BACKGROUND AND PURPOSE—Patients are classically at risk of delayed cerebral ischemia (DCI) after aneurysmal subarachnoid hemorrhage. We validated a grading scale—the VASOGRADE—for prediction of DCI.
...METHODS—We used data of 3 phase II randomized clinical trials and a single hospital series to assess the relationship between the VASOGRADE and DCI. The VASOGRADE derived from previously published risk charts and consists of 3 categoriesVASOGRADE-Green (modified Fisher scale 1 or 2 and World Federation of Neurosurgical Societies scale WFNS 1 or 2); VASOGRADE-Yellow (modified Fisher 3 or 4 and WFNS 1–3); and VASOGRADE-Red (WFNS 4 or 5, irrespective of modified Fisher grade). The relation between the VASOGRADE and DCI was assessed by logistic regression models. The predictive accuracy of the VASOGRADE was assessed by receiver operating characteristics curve and calibration plots.
RESULTS—In a cohort of 746 patients, the VASOGRADE significantly predicted DCI (P<0.001). The VASOGRADE-Yellow had a tendency for increased risk for DCI (odds ratio OR, 1.31; 95% CI, 0.77–2.23) when compared with VASOGRADE-Green; those with VASOGRADE-Red had a 3-fold higher risk of DCI (OR, 3.19; 95% CI, 2.07–4.50). Studies were not a significant confounding factor between the VASOGRADE and DCI. The VASOGRADE had an adequate discrimination for prediction of DCI (area under the receiver operating characteristics curve=0.63) and good calibration.
CONCLUSIONS—The VASOGRADE results validated previously published risk charts in a large and diverse sample of subarachnoid hemorrhage patients, which allows DCI risk stratification on presentation after subarachnoid hemorrhage. It could help to select patients at high risk of DCI, as well as standardize treatment protocols and research studies.
We study Milky Way kinematics using a sample of 18.8 million main-sequence stars with r < 20 and proper-motion measurements derived from Sloan Digital Sky Survey (SDSS) and POSS astrometry, including ...{approx}170,000 stars with radial-velocity measurements from the SDSS spectroscopic survey. Distances to stars are determined using a photometric-parallax relation, covering a distance range from {approx}100 pc to 10 kpc over a quarter of the sky at high Galactic latitudes (|b|>20{sup 0}). We find that in the region defined by 1 kpc <Z< 5 kpc and 3 kpc <R< 13 kpc, the rotational velocity for disk stars smoothly decreases, and all three components of the velocity dispersion increase, with distance from the Galactic plane. In contrast, the velocity ellipsoid for halo stars is aligned with a spherical coordinate system and appears to be spatially invariant within the probed volume. The velocity distribution of nearby (Z < 1 kpc) K/M stars is complex, and cannot be described by a standard Schwarzschild ellipsoid. For stars in a distance-limited subsample of stars (<100 pc), we detect a multi-modal velocity distribution consistent with that seen by HIPPARCOS. This strong non-Gaussianity significantly affects the measurements of the velocity-ellipsoid tilt and vertex deviation when using the Schwarzschild approximation. We develop and test a simple descriptive model for the overall kinematic behavior that captures these features over most of the probed volume, and can be used to search for substructure in kinematic and metallicity space. We use this model to predict further improvements in kinematic mapping of the Galaxy expected from Gaia and the Large Synoptic Survey Telescope.
