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1.  Mutational Signature of Aristolochic Acid Exposure as Revealed by Whole-Exome Sequencing 
Science translational medicine  2013;5(197):197ra102.
In humans, exposure to aristolochic acid (AA) is associated with urothelial carcinoma of the upper urinary tract (UTUC). Exome sequencing of UTUCs from 19 individuals with documented exposure to AA revealed a remarkably large number of somatic mutations and an unusual mutational signature attributable to AA. Most of the mutations (72%) in these tumors were A:T-to-T:A transversions, located predominantly on the nontranscribed strand, with a strong preference for deoxyadenosine in a consensus sequence (T/CAG). This trinucleotide motif overlaps the canonical splice acceptor site, possibly accounting for the excess of splice site mutations observed in these tumors. The AA mutational fingerprint was found frequently in oncogenes and tumor suppressor genes in AA-associated UTUC. The AA mutational signature was observed in one patient’s tumor from a UTUC cohort without previous indication of AA exposure. Together, these results directly link an established environmental mutagen to cancer through genome-wide sequencing and highlight its power to reveal individual exposure to carcinogens.
doi:10.1126/scitranslmed.3006200
PMCID: PMC3973132  PMID: 23926200
2.  Prooxidant Properties of p66shc Are Mediated by Mitochondria in Human Cells 
PLoS ONE  2014;9(3):e86521.
p66shc is a protein product of an mRNA isoform of SHC1 gene that has a pro-oxidant and pro-apoptotic activity and is implicated in the aging process. Mitochondria were suggested as a major source of the p66shc-mediated production of reactive oxygen species (ROS), although the underlying mechanisms are poorly understood. We studied effects of p66shc on oxidative stress induced by hydrogen peroxide or by serum deprivation in human colon carcinoma cell line RKO and in diploid human dermal fibroblasts (HDFs). An shRNA-mediated knockdown of p66shc suppressed and an overexpression of a recombinant p66shc stimulated the production of ROS in the both models. This effect was not detected in the mitochondrial DNA-depleted ρ0-RKO cells that do not have the mitochondrial electron transport chain (ETC). The p66shc-dependent accumulation of mitochondrial ROS was detected with HyPer-mito, a mitochondria-targeted fluorescent protein sensor for hydrogen peroxide. The fragmentation of mitochondria induced by mitochondrial ROS was significantly reduced in the p66shc deficient RKO cells. Mitochondria-targeted antioxidants SkQ1 and SkQR1 also decreased the oxidative stress induced by hydrogen peroxide or by serum deprivation. Together the data indicate that the p66shc-dependant ROS production during oxidative stress has mitochondrial origin in human normal and cancer cells.
doi:10.1371/journal.pone.0086521
PMCID: PMC3950296  PMID: 24618848
3.  Specific Tandem Repeats Are Sufficient for Paramutation-Induced Trans-Generational Silencing 
PLoS Genetics  2013;9(10):e1003773.
Paramutation is a well-studied epigenetic phenomenon in which trans communication between two different alleles leads to meiotically heritable transcriptional silencing of one of the alleles. Paramutation at the b1 locus involves RNA-mediated transcriptional silencing and requires specific tandem repeats that generate siRNAs. This study addressed three important questions: 1) are the tandem repeats sufficient for paramutation, 2) do they need to be in an allelic position to mediate paramutation, and 3) is there an association between the ability to mediate paramutation and repeat DNA methylation levels? Paramutation was achieved using multiple transgenes containing the b1 tandem repeats, including events with tandem repeats of only one half of the repeat unit (413 bp), demonstrating that these sequences are sufficient for paramutation and an allelic position is not required for the repeats to communicate. Furthermore, the transgenic tandem repeats increased the expression of a reporter gene in maize, demonstrating the repeats contain transcriptional regulatory sequences. Transgene-mediated paramutation required the mediator of paramutation1 gene, which is necessary for endogenous paramutation, suggesting endogenous and transgene-mediated paramutation both require an RNA-mediated transcriptional silencing pathway. While all tested repeat transgenes produced small interfering RNAs (siRNAs), not all transgenes induced paramutation suggesting that, as with endogenous alleles, siRNA production is not sufficient for paramutation. The repeat transgene-induced silencing was less efficiently transmitted than silencing induced by the repeats of endogenous b1 alleles, which is always 100% efficient. The variability in the strength of the repeat transgene-induced silencing enabled testing whether the extent of DNA methylation within the repeats correlated with differences in efficiency of paramutation. Transgene-induced paramutation does not require extensive DNA methylation within the transgene. However, increased DNA methylation within the endogenous b1 repeats after transgene-induced paramutation was associated with stronger silencing of the endogenous allele.
Author Summary
Paramutation is a fascinating process in which genes communicate to efficiently establish changes in their expression that are stably transmitted to future generations without any changes in DNA sequences. While paramutation was first described in the 1950s and extensively studied through the 1960s, its underlying mechanism remained mysterious for many years. Over the past ten years paramutation at the b1 locus in maize was shown to require transcribed, non-coding tandem repeats located 100 kb upstream of b1. These repeats generate small RNAs, and mutations in multiple genes mediating small RNA silencing at the transcriptional level prevent paramutation. While underlying mechanisms are shared, current models for RNA-mediated transcriptional silencing that are based on experiments with S. pombe and Arabidopsis do not explain many aspects of paramutation. In this manuscript we used a transgenic approach to demonstrate that the b1 non-coding tandem repeats are sufficient to send and respond to the paramutation signals and that this occurs even when the repeats are not at their normal chromosomal location.
doi:10.1371/journal.pgen.1003773
PMCID: PMC3798267  PMID: 24146624
4.  A fluorescence-based analysis of aristolochic acid-derived DNA adducts 
Analytical Biochemistry  2012;427(1):49-51.
