Nadiya Byts and Anna-Leena Siren
Experimental & Translational Stroke Medicine 2009, 1:4doi:10.1186/2040-7378-1-4
Published: 21 October 2009
OPEN ACCESS
Abstract (provisional)
The tissue protective functions of the hematopoietic growth factor erythropoietin (EPO) are independent of its action on erythropoiesis. EPO and its receptors (EPOR) are expressed in multiple brain cells during brain development and upregulated in the adult brain after injury. Peripherally administered EPO crosses the blood-brain barrier and activates in the brain anti-apoptotic, anti-oxidant and anti-inflammatory signaling in neurons, glial and cerebrovascular endothelial cells and stimulates angiogenesis and neurogenesis. These mechanisms underlie its potent tissue protective effects in experimental models of stroke, cerebral hemorrhage, traumatic brain injury, neuroinflammatory and neurodegenerative disease. The preclinical data in support of the use of EPO in brain disease have already been translated to first clinical pilot studies with encouraging results with the use of EPO as a neuroprotective agent.
The complete article is available as a provisional PDF . CLICK HERE
Saturday, October 24, 2009
Direct Fe2+ Sensing by Iron-responsive Messenger RNA·Repressor Complexes Weakens Binding*
October 30, 2009 The Journal of Biological Chemistry, 284, 30122-30128.
1. Mateen A. Khan‡, 2. William E. Walden§, 3. Dixie J. Goss‡,1 and 4. Elizabeth C. Theil¶‖,2
1. From the ‡Department of Chemistry, Hunter College, City University of New York, New York, New York 10065,
2. the §Department of Microbiology and Immunology, University of Illinois, Chicago, Illinois 60612-7334,
3. the ¶Children's Hospital Oakland Research Institute, Oakland, California 94609, and
4. the ‖Department of Nutrition Science and Toxicolology, University of California, Berkeley, California 94720
Keywords: Fe2+, ferritin, mitochondrial aconitase messenger, regulatory proteins (IRPs),iron-induced mRNA translation.
1. Mateen A. Khan‡, 2. William E. Walden§, 3. Dixie J. Goss‡,1 and 4. Elizabeth C. Theil¶‖,2
1. From the ‡Department of Chemistry, Hunter College, City University of New York, New York, New York 10065,
2. the §Department of Microbiology and Immunology, University of Illinois, Chicago, Illinois 60612-7334,
3. the ¶Children's Hospital Oakland Research Institute, Oakland, California 94609, and
4. the ‖Department of Nutrition Science and Toxicolology, University of California, Berkeley, California 94720
Keywords: Fe2+, ferritin, mitochondrial aconitase messenger, regulatory proteins (IRPs),iron-induced mRNA translation.
Friday, October 23, 2009
Next generation sequence analysis for mitochondrial disorders
Valeria Vasta , Sarah B Ng , Emily H Turner , Jay Shendure and Si Houn Hahn
Genome Medicine 2009, 1:100doi:10.1186/gm100
Published: 23 October 2009
OPEN ACCESS
Link to full text
Background
Mitochondrial disorders can originate from mutations in one of many nuclear genes controlling the organelle function or in the mitochondrial genome (mitochondrial DNA (mtDNA)). The large numbers of potential culprit genes, together with the little guidance offered by most clinical phenotypes as to which gene may be causative, are a great challenge for the molecular diagnosis of these disorders.
Methods
We developed a novel targeted resequencing assay for mitochondrial disorders relying on microarray-based hybrid capture coupled to next-generation sequencing. Specifically, we subjected the entire mtDNA genome and the exons and intron-exon boundary regions of 362 known or candidate causative nuclear genes to targeted capture and resequencing. We here provide proof-of-concept data by testing one HapMap DNA sample and two positive control samples.
