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Article ; Online: Epigenetic Effects of Polybrominated Diphenyl Ethers on Human Health.

Poston, Robert G / Saha, Ramendra N

International journal of environmental research and public health

2019 Volume 16, Issue 15

Abstract: Disruption of epigenetic regulation by environmental toxins is an emerging area of focus for understanding the latter's impact on human health. Polybrominated diphenyl ethers (PBDEs), one such group of toxins, are an environmentally pervasive class of ... ...

Abstract	Disruption of epigenetic regulation by environmental toxins is an emerging area of focus for understanding the latter's impact on human health. Polybrominated diphenyl ethers (PBDEs), one such group of toxins, are an environmentally pervasive class of brominated flame retardants that have been extensively used as coatings on a wide range of consumer products. Their environmental stability, propensity for bioaccumulation, and known links to adverse health effects have evoked extensive research to characterize underlying biological mechanisms of toxicity. Of particular concern is the growing body of evidence correlating human exposure levels to behavioral deficits related to neurodevelopmental disorders. The developing nervous system is particularly sensitive to influence by environmental signals, including dysregulation by toxins. Several major modes of actions have been identified, but a clear understanding of how observed effects relate to negative impacts on human health has not been established. Here, we review the current body of evidence for PBDE-induced epigenetic disruptions, including DNA methylation, chromatin dynamics, and non-coding RNA expression while discussing the potential relationship between PBDEs and neurodevelopmental disorders.
MeSH term(s)	DNA Methylation ; Environmental Pollutants/toxicity ; Epigenesis, Genetic/drug effects ; Flame Retardants/toxicity ; Halogenated Diphenyl Ethers/toxicity ; Humans
Chemical Substances	Environmental Pollutants ; Flame Retardants ; Halogenated Diphenyl Ethers ; pentabromodiphenyl ether (7REL09ZX35)
Language	English
Publishing date	2019-07-29
Publishing country	Switzerland
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Review
ISSN	1660-4601
ISSN (online)	1660-4601
DOI	10.3390/ijerph16152703
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Article ; Online: Merits and Limitations of Studying Neuronal Depolarization-Dependent Processes Using Elevated External Potassium.

Rienecker, Kira D A / Poston, Robert G / Saha, Ramendra N

ASN neuro

2020 Volume 12, Page(s) 1759091420974807

Abstract: Elevated extracellular potassium chloride is widely used to achieve membrane depolarization of cultured neurons. This technique has illuminated mechanisms of calcium influx through L-type voltage sensitive calcium channels, activity-regulated signaling, ... ...

Abstract	Elevated extracellular potassium chloride is widely used to achieve membrane depolarization of cultured neurons. This technique has illuminated mechanisms of calcium influx through L-type voltage sensitive calcium channels, activity-regulated signaling, downstream transcriptional events, and many other intracellular responses to depolarization. However, there is enormous variability in these treatments, including durations from seconds to days and concentrations from 3mM to 150 mM KCl. Differential effects of these variable protocols on neuronal activity and transcriptional programs are underexplored. Furthermore, potassium chloride treatments
MeSH term(s)	Action Potentials/drug effects ; Action Potentials/physiology ; Animals ; Calcium Channels, L-Type/physiology ; Humans ; Membrane Potentials/drug effects ; Membrane Potentials/physiology ; Neuromuscular Depolarizing Agents/pharmacology ; Neurons/drug effects ; Neurons/physiology ; Potassium Chloride/pharmacology
Chemical Substances	Calcium Channels, L-Type ; Neuromuscular Depolarizing Agents ; Potassium Chloride (660YQ98I10)
Language	English
Publishing date	2020-11-30
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Review
ZDB-ID	2485467-0
ISSN	1759-0914 ; 1759-0914
ISSN (online)	1759-0914
ISSN	1759-0914
DOI	10.1177/1759091420974807
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Article: Activity-assembled nBAF complex mediates rapid immediate early gene transcription by regulating RNA Polymerase II productive elongation.

Cornejo, Karen G / Venegas, Andie / Sono, Morgan H / Door, Madeline / Gutierrez-Ruiz, Brenda / Karabedian, Lucy B / Nandi, Supratik G / Dykhuizen, Emily C / Saha, Ramendra N

bioRxiv : the preprint server for biology

2023

Abstract: Signal-dependent RNA Polymerase II (Pol2) productive elongation is an integral component of gene transcription, including those of immediate early genes (IEGs) induced by neuronal activity. However, it remains unclear how productively elongating Pol2 ... ...

