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Book ; Online ; Thesis: Interaktion der Ihh-Pthlh-, BMP- und FGF-Signalwege in der Regulierung der Chondrozytenproliferation und Differenzierung

Minina, Eleonora

2002

Author's details	vorgelegt von Eleonora Minina
Keywords	Knorpelzelle ; Genregulation ; Zelldifferenzierung ; Wirbeltiere ; Signaltransduktion
Language	English
Size	Online-Ressource
Document type	Book ; Online ; Thesis
Thesis / German Habilitation thesis	Freie Univ., Diss--Berlin, 2002
Note	Dateiformat: zip, Dateien im PDF-Format ; Text engl
Database	Former special subject collection: coastal and deep sea fishing

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Book ; Online ; Thesis: Interaktion der Ihh-Pthlh-, BMP- und FGF-Signalwege in der Regulierung der Chondrozytenproliferation und Differenzierung

Minina, Eleonora [Verfasser]

2002

Author's details	vorgelegt von Eleonora Minina
Keywords	Pflanzen (Botanik) ; Plants (Botany)
Subject code	sg580
Language	English
Document type	Book ; Online ; Thesis
Database	Digital theses on the web

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Article: Expression of Fgf and Tgfbeta signaling related genes during embryonic endochondral ossification.

Minina, Eleonora / Schneider, Sabine / Rosowski, Mark / Lauster, Roland / Vortkamp, Andrea

Gene expression patterns : GEP

2005 Volume 6, Issue 1, Page(s) 102–109

Abstract: Disturbed fibroblast growth factor (Fgf) and transforming growth factor beta (Tgfbeta) signaling lead to a variety of human skeletal disorders. To reveal the possible function and interaction of these signaling systems we have started to analyze the ... ...

Abstract	Disturbed fibroblast growth factor (Fgf) and transforming growth factor beta (Tgfbeta) signaling lead to a variety of human skeletal disorders. To reveal the possible function and interaction of these signaling systems we have started to analyze the expression patterns of signaling factors, antagonists, receptors and transducers of these pathways in forelimbs of mouse embryos and compared them to the expression of established markers including Ihh. In addition to defining their expression domains in the developing bone, our study identified new subpopulations of chondrocytes characterized by the expression of distinct combinations of markers.
MeSH term(s)	Animals ; Bone Morphogenetic Protein Receptors/analysis ; Bone Morphogenetic Protein Receptors/genetics ; Bone Morphogenetic Proteins/analysis ; Bone Morphogenetic Proteins/genetics ; Chondrocytes/chemistry ; Chondrocytes/metabolism ; Embryo, Mammalian/chemistry ; Embryo, Mammalian/metabolism ; Fibroblast Growth Factors/analysis ; Fibroblast Growth Factors/genetics ; Fibroblast Growth Factors/metabolism ; Forelimb/chemistry ; Forelimb/embryology ; Forelimb/metabolism ; Gene Expression Regulation, Developmental ; Inhibins/analysis ; Inhibins/genetics ; Mice ; Osteoblasts/chemistry ; Osteoblasts/metabolism ; Osteogenesis/genetics ; Receptors, Fibroblast Growth Factor/analysis ; Receptors, Fibroblast Growth Factor/genetics ; Receptors, Transforming Growth Factor beta/analysis ; Receptors, Transforming Growth Factor beta/genetics ; Signal Transduction/genetics ; Transforming Growth Factor beta/analysis ; Transforming Growth Factor beta/genetics ; Transforming Growth Factor beta/metabolism
Chemical Substances	Bone Morphogenetic Proteins ; Receptors, Fibroblast Growth Factor ; Receptors, Transforming Growth Factor beta ; Transforming Growth Factor beta ; Inhibins (57285-09-3) ; Fibroblast Growth Factors (62031-54-3) ; Bone Morphogenetic Protein Receptors (EC 2.7.11.30)
Language	English
Publishing date	2005-12
Publishing country	Netherlands
Document type	Journal Article
ZDB-ID	2058346-1
ISSN	1872-7298 ; 1567-133X
ISSN (online)	1872-7298
ISSN	1567-133X
DOI	10.1016/j.modgep.2005.04.012
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Article: Characterization of FBX25, encoding a novel brain-expressed F-box protein.

