Linh Tran - Academia.edu (original) (raw)
Papers by Linh Tran
Prediction of human Plasmodium sex specific gene by homology search: a systematic review and meta-synthesis
Human Plasmodium species have a sex specific process in the life cycle namely gametocytogenesis o... more Human Plasmodium species have a sex specific process in the life cycle namely gametocytogenesis or gametogenesis. Gametocytes production and subsequent gametes zygosis are critical for malaria parasites to link to mosquito stage and to merge to sexual reproduction. Here, we aimed at the identification of genes related to gametocytogenesis or gametogenesis in human malaria using systematic review, meta-synthesis and homology search. Based on our search terms, we conducted a systematic search of published data in nine databases resulting in 96 finally included papers with a total of 255 genes from apicomplexan species. We found more papers involved in Plasmodium than we had expected, which reflects that the extensive amount of research on Plasmodium genes have been examined. Subsequently we searched sequence homology between FASTA sequences of apicomplexan sex specific genes other than human malaria parasites and those of human malaria parasites genome on PlasmoDB. We focused on eight...
Journal of Clinical Epidemiology, 2019
This is a PDF file of an article that has undergone enhancements after acceptance, such as the ad... more This is a PDF file of an article that has undergone enhancements after acceptance, such as the addition of a cover page and metadata, and formatting for readability, but it is not yet the definitive version of record. This version will undergo additional copyediting, typesetting and review before it is published in its final form, but we are providing this version to give early visibility of the article. Please note that, during the production process, errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
arXiv (Cornell University), Oct 17, 2013
We prove a local law for eigenvalues of the random Hermitian matrices with external source Wn = 1... more We prove a local law for eigenvalues of the random Hermitian matrices with external source Wn = 1 n Xn + An where Xn is Wigner matrix and An is diagonal matrix with only two values a, −a on the diagonal. The local law is an essential step to prove the universality conjecture for this random matrix model.
PLOS Pathogens, 2021
Prions are infectious proteins causing fatal, transmissible neurodegenerative diseases of animals... more Prions are infectious proteins causing fatal, transmissible neurodegenerative diseases of animals and humans. Replication involves template-directed refolding of host encoded prion protein, PrPC, by its infectious conformation, PrPSc. Following its discovery in captive Colorado deer in 1967, uncontrollable contagious transmission of chronic wasting disease (CWD) led to an expanded geographic range in increasing numbers of free-ranging and captive North American (NA) cervids. Some five decades later, detection of PrPSc in free-ranging Norwegian (NO) reindeer and moose marked the first indication of CWD in Europe. To assess the properties of these emergent NO prions and compare them with NA CWD we used transgenic (Tg) and gene targeted (Gt) mice expressing PrP with glutamine (Q) or glutamate (E) at residue 226, a variation in wild type cervid PrP which influences prion strain selection in NA deer and elk. Transmissions of NO moose and reindeer prions to Tg and Gt mice recapitulated th...
Physiotherapy, 2019
This is a PDF file of an article that has undergone enhancements after acceptance, such as the ad... more This is a PDF file of an article that has undergone enhancements after acceptance, such as the addition of a cover page and metadata, and formatting for readability, but it is not yet the definitive version of record. This version will undergo additional copyediting, typesetting and review before it is published in its final form, but we are providing this version to give early visibility of the article. Please note that, during the production process, errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
Validation of a sensitive and quantitative biomarker method for the determination of hepcidin in human serum
Journal of Clinical Oncology, 2008
20612 Background: Human hepcidin-25 plays an important regulatory role in iron metabolism and is ... more 20612 Background: Human hepcidin-25 plays an important regulatory role in iron metabolism and is known to be induced by inflammation. To allow accurate measurement of hepcidin concentrations in clinical samples, a quantitative serum hepcidin assay was developed using HPLC-MS/MS. This assay improves on previous mass spectrometry methods by the addition of a stable labeled internal standard, and is capable of differentiating full length hepcidin and biologically inactive breakdown products such as hepcidin-22 and hepcidin-20. Methods: Human serum samples were pretreated with a high-throughput, 96-well solid phase extraction method and then analyzed using HPLC-MS/MS. The method was validated according to the current FDA guidelines and met the criteria for bioanalytical methods validation. Results: The method was able to accurately determine hepcidin concentrations in human serum between 2.5 and 2000 ng/mL, and its applicability was demonstrated in healthy subjects and in patients expected to have inflammatio...