Abstract	Signal-dependent RNA Polymerase II (Pol2) productive elongation is an integral component of gene transcription, including those of immediate early genes (IEGs) induced by neuronal activity. However, it remains unclear how productively elongating Pol2 overcome nucleosomal barriers. Using RNAi, three degraders, and several small molecule inhibitors, we show that the mammalian SWI/SNF complex of neurons (neuronal BAF, or nBAF) is required for activity-induced transcription of neuronal IEGs, including
Language	English
Publishing date	2023-12-30
Publishing country	United States
Document type	Preprint
DOI	10.1101/2023.12.30.573688
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Article ; Online: Persistent 6-OH-BDE-47 exposure impairs functional neuronal maturation and alters expression of neurodevelopmentally-relevant chromatin remodelers.

Poston, Robert G / Dunn, Carissa J / Sarkar, Pushpita / Saha, Ramendra N

Environmental epigenetics

2018 Volume 4, Issue 1, Page(s) dvx020

Abstract: Polybrominated diphenyl ethers (PBDEs) are a pervasive class of brominated flame retardants that are present in the environment at particularly high levels, especially in the United States. Their environmental stability, propensity for bioaccumulation, ... ...

Abstract	Polybrominated diphenyl ethers (PBDEs) are a pervasive class of brominated flame retardants that are present in the environment at particularly high levels, especially in the United States. Their environmental stability, propensity for bioaccumulation, and known potential for neurotoxicity has evoked interest regarding their effects on the developing nervous system. Exposure to PBDEs has been strongly associated with neurodevelopmental disorders. However, the details of their mechanistic roles in such disorders are incompletely understood. Here, we report the effects of one of the most prevalent congeners, BDE-47, and its hydroxylated metabolites on the maturation and function of embryonic rat cortical neurons. Prolonged exposure to 6OH-BDE-47 produces the strongest effects amongst the parent BDE-47 congener and its tested hydroxylated metabolites. These effects include: i) disruption of transcriptional responses to neuronal activity, ii) dysregulation of multiple genes associated with neurodevelopmental disorders, and intriguingly, iii) altered expression of several subunits of the developmentally-relevant BAF (Brg1-associated factors) chromatin remodeling complex, including the key subunit BAF170. Taken together, our data indicate that persistent exposure to 6OH-BDE-47 may interfere with neurodevelopmental chromatin remodeling mechanisms and gene transcription programs, which in turn are likely to interfere with downstream processes such as synapse development and overall functional maturity of neurons. Results from this study have identified a novel aspect of 6OH-BDE-47 toxicity and open new avenues to explore the effects of a ubiquitous environmental toxin on epigenetic regulation of neuronal maturation and function.
Language	English
Publishing date	2018-01-12
Publishing country	England
Document type	Journal Article
ZDB-ID	2831217-X
ISSN	2058-5888 ; 2058-5888
ISSN (online)	2058-5888
ISSN	2058-5888
DOI	10.1093/eep/dvx020
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Article ; Online: Certain ortho-hydroxylated brominated ethers are promiscuous kinase inhibitors that impair neuronal signaling and neurodevelopmental processes.

Poston, Robert G / Murphy, Lillian / Rejepova, Ayna / Ghaninejad-Esfahani, Mina / Segales, Joshua / Mulligan, Kimberly / Saha, Ramendra N

The Journal of biological chemistry

2020 Volume 295, Issue 18, Page(s) 6120–6137

Abstract: The developing nervous system is remarkably sensitive to environmental signals, including disruptive toxins, such as polybrominated diphenyl ethers (PBDEs). PBDEs are an environmentally pervasive class of brominated flame retardants whose ... ...

Abstract	The developing nervous system is remarkably sensitive to environmental signals, including disruptive toxins, such as polybrominated diphenyl ethers (PBDEs). PBDEs are an environmentally pervasive class of brominated flame retardants whose neurodevelopmental toxicity mechanisms remain largely unclear. Using dissociated cortical neurons from embryonic
MeSH term(s)	Animals ; Drosophila melanogaster ; Ethers/chemistry ; Ethers/pharmacology ; Halogenation ; Hydroxylation ; Intracellular Space/drug effects ; Intracellular Space/metabolism ; Nervous System/cytology ; Nervous System/drug effects ; Nervous System/growth & development ; Neurons/cytology ; Neurons/drug effects ; Protein Kinase Inhibitors/chemistry ; Protein Kinase Inhibitors/pharmacology ; Signal Transduction/drug effects
Chemical Substances	Ethers ; Protein Kinase Inhibitors
Language	English
Publishing date	2020-03-30
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural
ZDB-ID	2997-x
ISSN	1083-351X ; 0021-9258
ISSN (online)	1083-351X
ISSN	0021-9258
DOI	10.1074/jbc.RA119.011138
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Article ; Online: Mild membrane depolarization in neurons induces immediate early gene transcription and acutely subdues responses to a successive stimulus.