Hagens, Olivier / Minina, Eleonora / Schweiger, Susann / Ropers, Hans-Hilger / Kalscheuer, Vera

Biochimica et biophysica acta

2006 Volume 1760, Issue 1, Page(s) 110–118

Abstract: F-box proteins (FBPs) confer substrate specificity to the SCF-type (Skp1/Cul1/FBP) of ubiquitin ligase complexes through their F-box. Multiple FBPs have been predicted, but experimental evidence is lagging. We report on the predicted human FBP hFBX25 ... ...

Abstract	F-box proteins (FBPs) confer substrate specificity to the SCF-type (Skp1/Cul1/FBP) of ubiquitin ligase complexes through their F-box. Multiple FBPs have been predicted, but experimental evidence is lagging. We report on the predicted human FBP hFBX25 which we found to be disrupted in a mentally retarded translocation carrier suffering from epileptic seizures. We investigated hFBX25's genomic organization and established hFBX25 as an FBP by verifying its interaction with Skp1 and Cul1. In the process, we identified an atypical serine residue in the F-box which is crucial for the hFBX25-Skp1 binding. We determined hFBX25's subcellular localization. We found strong transcription in human brain. In mouse embryonic sections, mFbx25 shows predominantly neuronal expression and in adult mouse brain, expression is confined to the hippocampus, the cerebral cortex and the Purkinje cell layer. Interestingly, aberrations in the ubiquitin pathway have been linked to neurological conditions.
MeSH term(s)	Amino Acid Sequence ; Animals ; Binding Sites ; Brain/cytology ; Brain/metabolism ; Brain Chemistry ; Cell Cycle Proteins/metabolism ; Cullin Proteins/metabolism ; F-Box Proteins/analysis ; F-Box Proteins/genetics ; F-Box Proteins/metabolism ; Gene Components ; Humans ; Mice ; Nerve Tissue Proteins/analysis ; Nerve Tissue Proteins/genetics ; Nerve Tissue Proteins/metabolism ; S-Phase Kinase-Associated Proteins/metabolism ; Serine ; Substrate Specificity ; Tissue Distribution ; Transcription, Genetic
Chemical Substances	Cell Cycle Proteins ; Cullin 1 ; Cullin Proteins ; F-Box Proteins ; FBXO25 protein, human ; Nerve Tissue Proteins ; S-Phase Kinase-Associated Proteins ; Serine (452VLY9402)
Language	English
Publishing date	2006-01
Publishing country	Netherlands
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	60-7
ISSN	1879-2596 ; 1879-260X ; 1872-8006 ; 1879-2642 ; 1879-2618 ; 1879-2650 ; 0006-3002 ; 0005-2728 ; 0005-2736 ; 0304-4165 ; 0167-4838 ; 1388-1981 ; 0167-4889 ; 0167-4781 ; 0304-419X ; 1570-9639 ; 0925-4439 ; 1874-9399
ISSN (online)	1879-2596 ; 1879-260X ; 1872-8006 ; 1879-2642 ; 1879-2618 ; 1879-2650
ISSN	0006-3002 ; 0005-2728 ; 0005-2736 ; 0304-4165 ; 0167-4838 ; 1388-1981 ; 0167-4889 ; 0167-4781 ; 0304-419X ; 1570-9639 ; 0925-4439 ; 1874-9399
DOI	10.1016/j.bbagen.2005.09.018
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Article ; Online: Dickkopf 3 Promotes the Differentiation of a Rostrolateral Midbrain Dopaminergic Neuronal Subset In Vivo and from Pluripotent Stem Cells In Vitro in the Mouse.

Fukusumi, Yoshiyasu / Meier, Florian / Götz, Sebastian / Matheus, Friederike / Irmler, Martin / Beckervordersandforth, Ruth / Faus-Kessler, Theresa / Minina, Eleonora / Rauser, Benedict / Zhang, Jingzhong / Arenas, Ernest / Andersson, Elisabet / Niehrs, Christof / Beckers, Johannes / Simeone, Antonio / Wurst, Wolfgang / Prakash, Nilima

The Journal of neuroscience : the official journal of the Society for Neuroscience

2015 Volume 35, Issue 39, Page(s) 13385–13401

Abstract: Wingless-related MMTV integration site 1 (WNT1)/β-catenin signaling plays a crucial role in the generation of mesodiencephalic dopaminergic (mdDA) neurons, including the substantia nigra pars compacta (SNc) subpopulation that preferentially degenerates ... ...

