The Experts below are selected from a list of 130548 Experts worldwide ranked by ideXlab platform
Lee-jun C. Wong - One of the best experts on this subject based on the ideXlab platform.
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Sequence Homology at the Breakpoint and Clinical Phenotype of Mitochondrial DNA Deletion Syndromes
2013Co-Authors: Bekim Sadikovic, Jing Wang, Ayman El-hattab, Megan L, Ganka Douglas, Ellen K. Brundage, William J. Craigen, Eric S. Schmitt, Lee-jun C. WongAbstract:Mitochondrial DNA (mtDNA) deletions are a common cause of mitochondrial disorders. Large mtDNA deletions can lead to a broad spectrum of clinical features with different age of onset, ranging from mild mitochondrial myopathies (MM), progressive external ophthalmoplegia (PEO), and Kearns-Sayre syndrome (KSS), to severe Pearson syndrome. The aim of this study is to investigate the molecular signatures surrounding the deletion breakpoints and their association with the clinical phenotype and age at onset. MtDNA deletions in 67 patients were characterized using array comparative genomic hybridization (aCGH) followed by PCR-sequencing of the deletion junctions. Sequence Homology including both perfect and imperfect short repeats flanking the deletion regions were analyzed and correlated with clinical features and patients’ age group. In all age groups, there was a significant increase in Sequence Homology flanking the deletion compared to mtDNA background. The youngest patient group (,6 years old) showed a diffused pattern of deletion distribution in size and locations, with a significantly lower Sequence Homology flanking the deletion, and the highest percentage of deletion mutant heteroplasmy. The older age groups showed rather discrete pattern of deletions with 44 % of all patients over 6 years old carrying the most common 5 kb mtDNA deletion, which was found mostly in muscle specimens (22/41). Only 15% (3/20) of the young patients (,6 years old) carry the 5 kb common deletion, which is usually present in blood rather than muscle. This group of patients predominantly (16 out of 17) exhibit multisystem disorder and/or Pearson syndrome, whil
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Sequence Homology at the breakpoint and clinical phenotype of mitochondrial DNA deletion syndromes.
PloS one, 2010Co-Authors: Bekim Sadikovic, Jing Wang, Ganka Douglas, Ellen K. Brundage, William J. Craigen, Eric S. Schmitt, Ayman W. El-hattab, Megan Landsverk, Lee-jun C. WongAbstract:Mitochondrial DNA (mtDNA) deletions are a common cause of mitochondrial disorders. Large mtDNA deletions can lead to a broad spectrum of clinical features with different age of onset, ranging from mild mitochondrial myopathies (MM), progressive external ophthalmoplegia (PEO), and Kearns-Sayre syndrome (KSS), to severe Pearson syndrome. The aim of this study is to investigate the molecular signatures surrounding the deletion breakpoints and their association with the clinical phenotype and age at onset. MtDNA deletions in 67 patients were characterized using array comparative genomic hybridization (aCGH) followed by PCR-sequencing of the deletion junctions. Sequence Homology including both perfect and imperfect short repeats flanking the deletion regions were analyzed and correlated with clinical features and patients' age group. In all age groups, there was a significant increase in Sequence Homology flanking the deletion compared to mtDNA background. The youngest patient group (
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Sequence Homology at the breakpoint and clinical phenotype of mitochondrial dna deletion syndromes
