Induction of antibody-mediated neutralization in SIVmac239 by a naturally acquired V3 mutation

AbstractAchieving humoral immunity against human immunodeficiency virus (HIV) is a major obstacle in AIDS vaccine development. Despite eliciting robust humoral responses to HIV, exposed hosts rarely produce broadly neutralizing antibodies. The present study utilizes simian immunodeficiency virus (SIV) to identify viral epitopes that conferred antibody neutralization to clone SIV/17E-CL, an in vivo variant derived from neutralization resistant SIVmac239. Neutralization assays using rhesus macaque monoclonal antibodies were performed on viruses engineered to express single or multiple amino acid mutations. Results identified a single amino acid mutation, P334R, in the carboxy-terminal half of the V3 loop as a critical residue that induced neutralization while retaining normal glycoprotein expression on the surface of the virus. Furthermore, the R334 residue yielded neutralization sensitivity by antibodies recognizing diverse conformational and linear epitopes of gp120, suggesting that neutralization phenotype was a consequence of global structural changes of the envelope protein rather than a specific site epitope

Neurofibromatosis 1 (NF1) mutation results in impaired function of human induced pluripotent stem cell-derived microglia

Neurofibromatosis type 1 (NF1) is an autosomal dominant condition caused by germline mutations in the NF1 gene. Children with NF1 are prone to the development of multiple nervous system abnormalities, including autism and brain tumors, which could reflect the effect of NF1 mutation on microglia function. Using heterozygous Nf1-mutant mice, we previously demonstrated that impaired purinergic signaling underlies deficits in microglia process extension and phagocytosis in situ. To determine whether these abnormalities are also observed in human microglia in the setting of NF1, we leveraged an engineered isogenic series of human induced pluripotent stem cells to generate human microglia-like (hiMGL) cells heterozygous for three different NF1 patient-derived NF1 gene mutations. While all NF1-mutant and isogenic control hiMGL cells expressed classical microglia markers and exhibited similar transcriptomes and cytokine/chemokine release profiles, only NF1-mutant hiMGL cells had defects in P2X receptor activation, phagocytosis and motility. Taken together, heterozygous NF1 mutation impairs a subset of human microglia functional properties, which could contribute to the neurological abnormalities seen in children with NF1

Microglia/macrophage derived human CCL18 promotes glioma progression via CCR8-ACP5 axis analyzed in humanized slice model

Factors released from glioma-associated microglia/macrophages (GAMs) play a crucial role in glioblastoma multiforme (GBM) progression. Here, we study the importance of CCL18, a cytokine expressed in human but not in rodent GAMs, as a modulator of glioma growth. Since CCL18 signaling could not be studied in classical mouse glioma models, we developed an approach by transplanting induced pluripotent stem cell-derived human microglia and human glioma cells into mouse brain slices depleted of their intrinsic microglia. We observe that CCL18 promotes glioma cell growth and invasion. Chemokine (C-C motif) receptor 8 (CCR8) is identified as a functional receptor for CCL18 on glioma cells, and ACP5 (acid phosphatase 5) is revealed as an important part of the downstream signaling cascade for mediating glioma growth. We conclude, based on the results from an in vitro, ex vivo humanized glioma model and an in vivo GBM model that microglia/macrophage-derived CCL18 promotes glioma growth

Post-perihelion photometry of dust grains in the coma of 67P Churyumov-Gerasimenko

We present a photometric analysis of individual dust grains in the coma of comet 67P/Churyumov-Gerasimenko using OSIRIS images taken from 2015 July to 2016 January. We analysed a sample of 555 taken during 18 d at heliocentric distances ranging between 1.25 and 2.04 au and at nucleocentric distances between 80 and 437 km. An automated method to detect the tracks was specifically developed. The images were taken by OSIRIS NAC in four different filters: Near-IR (882 nm), Orange (649 nm), FarOrange (649 nm) and Blue (480 nm). It was not always possible to recognize all the grains in the four filters, hence we measured the spectral slope in two wavelengths ranges: in the interval [480-649] nm, for 1179 grains, and in the interval [649-882] nm, for 746 grains. We studied the evolution of the two populations' average spectral slopes. The data result scattered around the average value in the range [480-649] nm, while in the [649-882] nm we observe a slight decreasing moving away from the Sun as well as a slight increasing with the nucleocentric distance. A spectrophotometric analysis was performed on a subsample of 339 grains. Three major groups were defined, based on the spectral slope between [535-882] nm: (i) the steep spectra that may be related with organic material, (ii) the spectra with an intermediate slope, likely a mixture of silicates and organics and (iii) flat spectra that may be associated with a high abundance of water ice