Abstract	Wingless-related MMTV integration site 1 (WNT1)/β-catenin signaling plays a crucial role in the generation of mesodiencephalic dopaminergic (mdDA) neurons, including the substantia nigra pars compacta (SNc) subpopulation that preferentially degenerates in Parkinson's disease (PD). However, the precise functions of WNT1/β-catenin signaling in this context remain unknown. Stem cell-based regenerative (transplantation) therapies for PD have not been implemented widely in the clinical context, among other reasons because of the heterogeneity and incomplete differentiation of the transplanted cells. This might result in tumor formation and poor integration of the transplanted cells into the dopaminergic circuitry of the brain. Dickkopf 3 (DKK3) is a secreted glycoprotein implicated in the modulation of WNT/β-catenin signaling. Using mutant mice, primary ventral midbrain cells, and pluripotent stem cells, we show that DKK3 is necessary and sufficient for the correct differentiation of a rostrolateral mdDA neuron subset. Dkk3 transcription in the murine ventral midbrain coincides with the onset of mdDA neurogenesis and is required for the activation and/or maintenance of LMX1A (LIM homeobox transcription factor 1α) and PITX3 (paired-like homeodomain transcription factor 3) expression in the corresponding mdDA precursor subset, without affecting the proliferation or specification of their progenitors. Notably, the treatment of differentiating pluripotent stem cells with recombinant DKK3 and WNT1 proteins also increases the proportion of mdDA neurons with molecular SNc DA cell characteristics in these cultures. The specific effects of DKK3 on the differentiation of rostrolateral mdDA neurons in the murine ventral midbrain, together with its known prosurvival and anti-tumorigenic properties, make it a good candidate for the improvement of regenerative and neuroprotective strategies in the treatment of PD. Significance statement: We show here that Dickkopf 3 (DKK3), a secreted modulator of WNT (Wingless-related MMTV integration site)/β-catenin signaling, is both necessary and sufficient for the proper differentiation and survival of a rostrolateral (parabrachial pigmented nucleus and dorsomedial substantia nigra pars compacta) mesodiencephalic dopaminergic neuron subset, using Dkk3 mutant mice and murine primary ventral midbrain and pluripotent stem cells. The progressive loss of these dopamine-producing mesodiencephalic neurons is a hallmark of human Parkinson's disease, which can up to now not be halted by clinical treatments of this disease. Thus, the soluble DKK3 protein might be a promising new agent for the improvement of current protocols for the directed differentiation of pluripotent and multipotent stem cells into mesodiencephalic dopaminergic neurons and for the promotion of their survival in situ.
MeSH term(s)	Animals ; Cell Count ; Cell Differentiation/genetics ; Cell Differentiation/physiology ; Cell Survival/genetics ; Cells, Cultured ; Deoxyuridine/analogs & derivatives ; Deoxyuridine/pharmacology ; Intercellular Signaling Peptides and Proteins/genetics ; Intercellular Signaling Peptides and Proteins/physiology ; Mesencephalon/cytology ; Mesencephalon/physiology ; Mice ; Mice, Inbred C57BL ; Mice, Knockout ; Neural Stem Cells/physiology ; Pluripotent Stem Cells/physiology ; Transcriptome ; Wnt1 Protein/genetics ; Wnt1 Protein/physiology
Chemical Substances	Dkk3 protein, mouse ; Intercellular Signaling Peptides and Proteins ; Wnt1 Protein ; Wnt1 protein, mouse ; 5-ethynyl-2'-deoxyuridine (G373S00W2J) ; Deoxyuridine (W78I7AY22C)
Language	English
Publishing date	2015-09-29
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	604637-x
ISSN	1529-2401 ; 0270-6474
ISSN (online)	1529-2401
ISSN	0270-6474
DOI	10.1523/JNEUROSCI.1722-15.2015
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Article: Interaction of FGF, Ihh/Pthlh, and BMP signaling integrates chondrocyte proliferation and hypertrophic differentiation.

Minina, Eleonora / Kreschel, Conny / Naski, Michael C / Ornitz, David M / Vortkamp, Andrea

Developmental cell

2002 Volume 3, Issue 3, Page(s) 439–449

Abstract: Mutations in fibroblast growth factor (FGF) receptor 3 lead to the human dwarfism syndrome achondroplasia. Using a limb culture system, we have analyzed the role of FGF signaling and its interaction with the Ihh/Pthlh and BMP pathways in regulating ... ...