Cell Metabolism, 2009
Given the success in engineering synthetic phenotypes in microbes and mammalian cells, constructi... more Given the success in engineering synthetic phenotypes in microbes and mammalian cells, constructing non-native pathways in mammals has become increasingly attractive for understanding and identifying potential targets for treating metabolic disorders. Here, we introduced the glyoxylate shunt into mouse liver to investigate mammalian fatty acid metabolism. Mice expressing the shunt showed resistance to diet-induced obesity on a high-fat diet despite similar food consumption. This was accompanied by a decrease in total fat mass, circulating leptin levels, plasma triglyceride concentration, and a signaling metabolite in liver, malonyl-CoA, that inhibits fatty acid degradation. Contrary to plants and bacteria, in which the glyoxylate shunt prevents the complete oxidation of fatty acids, this pathway when introduced in mice increases fatty acid oxidation such that resistance to diet-induced obesity develops. This work suggests that using non-native pathways in higher organisms to explore and modulate metabolism may be a useful approach.
Efficient protection in MPλS networks using backup trees: Part oneConcepts and heuristics
Photonic Network …, 2003
Adelbert Groebbens*, Didier Colle, Sophie De Maesschalck, Ilse Lievens, Mario Pickavet, Piet Deme... more Adelbert Groebbens*, Didier Colle, Sophie De Maesschalck, Ilse Lievens, Mario Pickavet, Piet Demeester Ghent UniversityÐIMEC, Department of Information Technology, Sint-Pietersnieuwstraat 41, 9000 Gent, Belgium E-mail: {adelbert.groebbens, dcolle, sdemaess, mario.pickavet, ...
Characterization of Genetic Networks Associated with Alzheimer’s Disease
Methods in Molecular Biology, 2016
At the molecular level, the genetics of complex disease such as Alzheimer&amp... more At the molecular level, the genetics of complex disease such as Alzheimer's disease (AD) manifests itself as series of alterations in the molecular interactions in pathways and networks that define biological processes underlying the pathophysiological states of disease. While large-scale genome-wide association (GWA) studies of late-onset alzheimer's disease (LOAD) have uncovered prominent genomic regions linked to the disease, the cause for the vast majority of LOAD cases still remains unknown. Increasingly available large-scale genomic and genetic data related to LOAD has made it possible to comprehensively uncover the mechanisms causally lined to LOAD in a completely data-driven manner. Here we review the various aspects of systems/network biology approaches and methodology in constructing genetic networks associated with AD from large sampling of postmortem brain tissues. We describe in detail a multiscale network modeling approach (MNMA) that integrates interaction and causal gene networks to analyze large-scale DNA, gene expression and pathophysiological data from multiple post-mortem brain regions of LOAD patients as well non-demented normal controls. MNMA first employs weighted gene co-expression network analysis (WGCNA) to construct multi-tissue networks that…
imeko.org
Abstract: The paper presents different methods of combining many neural classifiers into one ense... more Abstract: The paper presents different methods of combining many neural classifiers into one ensemble system for recognition and classification of arrhythmia. Majority and weighted voting, Kullback-Leibler divergence and modified Bayes methods will be presented and ...
Strategy in structure-based drug design for influenza A virus targeting M2 channel proteins
Medicinal Chemistry Research, 2013
ABSTRACT The 2009 influenza A virus pandemic, with high level of drug resistance reported, has hi... more ABSTRACT The 2009 influenza A virus pandemic, with high level of drug resistance reported, has highlighted the urgent need of more effective anti-influenza drugs. M2 channel proteins on the influenza A virus membrane have emerged as an efficient structure-based drug design target since variety of M2 channel protein structures were constructed by different experiment methods to generate the high resolution of crystal, solution NMR and solid-state NMR structure. In an effort to facilitate the future design of M2 channel inhibitors, the binding modes of 200 Adamantane-based drugs in four different types of M2 channel protein structures were evaluated the critical interactions in terms of ligand binding affinity. The molecular docking results and statistic testing of binding affinity showed that the effect of each representative type from M2 channel protein structures was significantly different. Moreover, pharmacophore analysis revealed that there are two mechanisms of binding interactions to critical residues, Ser31 in holo structures and Ala30 in apo structures respectively. Molecular docking studies, drug-like filters and structure-based pharmacophore approaches successfully led us identifying the final hits reduced the false positives and false negatives in strategy of designing new potential group of future M2 channel inhibitors.
