Publications by authors named "Ramin M Farahani"

27 Publications

  • Page 1 of 1

The fate of notch-1 transcript is linked to cell cycle dynamics by activity of a natural antisense transcript.

Nucleic Acids Res 2021 Sep 14. Epub 2021 Sep 14.

IDR/Westmead Institute for Medical Research, NSW 2145, Australia.

A core imprint of metazoan life is that perturbations of cell cycle are offset by compensatory changes in successive cellular generations. This trait enhances robustness of multicellular growth and requires transmission of signaling cues within a cell lineage. Notably, the identity and mode of activity of transgenerational signals remain largely unknown. Here we report the discovery of a natural antisense transcript encoded in exon 25 of notch-1 locus (nAS25) by which mother cells control the fate of notch-1 transcript in daughter cells to buffer against perturbations of cell cycle. The antisense transcript is transcribed at G1 phase of cell cycle from a bi-directional E2F1-dependent promoter in the mother cell where the titer of nAS25 is calibrated to the length of G1. Transmission of the antisense transcript from mother to daughter cells stabilizes notch-1 sense transcript in G0 phase of daughter cells by masking it from RNA editing and resultant nonsense-mediated degradation. In consequence, nAS25-mediated amplification of notch-1 signaling reprograms G1 phase in daughter cells to compensate for the altered dynamics of the mother cell. The function of nAS25/notch-1 in integrating G1 phase history of the mother cell into that of daughter cells is compatible with the predicted activity of a molecular oscillator, slower than cyclins, that coordinates cell cycle within cell lineage.
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http://dx.doi.org/10.1093/nar/gkab800DOI Listing
September 2021

Cannibalized erythroblasts accelerate developmental neurogenesis by regulating mitochondrial dynamics.

Cell Rep 2021 Apr;35(1):108942

IDR/Westmead Institute for Medical Research, Westmead, NSW, Australia; Faculty of Medicine and Health, University of Sydney, Sydney, NSW, Australia. Electronic address:

Metabolic support was long considered to be the only developmental function of hematopoiesis, a view that is gradually changing. Here, we disclose a mechanism triggered during neurulation that programs brain development by donation of sacrificial yolk sac erythroblasts to neuroepithelial cells. At embryonic day (E) 8.5, neuroepithelial cells transiently integrate with the endothelium of yolk sac blood vessels and cannibalize intravascular erythroblasts as transient heme-rich endosymbionts. This cannibalistic behavior instructs precocious neuronal differentiation of neuroepithelial cells in the proximity of blood vessels. By experiments in vitro, we show that access to erythroblastic heme accelerates the pace of neurogenesis by induction of a truncated neurogenic differentiation program from a poised state. Mechanistically, the poised state is invoked by activation of the mitochondrial electron transport chain that leads to amplified production of reactive oxygen species in addition to omnipresent guanosine triphosphate (GTP) with consequential upregulation of pro-differentiation β-catenin.
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http://dx.doi.org/10.1016/j.celrep.2021.108942DOI Listing
April 2021

Genomic competition for noise reduction shaped evolutionary landscape of mir-4673.

NPJ Syst Biol Appl 2020 05 6;6(1):12. Epub 2020 May 6.

IDR/Westmead Institute for Medical Research and Westmead Centre for Oral Health, Sydney, NSW, Australia.

The genomic platform that informs evolution of microRNA cascades remains unknown. Here we capitalised on the recent evolutionary trajectory of hominin-specific miRNA-4673, encoded in intron 4 of notch-1, to uncover the identity of one such precursor genomic element and the selective forces acting upon it. The miRNA targets genes that regulate Wnt/β-catenin signalling cascade. Primary sequence of the microRNA and its target region in Wnt modulating genes evolved from homologous signatures mapped to homotypic cis-clusters recognised by TCF3/4 and TFAP2A/B/C families. Integration of homologous TFAP2A/B/C cis-clusters (short range inhibitor of β-catenin) into the transcriptional landscape of Wnt cascade genes can reduce noise in gene expression. Probabilistic adoption of miRNA secondary structure by one such cis-signature in notch-1 reflected selection for superhelical curvature symmetry of precursor DNA to localise a nucleosome that overlapped the latter cis-cluster. By replicating the cis-cluster signature, non-random interactions of the miRNA with key Wnt modulator genes expanded the transcriptional noise buffering capacity via a coherent feed-forward loop mechanism. In consequence, an autonomous transcriptional noise dampener (the cis-cluster/nucleosome) evolved into a post-transcriptional one (the miRNA). The findings suggest a latent potential for remodelling of transcriptional landscape by miRNAs that capitalise on non-random distribution of genomic cis-signatures.
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http://dx.doi.org/10.1038/s41540-020-0131-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7203229PMC
May 2020

Coupled cycling and regulation of metazoan morphogenesis.

Cell Div 2020 27;15. Epub 2020 Jan 27.

IDR/Westmead Institute for Medical Research, Westmead, Australia.