Abstract	Mutations in fibroblast growth factor (FGF) receptor 3 lead to the human dwarfism syndrome achondroplasia. Using a limb culture system, we have analyzed the role of FGF signaling and its interaction with the Ihh/Pthlh and BMP pathways in regulating chondrocyte differentiation. In contrast to previous suggestions, we demonstrate that FGF signaling accelerates both the onset and the pace of hypertrophic differentiation. We furthermore found that FGF and BMP signaling act in an antagonistic relationship regulating chondrocyte proliferation, Ihh expression, and the process of hypertrophic differentiation. Importantly, BMP signaling rescues the reduced domains of proliferating and hypertrophic chondrocytes in a mouse model for achondroplasia. We propose a model in which the balance of BMP and FGF signaling adjusts the pace of the differentiation process to the proliferation rate.
MeSH term(s)	Animals ; Bone Morphogenetic Proteins/metabolism ; Cell Differentiation ; Cell Division ; Chondrocytes/cytology ; Extremities/embryology ; Feedback, Physiological ; Fibroblast Growth Factor 2/metabolism ; Fibroblast Growth Factors/physiology ; Genetic Markers ; Hedgehog Proteins ; Hypertrophy ; Kinetics ; Mice ; Mice, Inbred Strains ; Mice, Mutant Strains ; Models, Biological ; Organ Culture Techniques ; Osteocalcin/metabolism ; Parathyroid Hormone-Related Protein ; Peptide Hormones/metabolism ; Signal Transduction ; Teratogens/pharmacology ; Trans-Activators/metabolism ; Veratrum Alkaloids/pharmacology
Chemical Substances	Bone Morphogenetic Proteins ; Genetic Markers ; Hedgehog Proteins ; Parathyroid Hormone-Related Protein ; Peptide Hormones ; Teratogens ; Trans-Activators ; Veratrum Alkaloids ; Fibroblast Growth Factor 2 (103107-01-3) ; Osteocalcin (104982-03-8) ; Fibroblast Growth Factors (62031-54-3) ; cyclopamine (ZH658AJ192)
Language	English
Publishing date	2002-10-02
Publishing country	United States
Document type	Comparative Study ; Journal Article ; Research Support, Non-U.S. Gov't ; Research Support, U.S. Gov't, P.H.S.
ZDB-ID	2054967-2
ISSN	1878-1551 ; 1534-5807
ISSN (online)	1878-1551
ISSN	1534-5807
DOI	10.1016/s1534-5807(02)00261-7
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Article ; Online: Delayed dopaminergic neuron differentiation in Lrp6 mutant mice.

Castelo-Branco, Gonçalo / Andersson, Emma R / Minina, Eleonora / Sousa, Kyle M / Ribeiro, Diogo / Kokubu, Chikara / Imai, Kenji / Prakash, Nilima / Wurst, Wolfgang / Arenas, Ernest

Developmental dynamics : an official publication of the American Association of Anatomists

2010 Volume 239, Issue 1, Page(s) 211–221

Abstract: Wnts are known to bind and activate multiple membrane receptors/coreceptors and to regulate dopaminergic (DA) neuron development and ventral midbrain (VM) morphogenesis. The low density lipoprotein receptor-related protein (Lrp6) is a Wnt co-receptor, ... ...