Aristolochic acids (AAs), major components of plant extracts from Aristolochia species form, after metabolic activation, pro-mutagenic DNA adducts in renal tissue. The DNA adducts can be used as biomarkers for studies of AA toxicity. Identification of these adducts is a complicated and time-consuming procedure. We present herein a fast, non-isotopic, fluorescence-based assay for the detection of AA-DNA adducts in multiple samples. This approach allows analysis of AA adducts in synthetic DNA with known nucleotide composition, analysis of DNA adducts formed from chemically diverse AAs in vitro. The method can be applied to compare AA-DNA adduct formation in cells and tissues.
doi:10.1016/j.ab.2012.03.027
PMCID: PMC3383895  PMID: 22484040
DNA adducts; aristolochic acids; fluorescence detection
5.  Biomonitoring of Aristolactam-DNA Adducts in Human Tissues using Ultra-Performance Liquid Chromatography/Ion-Trap Mass Spectrometry 
Chemical research in toxicology  2012;25(5):1119-1131.
Aristolochic acids (AAs) are a structurally-related family of nephrotoxic and carcinogenic nitrophenanthrene compounds found in Aristolochia herbaceous plants, many of which have been used worldwide for medicinal purposes. AAs have been implicated in the etiology of so-called Chinese herbs nephropathy and of Balkan endemic nephropathy. Both of these disease syndromes are associated with carcinomas of the upper urinary tract (UUC). 8-Methoxy-6-nitrophenanthro-[3,4-d]-1,3-dioxolo-5-carboxylic acid (AA-I) is a principal component of Aristolochia herbs. Following metabolic activation, AA-I reacts with DNA to form aristolactam (AL-I)-DNA adducts. We have developed a sensitive analytical method, using ultra-performance liquid chromatography-electrospray ionization/multistage mass spectrometry (UPLC-ESI/MSn) with a linear quadrupole ion-trap mass spectrometer, to measure 7-(deoxyadenosin-N6-yl) aristolactam I (dA-AL-I) and 7-(deoxyguanosin-N2-yl) aristolactam I (dG-AL-I) adducts. Using 10 μg of DNA for measurements, the lower limits of quantitation of dA-AL-I and dG-AL-I are, respectively, 0.3 and 1.0 adducts per 108 DNA bases. We have used UPLC-ESI/MSn to quantify AL-DNA adducts in tissues of rodents exposed to AA, and in the renal cortex of patients with UUC who reside in Taiwan, where the incidence of this uncommon cancer is the highest reported for any country in the world. In human tissues, dA-AL-I was detected at levels ranging from 9 to 338 adducts per 108 DNA bases, whereas dG-AL-I was not found. We conclude that UPLC-ESI/MSn is a highly sensitive, specific and robust analytical method, positioned to supplant 32P-postlabeling techniques currently used for biomonitoring of DNA adducts in human tissues. Importantly, UPLC-ESI/MSn could be used to document exposure to AA, the toxicant responsible for AA nephropathy and its associated UUC.
doi:10.1021/tx3000889
PMCID: PMC3536064  PMID: 22515372
6.  Baseline characteristics of patients in the Reduction of Events with Darbepoetin alfa in Heart Failure trial (RED-HF) 
McMurray, John J.V. | Anand, Inder S. | Diaz, Rafael | Maggioni, Aldo P. | O'Connor, Christopher | Pfeffer, Marc A. | Solomon, Scott D. | Tendera, Michal | van Veldhuisen, Dirk J. | Albizem, Moetaz | Cheng, Sunfa | Scarlata, Debra | Swedberg, Karl | Young, James B. | Amuchastegui, M. | Belziti, C. | Bluguermann, J. | Caccavo, M. | Cartasegna, L. | Colque, R. | Cuneo, C. | Fernandez, A. | Gabito, A. | Goicochea, R. | Gonzalez, M. | Gorosito, V. | Grinfeld, L. | Hominal, M. | Kevorkian, R. | Litvak Bruno, M. | Llanos, J. | Mackinnon, I. | Manuale, O. | Marzetti, E. | Nul, D. | Perna, E. | Riccitelli, M. | Sanchez, A. | Santos, D. | Schygiel, P. | Toblli, J. | Vogel, D. | Aggarwal, A. | Amerena, J. | De Looze, F. | Fletcher, P. | Hare, D. | Ireland, M. | Krum, H. | Lattimore, J. | Marwick, T. | Sindone, A. | Thompson, P. | Waites, J. | Altenberger, J. | Ebner, C. | Lenz, K. | Pacher, R. | Poelzl, G. | Charlier, F. | de Ceuninck, M. | De Keulenaer, G. | Dendale, P. | Maréchal, P. | Mullens, W. | Thoeng, J. | Vanderheyden, M. | Vanhaecke, J. | Weytjens, C. | Wollaert, B. | Albuquerque, D. | Almeida, D. | Aspe y Rosas, J. | Bocchi, E. | Bordignon, S. | Clausell, N. | Kaiser, S. | Leaes, P. | Martins Alves, S. | Montera, M. | Moura, L. | Pereira de Castro, R. | Rassi, S. | Reis, A. | Saraiva, J. | Simões, M. | Souza