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1.  A Ctf4 trimer couples the CMG helicase to DNA polymerase α in the eukaryotic replisome 
Nature  2014;510(7504):293-297.
Efficient duplication of the genome requires the concerted action of helicase and DNA polymerases at replication forks1, to avoid stalling of the replication machinery and consequent genomic instability2-4. In eukaryotes, the physical coupling between helicase and DNA polymerases remains poorly understood. Here we define the molecular mechanism by which the yeast Ctf4 protein links the Cdc45-MCM-GINS (CMG) DNA helicase to DNA polymerase α (Pol α) within the replisome. We use X-ray crystallography and electron microscopy to show that Ctf4 self-associates in a constitutive disk-shaped trimer. Trimerization depends on a β-propeller domain in the carboxy-terminal half of the protein, which is fused to a helical extension that protrudes from one face of the trimeric disk. Critically, Pol α and the CMG helicase share a common mechanism of interaction with Ctf4. We show that the N-terminal tails of the catalytic subunit of Pol α and the Sld5 subunit of GINS contain a conserved Ctf4-binding motif that docks onto the exposed helical extension of a Ctf4 protomer within the trimer. Accordingly, we demonstrate that one Ctf4 trimer can support binding of up to three partner proteins, including the simultaneous association with both Pol α and GINS. Our findings indicate that Ctf4 can couple two molecules of Pol α to one CMG helicase within the replisome, providing a new paradigm for lagging-strand synthesis in eukaryotes that resembles the emerging model for the simpler replisome of E. coli5-8. The ability of Ctf4 to act as a platform for multivalent interactions illustrates a mechanism for the concurrent recruitment of factors that act together at the fork.
PMCID: PMC4059944  PMID: 24805245
2.  Superconductivity in Strong Spin Orbital Coupling Compound Sb2Se3 
Scientific Reports  2014;4:6679.
Recently, A2B3 type strong spin orbital coupling compounds such as Bi2Te3, Bi2Se3 and Sb2Te3 were theoretically predicated to be topological insulators and demonstrated through experimental efforts. The counterpart compound Sb2Se3 on the other hand was found to be topological trivial, but further theoretical studies indicated that the pressure might induce Sb2Se3 into a topological nontrivial state. Here, we report on the discovery of superconductivity in Sb2Se3 single crystal induced via pressure. Our experiments indicated that Sb2Se3 became superconductive at high pressures above 10 GPa proceeded by a pressure induced insulator to metal like transition at ~3 GPa which should be related to the topological quantum transition. The superconducting transition temperature (TC) increased to around 8.0 K with pressure up to 40 GPa while it keeps ambient structure. High pressure Raman revealed that new modes appeared around 10 GPa and 20 GPa, respectively, which correspond to occurrence of superconductivity and to the change of TC slop as the function of high pressure in conjunction with the evolutions of structural parameters at high pressures.
PMCID: PMC4202213  PMID: 25327696
4.  Magnetic and structural transitions of SrFe2As2 at high pressure and low temperature 
Scientific Reports  2014;4:3685.
One of key issues in studying iron based superconductors is to understand how the magnetic phase of the parent compounds evolves. Here we report the systematic investigation of paramagnetic to antiferromagnetic and tetragonal to orthorhombic structural transitions of “122” SrFe2As2 parent compound using combined high resolution synchrotron Mössbauer spectroscopy and x-ray diffraction techniques in a cryogenically cooled high pressure diamond anvil cell. It is found that although the two transitions are coupled at 205 K at ambient pressure, they are concurrently suppressed to much lower temperatures near a quantum critical pressure of approximately 4.8 GPa where the antiferromagnetic state transforms into bulk superconducting state. Our results indicate that the lattice distortions and magnetism jointly play a critical role in inducing superconductivity in iron based compounds.
PMCID: PMC3890939  PMID: 24418845
5.  Conformational biosensors reveal adrenoceptor signalling from endosomes 
Nature  2013;495(7442):10.1038/nature12000.