Abstract	Wnts are known to bind and activate multiple membrane receptors/coreceptors and to regulate dopaminergic (DA) neuron development and ventral midbrain (VM) morphogenesis. The low density lipoprotein receptor-related protein (Lrp6) is a Wnt co-receptor, yet it remains unclear whether Lrp6 is required for DA neuron development or VM morphogenesis. Lrp6 is expressed ubiquitously in the developing VM. In this study, we show that Lrp6(-/-) mice exhibit normal patterning, proliferation and cell death in the VM, but display a delay in the onset of DA precursor differentiation. A transient 50% reduction in tyrosine hydroxylase-positive DA neurons and in the expression of DA markers such as Nurr1 and Pitx3, as well as a defect in midbrain morphogenesis was detected in the mutant embryos at embryonic day 11.5. Our results, therefore, suggest a role for Lrp6 in the onset of DA neuron development in the VM as well as a role in midbrain morphogenesis.
MeSH term(s)	Animals ; Bromodeoxyuridine ; Cell Differentiation/genetics ; Cell Differentiation/physiology ; Dopamine/metabolism ; Genotype ; Homeodomain Proteins/metabolism ; Immunohistochemistry ; In Situ Hybridization ; Mesencephalon/embryology ; Mice ; Mice, Knockout ; Microscopy, Confocal ; Morphogenesis/genetics ; Neurons/cytology ; Neurons/metabolism ; Nuclear Receptor Subfamily 4, Group A, Member 2/metabolism ; Transcription Factors/metabolism ; Tyrosine 3-Monooxygenase/metabolism
Chemical Substances	Homeodomain Proteins ; Nuclear Receptor Subfamily 4, Group A, Member 2 ; Transcription Factors ; homeobox protein PITX3 ; Tyrosine 3-Monooxygenase (EC 1.14.16.2) ; Bromodeoxyuridine (G34N38R2N1) ; Dopamine (VTD58H1Z2X)
Language	English
Publishing date	2010-01
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	1102541-4
ISSN	1097-0177 ; 1058-8388
ISSN (online)	1097-0177
ISSN	1058-8388
DOI	10.1002/dvdy.22094
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Article ; Online: Wnt5a regulates ventral midbrain morphogenesis and the development of A9-A10 dopaminergic cells in vivo.

Andersson, Emma R / Prakash, Nilima / Cajanek, Lukas / Minina, Eleonora / Bryja, Vitezslav / Bryjova, Lenka / Yamaguchi, Terry P / Hall, Anita C / Wurst, Wolfgang / Arenas, Ernest

PloS one

2008 Volume 3, Issue 10, Page(s) e3517

Abstract: Wnt5a is a morphogen that activates the Wnt/planar cell polarity (PCP) pathway and serves multiple functions during development. PCP signaling controls the orientation of cells within an epithelial plane as well as convergent extension (CE) movements. ... ...

Abstract	Wnt5a is a morphogen that activates the Wnt/planar cell polarity (PCP) pathway and serves multiple functions during development. PCP signaling controls the orientation of cells within an epithelial plane as well as convergent extension (CE) movements. Wnt5a was previously reported to promote differentiation of A9-10 dopaminergic (DA) precursors in vitro. However, the signaling mechanism in DA cells and the function of Wnt5a during midbrain development in vivo remains unclear. We hereby report that Wnt5a activated the GTPase Rac1 in DA cells and that Rac1 inhibitors blocked the Wnt5a-induced DA neuron differentiation of ventral midbrain (VM) precursor cultures, linking Wnt5a-induced differentiation with a known effector of Wnt/PCP signaling. In vivo, Wnt5a was expressed throughout the VM at embryonic day (E)9.5, and was restricted to the VM floor and basal plate by E11.5-E13.5. Analysis of Wnt5a-/- mice revealed a transient increase in progenitor proliferation at E11.5, and a precociously induced NR4A2+ (Nurr1) precursor pool at E12.5. The excess NR4A2+ precursors remained undifferentiated until E14.5, when a transient 25% increase in DA neurons was detected. Wnt5a-/- mice also displayed a defect in (mid)brain morphogenesis, including an impairment in midbrain elongation and a rounded ventricular cavity. Interestingly, these alterations affected mostly cells in the DA lineage. The ventral Sonic hedgehog-expressing domain was broadened and flattened, a typical CE phenotype, and the domains occupied by Ngn2+ DA progenitors, NR4A2+ DA precursors and TH+ DA neurons were rostrocaudally reduced and laterally expanded. In summary, we hereby describe a Wnt5a regulation of Wnt/PCP signaling in the DA lineage and provide evidence for multiple functions of Wnt5a in the VM in vivo, including the regulation of VM morphogenesis, DA progenitor cell division, and differentiation of NR4A2+ DA precursors.
MeSH term(s)	Animals ; Cell Differentiation/genetics ; Cell Polarity/genetics ; Cell Polarity/physiology ; Cell Proliferation ; Dopamine/metabolism ; Embryo, Mammalian ; Female ; Mesencephalon/embryology ; Mesencephalon/metabolism ; Mice ; Mice, Inbred C57BL ; Mice, Knockout ; Models, Biological ; Morphogenesis/genetics ; Neurogenesis/genetics ; Neurons/metabolism ; Neurons/physiology ; Pregnancy ; Wnt Proteins/genetics ; Wnt Proteins/metabolism ; Wnt Proteins/physiology ; Wnt-5a Protein ; rac1 GTP-Binding Protein/metabolism
Chemical Substances	Wnt Proteins ; Wnt-5a Protein ; Wnt5a protein, mouse ; rac1 GTP-Binding Protein (EC 3.6.5.2) ; Dopamine (VTD58H1Z2X)
Language	English
Publishing date	2008
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ISSN	1932-6203
ISSN (online)	1932-6203
DOI	10.1371/journal.pone.0003517
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Article ; Online: Integrating Clinical and Epidemiologic Data on Allergic Diseases Across Birth Cohorts: A Harmonization Study in the Mechanisms of the Development of Allergy Project.