Metazoan animals are characterized by restricted phenotypic heterogeneity (i.e. morphological disparity) of organisms within various species, a feature that contrasts sharply with intra-species morphological diversity observed in the plant kingdom. Robust emergence of morphogenic blueprint in metazoan animals reflects restricted autonomy of individual cells in adoption of fate outcomes such as differentiation. Fates of individual cells are linked to and influenced by fates of neighboring cells at the population level. Such coupling is a common property of all self-organising systems and propels emergence of order from simple interactions between individual cells without supervision by external directing forces. As a consequence of coupling, expected functional relationship between the constituent cells of an organ system is robustly established concurrent with multiple rounds of cell division during morphogenesis. Notably, the molecular regulation of multicellular coupling during morphogenic self-organisation remains largely unexplored. Here, we review the existing literature on multicellular self-organisation with particular emphasis on recent discovery that β-catenin is the key coupling factor that programs emergence of multi-cellular self-organisation by regulating synchronised cycling of individual cells.
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http://dx.doi.org/10.1186/s13008-020-0059-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6986050PMC
January 2020

β-Catenin: A Metazoan Filter for Biological Noise?

Front Genet 2019 16;10:1004. Epub 2019 Oct 16.

IDR/Westmead Institute for Medical Research, Sydney, NSW, Australia.

Molecular noise refers to fluctuations of biological signals that facilitate phenotypic heterogeneity in a population. While endogenous mechanisms exist to limit genetic noise in biological systems, such restrictions are sometimes removed to propel phenotypic variability as an adaptive strategy. Herein, we review evidence for the potential role of β-catenin in restricting gene expression noise by transcriptional and post-transcriptional mechanisms. We discuss mechanisms that restrict intrinsic noise subsequent to nuclear mobilization of β-catenin. Nuclear β-catenin promotes initiation of transcription but buffers against the resultant noise by restraining transcription elongation. Acceleration of cell cycle, mediated Wnt/β-catenin downstream signals, further diminishes intrinsic noise by curtailing the efficiency of protein synthesis. Extrinsic noise, on the other hand, is restricted by β-catenin-mediated regulation of major cellular stress pathways.
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http://dx.doi.org/10.3389/fgene.2019.01004DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6805772PMC
October 2019

Notch pathway: a bistable inducer of biological noise?

Cell Commun Signal 2019 10 22;17(1):133. Epub 2019 Oct 22.

IDR/Westmead Institute for Medical Research, Sydney, Australia.

Notch signalling pathway is central to development of metazoans. The pathway codes a binary fate switch. Upon activation, downstream signals contribute to resolution of fate dichotomies such as proliferation/differentiation or sub-lineage differentiation outcome. There is, however, an interesting paradox in the Notch signalling pathway. Despite remarkable predictability of fate outcomes instructed by the Notch pathway, the associated transcriptome is versatile and plastic. This inconsistency suggests the presence of an interface that compiles input from the plastic transcriptome of the Notch pathway but communicates only a binary output in biological decisions. Herein, we address the interface that determines fate outcomes. We provide an alternative hypothesis for the Notch pathway as a biological master switch that operates by induction of genetic noise and bistability in order to facilitate resolution of dichotomous fate outcomes in development.
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http://dx.doi.org/10.1186/s12964-019-0453-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6805690PMC
October 2019

Coupled cycling programs multicellular self-organization of neural progenitors.

Cell Cycle 2019 09 9;18(17):2040-2054. Epub 2019 Jul 9.

a IDR/Westmead Institute for Medical Research , Sydney , NSW , Australia.

Self-organization is central to the morphogenesis of multicellular organisms. However, the molecular platform that coordinates the robust emergence of complex morphological patterns from local interactions between cells remains unresolved. Here we demonstrate that neural self- organization is driven by coupled cycling of progenitor cells. In a coupled cycling mode, intercellular contacts relay extrinsic cues to override the intrinsic cycling rhythm of an individual cell and synchronize the population. The stringency of coupling and hence the synchronicity of the population is programmed by recruitment of a key coupler, β-catenin, into junctional complexes. As such, multicellular self-organization is driven by the same basic mathematical principle that governs synchronized behavior of macro-scale biological systems as diverse as the synchronized chirping of crickets, flashing of fireflies and schooling of fish; that is synchronization by coupling. It is proposed that coupled cycling foreshadows a fundamental adaptive change that facilitated evolution and diversification of multicellular life forms.
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http://dx.doi.org/10.1080/15384101.2019.1638692DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6681778PMC
September 2019

Evolution of Resistance in Cancer: A Cell Cycle Perspective.

Front Oncol 2019 9;9:376. Epub 2019 May 9.

Department of Life Sciences, Faculty of Medicine and Health, University of Sydney, Sydney, NSW, Australia.

Resistance of neoplastic cells to therapy is considered a key challenge in the treatment of cancer. Emergence of resistance is commonly attributed to the gradual mutational evolution of neoplastic cells. However, accumulating evidence suggests that exogenous stressors could significantly accelerate the emergence of resistant clones during the course of treatment. Herein, we review molecular mechanisms that regulate the evolution of resistance in a tumor with particular emphasis on the role of cell cycle.
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http://dx.doi.org/10.3389/fonc.2019.00376DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6520611PMC
May 2019

Neural microvascular pericytes contribute to human adult neurogenesis.

