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Article ; Online: Cell Division: Single-Cell Physiology Reveals Secrets of Chromosome Condensation.

Bloom, Kerry

2018 Volume 28, Issue 3, Page(s) R117–R119

Abstract: Our understanding of higher order chromosome structure has been transformed through statistical mechanics-based computer simulations of polymer chains. A new study exploring basic electrostatic interactions demystifies how chromosomes regulate their ... ...

Abstract	Our understanding of higher order chromosome structure has been transformed through statistical mechanics-based computer simulations of polymer chains. A new study exploring basic electrostatic interactions demystifies how chromosomes regulate their state of compaction over several orders of magnitude.
MeSH term(s)	Adenosine Triphosphate ; Cell Division ; Chromosomes ; Hydrolysis ; Ions
Chemical Substances	Ions ; Adenosine Triphosphate (8L70Q75FXE)
Language	English
Publishing date	2018-02-02
Publishing country	England
Document type	Journal Article ; Comment
ZDB-ID	1071731-6
ISSN	1879-0445 ; 0960-9822
ISSN (online)	1879-0445
ISSN	0960-9822
DOI	10.1016/j.cub.2017.12.032
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Article ; Online: Mechanisms of DNA Mobilization and Sequestration.

Bloom, Kerry / Kolbin, Daniel

Genes

2022 Volume 13, Issue 2

Abstract: The entire genome becomes mobilized following DNA damage. Understanding the mechanisms that act at the genome level requires that we embrace experimental and computational strategies to capture the behavior of the long-chain DNA polymer, which is the ... ...

Abstract	The entire genome becomes mobilized following DNA damage. Understanding the mechanisms that act at the genome level requires that we embrace experimental and computational strategies to capture the behavior of the long-chain DNA polymer, which is the building block for the chromosome. Long-chain polymers exhibit constrained, sub-diffusive motion in the nucleus. Cross-linking proteins, including cohesin and condensin, have a disproportionate effect on genome organization in their ability to stabilize transient interactions. Cross-linking proteins can segregate the genome into sub-domains through polymer-polymer phase separation (PPPS) and can drive the formation of gene clusters through small changes in their binding kinetics. Principles from polymer physics provide a means to unravel the mysteries hidden in the chains of life.
MeSH term(s)	Cell Nucleus ; Chromosomes ; DNA/genetics ; DNA Damage ; Polymers/chemistry
Chemical Substances	Polymers ; DNA (9007-49-2)
Language	English
Publishing date	2022-02-16
Publishing country	Switzerland
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Review
ZDB-ID	2527218-4
ISSN	2073-4425 ; 2073-4425
ISSN (online)	2073-4425
ISSN	2073-4425
DOI	10.3390/genes13020352
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Article ; Online: Shaping centromeres to resist mitotic spindle forces.

Lawrimore, Josh / Bloom, Kerry

Journal of cell science

2022 Volume 135, Issue 4

Abstract: The centromere serves as the binding site for the kinetochore and is essential for the faithful segregation of chromosomes throughout cell division. The point centromere in yeast is encoded by a ∼115 bp specific DNA sequence, whereas regional centromeres ...

Abstract	The centromere serves as the binding site for the kinetochore and is essential for the faithful segregation of chromosomes throughout cell division. The point centromere in yeast is encoded by a ∼115 bp specific DNA sequence, whereas regional centromeres range from 6-10 kbp in fission yeast to 5-10 Mbp in humans. Understanding the physical structure of centromere chromatin (pericentromere in yeast), defined as the chromatin between sister kinetochores, will provide fundamental insights into how centromere DNA is woven into a stiff spring that is able to resist microtubule pulling forces during mitosis. One hallmark of the pericentromere is the enrichment of the structural maintenance of chromosome (SMC) proteins cohesin and condensin. Based on studies from population approaches (ChIP-seq and Hi-C) and experimentally obtained images of fluorescent probes of pericentromeric structure, as well as quantitative comparisons between simulations and experimental results, we suggest a mechanism for building tension between sister kinetochores. We propose that the centromere is a chromatin bottlebrush that is organized by the loop-extruding proteins condensin and cohesin. The bottlebrush arrangement provides a biophysical means to transform pericentromeric chromatin into a spring due to the steric repulsion between radial loops. We argue that the bottlebrush is an organizing principle for chromosome organization that has emerged from multiple approaches in the field.
MeSH term(s)	Centromere ; Chromatin/metabolism ; Chromosome Segregation ; Humans ; Kinetochores ; Microtubules/metabolism ; Mitosis ; Spindle Apparatus/metabolism
Chemical Substances	Chromatin
Language	English
Publishing date	2022-02-18
Publishing country	England
Document type	Journal Article ; Research Support, N.I.H., Extramural
ZDB-ID	2993-2
ISSN	1477-9137 ; 0021-9533
ISSN (online)	1477-9137
ISSN	0021-9533
DOI	10.1242/jcs.259532
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Article: Mechanisms of DNA Mobilization and Sequestration

