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Article: Comparative modeling reveals the molecular determinants of aneuploidy fitness cost in a wild yeast model.

Rojas, Julie / Hose, James / Auguste Dutcher, H / Place, Michael / Wolters, John F / Hittinger, Chris Todd / Gasch, Audrey P

bioRxiv : the preprint server for biology

2024

Abstract: Although implicated as deleterious in many organisms, aneuploidy can underlie rapid phenotypic evolution. However, aneuploidy will only be maintained if the benefit outweighs the cost, which remains incompletely understood. To quantify this cost and the ... ...

Abstract	Although implicated as deleterious in many organisms, aneuploidy can underlie rapid phenotypic evolution. However, aneuploidy will only be maintained if the benefit outweighs the cost, which remains incompletely understood. To quantify this cost and the molecular determinants behind it, we generated a panel of chromosome duplications in
Language	English
Publishing date	2024-04-13
Publishing country	United States
Document type	Preprint
DOI	10.1101/2024.04.09.588778
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Article: The response to single-gene duplication implicates translation as a key vulnerability in aneuploid yeast.

Dutcher, H Auguste / Hose, James / Howe, Hollis / Rojas, Julie / Gasch, Audrey P

bioRxiv : the preprint server for biology

2024

Abstract: Aneuploidy produces myriad consequences in health and disease, yet models of the deleterious effects of chromosome amplification are still widely debated. To distinguish the molecular determinants of aneuploidy stress, we measured the effects of ... ...

Abstract	Aneuploidy produces myriad consequences in health and disease, yet models of the deleterious effects of chromosome amplification are still widely debated. To distinguish the molecular determinants of aneuploidy stress, we measured the effects of duplicating individual genes in cells with varying chromosome duplications, in wild-type cells and cells sensitized to aneuploidy by deletion of RNA-binding protein Ssd1. We identified gene duplications that are nearly neutral in wild-type euploid cells but significantly deleterious in euploids lacking
Language	English
Publishing date	2024-04-20
Publishing country	United States
Document type	Preprint
DOI	10.1101/2024.04.15.589582
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Article ; Online: A Peroxide-Responding sRNA Evolved from a Peroxidase mRNA.

Krieger, Madeline C / Dutcher, H Auguste / Ashford, Andrew J / Raghavan, Rahul

Molecular biology and evolution

2022 Volume 39, Issue 2

Abstract: Small RNAs (sRNAs) are important gene regulators in bacteria, but it is unclear how new sRNAs originate and become part of regulatory networks that coordinate bacterial response to environmental stimuli. Using a covariance modeling-based approach, we ... ...

Abstract	Small RNAs (sRNAs) are important gene regulators in bacteria, but it is unclear how new sRNAs originate and become part of regulatory networks that coordinate bacterial response to environmental stimuli. Using a covariance modeling-based approach, we analyzed the presence of hundreds of sRNAs in more than a thousand genomes across Enterobacterales, a bacterial order with a confluence of factors that allows robust genome-scale sRNA analyses: several well-studied organisms with fairly conserved genome structures, an established phylogeny, and substantial nucleotide diversity within a narrow evolutionary space. We discovered that a majority of sRNAs arose recently, and uncovered protein-coding genes as a potential source from which new sRNAs arise. A detailed investigation of the emergence of OxyS, a peroxide-responding sRNA, revealed that it evolved from a fragment of a peroxidase messenger RNA. Importantly, although it replaced the ancestral peroxidase, OxyS continues to be part of the ancestral peroxide-response regulon, indicating that an sRNA that arises from a protein-coding gene would inherently be part of the parental protein's regulatory network. This new insight provides a fresh framework for understanding sRNA origin and regulatory integration in bacteria.
MeSH term(s)	Enterobacteriaceae/genetics ; Gene Expression Regulation, Bacterial ; Peroxidase/genetics ; Peroxides ; RNA, Bacterial/genetics ; RNA, Messenger/genetics ; RNA, Small Untranslated/genetics
Chemical Substances	Peroxides ; RNA, Bacterial ; RNA, Messenger ; RNA, Small Untranslated ; Peroxidase (EC 1.11.1.7)
Language	English
Publishing date	2022-01-25
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural
ZDB-ID	998579-7
ISSN	1537-1719 ; 0737-4038
ISSN (online)	1537-1719
ISSN	0737-4038
DOI	10.1093/molbev/msac020
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Article ; Online: Origin, Evolution, and Loss of Bacterial Small RNAs.