Neto, J. | Teixeira, M. | Benov, H. | Chompalova, B. | Donova, T. | Georgiev, P. | Gotchev, D. | Goudev, A. | Grigorov, M. | Guenova, D. | Hergeldjieva, V. | Ivanov, D. | Kostova, E. | Manolova, A. | Marchev, S. | Nikolov, F. | Popov, A. | Raev, D. | Tzekova, M. | Czarnecki, W. | Giannetti, N. | Haddad, H. | Heath, J. | Huynh, T. | Lepage, S. | Liu, P. | Lonn, E. | Ma, P. | Manyari, D. | Moe, G. | Parker, J. | Pesant, Y. | Rajda, M. | Ricci, J. | Roth, S. | Sestier, F. | Sluzar, V. | Sussex, B. | Vizel, S. | Antezana, G. | Bugueno, C. | Castro, P. | Conejeros, C. | Manriquez, L. | Martinez, D. | Potthoff, S. | Stockins, B. | Vukasovic, J. | Gregor, 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M. | Ranjith, N. | Van Zyl, L. | Weich, H. | Anguita, M. | Berrazueta, J. | Bruguera i Cortada, J. | de Teresa, E. | Gómez Sánchez, M. | González Juanatey, J. | Gonzalez-Maqueda, I. | Jordana, R. | Lupon, J. | Manzano, L. | Pascual Figal, D. | Pulpón, L. | Recio, J. | Ridocci Soriano, F. | Rodríguez Lambert, J. | Roig Minguell, E. | Roig Minguell, E. | Romero, J. | Valdovinos, P. | Klintberg, L. | Kronvall, T. | Lycksell, M. | Morner, S. | Rydberg, E. | Swedberg, K. | Timberg, I. | Wikstrom, G. | Moccetti, T.4 | Ashok, J. | Banerjee, P. | Carr-White, G. | Cleland, J. | Connolly, E. | Francis, M. | Greenbaum, R. | Kadr, H. | Lindsay, S. | McMurray, J. | Megarry, S. | Memon, A. | Murdoch, D. | Senior, R. | Squire, I. | Tan, L. | Witte, K. | Adams, K. | Adamson, P. | Adler, A. | Altschul, L. | Altschuller, A. | Amirani, H. | Anand, I. | Andreou, C. | Ansari, M. | Antonishen, M. | Banchs, H. | Banerjee, S. | Banish, D. | Bank, A. | Barbagelata, A. | Barnard, D. | Bellinger, R. | Benn, A. | Berk, M. | Berry, B. | Bethala, V. | Bilazarian, S. | Bisognano, J. | Bleyer, F. | Blum, M. | Boehmer, J. | Bouchard, A. | Boyle, A. | Bozkurt, B. | Brown, C. | Burlew, B. | Burnham, K. | Butler, J. | Call, J. | Cambier, P. | Cappola, T. | Carlson, R. | Chandler, B. | Chandra, R. | Chandraratna, P. | Chernick, R. | Colan, D. | Colfer, H. | Colucci, W. | Connelly, T. | Costantini, O. | Dadkhah, S. | Dauber, I. | Davis, J. | Davis, S. | Denning, S. | Drazner, M. | Dunlap, S. | Egbujiobi, L. | Elkayam, U. | Elliott, J. | El-Shahawy, M. | Essandoh, L. | Ewald, G. | Fang, J. | Farhoud, H. | Felker, G. | Fernandez, J. | Festin, R. | Fishbein, G. | Florea, V. | Flores, E. | Floro, J. | Gabris, M. | Garg, M. | Gatewood, R. | Geller, M. | Ghali, J. | Ghumman, W. | Gibbs, G. | Gillespie, E. | Gilmore, R. | Gogia, H. | Goldberg, L. | Gradus-Pizlo, I. | Grainger, T. | Gudmundsson, G. | Gunawardena, D. | Gupta, D. | Hack, T. | Hall, S. | Hamroff, G. | Hankins, S. | Hanna, M. | Hargrove, J. | Haught, W. | Hauptman, P. | Hazelrigg, M. | Herzog, C. | Heywood, J. | Hill, T. | Hilton, T. | Hirsch, H. | Hunter, J. | Ibrahim, H. | Imburgia, M. | Iteld, B. | Jackson, B. | Jaffrani, N. | Jain, D. | Jain, A. | James, M. | Jimenez, J. | Johnson, E. | Kale, P. | Kaneshige, A. | Kapadia, S. | Karia, D. | Karlsberg, R. | Katholi, R. | Kerut, E. | Khoury, W. | Kipperman, R. | Klapholz, M. | Kosinski, E. | Kozinn, M. | Kraus, D. | Krueger, S. | Krum, H. | Kumar, S. | Lader, E. | Lee, C. | Levy, W. | Lewis, E. | Light-McGroary, K. | Loh, I. | Lombardi, W. | Machado, C. | Maislos, F. | Mancini, D. | Markus, T. | Mather, P. | McCants, K. | McGrew, F. | McLaurin, B. | McMillan, E. | McNamara, D. | Meyer, T. | Meymandi, S. | Miller, A. | Minami, E. | Modi, M. | Mody, F. | Mohanty, P. | Moscoso, R. | Moskowitz, R. | Moustafa, M. | Mullen, M. | Naz, T. | Noonan, T. | O'Brien, T. | Oellerich, W. | Oren, R. | Pamboukian, S. | Pereira, N. | Pitt, W. | Porter, C. | Prabhu, S. | Promisloff, S. | Ratkovec, R. | Richardson, R. | Ross, A. | Saleh, N. | Saltzberg, M. | Sarkar, S. | Schmedtje, J. | Schneider, R. | Schuyler, G. | Shanes, J. | Sharma, A. | Siegel, C. | Siegel, R. | Silber, D. | Singh, V. | Singh, N. | Singh, J. | Sklar, J. | Small, R. | Smith, A. | Smith, E. | Smith, E. | Smull, D. | Sotolongo, R. | Staniloae, C. | Stapleton, D. | Steele, P. | Stehlik, J. | Stein, M. | Tang, W. | Thadani, U. | Torre-Amoine, G. | Trichon, B. | Tsai, C. | Tummala, R. | Van Bakel, A. | Vicari, R. | Vijay, N. | Vijayaraghavan, K. | Vittorio, T. | Vossler, M. | Wagoner, L. | Wallis, D. | Ward, N. | Widmer, M. | Wight, J. | Wilkins, C. | Williams, C. | Williams, G. | Winchester, M. | Winkel, E. | Wittmer, B. | Wood, D. | Wormer, D. | Wright, R. | Xu, Z. | Yasin, M. | Zolty, R.