A long-held tenet of molecular pharmacology is that canonical signal transduction mediated by G-protein-coupled receptor (GPCR) coupling to heterotrimeric G proteins is confined to the plasma membrane. Evidence supporting this traditional view is based on analytical methods that provide limited or non-subcellular resolution1. It has been subsequently proposed that signalling by internalized GPCR is restricted to G-protein-independent mechanisms such as scaffolding by arrestins2,3, or GPCR activation elicits a discrete form of persistent G protein activation4–9, or that internalized GPCR can indeed contribute to the acute G protein-mediated response10. Evidence supporting these various latter hypotheses is indirect or subject to alternate interpretation, and it remains unknown if endosome-localized GPCR are even present in an active form. Here we describe the application of conformation-specific single domain antibodies (nanobodies) to directly probe activation of the β2-adrenoceptor, a prototypical GPCR11, and its cognate G protein, Gs (ref. 12) in living mammalian cells. We show that the adrenergic agonist isoprenaline promotes receptor and G protein activation in the plasma membrane as expected, but also in the early endosome membrane; and that internalized receptors contribute to the overall cellular cyclic AMP response within several minutes after agonist application. These findings provide direct support for the hypothesis that canonical GPCR signalling occurs from endosomes as well as the plasma membrane, and suggest a versatile strategy for probing dynamic conformational change in vivo.
PMCID: PMC3835555  PMID: 23515162
6.  Androgen receptor-mediated apoptosis in bovine testicular induced pluripotent stem cells in response to phthalate esters 
Cell Death & Disease  2013;4(11):e907-.
The androgen receptor (AR) has a critical role in promoting androgen-dependent and -independent apoptosis in testicular cells. However, the molecular mechanisms that underlie the ligand-independent apoptosis, including the activity of AR in testicular stem cells, are not completely understood. In the present study, we generated induced pluripotent stem cells (iPSCs) from bovine testicular cells by electroporation of octamer-binding transcription factor 4 (OCT4). The cells were supplemented with leukemia inhibitory factor and bone morphogenetic protein 4, which maintained and stabilized the expression of stemness genes and pluripotency. The iPSCs were used to assess the apoptosis activity following exposure to phthalate esters, including di (2-ethyhexyl) phthalates, di (n-butyl) phthalate, and butyl benzyl phthalate. Phthalate esters significantly reduced the expression of AR in iPSCs and induced a higher ratio of BAX/BCL-2, thereby favoring apoptosis. Phthalate esters also increased the expression of cyclin-dependent kinase inhibitor 1 (p21Cip1) in a p53-dependent manner and enhanced the transcriptional activity of p53. The forced expression of AR and knockdown of p21Cip1 led to the rescue of the phthalate-mediated apoptosis. Overall, this study suggests that testicular iPSCs are a useful system for screening the toxicity of environmental disruptors and examining their effect on the maintenance of stemness and pluripotency, as well as for identifying the iPSC signaling pathway(s) that are deregulated by these chemicals.
PMCID: PMC3847308  PMID: 24201806
environmental hormone; nuclear reprogramming; p53; testis cells; toxicity screening
7.  Jun dimerization protein 2 is a critical component of the Nrf2/MafK complex regulating the response to ROS homeostasis 
Cell Death & Disease  2013;4(11):e921-.
Oxidative stress and reactive oxygen species (ROS) are associated with diseases such as cancer, cardiovascular complications, inflammation and neurodegeneration. Cellular defense systems must work constantly to control ROS levels and to prevent their accumulation. We report here that the Jun dimerization protein 2 (JDP2) has a critical role as a cofactor for transcription factors nuclear factor-erythroid 2-related factor 2 (Nrf2) and small Maf protein family K (MafK) in the regulation of the antioxidant-responsive element (ARE) and production of ROS. Chromatin immunoprecipitation–quantitative PCR (qPCR), electrophoresis mobility shift and ARE-driven reporter assays were carried out to examine the role of JDP2 in ROS production. JDP2 bound directly to the ARE core sequence, associated with Nrf2 and MafK (Nrf2–MafK) via basic leucine zipper domains, and increased DNA-binding activity of the Nrf2–MafK complex to the ARE and the transcription of ARE-dependent genes. In mouse embryonic fibroblasts from Jdp2-knockout (Jdp2 KO) mice, the coordinate transcriptional activation of several ARE-containing genes and the ability of Nrf2 to activate expression of target genes were impaired. Moreover, intracellular accumulation of ROS and increased thickness of the epidermis were detected in Jdp2 KO mice in response to oxidative stress-inducing reagents. These data suggest that JDP2 is required to protect against intracellular oxidation, ROS activation and DNA oxidation. qPCR demonstrated that several Nrf2 target genes such as heme oxygenase-1, glutamate–cysteine ligase catalytic and modifier subunits, the notch receptor ligand jagged 1 and NAD(P)H dehydrogenase quinone 1 are also dependent on JDP2 for full expression. Taken together, these results suggest that JDP2 is an integral component of the Nrf2–MafK complex and that it modulates antioxidant and detoxification programs by acting via the ARE.
