Continental shelf sediments are globally important for biogeochemical activity. Quantification of shelf-scale stocks and fluxes of carbon and nutrients requires the extrapolation of observations made ...at limited points in space and time. The procedure for selecting exemplar sites to form the basis of this upscaling is discussed in relation to a UK-funded research programme investigating biogeochemistry in shelf seas. A three-step selection process is proposed in which (1) a target area representative of UK shelf sediment heterogeneity is selected, (2) the target area is assessed for spatial heterogeneity in sediment and habitat type, bed and water column structure and hydrodynamic forcing, and (3) study sites are selected within this target area encompassing the range of spatial heterogeneity required to address key scientific questions regarding shelf scale biogeochemistry, and minimise confounding variables. This led to the selection of four sites within the Celtic Sea that are significantly different in terms of their sediment, bed structure, and macrofaunal, meiofaunal and microbial community structures and diversity, but have minimal variations in water depth, tidal and wave magnitudes and directions, temperature and salinity. They form the basis of a research cruise programme of observation, sampling and experimentation encompassing the spring bloom cycle. Typical variation in key biogeochemical, sediment, biological and hydrodynamic parameters over a pre to post bloom period are presented, with a discussion of anthropogenic influences in the region. This methodology ensures the best likelihood of site-specific work being useful for up-scaling activities, increasing our understanding of benthic biogeochemistry at the UK-shelf scale.
Vitamin fortification of dairy products, including fluid milk and fortified whey protein beverages, is an industry standard but can lead to the development of off-flavor compounds that are difficult ...to extract and detect by instrumental methods. Previous work has identified these compounds and their specific role in off-flavors in skim milk, but efficient extraction and quantification of these compounds remains a challenge. Three rapid methods (stir bar sorptive extraction, solvent-assisted stir bar sorptive extraction, and solid-phase microextraction) were compared for their ability to effectively recover vitamin degradation volatiles from fluid skim milk. The performance of the 3 methods for detecting and quantifying vitamin degradation-related volatile compounds was determined by linear regression of standard curves prepared from spiked standards of 5 vitamin degradation volatiles, the reproducibility on the same day and between days as measured by the average relative standard deviation of each standard curve, and the limits of detection and quantitation. Measurement of vitamin degradation compounds in commercial pasteurized fortified skim milks was also conducted using each method. Detection of selected vitamin degradation volatiles was linear in skim milk (0.005–200 μg/kg). Coefficient of determination values differed between methods and compounds. Within-day and between-day percentage of relative standard deviation also varied with compound and method. Limits of detection and quantitation values for all methods except solid-phase microextraction were lower than concentrations of selected volatile compounds typically found in commercial milk. Solvent-assisted stir bar sorptive extraction with a 10-mL sample volume provided the most consistent detection of selected compounds in commercial milks. Based on linearity, relative standard deviation, and limits of detection and quantitation, cyclohexane solvent-assisted stir bar sorptive extraction with 10-mL sample volume is recommended for the quantitation of vitamin degradation-related volatiles in fluid skim milk.
To better delineate the natural history of patients with methylmalonic aciduria (MMA).
Thirty patients with vitamin-B
12-unresponsive MMA (25 aged 1.5 to 22.0
years (y) at the end of the study and 5 ...who died during a metabolic crisis) were managed following standardized guidelines and studied retrospectively. The median follow-up was 8.3
y (range: 1.4–19.5). Patients were investigated with neuropsychological testing, brain MRIs, inulin clearances, biochemical and genetic studies.
Fifteen patients had a neonatal onset. Thirteen patients (43%) had significant neurological impairment. Chronic renal disease (CRD) occurred in 14 patients (47%) with a median age of onset of 6.5
y (range 1.5–18.6). Renal function further deteriorated in 4 patients within a median period of 5.8
y (range 2–7.4). Of 25 patients investigated at the enzymatic level, 17 were classified mut°, 3 mut- and 5 cblA. Mortality, number of acute decompensations (
p
=
0.031), median MMA urinary excretion (
p
=
0.006) and neurological impairment (
p
<
0.0001) were higher in mut° patients compared to mut-/cblA patients. Concerning the CRD, no difference incidence was found although the onset of CRD occurred earlier in mut° patients and was more severe.
