Diamond is an important material for electrical and electronic devices. Because the diamond is in contact with the metal in these applications, it becomes necessary to study the metal-diamond ...interaction and the structure of the interface, in particular, at elevated temperatures. In this work, we study the interaction of the (100) and (111) surfaces of a synthetic diamond single crystal with spattered titanium and molybdenum films. Atomic force microscopy reveals a uniform coating of titanium and the formation of flattened molybdenum nanoparticles. A thin titanium film is completely oxidized upon contact with air and passes from the oxidized state to the carbide state upon annealing in an ultrahigh vacuum at 800 °C. Molybdenum interacts with the (111) diamond surface already at 500 °C, which leads to the carbidization of its nanoparticles and catalytic graphitization of the diamond surface. This process is much slower on the (100) diamond surface; sp
-hybridized carbon is formed on the diamond and the top of molybdenum carbide nanoparticles, only when the annealing temperature is raised to 800 °C. The conductivity of the resulting sample is improved when compared to the Ti-coated diamond substrates and the Mo-coated (111) substrate annealed at 800 °C. The presented results could be useful for the development of graphene-on-diamond electronics.
Single-walled carbon nanotubes (SWCNTs) possess the unique ability to tune their functional properties by modifying the outer surface or interior space. Using the same modifier – sulfur, we ...demonstrate a difference in sensing properties of coated and filled single-walled carbon nanotubes to gaseous nitrogen dioxide. A comprehensive investigation of materials by transmission electron microscopy, X-ray photoelectron spectroscopy, density functional theory, and kinetics simulation led to an in-depth understanding of the factors influencing the sensor response of sulfur-modified SWCNTs, such as the role of surface and volumetric processes and interface effects. The sulfur-filled nanotubes with sulfur coating showed an outstanding sensitivity to detect nitrogen dioxide over a range from 1 ppb to 10 ppm due to the involvement of sulfur species in charge transfer between nanotubes and adsorbed molecules. Our data create a platform for the development of sensitive and reversible gas sensors using nanotube-based networks.
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γH2AX and cancer Bonner, William M; Redon, Christophe E; Dickey, Jennifer S ...
Nature reviews. Cancer,
12/2008, Letnik:
8, Številka:
12
Journal Article
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Histone H2AX phosphorylation on a serine four residues from the carboxyl terminus (producing γH2AX) is a sensitive marker for DNA double-strand breaks (DSBs). DSBs may lead to cancer but, ...paradoxically, are also used to kill cancer cells. Using γH2AX detection to determine the extent of DSB induction may help to detect precancerous cells, to stage cancers, to monitor the effectiveness of cancer therapies and to develop novel anticancer drugs.
Genome stability is essential for maintaining cellular and organismal homeostasis, but it is subject to many threats. One ubiquitous threat is from a class of compounds known as reactive oxygen ...species (ROS), which can indiscriminately react with many cellular biomolecules including proteins, lipids, and DNA to produce a variety of oxidative lesions. These DNA oxidation products are a direct risk to genome stability, and of particular importance are oxidative clustered DNA lesions (OCDLs), defined as two or more oxidative lesions present within 10
bp of each other. ROS can be produced by exposure of cells to exogenous environmental agents including ionizing radiation, light, chemicals, and metals. In addition, they are produced by cellular metabolism including mitochondrial ATP generation. However, ROS also serve a variety of critical cellular functions and optimal ROS levels are maintained by multiple cellular antioxidant defenses. Oxidative DNA lesions can be efficiently repaired by base excision repair or nucleotide excision repair. If ROS levels increase beyond the capacity of its antioxidant defenses, the cell's DNA repair capacity can become overwhelmed, leading to the accumulation of oxidative DNA damage products including OCDLs, which are more difficult to repair than individual isolated DNA damage products. Here we focus on the induction and repair of OCDLs and other oxidatively induced DNA lesions. If unrepaired, these lesions can lead to the formation of mutations, DNA DSBs, and chromosome abnormalities. We discuss the roles of these lesions in human pathologies including aging and cancer, and in bystander effects.
The "radiation-induced bystander effect," in which irradiated cells can induce genomic instability in unirradiated neighboring cells, has important implications for cancer radiotherapy and diagnostic ...radiology as well as for human health in general. Although the mechanisms of this effect remain to be elucidated, we reported previously that DNA double-strand breaks (DSBs), directly measured by gamma-H2AX focus formation assay, are induced in bystander cultured cells. To overcome the deficiencies of cultured cell studies, we examined alpha-particle microbeam irradiation-induced bystander effects in human tissue models, which preserve the three-dimensional geometric arrangement and communication of cells present in tissues in vivo. In marked contrast to DNA DSB dynamics in irradiated cells, in which maximal DSB formation is seen 30 min after irradiation, the incidence of DSBs in bystander cells reached a maximum by 12 to 48 h after irradiation, gradually decreasing over the 7-day time course. At the maxima, 40% to 60% of bystander cells were affected, a 4- to 6-fold increase over controls. These increases in bystander DSB formation were followed by increased levels of apoptosis and micronucleus formation, by loss of nuclear DNA methylation, and by an increased fraction of senescent cells. These findings show the involvement of DNA DSBs in tissue bystander responses and support the notion that bystander DNA DSBs are precursors to widespread downstream effects in human tissues. Bystander cells exhibiting postirradiation signs of genomic instability may be more prone than unaffected cells to become cancerous. Thus, this study points to the importance of considering the indirect biological effects of radiation in cancer risk assessment.