PMCID: PMC3847324  PMID: 24232097
JDP2; Nrf2–MafK; ROS regulation; antioxidant enzymes; antioxidation
8.  FUT family mediates the multidrug resistance of human hepatocellular carcinoma via the PI3K/Akt signaling pathway 
Cheng, L | Luo, S | Jin, C | Ma, H | Zhou, H | Jia, L
Cell Death & Disease  2013;4(11):e923-.
The fucosyltransferase (FUT) family is the key enzymes in cell-surface antigen synthesis during various biological processes such as tumor multidrug resistance (MDR). The aim of this work was to analyze the alteration of FUTs involved in MDR in human hepatocellular carcinoma (HCC) cell lines. Using mass spectrometry (MS) analysis, the composition profiling of fucosylated N-glycans differed between drug-resistant BEL7402/5-FU (BEL/FU) cells and the sensitive line BEL7402. Further analysis of the expressional profiles of the FUT family in three pairs of parental and chemoresistant human HCC cell lines showed that FUT4, FUT6 and FUT8 were predominant expressed in MDR cell lines. The altered levels of FUT4, FUT6 and FUT8 were responsible for changed drug-resistant phenotypes of BEL7402 and BEL/FU cells both in vitro and in vivo. In addition, regulating FUT4, FUT6 or FUT8 expression markedly modulated the activity of the phosphoinositide 3 kinase (PI3K)/Akt signaling pathway and MDR-related protein 1 (MRP1) expression. Inhibition of the PI3K/Akt pathway by its specific inhibitor wortmannin, or by Akt small interfering RNA (siRNA), resulted in decreased MDR of BEL/FU cells, partly through the downregulation of MRP1. Taken together, our results suggest that FUT4-, FUT6- or FUT8-mediated MDR in human HCC is associated with the activation of the PI3K/Akt pathway and the expression of MRP1, but not of P-gp, indicating a possible novel mechanism by which the FUT family regulates MDR in human HCC.
PMCID: PMC3847326  PMID: 24232099
FUT family; multidrug resistance; human hepatocellular carcinoma cell line; PI3K/Akt signaling; P-glycoprotein; MRP1
9.  Superconductivity in Topological Insulator Sb2Te3 Induced by Pressure 
Scientific Reports  2013;3:2016.
Topological superconductivity is one of most fascinating properties of topological quantum matters that was theoretically proposed and can support Majorana Fermions at the edge state. Superconductivity was previously realized in a Cu-intercalated Bi2Se3 topological compound or a Bi2Te3 topological compound at high pressure. Here we report the discovery of superconductivity in the topological compound Sb2Te3 when pressure was applied. The crystal structure analysis results reveal that superconductivity at a low-pressure range occurs at the ambient phase. The Hall coefficient measurements indicate the change of p-type carriers at a low-pressure range within the ambient phase, into n-type at higher pressures, showing intimate relation to superconducting transition temperature. The first principle calculations based on experimental measurements of the crystal lattice show that Sb2Te3 retains its Dirac surface states within the low-pressure ambient phase where superconductivity was observed, which indicates a strong relationship between superconductivity and topology nature.
PMCID: PMC3687246  PMID: 23783511
10.  Spontaneous Healing of Iatrogenic Direct Carotid Cavernous Fistula 
Interventional Neuroradiology  2012;18(2):187-190.
Direct carotid-cavernous fistula (CCF) by selective navigation using a microcatheter or microwire is a rare complication, and its timing of treatment has not been elucidated. We report two cases of direct CCFs resulting from injury to the cavernous posterior segment of the internal carotid artery during selective navigation. We did not plan to perform emergent endovascular treatment for these direct CCFs because no symptoms related to direct CCFs developed. Follow-up angiography revealed spontaneous healing of both direct CCFs. Close observation rather than emergent treatment may represent another option for direct CCF by selective navigation during the endovascular procedure.
