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PubMed | Musculoskeletal Rehabilitation Research Group, Center for Molecular and Vascular Biology, University College Ghent, Cliniques Universitaires Saint Luc and 2 more.
Type: | Journal: Gait & posture | Year: 2016

The relationship between age and 3D rotations objectivized with multisegment foot models has not been quantified until now. The purpose of this study was therefore to investigate the relationship between age and multi-segment foot kinematics in a cross-sectional database.Barefoot multi-segment foot kinematics of thirty two typically developing boys, aged 6-20 years, were captured with the Rizzoli Multi-segment Foot Model. One-dimensional statistical parametric mapping linear regression was used to examine the relationship between age and 3D inter-segment rotations of the dominant leg during the full gait cycle.Age was significantly correlated with sagittal plane kinematics of the midfoot and the calcaneus-metatarsus inter-segment angle (p<0.0125). Age was also correlated with the transverse plane kinematics of the calcaneus-metatarsus angle (p<0.0001).Gait labs should consider age related differences and variability if optimal decision making is pursued. It remains unclear if this is of interest for all foot models, however, the current study highlights that this is of particular relevance for foot models which incorporate a separate midfoot segment.

Schoors S.,Catholic University of Leuven | Schoors S.,Vesalius Research Center | Bruning U.,Catholic University of Leuven | Bruning U.,Vesalius Research Center | And 41 more authors.
Nature | Year: 2015

The metabolism of endothelial cells during vessel sprouting remains poorly studied. Here we report that endothelial loss of CPT1A, a rate-limiting enzyme of fatty acid oxidation (FAO), causes vascular sprouting defects due to impaired proliferation, not migration, of human and murine endothelial cells. Reduction of FAO in endothelial cells did not cause energy depletion or disturb redox homeostasis, but impaired de novo nucleotide synthesis for DNA replication. Isotope labelling studies in control endothelial cells showed that fatty acid carbons substantially replenished the Krebs cycle, and were incorporated into aspartate (a nucleotide precursor), uridine monophosphate (a precursor of pyrimidine nucleoside triphosphates) and DNA. CPT1A silencing reduced these processes and depleted endothelial cell stores of aspartate and deoxyribonucleoside triphosphates. Acetate (metabolized to acetyl-CoA, thereby substituting for the depleted FAO-derived acetyl-CoA) or a nucleoside mix rescued the phenotype of CPT1A-silenced endothelial cells. Finally, CPT1 blockade inhibited pathological ocular angiogenesis in mice, suggesting a novel strategy for blocking angiogenesis. ©2015 Macmillan Publishers Limited. All rights reserved.

PubMed | University Hospital Leuven, Institute of Tropical Medicine, Institute Of Recherche En Science Of La Sante Irss Clinical Research Unit Of Nanoro Crun and Center for Molecular and Vascular Biology
Type: | Journal: Malaria journal | Year: 2016

Plasmodium falciparum infection may cause severe anaemia, particularly in children. When planning a diagnostic study on children suspected of severe malaria in sub-Saharan Africa, it was questioned how much blood could be safely sampled; intended blood volumes (blood cultures and EDTA blood) were 6mL (children aged <6years) and 10mL (6-12years). A previous review [Bull World Health Organ. 89: 46-53. 2011] recommended not to exceed 3.8% of total blood volume (TBV). In a simulation exercise using data of children previously enrolled in a study about severe malaria and bacteraemia in Burkina Faso, the impact of this 3.8% safety guideline was evaluated.For a total of 666 children aged >2months to <12years, data of age, weight and haemoglobin value (Hb) were available. For each child, the estimated TBV (TBVe) (mL) was calculated by multiplying the body weight (kg) by the factor 80 (ml/kg). Next, TBVe was corrected for the degree of anaemia to obtain the functional TBV (TBVf). The correction factor consisted of the rate Hb of the child divided by the reference Hb; both the lowest (best case) and highest (worst case) reference Hb values were used. Next, the exact volume that a 3.8% proportion of this TBVf would present was calculated and this volume was compared to the blood volumes that were intended to be sampled.When applied to the Burkina Faso cohort, the simulation exercise pointed out that in 5.3% (best case) and 11.4% (worst case) of children the blood volume intended to be sampled would exceed the volume as defined by the 3.8% safety guideline. Highest proportions would be in the age groups 2-6months (19.0%; worst scenario) and 6months-2years (15.7%; worst case scenario). A positive rapid diagnostic test for P. falciparum was associated with an increased risk of violating the safety guideline in the worst case scenario (p = 0.016).Blood sampling in children for research in P. falciparum endemic settings may easily violate the proposed safety guideline when applied to TBVf. Ethical committees and researchers should be wary of this and take appropriate precautions.

