Primary immunodeficiencies (PIDs) are a group of over 300 hereditary, heterogeneous, and mainly r... more Primary immunodeficiencies (PIDs) are a group of over 300 hereditary, heterogeneous, and mainly rare disorders that affect the immune system. Various aspects of immune system and PID proteins and genes have been investigated and facilitate systems biological studies of effects of PIDs on B cell physiology and response. We reconstructed a B cell network model based on data for the core B cell receptor activation and response processes and performed semi-quantitative dynamic simulations for normal and B cell PID failure modes. The results for several knockout simulations correspond to previously reported molecular studies and reveal novel mechanisms for PIDs. The simulations for CD21, CD40, LYN, MS4A1, ORAI1, PLCG2, PTPRC, and STIM1 indicated profound changes to major transcription factor signaling and to the network. Significant effects were observed also in the BCL10, BLNK, BTK, loss-offunction CARD11, IKKB, MALT1, and NEMO, simulations whereas only minor effects were detected for PIDs that are caused by constitutively active proteins (PI3K, gain-offunction CARD11, KRAS, and NFKBIA). This study revealed the underlying dynamics of PID diseases, confirms previous observations, and identifies novel candidates for PID diagnostics and therapy.
Somatic variations are frequent and important drivers in cancers. Amino acid substitutions can yi... more Somatic variations are frequent and important drivers in cancers. Amino acid substitutions can yield neoantigens that are detected by the immune system. Neoantigens can lead to immune response and tumor rejection. Although neoantigen load and occurrence have been widely studied, a detailed pancancer analysis of the occurrence and characterization of neoepitopes is missing. We investigated the proteome-wide amino acid substitutions in 8-, 9-, 10-, and 11-mer peptides in 30 cancer types with the NetMHC 4.0 software. 11,316,078 (0.24%) of the predicted 8-, 9-, 10-, and 11-mer peptides were highly likely neoepitope candidates and were derived from 95.44% of human proteins. Binding affinity to MHC molecules is just one of the many epitope features. The most likely epitopes are those which are detected by several MHCs and of several peptide lengths. 9-mer peptides are the most common among the high binding neoantigens. 0.17% of all variants yield more than 100 neoepitopes and are considered as the best candidates for any application. Amino acid distributions indicate that variants at all positions in neoepitopes of any length are, on average, more hydrophobic than the wild-type residues. We characterized properties of neoepitopes in 30 cancer types and estimated the likely numbers of tumor-derived epitopes that could induce an immune response. We found that amino acid distributions, at all positions in neoepitopes of all lengths, contain more hydrophobic residues than the wild-type sequences implying that the hydropathy nature of neoepitopes is an important property. The neoepitope characteristics can be employed for various applications including targeted cancer vaccine development for precision medicine. The task of the immune system is to detect and destroy foreign molecules and organisms. This is achieved by the numerous mechanisms and processes that form the innate and adaptive arms of the immune system. Three complementary adaptive systems have evolved to recognize foreign materials. First, antibodies recognize and neutralize non-self-molecules. Second, the major histocompatibility complexes (MHCs) I and II bind to and present short fragments of foreign peptides to T cells. Third, T cell receptors are produced with a similar recombination process as antibodies. The binding sites of these molecules are highly variable due to genetic recombination processes. Therefore, it is essential that the immune system does not react against natural human molecules to prevent autoimmune diseases. Safeguards against self-reactivity and induced tolerance prevent this from happening. These mechanisms are still poorly understood. Recently, antigen-specific regulatory T-cells were shown to be responsible for autoimmunity protection 1 . Variations accumulate during a lifetime. It has been estimated that in fibroblasts, B, and T cells, the mutation rate is 2-10 variations per diploid genome per cell division 2 . This means that normal cells can have from hundreds to several thousands of variations in comparison to the original genome of the individual 3 . In cancers, the variation rate can be much higher, for example, lung cancer cells typically contain over a million variants 4 . It is thus highly likely that cancer tissues include numerous immunogenic proteins because substitutions in the DNA, the most abundant changes in cancers, can lead to amino acid substitutions (AASs) in proteins. Such immunogenic epitopes are called neoantigens. To use neoantigens for therapeutic purposes, numerous research projects aim at detecting cancer variant peptides for diagnosis and treatment, including vaccination. Although next-generation sequencing methods are efficient for sequencing and detecting variants in tumors, the translation to neoantigens is not straightforward. Neoantigen-based treatment would facilitate personalized medicine for cancer patients. In addition to the possibilities for treatment, neoantigens could possibly be used for diagnosis especially in the case of relapse. Numerous methods have been developed to predict the antigenicity of peptides, especially those binding to MHC type I molecules 5 . The performance of these tools varies 6,7 depending on the size and composition of the used benchmark dataset 8 . Despite intensive research, the number of experimentally defined epitopes is still relatively small 7,9 and affects the performance of the predictors. By combining the epitope predictions with experimental validation assays, the performance can be improved. NetMHC 10,11 is a predictor for epitopes and
