Biomedical subjects

S H Ong

Publications and source records attributed to S H Ong.

At least 19 recordsLinked to original sources

PubMed2006

Heterogeneous meshing and biomechanical modeling of human spine.

We aim to develop a patient-specific biomechanical model of human spine for the purpose of surgical training and planning. In this paper, we describe the development of a finite-element model of the spine from the VHD Male Data. The finite-element spine model comprises volumetric elements suitable for deformation and other finite-element analysis using ABAQUS. The mesh generation solution accepts segmented radiological slices as input, and outputs three-dimensional (3D) volumetric finite element meshes that are ABAQUS compliant. The proposed mesh generation method first uses a grid plane to divide the contours of the anatomical boundaries and its inclusions into discrete meshes. A grid frame is then built to connect the grid planes between any two adjacent planes using a novel scheme. The meshes produced consist of brick elements in the interior of the contours and with tetrahedral and wedge elements at the boundaries. The nodal points are classified according to their materials and hence, elements can be assigned different properties. The resultant spine model comprises a detailed model of the 7 cervical vertebrae, 12 thoracic vertebrae, 5 lumbar vertebrae, and S1. Each of the vertebrae and intervertebral disc has between 1200 and 6000 elements, and approximately 1200 elements, respectively. The accuracy of the resultant VHD finite element spine model was good based on visual comparison of volume-rendered images of the original CT data, and has been used in a computational analysis involving needle insertion and static deformation. We also compared the mesh generated using our method against two automatically generated models; one consists of purely tetrahedral elements and the other hexahedral elements.

Adult↗

PubMed2005

Computational biomechanical modelling of the lumbar spine using marching-cubes surface smoothened finite element voxel meshing.

There is a need for the development of finite element (FE) models based on medical datasets, such as magnetic resonance imaging and computerized tomography in computation biomechanics. Direct conversion of graphic voxels to FE elements is a commonly used method for the generation of FE models. However, conventional voxel-based methods tend to produce models with jagged surfaces. This is a consequence of the inherent characteristics of voxel elements; such a model is unable to capture the geometries of anatomical structures satisfactorily. We have developed a robust technique for the automatic generation of voxel-based patient-specific FE models. Our approach features a novel tetrahedronization scheme that incorporates marching-cubes surface smoothing together with a smooth-distortion factor (SDF). The models conform to the actual geometries of anatomical structures of a lumbar spine segment (L3). The resultant finite element analysis (FEA) at the surfaces is more accurate compared to the use of conventional voxel-based generated FE models. In general, models produced by our method were superior compared to that obtained using the commercial software ScanFE.

Biomechanical Phenomena↗

PubMed2004

Computer-based extraction of the inferior alveolar nerve canal in 3-D space.

Computed tomography (CT) is increasingly employed in orthodontic treatment. One of the most successful applications is in dental implantology, in which an artificial root is surgically inserted into the jawbone to provide anchorage for a dental prosthesis. For successful implant surgery, it is crucial to locate internal structures such as the inferior alveolar nerve canal (IAC). This paper presents a computerized technique for extracting the IAC. To facilitate the extraction, we first generate panoramic CT images (panoramics) by reformatting the original CT images. The panoramics are a series of cross-sectional images along curved planes through the mandible (lower jawbone). Hollow canals are subsequently detected by analyzing the voxel intensities and 3-D gradient orientations in the panoramics. The axis of the IAC is then traced out by a novel 3-D line-tracking technique. The method is effective for extracting the IAC despite the open structure of the surrounding bone.

Algorithms↗

PubMed2004

Tooth segmentation of dental study models using range images.

