Glycosylation is the most abundant and diverse posttranslational modification of proteins. While several types of glycosylation can be predicted by the protein sequence context, and substantial ...knowledge of these glycoproteomes is available, our knowledge of the GalNAc‐type O‐glycosylation is highly limited. This type of glycosylation is unique in being regulated by 20 polypeptide GalNAc‐transferases attaching the initiating GalNAc monosaccharides to Ser and Thr (and likely some Tyr) residues. We have developed a genetic engineering approach using human cell lines to simplify O‐glycosylation (SimpleCells) that enables proteome‐wide discovery of O‐glycan sites using ‘bottom‐up’ ETD‐based mass spectrometric analysis. We implemented this on 12 human cell lines from different organs, and present a first map of the human O‐glycoproteome with almost 3000 glycosites in over 600 O‐glycoproteins as well as an improved NetOGlyc4.0 model for prediction of O‐glycosylation. The finding of unique subsets of O‐glycoproteins in each cell line provides evidence that the O‐glycoproteome is differentially regulated and dynamic. The greatly expanded view of the O‐glycoproteome should facilitate the exploration of how site‐specific O‐glycosylation regulates protein function.
Comprehensive proteomics survey in 12 human cell lines and development of an improved NetOGlyc4.0 prediction tool greatly expand the view on mucin‐type protein O‐glycosylation.
Abstract Subchronic phencyclidine (subPCP) treatment induces schizophrenic-like behavior in rodents, including cognitive deficits and increased locomotor sensitivity towards acute administration of ...PCP. Evidence is accumulating that the gut microbiota (GM) influences behavior through modulation of the microbiota–gut–brain axis, and hence, part of the variation within this animal model may derive from variation in the GM. The aims of this study was to investigate first, the duration of subPCP-induced cognitive impairment in the novel object recognition test, and second, the possible effect of subchronic PCP-treatment on the GM, and the association between the GM and the behavioral parameters. The association was further investigated by antibiotic reduction of the GM. Male Lister Hooded rats were dosed twice daily i.p. with either 5 mg/kg PCP or sterile isotonic saline for seven days followed by a seven-day washout period. Rats were tested in the novel object recognition and the locomotor activity assays immediately after, three weeks after, or six weeks after washout, and the fecal GM was analyzed by high throughput sequencing. Antibiotic- and control-treated rats were tested in the same manner following washout. In conclusion, subPCP-treatment impaired novel object recognition up to three weeks after washout, whereas locomotor sensitivity was increased for at least six weeks after washout. Differences in the core gut microbiome immediately after washout suggested subPCP treatment to alter the GM. GM profiles correlated to memory performance. Administration of ampicillin abolished the subPCP-induced memory deficit. It thus seems reasonable to speculate that the GM influences memory performance, contributing to variation within the model.
Our knowledge of the O-glycoproteome N-acetylgalactosamine (GalNAc) type is highly limited. The O-glycoproteome is differentially regulated in cells by dynamic expression of a subset of 20 ...polypeptide GalNAc-transferases (GalNAc-Ts), and methods to identify important functions of individual GalNAc-Ts are largely unavailable. We recently introduced SimpleCells, i.e., human cell lines made deficient in O-glycan extension by zinc finger nuclease targeting of a key gene in O-glycan elongation (Cosmc), which allows for proteome-wide discovery of O-glycoproteins. Here we have extended the SimpleCell concept to include proteome-wide discovery of unique functions of individual GalNAc-Ts. We used the GalNAc-T2 isoform implicated in dyslipidemia and the human HepG2 liver cell line to demonstrate unique functions of this isoform. We confirm that GalNAc-T2–directed site-specific O-glycosylation inhibits proprotein activation of the lipase inhibitor ANGPTL3 in HepG2 cells and further identify eight O-glycoproteins exclusively glycosylated by T2 of which one, ApoC-III, is implicated in dyslipidemia. Our study supports an essential role for GalNAc-T2 in lipid metabolism, provides serum biomarkers for GalNAc-T2 enzyme function, and validates the use of GALNT gene targeting with SimpleCells for broad discovery of disease-causing deficiencies in O-glycosylation. The presented glycoengineering strategy opens the way for proteome-wide discovery of functions of GalNAc-T isoforms and their role in congenital diseases and disorders.
