IL‐27: a double agent in the IL‐6 family Jones, G. W.; Hill, D. G.; Cardus, A. ...
Clinical and experimental immunology,
July 2018, Letnik:
193, Številka:
1
Journal Article
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Summary
The cytokine interleukin (IL)‐6 is a major therapeutic target for the treatment of various inflammatory and autoimmune diseases. While IL‐6 receives considerable attention in studies of ...innate and adaptive immunity, the IL‐6‐related family member IL‐27 is recognized increasingly for its effects on cellular proliferation, differentiation and leucocyte effector functions. Both cytokines activate responses in myeloid and stromal tissue cells, where they direct the transition from innate to adaptive immunity. However, they are identified frequently as lymphokines that control responses in T cells and B cells. In this regard, IL‐27 often opposes the action of IL‐6. Here, we will review the role of IL‐6 and IL‐27 in inflammation, with a particular focus on inflammatory arthritis, and discuss their importance in the diagnosis, stratification and treatment of autoimmune disease.
Review of IL‐6 and IL‐27 biology in the context of inflammatory arthritis and inflammation.
The poly (ADP-ribose) polymerase (PARP) inhibitor olaparib is FDA approved for the treatment of BRCA-mutated breast, ovarian and pancreatic cancers. Olaparib inhibits PARP1/2 enzymatic activity and ...traps PARP1 on DNA at single-strand breaks, leading to replication-induced DNA damage that requires BRCA1/2-dependent homologous recombination repair. Moreover, DNA damage response pathways mediated by the ataxia-telangiectasia mutated (ATM) and ataxia-telangiectasia mutated and Rad3-related (ATR) kinases are hypothesised to be important survival pathways in response to PARP-inhibitor treatment. Here, we show that olaparib combines synergistically with the ATR-inhibitor AZD6738 (ceralasertib), in vitro, leading to selective cell death in ATM-deficient cells. We observe that 24 h olaparib treatment causes cells to accumulate in G2-M of the cell cycle, however, co-administration with AZD6738 releases the olaparib-treated cells from G2 arrest. Selectively in ATM-knockout cells, we show that combined olaparib/AZD6738 treatment induces more chromosomal aberrations and achieves this at lower concentrations and earlier treatment time-points than either monotherapy. Furthermore, single-agent olaparib efficacy in vitro requires PARP inhibition throughout multiple rounds of replication. Here, we demonstrate in several ATM-deficient cell lines that the olaparib and AZD6738 combination induces cell death within 1-2 cell divisions, suggesting that combined treatment could circumvent the need for prolonged drug exposure. Finally, we demonstrate in vivo combination activity of olaparib and AZD6738 in xenograft and PDX mouse models with complete ATM loss. Collectively, these data provide a mechanistic understanding of combined PARP and ATR inhibition in ATM-deficient models, and support the clinical development of AZD6738 in combination with olaparib.
Catalog of Nearby Exoplanets Butler, R. P; Wright, J. T; Marcy, G. W ...
The Astrophysical journal,
07/2006, Letnik:
646, Številka:
1
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We present a catalog of nearby exoplanets. It contains the 172 known low-mass companions with orbits established through radial velocity and transit measurements around stars within 200 pc. We ...include five previously unpublished exoplanets orbiting the stars HD 11964, HD 66428, HD 99109, HD 107148, and HD 164922. We update orbits for 83 additional exoplanets, including many whose orbits have not been revised since their announcement, and include radial velocity time series from the Lick, Keck, and Anglo-Australian Observatory planet searches. Both these new and previously published velocities are more precise here due to improvements in our data reduction pipeline, which we applied to archival spectra. We present a brief summary of the global properties of the known exoplanets, including their distributions of orbital semimajor axis, minimum mass, and orbital eccentricity.