European Journal of Heart Failure  2013;15(3):334-341.
Aims
This report describes the baseline characteristics of patients in the Reduction of Events with Darbepoetin alfa in Heart Failure trial (RED-HF) which is testing the hypothesis that anaemia correction with darbepoetin alfa will reduce the composite endpoint of death from any cause or hospital admission for worsening heart failure, and improve other outcomes.
Methods and results
Key demographic, clinical, and laboratory findings, along with baseline treatment, are reported and compared with those of patients in other recent clinical trials in heart failure. Compared with other recent trials, RED-HF enrolled more elderly [mean age 70 (SD 11.4) years], female (41%), and black (9%) patients. RED-HF patients more often had diabetes (46%) and renal impairment (72% had an estimated glomerular filtration rate <60 mL/min/1.73 m2). Patients in RED-HF had heart failure of longer duration [5.3 (5.4) years], worse NYHA class (35% II, 63% III, and 2% IV), and more signs of congestion. Mean EF was 30% (6.8%). RED-HF patients were well treated at randomization, and pharmacological therapy at baseline was broadly similar to that of other recent trials, taking account of study-specific inclusion/exclusion criteria. Median (interquartile range) haemoglobin at baseline was 112 (106–117) g/L.
Conclusion
The anaemic patients enrolled in RED-HF were older, moderately to markedly symptomatic, and had extensive co-morbidity.
doi:10.1093/eurjhf/hfs204
PMCID: PMC3576902  PMID: 23329651
Heart failure; Anaemia
7.  Active Ageing in CIS Countries: Semantics, Challenges, and Responses 
Although the CIS countries are connected together by the legacy of breaking away from the Soviet Union, they have had a distinctive transition course and are rather diverse in terms of the population ageing challenges and policy responses in place. The commonality is that a comprehensive national strategy on ageing is lacking, and many of necessary reforms were put aside owing to political uncertainties, lack of societal consensus, and financial instability. The notion of active ageing is associated with the term “accelerated ageing,” which is understood to be an individual living a life under harsh living conditions or a society experiencing rapid increases in the relative number of older persons, and therefore it carries a negative connotation. Yet, in the same spirit as the European Year for Active Ageing and Solidarity between Generations 2012, the CIS countries have initiated sectoral programmes towards enhancing employment of older workers, social participation of older people in the society in a wider sense and also measures promoting health and independent living of older persons.
doi:10.1155/2013/261819
PMCID: PMC3549383  PMID: 23346109
8.  Major approaches in early diagnostics of common variable immunodeficiency in adults in Moscow 
F1000Research  2012;1:46.
Common variable immunodeficiency (CVID) is a primary immunological disease characterized predominantly by hypogammaglobulinemia. The main clinical manifestations are severe recurrent infections that often lead to structural damage of affected organs. The early start of adequate intravenous immunoglobulin therapy has significantly improved the prognosis of this serious disorder. Patients with CVID are also predisposed to autoimmune and lymphoproliferative complications. This article deals with the features of this primary immunodeficiency in adults. Clinical manifestations, immunological features and treatment concepts were gathered during 21 years of observation of such patients in Moscow. The authors suggest early predictive clinical signs of CVID in adults.
doi:10.12688/f1000research.1-46.v1
PMCID: PMC3782364  PMID: 24358827
9.  Maize Unstable factor for orange1 Is Required for Maintaining Silencing Associated with Paramutation at the pericarp color1 and booster1 Loci 
PLoS Genetics  2012;8(10):e1002980.
To understand the molecular mechanisms underlying paramutation, we examined the role of Unstable factor for orange1 (Ufo1) in maintaining paramutation at the maize pericarp color1 (p1) and booster1 (b1) loci. Genetic tests revealed that the Ufo1-1 mutation disrupted silencing associated with paramutation at both p1 and b1. The level of up regulation achieved at b1 was lower than that at p1, suggesting differences in the role Ufo1-1 plays at these loci. We characterized the interaction of Ufo1-1 with two silenced p1 epialleles, P1-rr′ and P1-prTP, that were derived from a common P1-rr ancestor. Both alleles are phenotypically indistinguishable, but differ in their paramutagenic activity; P1-rr′ is paramutagenic to P1-rr, while P1-prTP is non-paramutagenic. Analysis of cytosine methylation revealed striking differences within an enhancer fragment that is required for paramutation; P1-rr′ exhibited increased methylation at symmetric (CG and CHG) and asymmetric (CHH) sites, while P1-prTP was methylated only at symmetric sites. Both silenced alleles had higher levels of dimethylation of lysine 9 on histone 3 (H3K9me2), an epigenetic mark of silent chromatin, in the enhancer region. Both epialleles were reactivated in the Ufo1-1 background; however, reactivation of P1-rr′ was associated with dramatic loss of symmetric and asymmetric cytosine methylation in the enhancer, while methylation of up-regulated P1-prTP was not affected. Interestingly, Ufo1-1–mediated reactivation of both alleles was accompanied with loss of H3K9me2 mark from the enhancer region. Therefore, while earlier studies have shown correlation between H3K9me2 and DNA methylation, our study shows that these two epigenetic marks are uncoupled in the Ufo1-1–reactivated p1 alleles. Furthermore, while CHH methylation at the enhancer region appears to be the major distinguishing mark between paramutagenic and non-paramutagenic p1 alleles, H3K9me2 mark appears to be important for maintaining epigenetic silencing.