Objectives. SSc-associated pulmonary arterial hypertension (SSc-APAH) is a late but devastating c... more Objectives. SSc-associated pulmonary arterial hypertension (SSc-APAH) is a late but devastating complication of SSc. Early identification of SSc-APAH may improve survival. We examined the role of circulating miRNAs in SSc-APAH. Methods. Using quantitative RT-PCR the abundance of mature miRNAs in plasma was determined in 85 female patients with ACA-positive lcSSc. Twenty-two of the patients had SSc-APAH. Sixty-three SSc controls without PAH were matched for disease duration. Forty-six selected miRNA plasma levels were correlated with clinical data. Longitudinal samples were analysed from 14 SSc-APAH and 27 SSc patients. Results. The disease duration was 12 years for the SSc-APAH patients and 12.7 years for the SSc controls. Plasma expression levels of 11 miRNAs were lower in patients with SSc-APAH. Four miRNAs displayed higher plasma levels in SSc-APAH patients compared with SSc controls. There was significant difference between groups for miR-20a-5p and miR-203a-3p when correcting for multiple comparisons (P ¼ 0.002 for both). Receiver operating characteristics curve showed AUC ¼ 0.69-0.83 for miR-21-5p and miR-20a-5p or their combination. miR-20a-5p and miR-203a-3p correlated inversely with NT-pro-Brain Natriuretic Protein levels (r ¼ À0.42 and À0.47). Mixed effect model analysis could not identify any miRNAs as predictor of PAH development. However, miR-20a-5p plasma levels were lower in the longitudinal samples of SSc-APAH patients than in the SSc controls. Our study links expression levels of the circulating plasma miRNAs, especially miR-20a-5p and miR-203a-3p, to the occurrence of SSc-APAH in female patients with ACA-positive lcSSc.
Primary immunodeficiencies (PIDs) are a group of over 300 hereditary, heterogeneous, and mainly r... more Primary immunodeficiencies (PIDs) are a group of over 300 hereditary, heterogeneous, and mainly rare disorders that affect the immune system. Various aspects of immune system and PID proteins and genes have been investigated and facilitate systems biological studies of effects of PIDs on B cell physiology and response. We reconstructed a B cell network model based on data for the core B cell receptor activation and response processes and performed semi-quantitative dynamic simulations for normal and B cell PID failure modes. The results for several knockout simulations correspond to previously reported molecular studies and reveal novel mechanisms for PIDs. The simulations for CD21, CD40, LYN, MS4A1, ORAI1, PLCG2, PTPRC, and STIM1 indicated profound changes to major transcription factor signaling and to the network. Significant effects were observed also in the BCL10, BLNK, BTK, loss-offunction CARD11, IKKB, MALT1, and NEMO, simulations whereas only minor effects were detected for PIDs that are caused by constitutively active proteins (PI3K, gain-offunction CARD11, KRAS, and NFKBIA). This study revealed the underlying dynamics of PID diseases, confirms previous observations, and identifies novel candidates for PID diagnostics and therapy.
Primary immunodeficiencies (PIDs) are a group of over 300 hereditary, heterogeneous, and mainly r... more Primary immunodeficiencies (PIDs) are a group of over 300 hereditary, heterogeneous, and mainly rare disorders that affect the immune system. Various aspects of immune system and PID proteins and genes have been investigated and facilitate systems biological studies of effects of PIDs on B cell physiology and response. We reconstructed a B cell network model based on data for the core B cell receptor activation and response processes and performed semi-quantitative dynamic simulations for normal and B cell PID failure modes. The results for several knockout simulations correspond to previously reported molecular studies and reveal novel mechanisms for PIDs. The simulations for CD21, CD40, LYN, MS4A1, ORAI1, PLCG2, PTPRC, and STIM1 indicated profound changes to major transcription factor signaling and to the network. Significant effects were observed also in the BCL10, BLNK, BTK, loss-offunction CARD11, IKKB, MALT1, and NEMO, simulations whereas only minor effects were detected for PIDs that are caused by constitutively active proteins (PI3K, gain-offunction CARD11, KRAS, and NFKBIA). This study revealed the underlying dynamics of PID diseases, confirms previous observations, and identifies novel candidates for PID diagnostics and therapy.
