Distinct CD4:CD8 T cell ratio in adult and neonatal mice correlates with either Th1 or Th2 CD4 immunity, respectively, specific for transplantation antigens

Previous studies employing the generation of MHC-incompatible embryonic chicken chimaeras by injecting MHC-incompatible stem cells resulted in an unexpected finding. Chimaeras made late in gestation developed as adults a severe autoimmune syndrome resembling the human syndrome of Systemic Lupus Erythematosus. Work in our laboratory aims to understand the role of CD8 T cells in immunity and/or autoimmunity. We have tested a three-cell model of CD4 T cell activation and differentiation during the development of the immune response specific for MHC transplantation antigens in one way mixed lymphocyte reactions. Our model proposes that whether Th1 or Th2 immunity is generated depends on both the ratio of CD4:CD8 T cells specific for antigen at the initiation of the immune response and on the ability of antigens to coordinately induce both CD4 and CD8 T cells. Previous studies employing parent into F1 models of graft-versus-host disease in mice have shown that the injection of parental cells results in two distinct outcomes. Parental cells which do not have a sufficient number of CD8 T cells present produce an autoimmune syndrome characteristic of systemic lupus erythematosus and a chronic graft-versus-host disease mediated by a Th2 response. Conversely, the presence of an adequate number of CD8 T cells results in a Th1 immune response and acute graft-versus-host disease resulting in the death of the F1 host. Our findings indicate that the ratio of the number of CD4 T cells to the number of CD8 T cells present in the spleen is crucial in whether naive CD4 T cells differentiate into Th1 or Th2 cells. We refer to this ratio as the CD4:CD8 T cell ratio or CD4:CD8 ratio. Thus, the differentiation of naive CD4+ T cells towards a differentiated Th1 phenotype is critically dependent on the concomitant induction of CD8 T cells by the same antigen, driven by a low CD4:CD8 ratio. In contrast, inefficient induction of CD8 T cells during the initial priming of lymphocytes greatly facilitates the differentiation of CD4 T cells towards the Th2-type lineage, and occurs when the CD4:CD8 ratio is high. Given our findings on the significance of the ratio of CD4:CD8 T cells in the decision making process of CD4 differentiation stimulated by antigen, we hypothesized that different CD4: CD8 ratios at different stages of development might contribute to the immune response generated at these stages. We tested this hypothesis in mice by comparing the CD4:CD8 ratio in adults and neonates and the Th1/Th2 responses generated in vitro. This CD4:CD8 T cell ratio is significantly higher in neonates than adults resulting in predominant Th1 responses by adult spleen cells and Th1/Th2 responses by neonatal spleen cells as demonstrated by the ELISPOT assay. We have compared the CD4:CD8 T cell ratio of a large number of adult and neonatal spleens in several mouse strains and have studied it systematically in BALB/c and C57BL/6 mice by flow-cytometry. We have consistently found a 3-5 fold higher CD4:CD8 T cell ratio in neonates as compared to adults in the strains tested. Furthermore, we found that neonatal spleen cells generate a predominant Th2 response whereas adult spleen cells generate CD4 and CD8 Th1 immunity when activated under the same conditions. We have further studied the role of CD8 T cells in CD4 T cell differentiation by reconstructing the adult CD4:CD8 T cell ratio in neonatal spleen cells with age-matched, isolated CD8 T cells. We found that in these “CD4:CD8 ratio-reconstructed cultures”, the Th2/IL-4 immunity is suppressed with concomitant generation of Th1/IFN-γ immunity upon activation by allo-antigen. Additionally, we have characterized the phenotype of the T cell mediating Th1/IFNγ immunity in the “CD4:CD8 ratio reconstructed cultures” and we found that while CD8 T cells produce exclusively IFN-γ, CD4 T cells now produce IFN-γ rather than IL-4. We suggest that physiologically distinct CD4:CD8 ratios at different stages of life should be considered in designing protocols of neonatal vaccination against pathogens that are contained by Th1-type immunity upon infection as adults. Moreover, as elaborated in the discussion, our studies might be pertinent in understanding by which mechanism autoimmunity arises in some cases

Characterization of a Novel STAT 2 Knock Out Hamster Model of Crimean Congo Hemorrhagic Fever Virus Pathogenesis

Crimean-Congo hemorrhagic fever virus (CCHFV) is a tick-borne pathogen causing a febrile illness in humans, which can progress to hemorrhagic manifestations, multi-organ failure, and death. Current mouse models of CCHFV infection reliably succumb to virus challenge but vary in their ability to reflect signs of disease similar to humans. In this study, we established a signal transducer and activator of transcription 2 (STAT2) knockout hamster model to expand the repertoire of animal models of CCHFV pathogenesis that can be used for therapeutic development. These hamsters demonstrated a systemic and lethal disease in response to infection. Hallmarks of human disease were observed including petechial rash, blood coagulation dysfunction, and various biochemistry and blood cell count abnormalities. Furthermore, we also demonstrated the utility of this model for anti-CCHFV therapeutic evaluation. The STAT2 knock-out hamster model of CCHFV infection may provide some further insights into clinical disease, viral pathogenesis, and pave the way for testing of potential drug and vaccine candidates

