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Article ; Online: American Shoulder and Elbow Surgeons score: what does it tell us about patients selecting operative treatment of a rotator cuff injury?

Agel, Julie / Hebert-Davies, Jonah / Braman, Jonathan P

JSES international

2023 Volume 7, Issue 5, Page(s) 751–755

Abstract: Background: As shared decision-making rises in importance and minimum clinically important differences become benchmarks for treatment success or failure based on the increased usage of patient-reported outcomes, it is important to understand the ... ...

Abstract	Background: As shared decision-making rises in importance and minimum clinically important differences become benchmarks for treatment success or failure based on the increased usage of patient-reported outcomes, it is important to understand the breadth of starting points for patients as that should affect the interpretation of individual postoperative score changes. Methods: This is a retrospective data review of prospectively collected American Shoulder and Elbow Surgeons (ASES) score of patients electing to undergo rotator cuff repair with 1-year follow-up. A residual improvement: possible to achieve ratio (RIPAR) was calculated to demonstrate what percent of maximal possible improvement was gained at 1 year. A minimal clinically important difference (MCID) of 12 was used. Results: Three hundred thirty-five patients with an age range of 32-79 years form the population. Baseline ASES score ranged from 0 to 97.5, with a mean of 47.8. At 1 year, the mean was 84.7 (range, 30-100). There was no statistical difference by age, but men reported more overall preoperative dysfunction than women (50.3 vs. 44.1, Conclusions: The ASES scores showed a broad range of baseline scores for patients choosing to undergo rotator cuff repair highlighting the need for individual patient rather than population review of patient-reported outcome measures. As shared decision-making is taking on a larger role in clinical care, it is important to counsel patients accurately. Evaluating the ASES score by MCID and maximal possible improvement provides different population perspectives with the concept of RIPAR allowing for personalization of decision-making on the individual patient level.
Language	English
Publishing date	2023-05-19
Publishing country	United States
Document type	Journal Article
ISSN	2666-6383
ISSN (online)	2666-6383
DOI	10.1016/j.jseint.2023.04.007
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Article ; Online: The histone chaperone NASP maintains H3-H4 reservoirs in the early Drosophila embryo.

Tirgar, Reyhaneh / Davies, Jonathan P / Plate, Lars / Nordman, Jared T

PLoS genetics

2023 Volume 19, Issue 3, Page(s) e1010682

Abstract: Histones are essential for chromatin packaging, and histone supply must be tightly regulated as excess histones are toxic. To drive the rapid cell cycles of the early embryo, however, excess histones are maternally deposited. Therefore, soluble histones ... ...

Abstract	Histones are essential for chromatin packaging, and histone supply must be tightly regulated as excess histones are toxic. To drive the rapid cell cycles of the early embryo, however, excess histones are maternally deposited. Therefore, soluble histones must be buffered by histone chaperones, but the chaperone necessary to stabilize soluble H3-H4 pools in the Drosophila embryo has yet to be identified. Here, we show that CG8223, the Drosophila homolog of NASP, is a H3-H4-specific chaperone in the early embryo. We demonstrate that, while a NASP null mutant is viable in Drosophila, NASP is a maternal effect gene. Embryos laid by NASP mutant mothers have a reduced rate of hatching and show defects in early embryogenesis. Critically, soluble H3-H4 pools are degraded in embryos laid by NASP mutant mothers. Our work identifies NASP as the critical H3-H4 histone chaperone in the Drosophila embryo.
MeSH term(s)	Animals ; Histones/genetics ; Histones/metabolism ; Histone Chaperones/genetics ; Drosophila/genetics ; Drosophila/metabolism ; Chromatin ; Molecular Chaperones/genetics ; Molecular Chaperones/metabolism
Chemical Substances	Histones ; Histone Chaperones ; Chromatin ; Molecular Chaperones
Language	English
Publishing date	2023-03-17
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural
ZDB-ID	2186725-2
ISSN	1553-7404 ; 1553-7390
ISSN (online)	1553-7404
ISSN	1553-7390
DOI	10.1371/journal.pgen.1010682
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Article ; Online: Quantifying the proportion of different cell types in the human cortex using DNA methylation profiles.