Author Summary
Natural allelic variability is crucial for genetic improvement. While the genetic mechanisms leading to such variation have been studied in depth, relatively less is known about the role of epigenetic mechanisms in generation of allelic diversity. Paramutation is a phenomenon in which one allele can silence another allele in trans and, once established, such epigenetic silencing is heritable. To further understand the molecular components of paramutation, we characterized two epialleles of the pericarp color1 (p1) gene of maize, which originated from a common progenitor; however, only one of these alleles is paramutagenic. Results show that, while both alleles have high levels of symmetric (CG and CHG) methylation in a distal enhancer element, only the paramutagenic allele has higher levels of asymmetric (CHH) methylation. Since CHH methylation is imposed and maintained through RNA–mediated mechanisms, these results indicate that paramutation at the p1 locus involves RNA–mediated silencing pathway. Further, both silent epialleles are reactivated in the presence of an unlinked dominant mutation Ufo1-1, and reactivation is accompanied by the loss of suppressive histone mark H3K9me2. Finally, we show that ufo1 is also required for epigenetic silencing at the booster1 locus and thus affects additional loci in maize that participate in paramutation.
doi:10.1371/journal.pgen.1002980
PMCID: PMC3464198  PMID: 23055943
10.  Enhancement of the critical current density in FeO-coated MgB2 thin films at high magnetic fields 
Summary
The effect of depositing FeO nanoparticles with a diameter of 10 nm onto the surface of MgB2 thin films on the critical current density was studied in comparison with the case of uncoated MgB2 thin films. We calculated the superconducting critical current densities (J c) from the magnetization hysteresis (M–H) curves for both sets of samples and found that the J c value of FeO-coated films is higher at all fields and temperatures than the J c value for uncoated films, and that it decreases to ~105 A/cm2 at B = 1 T and T = 20 K and remains approximately constant at higher fields up to 7 T.
doi:10.3762/bjnano.2.89
PMCID: PMC3257506  PMID: 22259764
critical current; magnesium diboride; nanoparticles; pinning; superconductivity
11.  Lack of recognition by global-genome nucleotide excision repair accounts for the high mutagenicity and persistence of aristolactam-DNA adducts 
Nucleic Acids Research  2011;40(6):2494-2505.
Exposure to aristolochic acid (AA), a component of Aristolochia plants used in herbal remedies, is associated with chronic kidney disease and urothelial carcinomas of the upper urinary tract. Following metabolic activation, AA reacts with dA and dG residues in DNA to form aristolactam (AL)-DNA adducts. These mutagenic lesions generate a unique TP53 mutation spectrum, dominated by A : T to T : A transversions with mutations at dA residues located almost exclusively on the non-transcribed strand. We determined the level of AL-dA adducts in human fibroblasts treated with AA to determine if this marked strand bias could be accounted for by selective resistance to global-genome nucleotide excision repair (GG-NER). AL-dA adduct levels were elevated in cells deficient in GG-NER and transcription-coupled NER, but not in XPC cell lines lacking GG-NER only. In vitro, plasmids containing a single AL-dA adduct were resistant to the early recognition and incision steps of NER. Additionally, the NER damage sensor, XPC-RAD23B, failed to specifically bind to AL-DNA adducts. However, placing AL-dA in mismatched sequences promotes XPC-RAD23B binding and renders this adduct susceptible to NER, suggesting that specific structural features of this adduct prevent processing by NER. We conclude that AL-dA adducts are not recognized by GG-NER, explaining their high mutagenicity and persistence in target tissues.
doi:10.1093/nar/gkr1095
PMCID: PMC3315299  PMID: 22121226
12.  Substrate specificity and excision kinetics of natural polymorphic variants and phosphomimetic mutants of human 8-oxoguanine-DNA glycosylase 
The FEBS journal  2009;276(18):5149-5162.
Summary
Human 8-oxoguanine-DNA-glycosylase (OGG1) efficiently removes mutagenic 8-oxoguanine (8-oxoGua) and 2,6-diamino-4-hydroxy-5-formamidopyrimidine (FapyGua) when paired with cytosine in oxidatively damaged DNA. Excision of 8-oxoGua mispaired with adenine may lead to G→T transversions. Posttranslational modifications such as phosphorylation could affect cellular distribution and enzymatic activity of OGG1. Mutations and polymorphisms of OGG1 may affect enzymatic activity and have been associated with increased risk of several cancers. In this study we use double-stranded oligodeoxynucleotides containing 8-oxoGua:Cyt or 8-oxoGua:Ade pairs, as well as γ-irradiated calf thymus DNA, to investigate the kinetics and substrate specificity of several known OGG1 polymorphic variants and phosphomimetic Ser→Glu mutants. Among the polymorphic variants, A288V and S326C displayed opposite-base specificity similar to that of wild type OGG1, while OGG1-D322N was 2.3-fold more specific for the correct opposite base than the wild type enzyme. All phosphomimetic mutants displayed ~1.5–3-fold lower ability to remove 8-oxoGua in both assays, whereas the substrate specificity of the phosphomimetic mutants was similar to that of the wild type enzyme. OGG1-S326C efficiently excised 8-oxoGua from oligodeoxynucleotides and FapyGua from γ-irradiated DNA but excised 8-oxoG rather inefficiently from γ-irradiated DNA. Otherwise, kcat values for 8-oxoGua excision obtained from both types of experiments were similar for all OGG1 variants studied. It is known that human AP endonuclease APEX1 can stimulate OGG1 activity by increasing its turnover rate. However, when wild type OGG1 was replaced with one of the phosphomimetic mutants, very little stimulation of 8-oxoGua removal was observed in the presence of APEX1.