PubMed | University of Perugia and Center for Molecular and Vascular Biology
Type: | Journal: Blood | Year: 2016

Platelets contain and release several matrix metalloproteinases (MMPs). Among these, active MMP-2 enhances platelet aggregation by favouring the activation of phosphatidyl-inositol-3- kinase (PI3-K) and contributes to arterial thrombosis. The platelet surface target of MMP-2 and the mechanism through which it primes platelets to respond to subsequent stimuli are still unknown. We show that active MMP-2 enhances platelet activation induced by weak stimuli by cleaving PAR1 at a non-canonical extracellular site different from the thrombin-cleavage site, and thus starts biased receptor signaling triggering only some of the signaling pathways normally activated by full PAR1 agonism. The novel PAR1 tethered ligand exposed by MMP-2 stimulates PAR1-dependent G

PubMed | Catholic University of Leuven, Stem Cell Institute and and Center for Molecular and Vascular Biology
Type: Journal Article | Journal: Blood | Year: 2016

Genetic variation in the PEAR1 locus is linked to platelet reactivity and cardiovascular disease. The major G allele of rs12041331, an intronic cytosine guanine dinucleotide-single-nucleotide polymorphism (CpG-SNP), is associated with higher PEAR1 expression in platelets and endothelial cells than the minor A allele. The molecular mechanism underlying this difference remains elusive. We have characterized the histone modification profiles of the intronic region surrounding rs12041331 and identified H3K4Me1 enhancer-specific enrichment for the region that covers the CpG-SNP. Interestingly, methylation studies revealed that the CpG site is fully methylated in leukocytes of GG carriers. Nuclear protein extracts from megakaryocytes, endothelial cells, vs control HEK-293 cells show a 3-fold higher affinity for the methylated G allele compared with nonmethylated G or A alleles in a gel electrophoretic mobility shift assay. To understand the positive relationship between methylation and gene expression, we studied DNA methylation at 4 different loci of PEAR1 during in vitro megakaryopoiesis. During differentiation, the CpG-SNP remained fully methylated, while we observed rapid methylation increases at the CpG-island overlapping the first 5-untranslated region exon, paralleling the increased PEAR1 expression. In the same region, A-allele carriers of rs12041331 showed significantly lower DNA methylation at CGI1 compared with GG homozygote. This CpG-island contains binding sites for the methylation-sensitive transcription factor CTCF, whose binding is known to play a role in enhancer activation and/or repression. In conclusion, we report the molecular characterization of the first platelet function-related CpG-SNP, a genetic predisposition that reinforces PEAR1 enhancer activity through allele-specific DNA methylation.

Singh N.,Center for Molecular and Vascular Biology | Heggermont W.,Center for Molecular and Vascular Biology | Heggermont W.,Catholic University of Leuven | Fieuws S.,Hasselt University | And 3 more authors.
Journal of Heart and Lung Transplantation | Year: 2015

