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Article ; Online: The double-edged sword of bivalency.

Bulut-Karslıoğlu, Aydan

2023 Volume 25, Issue 1, Page(s) 6

Language	English
Publishing date	2023-09-19
Publishing country	England
Document type	Journal Article
ZDB-ID	2031313-5
ISSN	1471-0080 ; 1471-0072
ISSN (online)	1471-0080
ISSN	1471-0072
DOI	10.1038/s41580-023-00665-0
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Zs.A 5446: Show issues			Location: Je nach Verfügbarkeit (siehe Angabe bei Bestand) bis Jg. 1994: Bestellungen von Artikeln über das Online-Bestellformular Jg. 1995 - 2021: Lesesall (2.OG) ab Jg. 2022: Lesesaal (EG)
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Article ; Online: On time: developmental timing within and across species.

Garcia-Ojalvo, Jordi / Bulut-Karslioglu, Aydan

Development (Cambridge, England)

2023 Volume 150, Issue 14

Abstract: Organisms across species differ in the relative size and complexity of their tissues to serve the specific purposes of the host. Correct timing is a crucial ingredient in the development of tissues, as reaching the right size and complexity requires a ... ...

Abstract	Organisms across species differ in the relative size and complexity of their tissues to serve the specific purposes of the host. Correct timing is a crucial ingredient in the development of tissues, as reaching the right size and complexity requires a careful balance between cellular proliferation and differentiation. Premature or delayed differentiation, for instance, can result in tissue imbalance, malformation or malfunction. Despite seemingly rigid constraints on development, however, there is flexibility in both the timing and differentiation trajectories within and between species. In this Spotlight, we discuss how time is measured and regulated in development, and question whether developmental timing is in fact different between species.
MeSH term(s)	Biological Evolution ; Time Factors
Language	English
Publishing date	2023-07-17
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	90607-4
ISSN	1477-9129 ; 0950-1991
ISSN (online)	1477-9129
ISSN	0950-1991
DOI	10.1242/dev.201045
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Article: Molecular Regulation of Paused Pluripotency in Early Mammalian Embryos and Stem Cells.

van der Weijden, Vera A / Bulut-Karslioglu, Aydan

Frontiers in cell and developmental biology

2021 Volume 9, Page(s) 708318

Abstract: The energetically costly mammalian investment in gestation and lactation requires plentiful nutritional sources and thus links the environmental conditions to reproductive success. Flexibility in adjusting developmental timing enhances chances of ... ...

Abstract	The energetically costly mammalian investment in gestation and lactation requires plentiful nutritional sources and thus links the environmental conditions to reproductive success. Flexibility in adjusting developmental timing enhances chances of survival in adverse conditions. Over 130 mammalian species can reversibly pause early embryonic development by switching to a near dormant state that can be sustained for months, a phenomenon called
Language	English
Publishing date	2021-07-27
Publishing country	Switzerland
Document type	Journal Article ; Review
ZDB-ID	2737824-X
ISSN	2296-634X
ISSN	2296-634X
DOI	10.3389/fcell.2021.708318
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Article ; Online: Molecular Regulation of Paused Pluripotency in Early Mammalian Embryos and Stem Cells

Vera A. van der Weijden / Aydan Bulut-Karslioglu

Frontiers in Cell and Developmental Biology, Vol

2021 Volume 9

Abstract	The energetically costly mammalian investment in gestation and lactation requires plentiful nutritional sources and thus links the environmental conditions to reproductive success. Flexibility in adjusting developmental timing enhances chances of survival in adverse conditions. Over 130 mammalian species can reversibly pause early embryonic development by switching to a near dormant state that can be sustained for months, a phenomenon called embryonic diapause. Lineage-specific cells are retained during diapause, and they proliferate and differentiate upon activation. Studying diapause thus reveals principles of pluripotency and dormancy and is not only relevant for development, but also for regeneration and cancer. In this review, we focus on the molecular regulation of diapause in early mammalian embryos and relate it to maintenance of potency in stem cells in vitro. Diapause is established and maintained by active rewiring of the embryonic metabolome, epigenome, and gene expression in communication with maternal tissues. Herein, we particularly discuss factors required at distinct stages of diapause to induce, maintain, and terminate dormancy.
Keywords	embryonic diapause ; pluripotency ; dormancy ; metabolism ; transcription ; miRNA ; Biology (General) ; QH301-705.5
Subject code	571
Language	English
Publishing date	2021-07-01T00:00:00Z
Publisher	Frontiers Media S.A.
Document type	Article ; Online
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Article ; Online: FOXO1-mediated lipid metabolism maintains mammalian embryos in dormancy.