The accurate segmentation of the teeth from the digitized representation of a dental study model is an important component in computer-based algorithms for orthodontic feature detection and measurement and in the simulation of orthodontic procedures such as tooth rearrangement. This paper presents an automated method for tooth segmentation from the three-dimensional (3-D) digitized image captured by a laser scanner. We avoid the complexity of directly processing 3-D mesh data by proposing the innovative idea of detecting features on two range images computed from the 3-D image. The dental arch is first obtained from the plan-view range image. Using the arch as the reference, a panoramic range image of the dental model can be computed. The interstices between the teeth are detected separately in the two range images, and results from both views are combined for a determination of interstice locations and orientations. Finally, the teeth are separated from the gums by delineating the gum margin. The algorithm was tested on 34 dental models representing a variety of malocclusions and was found to be robust and accurate.

Algorithms↗

PubMed2002

Personality of males charged with outrage of modesty.

Outrage of modesty (OOM) is considered a serious crime in Singapore and offenders are often charged with a period of imprisonment with or without a fine and caning. Previous studies have indicated that non-violent sexual offenders tend to have a socially inhibited personality. No published study has yet been conducted to investigate the personality of OOM offenders. The purpose of the current study was to assess the personality of males charged with outrage of modesty and compare them to a group of males charged with theft using the 16 Personality Factors questionnaire (16PF; Cattell, Eber, and Tatsuoka, 1970). Participants were selected over a two-year study period from a cohort of prisoners serving sentence at Changi Prison. A total of 30 OOM and 22 theft offenders completed the 16PF. All OOM subjects had been charged for molesting an adult female. Unexpectedly, planned comparisons revealed that OOM subjects had marginally higher scores on Factor H (boldness) compared to theft subjects. Exploratory analyses revealed no other significant differences between OOM and theft subjects. Implications of findings and limitations of the study are discussed.

Adult↗

PubMed2001

ShcA and Grb2 mediate polyoma middle T antigen-induced endothelial transformation and Gab1 tyrosine phosphorylation.

Middle T antigen (PymT) is the principal transforming component of polyomavirus, and rapidly induces hemangiomas in neonatal mice. PymT, a membrane-associated scaffold, recruits and activates Src family tyrosine kinases, and, once tyrosine phosphorylated, binds proteins with PTB and SH2 domains such as ShcA, phosphatidylinositol 3-kinase (PI3K) and phospholipase Cgamma-1 (PLCgamma-1). To explore the pathways required for endothelial transformation in vivo, we introduced PymT mutant forms into mice. PymT variants unable to bind PI3K and PLCgamma-1 directly induced hemangiomas similarly to wild type, but a mutant unable to bind ShcA was transformation compromised. Requirement for a ShcA PTB domain- binding site was suppressed by replacing this motif in PymT with YXN sequences, which bind the Grb2 SH2 domain upon phosphorylation. Surprisingly, PymT recruitment of ShcA and Grb2 correlated with PI3K activation. PymT mimics activated receptor tyrosine kinases by forming a ShcA-Grb2-Gab1 complex, thus inducing Gab1 tyrosine phosphorylation, which itself is associated with PI3K. Therefore, PymT activation of ShcA-Grb2 signaling is critical for endothelial transformation, and PymT can stimulate Grb2 signaling to both the MAP kinase and PI3K pathways.

3T3 Cells↗

PubMed2001

Structural basis for autoinhibition of the Ephb2 receptor tyrosine kinase by the unphosphorylated juxtamembrane region.

The Eph receptor tyrosine kinase family is regulated by autophosphorylation within the juxtamembrane region and the kinase activation segment. We have solved the X-ray crystal structure to 1.9 A resolution of an autoinhibited, unphosphorylated form of EphB2 comprised of the juxtamembrane region and the kinase domain. The structure, supported by mutagenesis data, reveals that the juxtamembrane segment adopts a helical conformation that distorts the small lobe of the kinase domain, and blocks the activation segment from attaining an activated conformation. Phosphorylation of conserved juxtamembrane tyrosines would relieve this autoinhibition by disturbing the association of the juxtamembrane segment with the kinase domain, while liberating phosphotyrosine sites for binding SH2 domains of target proteins. We propose that the autoinhibitory mechanism employed by EphB2 is a more general device through which receptor tyrosine kinases are controlled.