Quinones represent an important group of highly structurally diverse, mainly polyketide-derived secondary metabolites widely distributed among filamentous fungi. Many quinones have been reported to ...have important biological functions such as inhibition of bacteria or repression of the immune response in insects. Other quinones, such as ubiquinones are known to be essential molecules in cellular respiration, and many quinones are known to protect their producing organisms from exposure to sunlight. Most recently, quinones have also attracted a lot of industrial interest since their electron-donating and -accepting properties make them good candidates as electrolytes in redox flow batteries, like their often highly conjugated double bond systems make them attractive as pigments. On an industrial level, quinones are mainly synthesized from raw components in coal tar. However, the possibility of producing quinones by fungal cultivation has great prospects since fungi can often be grown in industrially scaled bioreactors, producing valuable metabolites on cheap substrates. In order to give a better overview of the secondary metabolite quinones produced by and shared between various fungi, mainly belonging to the genera
Aspergillus
,
Penicillium
,
Talaromyces
,
Fusarium
, and
Arthrinium
, this review categorizes quinones into families such as emodins, fumigatins, sorbicillinoids, yanuthones, and xanthomegnins, depending on structural similarities and information about the biosynthetic pathway from which they are derived, whenever applicable. The production of these quinone families is compared between the different genera, based on recently revised taxonomy.
Key points
•
Quinones represent an important group of secondary metabolites widely distributed in important fungal genera such as Aspergillus, Penicillium, Talaromyces, Fusarium, and Arthrinium.
•
Quinones are of industrial interest and can be used in pharmacology, as colorants and pigments, and as electrolytes in redox flow batteries.
•
Quinones are grouped into families and compared between genera according to the revised taxonomy.
Objective
To investigate the impact of prenatal antidepressant exposure on behavioural problems in children at 7 years of age.
Design
Nationwide population‐based study.
Setting
Danish National Birth ...Cohort.
Population
A cohort of 49 178 pregnant women recruited between 1996 and 2002.
Methods
Data obtained from computer‐assisted telephone interviews twice during pregnancy were used to identify children born to: (i) depressed women who took antidepressants during pregnancy (n = 210); (ii) depressed women who did not take any antidepressants during pregnancy (n = 231); and (iii) healthy women who were not depressed (n = 48 737). Childhood behavioural problems at 7 years of age were examined using the validated Danish parent‐report version of the Strengths and Difficulties Questionnaire (SDQ).
Main outcome measures
SDQ scores.
Results
No associations were observed between prenatal antidepressant exposure and abnormal SDQ scores for overall problem behaviour (adjusted relative risk, aRR 1.00; 95% confidence interval, 95% CI 0.49–2.05), hyperactivity/inattention (aRR 0.99; 95% CI 0.56–1.75), or peer problems (aRR 1.04; 95% CI 0.57–1.91). Although prenatal antidepressant exposure appeared to be associated with abnormal SDQ scores on the subscales of emotional symptoms (aRR 1.68; 95% CI 1.18–2.38) and conduct problems (aRR 1.58; 95% CI 1.03–2.42), these associations were significantly attenuated following adjustment for antenatal mood status (aRR 1.20; 95% CI 0.85–1.70 and aRR 1.19; 95% CI 0.77 1.83, respectively). Untreated prenatal depression was associated with an increased risk of all behavioural outcomes evaluated, compared with unexposed children, with significant attenuation following adjustment for antenatal mood status.
Conclusions
The results of this study suggest that independent of maternal illness, prenatal antidepressant exposure is not associated with an increased risk of behavioural problems in children at 7 years of age.
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Prenatal antidepressant exposure is not associated with an increased risk of child behavioural problems.
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Prenatal antidepressant exposure is not associated with an increased risk of child behavioural problems.
Paclitaxel is mainly eliminated by CYP2C8 in the liver. CYP2C8 is strongly inhibited by the clopidogrel metabolite acyl‐β‐D‐glucuronide. To determine if this interaction has clinical relevance, we ...identified 48 patients treated with clopidogrel and paclitaxel using databases and a prescription register. Peripheral sensory neuropathy was retrospectively evaluated from medical charts and compared to that of 88 age‐ and sex‐matched controls treated with paclitaxel and low‐dose aspirin. By a cumulative dose of 1,500 mg paclitaxel, 35% of the patients had developed severe neuropathy. The overall hazard ratio between clopidogrel use and severe paclitaxel neuropathy was 1.7 (95% confidence interval, 0.9–3.0). Among those receiving a high‐dose paclitaxel regimen, the hazard ratio was 2.3 (95% confidence interval, 1.1–4.5). Our study indicates that clopidogrel is associated with a clinically relevant increased risk of neuropathy in patients treated with high‐dose paclitaxel.