van der Weijden, Vera A / Stötzel, Maximilian / Iyer, Dhanur P / Fauler, Beatrix / Gralinska, Elzbieta / Shahraz, Mohammed / Meierhofer, David / Vingron, Martin / Rulands, Steffen / Alexandrov, Theodore / Mielke, Thorsten / Bulut-Karslioglu, Aydan

Nature cell biology

2024 Volume 26, Issue 2, Page(s) 181–193

Abstract: Mammalian developmental timing is adjustable in vivo by preserving pre-implantation embryos in a dormant state called diapause. Inhibition of the growth regulator mTOR (mTORi) pauses mouse development in vitro, yet how embryonic dormancy is maintained is ...

Abstract	Mammalian developmental timing is adjustable in vivo by preserving pre-implantation embryos in a dormant state called diapause. Inhibition of the growth regulator mTOR (mTORi) pauses mouse development in vitro, yet how embryonic dormancy is maintained is not known. Here we show that mouse embryos in diapause are sustained by using lipids as primary energy source. In vitro, supplementation of embryos with the metabolite L-carnitine balances lipid consumption, puts the embryos in deeper dormancy and boosts embryo longevity. We identify FOXO1 as an essential regulator of the energy balance in dormant embryos and propose, through meta-analyses of dormant cell signatures, that it may be a common regulator of dormancy across adult tissues. Our results lift a constraint on in vitro embryo survival and suggest that lipid metabolism may be a critical metabolic transition relevant for longevity and stem cell function across tissues.
MeSH term(s)	Animals ; Mice ; Embryo, Mammalian ; Embryonic Development/physiology ; Energy Metabolism ; Lipid Metabolism ; Mammals
Chemical Substances	Foxo1 protein, mouse
Language	English
Publishing date	2024-01-04
Publishing country	England
Document type	Journal Article
ZDB-ID	1474722-4
ISSN	1476-4679 ; 1465-7392
ISSN (online)	1476-4679
ISSN	1465-7392
DOI	10.1038/s41556-023-01325-3
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Zs.A 5169: Show issues			Location: Je nach Verfügbarkeit (siehe Angabe bei Bestand) bis Jg. 1994: Bestellungen von Artikeln über das Online-Bestellformular Jg. 1995 - 2021: Lesesall (2.OG) ab Jg. 2022: Lesesaal (EG)
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Article ; Online: Hypertranscription in Development, Stem Cells, and Regeneration.

Percharde, Michelle / Bulut-Karslioglu, Aydan / Ramalho-Santos, Miguel

Developmental cell

2017 Volume 40, Issue 1, Page(s) 9–21

Abstract: Cells can globally upregulate their transcriptome during specific transitions, a phenomenon called hypertranscription. Evidence for hypertranscription dates back over 70 years but has gone largely ignored in the genomics era until recently. We discuss ... ...

Abstract	Cells can globally upregulate their transcriptome during specific transitions, a phenomenon called hypertranscription. Evidence for hypertranscription dates back over 70 years but has gone largely ignored in the genomics era until recently. We discuss data supporting the notion that hypertranscription is a unifying theme in embryonic development, stem cell biology, regeneration, and cell competition. We review the history, methods for analysis, underlying mechanisms, and biological significance of hypertranscription.
MeSH term(s)	Animals ; Embryonic Development/genetics ; Humans ; Lymphocyte Activation/genetics ; Regeneration/genetics ; Stem Cells/metabolism ; Transcription, Genetic ; Zygote/metabolism
Language	English
Publishing date	2017-01-09
Publishing country	United States
Document type	Journal Article ; Review
ZDB-ID	2054967-2
ISSN	1878-1551 ; 1534-5807
ISSN (online)	1878-1551
ISSN	1534-5807
DOI	10.1016/j.devcel.2016.11.010
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Zs.A 5742: Show issues			Location: Je nach Verfügbarkeit (siehe Angabe bei Bestand) bis Jg. 1994: Bestellungen von Artikeln über das Online-Bestellformular Jg. 1995 - 2021: Lesesall (2.OG) ab Jg. 2022: Lesesaal (EG)
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Article ; Online: Hypoxia induces an early primitive streak signature, enhancing spontaneous elongation and lineage representation in gastruloids.