PMCID: PMC3380397  PMID: 22681734
carotid cavernous fistula, endovacscular, internal carotid artery, spontaneous healing
11.  Modelling of an Oesophageal Electrode for Cardiac Function Tomography 
There is a need in critical care units for continuous cardiopulmonary monitoring techniques. ECG gated electrical impedance tomography is able to localize the impedance variations occurring during the cardiac cycle. This method is a safe, inexpensive and potentially fast technique for cardiac output imaging but the spatial resolution is presently low, particularly for central locations such as the heart. Many parameters including noise deteriorate the reconstruction result. One of the main obstacles in cardiac imaging at the heart location is the high impedance of lungs and muscles on the dorsal and posterior side of body. In this study we are investigating improvements of the measurement and initial conductivity estimation of the internal electrode by modelling an internal electrode inside the esophagus. We consider 16 electrodes connected around a cylindrical mesh. With the random noise level set near 0.05% of the signal we evaluated the Graz consensus reconstruction algorithm for electrical impedance tomography. The modelling and simulation results showed that the quality of the target in reconstructed images was improved by up to 5 times for amplitude response, position error, resolution, shape deformation and ringing effects with perturbations located in cardiac related positions when using an internal electrode.
PMCID: PMC3312547  PMID: 22481975
12.  Adhesion and growth of dental pulp stem cells (DPSCs) on enamel-like fluorapatite (FA) surfaces 
To study how apatite crystal alignment of an enamel-like substrate affects DPSC cellular adhesion and growth as a precursor to produce an in vitro enamel/dentin superstructure for future studies.
The cells were subcultured in 10% FBS DMEM up to 7 weeks on the two surfaces. Specimens were observed under SEM, counted, and analyzed using the human pathway-focused matrix and adhesion PCR array.
After 3 days, the cell number on ordered FA surface was significantly higher than on the disordered surface. Of the 84 focused pathway genes, a total of 20 genes were either up or down regulated in the cells on ordered FA surface compared to the disordered surface. More interestingly, of the cell-matrix adhesion molecules, integrin alpha 7 and 8 (ITGA 7 and 8), integrin beta 3 and 4 (ITGB3 and 4), and the vitronectin receptor-integrin alpha V (ITGAV) and the key adhesion protein-fibronectin1 (FN1) were up-regulated. In SEM, both surfaces showed good biocompatibility and supported long term growth of DPSC cells but with functional cell-matrix interaction on the ordered FA surfaces.
The enhanced cellular response of DPSC cell to the ordered FA crystal surface involves a set of delicately regulated matrix and adhesion molecules which could be manipulated by treating the cells with a dentin extract, to produce a dentin/enamel superstructure.
PMCID: PMC3080027  PMID: 21254384
Fluorapatite; stem cell; PCR array; Matrix; Adhesion
13.  Recognition of CpG Island Chromatin by KDM2A Requires Direct and Specific Interaction with Linker DNA 
Molecular and Cellular Biology  2012;32(2):479-489.
Up to 70% of human genes are associated with regions of nonmethylated DNA called CpG islands (S. Saxonov, P. Berg, and D. L. Brutlag, Proc. Natl. Acad. Sci. U. S. A. 103:1412–1417, 2006). Usually associated with the 5′ end of genes, CpG islands are thought to impact gene expression. We previously demonstrated that the histone demethylase KDM2A is specifically recruited to CpG islands to define a unique chromatin architecture and highlight gene regulatory regions in large and complex mammalian genomes. This targeting relies on a zinc finger CXXC DNA binding domain (ZF-CXXC), but how this demethylase interfaces with CpG island chromatin in vivo remains unknown. Here we demonstrate, using defined chromatin templates in vitro and chromatin profiling in vivo, that nucleosomes are a major barrier to KDM2A binding and that CpG islands are directly interpreted by the ZF-CXXC domain through specific interaction with linker DNA. Furthermore, KDM2A appears to be constrained to CpG islands not only by their nonmethylated state but also by a combination of methylated DNA and nucleosome occlusion elsewhere in the genome. Our observations suggest that both DNA sequence and chromatin structure are defining factors in interpreting CpG island chromatin and translation of the CpG signal. More generally, these features of CpG island recognition suggest that chromatin structure and accessibility play a major role in defining how transcription factors recognize DNA and regulatory elements genome-wide.