Hannon, Eilis / Dempster, Emma L / Davies, Jonathan P / Chioza, Barry / Blake, Georgina E T / Burrage, Joe / Policicchio, Stefania / Franklin, Alice / Walker, Emma M / Bamford, Rosemary A / Schalkwyk, Leonard C / Mill, Jonathan

BMC biology

2024 Volume 22, Issue 1, Page(s) 17

Abstract: Background: Due to interindividual variation in the cellular composition of the human cortex, it is essential that covariates that capture these differences are included in epigenome-wide association studies using bulk tissue. As experimentally derived ... ...

Abstract	Background: Due to interindividual variation in the cellular composition of the human cortex, it is essential that covariates that capture these differences are included in epigenome-wide association studies using bulk tissue. As experimentally derived cell counts are often unavailable, computational solutions have been adopted to estimate the proportion of different cell types using DNA methylation data. Here, we validate and profile the use of an expanded reference DNA methylation dataset incorporating two neuronal and three glial cell subtypes for quantifying the cellular composition of the human cortex. Results: We tested eight reference panels containing different combinations of neuronal- and glial cell types and characterised their performance in deconvoluting cell proportions from computationally reconstructed or empirically derived human cortex DNA methylation data. Our analyses demonstrate that while these novel brain deconvolution models produce accurate estimates of cellular proportions from profiles generated on postnatal human cortex samples, they are not appropriate for the use in prenatal cortex or cerebellum tissue samples. Applying our models to an extensive collection of empirical datasets, we show that glial cells are twice as abundant as neuronal cells in the human cortex and identify significant associations between increased Alzheimer's disease neuropathology and the proportion of specific cell types including a decrease in NeuNNeg/SOX10Neg nuclei and an increase of NeuNNeg/SOX10Pos nuclei. Conclusions: Our novel deconvolution models produce accurate estimates for cell proportions in the human cortex. These models are available as a resource to the community enabling the control of cellular heterogeneity in epigenetic studies of brain disorders performed on bulk cortex tissue.
MeSH term(s)	Female ; Pregnancy ; Infant, Newborn ; Humans ; DNA Methylation ; Epigenesis, Genetic ; Neuroglia ; Cerebral Cortex ; Neurons/metabolism
Language	English
Publishing date	2024-01-25
Publishing country	England
Document type	Journal Article
ZDB-ID	2133020-7
ISSN	1741-7007 ; 1741-7007
ISSN (online)	1741-7007
ISSN	1741-7007
DOI	10.1186/s12915-024-01827-y
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Article: SARS-CoV-2 Nonstructural Proteins 3 and 4 tune the Unfolded Protein Response.

Davies, Jonathan P / Sivadas, Athira / Keller, Katherine R / Wojcikiewicz, Richard J H / Plate, Lars

bioRxiv : the preprint server for biology

2023

Abstract: Coronaviruses (CoV), including SARS-CoV-2, modulate host proteostasis through activation of stress-responsive signaling pathways such as the Unfolded Protein Response (UPR), which remedies misfolded protein accumulation by attenuating translation and ... ...

Abstract	Coronaviruses (CoV), including SARS-CoV-2, modulate host proteostasis through activation of stress-responsive signaling pathways such as the Unfolded Protein Response (UPR), which remedies misfolded protein accumulation by attenuating translation and increasing protein folding capacity. While CoV nonstructural proteins (nsps) are essential for infection, little is known about the role of nsps in modulating the UPR. We characterized the impact of SARS-CoV-2 nsp4, a key driver of replication, on the UPR using quantitative proteomics to sensitively detect pathway-wide upregulation of effector proteins. We find nsp4 preferentially activates the ATF6 and PERK branches of the UPR. Previously, we found an N-terminal truncation of nsp3 (nsp3.1) can suppress pharmacological ATF6 activation. To determine how nsp3.1 and nsp4 tune the UPR, their co-expression demonstrated that nsp3.1 suppresses nsp4-mediated PERK, but not ATF6 activation. Re-analysis of SARS-CoV-2 infection proteomics data revealed time-dependent activation of PERK targets early in infection, which subsequently fades. This temporal regulation suggests a role for nsp3 and nsp4 in tuning the PERK pathway to attenuate host translation beneficial for viral replication while avoiding later apoptotic signaling caused by chronic activation. This work furthers our understanding of CoV-host proteostasis interactions and highlights the power of proteomic methods for systems-level analysis of the UPR.
Language	English
Publishing date	2023-06-12
Publishing country	United States
Document type	Preprint
DOI	10.1101/2023.04.22.537917
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Article ; Online: BRWD3 promotes KDM5 degradation to maintain H3K4 methylation levels.