doi:10.1111/j.1742-4658.2009.07212.x
PMCID: PMC2746928  PMID: 19674107
DNA damage; DNA repair; 8-oxoguanine; DNA glycosylase; substrate specificity
13.  Down-regulation of Epidermal Growth Factor Receptor by Selective Expansion of a 5′-End Regulatory Dinucleotide Repeat in Colon Cancer with Microsatellite Instability 
Purpose
The epidermal growth factor receptor (EGFR) is overexpressed in several tumor types, and its expression is influenced by the length of a 5′-end microsatellite repeat (CA)n: the longer the repeat, the lower the expression. Dinucleotide repeats accumulate insertion/deletion types of mutations in tumors with microsatellite instability. We designed this study to estimate the occurrence of these mutations in EGFR(CA)n and their relevance in carcinogenesis of microsatellite instability – positive colon and gastric tumors.
Experimental Design
We analyzed the frequency of EGFR(CA)n mutations in vivo in 55 colorectal and 14 gastric microsatellite instability – positive cancers, and in vitro in single-cell clone cultures of microsatellite instability – positive colon tumor cell line LS174. Single-cell clone cultures with different repeat lengths were analyzed by fluorescent-activated cell sorter for EGFR cell-surface expression. A correlation analysis was done between EGFR(CA)n mutations and mutations in KRAS, BRAF, and p53.
Results
Unlike single-cell clone cultures, which exhibited higher rate of deletions compared with insertions, most of EGFR(CA)n mutations in colon and gastric tumors were insertions. Longer EGFR(CA)n correlated with lower EGFR cell-surface expression in single-cell clone cultures. In colon cancers, the elongation of the repeat was associated negatively with mutations in KRAS and BRAF, but not in p53.
Conclusions
The EGFR(CA)n elongation observedin tumors cannot be explained by anintrinsic property of this repeat favoring insertions versus deletions. Instead, a selection for repeat elongation occurs in microsatellite instability – positive tumors, leading to EGFR down-regulation. These findings suggest that in microsatellite instability – positive tumors current therapies targeting EGFR overexpression may have either no effect or an opposite to the expected effect.
doi:10.1158/1078-0432.CCR-08-1282
PMCID: PMC2885604  PMID: 19584170
14.  A Dominant Mutation in mediator of paramutation2, One of Three Second-Largest Subunits of a Plant-Specific RNA Polymerase, Disrupts Multiple siRNA Silencing Processes 
PLoS Genetics  2009;5(11):e1000725.
Paramutation involves homologous sequence communication that leads to meiotically heritable transcriptional silencing. We demonstrate that mop2 (mediator of paramutation2), which alters paramutation at multiple loci, encodes a gene similar to Arabidopsis NRPD2/E2, the second-largest subunit of plant-specific RNA polymerases IV and V. In Arabidopsis, Pol-IV and Pol-V play major roles in RNA–mediated silencing and a single second-largest subunit is shared between Pol-IV and Pol-V. Maize encodes three second-largest subunit genes: all three genes potentially encode full length proteins with highly conserved polymerase domains, and each are expressed in multiple overlapping tissues. The isolation of a recessive paramutation mutation in mop2 from a forward genetic screen suggests limited or no functional redundancy of these three genes. Potential alternative Pol-IV/Pol-V–like complexes could provide maize with a greater diversification of RNA–mediated transcriptional silencing machinery relative to Arabidopsis. Mop2-1 disrupts paramutation at multiple loci when heterozygous, whereas previously silenced alleles are only up-regulated when Mop2-1 is homozygous. The dramatic reduction in b1 tandem repeat siRNAs, but no disruption of silencing in Mop2-1 heterozygotes, suggests the major role for tandem repeat siRNAs is not to maintain silencing. Instead, we hypothesize the tandem repeat siRNAs mediate the establishment of the heritable silent state—a process fully disrupted in Mop2-1 heterozygotes. The dominant Mop2-1 mutation, which has a single nucleotide change in a domain highly conserved among all polymerases (E. coli to eukaryotes), disrupts both siRNA biogenesis (Pol-IV–like) and potentially processes downstream (Pol-V–like). These results suggest either the wild-type protein is a subunit in both complexes or the dominant mutant protein disrupts both complexes. Dominant mutations in the same domain in E. coli RNA polymerase suggest a model for Mop2-1 dominance: complexes containing Mop2-1 subunits are non-functional and compete with wild-type complexes.
Author Summary
How an individual's genes are activated or silenced is an essential question impacting all fields of biology. Usually gene expression patterns, i.e., which genes are on and which are off in different tissues and during development, are highly reproducible; and those patterns are efficiently reset in the next generation of progeny. Paramutation represents an exception to these genetic rules, in that for certain genes the silencing that is established in an individual is efficiently transmitted to their progeny. Importantly, in these subsequent generations, the silenced gene continues to silence active versions of that gene. Prior work has demonstrated that these heritable gene expression changes are not accompanied by changes in DNA sequence: they are epigenetic. Understanding mechanisms for heritable changes in gene expression has major implications for researchers studying complex traits, including diseases. In this manuscript we demonstrate that a subunit of a RNA polymerase is required for paramutation in maize and other gene silencing processes that also involve RNA–mediated chromatin changes. We show that the multiple, closely related, plant-specific RNA polymerases mediating gene silencing have diverged functions in maize. Results from our experiments suggest testable models for the role of these polymerases in multiple gene-silencing processes.
