OPEN ACCESS
Journal of NeuroEngineering and Rehabilitation 2009, 6:38doi:10.1186/1743-0003-6-38
Published: 30 October 2009
Abstract (provisional)
Background
One of the main scientific and technological challenges of rehabilitation bioengineering is the development of innovative methodologies, based on the use of appropriate technological devices, for an objective assessment of patients undergoing a rehabilitation treatment. Such tools should be as fast and cheap to use as clinical scales, which are currently the daily instruments most widely used in the routine clinical practice.
Methods
A human-centered approach was used in the design and development of a mechanical structure equipped with eight force/torque sensors that record quantitative data during the initiation of a predefined set of Activities of Daily Living (ADL) tasks, in isometric conditions.
Results
Preliminary results validated the appropriateness, acceptability and functionality of the proposed platform, that has become now a tool used for clinical research in three clinical centres.
Conclusions
This paper presented the design and development of an innovative platform for whole-body force and torque measurements on human subjects. The platform has been designed to perform accurate quantitative measurements in isometric conditions with the specific aim to address the needs for functional assessment tests of patients undergoing a rehabilitation treatment as a consequence of a stroke. The versatility of the system also enlightens several other interesting possible areas of application for therapy in neurorehabilitation, for research in basic neuroscience, and more.
Link to full text: http://www.jneuroengrehab.com/content/pdf/1743-0003-6-38.pdf
Saturday, October 31, 2009
Friday, October 30, 2009
Progressive GAA·TTC Repeat Expansion in Human Cell Lines
OPEN ACCESS
Scott Ditch, Mimi C. Sammarco, Ayan Banerjee, Ed Grabczyk*
Department of Genetics, Louisiana State University Health Sciences Center, New Orleans, Louisiana, United States of America
Abstract
Trinucleotide repeat expansion is the genetic basis for a sizeable group of inherited neurological and neuromuscular disorders. Friedreich ataxia (FRDA) is a relentlessly progressive neurodegenerative disorder caused by GAA·TTC repeat expansion in the first intron of the FXN gene. The expanded repeat reduces FXN mRNA expression and the length of the repeat tract is proportional to disease severity. Somatic expansion of the GAA·TTC repeat sequence in disease-relevant tissues is thought to contribute to the progression of disease severity during patient aging. Previous models of GAA·TTC instability have not been able to produce substantial levels of expansion within an experimentally useful time frame, which has limited our understanding of the molecular basis for this expansion. Here, we present a novel model for studying GAA·TTC expansion in human cells. In our model system, uninterrupted GAA·TTC repeat sequences display high levels of genomic instability, with an overall tendency towards progressive expansion. Using this model, we characterize the relationship between repeat length and expansion. We identify the interval between 88 and 176 repeats as being an important length threshold where expansion rates dramatically increase. We show that expansion levels are affected by both the purity and orientation of the repeat tract within the genomic context. We further demonstrate that GAA·TTC expansion in our model is independent of cell division. Using unique reporter constructs, we identify transcription through the repeat tract as a major contributor to GAA·TTC expansion. Our findings provide novel insight into the mechanisms responsible for GAA·TTC expansion in human cells.
Link to full text: http://www.plosgenetics.org/article/fetchObjectAttachment.action;jsessionid=1C3EDADDCEC7DDCE3438B379DC71EE00?uri=info%3Adoi%2F10.1371%2Fjournal.pgen.1000704&representation=PDF
Scott Ditch, Mimi C. Sammarco, Ayan Banerjee, Ed Grabczyk*
Department of Genetics, Louisiana State University Health Sciences Center, New Orleans, Louisiana, United States of America
Abstract
Trinucleotide repeat expansion is the genetic basis for a sizeable group of inherited neurological and neuromuscular disorders. Friedreich ataxia (FRDA) is a relentlessly progressive neurodegenerative disorder caused by GAA·TTC repeat expansion in the first intron of the FXN gene. The expanded repeat reduces FXN mRNA expression and the length of the repeat tract is proportional to disease severity. Somatic expansion of the GAA·TTC repeat sequence in disease-relevant tissues is thought to contribute to the progression of disease severity during patient aging. Previous models of GAA·TTC instability have not been able to produce substantial levels of expansion within an experimentally useful time frame, which has limited our understanding of the molecular basis for this expansion. Here, we present a novel model for studying GAA·TTC expansion in human cells. In our model system, uninterrupted GAA·TTC repeat sequences display high levels of genomic instability, with an overall tendency towards progressive expansion. Using this model, we characterize the relationship between repeat length and expansion. We identify the interval between 88 and 176 repeats as being an important length threshold where expansion rates dramatically increase. We show that expansion levels are affected by both the purity and orientation of the repeat tract within the genomic context. We further demonstrate that GAA·TTC expansion in our model is independent of cell division. Using unique reporter constructs, we identify transcription through the repeat tract as a major contributor to GAA·TTC expansion. Our findings provide novel insight into the mechanisms responsible for GAA·TTC expansion in human cells.
