Long-term human hematopoiesis in the SCID-hu mouse.

Coimplantation of small fragments of human fetal thymus and fetal liver into immunodeficient SCID mice resulted in the formation of a unique structure (Thy/Liv). Thereafter, the SCID-hu mice showed reproducible and long-term reconstitution of human hematopoietic activity. For periods lasting 5-11 mo after transplantation, active T lymphopoiesis was observed inside the grafts and cells that were negative for T cell markers were found to have colony-forming units for granulocyte/macrophage (CFU-GM) and erythroid burst-forming unit (BFU-E) activity in the methylcellulose colony assay. In addition, structures similar to normal human bone marrow were observed inside the Thy/Liv grafts, consisting of blast cells, mature and immature forms of myelomonocytic cells, and megakaryocytes. These data indicate long-term maintenance, in vivo, of human progenitor cells for the T lymphoid, myelomonocytic, erythroid, and megakaryocytic lineages. The role of the implanted fetal liver fragments was analyzed using HLA-mismatched Thy/Liv implants. The HLA type of the liver donor was found on T cells and macrophages in the graft. In addition, cells grown in the methylcellulose colony assay and cells in a bone marrow-like structure, the thymic isle, expressed the HLA type of the liver donor. Thus, the Thy/Liv implants provided a microenvironment in which to follow human hematopoietic progenitor cells for multiple lineages. The formation of the Thy/Liv structures also results in a continuous source of human T cells in the peripheral circulation of the SCID-hu mouse. Though present for 5-11 mo, these cells did not engage in a xenograft (graft-versus-host) reaction. This animal model, the first in which multilineage human hematopoietic activity is maintained for long periods of time, should be useful for the analysis of human hematopoiesis in vivo

Human immunodeficiency virus infection of the human thymus and disruption of the thymic microenvironment in the SCID-hu mouse.

Infection with the human immunodeficiency virus (HIV) results in immunosuppression and depletion of circulating CD4+ T cells. Since the thymus is the primary organ in which T cells mature it is of interest to examine the effects of HIV infection in this tissue. HIV infection has been demonstrated in the thymuses of infected individuals and thymocytes have been previously demonstrated to be susceptible to HIV infection both in vivo, using the SCID-hu mouse, and in vitro. The present study sought to determine which subsets of thymocytes were infected in the SCID-hu mouse model and to evaluate HIV-related alterations in the thymic microenvironment. Using two different primary HIV isolates, infection was found in CD4+/CD8+ double positive thymocytes as well as in both the CD4+ and CD8+ single positive subsets of thymocytes. The kinetics of infection and resulting viral burden differed among the three thymocyte subsets and depended on which HIV isolate was used for infection. Thymic epithelial (TE) cells were also shown to endocytose virus and to often contain copious amounts of viral RNA in the cytoplasm by in situ hybridization, although productive infection of these cells could not be definitively shown. Furthermore, degenerating TE cells were observed even without detection of HIV in the degenerating cells. Two striking morphologic patterns of infection were seen, involving either predominantly thymocyte infection and depletion, or TE cell involvement with detectable cytoplasmic viral RNA and/or TE cell toxicity. Thus, a variety of cells in the human thymus is susceptible to HIV infection, and infection with HIV results in a marked disruption of the thymic microenvironment leading to depletion of thymocytes and degeneration of TE cells

Validation of the SCID-hu Thy/Liv mouse model with four classes of licensed antiretrovirals.

BackgroundThe SCID-hu Thy/Liv mouse model of HIV-1 infection is a useful platform for the preclinical evaluation of antiviral efficacy in vivo. We performed this study to validate the model with representatives of all four classes of licensed antiretrovirals.Methodology/principal findingsEndpoint analyses for quantification of Thy/Liv implant viral load included ELISA for cell-associated p24, branched DNA assay for HIV-1 RNA, and detection of infected thymocytes by intracellular staining for Gag-p24. Antiviral protection from HIV-1-mediated thymocyte depletion was assessed by multicolor flow cytometric analysis of thymocyte subpopulations based on surface expression of CD3, CD4, and CD8. These mice can be productively infected with molecular clones of HIV-1 (e.g., the X4 clone NL4-3) as well as with primary R5 and R5X4 isolates. To determine whether results in this model are concordant with those found in humans, we performed direct comparisons of two drugs in the same class, each of which has known potency and dosing levels in humans. Here we show that second-generation antiretrovirals were, as expected, more potent than their first-generation predecessors: emtricitabine was more potent than lamivudine, efavirenz was more potent than nevirapine, and atazanavir was more potent than indinavir. After interspecies pharmacodynamic scaling, the dose ranges found to inhibit viral replication in the SCID-hu Thy/Liv mouse were similar to those used in humans. Moreover, HIV-1 replication in these mice was genetically stable; treatment of the mice with lamivudine did not result in the M184V substitution in reverse transcriptase, and the multidrug-resistant NY index case HIV-1 retained its drug-resistance substitutions.ConclusionGiven the fidelity of such comparisons, we conclude that this highly reproducible mouse model is likely to predict clinical antiviral efficacy in humans