<p>The node states for the wild type and the PID-perturbed attractors (knockout perturbatio... more <p>The node states for the wild type and the PID-perturbed attractors (knockout perturbation of LCK, ZAP70, ITK, IKKB, NEMO, CARD11, MALT1, BCL10, NFKBIA, PTPRC, MAP3K14 and knockin perturbation of PI3K) attractors. The attractors are represented by the rows while the states of the nodes in the attractors are represented on the columns. The state of a node for an attractor is represented by the color of the cell on the row of the attractor; black means inactive whereas white means activate.</p
<p>The strongly connected component of the interaction graph consists of 25 nodes and 48 li... more <p>The strongly connected component of the interaction graph consists of 25 nodes and 48 links. This subnet shows the interconnectedness and cross-talk of the early signals after the antigen-TCR ligation.</p
<p>The basin of attractors of the CD4+ T-cell network model simulated using the normalized ... more <p>The basin of attractors of the CD4+ T-cell network model simulated using the normalized HillCube algorithm. The horizontal axis denotes time in arbitrary units.</p
<p>Signaling paths having FBLs from signals 1 and 2 to the major transcription factors iden... more <p>Signaling paths having FBLs from signals 1 and 2 to the major transcription factors identified from the interaction graph. The columns represent the Boolean update equations and are labeled with the updated protein. Each row represents an FBL, and consists of the proteins located along it. On each row, cells with a black background indicate proteins that are along the FBL. There are 419 loops, containing on average 14 proteins.</p
The glutamate transporter 1 (GLT1) is upregulated during astrocyte development and maturation in ... more The glutamate transporter 1 (GLT1) is upregulated during astrocyte development and maturation in vivo and is vital for astrocyte function. Yet it is expressed at low levels by most cultured astrocytes. We previously showed that maturation of human and mouse stem cell-derived astrocytes-including functional glutamate uptake-could be enhanced by fibroblast growth factor (FGF)1 or FGF2. Here, we examined the specificity and mechanism of action of FGF2 and other FGF family members, as well as neurotrophic and differentiation factors, on mouse embryonic stem cell-derived astrocytes. We found that some FGFs-including FGF2, strongly increased GLT1 expression and enhanced astrocyte proliferation, while others (FGF16 and FGF18) mainly affected maturation. Interestingly, BMP4 increased astrocytic GFAP expression, and BMP4-treated astrocytes failed to promote the survival of motor neurons in vitro. Whole transcriptome analysis showed that FGF2 treatment regulated multiple genes linked to cell division, and that the mRNA encoding GLT1 was one of the most strongly upregulated of all astrocyte canonical markers. Since GLT1 is expressed at reduced levels in many neurodegenerative diseases, activation of this pathway is of potential therapeutic interest. Furthermore, treatment with FGFs provides a robust means for expansion of functionally mature stem cell-derived astrocytes for preclinical investigation.