PMCID: PMC3255781  PMID: 22083960
14.  Bio-CAP: a versatile and highly sensitive technique to purify and characterise regions of non-methylated DNA 
Nucleic Acids Research  2011;40(4):e32.
Across vertebrate genomes methylation of cytosine residues within the context of CpG dinucleotides is a pervasive epigenetic mark that can impact gene expression and has been implicated in various developmental and disease-associated processes. Several biochemical approaches exist to profile DNA methylation, but recently an alternative approach based on profiling non-methylated CpGs was developed. This technique, called CxxC affinity purification (CAP), uses a ZF-CxxC (CxxC) domain to specifically capture DNA containing clusters of non-methylated CpGs. Here we describe a new CAP approach, called biotinylated CAP (Bio-CAP), which eliminates the requirement for specialized equipment while dramatically improving and simplifying the CxxC-based DNA affinity purification. Importantly, this approach isolates non-methylated DNA in a manner that is directly proportional to the density of non-methylated CpGs, and discriminates non-methylated CpGs from both methylated and hydroxymethylated CpGs. Unlike conventional CAP, Bio-CAP can be applied to nanogram quantities of genomic DNA and in a magnetic format is amenable to efficient parallel processing of samples. Furthermore, Bio-CAP can be applied to genome-wide profiling of non-methylated DNA with relatively small amounts of input material. Therefore, Bio-CAP is a simple and streamlined approach for characterizing regions of the non-methylated DNA, whether at specific target regions or genome wide.
PMCID: PMC3287171  PMID: 22156374
15.  Study of T Cell subsets and IL-7 protein expression in HIV-1-infected patients after 7 years HAART 
To study the changes in T cell subsets and IL-7 in HIV-1-infected patients after seven years of highly active antiretroviral therapy (HAART).
Seventy-five individuals were included in this study (25 with effective HAART, 18 with ineffective HAART, 17 untreated HIV+ patients, and 15 volunteers in the HIV negative control group). The counts of CD4+, CD8+, CD8/CD38+, and CD8/HLADR+ T cells as well as the IL-7 protein expression was measured at 5 time points during a period of seven years in patients starting HAART (baseline) and in the HIV negative control group. The expression of CD127 on CD3+ T cells was measured by flow cytometry at a single time point (after 7 years) in patients with HAART and was compared with untreated HIV+ patients and the HIV negative control group.
At baseline CD4+ T cell counts of HIV-1-infected patients were lower than that in the control group (p < 0.01), whereas the CD8+, CD8/HLADR+ and CD8/CD38+ T cell counts were higher than those in the control group (p <0.01). After seven years of effective HAART, the CD4+ T cell counts had increased and the CD8+ T cell count had decreased, although not to the normal levels (p < 0.05). Both the CD8/HLADR+ and CD8/CD38+ T cell counts had gradually approached those of the control group (p > 0.05). In the ineffective HAART group, the CD8/CD38+ T cell count had not decreased significantly, and CD8/HLADR+ T cell count gradually decreased. Before treatment, IL-7 serum levels of patients were significantly higher than that in the control group (p < 0.01). After seven years of effective HAART, IL-7 levels had gradually decreased, but were still higher than in the control group (p < 0.01). The CD127 expression on CD3+ CD8+ T cells in effective HAART patients was higher than in untreated HIV+ patients (p < 0.05), but was lower than that in the control group (p < 0.05). CD127 expression on CD3+ CD4+ T cells was not significantly different among the control group, untreated HIV+ patients and effective HAART group.
After seven years of effective HAART, the quantity and capacity of T cell subsets and IL-7 in HIV-1-infected patients had been partially restored, and the abnormal immune activation has significantly diminished.
PMCID: PMC3351803  PMID: 22027639
HIV-1; highly active antiretroviral therapy (HAART); T cell subsets; IL-7
16.  Penicillium marneffei infection presenting as vulv-ulcer in an HIV-infected woman 
Cui, Y | Jin, C | Li, X | Wu, N
We report the case of an HIV-infected patient with vulv-ulcer as first manifestation associated with Penicillium marneffei, which is of special interest for healthcare workers in all fields.