Dutcher, H Auguste / Raghavan, Rahul

Microbiology spectrum

2018 Volume 6, Issue 2

Abstract: Despite the central role of bacterial noncoding small RNAs (sRNAs) in posttranscriptional regulation, little is understood about their evolution. Here we compile what has been studied to date and trace a life cycle of sRNAs-from their mechanisms of ... ...

Abstract	Despite the central role of bacterial noncoding small RNAs (sRNAs) in posttranscriptional regulation, little is understood about their evolution. Here we compile what has been studied to date and trace a life cycle of sRNAs-from their mechanisms of emergence, through processes of change and frequent neofunctionalization, to their loss from bacterial lineages. Because they possess relatively unrestrictive structural requirements, we find that sRNA origins are varied, and include
MeSH term(s)	Bacteria/genetics ; Bacteria/metabolism ; Binding Sites ; Evolution, Molecular ; Gene Expression Regulation, Bacterial ; Gene Transfer, Horizontal/genetics ; Genome, Bacterial/genetics ; MicroRNAs/genetics ; MicroRNAs/physiology ; Molecular Sequence Annotation ; Mutation ; Phylogeny ; Protein Binding ; RNA, Bacterial/genetics ; RNA, Bacterial/physiology ; RNA, Small Untranslated/genetics ; RNA, Small Untranslated/physiology ; Sigma Factor
Chemical Substances	MicroRNAs ; RNA, Bacterial ; RNA, Small Untranslated ; Sigma Factor
Language	English
Publishing date	2018-04-04
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Review
ISSN	2165-0497
ISSN (online)	2165-0497
DOI	10.1128/microbiolspec.RWR-0004-2017
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Article ; Online: A small RNA is functional in

Wright, Austin P / Dutcher, H Auguste / Butler, Brianna / Nice, Timothy J / Raghavan, Rahul

Microbiology (Reading, England)

2021 Volume 167, Issue 10

Abstract: Bacterial small RNAs (sRNAs) are important regulators of gene expression; however, the impact of natural mutations on sRNA functions has not been studied extensively. Here we show that the sRNA MgrR contains a unique 53 bp insertion ... ...

Abstract	Bacterial small RNAs (sRNAs) are important regulators of gene expression; however, the impact of natural mutations on sRNA functions has not been studied extensively. Here we show that the sRNA MgrR contains a unique 53 bp insertion in
MeSH term(s)	Enterobacteriaceae/classification ; Enterobacteriaceae/genetics ; Escherichia/classification ; Escherichia/genetics ; Escherichia/metabolism ; Gene Expression Regulation, Bacterial ; Hydrogen Peroxide/metabolism ; Magnesium/metabolism ; Mutation ; Phylogeny ; RNA, Bacterial/genetics ; RNA, Bacterial/metabolism ; RNA, Small Untranslated/genetics ; RNA, Small Untranslated/metabolism
Chemical Substances	RNA, Bacterial ; RNA, Small Untranslated ; Hydrogen Peroxide (BBX060AN9V) ; Magnesium (I38ZP9992A)
Language	English
Publishing date	2021-10-25
Publishing country	England
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	1180712-x
ISSN	1465-2080 ; 1350-0872
ISSN (online)	1465-2080
ISSN	1350-0872
DOI	10.1099/mic.0.001099
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Article ; Online: Multiple Acquisitions of Pathogen-Derived Francisella Endosymbionts in Soft Ticks.

Gerhart, Jonathan G / Auguste Dutcher, H / Brenner, Amanda E / Moses, Abraham S / Grubhoffer, Libor / Raghavan, Rahul

Genome biology and evolution

2018 Volume 10, Issue 2, Page(s) 607–615

Abstract: Bacterial endosymbionts of ticks are of interest due to their close evolutionary relationships with tick-vectored pathogens. For instance, whereas many ticks contain Francisella-like endosymbionts (FLEs), others transmit the mammalian pathogen ... ...