Our study provides unique data concerning the progression of renal disease in MMA. Patients with mut° phenotype have a more severe phenotype and probably an earlier and more severe CRD than patients with mut-/cblA phenotype.
Purpose
To evaluate the effect of a new-generation positional device, the sleep position trainer (SPT), in non-apneic position-dependent snorers.
Methods
Non-apneic position-dependent snorers with an ...apnea–hypopnea index (AHI) < 5 events/h were included between February 2015 and September 2016. After inclusion, study subjects used the SPT at home for 6 weeks. The Snore Outcome Survey (SOS) was filled out by the subjects at baseline and after 6 weeks, and at the same time, the Spouse/Bed Partner Survey (SBPS) was filled out by their bed partners.
Results
A total of 36 participants were included and 30 completed the study. SOS score improved significantly after 6 weeks from 35.0 ± 13.5 to 55.3 ± 18.6,
p
< 0.001. SBPS score also improved significantly after 6 weeks from 24.7 ± 16.0 versus 54.5 ± 25.2,
p
< 0.001. The severity of snoring assessed with a numeric visual analogue scale (VAS) by the bed partner decreased significantly from a median of 8.0 with an interquartile range (IQR) of 7.0–8.5 to 7.0 3.8–8.0 after 6 weeks (
p
= 0.004).
Conclusions
Results of this study indicate that positional therapy with the SPT improved several snoring-related outcome measures in non-apneic position-dependent snorers. The results of this non-controlled study demonstrate that this SPT could be considered as an alternative therapeutic option to improve sleep-related health status of snorers and their bed partners.
Patients with methylmalonic acidemia (MMA) may develop many complications despite medical treatment, in particular, severe central nervous system damage and chronic kidney disease (CKD). A kidney ...transplant may partially correct the metabolic dysfunctions. Liver, kidney and combined liver–kidney transplantations have been advocated but no guidelines are available to identify the most suitable organ to transplant.
Four patients with MMA (mut° phenotype) received a kidney graft because of repeated metabolic decompensations, with progression to CKD in 3 patients (end-stage kidney disease in two patients and CKD stage III in one patient with an estimated glomerular filtration rate eGFR of 40ml/min/1.73m2) but normal renal function in one (eGFR of 93ml/min/1.73m2) before transplantation.
The medium age at transplantation was 7.9y (5–10.2) and the median follow-up was 2.8years (1.8–4.6). Renal transplantation improved the relevant metabolic parameters in 4/4 patients and renal function in the patients with CKD. Plasma and urinary MMA levels immediately decreased and remained normal or subnormal (mean values of plasma MMA before transplantation 1530μmol/L versus 240μmol/L after transplantation, and mean values of urine MMA before transplantation 4700mmol/mol creatinine versus 2300mmol/mol creatinine after transplantation). No further acute metabolic decompensation was observed and protein-intake was increased from 0.60 to 0.83g/Kg/day. One patient transplanted at age 9.7years developed a hepatoblastoma at age 11years with subsequent neurological complications and eventually died. The three other patients are alive. Two of them remained neurologically stable. The 3rd patient who displayed choreoathetosis transiently improved his neurological condition immediately after transplantation and then remained stable.
Kidney transplantation represents an interesting alternative therapeutic option in methylmalonic aciduria, for renal complications but also as a “cellular therapy” that may significantly reduce metabolic decompensations and hospitalizations. However, further neurological impairment remains possible.
•Chronic kidney disease is an important complication in methylmalonic aciduria (MMA).•Kidney transplantation is a therapeutic option to correct end stage kidney disease.•Kidney transplantation significantly improves metabolic condition.•However, this treatment doesn't prevent neurological complications.