PLOS ONE, 2010Co-Authors: Bekim Sadikovic, Jing Wang, Ganka Douglas, Ellen K. Brundage, William J. Craigen, Eric S. Schmitt, Megan Landsverk, Ayman W Elhattab, Lee-jun C. WongAbstract:Mitochondrial DNA (mtDNA) deletions are a common cause of mitochondrial disorders. Large mtDNA deletions can lead to a broad spectrum of clinical features with different age of onset, ranging from mild mitochondrial myopathies (MM), progressive external ophthalmoplegia (PEO), and Kearns-Sayre syndrome (KSS), to severe Pearson syndrome. The aim of this study is to investigate the molecular signatures surrounding the deletion breakpoints and their association with the clinical phenotype and age at onset. MtDNA deletions in 67 patients were characterized using array comparative genomic hybridization (aCGH) followed by PCR-sequencing of the deletion junctions. Sequence Homology including both perfect and imperfect short repeats flanking the deletion regions were analyzed and correlated with clinical features and patients' age group. In all age groups, there was a significant increase in Sequence Homology flanking the deletion compared to mtDNA background. The youngest patient group (<6 years old) showed a diffused pattern of deletion distribution in size and locations, with a significantly lower Sequence Homology flanking the deletion, and the highest percentage of deletion mutant heteroplasmy. The older age groups showed rather discrete pattern of deletions with 44% of all patients over 6 years old carrying the most common 5 kb mtDNA deletion, which was found mostly in muscle specimens (22/41). Only 15% (3/20) of the young patients (<6 years old) carry the 5 kb common deletion, which is usually present in blood rather than muscle. This group of patients predominantly (16 out of 17) exhibit multisystem disorder and/or Pearson syndrome, while older patients had predominantly neuromuscular manifestations including KSS, PEO, and MM. In conclusion, Sequence Homology at the deletion flanking regions is a consistent feature of mtDNA deletions. Decreased levels of Sequence Homology and increased levels of deletion mutant heteroplasmy appear to correlate with earlier onset and more severe disease with multisystem involvement.
Hideaki Kamata - One of the best experts on this subject based on the ideXlab platform.
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on off system for pi3 kinase akt signaling through s nitrosylation of phosphatase with Sequence Homology to tensin pten
Proceedings of the National Academy of Sciences of the United States of America, 2011Co-Authors: Naoki Numajiri, Kumi Takasawa, Tadashi Nishiya, Hirotaka Tanaka, Kazuki Ohno, Wataru Hayakawa, Mariko Asada, Hiromi Matsuda, Kaoru Azumi, Hideaki KamataAbstract:Nitric oxide (NO) physiologically regulates numerous cellular responses through S-nitrosylation of protein cysteine residues. We performed antibody-array screening in conjunction with biotin-switch assays to look for S-nitrosylated proteins. Using this combination of techniques, we found that phosphatase with Sequence Homology to tensin (PTEN) is selectively S-nitrosylated by low concentrations of NO at a specific cysteine residue (Cys-83). S-nitrosylation of PTEN (forming SNO-PTEN) inhibits enzymatic activity and consequently stimulates the downstream Akt cascade, indicating that Cys-83 is a critical site for redox regulation of PTEN function. In ischemic mouse brain, we observed SNO-PTEN in the core and penumbra regions but found SNO-Akt, which is known to inhibit Akt activity, only in the ischemic core. These findings suggest that low concentrations of NO, as found in the penumbra, preferentially S-nitrosylate PTEN, whereas higher concentrations of NO, known to exist in the ischemic core, also S-nitrosylate Akt. In the penumbra, inhibition of PTEN (but not Akt) activity by S-nitrosylation would be expected to contribute to cell survival by means of enhanced Akt signaling. In contrast, in the ischemic core, SNO-Akt formation would inhibit this neuroprotective pathway. In vitro model systems support this notion. Thus, we identify unique sites of PTEN and Akt regulation by means of S-nitrosylation, resulting in an “on–off” pattern of control of Akt signaling.