López-Anguita, Natalia / Gassaloglu, Seher Ipek / Stötzel, Maximilian / Bolondi, Adriano / Conkar, Deniz / Typou, Marina / Buschow, René / Veenvliet, Jesse V / Bulut-Karslioglu, Aydan

Development (Cambridge, England)

2022 Volume 149, Issue 20

Abstract: The cellular microenvironment, together with intrinsic regulators, shapes stem cell identity and differentiation capacity. Mammalian early embryos are exposed to hypoxia in vivo and appear to benefit from hypoxic culture in vitro. Yet, how hypoxia ... ...

Abstract	The cellular microenvironment, together with intrinsic regulators, shapes stem cell identity and differentiation capacity. Mammalian early embryos are exposed to hypoxia in vivo and appear to benefit from hypoxic culture in vitro. Yet, how hypoxia influences stem cell transcriptional networks and lineage choices remain poorly understood. Here, we investigated the molecular effects of acute and prolonged hypoxia on embryonic and extra-embryonic stem cells as well as the functional impact on differentiation potential. We find a temporal and cell type-specific transcriptional response including an early primitive streak signature in hypoxic embryonic stem cells mediated by HIF1α. Using a 3D gastruloid differentiation model, we show that hypoxia-induced T expression enables symmetry breaking and axial elongation in the absence of exogenous WNT activation. When combined with exogenous WNT activation, hypoxia enhances lineage representation in gastruloids, as demonstrated by highly enriched signatures of gut endoderm, notochord, neuromesodermal progenitors and somites. Our findings directly link the microenvironment to stem cell function and provide a rationale supportive of applying physiological conditions in models of embryo development.
MeSH term(s)	Animals ; Cell Differentiation/physiology ; Embryonic Stem Cells ; Endoderm/metabolism ; Hypoxia/metabolism ; Mammals ; Primitive Streak
Language	English
Publishing date	2022-09-14
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	90607-4
ISSN	1477-9129 ; 0950-1991
ISSN (online)	1477-9129
ISSN	0950-1991
DOI	10.1242/dev.200679
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Article ; Online: Chd1 protects genome integrity at promoters to sustain hypertranscription in embryonic stem cells.

Bulut-Karslioglu, Aydan / Jin, Hu / Kim, Yun-Kyo / Cho, Brandon / Guzman-Ayala, Marcela / Williamson, Andrew J K / Hejna, Miroslav / Stötzel, Maximilian / Whetton, Anthony D / Song, Jun S / Ramalho-Santos, Miguel

Nature communications

2021 Volume 12, Issue 1, Page(s) 4859

Abstract: Stem and progenitor cells undergo a global elevation of nascent transcription, or hypertranscription, during key developmental transitions involving rapid cell proliferation. The chromatin remodeler Chd1 mediates hypertranscription in pluripotent cells ... ...

Abstract	Stem and progenitor cells undergo a global elevation of nascent transcription, or hypertranscription, during key developmental transitions involving rapid cell proliferation. The chromatin remodeler Chd1 mediates hypertranscription in pluripotent cells but its mechanism of action remains poorly understood. Here we report a novel role for Chd1 in protecting genome integrity at promoter regions by preventing DNA double-stranded break (DSB) accumulation in ES cells. Chd1 interacts with several DNA repair factors including Atm, Parp1, Kap1 and Topoisomerase 2β and its absence leads to an accumulation of DSBs at Chd1-bound Pol II-transcribed genes and rDNA. Genes prone to DNA breaks in Chd1 KO ES cells are longer genes with GC-rich promoters, a more labile nucleosomal structure and roles in chromatin regulation, transcription and signaling. These results reveal a vulnerability of hypertranscribing stem cells to accumulation of endogenous DNA breaks, with important implications for developmental and cancer biology.
MeSH term(s)	Animals ; Chromatin/metabolism ; DNA Breaks, Double-Stranded ; DNA Repair ; DNA Topoisomerases, Type II/metabolism ; DNA, Ribosomal/metabolism ; DNA-Binding Proteins/genetics ; DNA-Binding Proteins/metabolism ; Mice ; Mouse Embryonic Stem Cells/metabolism ; Poly-ADP-Ribose Binding Proteins/metabolism ; Promoter Regions, Genetic ; Signal Transduction ; Transcription Initiation Site ; Transcription, Genetic
Chemical Substances	Chd1 protein, mouse ; Chromatin ; DNA, Ribosomal ; DNA-Binding Proteins ; Poly-ADP-Ribose Binding Proteins ; DNA Topoisomerases, Type II (EC 5.99.1.3) ; Top2b protein, mouse (EC 5.99.1.3)
Language	English
Publishing date	2021-08-11
Publishing country	England
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	2553671-0
ISSN	2041-1723 ; 2041-1723
ISSN (online)	2041-1723
ISSN	2041-1723
DOI	10.1038/s41467-021-25088-3
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Article ; Online: Chd1 protects genome integrity at promoters to sustain hypertranscription in embryonic stem cells

