LAG-3 Confers a Competitive Disadvantage upon Antiviral CD8 + T Cell Responses

Ongoing clinical trials are evaluating the benefits of systemic blockade of lymphocyte activation gene-3 (LAG-3) signals to improve immunity to tumors. Those studies are founded on the well-established inhibitory role of LAG-3 in regulating CD8+ T cells during chronic virus infection and anti-tumor responses. However, the T cell response in LAG-3 deficient mice is similar in size and function to that in wild type animals, suggesting LAG-3 has nuanced immune-regulatory functions. We performed a series of adoptive transfer experiments in mice to better understand the T cell-intrinsic functions of LAG-3 in the regulation of CD8+ T cell responses. Our results indicate that LAG-3 expression by CD8+ T cells inhibits their competitive fitness and results in a slightly reduced rate of cell division in comparison to LAG-3 deficient cells. This cell-intrinsic effect of LAG-3 was consistent across both acute and chronic virus infections. These data show that LAG-3 directly modulates the size of the T cell response and support the use of LAG-3 blockade regimens to enhance CD8+ T cell responses

The Depletion of NK Cells Prevents T Cell Exhaustion to Efficiently Control Disseminating Virus Infection

NK cells have well-established functions in immune defense against virus infections and cancer through their cytolytic activity and production of cytokines. In this study, we examined the frequency of NK cells and their influence on T cell responses in mice given variants of lymphocytic choriomeningitis virus that cause acute or persisting infection. We found increased frequencies of circulating NK cells during disseminating infection compared with uninfected or acutely infected mice. Consistent with recent reports, we observed that the depletion of NK cells in mice with disseminated infection increased peak numbers of virus-specific cytokine producing CD8(+) T cells and resulted in the rapid resolution of disseminated infection. Additionally, we show that NK cell depletion sustained T cell responses across time and protected against T cell exhaustion. The positive effects of NK cell depletion on T cell responses only occurred when NK cells were depleted within the first 2 d of infection. We find that the improved CD8(+) T cell response correlated with an enhanced ability of APCs from NK cell-depleted mice to stimulate T cell proliferation, independently of the effects of NK cells on CD4(+) T cells. These results indicate that NK cells play an integral role in limiting the CD8 T cell response and contribute to T cell exhaustion by diminishing APC function during persisting virus infection

Diel Variation in the Vertical Distribution of Deep-Water Scattering Layers in the Gulf of Mexico

Sound scattering layers (SSLs) are important components of oceanic ecosystems with ubiquitous distribution throughout the world\u27s oceans. This vertical movement is an important mechanism for exchanging organic matter from the surface to the deep ocean, as many of the organisms comprising SSLs serve as prey resources for linking the lower trophic levels to larger predators. Variations in abundance and taxonomic composition of mesopelagic organisms were quantified using repeated discrete net sampling and acoustics over a 30-h survey, performed during 26–27 June 2011 at single site (27°28’51”N and 88°27’54”W) in the northern Gulf of Mexico. We acoustically classified the mesopelagic SSL into four broad taxonomic categories, crustacean and small non-swimbladdered fish (CSNSBF), large non-swimbladdered fish (LNSBF), swimbladdered fish (SBF) and unclassified and we quantified the abundance of mesopelagic organisms over three discrete depth intervals; epipelagic (0–200 m); upper mesopelagic (200–600 m) and lower mesopelagic (600–1000 m). Irrespective of the acoustic categories at dusk part of the acoustic energy redistributed from the mesopelagic into the upper epipelagic (shallower than 100 m) remaining however below the thermocline depth. At night higher variability in species composition was observed between 100 and 200 m suggested that a redistribution of organisms may also occur within the upper portion of the water column. Along the upper mesopelagic backscatter spectra from CSNSBF migrated between 400 and 460 m while spectra from the other categories moved to shallower depths (300 and 350 m), resulting in habitat separation from CSNSBF. Relatively small vertical changes in both acoustic backscatter and center of mass metrics of the deep mesopelagic were observed for CNSBF and LNSBF suggesting that these animals may be tightly connected to deeper (below 1000 m) mesopelagic habitats, and do not routinely migrate into the epipelagic

