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Book ; Online: Hamiltonian Neural Networks

Greydanus, Sam / Dzamba, Misko / Yosinski, Jason

2019

Abstract: Even though neural networks enjoy widespread use, they still struggle to learn the basic laws of physics. How might we endow them with better inductive biases? In this paper, we draw inspiration from Hamiltonian mechanics to train models that learn and ... ...

Abstract	Even though neural networks enjoy widespread use, they still struggle to learn the basic laws of physics. How might we endow them with better inductive biases? In this paper, we draw inspiration from Hamiltonian mechanics to train models that learn and respect exact conservation laws in an unsupervised manner. We evaluate our models on problems where conservation of energy is important, including the two-body problem and pixel observations of a pendulum. Our model trains faster and generalizes better than a regular neural network. An interesting side effect is that our model is perfectly reversible in time. Comment: Conference paper at NeurIPS 2019. Main paper has 8 pages and 5 figures
Keywords	Computer Science - Neural and Evolutionary Computing
Publishing date	2019-06-04
Publishing country	us
Document type	Book ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Structural Variant in Mitochondrial-Associated Gene (MRPL3) Induces Adult-Onset Neurodegeneration with Memory Impairment in the Mouse.

Cahill, Lindsay S / Cameron, Jessie M / Winterburn, Julie / Macos, Patrick / Hoggarth, Johnathan / Dzamba, Misko / Brudno, Michael / Nutter, Lauryl M J / Sproule, Thomas J / Burgess, Robert W / Henkelman, R Mark / Sled, John G

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

2020 Volume 40, Issue 23, Page(s) 4576–4585

Abstract: An impediment to the development of effective therapies for neurodegenerative disease is that available animal models do not reproduce important clinical features such as adult-onset and stereotypical patterns of progression. ... ...

Abstract	An impediment to the development of effective therapies for neurodegenerative disease is that available animal models do not reproduce important clinical features such as adult-onset and stereotypical patterns of progression. Using
MeSH term(s)	Age Factors ; Animals ; Female ; Genetic Variation/genetics ; Male ; Memory Disorders/diagnostic imaging ; Memory Disorders/genetics ; Mice ; Mice, Inbred C57BL ; Mice, Transgenic ; Mitochondrial Proteins/genetics ; Neurodegenerative Diseases/diagnostic imaging ; Neurodegenerative Diseases/genetics ; Ribosomal Proteins/genetics
Chemical Substances	MRPL3 protein, human ; Mitochondrial Proteins ; Ribosomal Proteins
Language	English
Publishing date	2020-04-27
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.0013-20.2020
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Article ; Online: Identification of complex genomic rearrangements in cancers using CouGaR.

Dzamba, Misko / Ramani, Arun K / Buczkowicz, Pawel / Jiang, Yue / Yu, Man / Hawkins, Cynthia / Brudno, Michael

Genome research

2017 Volume 27, Issue 1, Page(s) 107–117

Abstract: The genomic alterations associated with cancers are numerous and varied, involving both isolated and large-scale complex genomic rearrangements (CGRs). Although the underlying mechanisms are not well understood, CGRs have been implicated in tumorigenesis. ...

Abstract	The genomic alterations associated with cancers are numerous and varied, involving both isolated and large-scale complex genomic rearrangements (CGRs). Although the underlying mechanisms are not well understood, CGRs have been implicated in tumorigenesis. Here, we introduce CouGaR, a novel method for characterizing the genomic structure of amplified CGRs, leveraging both depth of coverage (DOC) and discordant pair-end mapping techniques. We applied our method to whole-genome sequencing (WGS) samples from The Cancer Genome Atlas and identify amplified CGRs in at least 5.2% (10+ copies) to 17.8% (6+ copies) of the samples. Furthermore, ∼95% of these amplified CGRs contain genes previously implicated in tumorigenesis, indicating the importance and widespread occurrence of CGRs in cancers. Additionally, CouGaR identified the occurrence of 'chromoplexy' in nearly 63% of all prostate cancer samples and 30% of all bladder cancer samples. To further validate the accuracy of our method, we experimentally tested 17 predicted fusions in two pediatric glioma samples and validated 15 of these (88%) with precise resolution of the breakpoints via qPCR experiments and Sanger sequencing, with nearly perfect copy count concordance. Additionally, to further help display and understand the structure of CGRs, we have implemented CouGaR-viz, a generic stand-alone tool for visualization of the copy count of regions, breakpoints, and relevant genes.
Language	English
Publishing date	2017-01
Publishing country	United States
Document type	Journal Article
ZDB-ID	1284872-4
ISSN	1549-5469 ; 1088-9051 ; 1054-9803
ISSN (online)	1549-5469
ISSN	1088-9051 ; 1054-9803
DOI	10.1101/gr.211201.116
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Article ; Online: SHRiMP2: sensitive yet practical SHort Read Mapping.