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on off system for pi3 kinase akt signaling through s nitrosylation of phosphatase with Sequence Homology to tensin pten
Proceedings of the National Academy of Sciences of the United States of America, 2011Co-Authors: Naoki Numajiri, Kumi Takasawa, Tadashi Nishiya, Hirotaka Tanaka, Kazuki Ohno, Wataru Hayakawa, Mariko Asada, Hiromi Matsuda, Kaoru Azumi, Hideaki KamataAbstract:Nitric oxide (NO) physiologically regulates numerous cellular responses through S-nitrosylation of protein cysteine residues. We performed antibody-array screening in conjunction with biotin-switch assays to look for S-nitrosylated proteins. Using this combination of techniques, we found that phosphatase with Sequence Homology to tensin (PTEN) is selectively S-nitrosylated by low concentrations of NO at a specific cysteine residue (Cys-83). S-nitrosylation of PTEN (forming SNO-PTEN) inhibits enzymatic activity and consequently stimulates the downstream Akt cascade, indicating that Cys-83 is a critical site for redox regulation of PTEN function. In ischemic mouse brain, we observed SNO-PTEN in the core and penumbra regions but found SNO-Akt, which is known to inhibit Akt activity, only in the ischemic core. These findings suggest that low concentrations of NO, as found in the penumbra, preferentially S-nitrosylate PTEN, whereas higher concentrations of NO, known to exist in the ischemic core, also S-nitrosylate Akt. In the penumbra, inhibition of PTEN (but not Akt) activity by S-nitrosylation would be expected to contribute to cell survival by means of enhanced Akt signaling. In contrast, in the ischemic core, SNO-Akt formation would inhibit this neuroprotective pathway. In vitro model systems support this notion. Thus, we identify unique sites of PTEN and Akt regulation by means of S-nitrosylation, resulting in an “on–off” pattern of control of Akt signaling.
Bekim Sadikovic - One of the best experts on this subject based on the ideXlab platform.
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Sequence Homology at the Breakpoint and Clinical Phenotype of Mitochondrial DNA Deletion Syndromes
2013Co-Authors: Bekim Sadikovic, Jing Wang, Ayman El-hattab, Megan L, Ganka Douglas, Ellen K. Brundage, William J. Craigen, Eric S. Schmitt, Lee-jun C. WongAbstract:Mitochondrial DNA (mtDNA) deletions are a common cause of mitochondrial disorders. Large mtDNA deletions can lead to a broad spectrum of clinical features with different age of onset, ranging from mild mitochondrial myopathies (MM), progressive external ophthalmoplegia (PEO), and Kearns-Sayre syndrome (KSS), to severe Pearson syndrome. The aim of this study is to investigate the molecular signatures surrounding the deletion breakpoints and their association with the clinical phenotype and age at onset. MtDNA deletions in 67 patients were characterized using array comparative genomic hybridization (aCGH) followed by PCR-sequencing of the deletion junctions. Sequence Homology including both perfect and imperfect short repeats flanking the deletion regions were analyzed and correlated with clinical features and patients’ age group. In all age groups, there was a significant increase in Sequence Homology flanking the deletion compared to mtDNA background. The youngest patient group (,6 years old) showed a diffused pattern of deletion distribution in size and locations, with a significantly lower Sequence Homology flanking the deletion, and the highest percentage of deletion mutant heteroplasmy. The older age groups showed rather discrete pattern of deletions with 44 % of all patients over 6 years old carrying the most common 5 kb mtDNA deletion, which was found mostly in muscle specimens (22/41). Only 15% (3/20) of the young patients (,6 years old) carry the 5 kb common deletion, which is usually present in blood rather than muscle. This group of patients predominantly (16 out of 17) exhibit multisystem disorder and/or Pearson syndrome, whil
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Sequence Homology at the breakpoint and clinical phenotype of mitochondrial DNA deletion syndromes.