Medicinal Chemistry Research, 2014
The M2 channel protein has become an attractive target for the design of new drugs against influe... more The M2 channel protein has become an attractive target for the design of new drugs against influenza because it plays a crucial role in the replication cycle of influenza A virus. Several adamantane-based drugs have recently been developed to inhibit the activity of the M2 channel and overcome the drug resistance issues observed in amantadine and rimantadine. Computer-aided drug design continues to play a critical role in the drug discovery process in terms of its contribution to the identification and development of new therapeutic agents. Scientists working in this field are currently facing significant challenges with regard to creating novel platforms capable of enhancing our understanding of these proteins, with computational techniques being used to search for new potential drugs against influenza. This review provides a summary of recent progress in drug discovery toward the development therapeutic agents targeting M2 channel proteins. It is hoped that this review will stimulate the development of new strategies for overcoming drug resistance problems and encourage the design of new and improved drugs against influenza A virus. Keywords M2 channel protein Á Drug development Á Influenza A virus Á Inhibition mechanism Á Structural characteristics Á M2 inhibitor
Development of a method for the sensitive and quantitative determination of hepcidin in human serum using LC-MS/MS
Journal of Pharmacological and Toxicological Methods, 2009
Hepcidin, a 25-amino acid peptide hormone, plays a crucial regulatory role in iron metabolism. El... more Hepcidin, a 25-amino acid peptide hormone, plays a crucial regulatory role in iron metabolism. Elevated hepcidin has been observed in response to inflammation and is speculated to be a causative factor in inflammatory anemia due to induction of functional iron deficiency. Hepcidin has been suggested as a biomarker of anemia of inflammation. An accurate assessment of human serum hepcidin is critical to understand its role in anemia. An LC-MS/MS method was developed to quantify hepcidin in human serum using chemically synthesized hepcidin as a standard and stable isotope labeled hepcidin as internal standard. Rabbit serum was used as a surrogate matrix for standards due to the presence of endogenous hepcidin in human serum. The method was validated to FDA criteria for bioanalytical assays. The calibration curve was validated over the range of 2.5 to 500 ng/mL. Hepcidin was stable in serum for at least 16 h at room temperature, 90 days at -60 to -80 degrees C, and after three F/T cycles. Interday accuracy (% RE) and precision (%CV) were -11.2% and 5.6%, respectively at the LLOQ, and less than +/-7.0% and 9.2%, respectively for higher concentrations. The mean accuracy of quality control samples (5.00, 15.0, 100 and 400 ng/mL) in 21 analytical batches was between -0.7 and +2.1%, with mean precision between 5.1% and 13.4%. Hepcidin was below 2.5 ng/mL in 31 of 60 healthy subjects, while the mean concentration was less than 10 ng/mL. Sepsis and chronic kidney disease patients had mean serum concentrations of 252 ng/mL (n=16, median 121 ng/mL) and 99 ng/mL (n=50, median 68 ng/mL), respectively. A fully validated LC-MS/MS method has been described for the determination of hepcidin in human serum. This method was applied to the determination of hepcidin in over 1200 human samples.
