Exhausted T cells express multiple co-inhibitory molecules that impair their function and limit immunity to chronic viral infection. Defining novel markers of exhaustion is important both for ...identifying and potentially reversing T cell exhaustion. Herein, we show that the ectonucleotidse CD39 is a marker of exhausted CD8+ T cells. CD8+ T cells specific for HCV or HIV express high levels of CD39, but those specific for EBV and CMV do not. CD39 expressed by CD8+ T cells in chronic infection is enzymatically active, co-expressed with PD-1, marks cells with a transcriptional signature of T cell exhaustion and correlates with viral load in HIV and HCV. In the mouse model of chronic Lymphocytic Choriomeningitis Virus infection, virus-specific CD8+ T cells contain a population of CD39high CD8+ T cells that is absent in functional memory cells elicited by acute infection. This CD39high CD8+ T cell population is enriched for cells with the phenotypic and functional profile of terminal exhaustion. These findings provide a new marker of T cell exhaustion, and implicate the purinergic pathway in the regulation of T cell exhaustion.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Dunes on Pluto Telfer, Matt W; Parteli, Eric J R; Radebaugh, Jani ...
Science (American Association for the Advancement of Science),
06/2018, Letnik:
360, Številka:
6392
Journal Article
Recenzirano
Odprti dostop
The surface of Pluto is more geologically diverse and dynamic than had been expected, but the role of its tenuous atmosphere in shaping the landscape remains unclear. We describe observations from ...the New Horizons spacecraft of regularly spaced, linear ridges whose morphology, distribution, and orientation are consistent with being transverse dunes. These are located close to mountainous regions and are orthogonal to nearby wind streaks. We demonstrate that the wavelength of the dunes (~0.4 to 1 kilometer) is best explained by the deposition of sand-sized (~200 to ~300 micrometer) particles of methane ice in moderate winds (<10 meters per second). The undisturbed morphology of the dunes, and relationships with the underlying convective glacial ice, imply that the dunes have formed in the very recent geological past.
The New Horizons spacecraft's encounter with the cold classical Kuiper Belt object (486958) Arrokoth (provisional designation 2014 MU
) revealed a contact-binary planetesimal. We investigated how ...Arrokoth formed and found that it is the product of a gentle, low-speed merger in the early Solar System. Its two lenticular lobes suggest low-velocity accumulation of numerous smaller planetesimals within a gravitationally collapsing cloud of solid particles. The geometric alignment of the lobes indicates that they were a co-orbiting binary that experienced angular momentum loss and subsequent merger, possibly because of dynamical friction and collisions within the cloud or later gas drag. Arrokoth's contact-binary shape was preserved by the benign dynamical and collisional environment of the cold classical Kuiper Belt and therefore informs the accretion processes that operated in the early Solar System.
The presence of systemic inflammation determined by elevations in C-reactive protein (CRP) has been associated with persistence of atrial fibrillation (AF). The relationship between CRP and ...prediction of AF has not been studied in a large population-based cohort.
CRP measurement and cardiovascular assessment were performed at baseline in 5806 subjects enrolled in the Cardiovascular Health Study. Patients were followed up for a mean of 6.9+/-1.6 (median 7.8) years. AF was identified by self-reported history and ECGs at baseline and by ECGs and hospital discharge diagnoses at follow-up. Univariate and multivariate analyses were used to assess CRP as a predictor of baseline and future development of AF. At baseline, 315 subjects (5%) had AF. Compared with subjects in the first CRP quartile (<0.97 mg/L), subjects in the fourth quartile (>3.41 mg/L) had more AF (7.4% versus 3.7%, adjusted OR 1.8, 95% CI 1.2 to 2.5; P=0.002). Of 5491 subjects without AF at baseline, 897 (16%) developed AF during follow-up. Baseline CRP predicted higher risk for developing future AF (fourth versus first quartile adjusted hazard ratio 1.31, 95% CI 1.08 to 1.58; P=0.005). When treated as a continuous variable, elevated CRP predicted increased risk for developing future AF (adjusted hazard ratio for 1-SD increase, 1.24; 95% CI 1.11 to 1.40; P<0.001).
CRP is not only associated with the presence of AF but may also predict patients at increased risk for future development of AF.
For many years, biologists have focused on the role of Pitx2, expressed on the left side of developing embryos, in governing organ laterality. Here, we identify a different pathway during left-right ...asymmetry initiated by the right side of the embryo. Surprisingly, this conserved mechanism is orchestrated by the extracellular glycosaminoglycan, hyaluronan (HA) and is independent of Pitx2 on the left. Whereas HA is normally synthesized bilaterally as a simple polysaccharide, we show that covalent modification of HA by the enzyme Tsg6 on the right triggers distinct cell behavior necessary to drive the conserved midgut rotation and to pattern gut vasculature. HA disruption in chicken and Tsg6−/− mice results in failure to initiate midgut rotation and perturbs vascular development predisposing to midgut volvulus. Our study leads us to revise the current symmetry-breaking paradigm in vertebrates and demonstrates how enzymatic modification of HA matrices can execute the blueprint of organ laterality.
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•Left-right asymmetry is initiated by the right side of the embryo•Extracellular hyaluronan determines gut and vascular laterality•Tsg6-catalyzed hyaluronan modification on the right is independent of Pitx2 on the left•Tsg6 null mice fail to initiate gut rotation predisposing to volvulus
Gut malrotation predisposes newborns to catastrophic strangulation of the intestine. Sivakumar et al. show that covalent modification of the extracellular matrix (ECM) component hyaluronan specifically on the right side of mouse and chick embryos regulates gut rotation key to intestinal morphogenesis. Disruption of modification of hyaluronan results in gut malrotation.
