Neurodegeneration is the umbrella term for the progressive loss of structure or function of neuro... more Neurodegeneration is the umbrella term for the progressive loss of structure or function of neurons. Incurable neurodegenerative disorders such as Alzheimer's disease (AD) and Parkinson's disease (PD) show dramatic rising trends particularly in the advanced age groups. However, the underlying mechanisms are not yet fully elucidated, and to date there are no biomarkers for early detection or effective treatments for the underlying causes of these diseases. Furthermore, due to species variation and differences between animal models (e.g., mouse transgenic and knockout models) of neurodegenerative diseases, substantial debate focuses on whether animal and cell culture disease models can correctly model the condition in human patients. In 2006, Yamanaka of Kyoto University first demonstrated a novel approach for the preparation of induced pluripotent stem cells (iPSCs), which displayed similar pluripotency potential to embryonic stem cells (ESCs). Currently, iPSCs studies are pe...
We reported the identification of a new family of DNA-binding proteins from our characterization ... more We reported the identification of a new family of DNA-binding proteins from our characterization of the dead ringer (dri) gene of Drosophila melanogaster. We show that dri encodes a nuclear protein that contains a sequence-specific DNA-binding domain that bears no similarity to known DNA-binding domains. A number of proteins were found to contain sequences homologous to this domain. Other proteins containing the conserved motif include yeast SWI1, two human retinoblastoma binding proteins, and other mammalian regulatory proteins. A mouse B-cell-specific regulator exhibits 75% identity with DRI over the 137-amino-acid DNA-binding domains of these proteins, indicating a high degree of conservation of this domain. Gel retardation and optimal binding site screens revealed that the in vitro sequence specificity of DRI is strikingly similar to that of many homeodomain proteins, although the sequence and predicted secondary structure do not resemble a homeodomain. The early general express...
Maternal decidua basalis tissue attached to the placenta following delivery is a source of decidu... more Maternal decidua basalis tissue attached to the placenta following delivery is a source of decidual mesenchymal stem cells (DMSCs). The in vitro characteristics of DMSCs have been partly defined but their in vivo function(s) are poorly understood. The anatomic location, or niche, provides clues regarding potential in vivo function(s) of DMSCs, but the niche has not been described. Cells were isolated from the decidua basalis and flow cytometric analyses showed the expected phenotypic profile for MSC cell surface markers. In vitro, the cells differentiated into adipocytes, osteocytes, and chondrocytes. DMSCs were then stained with antibodies by immunofluorescence detection. Immunocytochemistry revealed that DMSCs were positive for FZD-9, STRO-1, 3G5, and α-SMA as expected and lacked expression of vWF and Ck7. Fluorescence in situ hybridization analysis showed the cultured cells were of maternal origin. Immunofluorescence was carried out on placental bed biopsies using the FZD-9, STRO...
Increased Aβ clearance from brain is essential for restoring the pathological manifestation of Al... more Increased Aβ clearance from brain is essential for restoring the pathological manifestation of Alzheimer's disease (AD) and attenuating the cognitive disorder. The blood-brain barrier (BBB) plays a critical role in maintaining homeostasis of the brain, and transporters e.g. P-glycoprotein (P-gp) are essential for Aβ clearance from the brain. In addition, the Wnt/β-catenin signaling pathway contributes to BBB formation, induction and maturation, and induces BBB function. Dysfunctional Wnt/β-catenin signaling in the BBB reveals the importance of this pathway, since this contributes to the neurodegeneration characteristic of AD. Based on the above evidence, we propose that targeting the canonical Wnt signaling pathway could be promising therapeutic approach for treatment of AD.
Comparative gene expression studies in the placenta may provide insights into molecular mechanism... more Comparative gene expression studies in the placenta may provide insights into molecular mechanisms of important genomic alterations in pregnancy disorders. Endogenous reference genes often referred to as housekeeping genes, are routinely used to normalise gene expression levels. For this reason, it is important that these genes be empirically evaluated for stability between placental samples including samples from complicated pregnancies. To address this issue, six candidate housekeeping genes including several commonly used ones (ACTB, GAPDH, 18S rRNA, TBP, SDHA and YWHAZ) were investigated for their expression stability in placentae obtained from pregnancies complicated by idiopathic FGR (n=25) and gestation-matched control pregnancies (n=25). Real-time PCR was performed using pre-validated gene expression assay kits. The geNorm program was used for gene stability measure (M) for the entire housekeeping genes in all control and FGR-affected placental samples. Results showed that G...