Han, Dongsheng / Schaffner, Samantha H / Davies, Jonathan P / Benton, Mary Lauren / Plate, Lars / Nordman, Jared T

Proceedings of the National Academy of Sciences of the United States of America

2023 Volume 120, Issue 39, Page(s) e2305092120

Abstract: Histone modifications are critical for regulating chromatin structure and gene expression. Dysregulation of histone modifications likely contributes to disease states and cancer. Depletion of the chromatin-binding protein BRWD3 (Bromodomain and WD repeat- ...

Abstract	Histone modifications are critical for regulating chromatin structure and gene expression. Dysregulation of histone modifications likely contributes to disease states and cancer. Depletion of the chromatin-binding protein BRWD3 (Bromodomain and WD repeat-containing protein 3), a known substrate-specificity factor of the Cul4-DDB1 E3 ubiquitin ligase complex, results in increased H3K4me1 (H3 lysine 4 monomethylation) levels. The underlying mechanism linking BRWD3 and H3K4 methylation, however, has yet to be defined. Here, we show that depleting BRWD3 not only causes an increase in H3K4me1 levels but also causes a decrease in H3K4me3 (H3 lysine 4 trimethylation) levels, indicating that BRWD3 influences H3K4 methylation more broadly. Using immunoprecipitation coupled to quantitative mass spectrometry, we identified an interaction between BRWD3 and the H3K4-specific lysine demethylase 5 (KDM5/Lid), an enzyme that removes tri- and dimethyl marks from H3K4. Moreover, analysis of ChIP-seq (chromatin immunoprecipitation sequencing) data revealed that BRWD3 and KDM5 are significantly colocalized throughout the genome and H3K4me3 are highly enriched at BRWD3 binding sites. We show that BRWD3 promotes K48-linked polyubiquitination and degradation of KDM5 and that KDM5 degradation is dependent on both BRWD3 and Cul4. Critically, depleting KDM5 fully restores altered H3K4me3 levels and partially restores H3K4me1 levels upon BRWD3 depletion. Together, our results demonstrate that BRWD3 regulates KDM5 activity to balance H3K4 methylation levels.
MeSH term(s)	Chromatin ; Histone Code ; Lysine ; Methylation ; Protein Processing, Post-Translational ; Drosophila ; Animals
Chemical Substances	Chromatin ; Lysine (K3Z4F929H6) ; Lid protein, Drosophila (EC 1.14.11.-) ; BRWD3 protein, Drosophila
Language	English
Publishing date	2023-09-18
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural
ZDB-ID	209104-5
ISSN	1091-6490 ; 0027-8424
ISSN (online)	1091-6490
ISSN	0027-8424
DOI	10.1073/pnas.2305092120
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Article ; Online: Elevated CO

Taylor, Christopher R / England, Luke C / Keane, J Ben / Davies, Jessica A C / Leake, Jonathan R / Hartley, Iain P / Smart, Simon M / Janes-Bassett, Victoria / Phoenix, Gareth K

Global change biology

2024 Volume 30, Issue 1, Page(s) e17104

Abstract: Globally pervasive increases in atmospheric ... ...