<p>The network consists of 182 links and 118 nodes (including Boolean operators), 19 of whi... more <p>The network consists of 182 links and 118 nodes (including Boolean operators), 19 of which are input nodes, i.e., no link points to them (<a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0176500#pone.0176500.s001" target="_blank">S1 Table</a>). The Boolean network represents the naïve CD4+ T-cell activation events. The boxes represent non-PID (white) and PID proteins (gray). Spheres denote the AND gate. Activating links have a pointed head and solid line while inhibiting links have a blunt head and dashed line. Signal 1 represents peptide-MHC/TCR complex while Signal 2 represents co-receptor-ligand association, e.g. CD80-B7. Since the network focuses on TCR/CD28 signaling events, some events, e.g. for survival signaling that occur after antigen mediated T-cell activation and response through interleukin 2 (IL2), have not been fully considered.</p
Edited by Paul E. Fraser Parkinson's disease (PD) and multiple system atrophy (MSA) are distinct ... more Edited by Paul E. Fraser Parkinson's disease (PD) and multiple system atrophy (MSA) are distinct clinical syndromes characterized by the pathological accumulation of ␣-synuclein (␣-syn) protein fibrils in neurons and glial cells. These disorders and other neurodegenerative diseases may progress via prion-like mechanisms. The prion model of propagation predicts the existence of "strains" that link pathological aggregate structure and neuropathology. Prion strains are aggregated conformers that stably propagate in vivo and cause disease with defined incubation times and patterns of neuropathology. Indeed, tau prions have been well defined, and research suggests that both ␣-syn and -amyloid may also form strains. However, there is a lack of studies characterizing PDversus MSA-derived ␣-syn strains or demonstrating stable propagation of these unique conformers between cells or animals. To fill this gap, we used an assay based on FRET that exploits a HEK293T "biosensor" cell line stably expressing ␣-syn (A53T)-CFP/YFP fusion proteins to detect ␣-syn seeds in brain extracts from PD and MSA patients. Both soluble and insoluble fractions of MSA extracts had robust seeding activity, whereas only the insoluble fractions of PD extracts displayed seeding activity. The morphology of MSA-seeded inclusions differed from PD-seeded inclusions. These differences persisted upon propagation of aggregation to secondgeneration biosensor cells. We conclude that PD and MSA feature ␣-syn conformers with very distinct biochemical properties that can be transmitted to ␣-syn monomers in a cell system. These findings are consistent with the idea that distinct ␣-syn strains underlie PD and MSA and offer possible directions for synucleinopathy diagnosis.
Background Data-driven studies on the dynamics of reconstructed protein-protein interaction (PPI)... more Background Data-driven studies on the dynamics of reconstructed protein-protein interaction (PPI) networks facilitate investigation and identification of proteins important for particular processes or diseases and reduces time and costs of experimental verification. Modeling the dynamics of very large PPI networks is computationally costly. Results To circumvent this problem, we created a link-weighted human immunome interactome and performed filtering. We reconstructed the immunome interactome and weighed the links using jackknife gene expression correlation of integrated, time course gene expression data. Statistical significance of the links was computed using the Global Statistical Significance (GloSS) filtering algorithm. P-values from GloSS were computed for the integrated, time course gene expression data. We filtered the immunome interactome to identify core components of the T cell PPI network (TPPIN). The interconnectedness of the major pathways for T cell survival and res...
article doi:10.1093/rheumatology/kev234 Specific autoantibody profiles and disease subgroups corr... more article doi:10.1093/rheumatology/kev234 Specific autoantibody profiles and disease subgroups correlate with circulating micro-RNA in systemic sclerosis
BACKGROUND: About 11% of human genes occur in divergent pairs such that both genes are located on... more BACKGROUND: About 11% of human genes occur in divergent pairs such that both genes are located on opposite strands of DNA, and their immediate promoters are overlapping. The overlapping proximal promoter of both genes form an intergenic region called a bidirectional promoter which is less than 1000 base pairs in length. There is evidence that some cis-regulatory elements in bidirectional promoters control the transcription of both flanking genes. CCAAT boxes are one of the most abundant cis-regulatory elements in the human genome. NF-Y, a heterotrimeric transcription factor, activates CCAAT boxes and requires both the CCAAT box and specific flanking nucleotides for DNA binding. RESULTS: Using sequence analysis approach, data on the incidence of the NF-Y type CCAAT boxes in bidirectional promoters of both human and mouse genomes was used to deduce the functional and biological significance of NF-Y factor in the transcription mechanism of bidirectional gene pairs. In this study, four ...
Computational approaches are essential to study the effects of inborn and somatic variations. Res... more Computational approaches are essential to study the effects of inborn and somatic variations. Results from such studies contribute to better diagnosis and therapies. Primary immunodeficiencies (PIDs) are rare inborn defects of key immune response genes. Somatic variations are main drivers of most cancers. Large and diverse data on PID genes and proteins can enable systems biology studies on their dynamic effects on T and B cells. Amino acid substitutions (AASs) are somatic variations that drive cancers. However, AASs also cause cancer-associated antigens that are recognized by lymphocytes as non-self, and are called neoantigens. Detail analysis these neoantigens can be performed due to the availability of cancer data from many consortia.The purpose of this thesis was to investigate the effects of PIDs on T and B cells and to explore features of neoepitopes in cancers. The object of the first study was to detect the central T cell-specific protein network. The purpose of the second a...