Amino Acid Sequence↗

PubMed2001

Stimulation of phosphatidylinositol 3-kinase by fibroblast growth factor receptors is mediated by coordinated recruitment of multiple docking proteins.

The docking protein FRS2 is a major downstream effector that links fibroblast growth factor (FGF) and nerve growth factor receptors with the Ras/mitogen-activated protein kinase signaling cascade. In this report, we demonstrate that FRS2 also plays a pivotal role in FGF-induced recruitment and activation of phosphatidylinositol 3-kinase (PI3-kinase). We demonstrate that tyrosine phosphorylation of FRS2alpha leads to Grb2-mediated complex formation with the docking protein Gab1 and its tyrosine phosphorylation, resulting in the recruitment and activation of PI3-kinase. Furthermore, Grb2 bound to tyrosine-phosphorylated FRS2 through its SH2 domain interacts primarily via its carboxyl-terminal SH3 domain with a proline-rich region in Gab1 and via its amino-terminal SH3 domain with the nucleotide exchange factor Sos1. Assembly of FRS2alpha:Grb2:Gab1 complex induced by FGF stimulation results in activation of PI3-kinase and downstream effector proteins such as the S/T kinase Akt, whose cellular localization and activity are regulated by products of PI3-kinase. These experiments reveal a unique mechanism for generation of signal diversity by growth factor-induced coordinated assembly of a multidocking protein complex that can activate the Ras/mitogen-activated protein kinase cascade to induce cell proliferation and differentiation, and PI3-kinase to activate a mediator of a cell survival pathway.

3T3 Cells↗

PubMed2001

Gene dosage-dependent functions for phosphotyrosine-Grb2 signaling during mammalian tissue morphogenesis.

BACKGROUND: The mammalian Grb2 adaptor protein binds pTyr-X-Asn motifs through its SH2 domain, and engages downstream targets such as Sos1 and Gab1 through its SH3 domains. Grb2 thereby couples receptor tyrosine kinases to the Ras-MAP kinase pathway, and potentially to phosphatidylinositol (PI) 3'-kinase. By creating a null (Delta) allele of mouse Grb2, we have shown that Grb2 is required for endoderm differentiation at embryonic day 4.0. RESULTS: Grb2 likely has multiple embryonic and postnatal functions. To address this issue, a hypomorphic mutation, first characterized in the Caenorhabditis elegans Grb2 ortholog Sem-5, was engineered into the mouse Grb2 gene. This mutation (E89K) reduces phosphotyrosine binding by the SH2 domain. Embryos that are compound heterozygous for the null and hypomorphic alleles exhibit defects in placental morphogenesis and in the survival of a subset of migrating neural crest cells required for branchial arch formation. Furthermore, animals homozygous for the hypomorphic mutation die perinatally because of clefting of the palate, a branchial arch-derived structure. Analysis of E89K/Delta Grb2 mutant fibroblasts revealed a marked defect in ERK/MAP kinase activation and Gab1 tyrosine phosphorylation following growth factor stimulation. CONCLUSIONS: We have created an allelic series within mouse Grb2, which has revealed distinct functions for phosphotyrosine-Grb2 signaling in tissue morphogenesis and cell viability necessary for mammalian development. The placental defects in E89K/Delta mutant embryos are reminiscent of those seen in receptor tyrosine kinase-, Sos1-, and Gab1-deficient embryos, consistent with the finding that endogenous Grb2 is required for efficient RTK signaling to the Ras-MAP kinase and Gab1 pathways.

Adaptor Proteins, Signal Transducing↗

PubMed2001

Docking protein FRS2 links the protein tyrosine kinase RET and its oncogenic forms with the mitogen-activated protein kinase signaling cascade.