Angiogenesis is fundamental to normal placental development and aberrant angiogenesis contributes... more Angiogenesis is fundamental to normal placental development and aberrant angiogenesis contributes substantially to placental pathologies. The complex process of angiogenesis is regulated by transcription factors leading to the formation of endothelial cells that line the microvasculature. Homeobox genes are important transcription factors that regulate vascular development in embryonic and adult tissues. We have recently shown that placental homeobox genes HLX, DLX3, DLX4, MSX2 and GAX are expressed in placental endothelial cells. Hence, the novel homeobox genes TLX1, TLX2, TGIF, HEX, PHOX1, MEIS2, HOXB7, and LIM6 were detected that have not been reported in endothelial cells previously. Importantly, these homeobox genes have not been previously reported in placental endothelial cells and, with the exception of HEX, PHOX1 and HOXB7, have not been described in any other endothelial cell type. Reverse transcriptase PCR was performed on cDNA from freshly isolated placental microvascula...
Alterations in the control of gene expression is a key event in neoplastic transformation. Invest... more Alterations in the control of gene expression is a key event in neoplastic transformation. Investigating the expression of transcription factors such as homeodomain proteins may therefore allow better characterization of molecular mechanisms underlying the transformation process. Expression of homeodomain proteins DLX4 and HB9 was detected by RT-PCR and immunohistochemically in 24 breast tumors and their corresponding non-malignant tissue. Although the percentage of nuclei expressing both DLX4 (p = 0.001) and HB9 (p = 0.0001) is increased in breast carcinoma, their intensity of nuclear staining is decreased compared to non-malignant nuclei. Furthermore HB9 nuclear immunoreactivity decreased progressively with increasing tumor grade (p = 0.001). These data suggest that the reduction in malignant nuclear DLX4 immunoreactivity is an earlier event in breast carcinogenesis than the progressive loss of HB9 expression observed with increasing tumor grade. With further study and in conjunct...
Pregnancy Hypertension: An International Journal of Women's Cardiovascular Health, 2015
Preeclampsia (PE) is a common and serious pregnancy disorder with a strong genetic component. Num... more Preeclampsia (PE) is a common and serious pregnancy disorder with a strong genetic component. Numerous genetic studies performed, including our own, have yielded many susceptibility genes from distinct functional groups. Additionally, transcriptome profiling at the maternal-fetal interface has likewise yielded many differentially expressed genes. Often there is little overlap between the two approaches, although both are significantly informative with respect to PE. We have thus taken a novel approach by analysing pathways common to the susceptibility genes and the PE transcriptome. Using Illumina Human Ht12v4 and Wg6v3 BeadChips, transcriptome profiling was conducted on n=65 normotensive and n=60 PE decidua basalis tissues collected at delivery. R software was used to pre-process transcript data for pathway analysis. Pathways were analysed and constructed using Ariadne Pathway Studio 9. We examined the following susceptibility genes: ACVR1, ACVR1C, ACVR2A, COL4A1, COL4A2, ERAP1, ERAP2, INHA, INHBB and LNPEP (Yong et al., 2014). Significance was set at p<0.05. Major common targets/regulators of these susceptibility genes were AGT, IFNG, IL6, INHBA, SERPINE1, TGFB1 and VEGFA (Fig. 1). The top downstream pathway categories of susceptibility genes that were significantly altered in the PE decidual transcriptome were apoptosis and cell signalling. Susceptibility genes from distinct functional groups have similar downstream pathways through common targets/regulators. Several of these pathways matched those altered in PE. This study contributes to a better understanding on how susceptibility genes may interact in the development of PE. With this knowledge, more targeted functional analyses of PE susceptibility genes in these key pathways can be performed to examine their contributions to the pathogenesis and severity of PE. H.E. Yong: None. P.E. Melton: None. M.P. Johnson: None. K.A. Freed: None. B. Kalionis: None. P. Murthi: None. S.P. Brennecke: None. R.J. Keogh: None. E.K. Moses: None.