Background: The causal relevance of polyunsaturated fatty acids (PUFAs) for risk of site-specific cancers remains uncertain. Methods: Using a Mendelian randomization (MR) framework, we assessed the ...causal relevance of PUFAs for risk of cancer in European and East Asian ancestry individuals. We defined the primary exposure as PUFA desaturase activity, proxied by rs174546 at the FADS locus. Secondary exposures were defined as omega 3 and omega 6 PUFAs that could be proxied by genetic polymorphisms outside the FADS region. Our study used summary genetic data on 10 PUFAs and 67 cancers, corresponding to 562,871 cases and 1,619,465 controls, collected by the Fatty Acids in Cancer Mendelian Randomization Collaboration. We estimated odds ratios (ORs) for cancer per standard deviation increase in genetically proxied PUFA exposures. Findings: Genetically elevated PUFA desaturase activity was associated (P < 0.0007) with higher risk (OR 95% confidence interval) of colorectal cancer (1.09 1.07–1.11), esophageal squamous cell carcinoma (1.16 1.06–1.26), lung cancer (1.06 1.03–1.08) and basal cell carcinoma (1.05 1.02–1.07). There was little evidence for associations with reproductive cancers (OR = 1.00 95% CI: 0.99–1.01; Pheterogeneity = 0.25), urinary system cancers (1.03 0.99–1.06, Pheterogeneity = 0.51), nervous system cancers (0.99 0.95–1.03, Pheterogeneity = 0.92) or blood cancers (1.01 0.98–1.04, Pheterogeneity = 0.09). Findings for colorectal cancer and esophageal squamous cell carcinoma remained compatible with causality in sensitivity analyses for violations of assumptions. Secondary MR analyses highlighted higher omega 6 PUFAs (arachidonic acid, gamma-linolenic acid and dihomo-gamma-linolenic acid) as potential mediators. PUFA biosynthesis is known to interact with aspirin, which increases risk of bleeding and inflammatory bowel disease. In a phenome-wide MR study of non-neoplastic diseases, we found that genetic lowering of PUFA desaturase activity, mimicking a hypothetical intervention to reduce cancer risk, was associated (P < 0.0006) with increased risk of inflammatory bowel disease but not bleeding. Interpretation: The PUFA biosynthesis pathway may be an intervention target for prevention of colorectal cancer and esophageal squamous cell carcinoma but with potential for increased risk of inflammatory bowel disease. Funding: Cancer Resesrch UK (C52724/A20138, C18281/A19169). UK Medical Research Council (MR/P014054/1). National Institute for Health Research (NIHR202411). UK Medical Research Council (MC_UU_00011/1, MC_UU_00011/3, MC_UU_00011/6, and MC_UU_00011/4). National Cancer Institute (R00 CA215360). National Institutes of Health (U01 CA164973, R01 CA60987, R01 CA72520, U01 CA74806, R01 CA55874, U01 CA164973 and U01 CA164973).
Atmospheric black carbon (BC) warms Earth's climate, and its reduction has been targeted for near-term climate change mitigation. Models that include forcing by BC assume internal mixing with non-BC ...aerosol components that enhance BC absorption, often by a factor of ∼2; such model estimates have yet to be clearly validated through atmospheric observations. Here, direct in situ measurements of BC absorption enhancements (E abs ) and mixing state are reported for two California regions. The observed E abs is small—6% on average at 532 nm—and increases weakly with photochemical aging. The E abs is less than predicted from observationally constrained theoretical calculations, suggesting that many climate models may overestimate warming by BC. These ambient observations stand in contrast to laboratory measurements that show substantial E abs for BC are possible.
Small molecule modulators of epigenetic processes are currently sought as basic probes for biochemical mechanisms, and as starting points for development of therapeutic agents. N(ε)-Methylation of ...lysine residues on histone tails is one of a number of post-translational modifications that together enable transcriptional regulation. Histone lysine demethylases antagonize the action of histone methyltransferases in a site- and methylation state-specific manner. N(ε)-Methyllysine demethylases that use 2-oxoglutarate as co-factor are associated with diverse human diseases, including cancer, inflammation and X-linked mental retardation; they are proposed as targets for the therapeutic modulation of transcription. There are few reports on the identification of templates that are amenable to development as potent inhibitors in vivo and large diverse collections have yet to be exploited for the discovery of demethylase inhibitors.
High-throughput screening of a ∼236,000-member collection of diverse molecules arrayed as dilution series was used to identify inhibitors of the JMJD2 (KDM4) family of 2-oxoglutarate-dependent histone demethylases. Initial screening hits were prioritized by a combination of cheminformatics, counterscreening using a coupled assay enzyme, and orthogonal confirmatory detection of inhibition by mass spectrometric assays. Follow-up studies were carried out on one of the series identified, 8-hydroxyquinolines, which were shown by crystallographic analyses to inhibit by binding to the active site Fe(II) and to modulate demethylation at the H3K9 locus in a cell-based assay.