J Comp Neurol 2019 03 23;527(4):780-796. Epub 2018 Nov 23.

Institute of Dental Research, Westmead Institute for Medical Research and Westmead Centre for Oral Health, Westmead, New South Wales, Australia.

Consistent adult neurogenic activity in humans is observed in specific niches within the central nervous system. However, the notion of an adult neurogenic niche is challenged by accumulating evidence for ectopic neurogenic activity in other cerebral locations. Herein we interface precision of ultrastructural resolution and anatomical simplicity of accessible human dental pulp neurogenic zone to address this conflict. We disclose a basal level of adult neurogenic activity characterized by glial invasion of terminal microvasculature followed by release of individual platelet-derived growth factor receptor-β mural pericytes and subsequent reprogramming into NeuN local interneurons. Concomitant angiogenesis, a signature of adult neurogenic niches, accelerates the rate of neurogenesis by amplifying release and proliferation of the mural pericyte population by ≈10-fold. Subsequent in vitro and in vivo experiments confirmed gliogenic and neurogenic capacities of human neural pericytes. Findings foreshadow the bimodal nature of the glio-vascular assembly where pericytes, under instruction from glial cells, can stabilize the quiescent microvasculature or enrich local neuronal microcircuits upon differentiation.
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http://dx.doi.org/10.1002/cne.24565DOI Listing
March 2019

miR4673 improves fitness profile of neoplastic cells by induction of autophagy.

Cell Death Dis 2018 10 19;9(11):1068. Epub 2018 Oct 19.

Institute of Dental Research, Westmead Institute for Medical Research and Westmead Centre for Oral Health, Westmead, NSW, Australia.

Therapeutic resistance of neoplasms is mainly attributed to gradual evolution of mutational profile. Here, we demonstrate a microRNA-mediated mechanism that effectively improves fitness of SKBR3 mammary carcinoma cells by cytoplasmic reprogramming. The reprogramming is triggered by endogenous miR4673 transcribed from notch-1 locus. The miRNA downregulates cdk-18, a cyclin-dependent kinase that regulates M-G1 transition in cycling cells. Suppression of cdk-18 triggers mitophagy and autophagy. Due to high autophagic flux, oestrogen receptor-1/progesterone receptor/p53 (Esr1/Pr/p53) SKBR3 cells are coerced into an Esr1/Pr/p53profile. Increased mitophagy in combination with proteasomal degradation of p53 transiently arrests the cycling cells at G0 and enhances radio-resistance of the SKBR3 population. These findings highlight the impact on cancer therapy of non-encoded neoplastic resistance, arising as a consequence of miRNA-mediated autophagic reprogramming that uncouples phenotype and genotype.
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http://dx.doi.org/10.1038/s41419-018-1088-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6195512PMC
October 2018

A method for investigating the cellular response to cyclic tension or compression in three-dimensional culture.

J Mech Behav Biomed Mater 2018 12 8;88:11-17. Epub 2018 Aug 8.

The University of Sydney, Faculty of Dentistry, Department of Oral Pathology and Oral Medicine, Cellular and Molecular Pathology Research Unit, Westmead Centre for Oral Health, Westmead Hospital, NSW 2145, Australia. Electronic address:

We have an interest in the cellular response to mechanical stimuli, and here describe an in-vitro method to examine the response of cells cultured in a three-dimensional matrix to mechanical compressive and tensile stress. Synthetic aliphatic polyester scaffolds coated with 45S5 bioactive glass were seeded with human dental follicular cells (HDFC), and attached to well inserts and magnetic endplates in six well palates. Scaffolds were subjected to either cyclic 10% tensile deformation, or 8% compression, at 1 Hz and 2 Hz respectively for 6, 24 or 48 h, by uniaxial motion of magnetically-coupled endplates. It was possible to isolate high quality mRNA from cells in these scaffolds, as demonstrated by high RNA integrity numbers scores, and ability to perform meaningful cRNA microarray analysis, in which 669 and 727 genes were consistently upregulated, and 662 and 518 genes down regulated at all times studied under tensile and compressive loading conditions respectively. MetaCore analysis revealed the most regulated gene ontogenies under both loading conditions to be for: cytoskeletal remodelling; cell adhesion-chemokines and adhesion; cytoskeleton remodelling-TGF WNT and cytoskeletal remodelling pathways. We believe the method here described will be of value for analysis of the cellular response to cyclic loading.
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http://dx.doi.org/10.1016/j.jmbbm.2018.08.006DOI Listing
December 2018

Characterization of inter-crystallite peptides in human enamel rods reveals contribution by the Y allele of amelogenin.

J Struct Biol 2018 10 28;204(1):26-37. Epub 2018 Jun 28.

Institute of Dental Research, Westmead Institute for Medical Research and Centre for Oral Health, Westmead, New South Wales, Australia; Faculty of Dentistry, The University of Sydney, New South Wales, Australia.

