Canine hip dysplasia (CHD) is a common disease, with a complex genetic background. Dogs with severe CHD sometimes also suffer from osteoarthritis (OA), an inflammatory, often painful and incurable ...condition. Previous studies have reported breed-specific genetic loci associated with different hip dysplasia and OA phenotypes. However, the independent replication of the known associations within or across breeds has been difficult due to variable phenotype measures, inadequate sample sizes and the existence of population specific variants.
We execute a validation study of 46 genetic markers in a cohort of nearly 1600 dogs from ten different breeds. We categorize the dogs into cases and controls according to the hip scoring system defined by the Fédération Cynologique Internationale (FCI). We validate 21 different loci associated on fourteen chromosomes. Twenty of these associated with CHD in specific breeds, whereas one locus is unique to the across-breed study. We show that genes involved in the neddylation pathway are enriched among the genes in the validated loci. Neddylation contributes to many cellular functions including inflammation.
Our study successfully replicates many loci and highlights the complex genetic architecture of CHD. Further characterisation of the associated loci could reveal CHD-relevant genes and pathways for improved understanding of the disease pathogenesis.
The global environment is changing rapidly due to anthropogenic emissions and actions. Such activities modify aerosol and greenhouse gas concentrations in the atmosphere, leading to regional and ...global climate change and affecting, e.g., food and fresh-water security, sustainable use of natural resources and even demography. Here we present a conceptual design of a global, hierarchical observation network that can provide tools and increased understanding to tackle the inter-connected environmental and societal challenges that we will face in the coming decades. The philosophy behind the conceptual design relies on physical conservation laws of mass, energy and momentum, as well as on concentration gradients that act as driving forces for the atmosphere-biosphere exchange. The network is composed of standard, flux and/or advanced and flagship stations, each of which having specific and identified tasks. Each ecosystem type on the globe has its own characteristic features that have to be taken into consideration. The hierarchical network as a whole is able to tackle problems related to large spatial scales, heterogeneity of ecosystems and their complexity. The most comprehensive observations are envisioned to occur in flagship stations, with which the process-level understanding can be expanded to continental and global scales together with advanced data analysis, Earth system modelling and satellite remote sensing. The denser network of the flux and standard stations allows application and up-scaling of the results obtained from flagship stations to the global level.
Chronic inflammation of the arterial wall is a key element in the pathogenesis of atherosclerosis, yet the factors that trigger and sustain the inflammation remain elusive. Inflammasomes are ...cytoplasmic caspase-1-activating protein complexes that promote maturation and secretion of the proinflammatory cytokines interleukin(IL)-1beta and IL-18. The most intensively studied inflammasome, NLRP3 inflammasome, is activated by diverse substances, including crystalline and particulate materials. As cholesterol crystals are abundant in atherosclerotic lesions, and IL-1beta has been linked to atherogenesis, we explored the possibility that cholesterol crystals promote inflammation by activating the inflammasome pathway.
Here we show that human macrophages avidly phagocytose cholesterol crystals and store the ingested cholesterol as cholesteryl esters. Importantly, cholesterol crystals induced dose-dependent secretion of mature IL-1beta from human monocytes and macrophages. The cholesterol crystal-induced secretion of IL-1beta was caspase-1-dependent, suggesting the involvement of an inflammasome-mediated pathway. Silencing of the NLRP3 receptor, the crucial component in NLRP3 inflammasome, completely abolished crystal-induced IL-1beta secretion, thus identifying NLRP3 inflammasome as the cholesterol crystal-responsive element in macrophages. The crystals were shown to induce leakage of the lysosomal protease cathepsin B into the cytoplasm and inhibition of this enzyme reduced cholesterol crystal-induced IL-1beta secretion, suggesting that NLRP3 inflammasome activation occurred via lysosomal destabilization.
The cholesterol crystal-induced inflammasome activation in macrophages may represent an important link between cholesterol metabolism and inflammation in atherosclerotic lesions.
The role of polar regions is increasing in terms of
megatrends such as globalization, new transport routes, demography, and the use
of natural resources with consequent effects on regional and ...transported
pollutant concentrations. We set up the ERA-PLANET Strand 4 project “iCUPE
– integrative and Comprehensive Understanding on Polar Environments” to
provide novel insights and observational data on global grand challenges
with an Arctic focus. We utilize an integrated approach combining in situ
observations, satellite remote sensing Earth observations (EOs), and
multi-scale modeling to synthesize data from comprehensive long-term
measurements, intensive campaigns, and satellites to deliver data products,
metrics, and indicators to stakeholders concerning the environmental
status, availability, and extraction of natural resources in the polar areas.