PMCID: PMC3352150  PMID: 22024445
17.  Pulsed Laser Deposition of Antimicrobial Silver Coating on Ormocer® Microneedles 
Biofabrication  2009;1(4):41001.
One promising option for transdermal delivery of protein- and nucleic acid-based pharmacologic agents involves the use of microneedles. However, microneedle-generated pores may allow microorganisms to penetrate the stratum corneum layer of the epidermis and cause local or systemic infection. In this study, microneedles with antimicrobial functionality were fabricated using two photon polymerization-micromolding and pulsed laser deposition. The antibacterial activity of the silver-coated organically modified ceramic (Ormocer®) microneedles was demonstrated using an agar diffusion assay. Human epidermal keratinocyte (HEK) viability on the Ormocer® surfaces coated with silver was similar to that on uncoated Ormocer® surfaces. This study indicates that coating microneedles with silver thin films using pulsed laser deposition is a useful and novel approach for creating microneedles with antimicrobial functionality.
PMCID: PMC2909131  PMID: 20661316
silver; antimicrobial; microneedle; transdermal drug delivery
18.  CpG Islands Recruit a Histone H3 Lysine 36 Demethylase 
Molecular Cell  2010;38(2-2):179-190.
In higher eukaryotes, up to 70% of genes have high levels of nonmethylated cytosine/guanine base pairs (CpGs) surrounding promoters and gene regulatory units. These features, called CpG islands, were identified over 20 years ago, but there remains little mechanistic evidence to suggest how these enigmatic elements contribute to promoter function, except that they are refractory to epigenetic silencing by DNA methylation. Here we show that CpG islands directly recruit the H3K36-specific lysine demethylase enzyme KDM2A. Nucleation of KDM2A at these elements results in removal of H3K36 methylation, creating CpG island chromatin that is uniquely depleted of this modification. KDM2A utilizes a zinc finger CxxC (ZF-CxxC) domain that preferentially recognizes nonmethylated CpG DNA, and binding is blocked when the CpG DNA is methylated, thus constraining KDM2A to nonmethylated CpG islands. These data expose a straightforward mechanism through which KDM2A delineates a unique architecture that differentiates CpG island chromatin from bulk chromatin.
► A ZF-CxxC domain in KDM2A specifically binds nonmethylated CpG dinucleotides ► KDM2A is targeted to nonmethylated CpG islands genome-wide ► KDM2A actively removes histone H3 lysine 36 dimethylation from CpG islands ► This unique chromatin architecture distinguishes CpG islands from bulk chromatin
PMCID: PMC3098377  PMID: 20417597
19.  Proximal versus distal hyperplastic polyps of the colorectum: different lesions or a biological spectrum? 
Journal of Clinical Pathology  2004;57(10):1089-1093.
Background: Because of their suggested link with microsatellite instability high colorectal cancers, right sided hyperplastic polyps (HPs) may differ from their distally located counterparts. This is highlighted by the recognition of a variant HP, termed sessile serrated adenoma (SSA), which predominates in the proximal colon. HPs displaying the morphological features now associated with SSAs have been shown to have altered expression of “cancer associated” markers, but no studies have investigated whether this is dependent on anatomical location of the polyps.
Aims: To evaluate morphological and functional features in right versus left sided HPs from patients without colorectal cancer with the aim of identifying distinguishing characteristics.
Methods: HPs originating in the proximal and distal colorectum were histochemically and immunohistochemically stained to evaluate a panel of markers related to proliferation and differentiation. In addition, a series of morphological features was evaluated for each polyp.
Results: Crypt serration, crypt dilatation, and horizontal crypt growth were more common among HPs from the right side, whereas histochemical factors including mucin changes, global methylation status, and expression of carcinoembryonic antigen were not significantly different. An age disparity was also seen between patients with right versus left sided lesions, with patients with right sided lesions being an average of more than 10 years younger than those with left sided lesions.
Conclusions: These findings suggest that right and left sided HPs differ mainly in terms of growth regulation rather than cellular differentiation, implying that these lesions belong to a continuous spectrum of serrated polyps that differ quantitatively rather than qualitatively.