LSST: from Science Drivers to Reference Design and Anticipated Data Products

(Abridged) We describe here the most ambitious survey currently planned in the optical, the Large Synoptic Survey Telescope (LSST). A vast array of science will be enabled by a single wide-deep-fast sky survey, and LSST will have unique survey capability in the faint time domain. The LSST design is driven by four main science themes: probing dark energy and dark matter, taking an inventory of the Solar System, exploring the transient optical sky, and mapping the Milky Way. LSST will be a wide-field ground-based system sited at Cerro Pach\'{o}n in northern Chile. The telescope will have an 8.4 m (6.5 m effective) primary mirror, a 9.6 deg$^2$ field of view, and a 3.2 Gigapixel camera. The standard observing sequence will consist of pairs of 15-second exposures in a given field, with two such visits in each pointing in a given night. With these repeats, the LSST system is capable of imaging about 10,000 square degrees of sky in a single filter in three nights. The typical 5$\sigma$ point-source depth in a single visit in $r$ will be $\sim 24.5$ (AB). The project is in the construction phase and will begin regular survey operations by 2022. The survey area will be contained within 30,000 deg$^2$ with $\delta<+34.5^\circ$, and will be imaged multiple times in six bands, $ugrizy$, covering the wavelength range 320--1050 nm. About 90\% of the observing time will be devoted to a deep-wide-fast survey mode which will uniformly observe a 18,000 deg$^2$ region about 800 times (summed over all six bands) during the anticipated 10 years of operations, and yield a coadded map to $r\sim27.5$. The remaining 10\% of the observing time will be allocated to projects such as a Very Deep and Fast time domain survey. The goal is to make LSST data products, including a relational database of about 32 trillion observations of 40 billion objects, available to the public and scientists around the world.Comment: 57 pages, 32 color figures, version with high-resolution figures available from https://www.lsst.org/overvie

Search for gravitational-lensing signatures in the full third observing run of the LIGO-Virgo network

Gravitational lensing by massive objects along the line of sight to the source causes distortions of gravitational wave-signals; such distortions may reveal information about fundamental physics, cosmology and astrophysics. In this work, we have extended the search for lensing signatures to all binary black hole events from the third observing run of the LIGO--Virgo network. We search for repeated signals from strong lensing by 1) performing targeted searches for subthreshold signals, 2) calculating the degree of overlap amongst the intrinsic parameters and sky location of pairs of signals, 3) comparing the similarities of the spectrograms amongst pairs of signals, and 4) performing dual-signal Bayesian analysis that takes into account selection effects and astrophysical knowledge. We also search for distortions to the gravitational waveform caused by 1) frequency-independent phase shifts in strongly lensed images, and 2) frequency-dependent modulation of the amplitude and phase due to point masses. None of these searches yields significant evidence for lensing. Finally, we use the non-detection of gravitational-wave lensing to constrain the lensing rate based on the latest merger-rate estimates and the fraction of dark matter composed of compact objects

Search for eccentric black hole coalescences during the third observing run of LIGO and Virgo

Despite the growing number of confident binary black hole coalescences observed through gravitational waves so far, the astrophysical origin of these binaries remains uncertain. Orbital eccentricity is one of the clearest tracers of binary formation channels. Identifying binary eccentricity, however, remains challenging due to the limited availability of gravitational waveforms that include effects of eccentricity. Here, we present observational results for a waveform-independent search sensitive to eccentric black hole coalescences, covering the third observing run (O3) of the LIGO and Virgo detectors. We identified no new high-significance candidates beyond those that were already identified with searches focusing on quasi-circular binaries. We determine the sensitivity of our search to high-mass (total mass M&gt;70 M⊙) binaries covering eccentricities up to 0.3 at 15 Hz orbital frequency, and use this to compare model predictions to search results. Assuming all detections are indeed quasi-circular, for our fiducial population model, we place an upper limit for the merger rate density of high-mass binaries with eccentricities 0&lt;e≤0.3 at 0.33 Gpc−3 yr−1 at 90\% confidence level

Ultralight vector dark matter search using data from the KAGRA O3GK run

Among the various candidates for dark matter (DM), ultralight vector DM can be probed by laser interferometric gravitational wave detectors through the measurement of oscillating length changes in the arm cavities. In this context, KAGRA has a unique feature due to differing compositions of its mirrors, enhancing the signal of vector DM in the length change in the auxiliary channels. Here we present the result of a search for U(1)B−L gauge boson DM using the KAGRA data from auxiliary length channels during the first joint observation run together with GEO600. By applying our search pipeline, which takes into account the stochastic nature of ultralight DM, upper bounds on the coupling strength between the U(1)B−L gauge boson and ordinary matter are obtained for a range of DM masses. While our constraints are less stringent than those derived from previous experiments, this study demonstrates the applicability of our method to the lower-mass vector DM search, which is made difficult in this measurement by the short observation time compared to the auto-correlation time scale of DM

Advanced Design of a Binding Plate to Reduce Anterior Cruciate Ligament Injury during Alpine Skiing

The objective of this project is to reduce the incidence of Anterior Crucial Ligament (ACL) injury in skiing by designing, prototyping, and testing a plate between the ski and binding to filter out injurious loads that would otherwise be transmitted to the skier. Ski technology in the past 5 decades has adapted to protect the skier’s foot, ankle, and tibia, the knee and ACL are still susceptible to injury. There are two types of ACL injuries; Boot-Induced Anterior Drawer (BIAD) and phantom foot. Axiomatic Design was used to design a ski binding plate to minimize BIAD ACL injuries. After the design was chosen, calculations, material selection, computer aided design drawings, and finite element analysis were conducted. This project holds importance in both a societal and economic context