These studies demonstrate that diverse compound screening can yield novel inhibitors of 2OG dependent histone demethylases and provide starting points for the development of potent and selective agents to interrogate epigenetic regulation.
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Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
The efficacy of vaccine adjuvants such as Toll-like receptor agonists (TLRa) can be improved through formulation and delivery approaches. Here, we attached small molecule TLR-7/8a to polymer ...scaffolds (polymer-TLR-7/8a) and evaluated how different physicochemical properties of the TLR-7/8a and polymer carrier influenced the location, magnitude and duration of innate immune activation in vivo. Particle formation by polymer-TLR-7/8a was the most important factor for restricting adjuvant distribution and prolonging activity in draining lymph nodes. The improved pharmacokinetic profile by particulate polymer-TLR-7/8a was also associated with reduced morbidity and enhanced vaccine immunogenicity for inducing antibodies and T cell immunity. We extended these findings to the development of a modular approach in which protein antigens are site-specifically linked to temperature-responsive polymer-TLR-7/8a adjuvants that self-assemble into immunogenic particles at physiologic temperatures in vivo. Our findings provide a chemical and structural basis for optimizing adjuvant design to elicit broad-based antibody and T cell responses with protein antigens.
Abstract We analyze and compare the satellite halo populations at z ∼ 2 in the high-resolution cosmological zoom-in simulations of a 10 12 M ⊙ target halo ( z = 0 mass) carried out on eight widely ...used astrophysical simulation codes ( Art-I , Enzo , Ramses , Changa , Gadget-3 , Gear , Arepo-t , and Gizmo ) for the AGORA High-resolution Galaxy Simulations Comparison Project. We use slightly different redshift epochs near z = 2 for each code (hereafter “ z ∼ 2”) at which the eight simulations are in the same stage in the target halo’s merger history. After identifying the matched pairs of halos between the CosmoRun simulations and the DMO simulations, we discover that each CosmoRun halo tends to be less massive than its DMO counterpart. When we consider only the halos containing stellar particles at z ∼ 2, the number of satellite galaxies is significantly fewer than that of dark matter halos in all participating AGORA simulations and is comparable to the number of present-day satellites near the Milky Way or M31. The so-called “missing satellite problem” is fully resolved across all participating codes simply by implementing the common baryonic physics adopted in AGORA and the stellar feedback prescription commonly used in each code, with sufficient numerical resolution (≲100 proper pc at z = 2). We also compare other properties such as the stellar mass–halo mass relation and the mass–metallicity relation. Our work highlights the value of comparison studies such as AGORA, where outstanding problems in galaxy formation theory are studied simultaneously on multiple numerical platforms.
Europe has set ambitious green energy targets, to which offshore renewable developments (ORDs) will make a significant contribution. Governments are legally required to deliver ORDs sustainably; ...however, they may have detrimental impacts on wildlife, especially those already experiencing declines due to climate change. Population viability analysis (PVA) is the standard method for forecasting population change in ORD assessments, but PVAs do not currently account for climate effects. We quantified climate effects on seabird breeding success for 8 UK species breeding in the North Sea. We assessed the potential for seabirds to mitigate climate-driven changes in breeding success by accessing wider resources through increased foraging ranges around colonies. We demonstrate strong links between breeding success and climate in 5 species. In 4 of these species, future climate projections indicated large declines in breeding success relative to current rates. Only one species was predicted to increase breeding success under future climate. In all 5 species, there was limited opportunity for species to increase breeding success by expanding foraging ranges to access more suitable future climatic conditions. Climate change will have significant ramifications for future breeding success of seabirds breeding in the North Sea, an area undergoing extensive and rapid offshore renewable energy development. We recommend 3 methods for including climate-driven changes to seabird breeding success within ORD assessments: development of predictive climate-driven habitat use models to estimate ORD-wildlife interactions; delivery of a new ORD assessment framework that includes dynamic predictions of climate-driven habitat use and demography of wildlife populations; and consideration of climate-driven changes in the implementation of compensatory measures.
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