PloS one, 2010Co-Authors: Bekim Sadikovic, Jing Wang, Ganka Douglas, Ellen K. Brundage, William J. Craigen, Eric S. Schmitt, Ayman W. El-hattab, Megan Landsverk, Lee-jun C. WongAbstract:Mitochondrial DNA (mtDNA) deletions are a common cause of mitochondrial disorders. Large mtDNA deletions can lead to a broad spectrum of clinical features with different age of onset, ranging from mild mitochondrial myopathies (MM), progressive external ophthalmoplegia (PEO), and Kearns-Sayre syndrome (KSS), to severe Pearson syndrome. The aim of this study is to investigate the molecular signatures surrounding the deletion breakpoints and their association with the clinical phenotype and age at onset. MtDNA deletions in 67 patients were characterized using array comparative genomic hybridization (aCGH) followed by PCR-sequencing of the deletion junctions. Sequence Homology including both perfect and imperfect short repeats flanking the deletion regions were analyzed and correlated with clinical features and patients' age group. In all age groups, there was a significant increase in Sequence Homology flanking the deletion compared to mtDNA background. The youngest patient group (
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Sequence Homology at the breakpoint and clinical phenotype of mitochondrial dna deletion syndromes
PLOS ONE, 2010Co-Authors: Bekim Sadikovic, Jing Wang, Ganka Douglas, Ellen K. Brundage, William J. Craigen, Eric S. Schmitt, Megan Landsverk, Ayman W Elhattab, Lee-jun C. WongAbstract:Mitochondrial DNA (mtDNA) deletions are a common cause of mitochondrial disorders. Large mtDNA deletions can lead to a broad spectrum of clinical features with different age of onset, ranging from mild mitochondrial myopathies (MM), progressive external ophthalmoplegia (PEO), and Kearns-Sayre syndrome (KSS), to severe Pearson syndrome. The aim of this study is to investigate the molecular signatures surrounding the deletion breakpoints and their association with the clinical phenotype and age at onset. MtDNA deletions in 67 patients were characterized using array comparative genomic hybridization (aCGH) followed by PCR-sequencing of the deletion junctions. Sequence Homology including both perfect and imperfect short repeats flanking the deletion regions were analyzed and correlated with clinical features and patients' age group. In all age groups, there was a significant increase in Sequence Homology flanking the deletion compared to mtDNA background. The youngest patient group (<6 years old) showed a diffused pattern of deletion distribution in size and locations, with a significantly lower Sequence Homology flanking the deletion, and the highest percentage of deletion mutant heteroplasmy. The older age groups showed rather discrete pattern of deletions with 44% of all patients over 6 years old carrying the most common 5 kb mtDNA deletion, which was found mostly in muscle specimens (22/41). Only 15% (3/20) of the young patients (<6 years old) carry the 5 kb common deletion, which is usually present in blood rather than muscle. This group of patients predominantly (16 out of 17) exhibit multisystem disorder and/or Pearson syndrome, while older patients had predominantly neuromuscular manifestations including KSS, PEO, and MM. In conclusion, Sequence Homology at the deletion flanking regions is a consistent feature of mtDNA deletions. Decreased levels of Sequence Homology and increased levels of deletion mutant heteroplasmy appear to correlate with earlier onset and more severe disease with multisystem involvement.
Vasant Honavar - One of the best experts on this subject based on the ideXlab platform.
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rnabindrplus a predictor that combines machine learning and Sequence Homology based methods to improve the reliability of predicted rna binding residues in proteins
PLOS ONE, 2014Co-Authors: Rasna R Walia, Li C Xue, Drena Dobbs, Vasant Honavar, Katherine Wilkins, Yasser ElmanzalawyAbstract:Protein-RNA interactions are central to essential cellular processes such as protein synthesis and regulation of gene expression and play roles in human infectious and genetic diseases. Reliable identification of protein-RNA interfaces is critical for understanding the structural bases and functional implications of such interactions and for developing effective approaches to rational drug design. Sequence-based computational methods offer a viable, cost-effective way to identify putative RNA-binding residues in RNA-binding proteins. Here we report two novel approaches: (i) HomPRIP, a Sequence Homology-based method for predicting RNA-binding sites in proteins; (ii) RNABindRPlus, a new method that combines predictions from HomPRIP with those from an optimized Support Vector Machine (SVM) classifier trained on a benchmark dataset of 198 RNA-binding proteins. Although highly reliable, HomPRIP cannot make predictions for the unaligned parts of query proteins and its coverage is limited by the availability of close Sequence homologs of the query protein with experimentally determined RNA-binding sites. RNABindRPlus overcomes these limitations. We compared the performance of HomPRIP and RNABindRPlus with that of several state-of-the-art predictors on two test sets, RB44 and RB111. On a subset of proteins for which homologs with experimentally determined interfaces could be reliably identified, HomPRIP outperformed all other methods achieving an MCC of 0.63 on RB44 and 0.83 on RB111. RNABindRPlus was able to predict RNA-binding residues of all proteins in both test sets, achieving an MCC of 0.55 and 0.37, respectively, and outperforming all other methods, including those that make use of structure-derived features of proteins. More importantly, RNABindRPlus outperforms all other methods for any choice of tradeoff between precision and recall. An important advantage of both HomPRIP and RNABindRPlus is that they rely on readily available Sequence and Sequence-derived features of RNA-binding proteins. A webserver implementation of both methods is freely available at http://einstein.cs.iastate.edu/RNABindRPlus/.