Background Cardiac allograft vasculopathy (CAV) is a limiting factor for the long-term survival of heart transplant recipients. Clinical decisions and care may be improved by the development of prediction models based on circulating biomarkers. The endothelium may play a central pathogenetic role in the development of CAV. We evaluated the hypothesis that endothelium-enriched microRNAs (miRNAs) discriminate between patients with and without CAV. Methods This cross-sectional study recruited 52 patients undergoing coronary angiography between 5 and 15 years after heart transplantation. Circulating levels of endothelium-enriched miRNAs (miR-21-5p, miR-92a-3p, miR-92a-1-5p, miR-126-3p, and miR-126-5p) were quantified by real-time reverse transcription polymerase chain reaction. The discriminative ability of logistic regression models was evaluated using the concordance (C) statistic. Results Median plasma levels of miR-210-5p, miR-92a-3p, miR-126-3p, and miR-126-5p were 1.82-fold (p = not significant), 1.87-fold (p < 0.05), 1.94-fold (p = 0.074), and 1.59-fold (p = 0.060) higher in patients with CAV than in patients without CAV. Recipient age (C statistic = 0.689; 95% confidence interval [CI], 0.537-0.842), and levels of serum creatinine (C statistic = 0.703; 95% CI, 0.552-0.854), miR-92a-3p (C statistic = 0.682; 95% CI, 0.533-0.831), and miR-126-5p (C statistic = 0.655; 95% CI, 0.502-0.807) predicted CAV status in univariable models. In multivariable logistic regression models with recipient age and creatinine as covariates, miR-126-5p (chi-square = 4.371, p = 0.037), miR-92a-3p (chi-square = 6.011, p = 0.014), and the combination of miR-126-5p and miR-92a-3p (chi-square = 8.162, p = 0.017) added significant information. The model with age, creatinine, miR-126-5p, and miR-92a-3p as covariables conferred good discrimination between patients without and with CAV (C statistic = 0.800; 95% CI, 0.674-0.926). Conclusions Endothelium-enriched miRNAs have diagnostic ability for CAV beyond clinical predictors. © 2015 International Society for Heart and Lung Transplantation.

Scroyen I.,Center for Molecular and Vascular Biology | Frederix L.,Center for Molecular and Vascular Biology | Lijnen H.R.,Center for Molecular and Vascular Biology
Obesity | Year: 2012

To evaluate a potential role of Axl, the high-affinity receptor of growth arrest-specific protein 6 (GAS6) in adiposity, murine embryonic fibroblasts (MEF) derived from mice with genetic deficiency of Axl (Axl -/-) or wild-type littermates (Axl ++) were differentiated into mature adipocytes. In addition, Axl/and Axl -/- mice were kept on standard fat diet (SFD) or on high-fat diet (HFD) for 15 weeks. Deficiency of Axl in MEF did not affect differentiation, as shown by a similar uptake of Oil Red O and expression of the adipogenic markers aP2 and peroxisome proliferator activator receptor γ (PPARγ) at the end of the differentiation. In the first 7 weeks of HFD feeding, Axl -/- mice gained less weight than their wild-type littermates. Weight gain for both genotypes on either SFD of HFD over 15 weeks was, however, not significantly different, resulting in comparable body weights, as well as subcutaneous (s.c.) and gonadal (GON) fat mass. Adipocyte size in the fat tissues was not affected by Axl deficiency. Gene expression analysis indicated that the absence of Axl in vivo may be compensated for by the other TAM family members Mer and Tyro3. Glucose and insulin tolerance tests (ITT) in Axl -/- and Axl ++ mice did not reveal significant differences in glucose homeostasis. Thus, Axl deficiency had no significant effect on adipogenesis in vitro or in vivo. © 2011 The Obesity Society.