Primary immunodeficiencies (PIDs) are a group of over 300 hereditary, heterogeneous, and mainly r... more Primary immunodeficiencies (PIDs) are a group of over 300 hereditary, heterogeneous, and mainly rare disorders that affect the immune system. Various aspects of immune system and PID proteins and genes have been investigated and facilitate systems biological studies of effects of PIDs on B cell physiology and response. We reconstructed a B cell network model based on data for the core B cell receptor activation and response processes and performed semi-quantitative dynamic simulations for normal and B cell PID failure modes. The results for several knockout simulations correspond to previously reported molecular studies and reveal novel mechanisms for PIDs. The simulations for CD21, CD40, LYN, MS4A1, ORAI1, PLCG2, PTPRC, and STIM1 indicated profound changes to major transcription factor signaling and to the network. Significant effects were observed also in the BCL10, BLNK, BTK, loss-offunction CARD11, IKKB, MALT1, and NEMO, simulations whereas only minor effects were detected for PIDs that are caused by constitutively active proteins (PI3K, gain-offunction CARD11, KRAS, and NFKBIA). This study revealed the underlying dynamics of PID diseases, confirms previous observations, and identifies novel candidates for PID diagnostics and therapy.
Somatic variations are frequent and important drivers in cancers. Amino acid substitutions can yi... more Somatic variations are frequent and important drivers in cancers. Amino acid substitutions can yield neoantigens that are detected by the immune system. Neoantigens can lead to immune response and tumor rejection. Although neoantigen load and occurrence have been widely studied, a detailed pancancer analysis of the occurrence and characterization of neoepitopes is missing. We investigated the proteome-wide amino acid substitutions in 8-, 9-, 10-, and 11-mer peptides in 30 cancer types with the NetMHC 4.0 software. 11,316,078 (0.24%) of the predicted 8-, 9-, 10-, and 11-mer peptides were highly likely neoepitope candidates and were derived from 95.44% of human proteins. Binding affinity to MHC molecules is just one of the many epitope features. The most likely epitopes are those which are detected by several MHCs and of several peptide lengths. 9-mer peptides are the most common among the high binding neoantigens. 0.17% of all variants yield more than 100 neoepitopes and are considered as the best candidates for any application. Amino acid distributions indicate that variants at all positions in neoepitopes of any length are, on average, more hydrophobic than the wild-type residues. We characterized properties of neoepitopes in 30 cancer types and estimated the likely numbers of tumor-derived epitopes that could induce an immune response. We found that amino acid distributions, at all positions in neoepitopes of all lengths, contain more hydrophobic residues than the wild-type sequences implying that the hydropathy nature of neoepitopes is an important property. The neoepitope characteristics can be employed for various applications including targeted cancer vaccine development for precision medicine. The task of the immune system is to detect and destroy foreign molecules and organisms. This is achieved by the numerous mechanisms and processes that form the innate and adaptive arms of the immune system. Three complementary adaptive systems have evolved to recognize foreign materials. First, antibodies recognize and neutralize non-self-molecules. Second, the major histocompatibility complexes (MHCs) I and II bind to and present short fragments of foreign peptides to T cells. Third, T cell receptors are produced with a similar recombination process as antibodies. The binding sites of these molecules are highly variable due to genetic recombination processes. Therefore, it is essential that the immune system does not react against natural human molecules to prevent autoimmune diseases. Safeguards against self-reactivity and induced tolerance prevent this from happening. These mechanisms are still poorly understood. Recently, antigen-specific regulatory T-cells were shown to be responsible for autoimmunity protection 1 . Variations accumulate during a lifetime. It has been estimated that in fibroblasts, B, and T cells, the mutation rate is 2-10 variations per diploid genome per cell division 2 . This means that normal cells can have from hundreds to several thousands of variations in comparison to the original genome of the individual 3 . In cancers, the variation rate can be much higher, for example, lung cancer cells typically contain over a million variants 4 . It is thus highly likely that cancer tissues include numerous immunogenic proteins because substitutions in the DNA, the most abundant changes in cancers, can lead to amino acid substitutions (AASs) in proteins. Such immunogenic epitopes are called neoantigens. To use neoantigens for therapeutic purposes, numerous research projects aim at detecting cancer variant peptides for diagnosis and treatment, including vaccination. Although next-generation sequencing methods are efficient for sequencing and detecting variants in tumors, the translation to neoantigens is not straightforward. Neoantigen-based treatment would facilitate personalized medicine for cancer patients. In addition to the possibilities for treatment, neoantigens could possibly be used for diagnosis especially in the case of relapse. Numerous methods have been developed to predict the antigenicity of peptides, especially those binding to MHC type I molecules 5 . The performance of these tools varies 6,7 depending on the size and composition of the used benchmark dataset 8 . Despite intensive research, the number of experimentally defined epitopes is still relatively small 7,9 and affects the performance of the predictors. By combining the epitope predictions with experimental validation assays, the performance can be improved. NetMHC 10,11 is a predictor for epitopes and