The iCUPE work consists of thematic state-of-the-art research and the provision
of novel data in atmospheric pollution, local sources and transboundary
transport, the characterization of arctic surfaces and their changes, an assessment
of the concentrations and impacts of heavy metals and persistent organic
pollutants and their cycling, the quantification of emissions from natural
resource extraction, and the validation and optimization of satellite Earth
observation (EO) data streams. In this paper we introduce the iCUPE project
and summarize initial results arising out of the integration of comprehensive in
situ observations, satellite remote sensing, and multi-scale modeling in the
Arctic context.
The FIELDS instrumentation suite on the Magnetospheric Multiscale (MMS) mission provides comprehensive measurements of the full vector magnetic and electric fields in the reconnection regions ...investigated by MMS, including the dayside magnetopause and the night-side magnetotail acceleration regions out to 25 Re. Six sensors on each of the four MMS spacecraft provide overlapping measurements of these fields with sensitive cross-calibrations both before and after launch. The FIELDS magnetic sensors consist of redundant flux-gate magnetometers (AFG and DFG) over the frequency range from DC to 64 Hz, a search coil magnetometer (SCM) providing AC measurements over the full whistler mode spectrum expected to be seen on MMS, and an Electron Drift Instrument (EDI) that calibrates offsets for the magnetometers. The FIELDS three-axis electric field measurements are provided by two sets of biased double-probe sensors (SDP and ADP) operating in a highly symmetric spacecraft environment to reduce significantly electrostatic errors. These sensors are complemented with the EDI electric measurements that are free from all local spacecraft perturbations. Cross-calibrated vector electric field measurements are thus produced from DC to 100 kHz, well beyond the upper hybrid resonance whose frequency provides an accurate determination of the local electron density. Due to its very large geometric factor, EDI also provides very high time resolution (∼1 ms) ambient electron flux measurements at a few selected energies near 1 keV. This paper provides an overview of the FIELDS suite, its science objectives and measurement requirements, and its performance as verified in calibration and cross-calibration procedures that result in anticipated errors less than 0.1 nT in B and 0.5 mV/m in E. Summaries of data products that result from FIELDS are also described, as well as algorithms for cross-calibration. Details of the design and performance characteristics of AFG/DFG, SCM, ADP, SDP, and EDI are provided in five companion papers.
Haplotype phasing of genetic variants is important for clinical interpretation of the genome, population genetic analysis and functional genomic analysis of allelic activity. Here we present phASER, ...an accurate approach for phasing variants that are overlapped by sequencing reads, including those from RNA sequencing (RNA-seq), which often span multiple exons due to splicing. Using diverse RNA-seq data we demonstrate that this provides more accurate phasing of rare variants compared with population-based phasing and allows phasing of variants in the same gene up to hundreds of kilobases away that cannot be obtained from DNA sequencing (DNA-seq) reads. We show that in the context of medical genetic studies this improves the resolution of compound heterozygotes. Additionally, phASER provides measures of haplotypic expression that increase power and accuracy in studies of allelic expression. In summary, phasing using RNA-seq and phASER is accurate and improves studies where rare variant haplotypes or allelic expression is needed.
Background
Prolonged tissue hypoxia caused by chronic pulmonary disease is commonly regarded as an important mechanism in the development of secondary polycythemia, but little clinical data are ...available to support this hypothesis.
Objective
To study the prevalence and severity of erythrocytosis accompanying chronic hypoxic pulmonary disease in dogs.
Animals
Forty‐seven dogs with hypoxic chronic pulmonary disease, 27 dogs with nonhypoxic chronic pulmonary disease, and 60 healthy controls.
Methods
Dogs with chronic pulmonary disease and chronic hypoxemia (partial pressure of arterial oxygen PaO2 < 80 mm Hg on at least 2 arterial blood gas measurements a minimum of 1 month apart) were identified retrospectively from patient records. Association between arterial oxygen and red blood cell parameters was analyzed using Pearson's correlation coefficients and multivariable linear regression analysis.
Results
Red blood cell parameters measured at the end of the hypoxemia period were within the laboratory reference range in most dogs. In chronically hypoxemic dogs, hematocrit (Hct) was increased in 4/47 (8.5%; 95% confidence interval CI, 0‐17) dogs, erythrocyte count (Erytr) was increased in 12/47 (26%; 95%CI, 13‐38) dogs and hemoglobin concentration (Hb) was increased in 3/47 (6.4%; 95%CI, 0‐14) dogs. No marked polycythemia (Hct ≥65%) was noted in any of the dogs. Red blood cell parameters were not associated with the severity of hypoxemia (correlation to PaO2: Erytr, r = −.14; Hb, r = −.21; Hct, r = −.14; P > .05 for all).
Conclusions and Clinical Importance
Polycythemia is uncommon, and usually mild if present, in dogs with chronic hypoxia caused by pulmonary disease.
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