doi:10.1371/journal.pgen.1000725
PMCID: PMC2774164  PMID: 19936058
15.  Relation between Genetic Markers of Drug Resistance and Susceptibility Profile of Clinical Neisseria gonorrhoeae Strains▿  
The main goal of this work is to clarify the predictive value of known genetic markers of Neisseria gonorrhoeae resistance to penicillin, tetracycline, and fluoroquinolones. The correlation between the presence of certain genetic markers and susceptibility of N. gonorrhoeae isolates to penicillin, tetracycline, and fluoroquinolones has been analyzed by means of statistical methods. Susceptibility testing with penicillin, tetracycline, and fluoroquinolones was performed by the agar dilution method. N. gonorrhoeae genomic DNA was isolated. The presence of blaTEM-1 and tet(M) genes was analyzed by PCR. A novel method of polymorphism discovery based on a minisequencing reaction followed by matrix-assisted laser desorption ionization-time-of-flight mass spectrometry was applied for the analysis of chromosomal N. gonorrhoeae genes involved in antimicrobial resistance development. Clinical N. gonorrhoeae isolates (n = 464) were collected. Susceptibility levels to penicillin, tetracycline, and fluoroquinolones were found to be 25.9%, 35.9%, and 54.1%, respectively. Among the 19 N. gonorrhoeae isolates with penicillin MICs of ≥4 μg/ml, the blaTEM-1 gene was detected in 12. The Tet(M) determinant was found in 4 of 12 N. gonorrhoeae isolates with tetracycline MICs of ≥16 μg/ml. The chromosomal genetic markers of penicillin and tetracycline resistance were detected especially in isolates with penicillin MICs of 0.25 to 2.0 μg/ml and tetracycline MICs of 0.5 to 4 μg/ml. Mutations in GyrA and ParC were found in 208 of 211 quinolone-resistant N. gonorrhoeae isolates. This work is the first representative molecular research of the N. gonorrhoeae population in Russia. Information about the prevalence of antibiotic resistance mechanisms and the positive predictive value of certain genetic determinants is given. The positive predictive values of the analyzed genetic markers were found to be different for fluoroquinolones (90.3%), penicillin (91.1%), and tetracycline (81.9%).
doi:10.1128/AAC.01420-07
PMCID: PMC2415756  PMID: 18378705
16.  Mechanisms of Macrolide Resistance among Streptococcus pneumoniae Isolates from Russia▿  
Among 76 macrolide-nonsusceptible Streptococcus pneumoniae isolates collected between 2003 and 2005 from Central Russia, the resistance mechanisms detected in the isolates included erm(B) alone (50%), mef alone [mef(E), mef(I), or a different mef subclass; 19.7%], or both erm(B) and mef(E) (30.3%). Isolates with dual resistance genes [erm(B) and mef(E)] belonged to clonal complex CC81 or CC271.
doi:10.1128/AAC.01270-07
PMCID: PMC2415785  PMID: 18378707
17.  Hexacarbonyl­technetium(I) perchlorate 
The title compound, [Tc(CO)6]ClO4, was synthesized by the reaction of [TcCl(CO)5] with AgClO4, followed by acidification with HClO4 under a CO atmosphere. The [Tc(CO)6]+ cation has close to idealized octa­hedral geometry, with the bond angles between cis-CO groups close to 90° and the Tc—C bond lengths in the range 2.025 (3)–2.029 (3)Å. The perchlorate anion is disordered over two crystallographically equivalent half-occupied positions. The Tc atom in the [Tc(CO)6]+ cation is located on an inversion centre.
doi:10.1107/S1600536808025208
PMCID: PMC2960579  PMID: 21201600
18.  Are screening and surveillance for Barrett's oesophagus really worthwhile? 
Gut  2005;54(Suppl 1):i27-i32.
doi:10.1136/gut.2004.041566
PMCID: PMC1867790  PMID: 15711005
19.  Measuring and decomposing inequity in self-reported morbidity and self-assessed health in Thailand 
Background
In recent years, interest in the study of inequalities in health has not stopped at quantifying their magnitude; explaining the sources of inequalities has also become of great importance. This paper measures socioeconomic inequalities in self-reported morbidity and self-assessed health in Thailand, and the contributions of different population subgroups to those inequalities.
Methods
The Health and Welfare Survey 2003 conducted by the Thai National Statistical Office with 37,202 adult respondents is used for the analysis. The health outcomes of interest derive from three self-reported morbidity and two self-assessed health questions. Socioeconomic status is measured by adult-equivalent monthly income per household member. The concentration index (CI) of ill health is used as a measure of socioeconomic health inequalities, and is subsequently decomposed into contributing factors.
Results
The CIs reveal inequality gradients disadvantageous to the poor for both self-reported morbidity and self-assessed health in Thailand. The magnitudes of these inequalities were higher for the self-assessed health outcomes than for the self-reported morbidity outcomes. Age and sex played significant roles in accounting for the inequality in reported chronic illness (33.7 percent of the total inequality observed), hospital admission (27.8 percent), and self-assessed deterioration of health compared to a year ago (31.9 percent). The effect of being female and aged 60 years or older was by far the strongest demographic determinant of inequality across all five types of health outcome. Having a low socioeconomic status as measured by income quintile, education and work status were the main contributors disadvantaging the poor in self-rated health compared to a year ago (47.1 percent) and self-assessed health compared to peers (47.4 percent). Residence in the rural Northeast and rural North were the main regional contributors to inequality in self-reported recent and chronic illness, while residence in the rural Northeast was the major contributor to the tendency of the poor to report lower levels of self-assessed health compared to peers.