Abstract	Bacterial endosymbionts of ticks are of interest due to their close evolutionary relationships with tick-vectored pathogens. For instance, whereas many ticks contain Francisella-like endosymbionts (FLEs), others transmit the mammalian pathogen Francisella tularensis. We recently sequenced the genome of an FLE present in the hard tick Amblyomma maculatum (FLE-Am) and showed that it likely evolved from a pathogenic ancestor. In order to expand our understanding of FLEs, in the current study we sequenced the genome of an FLE in the soft tick Ornithodoros moubata and compared it to the genomes of FLE-Am, Francisella persica-an FLE in the soft tick Argus (Persicargas) arboreus, Francisella sp. MA067296-a clinical isolate responsible for an opportunistic human infection, and F. tularensis, the established human pathogen. We determined that FLEs and MA067296 belonged to a sister taxon of mammalian pathogens, and contained inactivated versions of virulence genes present in F. tularensis, indicating that the most recent common ancestor shared by FLEs and F. tularensis was a potential mammalian pathogen. Our analyses also revealed that the two soft ticks (O. moubata and A. arboreus) probably acquired their FLEs separately, suggesting that the virulence attenuation observed in FLEs are not the consequence of a single acquisition event followed by speciation, but probably due to independent transitions of pathogenic francisellae into nonpathogenic FLEs within separate tick lineages. Additionally, we show that FLEs encode intact pathways for the production of several B vitamins and cofactors, denoting that they could function as nutrient-provisioning endosymbionts in ticks.
MeSH term(s)	Animals ; Argasidae/microbiology ; Argasidae/physiology ; Biological Evolution ; Francisella/genetics ; Francisella/isolation & purification ; Francisella/physiology ; Genes, Bacterial ; Gram-Negative Bacterial Infections/microbiology ; Humans ; Phylogeny ; Symbiosis ; Virulence Factors/genetics
Chemical Substances	Virulence Factors
Language	English
Publishing date	2018-01-28
Publishing country	England
Document type	Journal Article ; Research Support, N.I.H., Extramural
ZDB-ID	2495328-3
ISSN	1759-6653 ; 1759-6653
ISSN (online)	1759-6653
ISSN	1759-6653
DOI	10.1093/gbe/evy021
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Article ; Online: The genetic basis of aneuploidy tolerance in wild yeast.

Hose, James / Escalante, Leah E / Clowers, Katie J / Dutcher, H Auguste / Robinson, DeElegant / Bouriakov, Venera / Coon, Joshua J / Shishkova, Evgenia / Gasch, Audrey P

eLife

2020 Volume 9

Abstract: Aneuploidy is highly detrimental during development yet common in cancers and pathogenic fungi - what gives rise to differences in aneuploidy tolerance remains unclear. We previously showed that wild isolates ... ...

Abstract	Aneuploidy is highly detrimental during development yet common in cancers and pathogenic fungi - what gives rise to differences in aneuploidy tolerance remains unclear. We previously showed that wild isolates of
MeSH term(s)	Aneuploidy ; Saccharomyces cerevisiae/genetics ; Saccharomyces cerevisiae/metabolism ; Saccharomyces cerevisiae Proteins/genetics ; Saccharomyces cerevisiae Proteins/metabolism
Chemical Substances	Saccharomyces cerevisiae Proteins ; Ssd1 protein, S cerevisiae
Language	English
Publishing date	2020-01-07
Publishing country	England
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, U.S. Gov't, Non-P.H.S.
ZDB-ID	2687154-3
ISSN	2050-084X ; 2050-084X
ISSN (online)	2050-084X
ISSN	2050-084X
DOI	10.7554/eLife.52063
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Article ; Online: The genetic basis of aneuploidy tolerance in wild yeast

James Hose / Leah E Escalante / Katie J Clowers / H Auguste Dutcher / DeElegant Robinson / Venera Bouriakov / Joshua J Coon / Evgenia Shishkova / Audrey P Gasch

eLife, Vol

2020 Volume 9

Abstract: Aneuploidy is highly detrimental during development yet common in cancers and pathogenic fungi – what gives rise to differences in aneuploidy tolerance remains unclear. We previously showed that wild isolates of Saccharomyces cerevisiae tolerate ... ...