Abstract	Globally pervasive increases in atmospheric CO
MeSH term(s)	Grassland ; Carbon Dioxide/analysis ; Phosphorus ; Plants ; Poaceae ; Nitrogen ; Soil/chemistry ; Calcium Carbonate
Chemical Substances	Carbon Dioxide (142M471B3J) ; Phosphorus (27YLU75U4W) ; Nitrogen (N762921K75) ; Soil ; Calcium Carbonate (H0G9379FGK)
Language	English
Publishing date	2024-01-25
Publishing country	England
Document type	Journal Article
ZDB-ID	1281439-8
ISSN	1365-2486 ; 1354-1013
ISSN (online)	1365-2486
ISSN	1354-1013
DOI	10.1111/gcb.17104
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Article: Comparative host interactomes of the SARS-CoV-2 nonstructural protein 3 and human coronavirus homologs.

Almasy, Katherine M / Davies, Jonathan P / Plate, Lars

bioRxiv : the preprint server for biology

2021

Abstract: Human coronaviruses have become an increasing threat to global health; three highly pathogenic strains have emerged since the early 2000s, including most recently SARS-CoV-2, the cause of COVID-19. A better understanding of the molecular mechanisms of ... ...

Abstract	Human coronaviruses have become an increasing threat to global health; three highly pathogenic strains have emerged since the early 2000s, including most recently SARS-CoV-2, the cause of COVID-19. A better understanding of the molecular mechanisms of coronavirus pathogenesis is needed, including how these highly virulent strains differ from those that cause milder, common-cold like disease. While significant progress has been made in understanding how SARS-CoV-2 proteins interact with the host cell, non-structural protein 3 (nsp3) has largely been omitted from the analyses. Nsp3 is a viral protease with important roles in viral protein biogenesis, replication complex formation, and modulation of host ubiquitinylation and ISGylation. Herein, we use affinity purification-mass spectrometry to study the host-viral protein-protein interactome of nsp3 from five coronavirus strains: pathogenic strains SARS-CoV-2, SARS-CoV, and MERS-CoV; and endemic common-cold strains hCoV-229E and hCoV-OC43. We divide each nsp3 into three fragments and use tandem mass tag technology to directly compare the interactors across the five strains for each fragment. We find that few interactors are common across all variants for a particular fragment, but we identify shared patterns between select variants, such as ribosomal proteins enriched in the N-terminal fragment (nsp3.1) dataset for SARS-CoV-2 and SARS-CoV. We also identify unique biological processes enriched for individual homologs, for instance nuclear protein important for the middle fragment of hCoV-229E, as well as ribosome biogenesis of the MERS nsp3.2 homolog. Lastly, we further investigate the interaction of the SARS-CoV-2 nsp3 N-terminal fragment with ATF6, a regulator of the unfolded protein response. We show that SARS-CoV-2 nsp3.1 directly binds to ATF6 and can suppress the ATF6 stress response. Characterizing the host interactions of nsp3 widens our understanding of how coronaviruses co-opt cellular pathways and presents new avenues for host-targeted antiviral therapeutics.
Language	English
Publishing date	2021-03-08
Publishing country	United States
Document type	Preprint
DOI	10.1101/2021.03.08.434440
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Article ; Online: Trends in Urethral Suspension With Robotic Prostatectomy Procedures Following Medicare Payment Policy Changes.

Li, Jonathan / Patil, Dattatraya / Davies, Benjamin J / Filson, Christopher P

JAMA network open

2022 Volume 5, Issue 10, Page(s) e2233636

Abstract: Importance: In 2016, the Centers for Medicare and Medicaid Services cut payments for robotic prostatectomy performed for Medicare beneficiaries. Although regulations mandate that billing for urethral suspension is only acceptable for preexisting urinary ...

