Correction of xeroderma pigmentosum repair defect by basal transcription factor BTF2 (TFIIH).

PubMed Central

van Vuuren, A J; Vermeulen, W; Ma, L; Weeda, G; Appeldoorn, E; Jaspers, N G; van der Eb, A J; Bootsma, D; Hoeijmakers, J H; Humbert, S

1994-01-01

ERCC3 was initially identified as a gene correcting the nucleotide excision repair (NER) defect of xeroderma pigmentosum complementation group B (XP-B). The recent finding that its gene product is identical to the p89 subunit of basal transcription factor BTF2(TFIIH), opened the possibility that it is not directly involved in NER but that it regulates the transcription of one or more NER genes. Using an in vivo microinjection repair assay and an in vitro NER system based on cell-free extracts we demonstrate that ERCC3 in BTF2 is directly implicated in excision repair. Antibody depletion experiments support the idea that the p62 BTF2 subunit and perhaps the entire transcription factor function in NER. Microinjection experiments suggest that exogenous ERCC3 can exchange with ERCC3 subunits in the complex. Expression of a dominant negative K436-->R ERCC3 mutant, expected to have lost all helicase activity, completely abrogates NER and transcription and concomitantly induces a dramatic chromatin collapse. These findings establish the role of ERCC3 and probably the entire BTF2 complex in transcription in vivo which was hitherto only demonstrated in vitro. The results strongly suggest that transcription itself is a critical component for maintenance of chromatin structure. The remarkable dual role of ERCC3 in NER and transcription provides a clue in understanding the complex clinical features of some inherited repair syndromes. Images PMID:8157004

DOE Office of Scientific and Technical Information (OSTI.GOV)

Shahrukh, Hassan; Oyedun, Adetoyese Olajire; Kumar, Amit

Here, a process model was developed to determine the net energy ratio (NER) for production of pellets from steam pretreated agricultural residue (AR) and energy crop (i.e. switchgrass in this case). The NER is a ratio of the net energy output to the total net energy input from non-renewable energy sources into a system. Scenarios were developed to measure the effects of temperature and level of steam pretreatment on the NER of steam pretreated AR- and switch grass-based pellets. The NER for the base case at 6 kg h -1 is 1.76 and 1.37 for steam-pretreated AR- and switchgrass-based pellets,more » respectively. The reason behind the difference is that more energy is required to dry switchgrass pellets than AR pellets. The sensitivity analysis for the model shows that the optimum temperature for steam pretreatment is 160 C with 50% pretreatment (half the feedstock is pretreated, while the rest is undergoes regular pelletization). The uncertainty results for NER for steam pretreated AR and switch grass pellets are 1.62 ± 0.10 and 1.42 ± 0.11, respectively.« less

CheNER: a tool for the identification of chemical entities and their classes in biomedical literature.

PubMed

Usié, Anabel; Cruz, Joaquim; Comas, Jorge; Solsona, Francesc; Alves, Rui

2015-01-01

Small chemical molecules regulate biological processes at the molecular level. Those molecules are often involved in causing or treating pathological states. Automatically identifying such molecules in biomedical text is difficult due to both, the diverse morphology of chemical names and the alternative types of nomenclature that are simultaneously used to describe them. To address these issues, the last BioCreAtIvE challenge proposed a CHEMDNER task, which is a Named Entity Recognition (NER) challenge that aims at labelling different types of chemical names in biomedical text. To address this challenge we tested various approaches to recognizing chemical entities in biomedical documents. These approaches range from linear Conditional Random Fields (CRFs) to a combination of CRFs with regular expression and dictionary matching, followed by a post-processing step to tag those chemical names in a corpus of Medline abstracts. We named our best performing systems CheNER. We evaluate the performance of the various approaches using the F-score statistics. Higher F-scores indicate better performance. The highest F-score we obtain in identifying unique chemical entities is 72.88%. The highest F-score we obtain in identifying all chemical entities is 73.07%. We also evaluate the F-Score of combining our system with ChemSpot, and find an increase from 72.88% to 73.83%. CheNER presents a valid alternative for automated annotation of chemical entities in biomedical documents. In addition, CheNER may be used to derive new features to train newer methods for tagging chemical entities. CheNER can be downloaded from http://metres.udl.cat and included in text annotation pipelines.

Contribution of microorganisms to non-extractable residue formation from biodegradable organic contaminants in soil

NASA Astrophysics Data System (ADS)

Nowak, K. M.; Girardi, C.; Miltner, A.; Schäffer, A.; Kästner, M.