Izzi B.,Center for Molecular and Vascular Biology | van Geet C.,Center for Molecular and Vascular Biology | van Geet C.,Catholic University of Leuven | Freson K.,Center for Molecular and Vascular Biology
Current Molecular Medicine | Year: 2012

Endocrinopathies in patients with hypocalcemia and hyperphosphatemia that share resistance to parathyroid hormone (PTH) are grouped under the term pseudohypoparathyroidism (PHP). Patients with PHP type Ia (PHP-Ia) often present with additional hormonal resistance and show characteristic physical features that are jointly termed as having an Albright's hereditary osteodystrophy (AHO) phenotype. Alternatively, PHPIb patients predominantly have PTH and sometimes TSH resistance but do not present with AHO features. Most of these PHP forms are caused by defects in GNAS, an imprinted gene locus consisting of maternal, paternal and biallelic transcripts. PHP-Ia is caused by heterozygous inactivating mutations in those exons of GNAS encoding the alpha subunit of the stimulatory guanine nucleotide-binding protein (Gsalpha) while PHPIb results from epigenetic GNAS defects. Familial and sporadic forms of PHP-Ib have distinct GNAS imprinting patterns: familial PHP-Ib patients have an exon A/B-only imprinting defect whereas sporadic PHP-Ib cases have abnormal imprinting of the three differentially methylated regions (DMRs) in GNAS. This classification of PHP was made years ago but was recently questioned since different studies showed GNAS epigenetic defects in PHP-Ia patients. In this review, we focus on the epigenetic description and screening methods of GNAS, the associated pathology and the recent need for a PHP reclassification. © 2012 Bentham Science Publishers.

Di Michele M.,Center for Molecular and Vascular Biology | Van Geet C.,Center for Molecular and Vascular Biology | Van Geet C.,Catholic University of Leuven | Freson K.,Center for Molecular and Vascular Biology
Expert Review of Proteomics | Year: 2012

Platelets are the fundamental players in primary hemostasis, but are also involved in several pathological conditions. The remarkable advances in proteomic methodologies have allowed a better understanding of the basic physiological pathways underlying platelet biology. In addition, recent platelet proteomics focused on disease conditions, helping to elucidate the molecular mechanisms of complex and/or unknown human disorders and to find novel biomarkers for early diagnosis and drug targets. The most common and innovative proteomic techniques, both gel-based and gel-free, used in platelet proteomics will be reviewed here. A particular focus will be given to studies that used a subproteomic strategy to analyze specific platelet conditions (resting or activated), compartments (membrane, granules and microparticles) or fractions (phosphoproteome or glycoproteome). The thousands of platelet proteins and interactions discovered so far by these different powerful proteomic approaches represent a precious source of information for both basic science and clinical applications in the field of platelet biology. © 2012 Expert Reviews Ltd.

Di Michel M.,Center for Molecular and Vascular Biology | Van Geet C.,Center for Molecular and Vascular Biology | Van Geet C.,Catholic University of Leuven | Freson K.,Center for Molecular and Vascular Biology
Current Medicinal Chemistry | Year: 2012

Blood platelets play a fundamental role in primary haemostasis and wound repair, but are also involved in several thrombotic and bleeding disorders for which the underlying mechanisms are still largely unknown. Elucidating platelet biology would help in finding novel disease biomarkers and drug targets in complex and/or genetically unknown platelet-related disorders. Proteomics, which allows studying thousands of gene products at once, represents an efficient tool to quali-quantitatively analyze and compare the platelet protein patterns of different samples (i.e. control/patient, treated/untreated, drug sensitive/resistant), to investigate post-translation modifications, protein-protein interactions and the underlying molecular pathways. This review gives an overview of the applications of proteomic strategies to study platelet biology and function, as well as to unravel differences in protein expression according to specific platelet conditions (i.e. basic versus activated), compartments (i.e. membrane or granules) and fractions (i.e. phosphoproteins and glycoproteins). The use of innovative powerful proteomic technologies can lead to the identification of proteins whose expression is altered in pathological conditions, allowing the identification of candidate biomarkers for: i) understanding the molecular defects underlying platelet disorders, ii) obtaining novel insights in more complex diseases that involve platelets, iii) unraveling the drug mode of action or identifying the mechanisms of drug resistance and iv) detecting novel therapeutic antiplatelet targets based on fundamental platelet research studies. Several studies on how proteomics proved to be useful in our understanding of platelet function and its diseases are discussed. Eventually, this could result in the discovery of novel drug targets for antiplatelet therapy. © 2012 Bentham Science Publishers.

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