Abstract	Importance: In 2016, the Centers for Medicare and Medicaid Services cut payments for robotic prostatectomy performed for Medicare beneficiaries. Although regulations mandate that billing for urethral suspension is only acceptable for preexisting urinary incontinence, reductions in reimbursement may incentivize billing for the use of this procedure in other scenarios. Objective: To assess trends and geographic variations in payments for urethral suspension with robotic prostatectomy in the context of Medicare payment policy. Design, setting, and participants: This US population-based retrospective cohort study analyzed data from the IBM MarketScan Commercial Claims and Encounters and Medicare Supplemental Database for men with employer-based insurance (primary commercial or Medicare supplemental coverage) who underwent robotic prostatectomy (Current Procedural Terminology [CPT] code 55866) between 2009 and 2019. Exposures: Time period and metropolitan statistical area of patient residence. Main outcomes and measures: Payment for urethral suspension (CPT code 51990) with robotic prostatectomy. Results: We identified 87 774 men with prostate cancer treated with robotic prostatectomy; 3352 (3.8%) had undergone urethral suspension. The mean (SD) patient age was 59.7 (6.5) years; 16 870 patients (19.2%) had Medicare supplemental coverage. From 2015 to 2016, median payments for robotic prostatectomy changed by -$358 (-17.0%) for Medicare beneficiaries vs -$9 (0%) for commercially insured patients. With urethral suspension vs without, median (IQR) episode payments for robotic prostatectomy were higher for commercially insured men ($3678 [$3090-$4503] vs $3322 [$2601-$4306]) and Medicare beneficiaries ($2927 [$2450-$3909] vs $2379 [$2014-$3512]). Compared with men treated between 2013 and 2015, those treated between 2016 and 2017 were twice as likely to undergo urethral suspension (8.5% vs 4.1%; odds ratio, 2.17 [95% CI, 1.96-2.38]). The proportion of patients who underwent urethral suspension was stable for 2018 to 2019 and 2016 to 2017 (8.5% vs 9.0%; odds ratio, 1.06 [95% CI, 0.96-1.18]). From 2015 to 2019, the proportion of patients who underwent urethral suspension was highest in Charleston, South Carolina (92.0%), Knoxville, Tennessee (66.0%), and Columbia, South Carolina (58.0%). These regions neighbored high-volume areas without patients who underwent prostatectomy with urethral suspension (eg, 146 patients in Greenville, South Carolina, and 173 in Nashville, Tennessee). Conclusions and relevance: In this study, urethral suspension was associated with increased costs for patients with both commercial insurance and Medicare. Patients treated between 2016 and 2017 were more likely than those treated between 2013 and 2015 to undergo this procedure. Geographic variation in use exceeded what was expected for the preexisting condition for which billing is permitted for Medicare beneficiaries. Policy statements from professional societies highlighting appropriate billing for urethral suspension may have tempered, but not reversed, the broad adoption of this procedure.
MeSH term(s)	Aged ; Humans ; Male ; Medicare ; Middle Aged ; Policy ; Prostatectomy ; Retrospective Studies ; Robotic Surgical Procedures ; United States
Language	English
Publishing date	2022-10-03
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ISSN	2574-3805
ISSN (online)	2574-3805
DOI	10.1001/jamanetworkopen.2022.33636
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Article ; Online: Comparative Host Interactomes of the SARS-CoV-2 Nonstructural Protein 3 and Human Coronavirus Homologs.