IEEE Transactions on Biomedical Engineering, 2004
IEEE Transactions on Biomedical Engineering, 2001
This paper presents the application of the fuzzy neural network for electrocardiographic (ECG) be... more This paper presents the application of the fuzzy neural network for electrocardiographic (ECG) beat recognition and classification. The new classification algorithm of the ECG beats, applying the fuzzy hybrid neural network and the features drawn from the higher order statistics has been proposed in the paper. The cumulants of the second, third, and fourth orders have been used for the feature selection. The hybrid fuzzy neural network applied in the solution consists of the fuzzy self-organizing subnetwork connected in cascade with the multilayer perceptron, working as the final classifier. The c-means and Gustafson-Kessel algorithms for the self-organization of the neural network have been applied. The results of experiments of recognition of different types of beats on the basis of the ECG waveforms have confirmed good efficiency of the proposed solution. The investigations show that the method may find practical application in the recognition and classification of different type heart beats.
COMPEL - The international journal for computation and mathematics in electrical and electronic engineering, 2005
Purpose-This paper presents new approach to the integration of neural classifiers. Typically only... more Purpose-This paper presents new approach to the integration of neural classifiers. Typically only the best trained network is chosen, while the rest is discarded. However, combining the trained networks helps to integrate the knowledge acquired by the component classifiers and in this way improves the accuracy of the final classification. The aim of the research is to develop and compare the methods of combining neural classifiers of the heart beat recognition. Design/methodology/approach-Two methods of integration of the results of individual classifiers are proposed. One is based on the statistical reliability of post-processing performance on the trained data and the second uses the least mean square method in adjusting the weights of the weighted voting integrating network. Findings-The experimental results of the recognition of six types of arrhythmias and normal sinus rhythm have shown that the performance of individual classifiers could be improved significantly by the integration proposed in this paper. Practical implications-The presented application should be regarded as the first step in the direction of automatic recognition of the heart rhythms on the basis of the registered ECG waveforms. Originality/value-The results mean that instead of designing one high performance classifier one can build a number of classifiers, each of not superb performance. The appropriate combination of them may produce a performance of much higher quality.
Cell, 2013
The genetics of complex disease produce alterations in the molecular interactions of cellular pat... more The genetics of complex disease produce alterations in the molecular interactions of cellular pathways whose collective effect may become clear through the organized structure of molecular networks. To characterize molecular systems associated with late-onset Alzheimer's disease (LOAD), we constructed gene-regulatory networks in 1,647 postmortem brain tissues from LOAD patients and nondemented subjects, and we demonstrate that LOAD reconfigures specific portions of the molecular interaction structure. Through an integrative network-based approach, we rank-ordered these network structures for relevance to LOAD pathology, highlighting an immune-and microglia-specific module that is dominated by genes involved in pathogen phagocytosis, contains TYROBP as a key regulator, and is upregulated in LOAD. Mouse microglia cells overexpressing intact or truncated TYROBP revealed expression changes that significantly overlapped the human brain TYROBP network. Thus the causal network structure is a useful predictor of response to gene perturbations and presents a framework to test models of disease mechanisms underlying LOAD.
General LC-MS/MS Method Approach to Quantify Therapeutic Monoclonal Antibodies Using a Common Whole Antibody Internal Standard with Application to Preclinical Studies
Analytical Chemistry, 2012
Ligand binding assays (LBAs) are widely used for therapeutic monoclonal antibody (mAb) quantifica... more Ligand binding assays (LBAs) are widely used for therapeutic monoclonal antibody (mAb) quantification in biological samples. Major limitations are long method development times, reagent procurement, and matrix effects. LC-MS/MS methods using signature peptides are emerging as an alternative approach, which typically use a stable isotope labeled signature peptide as the internal standard (IS). However, a new IS has to be generated for every candidate, and the IS may not correct for variations at all processing steps. We have developed a general LC-MS/MS method approach employing a uniformly heavy-isotope labeled common whole mAb IS and a common immunocapture for sample processing. The method was streamlined with automation for consistency and throughput. Method qualification of four IgG(2) and four IgG(1) mAbs showed sensitivity of 0.1 μg/mL and linearity of 0.1-15 μg/mL. Quality control (QC) data of these eight mAbs were accurate and precise. The QC performance of the whole molecule labeled IS was better than those of synthetic labeled IS peptides tested. The pharmacokinetic results of two mAbs (an IgG(2) and IgG(1) candidate) dosed in rats were comparable to those of LBA. The general LC-MS/MS method approach overcomes the limitations of current methods to reduce time and resources required for preclinical studies.