David, Matei / Dzamba, Misko / Lister, Dan / Ilie, Lucian / Brudno, Michael

Bioinformatics (Oxford, England)

2011 Volume 27, Issue 7, Page(s) 1011–1012

Abstract: Unlabelled: We report on a major update (version 2) of the original SHort Read Mapping Program (SHRiMP). SHRiMP2 primarily targets mapping sensitivity, and is able to achieve high accuracy at a very reasonable speed. SHRiMP2 supports both letter space ... ...

Abstract	Unlabelled: We report on a major update (version 2) of the original SHort Read Mapping Program (SHRiMP). SHRiMP2 primarily targets mapping sensitivity, and is able to achieve high accuracy at a very reasonable speed. SHRiMP2 supports both letter space and color space (AB/SOLiD) reads, enables for direct alignment of paired reads and uses parallel computation to fully utilize multi-core architectures. Availability: SHRiMP2 executables and source code are freely available at: http://compbio.cs.toronto.edu/shrimp/.
MeSH term(s)	Algorithms ; Chromosome Mapping ; Genomics/methods ; Polymorphism, Genetic ; Sequence Alignment ; Sequence Analysis, DNA ; Software
Language	English
Publishing date	2011-04-01
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Research Support, U.S. Gov't, Non-P.H.S.
ZDB-ID	1422668-6
ISSN	1367-4811 ; 1367-4803
ISSN (online)	1367-4811
ISSN	1367-4803
DOI	10.1093/bioinformatics/btr046
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Article ; Online: Detecting copy number variation with mated short reads.

Medvedev, Paul / Fiume, Marc / Dzamba, Misko / Smith, Tim / Brudno, Michael

Genome research

2010 Volume 20, Issue 11, Page(s) 1613–1622

Abstract: The development of high-throughput sequencing (HTS) technologies has opened the door to novel methods for detecting copy number variants (CNVs) in the human genome. While in the past CNVs have been detected based on array CGH data, recent studies have ... ...

Abstract	The development of high-throughput sequencing (HTS) technologies has opened the door to novel methods for detecting copy number variants (CNVs) in the human genome. While in the past CNVs have been detected based on array CGH data, recent studies have shown that depth-of-coverage information from HTS technologies can also be used for the reliable identification of large copy-variable regions. Such methods, however, are hindered by sequencing biases that lead certain regions of the genome to be over- or undersampled, lowering their resolution and ability to accurately identify the exact breakpoints of the variants. In this work, we develop a method for CNV detection that supplements the depth-of-coverage with paired-end mapping information, where mate pairs mapping discordantly to the reference serve to indicate the presence of variation. Our algorithm, called CNVer, combines this information within a unified computational framework called the donor graph, allowing us to better mitigate the sequencing biases that cause uneven local coverage and accurately predict CNVs. We use CNVer to detect 4879 CNVs in the recently described genome of a Yoruban individual. Most of the calls (77%) coincide with previously known variants within the Database of Genomic Variants, while 81% of deletion copy number variants previously known for this individual coincide with one of our loss calls. Furthermore, we demonstrate that CNVer can reconstruct the absolute copy counts of segments of the donor genome and evaluate the feasibility of using CNVer with low coverage datasets.
MeSH term(s)	Algorithms ; Base Pairing/physiology ; Base Sequence/physiology ; Chromosome Breakage ; Chromosome Mapping/methods ; DNA Copy Number Variations/genetics ; DNA Mutational Analysis/methods ; DNA Shuffling ; High-Throughput Nucleotide Sequencing/methods ; Humans ; Reproducibility of Results
Language	English
Publishing date	2010-08-30
Publishing country	United States
Document type	Comparative Study ; Journal Article ; Validation Study
ZDB-ID	1284872-4
ISSN	1549-5469 ; 1088-9051 ; 1054-9803
ISSN (online)	1549-5469
ISSN	1088-9051 ; 1054-9803
DOI	10.1101/gr.106344.110
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Article ; Online: A novel strain of cynomolgus macaque cytomegalovirus: implications for host-virus co-evolution.

