We have previously described critical and nonredundant roles for the phosphoinositide 3-kinase p110δ during the activation and differentiation of naive T cells, and p110δ inhibitors are currently ...being developed for clinical use. However, to effectively treat established inflammatory or autoimmune diseases, it is important to be able to inhibit previously activated or memory T cells. In this study, using the isoform-selective inhibitor IC87114, we show that sustained p110δ activity is required for interferon-γ production. Moreover, acute inhibition of p110δ inhibits cytokine production and reduces hypersensitivity responses in mice. Whether p110δ played a similar role in human T cells was unknown. Here we show that IC87114 potently blocked T-cell receptor–induced phosphoinositide 3-kinase signaling by both naive and effector/memory human T cells. Importantly, IC87114 reduced cytokine production by memory T cells from healthy and allergic donors and from inflammatory arthritis patients. These studies establish that previously activated memory T cells are at least as sensitive to p110δ inhibition as naive T cells and show that mouse models accurately predict p110δ function in human T cells. There is therefore a strong rationale for p110δ inhibitors to be considered for therapeutic use in T-cell–mediated autoimmune and inflammatory diseases.
► Tempel 1 has two types of terrain, rough pitted and smoother, flow-like materials. ► The smooth materials are collected in low regions. ► Changes observed between the Deep Impact and Stardust-NExT ...encounters involve scarp retreat. ► Timescales for formation of the surface’s topography appear to be tens to perhaps hundreds of orbits.
The nucleus of comet Tempel 1 has been investigated at close range during two spacecraft missions separated by one comet orbit of the Sun, 5½years. The combined imaging covers ∼70% of the surface of this object which has a mean radius of 2.83±0.1km. The surface can be divided into two terrain types: rough, pitted terrain and smoother regions of varying local topography. The rough surface has round depressions from resolution limits (∼10m/pixel) up to ∼1km across, spanning forms from crisp steep-walled pits, to subtle albedo rings, to topographic rings, with all ranges of morphologic gradation. Three gravitationally low regions of the comet have smoother terrain, parts of which appear to be deposits from minimally modified flows, with other parts likely to be heavily eroded portions of multiple layer piles. Changes observed between the two missions are primarily due to backwasting of scarps bounding one of these probable flow deposits. This style of erosion is also suggested by remnant mesa forms in other areas of smoother terrain. The two distinct terrains suggest either an evolutionary change in processes, topographically-controlled processes, or a continuing interaction of erosion and deposition.
Guidelines strongly recommend patients with ST-elevation myocardial infarction (STEMI) receive timely mechanical reperfusion, defined as door-to-balloon time (DTBT) ≤90 minutes. The impact of timely ...reperfusion on clinical outcomes in patients aged 75–84 and ≥85 years is uncertain. We analysed 2,972 consecutive STEMI patients who underwent primary percutaneous coronary intervention from the Melbourne Interventional Group Registry (2005–2014). Patients aged <75 years were included in the younger group, those aged 75–84 years were in the elderly group and those ≥85 years were in the very elderly group. The primary endpoints were 12-month mortality and major adverse cardiovascular events (MACE). 2,307 (77.6%) patients were <75 years (mean age 59 ± 9 years), 495 (16.7%) were 75–84 years and 170 (5.7%) were ≥85 years. There has been a significant decrease in DTBT over 10 years in younger and elderly patients (p-for-trend <0.01 and 0.03) with a trend in the very elderly (p-for-trend 0.08). Compared to younger and elderly patients, the very elderly had higher 12-month mortality (3.6% vs 10.7% vs. 29.4%; p = 0.001) and MACE (10.8% vs 20.6% vs 33.5%; p = 0.001). DTBT ≤90 minutes was associated with improved outcomes on univariate analysis but was not an independent predictor of improved 12-month mortality (OR 0.84, 95% CI 0.54–1.31) or MACE (OR 0.89, 95% CI 0.67–1.16). In conclusion, over a 10-year period, there was an improvement in DTBT in patients aged <75 years and 75–84 years however DTBT ≤90 minutes was not an independent predictor of 12-month outcomes. Thus assessing whether patients aged ≥85 years are suitable for invasive management does not necessarily translate to worse clinical outcomes.