Bloom, Kerry / Kolbin, Daniel

Genes. 2022 Feb. 16, v. 13, no. 2

2022

Abstract	The entire genome becomes mobilized following DNA damage. Understanding the mechanisms that act at the genome level requires that we embrace experimental and computational strategies to capture the behavior of the long-chain DNA polymer, which is the building block for the chromosome. Long-chain polymers exhibit constrained, sub-diffusive motion in the nucleus. Cross-linking proteins, including cohesin and condensin, have a disproportionate effect on genome organization in their ability to stabilize transient interactions. Cross-linking proteins can segregate the genome into sub-domains through polymer–polymer phase separation (PPPS) and can drive the formation of gene clusters through small changes in their binding kinetics. Principles from polymer physics provide a means to unravel the mysteries hidden in the chains of life.
Keywords	DNA ; DNA damage ; chromosomes ; crosslinking ; polymers ; separation
Language	English
Dates of publication	2022-0216
Publishing place	Multidisciplinary Digital Publishing Institute
Document type	Article
ZDB-ID	2527218-4
ISSN	2073-4425
ISSN	2073-4425
DOI	10.3390/genes13020352
Database	NAL-Catalogue (AGRICOLA)

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Article ; Online: Liberating cohesin from cohesion.

Bloom, Kerry

Genes & development

2017 Volume 31, Issue 21, Page(s) 2113–2114

Abstract: Cohesin was identified through its major role in holding sister chromatids together. We are learning through analysis of cohesin and other members of the protein family (SMC [structural maintenance of chromosomes]) and their regulators that these ring ... ...

Abstract	Cohesin was identified through its major role in holding sister chromatids together. We are learning through analysis of cohesin and other members of the protein family (SMC [structural maintenance of chromosomes]) and their regulators that these ring complexes contribute to chromosome organization and dynamics throughout the cell cycle. We need to consider not only how ring complexes are regulated but how they interact with their fluctuating chromatin substrate.
MeSH term(s)	Acetyltransferases/genetics ; Cell Cycle Proteins/genetics ; Chromatids ; Chromatin ; Chromosomal Proteins, Non-Histone/genetics ; Interphase ; Cohesins
Chemical Substances	Cell Cycle Proteins ; Chromatin ; Chromosomal Proteins, Non-Histone ; Acetyltransferases (EC 2.3.1.-)
Language	English
Publishing date	2017-12-13
Publishing country	United States
Document type	Journal Article ; Review ; Comment
ZDB-ID	806684-x
ISSN	1549-5477 ; 0890-9369
ISSN (online)	1549-5477
ISSN	0890-9369
DOI	10.1101/gad.309732.117
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Zs.MG 54: Show issues

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Book ; Online: Different relative scalings between transient forces and thermal fluctuations tune regimes of chromatin organization

Coletti, Anna / Walker, Benjamin / Bloom, Kerry / Newhall, Katherine

2024

Abstract: Within the nucleus, structural maintenance of chromosome protein complexes, namely condensin and cohesin, create an architecture to facilitate the organization and proper function of the genome. Condensin, in addition to performing loop extrusion, ... ...