Russell, Justen N Hoffman / Marsh, Angie K / Willer, David O / Ambagala, Aruna P N / Dzamba, Misko / Chan, Jacqueline K / Pilon, Richard / Fournier, Jocelyn / Brudno, Michael / Antony, Joseph M / Sandstrom, Paul / Evans, Ben J / MacDonald, Kelly S

BMC genomics

2016 Volume 17, Page(s) 277

Abstract: Background: Cytomegaloviruses belong to a large, ancient, genus of DNA viruses comprised of a wide array of species-specific strains that occur in diverse array of hosts.: Methods: In this study we sequenced the ~217 Kb genome of a cytomegalovirus ... ...

Abstract	Background: Cytomegaloviruses belong to a large, ancient, genus of DNA viruses comprised of a wide array of species-specific strains that occur in diverse array of hosts. Methods: In this study we sequenced the ~217 Kb genome of a cytomegalovirus isolated from a Mauritius cynomolgus macaque, CyCMV Mauritius, and compared it to previously sequenced cytomegaloviruses from a cynomolgus macaque of Filipino origin (CyCMV Ottawa) and two from Indian rhesus macaques (RhCMV 180.92 and RhCMV 68-1). Results: Though more closely related to CyCMV Ottawa, CyCMV Mauritius is less genetically distant from both RhCMV strains than is CyCMV Ottawa. Several individual genes, including homologues of CMV genes RL11B, UL123, UL83b, UL84 and a homologue of mammalian COX-2, show a closer relationship between homologues of CyCMV Mauritius and the RhCMVs than between homologues of CyCMV Mauritius and CyCMV Ottawa. A broader phylogenetic analysis of 12 CMV strains from eight species recovers evolutionary relationships among viral strains that mirror those amongst the host species, further demonstrating co-evolution of host and virus. Conclusions: Phylogenetic analyses of rhesus and cynomolgus macaque CMV genome sequences demonstrate co-speciation of the virus and host.
MeSH term(s)	Animals ; Biological Evolution ; Cytomegalovirus/classification ; Cytomegalovirus/genetics ; Cytomegalovirus/isolation & purification ; DNA, Viral/genetics ; Genome, Viral ; Macaca fascicularis/virology ; Macaca mulatta/virology ; Phylogeny ; Sequence Analysis, DNA ; Species Specificity
Chemical Substances	DNA, Viral
Language	English
Publishing date	2016-04-05
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ISSN	1471-2164
ISSN (online)	1471-2164
DOI	10.1186/s12864-016-2588-3
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Article ; Online: Variant detection and the Autism sequencing project

Buske Orion / Dzamba Misko / Foong Justin / Lau Lynette / Fiume Marc / Marshall Christian / Walker Susan / Prasad Aparna / Brudno Michael

BMC Bioinformatics, Vol 12, Iss Suppl 11, p A

2011 Volume 4

Keywords	Biology (General) ; QH301-705.5 ; Science ; Q ; DOAJ:Biology ; DOAJ:Biology and Life Sciences
Language	English
Publishing date	2011-11-01T00:00:00Z
Publisher	BioMed Central
Document type	Article ; Online
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Article ; Online: Genomic sequencing and characterization of cynomolgus macaque cytomegalovirus.

Marsh, Angie K / Willer, David O / Ambagala, Aruna P N / Dzamba, Misko / Chan, Jacqueline K / Pilon, Richard / Fournier, Jocelyn / Sandstrom, Paul / Brudno, Michael / MacDonald, Kelly S

Journal of virology

2011 Volume 85, Issue 24, Page(s) 12995–13009

Abstract: Cytomegalovirus (CMV) infection is the most common opportunistic infection in immunosuppressed individuals, such as transplant recipients or people living with HIV/AIDS, and congenital CMV is the leading viral cause of developmental disabilities in ... ...