Objectives. SSc-associated pulmonary arterial hypertension (SSc-APAH) is a late but devastating c... more Objectives. SSc-associated pulmonary arterial hypertension (SSc-APAH) is a late but devastating complication of SSc. Early identification of SSc-APAH may improve survival. We examined the role of circulating miRNAs in SSc-APAH. Methods. Using quantitative RT-PCR the abundance of mature miRNAs in plasma was determined in 85 female patients with ACA-positive lcSSc. Twenty-two of the patients had SSc-APAH. Sixty-three SSc controls without PAH were matched for disease duration. Forty-six selected miRNA plasma levels were correlated with clinical data. Longitudinal samples were analysed from 14 SSc-APAH and 27 SSc patients. Results. The disease duration was 12 years for the SSc-APAH patients and 12.7 years for the SSc controls. Plasma expression levels of 11 miRNAs were lower in patients with SSc-APAH. Four miRNAs displayed higher plasma levels in SSc-APAH patients compared with SSc controls. There was significant difference between groups for miR-20a-5p and miR-203a-3p when correcting for multiple comparisons (P ¼ 0.002 for both). Receiver operating characteristics curve showed AUC ¼ 0.69-0.83 for miR-21-5p and miR-20a-5p or their combination. miR-20a-5p and miR-203a-3p correlated inversely with NT-pro-Brain Natriuretic Protein levels (r ¼ À0.42 and À0.47). Mixed effect model analysis could not identify any miRNAs as predictor of PAH development. However, miR-20a-5p plasma levels were lower in the longitudinal samples of SSc-APAH patients than in the SSc controls. Our study links expression levels of the circulating plasma miRNAs, especially miR-20a-5p and miR-203a-3p, to the occurrence of SSc-APAH in female patients with ACA-positive lcSSc.
Primary immunodeficiencies (PIDs) are a group of over 300 hereditary, heterogeneous, and mainly r... more Primary immunodeficiencies (PIDs) are a group of over 300 hereditary, heterogeneous, and mainly rare disorders that affect the immune system. Various aspects of immune system and PID proteins and genes have been investigated and facilitate systems biological studies of effects of PIDs on B cell physiology and response. We reconstructed a B cell network model based on data for the core B cell receptor activation and response processes and performed semi-quantitative dynamic simulations for normal and B cell PID failure modes. The results for several knockout simulations correspond to previously reported molecular studies and reveal novel mechanisms for PIDs. The simulations for CD21, CD40, LYN, MS4A1, ORAI1, PLCG2, PTPRC, and STIM1 indicated profound changes to major transcription factor signaling and to the network. Significant effects were observed also in the BCL10, BLNK, BTK, loss-offunction CARD11, IKKB, MALT1, and NEMO, simulations whereas only minor effects were detected for PIDs that are caused by constitutively active proteins (PI3K, gain-offunction CARD11, KRAS, and NFKBIA). This study revealed the underlying dynamics of PID diseases, confirms previous observations, and identifies novel candidates for PID diagnostics and therapy.
Primary immunodeficiencies (PIDs) are a group of over 300 hereditary, heterogeneous, and mainly r... more Primary immunodeficiencies (PIDs) are a group of over 300 hereditary, heterogeneous, and mainly rare disorders that affect the immune system. Various aspects of immune system and PID proteins and genes have been investigated and facilitate systems biological studies of effects of PIDs on B cell physiology and response. We reconstructed a B cell network model based on data for the core B cell receptor activation and response processes and performed semi-quantitative dynamic simulations for normal and B cell PID failure modes. The results for several knockout simulations correspond to previously reported molecular studies and reveal novel mechanisms for PIDs. The simulations for CD21, CD40, LYN, MS4A1, ORAI1, PLCG2, PTPRC, and STIM1 indicated profound changes to major transcription factor signaling and to the network. Significant effects were observed also in the BCL10, BLNK, BTK, loss-offunction CARD11, IKKB, MALT1, and NEMO, simulations whereas only minor effects were detected for PIDs that are caused by constitutively active proteins (PI3K, gain-offunction CARD11, KRAS, and NFKBIA). This study revealed the underlying dynamics of PID diseases, confirms previous observations, and identifies novel candidates for PID diagnostics and therapy.
