Series, Bulletin 143

Report issued by the National Bureau of Standards documenting investigations conducted on construction failures of two suspended walkways in a Kansas City hotel. It includes tables, illustrations, photographs, and other details of the investigation

Assessment of the Vortex Particle-Mesh Method for Efficient LES of Hovering Rotors and their Wakes

Midway between a vortex method and a grid-based CFD, the Vortex Particle-Mesh method with Immersed Lifting Lines is intended to provide medium-fidelity results on rotor loadings, together with a realistic representation of the 3-D vortical wakes and their dynamics over long distances. We assess the potential of this hybrid approach for the Large-Eddy Simulation of helicopter rotors in hover. A novel Poisson solver with mixed unbounded-outflow boundary conditions here further enables the computation of turbulent hovering scenarios in tight domains. Considering the Knight and Hefner experiment and the S-76 test case as references, we present and compare blade integrated and distributed loads, induction velocities, and wake characteristics. While the quality of the performance predictions highly depends on external polar data, the obtained wakes exhibit similar characteristics to those recently identified in other CFD analyses, here at a moderate computational cost. Based on these results, we further investigate the secondary vortex structures forming between the main tip vortices, and we bring additional clues on their relation to the phenomenon of wake breakdown. We finally discuss the strengths and difficulties of hybrid vortex methods for the challenging analysis of hovering rotors