2012-04-01

Biodegradation of organic contaminants in soil is actually understood as their transformation into various primary metabolites, microbial biomass, mineralisation products and non-extractable residues (NER). NER are generally considered to be composed of parent compounds or primary metabolites with hazardous potential. Up to date, however, their chemical composition remains still unclear. Studies on NER formation are limited to quantitative analyses in soils or to simple humic acids-contaminant systems. However, in the case of biodegradable organic compounds, NER may also contain microbial biomass components, e.g. fatty acids (FA) and amino acids (AA). After cell death, these biomolecules are incorporated into soil organic matter (SOM) and stabilised, ultimately forming biogenic residues which are not any more extractable. We investigated the incorporation of the 13C-label into FA and AA and their fate during biodegradation experiments in soil with isotope-labelled 2,4-dichlorophenoxyacetic acid (13C6-2,4-D) and ibuprofen (13C6-ibu) as model organic contaminants. Our study proved for the first time that nearly all NER formed from 13C6-2,4-D and 13C6-ibu in soil derived from harmless microbial biomass components stabilised in SOM. 13C-FA and 13C-AA contents in the living microbial biomass fraction decreased over time and these components were continuously incorporated into the non-living SOM pool in biotic experiments with 13C6-2,4-D and 13C6-ibu. The 13C-AA in the non-living SOM were surprisingly stable from day 32 (13C6-2,4-D) and 58 (13C6-ibu) until the end of incubation. We also studied the transformation of 13C6-2,4-D and 13C6-ibu into NER in the abiotic soil experiments. In these experiments, the total NER contents were much lower than in the corresponding biotic experiments. The absence of labelled biomolecules in the NER fraction in abiotic soils demonstrated that they consist of the potentially hazardous parent compounds and / or their metabolites. Biogenic residue formation is relevant during biodegradation of organic contaminants, whereas abiotic NER are formed from the non-biodegraded residual contaminants. Abiotic NER and biogenic residue formation are competitive processes and do not occur in a similar extent. In the biotic treatment, the rapid mineralisation of an organic compound reduces the extent of abiotic NER formation via physico-chemical interactions between a parent compound and / or its primary metabolites with SOM. Therefore, in order to properly assess the potential risks of a target contaminant in soil to humans and the environment, it is necessary to distinguish between abiotic NER and biogenic residue formation in the mass balances of contaminants.

Comparative net energy ratio analysis of pellet produced from steam pretreated biomass from agricultural residues and energy crops

DOE PAGES

Shahrukh, Hassan; Oyedun, Adetoyese Olajire; Kumar, Amit; ...

2016-04-05

Here, a process model was developed to determine the net energy ratio (NER) for production of pellets from steam pretreated agricultural residue (AR) and energy crop (i.e. switchgrass in this case). The NER is a ratio of the net energy output to the total net energy input from non-renewable energy sources into a system. Scenarios were developed to measure the effects of temperature and level of steam pretreatment on the NER of steam pretreated AR- and switch grass-based pellets. The NER for the base case at 6 kg h -1 is 1.76 and 1.37 for steam-pretreated AR- and switchgrass-based pellets,more » respectively. The reason behind the difference is that more energy is required to dry switchgrass pellets than AR pellets. The sensitivity analysis for the model shows that the optimum temperature for steam pretreatment is 160 C with 50% pretreatment (half the feedstock is pretreated, while the rest is undergoes regular pelletization). The uncertainty results for NER for steam pretreated AR and switch grass pellets are 1.62 ± 0.10 and 1.42 ± 0.11, respectively.« less

Pesticide nonextractable residue formation in soil: insights from inverse modeling of degradation time series.

PubMed

Loos, Martin; Krauss, Martin; Fenner, Kathrin

2012-09-18

Formation of soil nonextractable residues (NER) is central to the fate and persistence of pesticides. To investigate pools and extent of NER formation, an established inverse modeling approach for pesticide soil degradation time series was evaluated with a Monte Carlo Markov Chain (MCMC) sampling procedure. It was found that only half of 73 pesticide degradation time series from a homogeneous soil source allowed for well-behaved identification of kinetic parameters with a four-pool model containing a parent compound, a metabolite, a volatile, and a NER pool. A subsequent simulation indeed confirmed distinct parameter combinations of low identifiability. Taking the resulting uncertainties into account, several conclusions regarding NER formation and its impact on persistence assessment could nonetheless be drawn. First, rate constants for transformation of parent compounds to metabolites were correlated to those for transformation of parent compounds to NER, leading to degradation half-lives (DegT50) typically not being larger than disappearance half-lives (DT50) by more than a factor of 2. Second, estimated rate constants were used to evaluate NER formation over time. This showed that NER formation, particularly through the metabolite pool, may be grossly underestimated when using standard incubation periods. It further showed that amounts and uncertainties in (i) total NER, (ii) NER formed from the parent pool, and (iii) NER formed from the metabolite pool vary considerably among data sets at t→∞, with no clear dominance between (ii) and (iii). However, compounds containing aromatic amine moieties were found to form significantly more total NER when extrapolating to t→∞ than the other compounds studied. Overall, our study stresses the general need for assessing uncertainties, identifiability issues, and resulting biases when using inverse modeling of degradation time series for evaluating persistence and NER formation.