<p>The node states for the wild type and the PID-perturbed attractors (knockout perturbatio... more <p>The node states for the wild type and the PID-perturbed attractors (knockout perturbation of LCK, ZAP70, ITK, IKKB, NEMO, CARD11, MALT1, BCL10, NFKBIA, PTPRC, MAP3K14 and knockin perturbation of PI3K) attractors. The attractors are represented by the rows while the states of the nodes in the attractors are represented on the columns. The state of a node for an attractor is represented by the color of the cell on the row of the attractor; black means inactive whereas white means activate.</p
<p>The strongly connected component of the interaction graph consists of 25 nodes and 48 li... more <p>The strongly connected component of the interaction graph consists of 25 nodes and 48 links. This subnet shows the interconnectedness and cross-talk of the early signals after the antigen-TCR ligation.</p
<p>The basin of attractors of the CD4+ T-cell network model simulated using the normalized ... more <p>The basin of attractors of the CD4+ T-cell network model simulated using the normalized HillCube algorithm. The horizontal axis denotes time in arbitrary units.</p
<p>Signaling paths having FBLs from signals 1 and 2 to the major transcription factors iden... more <p>Signaling paths having FBLs from signals 1 and 2 to the major transcription factors identified from the interaction graph. The columns represent the Boolean update equations and are labeled with the updated protein. Each row represents an FBL, and consists of the proteins located along it. On each row, cells with a black background indicate proteins that are along the FBL. There are 419 loops, containing on average 14 proteins.</p
The glutamate transporter 1 (GLT1) is upregulated during astrocyte development and maturation in ... more The glutamate transporter 1 (GLT1) is upregulated during astrocyte development and maturation in vivo and is vital for astrocyte function. Yet it is expressed at low levels by most cultured astrocytes. We previously showed that maturation of human and mouse stem cell-derived astrocytes-including functional glutamate uptake-could be enhanced by fibroblast growth factor (FGF)1 or FGF2. Here, we examined the specificity and mechanism of action of FGF2 and other FGF family members, as well as neurotrophic and differentiation factors, on mouse embryonic stem cell-derived astrocytes. We found that some FGFs-including FGF2, strongly increased GLT1 expression and enhanced astrocyte proliferation, while others (FGF16 and FGF18) mainly affected maturation. Interestingly, BMP4 increased astrocytic GFAP expression, and BMP4-treated astrocytes failed to promote the survival of motor neurons in vitro. Whole transcriptome analysis showed that FGF2 treatment regulated multiple genes linked to cell division, and that the mRNA encoding GLT1 was one of the most strongly upregulated of all astrocyte canonical markers. Since GLT1 is expressed at reduced levels in many neurodegenerative diseases, activation of this pathway is of potential therapeutic interest. Furthermore, treatment with FGFs provides a robust means for expansion of functionally mature stem cell-derived astrocytes for preclinical investigation.