Prediction of human Plasmodium sex specific gene by homology search: a systematic review and meta-synthesis
Human Plasmodium species have a sex specific process in the life cycle namely gametocytogenesis o... more Human Plasmodium species have a sex specific process in the life cycle namely gametocytogenesis or gametogenesis. Gametocytes production and subsequent gametes zygosis are critical for malaria parasites to link to mosquito stage and to merge to sexual reproduction. Here, we aimed at the identification of genes related to gametocytogenesis or gametogenesis in human malaria using systematic review, meta-synthesis and homology search. Based on our search terms, we conducted a systematic search of published data in nine databases resulting in 96 finally included papers with a total of 255 genes from apicomplexan species. We found more papers involved in Plasmodium than we had expected, which reflects that the extensive amount of research on Plasmodium genes have been examined. Subsequently we searched sequence homology between FASTA sequences of apicomplexan sex specific genes other than human malaria parasites and those of human malaria parasites genome on PlasmoDB. We focused on eight...
Journal of Clinical Epidemiology, 2019
This is a PDF file of an article that has undergone enhancements after acceptance, such as the ad... more This is a PDF file of an article that has undergone enhancements after acceptance, such as the addition of a cover page and metadata, and formatting for readability, but it is not yet the definitive version of record. This version will undergo additional copyediting, typesetting and review before it is published in its final form, but we are providing this version to give early visibility of the article. Please note that, during the production process, errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
arXiv (Cornell University), Oct 17, 2013
We prove a local law for eigenvalues of the random Hermitian matrices with external source Wn = 1... more We prove a local law for eigenvalues of the random Hermitian matrices with external source Wn = 1 n Xn + An where Xn is Wigner matrix and An is diagonal matrix with only two values a, −a on the diagonal. The local law is an essential step to prove the universality conjecture for this random matrix model.
PLOS Pathogens, 2021
Prions are infectious proteins causing fatal, transmissible neurodegenerative diseases of animals... more Prions are infectious proteins causing fatal, transmissible neurodegenerative diseases of animals and humans. Replication involves template-directed refolding of host encoded prion protein, PrPC, by its infectious conformation, PrPSc. Following its discovery in captive Colorado deer in 1967, uncontrollable contagious transmission of chronic wasting disease (CWD) led to an expanded geographic range in increasing numbers of free-ranging and captive North American (NA) cervids. Some five decades later, detection of PrPSc in free-ranging Norwegian (NO) reindeer and moose marked the first indication of CWD in Europe. To assess the properties of these emergent NO prions and compare them with NA CWD we used transgenic (Tg) and gene targeted (Gt) mice expressing PrP with glutamine (Q) or glutamate (E) at residue 226, a variation in wild type cervid PrP which influences prion strain selection in NA deer and elk. Transmissions of NO moose and reindeer prions to Tg and Gt mice recapitulated th...
Physiotherapy, 2019
This is a PDF file of an article that has undergone enhancements after acceptance, such as the ad... more This is a PDF file of an article that has undergone enhancements after acceptance, such as the addition of a cover page and metadata, and formatting for readability, but it is not yet the definitive version of record. This version will undergo additional copyediting, typesetting and review before it is published in its final form, but we are providing this version to give early visibility of the article. Please note that, during the production process, errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
Validation of a sensitive and quantitative biomarker method for the determination of hepcidin in human serum
Journal of Clinical Oncology, 2008
20612 Background: Human hepcidin-25 plays an important regulatory role in iron metabolism and is ... more 20612 Background: Human hepcidin-25 plays an important regulatory role in iron metabolism and is known to be induced by inflammation. To allow accurate measurement of hepcidin concentrations in clinical samples, a quantitative serum hepcidin assay was developed using HPLC-MS/MS. This assay improves on previous mass spectrometry methods by the addition of a stable labeled internal standard, and is capable of differentiating full length hepcidin and biologically inactive breakdown products such as hepcidin-22 and hepcidin-20. Methods: Human serum samples were pretreated with a high-throughput, 96-well solid phase extraction method and then analyzed using HPLC-MS/MS. The method was validated according to the current FDA guidelines and met the criteria for bioanalytical methods validation. Results: The method was able to accurately determine hepcidin concentrations in human serum between 2.5 and 2000 ng/mL, and its applicability was demonstrated in healthy subjects and in patients expected to have inflammatio...