Histone H2AX becomes phosphorylated in chromatin domains flanking sites of DNA double-strand breakage associated with γ-irradiation, meiotic recombination, DNA replication, and antigen receptor ...rearrangements. Here, we show that loss of a single
H2AX allele compromises genomic integrity and enhances the susceptibility to cancer in the absence of p53. In comparison with heterozygotes, tumors arise earlier in the H2AX homozygous null background, and
H2AX
−/−
p53
−/− lymphomas harbor an increased frequency of clonal nonreciprocal translocations and amplifications. These include complex rearrangements that juxtapose the c-
myc oncogene to antigen receptor loci. Restoration of the
H2AX null allele with wild-type
H2AX restores genomic stability and radiation resistance, but this effect is abolished by substitution of the conserved serine phosphorylation sites in H2AX with alanine or glutamic acid residues. Our results establish
H2AX as genomic caretaker that requires the function of both gene alleles for optimal protection against tumorigenesis.
Humans and animals undergo ageing, and although their primary cells undergo cellular senescence in culture, the relationship between these two processes is unclear. Here we show that γ-H2AX foci ...(γ-foci), which reveal DNA double-strand breaks (DSBs), accumulate in senescing human cell cultures and in ageing mice. They colocalize with DSB repair factors, but not significantly with telomeres. These cryptogenic γ-foci remain after repair of radiation-induced γ-foci, suggesting that they may represent DNA lesions with unrepairable DSBs. Thus, we conclude that accumulation of unrepairable DSBs may have a causal role in mammalian ageing.
That tumors cause changes in surrounding tissues is well documented, but whether they also affect distant tissues is uncertain. Such knowledge may be important in understanding the relationship ...between cancer and overall patient health. To address this question, we examined tissues distant to sites of implanted tumors for genomic damage using cohorts of C57BL/6 and BALB/c mice with early-stage subcutaneous syngeneic grafts, specifically, B16 melanoma, MO5076 sarcoma, and COLON26 carcinoma. Here we report that levels of two serious types of DNA damage, double-strand breaks (DSBs) measured by γ-H2AX focus formation and oxidatively induced non-DSB clustered DNA lesions (OCDLs), were elevated in tissues distant from the tumor site in tumor-bearing mice compared with their age- and sex-matched controls. Most affected were crypts in the gastrointestinal tract organs and skin, both highly proliferative tissues. Further investigation revealed that, compared with controls, tumor-bearing mice contained elevated amounts of activated macrophages in the distant gastrointestinal tissues, as well as elevated serum levels of several cytokines. One of these cytokines, CCL2/MCP-1, has been linked to several inflammation-related conditions and macrophage recruitment, and strikingly, CCL2-deficient mice lacked increased levels of DSBs and OCDLs in tissues distant from implanted tumors. Thus, this study is unique in being a direct demonstration that the presence of a tumor may induce a chronic inflammatory response in vivo, leading to increased systemic levels of DNA damage. Importantly, these findings suggest that tumors may have more profound effects on their hosts than heretofore expected.
Genomic Instability in Mice Lacking Histone H2AX Celeste, Arkady; Petersen, Simone; Romanienko, Peter J. ...
Science (American Association for the Advancement of Science),
05/2002, Letnik:
296, Številka:
5569
Journal Article
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Higher order chromatin structure presents a barrier to the recognition and repair of DNA damage. Double-strand breaks (DSBs) induce histone H2AX phosphorylation, which is associated with the ...recruitment of repair factors to damaged DNA. To help clarify the physiological role of H2AX, we targeted H2AX in mice. Although H2AX is not essential for irradiation-induced cell-cycle checkpoints, H2AX-/-mice were radiation sensitive, growth retarded, and immune deficient, and mutant males were infertile. These pleiotropic phenotypes were associated with chromosomal instability, repair defects, and impaired recruitment of Nbs1, 53bp1, and Brca1, but not Rad51, to irradiation-induced foci. Thus, H2AX is critical for facilitating the assembly of specific DNA-repair complexes on damaged DNA.
DNA double-strand breaks originating from diverse causes in eukaryotic cells are accompanied by the formation of phosphorylated H2AX (γH2AX) foci. Here we show that γH2AX formation is also a cellular ...response to topoisomerase I cleavage complexes known to induce DNA double-strand breaks during replication. In HCT116 human carcinoma cells exposed to the topoisomerase I inhibitor camptothecin, the resulting γH2AX formation can be prevented with the phosphatidylinositol 3-OH kinase-related kinase inhibitor wortmannin; however, in contrast to ionizing radiation, only camptothecin-induced γH2AX formation can be prevented with the DNA replication inhibitor aphidicolin and enhanced with the checkpoint abrogator 7-hydroxystaurosporine. This γH2AX formation is suppressed in ATR (ataxia telangiectasia and Rad3-related) deficient cells and markedly decreased in DNA-dependent protein kinase-deficient cells but is not abrogated in ataxia telangiectasia cells, indicating that ATR and DNA-dependent protein kinase are the kinases primarily involved in γH2AX formation at the sites of replication-mediated DNA double-strand breaks. Mre11- and Nbs1-deficient cells are still able to form γH2AX. However, H2AX-/- mouse embryonic fibroblasts exposed to camptothecin fail to form Mre11, Rad50, and Nbs1 foci and are hypersensitive to camptothecin. These results demonstrate a conserved γH2AX response for double-strand breaks induced by replication fork collision. γH2AX foci are required for recruiting repair and checkpoint protein complexes to the replication break sites.
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