The quest for the cosmological parameters that describe our universe continues to motivate the scientific community to undertake very large survey initiatives across the electromagnetic spectrum. ...Over the past two decades, the Chandra and XMM-Newton observatories have supported numerous studies of X-ray-selected clusters of galaxies, active galactic nuclei (AGNs), and the X-ray background. The present paper is the first in a series reporting results of the XXL-XMM survey; it comes at a time when the Planck mission results are being finalized. Aims. We present the XXL Survey, the largest XMM programme totaling some 6.9 Ms to date and involving an international consortium of roughly 100 members. The XXL Survey covers two extragalactic areas of 25 deg2 each at a point-source sensitivity of approx. 5 x 10(exp 15) erg/s/sq cm in the 0.5-2 keV band (completeness limit). The surveys main goals are to provide constraints on the dark energy equation of state from the space-time-distribution of clusters of galaxies and to serve as a pathfinder for future, wide-area X-ray missions. We review science objectives, including cluster studies, AGN evolution, and large-scale structure, that are being conducted with the support of approximately 30 follow-up programs. Methods. We describe the 542 XMM observations along with the associated multi- and numerical simulation programmes. We give a detailed account of the X-ray processing steps and describe innovative tools being developed for the cosmological analysis. Results. The paper provides a thorough evaluation of the X-ray data, including quality controls, photon statistics, exposure and background maps, and sky coverage. Source catalogue construction and multi-associations are briefly described. This material will be the basis for the calculation of the cluster and AGN selection functions, critical elements of the cosmological and science analyses. Conclusions. The XXL multi- data set will have a unique lasting legacy value for cosmological and extragalactic studies and will serve asa calibration resource for future dark energy studies with clusters and other X-ray selected sources. With the present article, we release the XMM XXL photon and smoothed images along with the corresponding exposure maps.
Abstract
Introduction
Heart Failure with Preserved Ejection Fraction (HFpEF) is proposed to be caused by endothelial dysfunction in cardiac small vessels. We previously identified Hhipl1,as a gene ...upregulated in the coronary vasculature of Leptin receptor deficient mice (Leprdb/db) a well-established mouse model of HFpEF. Importantly, Hhipl1 encodes for a decoy receptor of Desert Hedgehog (DHH) which is known to be critical for endothelial integrity.
Objective
Our objective is to investigate the functional consequences of impaired Hedgehog (HH) signaling in the adult heart in order to identify novel mechanisms underlying the development of diastolic dysfunction.
Method
To do so, Cdh5-Cre/ERT2, DhhFlox/Flox (DhhECKO) mice and their control littermates were administered with tamoxifen at 8 weeks of age to induce Dhh KO. Their cardiac function, exercise tolerance, and the phenotype of their coronary vasculature were assessed one month later.
Results
DhhECKO mice presented significantly reduced exercise tolerance, increased end diastolic pressure (EDP) and Tau, with no change in their ejection fraction consistent with diastolic dysfunction. At molecular and cellular level, impaired cardiac relaxation in DhhECKO mice was associated with a significantly decreased phospholamban phosphorylation on Thr17 and an alteration of sarcomeric shortening in ex-vivo. Besides, as expected, DhhECKO mice exhibited phenotypic changes in their coronary vasculature including a prominent pro-thrombotic phenotype (63±6,2 vs 25±5,2 thrombi/mm²; p<0,001) leading to an impaired capillary perfusion and local hypoxia. Notably, antiaggregant therapies (aspirin and clopidogrel) prevented the occurrence of both diastolic dysfunction and exercise intolerance in DhhECKO mice demonstrating for the first time that thrombosis may promote diastolic dysfunction. Importantly, we confirmed the critical role of thrombosis in Leprdb/db mice which also displayed increased cardiac small vessel thrombosis in comparison to control mice. Alike DhhECKO mice, we found that antiaggregants decreased EDP (6,3±0,4 mmHg in aspirin-treated vs 11,3 ± 0,79 in control mice; p=0,001) and improved exercise tolerance in Leprdb/db mice (34 ± 2,52 min in aspirin-treated vs 24 ± 3,55 in control mice; p=0,004).