Rienecker, Kira D A / Poston, Robert G / Segales, Joshua S / Finholm, Isabelle W / Sono, Morgan H / Munteanu, Sorina J / Ghaninejad-Esfahani, Mina / Rejepova, Ayna / Tejeda-Garibay, Susana / Wickman, Kevin / Marron Fernandez de Velasco, Ezequiel / Thayer, Stanley A / Saha, Ramendra N

The Journal of biological chemistry

2022 Volume 298, Issue 9, Page(s) 102278

Abstract: Immediate early genes (IEGs) are transcribed in response to neuronal activity from sensory stimulation during multiple adaptive processes in the brain. The transcriptional profile of IEGs is indicative of the duration of neuronal activity, but its ... ...

Abstract	Immediate early genes (IEGs) are transcribed in response to neuronal activity from sensory stimulation during multiple adaptive processes in the brain. The transcriptional profile of IEGs is indicative of the duration of neuronal activity, but its sensitivity to the strength of depolarization remains unknown. Also unknown is whether activity history of graded potential changes influence future neuronal activity. In this work with dissociated rat cortical neurons, we found that mild depolarization-mediated by elevated extracellular potassium (K
MeSH term(s)	Action Potentials/drug effects ; Action Potentials/physiology ; Animals ; Bicuculline/pharmacology ; Calcineurin/genetics ; Calcineurin/metabolism ; Calcium/metabolism ; GABA-A Receptor Antagonists/pharmacology ; Genes, Immediate-Early/drug effects ; Mitogen-Activated Protein Kinases/metabolism ; Neurons/drug effects ; Neurons/physiology ; Potassium/metabolism ; Potassium/pharmacology ; Rats ; Receptors, N-Methyl-D-Aspartate/genetics ; Receptors, N-Methyl-D-Aspartate/metabolism ; Transcription, Genetic
Chemical Substances	GABA-A Receptor Antagonists ; Receptors, N-Methyl-D-Aspartate ; Mitogen-Activated Protein Kinases (EC 2.7.11.24) ; Calcineurin (EC 3.1.3.16) ; Potassium (RWP5GA015D) ; Calcium (SY7Q814VUP) ; Bicuculline (Y37615DVKC)
Language	English
Publishing date	2022-07-19
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural
ZDB-ID	2997-x
ISSN	1083-351X ; 0021-9258
ISSN (online)	1083-351X
ISSN	0021-9258
DOI	10.1016/j.jbc.2022.102278
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Article ; Online: Genome-wide RNA pol II initiation and pausing in neural progenitors of the rat.

Scheidegger, Adam / Dunn, Carissa J / Samarakkody, Ann / Koney, Nii Koney-Kwaku / Perley, Danielle / Saha, Ramendra N / Nechaev, Sergei

BMC genomics

2019 Volume 20, Issue 1, Page(s) 477

Abstract: Background: Global RNA sequencing technologies have revealed widespread RNA polymerase II (Pol II) transcription outside of gene promoters. Small 5'-capped RNA sequencing (Start-seq) originally developed for the detection of promoter-proximal Pol II ... ...

Abstract	Background: Global RNA sequencing technologies have revealed widespread RNA polymerase II (Pol II) transcription outside of gene promoters. Small 5'-capped RNA sequencing (Start-seq) originally developed for the detection of promoter-proximal Pol II pausing has helped improve annotation of Transcription Start Sites (TSSs) of genes as well as identification of non-genic regulatory elements. However, apart from the most well studied genomes of human and mouse, mammalian transcription has not been profiled with sufficiently high precision. Results: We prepared and sequenced Start-seq libraries from rat (Rattus norgevicus) primary neural progenitor cells. Over 48 million uniquely mappable reads from two independent biological replicates allowed us to define the TSSs of 7365 known genes in the rn6 genome, reannotating 2503 TSSs by more than 5 base pairs, characterize promoter-associated antisense transcription, and profile Pol II pausing. By combining TSS data with polyA-selected RNA sequencing, we also identified thousands of potential new genes producing stable RNA as well as non-genic transcripts representing possible regulatory elements. Conclusions: Our study has produced the first Start-seq dataset for the rat. Apart from profiling transcription initiation, our data reaffirm the prevalence of Pol II pausing across the rat genome and indicate conservation of pausing mechanisms across metazoan genomes. We suggest that pausing location, at least in mammals, is constrained by a distance from initiation of transcription, whether it occurs at or outside of a gene promoter. Abundant antisense transcription initiation around protein coding genes indicates that Pol II recruited to the vicinity of a promoter is distributed to available start sites of transcription at either DNA strand. Transcriptome profiling of neural progenitors presented here will facilitate further studies of other rat cell types as well as other organisms.
MeSH term(s)	Animals ; Female ; Genomics ; Neural Stem Cells/metabolism ; Pregnancy ; RNA Polymerase II/metabolism ; RNA, Antisense/genetics ; Rats ; Rats, Sprague-Dawley ; Sequence Analysis, RNA ; Transcription Initiation Site ; Transcription Initiation, Genetic
Chemical Substances	RNA, Antisense ; RNA Polymerase II (EC 2.7.7.-)
Language	English
Publishing date	2019-06-11
Publishing country	England
Document type	Journal Article
ISSN	1471-2164
ISSN (online)	1471-2164
DOI	10.1186/s12864-019-5829-4
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Article: Action potentials: to the nucleus and beyond.