Proteins of the inter-rod sheath and peptides within the narrow inter-crystallite space of the rod structure are considered largely responsible for visco-elastic and visco-plastic properties of enamel. The present study was designed to investigate putative peptides of the inter-crystallite space. Entities of 1-6 kDa extracted from enamel rods of erupted permanent teeth were analysed by mass spectrometry (MS) and shown to comprise N-terminal amelogenin (AMEL) peptides either containing or not containing exon 4 product. Other dominant entities consisted of an N-terminal peptide from ameloblastin (AMBN) and a series of the most hydrophobic peptides from serum albumin (ALBN). Amelogenin peptides encoded by the Y-chromosome allele were strongly detected in Enamel from male teeth. Location of N-terminal AMEL peptides as well as AMBN and ALBN, between apatite crystallites, was disclosed by immunogold scanning electron microscopy (SEM). Density plots confirmed the relative abundance of these products including exon 4+ AMEL peptides that have greater capacity for binding to hydroxyapatite. Hydrophilic X and Y peptides encoded in exon 4 differ only in substitution of non-polar isoleucine in Y for polar threonine in X with reduced disruption of the hydrophobic N-terminal structure in the Y form. Despite similarity of X and Y alleles of AMEL the non-coding region upstream from exon 4 shows significant variation with implications for segregation of processing of transcripts from exon 4. Detection of fragments from multiple additional proteins including keratins (KER), fetuin A (FETUA), proteinases and proteinase inhibitors, likely reflect biochemical events during enamel formation.
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http://dx.doi.org/10.1016/j.jsb.2018.06.006DOI Listing
October 2018

Uncovering system-specific stress signatures in primate teeth with multimodal imaging.

Sci Rep 2016 Jan 4;6:18802. Epub 2016 Jan 4.

Senator Frank R. Lautenberg Environmental Health Sciences Laboratory, Department of Preventive Medicine, Icahn School of Medicine at Mount Sinai, New York, New York 10029, USA.

Early life stress can disrupt development and negatively impact long-term health trajectories. Reconstructing histories of early life exposure to external stressors is hampered by the absence of retrospective time-specific biomarkers. Defects in tooth enamel have been used to reconstruct stress but the methods used are subjective and do not identify the specific biological systems impacted by external stressors. Here we show that external physical and social stressors impart biochemical signatures in primate teeth that can be retrieved to objectively reconstruct the timing of early life developmental disruptions. Using teeth from captive macaques, we uncovered elemental imprints specific to disruptions of skeletal growth, including major disruptions in body weight trajectory and moderate to severe illnesses. Discrete increases in heat shock protein-70 expression in dentine coincided with elemental signatures, confirming that elemental signals were associated with activation of stress-related pathways. To overcome limitations of conventional light-microscopic analysis, we used high resolution Raman microspectral imaging to identify structural and compositional alterations in enamel and dentine that coincided with elemental signatures and with detailed medical and behavioural data. Integrating these objective biochemical markers with temporal mapping of teeth enables the retrospective study of early life developmental disruptions and their ensuing health sequelae.
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http://dx.doi.org/10.1038/srep18802DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4698674PMC
January 2016

Platelet-Derived Growth Factor Receptor Alpha as a Marker of Mesenchymal Stem Cells in Development and Stem Cell Biology.

Stem Cells Int 2015 16;2015:362753. Epub 2015 Jul 16.

Bioengineering Unit, Department of Life Science, Faculty of Dentistry, University of Sydney, Sydney, NSW 2006, Australia.

Three decades on, the mesenchymal stem cells (MSCs) have been intensively researched on the bench top and used clinically. However, ambiguity still exists in regard to their anatomical locations, identities, functions, and extent of their differentiative abilities. One of the major impediments in the quest of the MSC research has been lack of appropriate in vivo markers. In recent years, this obstacle has been resolved to some degree as PDGFRα emerges as an important mesenchymal stem cell marker. Accumulating lines of evidence are showing that the PDGFRα (+) cells reside in the perivascular locations of many adult interstitium and fulfil the classic concepts of MSCs in vitro and in vivo. PDGFRα has long been recognised for its roles in the mesoderm formation and connective tissue development during the embryogenesis. Current review describes the lines of evidence regarding the role of PDGFRα in morphogenesis and differentiation and its implications for MSC biology.
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http://dx.doi.org/10.1155/2015/362753DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4519552PMC
August 2015

Directed glia-assisted angiogenesis in a mature neurosensory structure: pericytes mediate an adaptive response in human dental pulp that maintains blood-barrier function.

J Comp Neurol 2012 Dec;520(17):3803-26

Institute of Dental Research, Westmead Millennium Institute and Westmead Centre for Oral Health, Sydney, NSW 2006, Australia.