Results
Over 94% of the targeted regions were captured and sequenced with appropriate coverage and quality, allowing reliable variant calling. Pathogenic mutations blindly tested in patients' samples were 100% concordant with previous Sanger sequencing results: a known mutation in Pyruvate dehydrogenase alpha 1 subunit (PDHA1), a novel splicing and a known coding mutation in Hydroxyacyl-CoA dehydrogenase alpha subunit (HADHA) were correctly identified. Of the additional variants recognized, 90 to 94% were present in dbSNP while 6 to 10% represented new alterations. The novel nonsynonymous variants were all in heterozygote state and mostly predicted to be benign. The depth of sequencing coverage of mtDNA was extremely high, suggesting that it may be feasible to detect pathogenic mtDNA mutations confounded by low level heteroplasmy. Only one sequencing lane of an eight lane flow cell was utilized for each sample, indicating that a cost-effective clinical test can be achieved.
Conclusions
Our study indicates that the use of next generation sequencing technology holds great promise as a tool for screening mitochondrial disorders. The availability of a comprehensive molecular diagnostic tool will increase the capacity for early and rapid identification of mitochondrial disorders. In addition, the proposed approach has the potential to identify new mutations in candidate genes, expanding and redefining the spectrum of causative genes responsible for mitochondrial disorders.
................................................................
Focus: Genes targeted for capture and sequencing....Enzymes...FXN,
New variants and mutations identified in the samples..... FXN [Genbank:NM_000144.3]:c.626A>G (p.Asp209Gly) het
Genome Medicine 2009, 1:100doi:10.1186/gm100
Published: 23 October 2009
OPEN ACCESS
Link to full text
Background
Mitochondrial disorders can originate from mutations in one of many nuclear genes controlling the organelle function or in the mitochondrial genome (mitochondrial DNA (mtDNA)). The large numbers of potential culprit genes, together with the little guidance offered by most clinical phenotypes as to which gene may be causative, are a great challenge for the molecular diagnosis of these disorders.
Methods
We developed a novel targeted resequencing assay for mitochondrial disorders relying on microarray-based hybrid capture coupled to next-generation sequencing. Specifically, we subjected the entire mtDNA genome and the exons and intron-exon boundary regions of 362 known or candidate causative nuclear genes to targeted capture and resequencing. We here provide proof-of-concept data by testing one HapMap DNA sample and two positive control samples.
Results
Over 94% of the targeted regions were captured and sequenced with appropriate coverage and quality, allowing reliable variant calling. Pathogenic mutations blindly tested in patients' samples were 100% concordant with previous Sanger sequencing results: a known mutation in Pyruvate dehydrogenase alpha 1 subunit (PDHA1), a novel splicing and a known coding mutation in Hydroxyacyl-CoA dehydrogenase alpha subunit (HADHA) were correctly identified. Of the additional variants recognized, 90 to 94% were present in dbSNP while 6 to 10% represented new alterations. The novel nonsynonymous variants were all in heterozygote state and mostly predicted to be benign. The depth of sequencing coverage of mtDNA was extremely high, suggesting that it may be feasible to detect pathogenic mtDNA mutations confounded by low level heteroplasmy. Only one sequencing lane of an eight lane flow cell was utilized for each sample, indicating that a cost-effective clinical test can be achieved.
Conclusions
Our study indicates that the use of next generation sequencing technology holds great promise as a tool for screening mitochondrial disorders. The availability of a comprehensive molecular diagnostic tool will increase the capacity for early and rapid identification of mitochondrial disorders. In addition, the proposed approach has the potential to identify new mutations in candidate genes, expanding and redefining the spectrum of causative genes responsible for mitochondrial disorders.
................................................................
Focus: Genes targeted for capture and sequencing....Enzymes...FXN,
New variants and mutations identified in the samples..... FXN [Genbank:NM_000144.3]:c.626A>G (p.Asp209Gly) het
The conserved Trp-155 in human frataxin as a hotspot for oxidative stress related chemical modifications
Biochemical and Biophysical Research Communications
Ana R. Correiaa, Saw Y. Owb, Phillip C. Wrightb and Cláudio M. Gomesa, Corresponding Author Contact Information, E-mail The Corresponding Author
aInstituto Tecnologia Química e Biológica, Universidade Nova de Lisboa, 2780-756 Oeiras, Portugal
bDepartment of Chemical and Process Engineering, ChELSI, University of Sheffield, Sheffield S10 2TN, UK
Received 15 October 2009.