Abstract	Within the nucleus, structural maintenance of chromosome protein complexes, namely condensin and cohesin, create an architecture to facilitate the organization and proper function of the genome. Condensin, in addition to performing loop extrusion, creates localized clusters of chromatin in the nucleolus through transient crosslinks. Large-scale simulations revealed three different dynamic behaviors as a function of timescale: slow crosslinking leads to no clusters, fast crosslinking produces rigid slowly changing clusters, while intermediate timescales are optimal for producing flexible clusters that mediate gene interaction. By mathematically analyzing different relative scalings of the two sources of stochasticity, thermal fluctuations and the force induced by the transient crosslinks, we predict these three distinct regimes of cluster behavior. Standard time-averaging that takes the fluctuations of the transient crosslink force to zero can predict the existence of clusters, but not their timescale-dependent lifetimes. Accounting for the interaction of both fluctuations from the crosslinks and thermal noise with an effective energy landscape does capture the timescale-dependent flexible cluster lifetimes. No clusters are predicted when the fluctuations of the transient crosslink force are taken to be large relative to thermal fluctuations. This mathematical perturbation analysis illuminates the importance of accounting for stochasticity in local incoherent transient forces to predict emergent complex biological behavior. Comment: 9 pages, 5 figures
Keywords	Physics - Biological Physics ; Mathematics - Probability ; 37H05 ; 92C37 ; 35Q92 ; 37N25
Subject code	612
Publishing date	2024-01-12
Publishing country	us
Document type	Book ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: The safety of metronidazole in pregnancy.

Nwosu, Ozioma C / Bloom, Kathaleen

Health care for women international

2021 Volume 42, Issue 4-6, Page(s) 726–738

Abstract: Medication use during pregnancy carries risks of teratogenicity, preterm birth, and spontaneous abortion. CDC's guidelines advocate for the use of metronidazole for the treatment of bacterial vaginosis (BV) in pregnant women. A literature review ... ...

Abstract	Medication use during pregnancy carries risks of teratogenicity, preterm birth, and spontaneous abortion. CDC's guidelines advocate for the use of metronidazole for the treatment of bacterial vaginosis (BV) in pregnant women. A literature review assessing the safety of metronidazole during pregnancy was conducted. Metronidazole was found to be effective in preventing preterm births when used in conjunction with other antibiotics. Its use did not predict birth defects or congenital abnormalities. It was however associated with a 70% increased risk of spontaneous abortion. This risk should be interpreted cautiously in light of the confounder which is the severity of genitourinary infection.
MeSH term(s)	Anti-Bacterial Agents/adverse effects ; Female ; Humans ; Infant, Newborn ; Metronidazole/adverse effects ; Pregnancy ; Pregnancy Complications, Infectious/drug therapy ; Premature Birth ; Vaginosis, Bacterial/drug therapy
Chemical Substances	Anti-Bacterial Agents ; Metronidazole (140QMO216E)
Language	English
Publishing date	2021-03-19
Publishing country	England
Document type	Journal Article
ZDB-ID	632677-8
ISSN	1096-4665 ; 0739-9332
ISSN (online)	1096-4665
ISSN	0739-9332
DOI	10.1080/07399332.2021.1882462
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Article ; Online: Dicentric chromosomes are resolved through breakage and repair at their centromeres.

Cook, Diana / Kozmin, Stanislav G / Yeh, Elaine / Petes, Thomas D / Bloom, Kerry

Chromosoma

2024

Abstract: Chromosomes with two centromeres provide a unique opportunity to study chromosome breakage and DNA repair using completely endogenous cellular machinery. Using a conditional transcriptional promoter to control the second centromere, we are able to ... ...

Abstract	Chromosomes with two centromeres provide a unique opportunity to study chromosome breakage and DNA repair using completely endogenous cellular machinery. Using a conditional transcriptional promoter to control the second centromere, we are able to activate the dicentric chromosome and follow the appearance of DNA repair products. We find that the rate of appearance of DNA repair products resulting from homology-based mechanisms exceeds the expected rate based on their limited centromere homology (340 bp) and distance from one another (up to 46.3 kb). In order to identify whether DNA breaks originate in the centromere, we introduced 12 single-nucleotide polymorphisms (SNPs) into one of the centromeres. Analysis of the distribution of SNPs in the recombinant centromeres reveals that recombination was initiated with about equal frequency within the conserved centromere DNA elements CDEII and CDEIII of the two centromeres. The conversion tracts range from about 50 bp to the full length of the homology between the two centromeres (340 bp). Breakage and repair events within and between the centromeres can account for the efficiency and distribution of DNA repair products. We propose that in addition to providing a site for kinetochore assembly, the centromere may be a point of stress relief in the face of genomic perturbations.
Language	English
Publishing date	2024-01-02
Publishing country	Austria
Document type	Journal Article
ZDB-ID	203083-4
ISSN	1432-0886 ; 0009-5915
ISSN (online)	1432-0886
ISSN	0009-5915
DOI	10.1007/s00412-023-00814-6
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Article: Production, Characterization, and Assessment of Permanently Cationic and Ionizable Lipid Nanoparticles for Use in the Delivery of Self-Amplifying RNA Vaccines.