The specialized tightly controlled microcirculation of craniofacial neurosensory organs is an essential evolutionary adaptation and yet a dilemma where angiogenic remodeling occurs. Despite extreme plasticity of neurosensory structures, the capacity to reconcile barrier phenotype of the microcirculation with an angiogenic cascade is not known. Here we provide primary evidence for such a response in an elemental neurosensory structure, human dental pulp, following chronic carious insult. In response to hypoxic challenge neurosensory odontoblasts express hypoxia-inducible factor-1α and notch-1. Associated radial rearrangement of astrocyte-like telacytes that communicate through a cell-poor zone with the microvasculature is observed. Activated pericytes characterized by expression of α-smooth muscle actin are located adjacent to the telacyte attachment to the vasculature. In this location, endothelial expression of sonic hedgehog parallels expression of notch-1 by pericytes. The angiogenic response is initiated by pericyte contraction and altered endothelial polarity and proliferation leading to intussusception of endothelial cells and extensive remodeling of basement membrane with upregulation of laminin-8 and laminin-5. These responses guide intravascular loop formation that maintains both intact basement membrane and tight junctions. This initial phase is followed by formation of anastomoses that enhance the hemodynamic capacity of the intravascular loops. The formation of anastomoses is mediated by extension of cytonemes from pericytes guided by MHC-II(+)/CD-163(+) microglia aligned with the telacytes. The cytonemes seek out pericytes on adjacent intravascular loops to initiate migration of endothelial cells. These findings support a new paradigm for understanding angiogenic capacity of neurosensory structures and aberrations of this response manifest as neurovasculopathies.
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http://dx.doi.org/10.1002/cne.23162DOI Listing
December 2012

Streptococcus gordonii FSS2 Challisin affects fibrin clot formation by digestion of the αC region and cleavage of the N -terminal region of the Bβ chains of fibrinogen.

Thromb Haemost 2012 Aug 3;108(2):236-46. Epub 2012 May 3.

Institute of Dental Research, Westmead Millennium Institute and Westmead Centre for Oral Health, Wentworthville, NSW 2145, Australia.

Bacteria within endocarditis vegetations are encased in fibrin matrix that is resistant to resolution. We have previously shown that FSS2 Challisin, a serine protease from Streptococcus gordonii, is able to hydrolyse the Aα and Bβ chains of fibrinogen and has potent angiotensin converting enzyme (ACE) activity. The alteration in the structure of fibrin formed from FSS2 Challisin-degraded fibrinogen may therefore contribute to the resistant fibrin matrix. To this end, we have investigated the specific interactions of FSS2 Challisin with fibrinogen. FSS2 Challisin extensively degrades the αC region of fibrinogen Aα chains, hydrolysing both the αC-domain and αC-connnector. Additionally, the N-terminal region of the Bβ chains is cleaved twice, at Leu19 and Ser28, removing the B fibrinopeptides and 'B' knobs. Substrate analysis indicates FSS2 Challisin has specific requirement for proline two residues before the cleavage point and a neutral or basic un-branched amino acid preceding the cleavage point. Fibrin formation by thrombin was modified and the initiation of fibrinolysis extended, in FSS2 Challisin-treated plasma clots. Digestion of fibrinogen by FSS2 Challisin prior to thrombin action increased fiber density and fiber branch point density. The velocity of fibrinolysis was significantly slower for fibrin formed from FSS2 Challisin-treated fibrinogen but was faster when data was normalised for the increased fibrin density. Thromboelastography of whole blood treated with FSS2 Challisin indicated reduced clot coagulation time and increased shear resistance. Combined ACE and fibrinogenase activities of FSS2 Challisin suggest a pro-coagulant effect of this virulence factor which is conserved in the viridans streptococci.
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http://dx.doi.org/10.1160/TH12-01-0032DOI Listing
August 2012

Regulation of reactionary dentin formation by odontoblasts in response to polymicrobial invasion of dentin matrix.

Bone 2012 Jan 4;50(1):265-75. Epub 2011 Nov 4.

Institute of Dental Research, Westmead Millennium Institute and Westmead Centre for Oral Health, Westmead, Sydney, New South Wales, Australia.

Odontoblast synthesis of dentin proceeds through discrete but overlapping phases characterized by formation of a patterned organic matrix followed by remodelling and active mineralization. Microbial invasion of dentin in caries triggers an adaptive response by odontoblasts, culminating in formation of a structurally altered reactionary dentin, marked by biochemical and architectonic modifications including diminished tubularity. Scanning electron microscopy of the collagen framework in reactionary dentin revealed a radically modified yet highly organized meshwork as indicated by fractal and lacunarity analyses. Immuno-gold labelling demonstrated increased density and regular spatial distribution of dentin sialoprotein (DSP) in reactionary dentin. DSP contributes putative hydroxyapatite nucleation sites on the collagen scaffold. To further dissect the formation of this altered dentin matrix, the associated enzymatic machinery was investigated. Analysis of extracted dentin matrix indicated increased activity of matrix metalloproteinase-2 (MMP-2) in the reactionary zone referenced to physiologic dentin. Likewise, gene expression analysis of micro-dissected odontoblast layer revealed up-regulation of MMP-2. Parallel up-regulation of tissue inhibitor of metalloproteinase-2 (TIMP-2) and membrane type 1- matrix metalloproteinase (MT1-MMP) was observed in response to caries. Next, modulation of odontoblastic dentinogenic enzyme repertoire was addressed. In the odontoblast layer expression of Toll-like receptors was markedly altered in response to bacterial invasion. In carious teeth TLR-2 and the gene encoding the corresponding adaptor protein MyD88 were down-regulated whereas genes encoding TLR-4 and adaptor proteins TRAM and Mal/TIRAP were up-regulated. TLR-4 signalling mediated by binding of bacterial products has been linked to up-regulation of MMP-2. Further, increased expression of genes encoding components of the TGF-β signalling pathway, namely SMAD-2 and SMAD-4, may explain the increased synthesis of collagen by odontoblasts in caries. These findings indicate a radical adaptive response of odontoblasts to microbial invasion of dentin with resultant synthesis of modified mineralized matrix.
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http://dx.doi.org/10.1016/j.bone.2011.10.031DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3246533PMC
January 2012