<p>The network consists of 182 links and 118 nodes (including Boolean operators), 19 of whi... more <p>The network consists of 182 links and 118 nodes (including Boolean operators), 19 of which are input nodes, i.e., no link points to them (<a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0176500#pone.0176500.s001" target="_blank">S1 Table</a>). The Boolean network represents the naïve CD4+ T-cell activation events. The boxes represent non-PID (white) and PID proteins (gray). Spheres denote the AND gate. Activating links have a pointed head and solid line while inhibiting links have a blunt head and dashed line. Signal 1 represents peptide-MHC/TCR complex while Signal 2 represents co-receptor-ligand association, e.g. CD80-B7. Since the network focuses on TCR/CD28 signaling events, some events, e.g. for survival signaling that occur after antigen mediated T-cell activation and response through interleukin 2 (IL2), have not been fully considered.</p
Edited by Paul E. Fraser Parkinson's disease (PD) and multiple system atrophy (MSA) are distinct ... more Edited by Paul E. Fraser Parkinson's disease (PD) and multiple system atrophy (MSA) are distinct clinical syndromes characterized by the pathological accumulation of ␣-synuclein (␣-syn) protein fibrils in neurons and glial cells. These disorders and other neurodegenerative diseases may progress via prion-like mechanisms. The prion model of propagation predicts the existence of "strains" that link pathological aggregate structure and neuropathology. Prion strains are aggregated conformers that stably propagate in vivo and cause disease with defined incubation times and patterns of neuropathology. Indeed, tau prions have been well defined, and research suggests that both ␣-syn and -amyloid may also form strains. However, there is a lack of studies characterizing PDversus MSA-derived ␣-syn strains or demonstrating stable propagation of these unique conformers between cells or animals. To fill this gap, we used an assay based on FRET that exploits a HEK293T "biosensor" cell line stably expressing ␣-syn (A53T)-CFP/YFP fusion proteins to detect ␣-syn seeds in brain extracts from PD and MSA patients. Both soluble and insoluble fractions of MSA extracts had robust seeding activity, whereas only the insoluble fractions of PD extracts displayed seeding activity. The morphology of MSA-seeded inclusions differed from PD-seeded inclusions. These differences persisted upon propagation of aggregation to secondgeneration biosensor cells. We conclude that PD and MSA feature ␣-syn conformers with very distinct biochemical properties that can be transmitted to ␣-syn monomers in a cell system. These findings are consistent with the idea that distinct ␣-syn strains underlie PD and MSA and offer possible directions for synucleinopathy diagnosis.
Background Data-driven studies on the dynamics of reconstructed protein-protein interaction (PPI)... more Background Data-driven studies on the dynamics of reconstructed protein-protein interaction (PPI) networks facilitate investigation and identification of proteins important for particular processes or diseases and reduces time and costs of experimental verification. Modeling the dynamics of very large PPI networks is computationally costly. Results To circumvent this problem, we created a link-weighted human immunome interactome and performed filtering. We reconstructed the immunome interactome and weighed the links using jackknife gene expression correlation of integrated, time course gene expression data. Statistical significance of the links was computed using the Global Statistical Significance (GloSS) filtering algorithm. P-values from GloSS were computed for the integrated, time course gene expression data. We filtered the immunome interactome to identify core components of the T cell PPI network (TPPIN). The interconnectedness of the major pathways for T cell survival and res...
article doi:10.1093/rheumatology/kev234 Specific autoantibody profiles and disease subgroups corr... more article doi:10.1093/rheumatology/kev234 Specific autoantibody profiles and disease subgroups correlate with circulating micro-RNA in systemic sclerosis
BACKGROUND: About 11% of human genes occur in divergent pairs such that both genes are located on... more BACKGROUND: About 11% of human genes occur in divergent pairs such that both genes are located on opposite strands of DNA, and their immediate promoters are overlapping. The overlapping proximal promoter of both genes form an intergenic region called a bidirectional promoter which is less than 1000 base pairs in length. There is evidence that some cis-regulatory elements in bidirectional promoters control the transcription of both flanking genes. CCAAT boxes are one of the most abundant cis-regulatory elements in the human genome. NF-Y, a heterotrimeric transcription factor, activates CCAAT boxes and requires both the CCAAT box and specific flanking nucleotides for DNA binding. RESULTS: Using sequence analysis approach, data on the incidence of the NF-Y type CCAAT boxes in bidirectional promoters of both human and mouse genomes was used to deduce the functional and biological significance of NF-Y factor in the transcription mechanism of bidirectional gene pairs. In this study, four ...
Computational approaches are essential to study the effects of inborn and somatic variations. Res... more Computational approaches are essential to study the effects of inborn and somatic variations. Results from such studies contribute to better diagnosis and therapies. Primary immunodeficiencies (PIDs) are rare inborn defects of key immune response genes. Somatic variations are main drivers of most cancers. Large and diverse data on PID genes and proteins can enable systems biology studies on their dynamic effects on T and B cells. Amino acid substitutions (AASs) are somatic variations that drive cancers. However, AASs also cause cancer-associated antigens that are recognized by lymphocytes as non-self, and are called neoantigens. Detail analysis these neoantigens can be performed due to the availability of cancer data from many consortia.The purpose of this thesis was to investigate the effects of PIDs on T and B cells and to explore features of neoepitopes in cancers. The object of the first study was to detect the central T cell-specific protein network. The purpose of the second a...
Uploads
Papers by Gabriel Teku