Conclusion
Altogether, these results demonstrate that small vessel thrombosis may participate in the pathophysiology of heart failure with preserved ejection fraction.
Recently, we have shown that Ca2+-activated force generation in diaphragm single fibers is impaired in patients with mild to moderate chronic obstructive pulmonary disease (COPD). For optimal ...active-force generation, the passive elasticity provided by titin is indispensable.
In the present study, we determined the passive-tension-length relations of single fibers of patients with mild to moderate COPD, hypothesizing that passive-elastic properties of diaphragm fibers are compromised.
Passive-tension-length relations were determined in diaphragm fibers from patients with and without COPD (predicted mean FEV1, 76 and 102%, respectively). In diaphragm homogenates titin expression was studied at the protein level by gel electrophoresis and at the transcript level by using a novel titin exon microarray.
Diaphragm fibers from patients with COPD generate less passive tension on stretch. Titin content in the diaphragm did not differ between patients with and without COPD. However, titin exon transcript studies revealed up-regulation of seven exons, which code for spring elements in the elastic segment rich in proline, glutamate, valine, and lysine. Immunofluorescence analysis indicated elevated protein expression of the up-regulated splice variant in the COPD diaphragm. Simulation studies on titin molecules including the amino acids encoded by the seven up-regulated exons predicted reduced passive-tension generation on molecule stretch.
Passive-tension generation of diaphragm single fibers is reduced in patients with COPD. Our results suggest that alternative splicing of the titin gene, resulting in increased length of the elastic segment rich in proline, glutamate, valine, and lysine, is involved. Interestingly, these changes occur already in patients with mild to moderate COPD.
Little is known about how human genetic variation affects the responses to environmental stimuli in the context of complex diseases. Experimental and computational approaches were applied to ...determine the effects of genetic variation on the induction of pathogen-responsive genes in human dendritic cells. We identified 121 common genetic variants associated in cis with variation in expression responses to Escherichia coli lipopolysaccharide, influenza, or interferon-β (IFN-β). We localized and validated causal variants to binding sites of pathogen-activated STAT (signal transducer and activator of transcription) and IRF (IFN-regulatory factor) transcription factors. We also identified a common variant in IRF7 that is associated in trans with type I IFN induction in response to influenza infection. Our results reveal common alleles that explain interindividual variation in pathogen sensing and provide functional annotation for genetic variants that alter susceptibility to inflammatory diseases.
In this work, we present a new (2+1)D galaxy cluster finder based on photometric redshifts called Wavelet Z Photometric (WaZP) applied to DES first year (Y1A1) data. The results are compared to ...clusters detected by the South Pole Telescope (SPT) survey and the redMaPPer cluster finder, the latter based on the same photometric data. WaZP searches for clusters in wavelet-based density maps of galaxies selected in photometric redshift space without any assumption on the cluster galaxy populations. The comparison to other cluster samples was performed with a matching algorithm based on angular proximity and redshift difference of the clusters. It led to the development of a new approach to match two optical cluster samples, following an iterative approach to minimize incorrect associations. The WaZP cluster finder applied to DES Y1A1 galaxy survey (1511.13 deg2 up to mi = 23 mag) led to the detection of 60 547 galaxy clusters with redshifts 0.05 < z < 0.9 and richness Ngals ≥ 5. Furthermore, considering the overlapping regions and redshift ranges between the DES Y1A1 and SPT cluster surveys, all sz based SPT clusters are recovered by the WaZP sample. The comparison between WaZP and redMaPPer cluster samples showed an excellent overall agreement for clusters with richness Ngals (λ for redMaPPer) greater than 25 (20), with 95 per cent recovery on both directions. Based on the cluster cross-match, we explore the relative fragmentation of the two cluster samples and investigate the possible signatures of unmatched clusters.
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