Analysis of molecular changes induced by mineral trioxide aggregate on sPLA2

The aim of this study was to analyze the effects of MTA on the structure and enzymatic activity of sPLA2 in order to provide subsidies for improvement in the formulation of the product. MTA powder was incubated for 60 min in the presence of sPLA2 and was analyzed by chromatography, electrospray mass (ESI-MS) and small-angle X-ray scattering (SAXS). It was find that the elution profile, retention time, and fragmentation of sPLA2 were altered after treatment with MTA. Calcium was the MTA component that most amplified the inflammatory signal. Significant interactions were found between MTA and sPLA2, which could aid in our understanding of the mechanisms of action of MTA during the inflammatory process and it may facilitate the structural modification of MTA, thereby improving its biological safety and consequently the rate of the treatment success305453458The authors wish to thank the National Laboratory of Synchrotron Light (LNLS - Brazil) for the use of their facility and equipment and to Brazilian division of the IADR (SBPqO), which partially supported this study through PRONAC award. The authors also thanks to Prof. Marcos Toyama for its support on the chromatography graph

Mantle flow in regions of complex tectonics: insights from Indonesia

Indonesia is arguably one of the tectonically most complex regions on Earth today due to its location at the junction of several major tectonic plates and its long history of collision and accretion. It is thus an ideal location to study the interaction between subducting plates and mantle convection. Seismic anisotropy can serve as a diagnostic tool for identifying various subsurface deformational processes, such as mantle flow, for example. Here, we present novel shear wave splitting results across the Indonesian region. Using three different shear phases (local S, SKS, and downgoing S) to improve spatial resolution of anisotropic fabrics allows us to distinguish several deformational features. For example, the block rotation history of Borneo is reflected in coast-parallel fast directions, which we attribute to fossil anisotropy. Furthermore, we are able to unravel the mantle flow pattern in the Sulawesi and Banda region: We detect toroidal flow around the Celebes Sea slab, oblique corner flow in the Banda wedge, and sub-slab mantle flow around the arcuate Banda slab. We present evidence for deep, sub-520 km anisotropy at the Java subduction zone. In the Sumatran backarc, we measure trench-perpendicular fast orientations, which we assume to be due to mantle flow beneath the overriding Eurasian plate. These observations will allow to test ideas of, for example, slab–mantle coupling in subduction regions

Сучасний стан і проблеми управління залізничним транспортом України

Проаналізовано стан і тенденції розвитку залізничного транспорту. Розглянуті основні завдання державного регулювання галузі.Проанализировано состояние и тенденции развития железнодорожного транспорта. Рассмотренны основные задания государственного регулирования отрасли.The condition and trends of railway transport has been anilized. The main tasks of state regulation of railway transport has been considereted

Search for Cosmic-ray Boosted Sub-GeV Dark Matter using Recoil Protons at Super-Kamiokande

We report a search for cosmic-ray boosted dark matter with protons using the 0.37 megaton$\times$years data collected at Super-Kamiokande experiment during the 1996-2018 period (SKI-IV phase). We searched for an excess of proton recoils above the atmospheric neutrino background from the vicinity of the Galactic Center. No such excess is observed, and limits are calculated for two reference models of dark matter with either a constant interaction cross-section or through a scalar mediator. This is the first experimental search for boosted dark matter with hadrons using directional information. The results present the most stringent limits on cosmic-ray boosted dark matter and exclude the dark matter-nucleon elastic scattering cross-section between $10^{-33}\text{ cm}^{-2}$ and $10^{-27}\text{ cm}^{-2}$ for dark matter mass from 10 MeV/$c^2$ to 1 GeV/$c^2$.Comment: With 1-page appendi

Measurement of the cosmogenic neutron yield in Super-Kamiokande with gadolinium loaded water

Cosmic-ray muons that enter the Super-Kamiokande detector cause hadronic showers due to spallation in water, producing neutrons and radioactive isotopes. Those are a major background source for studies of MeV-scale neutrinos and searches for rare events. Since 2020, gadolinium was introduced in the ultra-pure water in the Super-Kamiokande detector to improve the detection efficiency of neutrons. In this study, the cosmogenic neutron yield was measured using data acquired during the period after the gadolinium loading. The yield was found to be $(2.76 \pm 0.02\,\mathrm{(stat.) \pm 0.19\,\mathrm{(syst.)}}) \times 10^{-4}\,\mu^{-1} \mathrm{g^{-1} cm^{2}}$ at 259 GeV of average muon energy at the Super-Kamiokande detector.Comment: 10 pages, 10 figures, 3 table