Abstract	Aneuploidy is highly detrimental during development yet common in cancers and pathogenic fungi – what gives rise to differences in aneuploidy tolerance remains unclear. We previously showed that wild isolates of Saccharomyces cerevisiae tolerate chromosome amplification while laboratory strains used as a model for aneuploid syndromes do not. Here, we mapped the genetic basis to Ssd1, an RNA-binding translational regulator that is functional in wild aneuploids but defective in laboratory strain W303. Loss of SSD1 recapitulates myriad aneuploidy signatures previously taken as eukaryotic responses. We show that aneuploidy tolerance is enabled via a role for Ssd1 in mitochondrial physiology, including binding and regulating nuclear-encoded mitochondrial mRNAs, coupled with a role in mitigating proteostasis stress. Recapitulating ssd1Δ defects with combinatorial drug treatment selectively blocked proliferation of wild-type aneuploids compared to euploids. Our work adds to elegant studies in the sensitized laboratory strain to present a mechanistic understanding of eukaryotic aneuploidy tolerance.
Keywords	aneuploidy ; natural variation ; proteotoxicity ; wild strains ; Medicine ; R ; Science ; Q ; Biology (General) ; QH301-705.5
Language	English
Publishing date	2020-01-01T00:00:00Z
Publisher	eLife Sciences Publications Ltd
Document type	Article ; Online
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Article ; Online: Overall survival by clinical risk category for high dose interleukin-2 (HD IL-2) treated patients with metastatic renal cell cancer (mRCC): data from the PROCLAIM

Fishman, M / Dutcher, J P / Clark, J I / Alva, A / Miletello, G P / Curti, B / Agarwal, Neeraj / Hauke, R / Mahoney, K M / Moon, H / Treisman, J / Tykodi, S S / Daniels, G / Morse, M A / Wong, M K K / Kaufman, H / Gregory, N / McDermott, D F

Journal for immunotherapy of cancer

2019 Volume 7, Issue 1, Page(s) 84

Abstract: ... with ClinicalTrials.gov on August 11, 2011, and initiated for retrospective data collection until 2006, and ...

Abstract	Background: Prognostic scoring systems are used to estimate the risk of mortality from metastatic renal cell carcinoma (mRCC). Outcomes from different therapies may vary within each risk group. These survival algorithms have been applied to assess outcomes in patients receiving T-cell checkpoint inhibitory immunotherapy and tyrosine kinase inhibitor therapy, but have not been applied extensively to patients receiving high dose interleukin-2 (HD IL-2) immunotherapy. Methods: Survival of 810 mRCC patients treated from 2006 to 2017 with high dose IL-2 (aldesleukin) and enrolled in the PROCLAIM Results: Among the 810 patients, 721 were treatment-naïve (89%) and 59% were intermediate risk. Overall, of the 249 patients with favorable risk, the median overall survival (OS) is 63.3 mo. and the 2-year OS is 77.6%. Of 480 patients with intermediate risk, median OS is 42.4 mo., 2-year OS 68.2%, and of 81 patients with poor risk, median OS 14 mo., 2-year OS 40.4%. Among those who received IL-2 alone (356 patients), median OS is 64.5, 57.6, and 14 months for favorable, intermediate and poor risk categories respectively. Two year survival among those treated only with HD IL-2 is 73.4, 63.7 and 39.8%, for favorable, intermediate and poor risk categories respectively. Conclusions: Among mRCC patients treated with HD IL-2, all risk groups have median and 2-year survival consistent with recent reports of checkpoint or targeted therapies for mRCC. Favorable and intermediate risk (by IMDC) patients treated with HD IL-2 have longer OS compared with poor risk patients, with most durable OS observed in favorable risk patients. Favorable risk patients treated with HD IL-2 alone have a 2-year OS of 74%. These data continue to support a recommendation for HD IL-2 for patients with mRCC who meet eligibility criteria. Trial registration: PROCLAIM, NCT01415167 was registered with ClinicalTrials.gov on August 11, 2011, and initiated for retrospective data collection until 2006, and prospective data collection ongoing since 2011.
MeSH term(s)	Aged ; Antineoplastic Agents/administration & dosage ; Antineoplastic Agents/therapeutic use ; Carcinoma, Renal Cell/drug therapy ; Dose-Response Relationship, Drug ; Female ; Humans ; Interleukin-2/administration & dosage ; Interleukin-2/therapeutic use ; Kidney Neoplasms/drug therapy ; Male ; Middle Aged ; Molecular Targeted Therapy ; Neoplasm Metastasis ; Prospective Studies ; Retrospective Studies ; Survival Analysis ; Treatment Outcome
Chemical Substances	Antineoplastic Agents ; Interleukin-2
Language	English
Publishing date	2019-03-27
Publishing country	England
Document type	Clinical Trial ; Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2719863-7
ISSN	2051-1426 ; 2051-1426
ISSN (online)	2051-1426
ISSN	2051-1426
DOI	10.1186/s40425-019-0567-3
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Article ; Online: Medication reconciliation during the transition to and from long-term care settings: a systematic review.