Cell Metabolism, 2009
Given the success in engineering synthetic phenotypes in microbes and mammalian cells, constructi... more Given the success in engineering synthetic phenotypes in microbes and mammalian cells, constructing non-native pathways in mammals has become increasingly attractive for understanding and identifying potential targets for treating metabolic disorders. Here, we introduced the glyoxylate shunt into mouse liver to investigate mammalian fatty acid metabolism. Mice expressing the shunt showed resistance to diet-induced obesity on a high-fat diet despite similar food consumption. This was accompanied by a decrease in total fat mass, circulating leptin levels, plasma triglyceride concentration, and a signaling metabolite in liver, malonyl-CoA, that inhibits fatty acid degradation. Contrary to plants and bacteria, in which the glyoxylate shunt prevents the complete oxidation of fatty acids, this pathway when introduced in mice increases fatty acid oxidation such that resistance to diet-induced obesity develops. This work suggests that using non-native pathways in higher organisms to explore and modulate metabolism may be a useful approach.
Efficient protection in MPλS networks using backup trees: Part oneConcepts and heuristics
Photonic Network …, 2003
Adelbert Groebbens*, Didier Colle, Sophie De Maesschalck, Ilse Lievens, Mario Pickavet, Piet Deme... more Adelbert Groebbens*, Didier Colle, Sophie De Maesschalck, Ilse Lievens, Mario Pickavet, Piet Demeester Ghent UniversityÐIMEC, Department of Information Technology, Sint-Pietersnieuwstraat 41, 9000 Gent, Belgium E-mail: {adelbert.groebbens, dcolle, sdemaess, mario.pickavet, ...
Characterization of Genetic Networks Associated with Alzheimer’s Disease
Methods in Molecular Biology, 2016
At the molecular level, the genetics of complex disease such as Alzheimer&amp... more At the molecular level, the genetics of complex disease such as Alzheimer's disease (AD) manifests itself as series of alterations in the molecular interactions in pathways and networks that define biological processes underlying the pathophysiological states of disease. While large-scale genome-wide association (GWA) studies of late-onset alzheimer's disease (LOAD) have uncovered prominent genomic regions linked to the disease, the cause for the vast majority of LOAD cases still remains unknown. Increasingly available large-scale genomic and genetic data related to LOAD has made it possible to comprehensively uncover the mechanisms causally lined to LOAD in a completely data-driven manner. Here we review the various aspects of systems/network biology approaches and methodology in constructing genetic networks associated with AD from large sampling of postmortem brain tissues. We describe in detail a multiscale network modeling approach (MNMA) that integrates interaction and causal gene networks to analyze large-scale DNA, gene expression and pathophysiological data from multiple post-mortem brain regions of LOAD patients as well non-demented normal controls. MNMA first employs weighted gene co-expression network analysis (WGCNA) to construct multi-tissue networks that…
imeko.org
Abstract: The paper presents different methods of combining many neural classifiers into one ense... more Abstract: The paper presents different methods of combining many neural classifiers into one ensemble system for recognition and classification of arrhythmia. Majority and weighted voting, Kullback-Leibler divergence and modified Bayes methods will be presented and ...
Strategy in structure-based drug design for influenza A virus targeting M2 channel proteins
Medicinal Chemistry Research, 2013
ABSTRACT The 2009 influenza A virus pandemic, with high level of drug resistance reported, has hi... more ABSTRACT The 2009 influenza A virus pandemic, with high level of drug resistance reported, has highlighted the urgent need of more effective anti-influenza drugs. M2 channel proteins on the influenza A virus membrane have emerged as an efficient structure-based drug design target since variety of M2 channel protein structures were constructed by different experiment methods to generate the high resolution of crystal, solution NMR and solid-state NMR structure. In an effort to facilitate the future design of M2 channel inhibitors, the binding modes of 200 Adamantane-based drugs in four different types of M2 channel protein structures were evaluated the critical interactions in terms of ligand binding affinity. The molecular docking results and statistic testing of binding affinity showed that the effect of each representative type from M2 channel protein structures was significantly different. Moreover, pharmacophore analysis revealed that there are two mechanisms of binding interactions to critical residues, Ser31 in holo structures and Ala30 in apo structures respectively. Molecular docking studies, drug-like filters and structure-based pharmacophore approaches successfully led us identifying the final hits reduced the false positives and false negatives in strategy of designing new potential group of future M2 channel inhibitors.