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homppi a class of Sequence Homology based protein protein interface prediction methods
BMC Bioinformatics, 2011Co-Authors: Li C Xue, Drena Dobbs, Vasant HonavarAbstract:Although Homology-based methods are among the most widely used methods for predicting the structure and function of proteins, the question as to whether interface Sequence conservation can be effectively exploited in predicting protein-protein interfaces has been a subject of debate. We studied more than 300,000 pair-wise alignments of protein Sequences from structurally characterized protein complexes, including both obligate and transient complexes. We identified Sequence similarity criteria required for accurate Homology-based inference of interface residues in a query protein Sequence. Based on these analyses, we developed HomPPI, a class of Sequence Homology-based methods for predicting protein-protein interface residues. We present two variants of HomPPI: (i) NPS-HomPPI (Non partner-specific HomPPI), which can be used to predict interface residues of a query protein in the absence of knowledge of the interaction partner; and (ii) PS-HomPPI (Partner-specific HomPPI), which can be used to predict the interface residues of a query protein with a specific target protein. Our experiments on a benchmark dataset of obligate homodimeric complexes show that NPS-HomPPI can reliably predict protein-protein interface residues in a given protein, with an average correlation coefficient (CC) of 0.76, sensitivity of 0.83, and specificity of 0.78, when Sequence homologs of the query protein can be reliably identified. NPS-HomPPI also reliably predicts the interface residues of intrinsically disordered proteins. Our experiments suggest that NPS-HomPPI is competitive with several state-of-the-art interface prediction servers including those that exploit the structure of the query proteins. The partner-specific classifier, PS-HomPPI can, on a large dataset of transient complexes, predict the interface residues of a query protein with a specific target, with a CC of 0.65, sensitivity of 0.69, and specificity of 0.70, when homologs of both the query and the target can be reliably identified. The HomPPI web server is available at http://homppi.cs.iastate.edu/ . Sequence Homology-based methods offer a class of computationally efficient and reliable approaches for predicting the protein-protein interface residues that participate in either obligate or transient interactions. For query proteins involved in transient interactions, the reliability of interface residue prediction can be improved by exploiting knowledge of putative interaction partners.
William J. Craigen - One of the best experts on this subject based on the ideXlab platform.
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Sequence Homology at the Breakpoint and Clinical Phenotype of Mitochondrial DNA Deletion Syndromes
2013Co-Authors: Bekim Sadikovic, Jing Wang, Ayman El-hattab, Megan L, Ganka Douglas, Ellen K. Brundage, William J. Craigen, Eric S. Schmitt, Lee-jun C. WongAbstract:Mitochondrial DNA (mtDNA) deletions are a common cause of mitochondrial disorders. Large mtDNA deletions can lead to a broad spectrum of clinical features with different age of onset, ranging from mild mitochondrial myopathies (MM), progressive external ophthalmoplegia (PEO), and Kearns-Sayre syndrome (KSS), to severe Pearson syndrome. The aim of this study is to investigate the molecular signatures surrounding the deletion breakpoints and their association with the clinical phenotype and age at onset. MtDNA deletions in 67 patients were characterized using array comparative genomic hybridization (aCGH) followed by PCR-sequencing of the deletion junctions. Sequence Homology including both perfect and imperfect short repeats flanking the deletion regions were analyzed and correlated with clinical features and patients’ age group. In all age groups, there was a significant increase in Sequence Homology flanking the deletion compared to mtDNA background. The youngest patient group (,6 years old) showed a diffused pattern of deletion distribution in size and locations, with a significantly lower Sequence Homology flanking the deletion, and the highest percentage of deletion mutant heteroplasmy. The older age groups showed rather discrete pattern of deletions with 44 % of all patients over 6 years old carrying the most common 5 kb mtDNA deletion, which was found mostly in muscle specimens (22/41). Only 15% (3/20) of the young patients (,6 years old) carry the 5 kb common deletion, which is usually present in blood rather than muscle. This group of patients predominantly (16 out of 17) exhibit multisystem disorder and/or Pearson syndrome, whil
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Sequence Homology at the breakpoint and clinical phenotype of mitochondrial DNA deletion syndromes.