The receptor tyrosine kinase RET functions as the signal transducing receptor for the GDNF (for "glial cell-derived neurotrophic factors") family of ligands. Mutations in the RET gene were implicated in Hirschsprung disease (HSCR), multiple endocrine neoplasia type 2 (MEN 2), and thyroid carcinomas. In this report we demonstrate that the docking protein FRS2 is tyrosine phosphorylated by ligand-stimulated and by constitutively activated oncogenic forms of RET. Complex formation between RET and FRS2 is mediated by binding of the phosphotyrosine-binding domain of FRS2 to pY1062, a residue in RET that also functions as a binding site for Shc. However, overexpression of FRS2 but not Shc potentiates mitogen-activated protein (MAP) kinase activation by RET oncoproteins. We demonstrate that oncogenic RET-PTC proteins are associated with FRS2 constitutively, leading to tyrosine phosphorylation of FRS2, MAP kinase stimulation, and cell proliferation. However, loss-of-function HSCR-associated RET mutants exhibit impaired FRS2 binding and reduced MAP kinase activation. These experiments demonstrate that FRS2 couples both ligand-regulated and oncogenic forms of RET, with the MAP kinase signaling cascade as part of the response of RET under normal biological conditions and pathological conditions, such as MEN 2 and papillary thyroid carcinomas.

Adaptor Proteins, Signal Transducing↗

PubMed2000

Sprouty proteins are targeted to membrane ruffles upon growth factor receptor tyrosine kinase activation. Identification of a novel translocation domain.

Sprouty (Spry) was first identified in a genetic screen in Drosophila to be an antagonist of fibroblast growth factor and epidermal growth factor (EGF) signaling, seemingly by inhibiting the Ras/MAP kinase pathway. Data base searches lead to the identification and cloning of, to date, four mammalian sprouty genes. The primary sequences of the mammalian sprouty gene products share a well conserved cysteine-rich C-terminal domain with the Drosophila protein. The N-terminal regions, however, do not exhibit significant homology. This study aimed at determining the disposition of Spry proteins in intact cells before and after stimulation of the EGF receptor tyrosine kinase. Full-length or deletion mutants of Spry, tagged at the N termini with the FLAG-epitope, were expressed in COS-1 cells by transient transfection and analyzed by immunofluorescence microscopy before and after EGF stimulation of the cells. In unstimulated cells, the Spry proteins were distributed throughout the cytosol except for human Sprouty2 (hSpry2), which, although generally located in the cytosol, co-localized with microtubules. In all cases, the Spry proteins underwent rapid translocation to membrane ruffles following EGF stimulation. The optimal translocation domain was identified by deletion and immunofluorescence analysis to be a highly conserved 105-amino acid domain in the C-terminal half of the hSpry2 protein. The translocation of this conserved domain, based on hSpry2 data, was independent of the activation of phosphatidylinositol-3 kinase.

Amino Acid Sequence↗

PubMed2000

FRS2 proteins recruit intracellular signaling pathways by binding to diverse targets on fibroblast growth factor and nerve growth factor receptors.

The docking protein FRS2 was implicated in the transmission of extracellular signals from the fibroblast growth factor (FGF) or nerve growth factor (NGF) receptors to the Ras/mitogen-activated protein kinase signaling cascade. The two members of the FRS2 family, FRS2alpha and FRS2beta, are structurally very similar. Each is composed of an N-terminal myristylation signal, a phosphotyrosine-binding (PTB) domain, and a C-terminal tail containing multiple binding sites for the SH2 domains of the adapter protein Grb2 and the protein tyrosine phosphatase Shp2. Here we show that the PTB domains of both the alpha and beta isoforms of FRS2 bind directly to the FGF or NGF receptors. The PTB domains of the FRS2 proteins bind to a highly conserved sequence in the juxtamembrane region of FGFR1. While FGFR1 interacts with FRS2 constitutively, independent of ligand stimulation and tyrosine phosphorylation, NGF receptor (TrkA) binding to FRS2 is strongly dependent on receptor activation. Complex formation with TrkA is dependent on phosphorylation of Y490, a canonical PTB domain binding site that also functions as a binding site for Shc (NPXpY). Using deletion and alanine scanning mutagenesis as well as peptide competition assays, we demonstrate that the PTB domains of the FRS2 proteins specifically recognize two different primary structures in two different receptors in a phosphorylation-dependent or -independent manner. In addition, NGF-induced tyrosine phosphorylation of FRS2alpha is diminished in cells that overexpress a kinase-inactive mutant of FGFR1. This experiment suggests that FGFR1 may regulate signaling via NGF receptors by sequestering a common key element which both receptors utilize for transmitting their signals. The multiple interactions mediated by FRS2 appear to play an important role in target selection and in defining the specificity of several families of receptor tyrosine kinases.