Neurodegeneration is the umbrella term for the progressive loss of structure or function of neuro... more Neurodegeneration is the umbrella term for the progressive loss of structure or function of neurons. Incurable neurodegenerative disorders such as Alzheimer's disease (AD) and Parkinson's disease (PD) show dramatic rising trends particularly in the advanced age groups. However, the underlying mechanisms are not yet fully elucidated, and to date there are no biomarkers for early detection or effective treatments for the underlying causes of these diseases. Furthermore, due to species variation and differences between animal models (e.g., mouse transgenic and knockout models) of neurodegenerative diseases, substantial debate focuses on whether animal and cell culture disease models can correctly model the condition in human patients. In 2006, Yamanaka of Kyoto University first demonstrated a novel approach for the preparation of induced pluripotent stem cells (iPSCs), which displayed similar pluripotency potential to embryonic stem cells (ESCs). Currently, iPSCs studies are pe...
We reported the identification of a new family of DNA-binding proteins from our characterization ... more We reported the identification of a new family of DNA-binding proteins from our characterization of the dead ringer (dri) gene of Drosophila melanogaster. We show that dri encodes a nuclear protein that contains a sequence-specific DNA-binding domain that bears no similarity to known DNA-binding domains. A number of proteins were found to contain sequences homologous to this domain. Other proteins containing the conserved motif include yeast SWI1, two human retinoblastoma binding proteins, and other mammalian regulatory proteins. A mouse B-cell-specific regulator exhibits 75% identity with DRI over the 137-amino-acid DNA-binding domains of these proteins, indicating a high degree of conservation of this domain. Gel retardation and optimal binding site screens revealed that the in vitro sequence specificity of DRI is strikingly similar to that of many homeodomain proteins, although the sequence and predicted secondary structure do not resemble a homeodomain. The early general express...
Maternal decidua basalis tissue attached to the placenta following delivery is a source of decidu... more Maternal decidua basalis tissue attached to the placenta following delivery is a source of decidual mesenchymal stem cells (DMSCs). The in vitro characteristics of DMSCs have been partly defined but their in vivo function(s) are poorly understood. The anatomic location, or niche, provides clues regarding potential in vivo function(s) of DMSCs, but the niche has not been described. Cells were isolated from the decidua basalis and flow cytometric analyses showed the expected phenotypic profile for MSC cell surface markers. In vitro, the cells differentiated into adipocytes, osteocytes, and chondrocytes. DMSCs were then stained with antibodies by immunofluorescence detection. Immunocytochemistry revealed that DMSCs were positive for FZD-9, STRO-1, 3G5, and α-SMA as expected and lacked expression of vWF and Ck7. Fluorescence in situ hybridization analysis showed the cultured cells were of maternal origin. Immunofluorescence was carried out on placental bed biopsies using the FZD-9, STRO...
Increased Aβ clearance from brain is essential for restoring the pathological manifestation of Al... more Increased Aβ clearance from brain is essential for restoring the pathological manifestation of Alzheimer's disease (AD) and attenuating the cognitive disorder. The blood-brain barrier (BBB) plays a critical role in maintaining homeostasis of the brain, and transporters e.g. P-glycoprotein (P-gp) are essential for Aβ clearance from the brain. In addition, the Wnt/β-catenin signaling pathway contributes to BBB formation, induction and maturation, and induces BBB function. Dysfunctional Wnt/β-catenin signaling in the BBB reveals the importance of this pathway, since this contributes to the neurodegeneration characteristic of AD. Based on the above evidence, we propose that targeting the canonical Wnt signaling pathway could be promising therapeutic approach for treatment of AD.
Comparative gene expression studies in the placenta may provide insights into molecular mechanism... more Comparative gene expression studies in the placenta may provide insights into molecular mechanisms of important genomic alterations in pregnancy disorders. Endogenous reference genes often referred to as housekeeping genes, are routinely used to normalise gene expression levels. For this reason, it is important that these genes be empirically evaluated for stability between placental samples including samples from complicated pregnancies. To address this issue, six candidate housekeeping genes including several commonly used ones (ACTB, GAPDH, 18S rRNA, TBP, SDHA and YWHAZ) were investigated for their expression stability in placentae obtained from pregnancies complicated by idiopathic FGR (n=25) and gestation-matched control pregnancies (n=25). Real-time PCR was performed using pre-validated gene expression assay kits. The geNorm program was used for gene stability measure (M) for the entire housekeeping genes in all control and FGR-affected placental samples. Results showed that G...