Aydan Bulut-Karslioglu / Hu Jin / Yun-Kyo Kim / Brandon Cho / Marcela Guzman-Ayala / Andrew J. K. Williamson / Miroslav Hejna / Maximilian Stötzel / Anthony D. Whetton / Jun S. Song / Miguel Ramalho-Santos

Nature Communications, Vol 12, Iss 1, Pp 1-

2021 Volume 11

Abstract: The chromatin remodeler Chd1 mediates hypertranscription in embryonic stem (ES) cells and has been shown to associate with genes transcribed by RNA Polymerase (Pol) I and II. Here the authors provide mechanistic insights into this process and reveal that ...

Abstract	The chromatin remodeler Chd1 mediates hypertranscription in embryonic stem (ES) cells and has been shown to associate with genes transcribed by RNA Polymerase (Pol) I and II. Here the authors provide mechanistic insights into this process and reveal that Chd1 is involved in protecting genome integrity at promoter regions by preventing DNA break accumulation.
Keywords	Science ; Q
Language	English
Publishing date	2021-08-01T00:00:00Z
Publisher	Nature Portfolio
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Inhibition of mTOR induces a paused pluripotent state.

Bulut-Karslioglu, Aydan / Biechele, Steffen / Jin, Hu / Macrae, Trisha A / Hejna, Miroslav / Gertsenstein, Marina / Song, Jun S / Ramalho-Santos, Miguel

Nature

2016 Volume 540, Issue 7631, Page(s) 119–123

Abstract: Cultured pluripotent stem cells are a cornerstone of regenerative medicine owing to their ability to give rise to all cell types of the body. Although pluripotent stem cells can be propagated indefinitely in vitro, pluripotency is paradoxically a ... ...

Abstract	Cultured pluripotent stem cells are a cornerstone of regenerative medicine owing to their ability to give rise to all cell types of the body. Although pluripotent stem cells can be propagated indefinitely in vitro, pluripotency is paradoxically a transient state in vivo, lasting 2-3 days around the time of blastocyst implantation. The exception to this rule is embryonic diapause, a reversible state of suspended development triggered by unfavourable conditions. Diapause is a physiological reproductive strategy widely employed across the animal kingdom, including in mammals, but its regulation remains poorly understood. Here we report that the partial inhibition of mechanistic target of rapamycin (mTOR), a major nutrient sensor and promoter of growth, induces reversible pausing of mouse blastocyst development and allows their prolonged culture ex vivo. Paused blastocysts remain pluripotent and competent-able to give rise to embryonic stem (ES) cells and live, fertile mice. We show that both naturally diapaused blastocysts in vivo and paused blastocysts ex vivo display pronounced reductions in mTOR activity, translation, histone modifications associated with gene activity and transcription. Pausing can be induced directly in cultured ES cells and sustained for weeks without appreciable cell death or deviations from cell cycle distributions. We show that paused ES cells display a remarkable global suppression of transcription, maintain a gene expression signature of diapaused blastocysts and remain pluripotent. These results uncover a new pluripotent stem cell state corresponding to the epiblast of the diapaused blastocyst and indicate that mTOR regulates developmental timing at the peri-implantation stage. Our findings have implications in the fields of assisted reproduction, regenerative medicine, cancer, metabolic disorders and ageing.
MeSH term(s)	Animals ; Blastocyst/cytology ; Cells, Cultured ; Down-Regulation ; Embryonic Development ; Female ; Germ Layers/cytology ; Histones/metabolism ; In Vitro Techniques ; Male ; Mice ; Mouse Embryonic Stem Cells/cytology ; Pluripotent Stem Cells/cytology ; Protein Biosynthesis ; TOR Serine-Threonine Kinases/antagonists & inhibitors ; TOR Serine-Threonine Kinases/metabolism ; Transcription, Genetic
Chemical Substances	Histones ; TOR Serine-Threonine Kinases (EC 2.7.1.1) ; mTOR protein, mouse (EC 2.7.1.1)
Language	English
Publishing date	2016-11-23
Publishing country	England
Document type	Journal Article ; Research Support, N.I.H., Extramural
ZDB-ID	120714-3
ISSN	1476-4687 ; 0028-0836
ISSN (online)	1476-4687
ISSN	0028-0836
DOI	10.1038/nature20578
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