Kairuz, Dylan / Samudh, Nazia / Ely, Abdullah / Arbuthnot, Patrick / Bloom, Kristie

Pharmaceutics

2023 Volume 15, Issue 4

Abstract: Africa bears the highest burden of infectious diseases, yet the continent is heavily reliant on First World countries for the development and supply of life-saving vaccines. The COVID-19 pandemic was a stark reminder of Africa's vaccine dependence and ... ...

Abstract	Africa bears the highest burden of infectious diseases, yet the continent is heavily reliant on First World countries for the development and supply of life-saving vaccines. The COVID-19 pandemic was a stark reminder of Africa's vaccine dependence and since then great interest has been generated in establishing mRNA vaccine manufacturing capabilities on the African continent. Herein, we explore alphavirus-based self-amplifying RNAs (saRNAs) delivered by lipid nanoparticles (LNPs) as an alternative to the conventional mRNA vaccine platform. The approach is intended to produce dose-sparing vaccines which could assist resource-constrained countries to achieve vaccine independence. Protocols to synthesize high-quality saRNAs were optimized and in vitro expression of reporter proteins encoded by saRNAs was achieved at low doses and observed for an extended period. Permanently cationic or ionizable LNPs (cLNPs and iLNPs, respectively) were successfully produced, incorporating saRNAs either exteriorly (saRNA-Ext-LNPs) or interiorly (saRNA-Int-LNPs). DOTAP and DOTMA saRNA-Ext-cLNPs performed best and were generally below 200 nm with good PDIs (<0.3). DOTAP and DDA saRNA-Int-cLNPs performed optimally, allowing for saRNA amplification. These were slightly larger, with higher PDIs as a result of the method used, which will require further optimization. In both cases, the N:P ratio and lipid molar ratio had a distinct effect on saRNA expression kinetics, and RNA was encapsulated at high percentages of >90%. These LNPs allow the delivery of saRNA with no significant toxicity. The optimization of saRNA production and identification of potential LNP candidates will facilitate saRNA vaccine and therapeutic development. The dose-sparing properties, versatility, and manufacturing simplicity of the saRNA platform will facilitate a rapid response to future pandemics.
Language	English
Publishing date	2023-04-07
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2527217-2
ISSN	1999-4923
ISSN	1999-4923
DOI	10.3390/pharmaceutics15041173
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Article ; Online: Anniversary of the discovery/isolation of the yeast centromere by Clarke and Carbon.

Bloom, Kerry

Molecular biology of the cell

2015 Volume 26, Issue 9, Page(s) 1575–1577

Abstract: The first centromere was isolated 35 years ago by Louise Clarke and John Carbon from budding yeast. They embarked on their journey with rudimentary molecular tools (by today's standards) and little knowledge of the structure of a chromosome, much less ... ...

Abstract	The first centromere was isolated 35 years ago by Louise Clarke and John Carbon from budding yeast. They embarked on their journey with rudimentary molecular tools (by today's standards) and little knowledge of the structure of a chromosome, much less the nature of a centromere. Their discovery opened up a new field, as centromeres have now been isolated from fungi and numerous plants and animals, including mammals. Budding yeast and several other fungi have small centromeres with short, well-defined sequences, known as point centromeres, whereas regional centromeres span several kilobases up to megabases and do not seem to have DNA sequence specificity. Centromeres are at the heart of artificial chromosomes, and we have seen the birth of synthetic centromeres in budding and fission yeast and mammals. The diversity in centromeres throughout phylogeny belie conserved functions that are only beginning to be understood.
MeSH term(s)	Anniversaries and Special Events ; Centromere/genetics ; Chromosomes, Fungal/genetics ; DNA, Fungal/genetics ; DNA, Fungal/ultrastructure ; Fungal Proteins/physiology ; Genetic Research/history ; History, 20th Century ; Laboratory Personnel ; Saccharomycetales/genetics
Chemical Substances	DNA, Fungal ; Fungal Proteins
Language	English
Publishing date	2015-05-01
Publishing country	United States
Document type	Historical Article ; Journal Article
ZDB-ID	1098979-1
ISSN	1939-4586 ; 1059-1524
ISSN (online)	1939-4586
ISSN	1059-1524
DOI	10.1091/mbc.E14-11-1512
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