Programmed cell death (PCD) is an integral part of plant development and of responses to abiotic stress or pathogens. Although the morphology of plant PCD is, in some cases, well characterised and ...molecular mechanisms controlling plant PCD are beginning to emerge, there is still confusion about the classification of PCD in plants. Here we suggest a classification based on morphological criteria. According to this classification, the use of the term 'apoptosis' is not justified in plants, but at least two classes of PCD can be distinguished: vacuolar cell death and necrosis. During vacuolar cell death, the cell contents are removed by a combination of autophagy-like process and release of hydrolases from collapsed lytic vacuoles. Necrosis is characterised by early rupture of the plasma membrane, shrinkage of the protoplast and absence of vacuolar cell death features. Vacuolar cell death is common during tissue and organ formation and elimination, whereas necrosis is typically found under abiotic stress. Some examples of plant PCD cannot be ascribed to either major class and are therefore classified as separate modalities. These are PCD associated with the hypersensitive response to biotrophic pathogens, which can express features of both necrosis and vacuolar cell death, PCD in starchy cereal endosperm and during self-incompatibility. The present classification is not static, but will be subject to further revision, especially when specific biochemical pathways are better defined.
Historical reanalyses that span more than a century are needed for a wide range of studies, from understanding large‐scale climate trends to diagnosing the impacts of individual historical extreme ...weather events. The Twentieth Century Reanalysis (20CR) Project is an effort to fill this need. It is supported by the National Oceanic and Atmospheric Administration (NOAA), the Cooperative Institute for Research in Environmental Sciences (CIRES), and the U.S. Department of Energy (DOE), and is facilitated by collaboration with the international Atmospheric Circulation Reconstructions over the Earth initiative. 20CR is the first ensemble of sub‐daily global atmospheric conditions spanning over 100 years. This provides a best estimate of the weather at any given place and time as well as an estimate of its confidence and uncertainty. While extremely useful, version 2c of this dataset (20CRv2c) has several significant issues, including inaccurate estimates of confidence and a global sea level pressure bias in the mid‐19th century. These and other issues can reduce its effectiveness for studies at many spatial and temporal scales. Therefore, the 20CR system underwent a series of developments to generate a significant new version of the reanalysis. The version 3 system (NOAA‐CIRES‐DOE 20CRv3) uses upgraded data assimilation methods including an adaptive inflation algorithm; has a newer, higher‐resolution forecast model that specifies dry air mass; and assimilates a larger set of pressure observations. These changes have improved the ensemble‐based estimates of confidence, removed spin‐up effects in the precipitation fields, and diminished the sea‐level pressure bias. Other improvements include more accurate representations of storm intensity, smaller errors, and large‐scale reductions in model bias. The 20CRv3 system is comprehensively reviewed, focusing on the aspects that have ameliorated issues in 20CRv2c. Despite the many improvements, some challenges remain, including a systematic bias in tropical precipitation and time‐varying biases in southern high‐latitude pressure fields.
A significant new version of the Twentieth Century Reanalysis data assimilation system, 20CRv3, has been developed. The 20CRv3 dataset will provide an ensemble of sub‐daily global atmospheric conditions spanning at least 180 years by assimilating only surface pressure observations into a coupled atmosphere–land forecast model. The new 20CRv3 system improves upon the previous system in several notable ways, including the use of upgraded data assimilation methods, a newer and higher‐resolution forecast model, and a larger set of available pressure observations.
First measurements of the in-flight shape of imploding inertial confinement fusion (ICF) capsules at the National Ignition Facility (NIF) were obtained by using two-dimensional x-ray radiography. The ...sequence of area-backlit, time-gated pinhole images is analyzed for implosion velocity, low-mode shape and density asymmetries, and the absolute offset and center-of-mass velocity of the capsule shell. The in-flight shell is often observed to be asymmetric even when the concomitant core self-emission is round. A ∼ 15 μm shell asymmetry amplitude of the Y(40) spherical harmonic mode was observed for standard NIF ICF hohlraums at a shell radius of ∼ 200 μm (capsule at ∼ 5× radial compression). This asymmetry is mitigated by a ∼ 10% increase in the hohlraum length.
The relative contribution of top-down and bottom-up processes regulating primary decomposers can influence the strength of the link between the soil animal community and ecosystem functioning. ...Although soil bacterial communities are regulated by bottom-up and top-down processes, the latter are considered to be less important in structuring the diversity and functioning of fungal-dominated ecosystems. Despite the huge diversity of mycophagous (fungal-feeding) soil fauna, and their potential to reverse the outcomes of competitive fungal interactions, top-down grazing effects have never been found to translate to community-level changes. We constructed soil mesocosms to investigate the potential of isopods grazing on cord-forming basidiomycete fungi to influence the community composition and functioning of a complex woodland soil microbial community. Using metagenomic sequencing we provide conclusive evidence of direct top-down control at the community scale in fungal-dominated woodland soil. By suppressing the dominant cord-forming basidiomycete fungi, isopods prevented the competitive exclusion of surrounding litter fungi, increasing diversity in a community containing several hundred fungal species. This isopod-induced modification of community composition drove a shift in the soil enzyme profile, and led to a restructuring of the wider mycophagous invertebrate community. We highlight characteristics of different soil ecosystems that will give rise to such top-down control. Given the ubiquity of isopods and basidiomycete fungi in temperate and boreal woodland ecosystems, such top-down community control could be of widespread significance for global carbon and nutrient cycling.