Available online 22 October 2009.
Keywords: Friedreich’s Ataxia, Frataxin, Protein Folding, Protein Flexibility, Metallochaperone, Oxidative Stress, Fenton reactions, carbonylation, nitration.
Ana R. Correiaa, Saw Y. Owb, Phillip C. Wrightb and Cláudio M. Gomesa, Corresponding Author Contact Information, E-mail The Corresponding Author
aInstituto Tecnologia Química e Biológica, Universidade Nova de Lisboa, 2780-756 Oeiras, Portugal
bDepartment of Chemical and Process Engineering, ChELSI, University of Sheffield, Sheffield S10 2TN, UK
Received 15 October 2009.
Available online 22 October 2009.
Keywords: Friedreich’s Ataxia, Frataxin, Protein Folding, Protein Flexibility, Metallochaperone, Oxidative Stress, Fenton reactions, carbonylation, nitration.
Thursday, October 22, 2009
Students Invite Chemists Everywhere To Help With Orphaned Drugs, Diseases
Medical News Today, 21 Oct 2009
Suppose you had a disease for which there's a proven cure, but nobody makes the drug. Where do you turn?
The Cure for Needy Project (http://www.cureforneedy.org)
Suppose you had a disease for which there's a proven cure, but nobody makes the drug. Where do you turn?
The Cure for Needy Project (http://www.cureforneedy.org)
Wednesday, October 21, 2009
Redox Control of the Cell Cycle in Health and Disease
Online Ahead of Print: October 21, 2009
Ehab H. Sarsour, Maneesh G. Kumar, Leena Chaudhuri, Amanda L. Kalen, Prabhat C. Goswami, Jurgen Bernhagen, Claudia Castro, Peter M. Chumakov, Tohru Fukai, Fuyuki Ishikawa, Hugo Monteiro, Hasan Mukhtar, Mark Smith, Rhian Touyz. Antioxidants & Redox Signaling. doi:10.1089/ars.2009.2513.
Free Radical and Radiation Biology Program, Department of Radiation Oncology, University of Iowa, Iowa City, Iowa.
Keywords: reactive oxygen species (ROS), second messengers, quiescence (G0),proliferation (G1, S, G2, and M), cancer, wound healing, fibrosis, cardiovascular diseases, diabetes, and neurodegenerative diseases.
Ehab H. Sarsour, Maneesh G. Kumar, Leena Chaudhuri, Amanda L. Kalen, Prabhat C. Goswami, Jurgen Bernhagen, Claudia Castro, Peter M. Chumakov, Tohru Fukai, Fuyuki Ishikawa, Hugo Monteiro, Hasan Mukhtar, Mark Smith, Rhian Touyz. Antioxidants & Redox Signaling. doi:10.1089/ars.2009.2513.
Free Radical and Radiation Biology Program, Department of Radiation Oncology, University of Iowa, Iowa City, Iowa.
Keywords: reactive oxygen species (ROS), second messengers, quiescence (G0),proliferation (G1, S, G2, and M), cancer, wound healing, fibrosis, cardiovascular diseases, diabetes, and neurodegenerative diseases.
Children With Brain-Damage Often Have Cold Feet
Medicalnewstoday, Article Date: 21 Oct 2009
Many wheelchair-using children with neurological disorders have much colder hands and feet than other children, and most receive no special help even though they have had these problems for a long time, is revealed in at thesis from the Sahlgrenska Academy at the University of Gothenburg, Sweden.
(read more)
Many wheelchair-using children with neurological disorders have much colder hands and feet than other children, and most receive no special help even though they have had these problems for a long time, is revealed in at thesis from the Sahlgrenska Academy at the University of Gothenburg, Sweden.