Saha, Ramendra N / Dudek, Serena M

Experimental biology and medicine (Maywood, N.J.)

2008 Volume 233, Issue 4, Page(s) 385–393

Abstract: The neuronal nucleus is now widely accepted as playing a vital role in maintaining long-term changes in synaptic effectiveness. To act, however, the nucleus must be appropriately relayed with information regarding the latest round of synaptic plasticity. ...

Abstract	The neuronal nucleus is now widely accepted as playing a vital role in maintaining long-term changes in synaptic effectiveness. To act, however, the nucleus must be appropriately relayed with information regarding the latest round of synaptic plasticity. Several constraints of doing so in a neuron pertain to the often significant spatial distance of synapses from the nucleus and the number of synapses required for such a signal to reach functional levels in the nucleus. Largely based on the sensitivity of transcriptional responses to NMDA receptor antagonists, it has been postulated that the signals are physically relayed by biochemical messengers from the synapse to the nucleus. Alternatively, a second, less often considered but equally viable method of signal transduction may be initiated by action potentials generated proximal to the nucleus, wherefrom the signal can be relayed directly by calcium or indirectly by biochemical second messengers. We consider action potential-dependent signaling to the nucleus to have its own computational advantages over the synapse-to-nucleus signal for some functions. This minireview summarizes the logic and experimental support for these two modes of signaling and attempts to validate the action potential model as playing an important role in transcriptional regulation relating specifically to long-term synaptic plasticity.
MeSH term(s)	Action Potentials/physiology ; Animals ; Calcium/metabolism ; Cell Nucleus/metabolism ; Neuronal Plasticity/physiology ; Neurons/cytology ; Neurons/physiology ; Signal Transduction/physiology ; Transcription, Genetic
Chemical Substances	Calcium (SY7Q814VUP)
Language	English
Publishing date	2008-04
Publishing country	England
Document type	Journal Article ; Research Support, N.I.H., Intramural ; Review
ISSN	1535-3702
ISSN	1535-3702
DOI	10.3181/0709-MR-241
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Article ; Online: Histone Hypervariants H2A.Z.1 and H2A.Z.2 Play Independent and Context-Specific Roles in Neuronal Activity-Induced Transcription of

Dunn, Carissa J / Sarkar, Pushpita / Bailey, Emma R / Farris, Shannon / Zhao, Meilan / Ward, James M / Dudek, Serena M / Saha, Ramendra N

eNeuro

2017 Volume 4, Issue 4

Abstract: The histone variant H2A.Z is an essential and conserved regulator of eukaryotic gene transcription. However, the exact role of this histone in the transcriptional process remains perplexing. In vertebrates, H2A.Z has two hypervariants, H2A.Z.1 and H2A.Z ... ...