Chhabra, Pankdeep T / Rattinger, Gail B / Dutcher, Sarah K / Hare, Melanie E / Parsons, Kelly L / Zuckerman, Ilene H

Research in social & administrative pharmacy : RSAP

2012 Volume 8, Issue 1, Page(s) 60–75

Abstract: ... A search was conducted on Ovid MEDLINE (1950-August 2010), Ovid HealthSTAR (1966-August 2010), Cumulative ... Index to Nursing and Allied Health Literature (1982-August 2010), PubMed (1980-August 2010 ... The Cochrane Database of Systematic Reviews (2005-August 2010), the Agency for Healthcare Research and Quality ...

Abstract	Background: Medication reconciliation has been recognized as an important process in care transitions to prevent adverse health outcomes. Because older adults have multiple comorbid conditions and use multiple medications, they are more likely to experience complicated transitions between acute and long-term care settings. Hence, it is important to develop effective interventions to protect older adults at transition points of care. Objective: To systematically review the literature and evaluate studies performing medication reconciliation interventions in patients transferred to and from long-term care settings. Methods: The literature search focused on studies that evaluated an intervention involving medication reconciliation in patients transferred to and/or from long-term care settings, such as nursing homes, skilled nursing facilities, residential care facilities, assisted living facilities, homes for the aged, and hospice care. A search was conducted on Ovid MEDLINE (1950-August 2010), Ovid HealthSTAR (1966-August 2010), Cumulative Index to Nursing and Allied Health Literature (1982-August 2010), PubMed (1980-August 2010), The Cochrane Database of Systematic Reviews (2005-August 2010), the Agency for Healthcare Research and Quality website, and reference lists of relevant articles were hand-searched. Two reviewers screened the titles and abstracts for potentially relevant studies. Data abstraction from the included articles was performed independently by 4 reviewers. Results: Seven studies met the inclusion criteria. Four studies were performed in the United States, whereas 3 studies were performed in other countries. A clinical pharmacist proved to be useful in providing medication reconciliation interventions by adopting specialized responsibilities such as serving as a transition pharmacist coordinator or working through a call center. Although improvement in the outcome(s) examined was shown in all of the studies, there were study design flaws. Conclusion: There is a need for well-designed studies demonstrating the effectiveness of medication reconciliation interventions in long-term care settings. Future studies should focus on employing appropriate methods so that their interventions can be evaluated more effectively.
MeSH term(s)	Continuity of Patient Care ; Humans ; Long-Term Care ; Medication Reconciliation ; Patient Transfer
Language	English
Publishing date	2012-01
Publishing country	United States
Document type	Journal Article ; Review
ZDB-ID	2192059-X
ISSN	1934-8150 ; 1551-7411
ISSN (online)	1934-8150
ISSN	1551-7411
DOI	10.1016/j.sapharm.2010.12.002
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