Benet, Marta / Albang, Richard / Pinart, Mariona / Hohmann, Cynthia / Tischer, Christina G / Annesi-Maesano, Isabella / Baïz, Nour / Bindslev-Jensen, Carsten / Lødrup Carlsen, Karin C / Carlsen, Kai-Hakon / Cirugeda, Lourdes / Eller, Esben / Fantini, Maria Pia / Gehring, Ulrike / Gerhard, Beatrix / Gori, Davide / Hallner, Eva / Kull, Inger / Lenzi, Jacopo /

McEachan, Rosemary / Minina, Eleonora / Momas, Isabelle / Narduzzi, Silvia / Petherick, Emily S / Porta, Daniela / Rancière, Fanny / Standl, Marie / Torrent, Maties / Wijga, Alet H / Wright, John / Kogevinas, Manolis / Guerra, Stefano / Sunyer, Jordi / Keil, Thomas / Bousquet, Jean / Maier, Dieter / Anto, Josep M / Garcia-Aymerich, Judith

American journal of epidemiology

2018 Volume 188, Issue 2, Page(s) 408–417

Abstract: The numbers of international collaborations among birth cohort studies designed to better understand asthma and allergies have increased in the last several years. However, differences in definitions and methods preclude direct pooling of original data ... ...

Abstract	The numbers of international collaborations among birth cohort studies designed to better understand asthma and allergies have increased in the last several years. However, differences in definitions and methods preclude direct pooling of original data on individual participants. As part of the Mechanisms of the Development of Allergy (MeDALL) Project, we harmonized data from 14 birth cohort studies (each with 3-20 follow-up periods) carried out in 9 European countries during 1990-1998 or 2003-2009. The harmonization process followed 6 steps: 1) organization of the harmonization panel; 2) identification of variables relevant to MeDALL objectives (candidate variables); 3) proposal of a definition for each candidate variable (reference definition); 4) assessment of the compatibility of each cohort variable with its reference definition (inferential equivalence) and classification of this inferential equivalence as complete, partial, or impossible; 5) convocation of a workshop to agree on the reference definitions and classifications of inferential equivalence; and 6) preparation and delivery of data through a knowledge management portal. We agreed on 137 reference definitions. The inferential equivalence of 3,551 cohort variables to their corresponding reference definitions was classified as complete, partial, and impossible for 70%, 15%, and 15% of the variables, respectively. A harmonized database was delivered to MeDALL investigators. In asthma and allergy birth cohorts, the harmonization of data for pooled analyses is feasible, and high inferential comparability may be achieved. The MeDALL harmonization approach can be used in other collaborative projects.
MeSH term(s)	Asthma/epidemiology ; Child ; Child, Preschool ; Cohort Studies ; Europe/epidemiology ; Female ; Humans ; Hypersensitivity/epidemiology ; Infant ; Infant, Newborn ; Male ; Pregnancy ; Research Design/standards
Language	English
Publishing date	2018-10-22
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2937-3
ISSN	1476-6256 ; 0002-9262
ISSN (online)	1476-6256
ISSN	0002-9262
DOI	10.1093/aje/kwy242
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Article: Targeted expression of SHH affects chondrocyte differentiation, growth plate organization, and Sox9 expression.

Tavella, Sara / Biticchi, Roberta / Schito, Anna / Minina, Eleonora / Di Martino, Davide / Pagano, Aldo / Vortkamp, Andrea / Horton, William A / Cancedda, Ranieri / Garofalo, Silvio

Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research

2004 Volume 19, Issue 10, Page(s) 1678–1688

Abstract: Unlabelled: The role of Hedgehogs (Hh) in murine skeletal development was studied by overexpressing human Sonic Hedgehog (SHH) in chondrocytes of transgenic mice using the collagen II promoter/enhancer. Overexpression caused a lethal craniorachischisis ... ...