The presence of large Northern Hemisphere ice sheets and reduced greenhouse gas concentrations during the Last Glacial Maximum fundamentally altered global ocean-atmosphere climate dynamics. Model ...simulations and palaeoclimate records suggest that glacial boundary conditions affected the El Niño-Southern Oscillation, a dominant source of short-term global climate variability. Yet little is known about changes in short-term climate variability at mid- to high latitudes. Here we use a high-resolution water isotope record from West Antarctica to demonstrate that interannual to decadal climate variability at high southern latitudes was almost twice as large at the Last Glacial Maximum as during the ensuing Holocene epoch (the past 11,700 years). Climate model simulations indicate that this increased variability reflects an increase in the teleconnection strength between the tropical Pacific and West Antarctica, owing to a shift in the mean location of tropical convection. This shift, in turn, can be attributed to the influence of topography and albedo of the North American ice sheets on atmospheric circulation. As the planet deglaciated, the largest and most abrupt decline in teleconnection strength occurred between approximately 16,000 years and 15,000 years ago, followed by a slower decline into the early Holocene.
Abstract We examine the evolution of the disk surrounding the Be star in the highly eccentric 10.8 yr binary system δ Scorpii over its three most recent periastron passages. V -band and B − V ...photometry, along with H α spectroscopy, are combined with a new set of extensive multiband polarimetry data to produce a detailed comparison of the disk's physical conditions during the time periods surrounding each closest approach of the secondary star. We use the three-dimensional Monte Carlo radiative transfer code HDUST and a smoothed particle hydrodynamics code to support our observations with models of disk evolution, discussing the behavior of the H α and He i 6678 Å lines, V -band magnitude, and polarization degree. We compare the characteristics of the disk immediately before each periastron passage to create a baseline for the unperturbed disk. We find that the extent of the H α emitting region increased between each periastron passage, and that transient asymmetries in the disk become more pronounced with each successive encounter. Asymmetries of the H α and He i 6678 Å lines in 2011 indicate that perturbations propagate inward through the disk near periastron. When the disk’s direction of orbit is opposite to that of the secondary, the parameters used in our models do not produce spiral density enhancements in the H α emitting region because the tidal interaction time is short due to the relative velocities of the disk particles with the secondary. The effects of the secondary star on the disk are short-lived and the disk shows independent evolution between each periastron event.
Systematic symptom reporting by patients and the use of questionnaires such as the Edmonton Symptom Assessment System (ESAS) have potential to improve clinical encounters and patient satisfaction. We ...review findings from published studies of the ESAS to guide use of the system and to focus research.
A systematic search for articles from 1991 through 2007 found thirty-nine peer-reviewed papers from 25 different institutions, thirty-three of which focused on patients with cancer. Observations, data, and statistics were collated according to relevance, reliability, validity, and responsiveness.
Findings apply predominantly to symptomatic palliative patients with advanced cancer who were no longer receiving active oncologic therapies. Uncertainty about summarizing findings arises from frequent modification of the ESAS (altered items, scales, and time periods). Overall, reliability is established for daily administration. Scores are skewed, with a floor effect, but the relative order of symptoms by mean scores is similar across studies. Emotional symptoms are poorly captured by the depression and anxiety items. An equally weighted summation of scores may estimate a construct of "physical symptom distress," which in turn is related to performance status, palliative goals, quality of life, and well-being.
The ESAS is reliable, but it has restricted validity, and its use requires a sound clinical process to help interpret scores and to give them an appropriate level of attention. Research priorities are to further develop the ESAS for assessing a greater number of important physical symptoms (and to target "physical symptom distress"), and to develop a similar instrument for emotional symptoms.
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