Adaptor Proteins, Signal Transducing↗

PubMed2000

A novel positive feedback loop mediated by the docking protein Gab1 and phosphatidylinositol 3-kinase in epidermal growth factor receptor signaling.

The Gab1 protein is tyrosine phosphorylated in response to various growth factors and serves as a docking protein that recruits a number of downstream signaling proteins, including phosphatidylinositol 3-kinase (PI-3 kinase). To determine the role of Gab1 in signaling via the epidermal growth factor (EGF) receptor (EGFR) we tested the ability of Gab1 to associate with and modulate signaling by this receptor. We show that Gab1 associates with the EGFR in vivo and in vitro via pTyr sites 1068 and 1086 in the carboxy-terminal tail of the receptor and that overexpression of Gab1 potentiates EGF-induced activation of the mitogen-activated protein kinase and Jun kinase signaling pathways. A mutant of Gab1 unable to bind the p85 subunit of PI-3 kinase is defective in potentiating EGFR signaling, confirming a role for PI-3 kinase as a downstream effector of Gab1. Inhibition of PI-3 kinase by a dominant-interfering mutant of p85 or by Wortmannin treatment similarly impairs Gab1-induced enhancement of signaling via the EGFR. The PH domain of Gab1 was shown to bind specifically to phosphatidylinositol 3,4,5-triphosphate [PtdIns(3,4,5)P3], a product of PI-3 kinase, and is required for activation of Gab1-mediated enhancement of EGFR signaling. Moreover, the PH domain mediates Gab1 translocation to the plasma membrane in response to EGF and is required for efficient tyrosine phosphorylation of Gab1 upon EGF stimulation. In addition, overexpression of Gab1 PH domain blocks Gab1 potentiation of EGFR signaling. Finally, expression of the gene for the lipid phosphatase PTEN, which dephosphorylates PtdIns(3,4, 5)P3, inhibits EGF signaling and translocation of Gab1 to the plasma membrane. These results reveal a novel positive feedback loop, modulated by PTEN, in which PI-3 kinase functions as both an upstream regulator and a downstream effector of Gab1 in signaling via the EGFR.

Adaptor Proteins, Signal Transducing↗

PubMed2000

A study of outrage of modesty offenders in a Singapore prison.

Outrage of modesty (OOM) offenders cause considerable annoyance and distress to their victims. The offending behaviours include touching, grabbing or fondling of erogenous or non-erogenous parts of the victim's body. The purpose of this study is to examine a prison cohort of OOM offenders and to compare them with a group of OOM offenders who had been remanded in a state mental hospital. All prisoners serving sentence over a two-year study period were interviewed. They were of similar mean age to the hospital cohort but were better educated, more likely to be married and most were working. Victims tended to be young females with an average age of 19 years. Psychotic disorders were rarely present, although 15% had a dissocial personality disorder. Those with previous OOM convictions were likely to have had past psychiatric consultations and were more likely to be unmarried. However, there were no statistically significant differences between convicted first-time offenders and repeat offenders with respect to age, educational level, nature of offences and alcohol consumption. The prisoners were less inclined to commit their offences in the mornings. Breasts and genitalia were the favoured targets for molest action, irrespective of time or place or whether the offence was committed by a first or repeat offender. The offences were often committed along staircases, corridors and in crowded public places.