Link to full text: http://www.plosgenetics.org/article/fetchObjectAttachment.action;jsessionid=1C3EDADDCEC7DDCE3438B379DC71EE00?uri=info%3Adoi%2F10.1371%2Fjournal.pgen.1000704&representation=PDF
Thursday, October 29, 2009
Researchers Find Brain Cell Transplants Help Repair Neural Damage
ScienceDaily (Oct. 29, 2009) — A Swiss research team has found that using an animal's own brain cells (autologous transplant) to replace degenerated neurons in select brain areas of donor primates with simulated but asymptomatic Parkinson's disease and previously in a motor cortex lesion model, provides a degree of brain protection and may be useful in repairing brain lesions and restoring function. (read more)
Neuroprotective effects of blockers for T-type calcium channels
Molecular Neurodegeneration 2009, 4:44doi:10.1186/1750-1326-4-44
Published: 28 October 2009
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Norelle C Wildburger , Avary Lin-Ye , Michelle A Baird , Debin Lei and Jianxin Bao
Abstract
Cognitive and functional decline with age is correlated with deregulation of intracellular calcium, which can lead to neuronal death in the brain. Previous studies have found protective effects of various calcium channel blockers in pathological conditions. However, little has been done to explore possible protective effects of blockers for T-type calcium channels, which forms a family of FDA approved anti-epileptic drugs. In this study, we found that neurons showed an increase in viability after treatment with either L-type or T-type calcium channel antagonists. The family of low-voltage activated, or T-type calcium channels, comprise of three members (Cav3.1, Cav3.2, and Cav3.3) based on their respective main pore-forming alpha subunits: alpha 1G, alpha 1H, and alpha 1I. Among these three subunits, alpha 1H is highly expressed in hippocampus and certain cortical regions. However, T-type calcium channel blockers can protect neurons derived from alpha 1H-/- mice, suggesting that neuroprotection demonstrated by these drugs is not through the alpha 1H subunit. In addition, blockers for T-type calcium channels were not able to confer any protection to neurons in long-term cultures, while blockers of L-type calcium channels could protect neurons. These data indicate a new function of blockers for T-type calcium channels, and also suggest different mechanisms to regulate neuronal survival by calcium signaling pathways. Thus, our findings have important implications in the development of new treatment for age-related neurodegenerative disorders.
Link to full text: http://www.molecularneurodegeneration.com/content/pdf/1750-1326-4-44.pdf
Published: 28 October 2009
OPEN ACCESS
Norelle C Wildburger , Avary Lin-Ye , Michelle A Baird , Debin Lei and Jianxin Bao
Abstract
Cognitive and functional decline with age is correlated with deregulation of intracellular calcium, which can lead to neuronal death in the brain. Previous studies have found protective effects of various calcium channel blockers in pathological conditions. However, little has been done to explore possible protective effects of blockers for T-type calcium channels, which forms a family of FDA approved anti-epileptic drugs. In this study, we found that neurons showed an increase in viability after treatment with either L-type or T-type calcium channel antagonists. The family of low-voltage activated, or T-type calcium channels, comprise of three members (Cav3.1, Cav3.2, and Cav3.3) based on their respective main pore-forming alpha subunits: alpha 1G, alpha 1H, and alpha 1I. Among these three subunits, alpha 1H is highly expressed in hippocampus and certain cortical regions. However, T-type calcium channel blockers can protect neurons derived from alpha 1H-/- mice, suggesting that neuroprotection demonstrated by these drugs is not through the alpha 1H subunit. In addition, blockers for T-type calcium channels were not able to confer any protection to neurons in long-term cultures, while blockers of L-type calcium channels could protect neurons. These data indicate a new function of blockers for T-type calcium channels, and also suggest different mechanisms to regulate neuronal survival by calcium signaling pathways. Thus, our findings have important implications in the development of new treatment for age-related neurodegenerative disorders.
Link to full text: http://www.molecularneurodegeneration.com/content/pdf/1750-1326-4-44.pdf
Epilepsy Drugs Could Treat Alzheimer's And Parkinson's
ScienceDaily (Oct. 29, 2009) — Researchers in the USA have discovered a potential new function for anti-epileptic drugs in treating neurodegenerative disorders such as Alzheimer's and Parkinson's disease. The study, published in BioMed Central's open access journal Molecular Neurodegeneration, found that neurons in the brain were protected after treatment with T-type calcium-channel blockers, which are commonly used to treat epilepsy. (read more)
Saturday, October 24, 2009
Erythropoietin: a multimodal neuroprotective agent
Nadiya Byts and Anna-Leena Siren
Experimental & Translational Stroke Medicine 2009, 1:4doi:10.1186/2040-7378-1-4
Published: 21 October 2009
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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
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
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.
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