Blueprint of an ancestral neurosensory organ revealed in glial networks in human dental pulp.

J Comp Neurol 2011 Nov;519(16):3306-26

Institute of Dental Research, Westmead Millennium Institute and Westmead Centre for Oral Health, Westmead Hospital, New South Wales 2145, Australia.

Sensory function of human dental pulp has long been known. A composite role has been suggested for odontoblasts as sensory cells in addition to the synthesis of dentinal matrix. However, the neural basis for such a composite sensory activity remains enigmatic. Here, we aimed to probe the question by pursuing an evolutionary logic; if dental pulp is a vestigial sensory organ co-opted to a function of synthesis of mineralized matrix, essential elements of neurosensory organs may persist in dental pulp. Through structural analysis by confocal laser scanning microscopy, three distinct cell populations adjacent to odontoblasts, glial fibrillary acidic protein (GFAP)(+) seracytes, S100(+) telacytes, and HLA-II(+) alacytes were identified in peripheral human dental pulp. Subsequent molecular fingerprinting by quantitative reverse transcriptase-polymerase chain reaction established these cells as analogous to radial glia (GFAP(+) cells), astrocytes (S100(+) cells), and microglia (HLA-II(+) cells) of central nervous system organs. In the cell-rich zone of the pulp, S100(+) cells formed a network, ensheathed unmyelinated axons, and extended end-feet around the capillaries. The microcirculation adjacent to the glial cells in the cell-rich zone possessed ultrastructural features and a gene expression profile typical of the blood-brain barrier system. These novel findings support a new paradigm for understanding sensory functionality of dental pulp by the demonstration of a sophisticated neural structure in the human dental pulp that is analogous to other central sensory organs. Further, the structure that is revealed informs the concept of the evolutionary origin of the dental pulp, suggesting that a neurosensory organ was the precursor structure of teeth.
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http://dx.doi.org/10.1002/cne.22701DOI Listing
November 2011

Adaptive calcified matrix response of dental pulp to bacterial invasion is associated with establishment of a network of glial fibrillary acidic protein+/glutamine synthetase+ cells.

Am J Pathol 2010 Oct 27;177(4):1901-14. Epub 2010 Aug 27.

Institute of Dental Research, Westmead Millennium Institute and Westmead Centre for Oral Health, Westmead, Australia.

We report evidence for anatomical and functional changes of dental pulp in response to bacterial invasion through dentin that parallel responses to noxious stimuli reported in neural crest-derived sensory tissues. Sections of resin-embedded carious adult molar teeth were prepared for immunohistochemistry, in situ hybridization, ultrastructural analysis, and microdissection to extract mRNA for quantitative analyses. In odontoblasts adjacent to the leading edge of bacterial invasion in carious teeth, expression levels of the gene encoding dentin sialo-protein were 16-fold greater than in odontoblasts of healthy teeth, reducing progressively with distance from this site of the carious lesion. In contrast, gene expression for dentin matrix protein-1 by odontoblasts was completely suppressed in carious teeth relative to healthy teeth. These changes in gene expression were related to a gradient of deposited reactionary dentin that displayed a highly modified structure. In carious teeth, interodontoblastic dentin sialo-protein(-) cells expressing glutamine synthetase (GS) showed up-regulation of glial fibrillary acidic protein (GFAP). These cells extended processes that associated with odontoblasts. Furthermore, connexin 43 established a linkage between adjacent GFAP(+)/GS(+) cells in carious teeth only. These findings indicate an adaptive pulpal response to encroaching caries that includes the deposition of modified, calcified, dentin matrix associated with networks of GFAP(+)/GS(+) interodontoblastic cells. A regulatory role for the networks of GFAP(+)/GS(+) cells is proposed, mediated by the secretion of glutamate to modulate odontoblastic response.
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http://dx.doi.org/10.2353/ajpath.2010.100073DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2947285PMC
October 2010

Site-specificity of pain sensitivity to intraoral anesthetic injections in children.

J Oral Sci 2009 Jun;51(2):239-43

Department of Pedodontics, School of Dentistry, Tabriz University (Medical Sciences), Tabriz, Iran.