Almasy, Katherine M / Davies, Jonathan P / Plate, Lars

Molecular & cellular proteomics : MCP

2021 Volume 20, Page(s) 100120

Abstract	Human coronaviruses have become an increasing threat to global health; three highly pathogenic strains have emerged since the early 2000s, including most recently SARS-CoV-2, the cause of COVID-19. A better understanding of the molecular mechanisms of coronavirus pathogenesis is needed, including how these highly virulent strains differ from those that cause milder, common-cold-like disease. While significant progress has been made in understanding how SARS-CoV-2 proteins interact with the host cell, nonstructural protein 3 (nsp3) has largely been omitted from the analyses. Nsp3 is a viral protease with important roles in viral protein biogenesis, replication complex formation, and modulation of host ubiquitinylation and ISGylation. Herein, we use affinity purification-mass spectrometry to study the host-viral protein-protein interactome of nsp3 from five coronavirus strains: pathogenic strains SARS-CoV-2, SARS-CoV, and MERS-CoV; and endemic common-cold strains hCoV-229E and hCoV-OC43. We divide each nsp3 into three fragments and use tandem mass tag technology to directly compare the interactors across the five strains for each fragment. We find that few interactors are common across all variants for a particular fragment, but we identify shared patterns between select variants, such as ribosomal proteins enriched in the N-terminal fragment (nsp3.1) data set for SARS-CoV-2 and SARS-CoV. We also identify unique biological processes enriched for individual homologs, for instance, nuclear protein import for the middle fragment of hCoV-229E, as well as ribosome biogenesis of the MERS nsp3.2 homolog. Lastly, we further investigate the interaction of the SARS-CoV-2 nsp3 N-terminal fragment with ATF6, a regulator of the unfolded protein response. We show that SARS-CoV-2 nsp3.1 directly binds to ATF6 and can suppress the ATF6 stress response. Characterizing the host interactions of nsp3 widens our understanding of how coronaviruses co-opt cellular pathways and presents new avenues for host-targeted antiviral therapeutics.
MeSH term(s)	Activating Transcription Factor 6/metabolism ; Coronavirus 229E, Human/metabolism ; Coronavirus 229E, Human/pathogenicity ; Coronavirus OC43, Human/metabolism ; Coronavirus OC43, Human/pathogenicity ; Coronavirus Papain-Like Proteases/genetics ; Coronavirus Papain-Like Proteases/metabolism ; Endoplasmic Reticulum-Associated Degradation ; HEK293 Cells ; Host-Pathogen Interactions/physiology ; Humans ; Middle East Respiratory Syndrome Coronavirus/metabolism ; Middle East Respiratory Syndrome Coronavirus/pathogenicity ; Protein Interaction Maps ; SARS-CoV-2/metabolism ; SARS-CoV-2/pathogenicity ; Unfolded Protein Response ; Viral Nonstructural Proteins/genetics ; Viral Nonstructural Proteins/metabolism
Chemical Substances	ATF6 protein, human ; Activating Transcription Factor 6 ; Nsp3 protein, Middle East respiratory syndrome coronavirus ; Viral Nonstructural Proteins ; Coronavirus Papain-Like Proteases (EC 3.4.22.2) ; papain-like protease, SARS-CoV-2 (EC 3.4.22.2)
Language	English
Publishing date	2021-06-27
Publishing country	United States
Document type	Comparative Study ; Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't ; Research Support, U.S. Gov't, Non-P.H.S.
ZDB-ID	2075924-1
ISSN	1535-9484 ; 1535-9476
ISSN (online)	1535-9484
ISSN	1535-9476
DOI	10.1016/j.mcpro.2021.100120
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Article ; Online: Seabird and reef conservation must include coral islands.

Berr, Tristan / Dias, Maria P / Andréfouët, Serge / Davies, Tammy / Handley, Jonathan / Le Corre, Matthieu / Millon, Alexandre / Vidal, Éric

Trends in ecology & evolution

2023 Volume 38, Issue 6, Page(s) 490–494

Abstract: Tropical seabirds exert key roles in reef ecosystems but face growing threats from climate change, especially on coral reef islands (CRIs). Therefore, we advocate for a more comprehensive, global data exchange on CRIs and CRI-dependent seabirds and ... ...

Abstract	Tropical seabirds exert key roles in reef ecosystems but face growing threats from climate change, especially on coral reef islands (CRIs). Therefore, we advocate for a more comprehensive, global data exchange on CRIs and CRI-dependent seabirds and outline steps for improving their study and conservation.
MeSH term(s)	Animals ; Anthozoa ; Ecosystem ; Islands ; Coral Reefs ; Climate Change ; Birds ; Conservation of Natural Resources
Language	English
Publishing date	2023-03-14
Publishing country	England
Document type	Journal Article
ZDB-ID	284965-3
ISSN	1872-8383 ; 0169-5347
ISSN (online)	1872-8383
ISSN	0169-5347
DOI	10.1016/j.tree.2023.02.004
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