(read more)
Monday, October 19, 2009
Inherited Neuromuscular Diseases (book )
Translation from Pathomechanisms to Therapies
Series: Advances in Experimental Medicine and Biology , Vol. 652
Espinós, Carmen; Felipo, Vicente; Palau, Francesc (Eds.)
2009, XIII, 304 p., Hardcover
ISBN: 978-90-481-2812-9
Keywords: muscular dystrophies, mitochondrial disorders, peripheral neuropathies, spinal muscular atrophy, motoneurone disease, Friedreich ataxia, genetics, neuromuscular disorders, peripheral nervous system, cellular biology, pathomechanisms, therapies and treatments.
Series: Advances in Experimental Medicine and Biology , Vol. 652
Espinós, Carmen; Felipo, Vicente; Palau, Francesc (Eds.)
2009, XIII, 304 p., Hardcover
ISBN: 978-90-481-2812-9
Keywords: muscular dystrophies, mitochondrial disorders, peripheral neuropathies, spinal muscular atrophy, motoneurone disease, Friedreich ataxia, genetics, neuromuscular disorders, peripheral nervous system, cellular biology, pathomechanisms, therapies and treatments.
Idebenone Appears Safe in Patients With Friedreich's Ataxia: Presented at ANA
Doctor's Guide Publishing Limited.
Presentation title: SNT-MC17/Idebenone to Treat Friedreich's Ataxia: Preliminary Phase 3 Safety Data. Poster T-80]
Keywords: blinded interim safety analysis, Friedreich's ataxia, clinical trial, idebenone, severe events, supraventricular extrasystole, reduced visual acuity, fatigue, anxiety, flatulence/abdominal discomfort, electrocardiograms, vital signs, laboratory test, SNT-MC17, headache, nausea, diarrhoea, vomiting, abdominal pain, upper abdominal pain, fatigue, hypercholesterolaemia, rash, flatulence, pruritus.
Presentation title: SNT-MC17/Idebenone to Treat Friedreich's Ataxia: Preliminary Phase 3 Safety Data. Poster T-80]
Keywords: blinded interim safety analysis, Friedreich's ataxia, clinical trial, idebenone, severe events, supraventricular extrasystole, reduced visual acuity, fatigue, anxiety, flatulence/abdominal discomfort, electrocardiograms, vital signs, laboratory test, SNT-MC17, headache, nausea, diarrhoea, vomiting, abdominal pain, upper abdominal pain, fatigue, hypercholesterolaemia, rash, flatulence, pruritus.
Saturday, October 17, 2009
The N-terminus of mature human frataxin is intrinsically unfolded
FEBS Journal, Early View (Articles online in advance of print)
Published Online: 16 Oct 2009
Journal compilation © 2009 Federation of European Biochemical Societies
Filippo Prischi 1 , Clelia Giannini 2 , Salvatore Adinolfi 3 and Annalisa Pastore 3
1 Dipartimento di Biologia Molecolare, University of Siena, Siena, Italy
2 Dipartimento di Chimica Organica ed Industriale, University of Milano, Italy
3 National Institute for Medical Research, MRC, The Ridgeway, London, UK
KEYWORDS: dynamics, Friedreich's ataxia, IUPs, NMR, structure, Frataxin, mitochondrial protein, neurodegenerative disease, globular domain, N-terminal, unfolded, iron-binding.
Published Online: 16 Oct 2009
Journal compilation © 2009 Federation of European Biochemical Societies
Filippo Prischi 1 , Clelia Giannini 2 , Salvatore Adinolfi 3 and Annalisa Pastore 3
1 Dipartimento di Biologia Molecolare, University of Siena, Siena, Italy
2 Dipartimento di Chimica Organica ed Industriale, University of Milano, Italy
3 National Institute for Medical Research, MRC, The Ridgeway, London, UK
KEYWORDS: dynamics, Friedreich's ataxia, IUPs, NMR, structure, Frataxin, mitochondrial protein, neurodegenerative disease, globular domain, N-terminal, unfolded, iron-binding.
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