Medicinal Chemistry Research, 2014
The M2 channel protein has become an attractive target for the design of new drugs against influe... more The M2 channel protein has become an attractive target for the design of new drugs against influenza because it plays a crucial role in the replication cycle of influenza A virus. Several adamantane-based drugs have recently been developed to inhibit the activity of the M2 channel and overcome the drug resistance issues observed in amantadine and rimantadine. Computer-aided drug design continues to play a critical role in the drug discovery process in terms of its contribution to the identification and development of new therapeutic agents. Scientists working in this field are currently facing significant challenges with regard to creating novel platforms capable of enhancing our understanding of these proteins, with computational techniques being used to search for new potential drugs against influenza. This review provides a summary of recent progress in drug discovery toward the development therapeutic agents targeting M2 channel proteins. It is hoped that this review will stimulate the development of new strategies for overcoming drug resistance problems and encourage the design of new and improved drugs against influenza A virus. Keywords M2 channel protein Á Drug development Á Influenza A virus Á Inhibition mechanism Á Structural characteristics Á M2 inhibitor
Development of a method for the sensitive and quantitative determination of hepcidin in human serum using LC-MS/MS
Journal of Pharmacological and Toxicological Methods, 2009
Hepcidin, a 25-amino acid peptide hormone, plays a crucial regulatory role in iron metabolism. El... more Hepcidin, a 25-amino acid peptide hormone, plays a crucial regulatory role in iron metabolism. Elevated hepcidin has been observed in response to inflammation and is speculated to be a causative factor in inflammatory anemia due to induction of functional iron deficiency. Hepcidin has been suggested as a biomarker of anemia of inflammation. An accurate assessment of human serum hepcidin is critical to understand its role in anemia. An LC-MS/MS method was developed to quantify hepcidin in human serum using chemically synthesized hepcidin as a standard and stable isotope labeled hepcidin as internal standard. Rabbit serum was used as a surrogate matrix for standards due to the presence of endogenous hepcidin in human serum. The method was validated to FDA criteria for bioanalytical assays. The calibration curve was validated over the range of 2.5 to 500 ng/mL. Hepcidin was stable in serum for at least 16 h at room temperature, 90 days at -60 to -80 degrees C, and after three F/T cycles. Interday accuracy (% RE) and precision (%CV) were -11.2% and 5.6%, respectively at the LLOQ, and less than +/-7.0% and 9.2%, respectively for higher concentrations. The mean accuracy of quality control samples (5.00, 15.0, 100 and 400 ng/mL) in 21 analytical batches was between -0.7 and +2.1%, with mean precision between 5.1% and 13.4%. Hepcidin was below 2.5 ng/mL in 31 of 60 healthy subjects, while the mean concentration was less than 10 ng/mL. Sepsis and chronic kidney disease patients had mean serum concentrations of 252 ng/mL (n=16, median 121 ng/mL) and 99 ng/mL (n=50, median 68 ng/mL), respectively. A fully validated LC-MS/MS method has been described for the determination of hepcidin in human serum. This method was applied to the determination of hepcidin in over 1200 human samples.