New neurons are continuously born in the hippocampus of several mammalian species throughout adulthood. Adult neurogenesis represents a natural model for understanding how to grow and incorporate new ...nerve cells into preexisting circuits in the brain. Finding molecules or biological pathways that increase neurogenesis has broad potential for regenerative medicine. One strategy is to identify mouse strains that display large vs. small increases in neurogenesis in response to wheel running so that the strains can be contrasted to find common genes or biological pathways associated with enhanced neuron formation. Therefore, mice from 12 different isogenic strains were housed with or without running wheels for 43 days to measure the genetic regulation of exercise‐induced neurogenesis. During the first 10 days mice received daily injections of 5‐bromo‐2′‐deoxyuridine (BrdU) to label dividing cells. Neurogenesis was measured as the total number of BrdU cells co‐expressing NeuN mature neuronal marker in the hippocampal granule cell layer by immunohistochemistry. Exercise increased neurogenesis in all strains, but the magnitude significantly depended on genotype. Strain means for distance run on wheels, but not distance traveled in cages without wheels, were significantly correlated with strain mean level of neurogenesis. Furthermore, certain strains displayed greater neurogenesis than others for a fixed level of running. Strain means for neurogenesis under sedentary conditions were not correlated with neurogenesis under runner conditions suggesting that different genes influence baseline vs. exercise‐induced neurogenesis. Genetic contributions to exercise‐induced hippocampal neurogenesis suggest that it may be possible to identify genes and pathways associated with enhanced neuroplastic responses to exercise.
1 Slow growth is associated with high mortality risk for trees, but few data exist to assess interspecific differences in the relationship between growth and mortality. Here we compare low growth ...tolerance for seven co-occurring species in the southern Appalachian Mountains: Acer rubrum, Betula lenta, Cornus florida, Liriodendron tulipifera, Quercus prinus, Quercus rubra and Robinia pseudo-acacia. 2 For all species, mortality was greater for understorey individuals than for canopy trees. Species varied widely in the length of growth decline prior to death, ranging from 6 years for L. tulipifera to more than 12 years for Q. rubra. 3 Growth-mortality functions differ among species, but we found little evidence of a trade-off between tolerance of slow growth and an ability to show rapid growth in high light conditions. 4 A. rubrum stands out in its ability both to grow rapidly and to tolerate slow growth, suggesting that its density may increase at our study site as in other parts of the eastern United States. In contrast, C. florida shows high mortality (15% per annum) as a result of infection with dogwood anthracnose. 5 We modified a forest simulation model, LINKAGES (which assumes that all species have the same ability to tolerate slow growth), to include our functions relating growth and mortality. The modified model gives radically altered predictions, reinforcing the need to rethink and re-parameterize existing computer models with field data.
Many standard statistical models used to examine population dynamics ignore significant sources of stochasticity. Usually only process error is included, and uncertainty due to errors in data ...collection is omitted or not directly specified in the model. We show how standard time-series models for population dynamics can be extended to include both observational and process error and how to perform inference on parameters in these models in the Bayesian setting. Using simulated data, we show how ignoring observation error can be misleading. We argue that the standard Bayesian techniques used to perform inference, including freely available software, are generally applicable to a variety of time-series models.
Background
Guidelines recommend prasugrel or ticagrelor instead of clopidogrel in patients with acute coronary syndromes (ACS) undergoing percutaneous coronary interventions (PCI).
Aim
We sought to ...describe the trends in uptake of the newer agents and analyse the clinical characteristics and short‐term outcomes of patients treated with clopidogrel, prasugrel or ticagrelor.