The flyby of Pluto and Charon by the New Horizons spacecraft provided high-resolution images of cratered surfaces embedded in the Kuiper belt, an extensive region of bodies orbiting beyond Neptune. ...Impact craters on Pluto and Charon were formed by collisions with other Kuiper belt objects (KBOs) with diameters from ~40 kilometers to ~300 meters, smaller than most KBOs observed directly by telescopes. We find a relative paucity of small craters ≲13 kilometers in diameter, which cannot be explained solely by geological resurfacing. This implies a deficit of small KBOs (≲1 to 2 kilometers in diameter). Some surfaces on Pluto and Charon are likely ≳4 billion years old, thus their crater records provide information on the size-frequency distribution of KBOs in the early Solar System.
The deep nitrogen-covered basin on Pluto, informally named Sputnik Planitia, is located very close to the longitude of Pluto's tidal axis and may be an impact feature, by analogy with other large ...basins in the Solar System. Reorientation of Sputnik Planitia arising from tidal and rotational torques can explain the basin's present-day location, but requires the feature to be a positive gravity anomaly, despite its negative topography. Here we argue that if Sputnik Planitia did indeed form as a result of an impact and if Pluto possesses a subsurface ocean, the required positive gravity anomaly would naturally result because of shell thinning and ocean uplift, followed by later modest nitrogen deposition. Without a subsurface ocean, a positive gravity anomaly requires an implausibly thick nitrogen layer (exceeding 40 kilometres). To prolong the lifetime of such a subsurface ocean to the present day and to maintain ocean uplift, a rigid, conductive water-ice shell is required. Because nitrogen deposition is latitude-dependent, nitrogen loading and reorientation may have exhibited complex feedbacks.
The vast, deep, volatile-ice-filled basin informally named Sputnik Planum is central to Pluto's vigorous geological activity. Composed of molecular nitrogen, methane, and carbon monoxide ices, but ...dominated by nitrogen ice, this layer is organized into cells or polygons, typically about 10 to 40 kilometres across, that resemble the surface manifestation of solid-state convection. Here we report, on the basis of available rheological measurements, that solid layers of nitrogen ice with a thickness in excess of about one kilometre should undergo convection for estimated present-day heat-flow conditions on Pluto. More importantly, we show numerically that convective overturn in a several-kilometre-thick layer of solid nitrogen can explain the great lateral width of the cells. The temperature dependence of nitrogen-ice viscosity implies that the ice layer convects in the so-called sluggish lid regime, a unique convective mode not previously definitively observed in the Solar System. Average surface horizontal velocities of a few centimetres a year imply surface transport or renewal times of about 500,000 years, well under the ten-million-year upper-limit crater retention age for Sputnik Planum. Similar convective surface renewal may also occur on other dwarf planets in the Kuiper belt, which may help to explain the high albedos shown by some of these bodies.
The New Horizons mission has provided resolved measurements of Pluto's moons Styx, Nix, Kerberos, and Hydra. All four are small, with equivalent spherical diameters of approx.40 kilometers for Nix ...and Hydra and approx. 10 kilometers for Styx and Kerberos. They are also highly elongated, with maximum to minimum axis ratios of approx. 2. All four moons have high albedos (approx.50 to 90%) suggestive of a water-ice surface composition. Crater densities on Nix and Hydra imply surface ages of at least 4 billion years. The small moons rotate much faster than synchronous, with rotational poles clustered nearly orthogonal to the common pole directions of Pluto and Charon. These results reinforce the hypothesis that the small moons formed in the aftermath of a collision that produced the Pluto-Charon binary.
The LOng Range Reconnaissance Imager (LORRI) is a panchromatic (360-910 nm for the wavelengths where the responsivity falls to 10% of the peak value), narrow-angle (field of view = 0 29), high ...spatial resolution (pixel scale = 1 02) visible light imager used on NASA's New Horizons (NH) mission for both science observations and optical navigation. Calibration observations began several months after the New Horizons launch on 2006 January 19 and have been repeated approximately annually throughout the course of the mission, which is ongoing. This paper describes the in-flight LORRI calibration measurements, and the results derived from our analysis of the calibration data. LORRI has been remarkably stable over time with no detectable changes (at the ∼1% level) in sensitivity or optical performance since launch. The point-spread function varies over the FOV but is well-characterized and stable, enabling accurate deconvolution to recover the highest possible spatial resolution during observations of resolved targets, especially when multiple, overlapping images are obtained. By employing 4 × 4 re-binning of the CCD pixels during read out, a special spacecraft tracking mode, exposure times of ∼30 s, and co-addition of ∼100 images, LORRI can detect unresolved targets down to V 22 with a signal-to-noise ratio (S/N) of ∼5. LORRI images have an instantaneous dynamic range of ∼3500, which combined with exposure time control ranging from 0 ms to 64,967 ms in 1 ms steps supports high resolution, high sensitivity imaging of planetary targets spanning heliocentric distances from Jupiter to deep in the Kuiper Belt, enabling a wide variety of scientific investigations. We describe here how to transform LORRI images from raw (engineering) units into scientific (calibrated) units for both resolved and unresolved targets. Assuming that the wavelength variation of LORRI's sensitivity is accurately described by the ground-based calibration, we estimate that LORRI's absolute sensitivity is accurate to ∼2% (1 ) for targets with solar-type spectral energy distributions (SEDs). The accuracy of the absolute calibration for targets with other SEDs should be comparably good when employing synthetic photometry techniques, which we do when deriving LORRI's photometry keywords. We also describe various instrumental artifacts that could affect the interpretation of LORRI images under some observing circumstances.
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