An Evaluation of the Susceptibility of Goats to Larkspur Toxicosis

Larkspurs (Delphinium spp.) are a major cause of cattle losses in western North America, whereas sheep have been shown to be resistant to larkspur toxicosis. Goats are often used as a small ruminant model to study poisonous plants, even though they can be more resistant to some poisonous plants. It is not known how susceptible goats are to the adverse effects of larkspurs. In this study, we evaluated the susceptibility of goats to larkspur toxicosis by performing a dose-response study. We dosed goats with D. barbeyi collected near Cedar City, Utah at 3.3, 4.4, 6.6, 8.8 and 10.0 g plant material per kg body weight. None of the goats, at any of the doses, exhibited clinical signs typical of larkspur poisoning, including no observable muscle weakness. We conclude that goats are resistant to larkspur toxicosis, and thus it is very unlikely that goats would be poisoned by larkspur

Comparison of Sheep and Goats to the Acute Toxic Effects of Foothill Death Camas

Death camas (Zigadenus spp) is a perennial forb found throughout the western United States, which is known to kill both sheep and cattle. In a previous study, goats appeared to be somewhat resistant to the adverse effects of death camas. Therefore, the objective of this study was to directly compare the susceptibility of goats and sheep to the acute toxic effects of death camas. Sheep and goats were dosed at 0.5, 1.0, 2.0, 4.0, and 6.0 g death camas per kg BW. The data presented in this manuscript suggest that goats are more susceptible to death camas than sheep. There were no differences in the serum concentrations of zygadenine in sheep versus goats. There was a difference between goats and sheep in the severity of observed clinical signs of poisoning. This is highlighted by the fact that five goats from the two highest doses died, whereas none of the sheep died. Consequently, when grazing goats in death camas infested pastures as much caution, if not more, should be taken than one would with sheep. Additionally, the data presented in the study suggests that goats can be used as a small ruminant model to study the toxic effects of death camas

NK Cells and Their Ability to Modulate T Cells during Virus Infections

Natural killer (NK) cells are important in protection against virus infections, and many viruses have evolved mechanisms to thwart NK cell activity. NK cells respond to inflammatory signals at an early stage of virus infection, resulting in proliferation, cytokine production, and cytolytic activity that can reduce virus loads. Moreover, the rapid kinetics of the NK cell response enables NK cells to influence other populations of innate immune cells, affect the inflammatory milieu, and guide adaptive immune responses to infection. Early NK cell interactions with other leukocytes can have long-lasting effects on the number and quality of memory T cells, as well as impact the exhaustion of T cells during chronic infections. The ability of NK cells to modulate T cell responses can be mediated through direct T-NK interactions, cytokine production, or indirectly through dendritic cells and other cell types. Herein, we summarize our current understanding of how NK cells interact with T cells, dendritic cells, B cells, and other cell types involved in adaptive immune responses to virus infection. We outline several mechanisms by which NK cells enhance or suppress adaptive immune response and long-lived immunological memory

A microRNA cluster in the Fragile-X region expressed during spermatogenesis targets FMR1.

Testis-expressed X-linked genes typically evolve rapidly. Here, we report on a testis-expressed X-linked microRNA (miRNA) cluster that despite rapid alterations in sequence has retained its position in the Fragile-X region of the X chromosome in placental mammals. Surprisingly, the miRNAs encoded by this cluster (Fx-mir) have a predilection for targeting the immediately adjacent gene, Fmr1, an unexpected finding given that miRNAs usually act in trans, not in cis Robust repression of Fmr1 is conferred by combinations of Fx-mir miRNAs induced in Sertoli cells (SCs) during postnatal development when they terminate proliferation. Physiological significance is suggested by the finding that FMRP, the protein product of Fmr1, is downregulated when Fx-mir miRNAs are induced, and that FMRP loss causes SC hyperproliferation and spermatogenic defects. Fx-mir miRNAs not only regulate the expression of FMRP, but also regulate the expression of eIF4E and CYFIP1, which together with FMRP form a translational regulatory complex. Our results support a model in which Fx-mir family members act cooperatively to regulate the translation of batteries of mRNAs in a developmentally regulated manner in SCs