Conclusion
The findings confirm that substantial socioeconomic inequalities in health as measured by self-reported morbidity and self-assessed health exist in Thailand. Decomposition analysis shows that inequalities in health status are associated with particular demographic, socioeconomic and geographic population subgroups. Vulnerable subgroups which are prone to both ill health and relative poverty warrant targeted policy attention.
doi:10.1186/1475-9276-6-23
PMCID: PMC2242789  PMID: 18088434
20.  Spread of a Salmonella typhimurium Clone Resistant to Expanded-Spectrum Cephalosporins in Three European Countries 
Journal of Clinical Microbiology  1999;37(11):3774-3777.
Twelve Salmonella typhimurium strains resistant to broad-spectrum cephalosporins were isolated from cases of gastroenteritis during 1996 to 1998 in Russia, Hungary, and Greece. Resistance was due to the production of CTX-M-type extended-spectrum β-lactamases encoded by similar 12-kb plasmids. By pulsed-field gel electrophoresis, all strains shared the same chromosomal type. These data suggest that an S. typhimurium clone resistant to broad-spectrum cephalosporins is present in at least three European countries.
PMCID: PMC85760  PMID: 10523600
21.  Sequence of the Gene Encoding a Plasmid-Mediated Cefotaxime-Hydrolyzing Class A β-Lactamase (CTX-M-4): Involvement of Serine 237 in Cephalosporin Hydrolysis 
The sequence of the gene encoding a novel cefotaxime-hydrolyzing β-lactamase (CTX-M-4) was determined. It was located in a plasmid harbored by a Salmonella typhimurium strain. CTX-M-4 was similar to the plasmidic cefotaxime-hydrolyzing β-lactamases CTX-M-2 and Toho-1 and related to the chromosomal β-lactamase of Klebsiella oxytoca. A Ser-237→Ala substitution, introduced by site-directed mutagenesis, caused minor alterations in the interaction of CTX-M-4 with β-lactams, reducing slightly the relative hydrolytic activity against cefotaxime and the susceptibility to inhibition by clavulanate.
PMCID: PMC105797  PMID: 9593162
22.  Phospholipase C-gamma1 interacts with conserved phosphotyrosyl residues in the linker region of Syk and is a substrate for Syk. 
Molecular and Cellular Biology  1996;16(4):1305-1315.
Antigen receptor ligation on lymphocytes activates protein tyrosine kinases and phospholipase C-gamma (PLC-gamma) isoforms. Glutathione S-transferase fusion proteins containing the C-terminal Src-homology 2 [SH2(C)] domain of PLC-gamma1 bound to tyrosyl phosphorylated Syk. Syk isolated from antigen receptor-activated B cells phosphorylated PLC-gamma1 on Tyr-771 and the key regulatory residue Tyr-783 in vitro, whereas Lyn from the same B cells phosphorylated PLC-gamma1 only on Tyr-771. The ability of Syk to phosphorylate PLC-gamma1 required antigen receptor ligation, while Lyn was constitutively active. An mCD8-Syk cDNA construct could be expressed as a tyrosyl-phosphorylated chimeric protein tyrosine kinase in COS cells, was recognized by PLC-gamma1 SH2(C) in vitro, and induced tyrosyl phosphorylation of endogenous PLC-gamma1 in vivo. Substitution of Tyr-525 and Tyr-526 at the autophosphorylation site of Syk in mCD8-Syk substantially reduced the kinase activity and the binding of this variant chimera to PLC-gamma1 SH2(C) in vitro; it also failed to induce tyrosyl phosphorylation of PLC-gamma1 in vivo. In contrast, substitution of Tyr-348 and Tyr-352 in the linker region of Syk in mCD8-Syk did not affect the kinase activity of this variant chimera but almost completely eliminated its binding to PLC-gamma1 SH(C) and completely eliminated its ability to induce tyrosyl phosphorylation of PLC-gamma1 in vivo. Thus, an optimal kinase activity of Syk and an interaction between the linker region of Syk with PLC-gamma1 are required for the tyrosyl phosphorylation of PLC-gamma1.
PMCID: PMC231114  PMID: 8657103
23.  Predicting toxicometric parameters on the basis of studying the concentration--time dependence. 
A short-time exposure on the concentration--time relationship base, a classification of substances according to the degree of hazard and the program for assessing safety coefficients have been suggested in order to predict the basic toxicometric parameters (chronic exposure thresholds, maximum allowable concentrations, safety coefficients, and others).
PMCID: PMC1637707  PMID: 446451
24.  Scientific basis for the study of demineralization of highly mineralized water for use in public water supply systems. 
New criteria (full physiological value and preservation of the properties of drinking water) are scientifically substantiated. Also discussed are indices (minimal admissible and optimal levels of basic water mineralization and calcium content, standards of microelements such as boron and bromine content, content of individual groups of microorganisms, water temperature) for evaluating the quality of demineralized water obtained from brackish and briny water (including water from the sea and ocean) by various methods which are designed for public water supply systems. Research results served as the scientific hygiene basis for the development of a new technology of obtaining drinking water. The necessity for developing a special quality standard for demineralized drinking water is shown.
PMCID: PMC1637700  PMID: 446445
25.  Study of the combined action of a group of chlorine derivatives of hydrocarbons entering the organism by inhalation. 
The combined action of substances having a munidirectional toxic effect on the organism was studied for several typical chlorine derivatives of hydrocarbons (1,2-dichloropropane, 1,2,3,-trichloropropane, and perchloroethylene). Since a correct assessment of the combined action of substances is based on the comparison of the effect of mixed compounds and the effects observed for each component alone, research was conducted on each individual substances on the basis of the "concentration--time" relationship. The reaction of several mixtures of substances was also studied at various concentration levels, from high to low concentration levels of substances which are actually present in the atmosphere. Research result showed that the character of the mixture at both high and low levels of concentration was identical and approximate to the overall effects.
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PMCID: PMC1637697  PMID: 446444

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