Abstract	Unlabelled: The role of Hedgehogs (Hh) in murine skeletal development was studied by overexpressing human Sonic Hedgehog (SHH) in chondrocytes of transgenic mice using the collagen II promoter/enhancer. Overexpression caused a lethal craniorachischisis with major alterations in long bones because of defects in chondrocyte differentiation. Introduction: Hedgehogs (Hhs) are a family of secreted polypeptides that play important roles in vertebrate development, controlling many critical steps of cell differentiation and patterning. Skeletal development is affected in many different ways by Hhs. Genetic defects and anomalies of Hhs signaling pathways cause severe abnormalities in the appendicular, axial, and cranial skeleton in man and other vertebrates. Materials and methods: Genetic manipulation of mouse embryos was used to study in vivo the function of SHH in skeletal development. By DNA microinjection into pronuclei of fertilized oocytes, we have generated transgenic mice that express SHH specifically in chondrocytes using the cartilage-specific collagen II promoter/enhancer. Transgenic skeletal development was studied at different embryonic stages by histology. The expression pattern of specific chondrocyte molecules was studied by immunohistochemistry and in situ hybridization. Results: Transgenic mice died at birth with severe craniorachischisis and other skeletal defects in ribs, sternum, and long bones. Detailed analysis of long bones showed that chondrocyte differentiation was blocked at prehypertrophic stages, hindering endochondral ossification and trabecular bone formation, with specific defects in different limb segments. The growth plate was highly disorganized in the tibia and was completely absent in the femur and humerus, leading to skeletal elements entirely made of cartilage surrounded by a thin layer of bone. In this cartilage, chondrocytes maintained a columnar organization that was perpendicular to the bone longitudinal axis and directed toward its outer surface. The expression of SHH receptor, Patched-1 (Ptc1), was greatly increased in all cartilage, as well as the expression of parathyroid hormone-related protein (PTHrP) at the articular surface; while the expression of Indian Hedgehog (Ihh), another member of Hh family that controls the rate of chondrocyte maturation, was greatly reduced and restricted to the displaced chondrocyte columns. Transgenic mice also revealed the ability of SHH to upregulate the expression of Sox9, a major transcription factor implicated in chondrocyte-specific gene expression, in vivo and in vitro, acting through the proximal 6.8-kb-long Sox9 promoter. Conclusion: Transgenic mice show that continuous expression of SHH in chondrocytes interferes with cell differentiation and growth plate organization and induces high levels and diffuse expression of Sox9 in cartilaginous bones.
MeSH term(s)	Animals ; Bone Development ; Bone and Bones/abnormalities ; Cartilage/metabolism ; Cell Differentiation ; Chondrocytes/cytology ; Chondrocytes/metabolism ; Growth Plate/abnormalities ; Hedgehog Proteins ; High Mobility Group Proteins/metabolism ; Humans ; In Vitro Techniques ; Intracellular Signaling Peptides and Proteins ; Membrane Proteins/metabolism ; Mice ; Mice, Transgenic ; Neural Tube Defects/metabolism ; Parathyroid Hormone-Related Protein/metabolism ; Patched Receptors ; Patched-1 Receptor ; Receptors, Cell Surface ; SOX9 Transcription Factor ; Trans-Activators/metabolism ; Transcription Factors/metabolism ; Up-Regulation
Chemical Substances	Hedgehog Proteins ; High Mobility Group Proteins ; Intracellular Signaling Peptides and Proteins ; Membrane Proteins ; PTCH1 protein, human ; Parathyroid Hormone-Related Protein ; Patched Receptors ; Patched-1 Receptor ; Ptch1 protein, mouse ; Receptors, Cell Surface ; SHH protein, human ; SOX9 Transcription Factor ; SOX9 protein, human ; Sox9 protein, mouse ; Trans-Activators ; Transcription Factors
Language	English
Publishing date	2004-07-12
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	632783-7
ISSN	1523-4681 ; 0884-0431
ISSN (online)	1523-4681
ISSN	0884-0431
DOI	10.1359/JBMR.040706
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