IEEE Transactions on Biomedical Engineering, 2004
IEEE Transactions on Biomedical Engineering, 2001
This paper presents the application of the fuzzy neural network for electrocardiographic (ECG) be... more This paper presents the application of the fuzzy neural network for electrocardiographic (ECG) beat recognition and classification. The new classification algorithm of the ECG beats, applying the fuzzy hybrid neural network and the features drawn from the higher order statistics has been proposed in the paper. The cumulants of the second, third, and fourth orders have been used for the feature selection. The hybrid fuzzy neural network applied in the solution consists of the fuzzy self-organizing subnetwork connected in cascade with the multilayer perceptron, working as the final classifier. The c-means and Gustafson-Kessel algorithms for the self-organization of the neural network have been applied. The results of experiments of recognition of different types of beats on the basis of the ECG waveforms have confirmed good efficiency of the proposed solution. The investigations show that the method may find practical application in the recognition and classification of different type heart beats.
COMPEL - The international journal for computation and mathematics in electrical and electronic engineering, 2005
Purpose-This paper presents new approach to the integration of neural classifiers. Typically only... more Purpose-This paper presents new approach to the integration of neural classifiers. Typically only the best trained network is chosen, while the rest is discarded. However, combining the trained networks helps to integrate the knowledge acquired by the component classifiers and in this way improves the accuracy of the final classification. The aim of the research is to develop and compare the methods of combining neural classifiers of the heart beat recognition. Design/methodology/approach-Two methods of integration of the results of individual classifiers are proposed. One is based on the statistical reliability of post-processing performance on the trained data and the second uses the least mean square method in adjusting the weights of the weighted voting integrating network. Findings-The experimental results of the recognition of six types of arrhythmias and normal sinus rhythm have shown that the performance of individual classifiers could be improved significantly by the integration proposed in this paper. Practical implications-The presented application should be regarded as the first step in the direction of automatic recognition of the heart rhythms on the basis of the registered ECG waveforms. Originality/value-The results mean that instead of designing one high performance classifier one can build a number of classifiers, each of not superb performance. The appropriate combination of them may produce a performance of much higher quality.
Cell, 2013
The genetics of complex disease produce alterations in the molecular interactions of cellular pat... more The genetics of complex disease produce alterations in the molecular interactions of cellular pathways whose collective effect may become clear through the organized structure of molecular networks. To characterize molecular systems associated with late-onset Alzheimer's disease (LOAD), we constructed gene-regulatory networks in 1,647 postmortem brain tissues from LOAD patients and nondemented subjects, and we demonstrate that LOAD reconfigures specific portions of the molecular interaction structure. Through an integrative network-based approach, we rank-ordered these network structures for relevance to LOAD pathology, highlighting an immune-and microglia-specific module that is dominated by genes involved in pathogen phagocytosis, contains TYROBP as a key regulator, and is upregulated in LOAD. Mouse microglia cells overexpressing intact or truncated TYROBP revealed expression changes that significantly overlapped the human brain TYROBP network. Thus the causal network structure is a useful predictor of response to gene perturbations and presents a framework to test models of disease mechanisms underlying LOAD.
General LC-MS/MS Method Approach to Quantify Therapeutic Monoclonal Antibodies Using a Common Whole Antibody Internal Standard with Application to Preclinical Studies
Analytical Chemistry, 2012
Ligand binding assays (LBAs) are widely used for therapeutic monoclonal antibody (mAb) quantifica... more Ligand binding assays (LBAs) are widely used for therapeutic monoclonal antibody (mAb) quantification in biological samples. Major limitations are long method development times, reagent procurement, and matrix effects. LC-MS/MS methods using signature peptides are emerging as an alternative approach, which typically use a stable isotope labeled signature peptide as the internal standard (IS). However, a new IS has to be generated for every candidate, and the IS may not correct for variations at all processing steps. We have developed a general LC-MS/MS method approach employing a uniformly heavy-isotope labeled common whole mAb IS and a common immunocapture for sample processing. The method was streamlined with automation for consistency and throughput. Method qualification of four IgG(2) and four IgG(1) mAbs showed sensitivity of 0.1 μg/mL and linearity of 0.1-15 μg/mL. Quality control (QC) data of these eight mAbs were accurate and precise. The QC performance of the whole molecule labeled IS was better than those of synthetic labeled IS peptides tested. The pharmacokinetic results of two mAbs (an IgG(2) and IgG(1) candidate) dosed in rats were comparable to those of LBA. The general LC-MS/MS method approach overcomes the limitations of current methods to reduce time and resources required for preclinical studies.