Abstract	Cytomegalovirus (CMV) infection is the most common opportunistic infection in immunosuppressed individuals, such as transplant recipients or people living with HIV/AIDS, and congenital CMV is the leading viral cause of developmental disabilities in infants. Due to the highly species-specific nature of CMV, animal models that closely recapitulate human CMV (HCMV) are of growing importance for vaccine development. Here we present the genomic sequence of a novel nonhuman primate CMV from cynomolgus macaques (Macaca fascicularis; CyCMV). CyCMV (Ottawa strain) was isolated from the urine of a healthy, captive-bred, 4-year-old cynomolgus macaque of Philippine origin, and the viral genome was sequenced using next-generation Illumina sequencing to an average of 516-fold coverage. The CyCMV genome is 218,041 bp in length, with 49.5% G+C content and 84% protein-coding density. We have identified 262 putative open reading frames (ORFs) with an average coding length of 789 bp. The genomic organization of CyCMV is largely colinear with that of rhesus macaque CMV (RhCMV). Of the 262 CyCMV ORFs, 137 are homologous to HCMV genes, 243 are homologous to RhCMV 68.1, and 200 are homologous to RhCMV 180.92. CyCMV encodes four ORFs that are not present in RhCMV strain 68.1 or 180.92 but have homologies with HCMV (UL30, UL74A, UL126, and UL146). Similar to HCMV, CyCMV does not produce the RhCMV-specific viral homologue of cyclooxygenase-2. This newly characterized CMV may provide a novel model in which to study CMV biology and HCMV vaccine development.
MeSH term(s)	Animals ; Base Composition ; Carrier State/veterinary ; Carrier State/virology ; Cytomegalovirus/genetics ; Cytomegalovirus/isolation & purification ; Cytomegalovirus Infections/veterinary ; Cytomegalovirus Infections/virology ; DNA, Viral/chemistry ; DNA, Viral/genetics ; Genome, Viral ; Macaca fascicularis/virology ; Molecular Sequence Data ; Open Reading Frames ; Philippines ; Sequence Analysis, DNA ; Urine/virology ; Viral Proteins/genetics
Chemical Substances	DNA, Viral ; Viral Proteins
Keywords	covid19
Language	English
Publishing date	2011-10-12
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	80174-4
ISSN	1098-5514 ; 0022-538X
ISSN (online)	1098-5514
ISSN	0022-538X
DOI	10.1128/JVI.05840-11
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Article: Genomic Sequencing and Characterization of Cynomolgus Macaque Cytomegalovirus

Marsh, Angie K / Willer, David O / Ambagala, Aruna P. N / Dzamba, Misko / Chan, Jacqueline K / Pilon, Richard / Fournier, Jocelyn / Sandstrom, Paul / Brudno, Michael / MacDonald, Kelly S

J Virol. 2011 Dec. 15, v. 85, no. 24

2011

Abstract	Cytomegalovirus (CMV) infection is the most common opportunistic infection in immunosuppressed individuals, such as transplant recipients or people living with HIV/AIDS, and congenital CMV is the leading viral cause of developmental disabilities in infants. Due to the highly species-specific nature of CMV, animal models that closely recapitulate human CMV (HCMV) are of growing importance for vaccine development. Here we present the genomic sequence of a novel nonhuman primate CMV from cynomolgus macaques (Macaca fascicularis; CyCMV). CyCMV (Ottawa strain) was isolated from the urine of a healthy, captive-bred, 4-year-old cynomolgus macaque of Philippine origin, and the viral genome was sequenced using next-generation Illumina sequencing to an average of 516-fold coverage. The CyCMV genome is 218,041 bp in length, with 49.5% G+C content and 84% protein-coding density. We have identified 262 putative open reading frames (ORFs) with an average coding length of 789 bp. The genomic organization of CyCMV is largely colinear with that of rhesus macaque CMV (RhCMV). Of the 262 CyCMV ORFs, 137 are homologous to HCMV genes, 243 are homologous to RhCMV 68.1, and 200 are homologous to RhCMV 180.92. CyCMV encodes four ORFs that are not present in RhCMV strain 68.1 or 180.92 but have homologies with HCMV (UL30, UL74A, UL126, and UL146). Similar to HCMV, CyCMV does not produce the RhCMV-specific viral homologue of cyclooxygenase-2. This newly characterized CMV may provide a novel model in which to study CMV biology and HCMV vaccine development.
Keywords	Human herpesvirus 5 ; Macaca fascicularis ; Macacine herpesvirus 3 ; animal models ; genes ; genomics ; humans ; open reading frames ; people ; prostaglandin synthase ; sequence analysis ; urine ; vaccine development ; viral diseases of animals and humans
Language	English
Dates of publication	2011-1215
Size	p. 12995-13009.
Publishing place	American Society for Microbiology
Document type	Article
ZDB-ID	80174-4
ISSN	1098-5514 ; 0022-538X
ISSN (online)	1098-5514
ISSN	0022-538X
Database	NAL-Catalogue (AGRICOLA)

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Article ; Online: Genomic analysis of diffuse intrinsic pontine gliomas identifies three molecular subgroups and recurrent activating ACVR1 mutations.