A total of 455 children (242 males and 213 females) aged 5-6 years were investigated for their pain reactions to maxillary and mandibular infiltration anesthesia, middle superior alveolar nerve block, posterior superior alveolar nerve block, greater palatine nerve block, nasopalatine nerve block, and inferior alveolar nerve block, and the responses were quantified using the sound, eye and motor (SEM) scale. Administration of nasopalatine nerve block produced maximum pain (median SEM score: 10) while that of posterior superior alveolar nerve block and inferior alveolar nerve block was accompanied by minimum pain (3 and 4, respectively). There was no significant gender-specific difference in pain reactions (P = 0.39). Administration of local anesthesia in the maxilla was more painful than injections into the mandible (7 versus 5, P < 0.05). Furthermore, infiltration into the anterior and posterior segments of the maxilla produced maximum and minimum pain reactions, respectively (8 versus 3, P < 0.001). It seems that the anatomical location of an injection is one of the most important determinants of pediatric pain reaction, and that mandibular injections are generally less painful. Prioritization of treatment by consideration of site-dependent variability in pain sensitivity may help to achieve optimal behavioral control during dental treatment in young children.
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http://dx.doi.org/10.2334/josnusd.51.239DOI Listing
June 2009

Dietary L-arginine and cutaneous wound healing.

Ital J Anat Embryol 2008 Jul-Sep;113(3):135-42

Department of Otolaryngology, Tabriz University of Medical Sciences, Tabriz, Iran.

Skin wound healing has been the subject of extensive studies and various drugs have been used in an attempt to improve wound healing. There are conflicting data regarding the effects of L-arginine, the substrate of nitric oxide, on wound healing. We examined the 1-week rate of cutaneous wound healing and collagen deposition in three groups of rats who received a (1) L-arginine (2% in drinking water)-supplemented diet from three days before until the seventh day following injury (Group 1), (2) L-arginine-supplemented diet for three days before injury (Group 2), and (3) a standard diet without L-arginine supplementation (Group 3). The wound length and width were measured each day and then the open wound area and cumulative percentage of open wound area reduction were calculated. Wound biopsy samples were examined with Trichrome-Masson stain in a subgroup of animals. Results showed that Group 1 rats had a significantly lower cumulative percentage of open wound area reduction on day 7 compared to other two groups (Mann-Whitney U test, P < 0.05). Relatively higher degrees of wound collagen deposit (day 7) were noted in groups 2 and 3. It may be concluded that L-arginine (2% in water) administered three days before until the seventh day following skin wound induction may diminish the rate of skin wound healing and collagen deposition.
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March 2009

Study of root canal accessibility in human primary molars.

J Oral Sci 2008 Mar;50(1):69-74

Department of Pediatric Dentistry, Tabriz University of Medical Sciences, Tabriz, Iran.

The aim of the present study was to provide a general scheme for pulpectomy of primary molars that may be useful for decision-making about negotiation of root canals and selection of appropriate instruments. A total of 160 vital primary molars in 85 patients (40 males, 45 females) aged 4-6 years were selected. After taking primary radiographs, local anesthesia was induced, and the teeth were isolated using a rubber dam. Canal accessibility index (CAI) and tooth accessibility index (TAI) were calculated according to initial file size. Mandibular first molars had either three canals (79.2%) or four canals (20.8%), and all second molars had four canals. Maxillary first molars had three canals and second molars had either three canals (70.9%) or four canals (29.1%). Lower accessibility of the mandibular first molar distobuccal root accounted for the lower accessibility of these teeth in comparison with mandibular second molars. While three-canal maxillary second molars were more accessible due to the lower accessibility of the distobuccal canal of the maxillary first molar, poor accessibility of the distal canal in four-canal second molars was responsible for the difficult accessibility of these teeth. In conclusion, it seems that the accessibility of a single canal in each tooth determines the difficulty of accessibility for any given tooth. Moreover, while primary second molars are more accessible than first molars, all of them are negotiable.
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http://dx.doi.org/10.2334/josnusd.50.69DOI Listing
March 2008

Neuroprotective effects of high-dose vs low-dose melatonin after blunt sciatic nerve injury.

Childs Nerv Syst 2008 Jan 15;24(1):111-7. Epub 2007 May 15.

Department of Neurosurgery and Anatomy, Tabriz University of Medical Sciences, Tabriz, Iran.

Introduction: Melatonin, the secretory product of the pineal gland, has potent antioxidant properties. The aim of this study was to compare the effects of low-dose (10 mg/kg) vs high-dose (50 mg/kg) melatonin on early lipid peroxidation levels and ultrastructural changes in experimental blunt sciatic nerve injury (SNI). We believe this to be the first study to assess the dose-dependent neuroprotective effects of melatonin after a blunt peripheral nerve injury.

Materials And Methods: Rats were randomly allocated into 5 groups of 10 animals each. The SNI only rats underwent a nerve injury procedure. The SNI plus vehicle group received SNI and intraperitoneal injection of vehicle (diluted ethanol) as a placebo. The SNI plus low-dose or high-dose melatonin groups received intraperitoneal melatonin at doses of 10 mg/kg or 50 mg/kg, respectively. Controls had no operation, melatonin or vehicle injection. SNI was induced by clamping the sciatic nerve at the upper border of the quadratus femoris for 2 min.