Methods
We analysed the temporal trends of antiplatelet use since the availability of prasugrel (2009–2013) in patients with ACS from the Melbourne Interventional Group registry. To assess clinical characteristics and outcomes, we included 1850 patients from 2012 to 2013, corresponding to the time all three agents were available. The primary outcome was major adverse cardiovascular events (MACE). The safety end‐point was in‐hospital bleeding.
Results
For the period of 2009–2013, the majority of patients were treated with clopidogrel (72%) compared with prasugrel (14%) or ticagrelor (14%). There was a clear trend towards ticagrelor by the end of 2013. Patients treated with clopidogrel were more likely to present with non‐ST‐elevation ACS, be older, and have more comorbidities. There was no difference in unadjusted 30‐day mortality (0.9 vs 0.5 vs 1.0%, P = 0.76), myocardial infarction (2 vs 1 vs 2%, P = 0.52) or MACE (3 vs 3 vs 4%, P = 0.57) between the three agents. There was no difference in in‐hospital bleeding (3 vs 2 vs 2%, P = 0.64).
Conclusion
Prasugrel and ticagrelor are increasingly used in ACS patients treated with PCI, predominantly in a younger cohort with less comorbidity. Although antiplatelet therapy should still be individualised based on the thrombotic and bleeding risk, our study highlights the safety of the new P2Y12
inhibitors in contemporary Australian practice.
Methylation analysis of individual cytosines in genomic DNA can be determined quantitatively by bisulphite treatment and PCR amplification of the target DNA sequence, followed by restriction enzyme ...digestion or sequencing. Methylated and unmethylated molecules, however, have different sequences after bisulphite conversion. For some sequences this can result in bias during the PCR amplification leading to an inaccurate estimate of methylation. PCR bias is sequence dependent and often strand-specific. This study presents a simple method for detection and measurement of PCR bias for any set of primers, and investigates parameters for overcoming PCR bias.
Evidence for a subsurface ocean on Europa Carr, Michael H; Belton, Michael J. S; Chapman, Clark R ...
Nature (London),
01/1998, Letnik:
391, Številka:
6665
Journal Article
Recenzirano
Ground-based spectroscopy of Jupiter's moon Europa, combined with gravity data, suggests that the satellite has an icy crust roughly 150 km thick and a rocky interior. In addition, images obtained by ...the Voyager spacecraft revealed that Europa's surface is crossed by numerous intersecting ridges and dark bands (called lineae) and is sparsely cratered, indicating that the terrain is probably significantly younger than that of Ganymede and Callisto. It has been suggested that Europa's thin outer ice shell might be separated from the moon's silicate interior by a liquid water layer, delayed or prevented from freezing by tidal heating; in this model, the lineae could be explained by repetitive tidal deformation of the outer ice shell. However, observational confirmation of a subsurface ocean was largely frustrated by the low resolution (>2 km per pixel) of the Voyager images. Here we present high-resolution (54 m per pixel) Galileo spacecraft images of Europa, in which we find evidence for mobile 'icebergs'. The detailed morphology of the terrain strongly supports the presence of liquid water at shallow depths below the surface, either today or at some time in the past. Moreover, lower-resolution observations of much larger regions suggest that the phenomena reported here are widespread.
Celotno besedilo
Dostopno za:
DOBA, IJS, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
We simulate three‐dimensional ice temperature fields to examine spatial‐temporal history of the subglacial thermal environment during the last glacial cycle. Model results suggest that 60–80% of the ...Laurentide Ice Sheet was cold‐based (frozen to the bed) at the LGM, and therefore unable to undergo large‐scale basal flow. The fraction of warm‐based ice increases significantly through the ensuing deglaciation, with only 10–20% of the Laurentide Ice Sheet frozen to the bed by 8 kyr BP. This basal thermal evolution, a function of both climatic and ice sheet history, could enable a dynamical switch to widespread basal flow through the deglacial period. Because basal flow has the capacity to evacuate large amounts of ice from the interior of continental ice sheets, creating thin and climatically‐vulnerable ice masses, this switch in flow regime may have played a significant role in glacial terminations and the 100‐kyr glacial cycle.
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