Regional unit definition for the nucleus of comet 67P/Churyumov-Gerasimenko on the SHAP7 model

The previously defined regions on the nucleus of comet 67P/Churyumov-Gerasimenko have been mapped back onto the 3D SHAP7 model of the nucleus (Preusker et al., 2017). The resulting regional definition is therefore self-consistent with boundaries that are well defined in 3 dimensions. The facets belonging to each region are provided as supplementary material. The shape model has then been used to assess inhomogeneity of nucleus surface morphology within individual regions. Several regions show diverse morphology. We propose sub-division of these regions into clearly identifiable units (sub-regions) and a comprehensive table is provided. The surface areas of each sub-region have been computed and statistics based on grouping of unit types are provided. The roughness of each region is also provided in a quantitative manner using a technique derived from computer graphics applications. The quantitative method supports the sub-region definition by showing that differences between sub-regions can be numerically justified

Distance determination method of dust particles using Rosetta OSIRIS NAC and WAC data

The ESA Rosetta spacecraft has been tracking its target, the Jupiter-family comet 67P/Churyumov-Gerasimenko, in close vicinity for over two years. It hosts the OSIRIS instruments: the Optical, Spectroscopic, and Infrared Remote Imaging System composed of two cameras, see e.g. Keller et al. (2007). In some imaging sequences dedicated to observe dust particles in the comet's coma, the two cameras took images at the same time. The aim of this work is to use these simultaneous double camera observations to calculate the dust particles’ distance to the spacecraft. As the two cameras are mounted on the spacecraft with an offset of 70 cm, the distance of particles observed by both cameras can be determined by a shift of the particles’ apparent trails on the images. This paper presents first results of the ongoing work, introducing the distance determination method for the OSIRIS instrument and the analysis of an example particle. We note that this method works for particles in the range of about 500–6000 m from the spacecraft

The scattering phase function of comet 67P/Churyumov-Gerasimenko coma as seen from the Rosetta/OSIRIS instrument

The study of dust, the most abundant material in cometary nuclei, is pivotal in understanding the original materials forming the Solar system. Measuring the coma phase function provides a tool to investigate the nature of cometary dust. Rosetta/OSIRIS sampled the coma phase function of comet 67P/Churyumov-Gerasimenko, covering a large phase angle range in a small amount of time. Twelve series were acquired in the period from 2015 March to 2016 February for this scientific purpose. These data allowed, after stray light removal, measuring the phase function shape, its reddening, and phase reddening while varying heliocentric and nucleocentric distances. Despite small dissimilarities within different series, we found a constant overall shape. The reflectance has a u-shape with minimum at intermediate phase angles, reaching similar values at the smallest and largest phase angle sampled. The comparison with cometary phase functions in literature indicates OSIRIS curves being consistent with the ones found in many other single comets. The dust has a negligible phase reddening at α < 90°, indicating a coma dominated by single scattering.We measured a reddening of [11-14] %/100 nm between 376 and 744 nm. No trend with heliocentric or nucleocentric distance was found, indicating the coma doesn't change its spectrum with time. These results are consistent with single coma grains and close-nucleus coma photometric results. Comparison with nucleus photometry indicates a different backscattering phase function shape and similar reddening values only at α < 30°. At larger phase angles, the nucleus becomes significantly redder than the coma

Dust mass distribution around comet 67P/Churyumov-Gerasimenko determined via parallax measurements using Rosetta's OSIRIS cameras

The OSIRIS (optical, spectroscopic and infrared remote imaging system) instrument on board the ESA Rosetta spacecraft collected data of 67P/Churyumov-Gerasimenko for over 2 yr. OSIRIS consists of two cameras, a Narrow Angle Camera and a Wide Angle Camera. For specific imaging sequences related to the observation of dust aggregates in 67P's coma, the two cameras were operating simultaneously. The two cameras are mounted 0.7 m apart from each other, as a result this baseline yields a parallax shift of the apparent particle trails on the analysed images directly proportional to their distance. Thanks to such shifts, the distance between observed dust aggregates and the spacecraft was determined. This method works for particles closer than 6000 m to the spacecraft and requires very few assumptions. We found over 250 particles in a suitable distance range with sizes of some centimetres, masses in the range of 10-6-102 kg and a mean velocity of about 2.4 m s-1 relative to the nucleus. Furthermore, the spectral slope was analysed showing a decrease in the median spectral slope of the particles with time. The further a particle is from the spacecraft the fainter is its signal. For this reason, this was counterbalanced by a debiasing. Moreover, the dust mass-loss rate of the nucleus could be computed as well as the Af ρ of the comet around perihelion. The summed-up dust mass-loss rate for the mass bins 10-4-102 kg is almost 8300 kg s-1