PMCID: PMC1770443  PMID: 15452166
colon; differentiation; hyperplastic; polyp; serration
20.  Vision impairment and older drivers: who’s driving? 
The British Journal of Ophthalmology  2002;86(10):1118-1121.
Aim: To establish the association between impaired vision and drivers’ decisions to stop driving, voluntarily restrict driving, and motor vehicle accidents.
Methods: Driving related questions were included in a population based study that determined the prevalence and incidence of eye disease. Stratified random cluster samples based on census collector districts were selected from the Melbourne Statistical Division. Eligible participants aged 44 years and over were interviewed and underwent a comprehensive ophthalmic examination. The outcomes of interest were the decision to stop driving, limiting driving in specified conditions, and driving accidents. The associations between these outcomes and the legally prescribed visual acuity (<6/12) for a driver’s licence were investigated.
Results: The mean age of the 2594/3040 (85%) eligible participants was 62.5 (range 44–101). People with visual acuity less than 6/12 were no more likely to have an accident than those with better vision (χ2 = 0.175, p>0.9). Older drivers with impaired vision, more so than younger adults, restrict their driving in visually demanding situations (p<0.05). Of the current drivers, 2.6% have vision less than that required to obtain a driver’s licence. The risk of having an accident increased with distance driven (OR 2.57, CL 1.63, 4.04 for distance >31 000 km) but not with age.
Conclusion: There was no greater likelihood of self reported driving accidents for drivers with impaired vision than those with good vision. While many older drivers with impaired vision limit their driving in adverse conditions and some drivers with impaired vision stop driving, there are a significant number of current drivers with impaired vision.
PMCID: PMC1771306  PMID: 12234890
vision impairment; visual acuity; driving; accidents
21.  Centrosomal abnormalities, multipolar mitoses, and chromosomal instability in head and neck tumours with dysfunctional telomeres 
British Journal of Cancer  2002;87(2):202-207.
Carcinomas of the head and neck typically exhibit complex chromosome aberrations but the underlying mutational mechanisms remain obscure. Evaluation of cell division dynamics in low-passage cell lines from three benign and five malignant head and neck tumours revealed a strong positive correlation between multipolarity of the mitotic spindle and the formation of bridges at anaphase in both benign and malignant tumours. Cells exhibiting a high rate of mitotic abnormalities also showed several chromosome termini lacking TTAGGG repeats and a high frequency of dicentric chromosomes. Multicolour karyotyping demonstrated a preferential involvement in structural rearrangements of chromosomes with deficient telomeres. The majority of malignant, mitotically unstable tumours expressed the reverse transcriptase subunit of telomerase. These data indicate that some of the genomic instability in head and neck tumours is initiated by telomere dysfunction, leading to the formation of dicentric chromosomes. These form chromosome bridges at mitosis that could prevent the normal anaphase-telophase transition. In turn, this may cause an accumulation of centrosomes and mitotic multipolarity. Telomerase expression does not confer total stability to the tumour genome but could be crucial for moderating the rate of chromosomal evolution.
British Journal of Cancer (2002) 37, 202–207. doi:10.1038/sj.bjc.6600438
© 2002 Cancer Research UK
PMCID: PMC2376110  PMID: 12107843
squamous cell carcinoma; pleomorphic adenoma; telomere; breakage-fusion-bridge cycle; centrosome
22.  Cytogenetic and molecular genetic demonstration of polyclonality in an acinic cell carcinoma. 
British Journal of Cancer  1998;78(3):292-295.
The paradigm that human malignancies are monoclonal has been questioned during recent years by the finding of unrelated, cytogenetically aberrant clones in short-term cultures from certain tumour types, notably carcinomas of the breast, skin and upper aerodigestive tract. In order to analyse whether cytogenetically unrelated clones are also unrelated at the molecular level, we analysed the X-chromosome inactivation status in cell cultures from a cytogenetically highly polyclonal acinic cell carcinoma of the parotid gland. By using cell cultures dominated by a single abnormal clone, obtained through in vitro culturing for 3-5 passages, we showed that the different clones must indeed have originated from different cells.