Abstract	The histone variant H2A.Z is an essential and conserved regulator of eukaryotic gene transcription. However, the exact role of this histone in the transcriptional process remains perplexing. In vertebrates, H2A.Z has two hypervariants, H2A.Z.1 and H2A.Z.2, that have almost identical sequences except for three amino acid residues. Due to such similarity, functional specificity of these hypervariants in neurobiological processes, if any, remain largely unknown. In this study with dissociated rat cortical neurons, we asked if H2A.Z hypervariants have distinct functions in regulating basal and activity-induced gene transcription. Hypervariant-specific RNAi and microarray analyses revealed that H2A.Z.1 and H2A.Z.2 regulate basal expression of largely nonoverlapping gene sets, including genes that code for several synaptic proteins. In response to neuronal activity, rapid transcription of our model gene
MeSH term(s)	Animals ; Cells, Cultured ; Cerebral Cortex/metabolism ; Cytoskeletal Proteins/metabolism ; Epigenesis, Genetic ; Gene Expression Regulation/physiology ; Green Fluorescent Proteins/genetics ; Green Fluorescent Proteins/metabolism ; Histones/genetics ; Histones/metabolism ; Nerve Tissue Proteins/metabolism ; Neurons/metabolism ; Nucleosomes/metabolism ; RNA Polymerase II/metabolism ; Rats, Sprague-Dawley ; Synaptic Transmission/physiology ; Transcription, Genetic/physiology
Chemical Substances	Cytoskeletal Proteins ; Histones ; Nerve Tissue Proteins ; Nucleosomes ; activity regulated cytoskeletal-associated protein ; histone H2A.F-Z ; Green Fluorescent Proteins (147336-22-9) ; RNA Polymerase II (EC 2.7.7.-)
Language	English
Publishing date	2017-08-24
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, N.I.H., Intramural ; Research Support, Non-U.S. Gov't
ZDB-ID	2800598-3
ISSN	2373-2822 ; 2373-2822
ISSN (online)	2373-2822
ISSN	2373-2822
DOI	10.1523/ENEURO.0040-17.2017
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Article: Differential regulation of Mn-superoxide dismutase in neurons and astroglia by HIV-1 gp120: Implications for HIV-associated dementia.

Saha, Ramendra N / Pahan, Kalipada

Free radical biology & medicine

2007 Volume 42, Issue 12, Page(s) 1866–1878

Abstract: HIV-associated dementia, like several other neurodegenerative diseases, is characterized by selective degeneration of neurons amidst survival of glial cells like astroglia. The molecular basis of such selective susceptibility within the same milieu ... ...

Abstract	HIV-associated dementia, like several other neurodegenerative diseases, is characterized by selective degeneration of neurons amidst survival of glial cells like astroglia. The molecular basis of such selective susceptibility within the same milieu remains largely unknown. Neurons are rarely infected by the virus. However, they are vulnerable to viral products, like HIV-1 coat protein gp120. Interestingly, gp120 induced oxidative stress in neurons, but not in astroglia. This led us to postulate that astroglia were armed with a more efficient antioxidant system than neurons. Here, we report that the constitutive level of MnSOD (SOD2), the major cellular antioxidant enzyme, is significantly higher in astroglia than in neurons. Furthermore, gp120 treatment enhanced MnSOD levels in astroglia but decreased the same in neurons. This increase in astroglial MnSOD was dependent on NF-kappaB, the crucial transcription factor required for sod2 gene transcription. Blocking NF-kappaB with p65-antisense, p65-si-RNA, or a specific inhibitor, NBD peptide, led to reduced MnSOD levels and enhanced vulnerability of astroglia to gp120. Additionally, neurons were found to have a lower constitutive level of NF-kappaB p65 than astrocytes. Overexpression of p65 increased the level of MnSOD in neurons. This, in turn, elicited greater neuronal resistance to gp120. Taken together, our study suggests that astroglia manifest a higher threshold for gp120-induced lethality than neurons due to greater MnSOD availability, which is demonstrated due to greater level of NF-kappaB p65.
MeSH term(s)	AIDS Dementia Complex/metabolism ; AIDS Dementia Complex/pathology ; Animals ; Antioxidants/pharmacology ; Apoptosis/physiology ; Astrocytes/drug effects ; Astrocytes/enzymology ; Astrocytes/metabolism ; Cells, Cultured ; Female ; Fetus/embryology ; Fetus/metabolism ; Fluorescent Antibody Technique ; HIV Envelope Protein gp120/pharmacology ; Humans ; Immunoblotting ; In Situ Nick-End Labeling ; Mitochondria/metabolism ; NF-kappa B/antagonists & inhibitors ; NF-kappa B/genetics ; NF-kappa B/metabolism ; Neurons/drug effects ; Neurons/enzymology ; Oxidative Stress ; Pregnancy ; Pregnancy Trimester, Second ; RNA, Small Interfering/pharmacology ; Rats ; Rats, Sprague-Dawley ; Superoxide Dismutase/metabolism ; Superoxides/metabolism
Chemical Substances	Antioxidants ; HIV Envelope Protein gp120 ; NF-kappa B ; RNA, Small Interfering ; Superoxides (11062-77-4) ; Superoxide Dismutase (EC 1.15.1.1)
Language	English
Publishing date	2007-06-15
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	807032-5
ISSN	1873-4596 ; 0891-5849
ISSN (online)	1873-4596
ISSN	0891-5849
DOI	10.1016/j.freeradbiomed.2007.03.022
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