Buczkowicz, Pawel / Hoeman, Christine / Rakopoulos, Patricia / Pajovic, Sanja / Letourneau, Louis / Dzamba, Misko / Morrison, Andrew / Lewis, Peter / Bouffet, Eric / Bartels, Ute / Zuccaro, Jennifer / Agnihotri, Sameer / Ryall, Scott / Barszczyk, Mark / Chornenkyy, Yevgen / Bourgey, Mathieu / Bourque, Guillaume / Montpetit, Alexandre / Cordero, Francisco /

Castelo-Branco, Pedro / Mangerel, Joshua / Tabori, Uri / Ho, King Ching / Huang, Annie / Taylor, Kathryn R / Mackay, Alan / Bendel, Anne E / Nazarian, Javad / Fangusaro, Jason R / Karajannis, Matthias A / Zagzag, David / Foreman, Nicholas K / Donson, Andrew / Hegert, Julia V / Smith, Amy / Chan, Jennifer / Lafay-Cousin, Lucy / Dunn, Sandra / Hukin, Juliette / Dunham, Chris / Scheinemann, Katrin / Michaud, Jean / Zelcer, Shayna / Ramsay, David / Cain, Jason / Brennan, Cameron / Souweidane, Mark M / Jones, Chris / Allis, C David / Brudno, Michael / Becher, Oren / Hawkins, Cynthia

Nature genetics

2014 Volume 46, Issue 5, Page(s) 451–456

Abstract: Diffuse intrinsic pontine glioma (DIPG) is a fatal brain cancer that arises in the brainstem of children, with no effective treatment and near 100% fatality. The failure of most therapies can be attributed to the delicate location of these tumors and to ... ...

Abstract	Diffuse intrinsic pontine glioma (DIPG) is a fatal brain cancer that arises in the brainstem of children, with no effective treatment and near 100% fatality. The failure of most therapies can be attributed to the delicate location of these tumors and to the selection of therapies on the basis of assumptions that DIPGs are molecularly similar to adult disease. Recent studies have unraveled the unique genetic makeup of this brain cancer, with nearly 80% found to harbor a p.Lys27Met histone H3.3 or p.Lys27Met histone H3.1 alteration. However, DIPGs are still thought of as one disease, with limited understanding of the genetic drivers of these tumors. To understand what drives DIPGs, we integrated whole-genome sequencing with methylation, expression and copy number profiling, discovering that DIPGs comprise three molecularly distinct subgroups (H3-K27M, silent and MYCN) and uncovering a new recurrent activating mutation affecting the activin receptor gene ACVR1 in 20% of DIPGs. Mutations in ACVR1 were constitutively activating, leading to SMAD phosphorylation and increased expression of the downstream activin signaling targets ID1 and ID2. Our results highlight distinct molecular subgroups and novel therapeutic targets for this incurable pediatric cancer.
MeSH term(s)	Activin Receptors, Type I/genetics ; Animals ; Brain Stem Neoplasms/classification ; Brain Stem Neoplasms/genetics ; Child ; DNA Copy Number Variations ; DNA Methylation ; Gene Expression Profiling ; Gene Expression Regulation, Neoplastic/genetics ; Genome, Human/genetics ; Glioma/classification ; Glioma/genetics ; Humans ; Inhibitor of Differentiation Protein 1/metabolism ; Inhibitor of Differentiation Protein 2/metabolism ; Phosphorylation ; Sequence Analysis, DNA ; Smad Proteins/metabolism ; Zebrafish
Chemical Substances	ID1 protein, human ; ID2 protein, human ; Inhibitor of Differentiation Protein 1 ; Inhibitor of Differentiation Protein 2 ; Smad Proteins ; ACVR1 protein, human (EC 2.7.11.30) ; Activin Receptors, Type I (EC 2.7.11.30)
Language	English
Publishing date	2014-04-06
Publishing country	United States
Document type	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	1108734-1
ISSN	1546-1718 ; 1061-4036
ISSN (online)	1546-1718
ISSN	1061-4036
DOI	10.1038/ng.2936
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