Adolescent↗

PubMed2000

The sexual habits of males who molest.

To gain better understanding into the causes of molesting behaviour in males, we examined a prison cohort of molesters and compared them with a control group comprising thieves. The molesters were older, had attained a higher educational level and were more likely to be married. They had their initial sexual intercourse at an older age but tended to have multiple sexual relationships and were less likely to report having viewed pornographic material. Three months prior to committing their offences, molesters seemed to engage in less sexual activity. The implications are that molesters had a need for more explicit sexual contact but were unable to sustain ongoing, stable, intimate sexual relationships.

Adult↗

PubMed1999

Surface laser scanning of the cleft palate deformity--validation of the method.

Innovations in laser technology have led to the development of three-dimensional surface laser digitisation techniques capable of registering surface topology accurately. The clinical application of this technology in cleft palate documentation requires validation of the technique. This study determined the reliability of the surface laser scanning technique and assessed the reliability of interactive three-dimensional landmark localization. Original and duplicate plaster models of an infant with a complete unilateral cleft lip and palate were digitised with the Cyberware 3030R-HIREZ surface laser scanner. Seven anatomic landmarks were marked permanently on the palatal surface of the duplicate model only, which acted as visual cues for landmark localisation. Each model was scanned ten times serially, and ten composite three-dimensional images were obtained for each. On-line interactive computer landmark localisation permitted the assessment of variance for the x, y and z coordinates of each landmark. The precision of the laser scanning technique was found to be less than 0.06 mm in all three axes. Anatomic landmarks with the clearest visual cue were the least variable after ten rounds of scanning. Significant differences existed between visually aided and non-aided landmark localisation (P < 0.05). While landmarks could be localised repeatedly without the aid of a visual marker, landmarks well defined by a clearly visible visual cue on the three-dimensional image were more reliable.

Cleft Palate↗

PubMed1997

Growth factors stimulate tyrosine dephosphorylation of p75 and its dissociation from the SH2 domain of Grb2.

The growth factor receptor-binding protein (Grb2) has a key role in initiating the mitogen-activated protein kinase signaling cascade in major cell regulatory pathways. The binding of proteins to the SH2 domain of Grb2 has been reported to occur mainly after they are tyrosine-phosphorylated following receptor activation. Using an in vitro binding assay, immunoprecipitation, and Far Western techniques, we report that in quiescent cells a 75-kDa protein binds directly to the SH2 domain of Grb2. All of the tyrosine-phosphorylated p75 protein co-localizes with Grb2.Sos complex in the cytosolic fraction of the cell in vivo and undergoes tyrosine dephosphorylation when cells are treated with mitogenic ligands such as epidermal, platelet-derived, and fibroblast growth factors, endothelin-1, and bombesin but not tumor necrosis factor-alpha, interferon-alpha and -gamma, interleukein-6, and leukemic inhibitory factor, which are either cell growth inhibitory or not significantly mitogenic. The dephosphorylation of p75 and the ensuing dissociation from Grb2 is rapid, occurring within 30 s following mitogenic stimulation by ligands such as epidermal growth factor, suggesting p75 to be an early component in the signal transduction pathways involving Grb2.

3T3 Cells↗

PubMed1997

SHP2 associates directly with tyrosine phosphorylated p90 (SNT) protein in FGF-stimulated cells.

In a number of cell lines responsive to basic fibroblast growth factor (bFGF), two major tyrosine phosphorylated proteins, of molecular weights around 120kDa and 90kDa, are precipitated along with the tyrosine phosphatase SHP2 from the lysates of stimulated cells. The docker protein Gab-1 represents at least part of the 120kDa protein(s). The p90 protein was identified as the SNT protein. The two SH2 domains of SHP2 bind directly and synergistically to tyrosine phosphorylated SNT. Tyrosine phosphorylated SNT does not bind SHP1 and does not appear to be an in vivo substrate of SHP2 but is likely to function as an adapter protein in FGF-signalling.

3T3 Cells↗