Kabuth, A.K.; Kroon, A., and Pedersen, J.B.T., 2014. Multidecadal shoreline changes in Denmark. Multidecadal shoreline changes along ca. 7000 km coastline around Denmark were computed for the time ...interval between 1862 AD and 2005 AD and were connected with a geomorphological coastal classification. The shoreline data set was based on shoreline positions from historical and modern topographic maps. Coastal landforms were identified on a digital terrain model in combination with aerial photographs. Two shoreline-change computation methods were evaluated at a test site, aiming for optimized time efficiency and accuracy of the countrywide application: a Nearest Neighbor search and a cross-shore transect method based on the ArcGIS-based Digital Shoreline Analysis System (DSAS). The cross-shore transect method was more robust and performed better in the detection of local extremes in shoreline changes, which was crucial for the scope of the mapping. Countrywide shoreline-change distances and rates were, therefore, computed with the DSAS method. Patterns in coastline dynamics were identified through the connection of shoreline-change rates with the occurrence of coastal landforms. Short-term changes and alterations of shoreline evolution through coastal structures were not resolved in this study. Because of the long time span covered, the relative errors originating from data and method are acceptable. The scope of the mapping was to provide a coastal management tool that allows screening for critical sites with respect to coastal erosion. As the first countrywide quantification of historical shoreline changes around Denmark, the mapping can contribute to enhanced adaptation and mitigation strategies in response to increased risks of erosion and flooding under a changing climate.
Celotno besedilo
Dostopno za:
BFBNIB, DOBA, IZUM, KILJ, NMLJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
Oxytocin has been proposed to possess glucose-stabilizing effects through the release of insulin and glucagon from the pancreas. Also, exogenous oxytocin has been shown to stimulate extrapancreatic ...glucagon secretion in depancreatized dogs. Here, we investigated the effect of exogenous oxytocin on circulating levels of pancreatic and gut-derived glucose-stabilizing hormones (insulin measured as C-peptide, glucagon, glucagon-like peptide 1 GLP-1, and glucose-dependent insulinotropic polypeptide). We studied nine pancreatectomized (PX) patients and nine healthy controls (CTRLs) (matched on age and body mass index) before, during, and after an intravenous infusion of 10 IU of oxytocin administered over 12 min. Oxytocin did not increase plasma glucagon levels, nor induce any changes in plasma glucose, C-peptide, or GIP in any of the groups. Oxytocin decreased plasma glucagon levels by 19 ± 10 % in CTRLs (from 2.0 ± 0.5 mean ± SEM to 1.3 ± 0.2 pmol/l, P = 0.0025) and increased GLP-1 by 42 ± 22 % in PX patients (from 9.0 ± 1.0–12.7 ± 1.0 pmol/l, P = 0.0003). Fasting plasma glucose levels were higher in PX patients compared with CTRLs (13.1 ± 1.1 vs. 5.1 ± 0.1 mmol/l, P < 0.0001). In conclusion, the present findings do not support pancreas-mediated glucose-stabilizing effects of acute oxytocin administration in humans and warrant further investigation of oxytocin’s gluco-metabolic effects.
•The effect of oxytocin on gluco-regulatory hormones in humans is scarcely described.•Oxytocin stimulates extra-pancreatic glucagon secretion in depancreatized dogs.•Here, oxytocin was neither glucagonotropic nor insulinotropic in healthy individuals.•In pancreatectomized patients, oxytocin increased levels of glucagon-like peptide 1.
BACKGROUND Adverse pregnancy outcomes have been associated with maternal celiac disease (CD). In this study, we investigate the effect of treated and untreated maternal CD on infant birthweight and ...preterm birth. METHODS A population-based cohort study consisted of all singleton live births in Denmark between 1 January 1979 and 31 December 2004 was used. A total of 1 504 342 babies were born to 836 241 mothers during the study period. Of those, 1105 babies were born to women with diagnosed CD and 346 were born to women with undiagnosed CD. Women with diagnosed CD were considered as treated with a gluten free diet while women with undiagnosed CD were considered as untreated. The outcome measures were: birthweight, small for gestational age (SGA: birthweight <10th centile), very small for gestational age (VSGA: birthweight <5th centile) and preterm birth. We compared these measures in treated and untreated women with those of a reference group (no history of CD). RESULTS Women with untreated CD delivered smaller babies difference = −98 g (95% CI: −130, −67), with a higher risk of SGA infants OR = 1.31 (95% CI: 1.06, 1.63), VSGA infants OR = 1.54 (95% CI: 1.17, 2.03) and preterm birth OR = 1.33 (95% CI: 1.02, 1.72) compared with women without CD. Women with treated CD had no increased risk of reduced mean birthweight, risk of delivering SGA and VSGA infants or preterm birth compared with women without CD. CONCLUSION Untreated maternal CD increases the risk of reduced birthweight, the risk of delivering SGA and VSGA infants and preterm birth. Diagnosis and presumed treatment of maternal CD with a gluten-free diet appeared to result in a birthweight and preterm birth rate similar to those in women without CD.
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