PMCID: PMC2063026  PMID: 9703273
23.  Exposure of workers to a mixture of toluene and xylenes. I. Metabolism. 
The urinary excretion of hippuric acid and methylhippuric acid was studied in workers (233 subjects; 122 men and 111 women) exposed to toluene and xylenes in combination and in non-exposed controls (281 subjects; 141 men and 140 women) recruited from the same factories or factories of the same regions. Smoking and drinking habits of the subjects were obtained by medical interviews. From each worker, one urine sample was collected at the end of a shift and analysed for hippuric and methylhippuric acids by high performance liquid chromatography. Air samples for the estimation of toluene and xylenes were collected with diffusive personal samplers. There was a linear correlation between the time weighted average exposure either to toluene or xylene isomers and the concentrations of hippuric acid or methylhippuric acid isomers in urine. Essentially no difference was found in the correlation between quantitative exposure and excretion in the three xylene isomers. Comparison of the slopes of regression lines indicated the absence of metabolic interaction between toluene and xylenes at the measured concentrations. The metabolism of toluene and xylenes was significantly reduced among smokers or drinkers compared with non-smokers and non-drinkers.
PMCID: PMC1127899  PMID: 8124462
24.  Excretion of 1,2,4-benzenetriol in the urine of workers exposed to benzene. 
Urine samples were collected from 152 workers (64 men, 88 women) who had been exposed to benzene, 53 workers (men only) exposed to a mixture of benzene and toluene, and 213 non-exposed controls (113 men, 100 women). The samples were analysed for 1,2,4-benzentriol (a minor metabolite of benzene) by high performance liquid chromatography. The time weighted average solvent exposure of each worker was monitored by diffusive sampling technique. The urinary concentration of 1,2,4-benzentriol related linearly to the intensity of exposure to benzene both in men and women among workers exposed to benzene, and was suppressed by toluene co-exposure among male workers exposed to a mixture of benzene and toluene. A cross sectional balance study in men at the end of the shift of a workday showed that only 0.47% of benzene absorbed will be excreted into urine as 1,2,4-benzenetriol, in close agreement with previous results in rabbits fed benzene. The concentration of 1,2,4-benzenetriol in urine was more closely related to the concentration of quinol than that of catechol. The fact that phenol and quinol, but not catechol, are precursors of 1,2,4-benzentriol in urine was further confirmed by the intraperitoneal injection of the three phenolic compounds to rats followed by urine analysis for 1,2,4-benzenetriol.
PMCID: PMC1009826  PMID: 2775675
25.  A retrospective cohort study of leukemia and other cancers in benzene workers 
A retrospective cohort study was carried out in 1982–1983 among 28,460 benzene-exposed workers (15,643 males, 12,817 females) from 233 factories and 28,257 control workers (16,621 males, 12,366 females) from 83 factories in 12 large cities in China. All-cause mortality was significantly higher among the exposed (265.46/100,000 person-years) than among the unexposed (139.06/100,000 person-years), as was mortality from all malignant neoplasms (123.21/100,000 versus 54.7/100,000, respectively). For certain cancers, increased mortality was noted among benzene-exposed males in comparison with that among unexposed males; the standardized mortality ratios (SMR) were elevated for leukemia (SMR = 5.74), lung cancer (SMR = 2.31), primary hepatocarcinoma (SMR = 1.12), and stomach cancer (SMR = 1.22). For females only leukemia occurred in excess among the exposed. Risk of leukemia rose as duration to exposure to benzene increased up to 15 years, and then declined with additional years of exposure. Leukemia occurred among some workers with as little as 6 to 10 ppm average exposure and 50 ppm-years (or possibly less) cumulative lifetime exposure (based on all available measurements for the exposed work units). Among the 30 leukemia cases identified in the exposed cohort, the proportion of subjects with acute lymphocytic leukemia was substantially lower and the proportion with acute nonlymphocytic leukemias was higher than in the general population. During 1972 to 1981, the annual incidence of leukemia ranged from 5.83 to 28.33 per 100,000 with higher rates occurring in the interval 1977 to 1981 than in the earlier years of the study period. Future studies should evaluate more precisely the relationship between exposure levels, job title, and development of leukemia among cases and noncases within the exposed cohort.
PMCID: PMC1568128  PMID: 2792042

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