Angiogenesis is fundamental to normal placental development and aberrant angiogenesis contributes... more Angiogenesis is fundamental to normal placental development and aberrant angiogenesis contributes substantially to placental pathologies. The complex process of angiogenesis is regulated by transcription factors leading to the formation of endothelial cells that line the microvasculature. Homeobox genes are important transcription factors that regulate vascular development in embryonic and adult tissues. We have recently shown that placental homeobox genes HLX, DLX3, DLX4, MSX2 and GAX are expressed in placental endothelial cells. Hence, the novel homeobox genes TLX1, TLX2, TGIF, HEX, PHOX1, MEIS2, HOXB7, and LIM6 were detected that have not been reported in endothelial cells previously. Importantly, these homeobox genes have not been previously reported in placental endothelial cells and, with the exception of HEX, PHOX1 and HOXB7, have not been described in any other endothelial cell type. Reverse transcriptase PCR was performed on cDNA from freshly isolated placental microvascula...
Alterations in the control of gene expression is a key event in neoplastic transformation. Invest... more Alterations in the control of gene expression is a key event in neoplastic transformation. Investigating the expression of transcription factors such as homeodomain proteins may therefore allow better characterization of molecular mechanisms underlying the transformation process. Expression of homeodomain proteins DLX4 and HB9 was detected by RT-PCR and immunohistochemically in 24 breast tumors and their corresponding non-malignant tissue. Although the percentage of nuclei expressing both DLX4 (p = 0.001) and HB9 (p = 0.0001) is increased in breast carcinoma, their intensity of nuclear staining is decreased compared to non-malignant nuclei. Furthermore HB9 nuclear immunoreactivity decreased progressively with increasing tumor grade (p = 0.001). These data suggest that the reduction in malignant nuclear DLX4 immunoreactivity is an earlier event in breast carcinogenesis than the progressive loss of HB9 expression observed with increasing tumor grade. With further study and in conjunct...
Pregnancy Hypertension: An International Journal of Women's Cardiovascular Health, 2015
Preeclampsia (PE) is a common and serious pregnancy disorder with a strong genetic component. Num... more Preeclampsia (PE) is a common and serious pregnancy disorder with a strong genetic component. Numerous genetic studies performed, including our own, have yielded many susceptibility genes from distinct functional groups. Additionally, transcriptome profiling at the maternal-fetal interface has likewise yielded many differentially expressed genes. Often there is little overlap between the two approaches, although both are significantly informative with respect to PE. We have thus taken a novel approach by analysing pathways common to the susceptibility genes and the PE transcriptome. Using Illumina Human Ht12v4 and Wg6v3 BeadChips, transcriptome profiling was conducted on n=65 normotensive and n=60 PE decidua basalis tissues collected at delivery. R software was used to pre-process transcript data for pathway analysis. Pathways were analysed and constructed using Ariadne Pathway Studio 9. We examined the following susceptibility genes: ACVR1, ACVR1C, ACVR2A, COL4A1, COL4A2, ERAP1, ERAP2, INHA, INHBB and LNPEP (Yong et al., 2014). Significance was set at p<0.05. Major common targets/regulators of these susceptibility genes were AGT, IFNG, IL6, INHBA, SERPINE1, TGFB1 and VEGFA (Fig. 1). The top downstream pathway categories of susceptibility genes that were significantly altered in the PE decidual transcriptome were apoptosis and cell signalling. Susceptibility genes from distinct functional groups have similar downstream pathways through common targets/regulators. Several of these pathways matched those altered in PE. This study contributes to a better understanding on how susceptibility genes may interact in the development of PE. With this knowledge, more targeted functional analyses of PE susceptibility genes in these key pathways can be performed to examine their contributions to the pathogenesis and severity of PE. H.E. Yong: None. P.E. Melton: None. M.P. Johnson: None. K.A. Freed: None. B. Kalionis: None. P. Murthi: None. S.P. Brennecke: None. R.J. Keogh: None. E.K. Moses: None.
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Papers by B. Kalionis