Investigating the physical properties of transiting hot Jupiters with the 1.5-m Kuiper Telescope

We present new photometric data of 11 hot Jupiter transiting exoplanets (CoRoT-12b, HAT-P-5b, HAT-P-12b, HAT-P-33b, HAT-P-37b, WASP-2b, WASP-24b, WASP-60b, WASP-80b, WASP-103b, XO-3b) in order to update their planetary parameters and to constrain information about their atmospheres. These observations of CoRoT-12b, HAT-P-37b and WASP-60b are the first follow-up data since their discovery. Additionally, the first near-UV transits of WASP-80b and WASP-103b are presented. We compare the results of our analysis with previous work to search for transit timing variations (TTVs) and a wavelength dependence in the transit depth. TTVs may be evidence of a third body in the system and variations in planetary radius with wavelength can help constrain the properties of the exoplanet's atmosphere. For WASP-103b and XO-3b, we find a possible variation in the transit depths that may be evidence of scattering in their atmospheres. The B-band transit depth of HAT-P-37b is found to be smaller than its near-IR transit depth and such a variation may indicate TiO/VO absorption. These variations are detected from 2-4.6$\sigma$, so follow-up observations are needed to confirm these results. Additionally, a flat spectrum across optical wavelengths is found for 5 of the planets (HAT-P-5b, HAT-P-12b, WASP-2b, WASP-24b, WASP-80b), suggestive that clouds may be present in their atmospheres. We calculate a refined orbital period and ephemeris for all the targets, which will help with future observations. No TTVs are seen in our analysis with the exception of WASP-80b and follow-up observations are needed to confirm this possible detection.Comment: 18 pages, 7 figures, 9 Tables. Light Curves available online. Accepted to MNRAS (2017 August 25

Three-dimensional adaptive evolution of gravitational waves in numerical relativity

Adaptive techniques are crucial for successful numerical modeling of gravitational waves from astrophysical sources such as coalescing compact binaries, since the radiation typically has wavelengths much larger than the scale of the sources. We have carried out an important step toward this goal, the evolution of weak gravitational waves using adaptive mesh refinement in the Einstein equations. The 2-level adaptive simulation is compared with unigrid runs at coarse and fine resolution, and is shown to track closely the features of the fine grid run.Comment: REVTeX, 7 pages, including three figures; submitted to Physical Review

Glomerulonephritis and autoimmune vasculitis are independent of P2RX7 but may depend on alternative inflammasome pathways

P2RX7, an ionotropic receptor for extracellular ATP, is expressed on immune cells, including macrophages, monocytes and dendritic cells and is up-regulated on non-immune cells following injury. P2RX7 plays a role in many biological processes, including production of pro-inflammatory cytokines such as IL-1β via the canonical inflammasome pathway. P2RX7 has been shown to be important in inflammation and fibrosis and may also play a role in autoimmunity. We have developed and phenotyped a novel P2RX7 knock-out (KO) inbred rat strain and taking advantage of the human-resembling unique histopathological features of rat models of glomerulonephritis, we induced three models of disease: nephrotoxic nephritis, experimental autoimmune glomerulonephritis, and experimental autoimmune vasculitis. We found that deletion of P2RX7 does not protect rats from models of experimental glomerulonephritis or the development of autoimmunity. Notably, treatment with A-438079, a P2RX7 antagonist, was equally protective in WKY WT and P2RX7 KO rats, revealing its 'off-target' properties. We identify a novel ATP/P2RX7/K+ efflux-independent and caspase-1/8-dependent pathway for production of IL-1β in rat dendritic cells, which was absent in macrophages. Taken together, these results comprehensively establish that inflammation and autoimmunity in glomerulonephritis is independent of P2RX7 and reveals the off-target properties of drugs previously known as selective P2RX7 antagonists. Rat mononuclear phagocytes may be able to utilise an 'alternative inflammasome' pathway to produce IL-1β independently of P2RX7, which may account for the susceptibility of P2RX7 KO rats to inflammation and autoimmunity in glomerulonephritis. This article is protected by copyright. All rights reserved