Results: Sciatic nerve samples were harvested 6 h after nerve injury and processed for biochemical and ultrastructural analysis. Trauma increased the lipid peroxidation of the sciatic nerve by 3.6-fold (153.85 +/- 18.73 in SNI only vs 41.73 +/- 2.23 in control rats, P < 0.01). Low (P = 0.02) and high (P < 0.01) doses of melatonin attenuated the nerve lipid peroxidation by 25% and 57.25%, respectively (65.76 +/- 2.47 in high-dose vs 115.08 +/- 7.03 in low-dose melatonin groups).

Discussion: Although low-dose melatonin reduced trauma-induced myelin breakdown and axonal changes in the sciatic nerve, high-dose melatonin almost entirely neutralized any ultrastructural changes.

Conclusion: Our results suggest that melatonin, especially at a dose of 50 mg/kg, has a potent neuroprotective effect and can preserve peripheral neural fibers from lipid peroxidative damage after blunt trauma. With further investigations, we hope that these data may prove useful to clinicians who treat patients with nerve injuries.
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http://dx.doi.org/10.1007/s00381-007-0366-xDOI Listing
January 2008

Simultaneous lateral and posterior ponticles resulting in the formation of a vertebral artery tunnel of the atlas: case report and review of the literature.

Folia Neuropathol 2007 ;45(1):43-6

Pediatric Neurosurgery, Children's Hospital, Birmingham, AL 35233, USA.

The foramen arcuale is infrequently found and is potentially a clinically/surgically significant anatomical variation of the atlas. When present, the vertebral artery travels through this bony ring after exiting the transverse foramen of the atlas and prior to entering the cranium. We present a case of an adult female skeleton noted to harbor both a foramen arcuale and a lateral ponticle that resulted in the formation of a canal for the vertebral artery. The literature regarding these osteological structures is reviewed regarding their presence and potential clinical significance. The simultaneous occurrence of fully developed lateral and posterior ponticuli resulting in encasement of the third part (atlantal segment) of the vertebral artery appears to be very rare. Based on the literature regarding only foramina arcuale and their presence predisposing one to symptomatic entrapment, additional compression, as seen in our specimen, of the vertebral artery by a lateral ponticle could very likely result in stenosis of the vertebral artery.
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July 2007

Proposal for the existence of a nasogastric reflex in humans, as a potential cause of upper gastrointestinal symptoms.

Med Hypotheses 2007 28;69(2):346-8. Epub 2007 Feb 28.

Tuberculosis and Lung Research Center, Tabriz Medical University, Daneshgah St., Tabriz, Iran.

The nose is a gateway of air from the environment to the body and with its rich innervation from the olfactory and trigeminal nerves plays a critical role as a sensor in both human beings and primitive animals. Irritation of the nasal or paranasal mucosa may initiate a severe bradycardia, apnea, and vasoconstriction and increase the pulmonary airflow resistance. However, the interaction between nasal mucosa and the upper gastrointestinal tract is more often than not neglected in the clinical literature. We propose that a nasogastric reflex might exist with its afferent and efferent loops being the trigeminal and vagus nerves, respectively. The central connection of these loops is located at the pontomedullary level. The sensory inputs from the nasal mucosa to the general somatic afferent component of the brainstem including the pontine and medullary trigeminal nucleuses may induce the neighboring nucleus of the solitary tract and dorsal motor nucleus of the vagus. This initiates, via the efferent fibers of the vagus nerve, the manifestations of the vagal stimulation. The presence of a nasogastric reflex may warrant considerations as diseases of nose and paranasal sinuses may be the cause upper gastrointestinal symptmatology.
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http://dx.doi.org/10.1016/j.mehy.2006.12.047DOI Listing
August 2007

Bipolar supernumerary renal artery.

Surg Radiol Anat 2007 Feb 24;29(1):89-92. Epub 2006 Oct 24.

Department of Radiology and Angiography, Tabriz University of Medical Sciences, Tabriz, Iran.

The variations of renal arteries are considered critical issues that surgeons should have thorough envision and appreciation of the condition. Variations of these vessels may influences urological, renal transplantation and laparoscopic surgeries. We present a case of bilateral accessory renal artery with a striking pre-hilar branching pattern encountered upon digital subtraction angiography (DSA) for imaging of the renal arteries of a healthy 30-year-old man, renal transplant donor. The right kidney received two renal arteries from the aorta including a main hilar and one lower polar. However, the left accessory artery while originated from the aorta, simultaneously, supplied both upper and lower renal poles following its pre-hilar division that replaced upper/apical and lower segmental arteries of the single main renal artery, respectively. The left main renal artery divided into two anterior and posterior segmental arteries. Whether this should be categorized either as an accessory hilar artery or a unique variant of renal arterial supply, the so-called bipolar supernumerary renal artery, is a matter of debate. We discuss possible embryologic origin and clinical aspects of accessory renal artery.
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http://dx.doi.org/10.1007/s00276-006-0158-0DOI Listing
February 2007
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