PloS one, 2010Co-Authors: Bekim Sadikovic, Jing Wang, Ganka Douglas, Ellen K. Brundage, William J. Craigen, Eric S. Schmitt, Ayman W. El-hattab, Megan Landsverk, Lee-jun C. WongAbstract:Mitochondrial DNA (mtDNA) deletions are a common cause of mitochondrial disorders. Large mtDNA deletions can lead to a broad spectrum of clinical features with different age of onset, ranging from mild mitochondrial myopathies (MM), progressive external ophthalmoplegia (PEO), and Kearns-Sayre syndrome (KSS), to severe Pearson syndrome. The aim of this study is to investigate the molecular signatures surrounding the deletion breakpoints and their association with the clinical phenotype and age at onset. MtDNA deletions in 67 patients were characterized using array comparative genomic hybridization (aCGH) followed by PCR-sequencing of the deletion junctions. Sequence Homology including both perfect and imperfect short repeats flanking the deletion regions were analyzed and correlated with clinical features and patients' age group. In all age groups, there was a significant increase in Sequence Homology flanking the deletion compared to mtDNA background. The youngest patient group (
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Sequence Homology at the breakpoint and clinical phenotype of mitochondrial dna deletion syndromes
PLOS ONE, 2010Co-Authors: Bekim Sadikovic, Jing Wang, Ganka Douglas, Ellen K. Brundage, William J. Craigen, Eric S. Schmitt, Megan Landsverk, Ayman W Elhattab, Lee-jun C. WongAbstract:Mitochondrial DNA (mtDNA) deletions are a common cause of mitochondrial disorders. Large mtDNA deletions can lead to a broad spectrum of clinical features with different age of onset, ranging from mild mitochondrial myopathies (MM), progressive external ophthalmoplegia (PEO), and Kearns-Sayre syndrome (KSS), to severe Pearson syndrome. The aim of this study is to investigate the molecular signatures surrounding the deletion breakpoints and their association with the clinical phenotype and age at onset. MtDNA deletions in 67 patients were characterized using array comparative genomic hybridization (aCGH) followed by PCR-sequencing of the deletion junctions. Sequence Homology including both perfect and imperfect short repeats flanking the deletion regions were analyzed and correlated with clinical features and patients' age group. In all age groups, there was a significant increase in Sequence Homology flanking the deletion compared to mtDNA background. The youngest patient group (<6 years old) showed a diffused pattern of deletion distribution in size and locations, with a significantly lower Sequence Homology flanking the deletion, and the highest percentage of deletion mutant heteroplasmy. The older age groups showed rather discrete pattern of deletions with 44% of all patients over 6 years old carrying the most common 5 kb mtDNA deletion, which was found mostly in muscle specimens (22/41). Only 15% (3/20) of the young patients (<6 years old) carry the 5 kb common deletion, which is usually present in blood rather than muscle. This group of patients predominantly (16 out of 17) exhibit multisystem disorder and/or Pearson syndrome, while older patients had predominantly neuromuscular manifestations including KSS, PEO, and MM. In conclusion, Sequence Homology at the deletion flanking regions is a consistent feature of mtDNA deletions. Decreased levels of Sequence Homology and increased levels of deletion mutant heteroplasmy appear to correlate with earlier onset and more severe disease with multisystem involvement.