Distinct pathways for repairing mutagenic lesions induced by methylating and ethylating agents

PubMed Central

Negishi, Tomoe

2013-01-01

DNA alkylation damage can be repaired by nucleotide excision repair (NER), base excision repair (BER) or by direct removal of alkyl groups from modified bases by O 6-alkylguanine DNA alkyltransferase (AGT; E.C. 2.1.1.63). DNA mismatch repair (MMR) is also likely involved in this repair. We have investigated alkylation-induced mutagenesis in a series of NER- or AGT-deficient Escherichia coli strains, alone or in combination with defects in the MutS, MutL or MutH components of MMR. All strains used contained the Fʹprolac from strain CC102 (FʹCC102) episome capable of detecting specifically lac GC to AT reverse mutations resulting from O 6-alkylguanine. The results showed the repair of O 6-methylguanine to be performed by AGT ≫ MMR > NER in order of importance, whereas the repair of O 6-ethylguanine followed the order NER > AGT > MMR. Studies with double mutants showed that in the absence of AGT or NER repair pathways, the lack of MutS protein generally increased mutant frequencies for both methylating and ethylating agents, suggesting a repair or mutation avoidance role for this protein. However, lack of MutL or MutH protein did not increase alkylation-induced mutagenesis under these conditions and, in fact, reduced mutagenesis by the N-alkyl-N-nitrosoureas MNU and ENU. The combined results suggest that little or no alkylation damage is actually corrected by the mutHLS MMR system; instead, an as yet unspecified interaction of MutS protein with alkylated DNA may promote the involvement of a repair system other than MMR to avoid a mutagenic outcome. Furthermore, both mutagenic and antimutagenic effects of MMR were detected, revealing a dual function of the MMR system in alkylation-exposed cells. PMID:23446177

Nucleotide Excision Repair and Transcription-coupled DNA Repair Abrogate the Impact of DNA Damage on Transcription.

PubMed

Nadkarni, Aditi; Burns, John A; Gandolfi, Alberto; Chowdhury, Moinuddin A; Cartularo, Laura; Berens, Christian; Geacintov, Nicholas E; Scicchitano, David A

2016-01-08

DNA adducts derived from carcinogenic polycyclic aromatic hydrocarbons like benzo[a]pyrene (B[a]P) and benzo[c]phenanthrene (B[c]Ph) impede replication and transcription, resulting in aberrant cell division and gene expression. Global nucleotide excision repair (NER) and transcription-coupled DNA repair (TCR) are among the DNA repair pathways that evolved to maintain genome integrity by removing DNA damage. The interplay between global NER and TCR in repairing the polycyclic aromatic hydrocarbon-derived DNA adducts (+)-trans-anti-B[a]P-N(6)-dA, which is subject to NER and blocks transcription in vitro, and (+)-trans-anti-B[c]Ph-N(6)-dA, which is a poor substrate for NER but also blocks transcription in vitro, was tested. The results show that both adducts inhibit transcription in human cells that lack both NER and TCR. The (+)-trans-anti-B[a]P-N(6)-dA lesion exhibited no detectable effect on transcription in cells proficient in NER but lacking TCR, indicating that NER can remove the lesion in the absence of TCR, which is consistent with in vitro data. In primary human cells lacking NER, (+)-trans-anti-B[a]P-N(6)-dA exhibited a deleterious effect on transcription that was less severe than in cells lacking both pathways, suggesting that TCR can repair the adduct but not as effectively as global NER. In contrast, (+)-trans-anti-B[c]Ph-N(6)-dA dramatically reduces transcript production in cells proficient in global NER but lacking TCR, indicating that TCR is necessary for the removal of this adduct, which is consistent with in vitro data showing that it is a poor substrate for NER. Hence, both global NER and TCR enhance the recovery of gene expression following DNA damage, and TCR plays an important role in removing DNA damage that is refractory to NER. © 2016 by The American Society for Biochemistry and Molecular Biology, Inc.

Nucleotide Excision Repair and Transcription-coupled DNA Repair Abrogate the Impact of DNA Damage on Transcription*

PubMed Central

Nadkarni, Aditi; Burns, John A.; Gandolfi, Alberto; Chowdhury, Moinuddin A.; Cartularo, Laura; Berens, Christian; Geacintov, Nicholas E.; Scicchitano, David A.

2016-01-01

DNA adducts derived from carcinogenic polycyclic aromatic hydrocarbons like benzo[a]pyrene (B[a]P) and benzo[c]phenanthrene (B[c]Ph) impede replication and transcription, resulting in aberrant cell division and gene expression. Global nucleotide excision repair (NER) and transcription-coupled DNA repair (TCR) are among the DNA repair pathways that evolved to maintain genome integrity by removing DNA damage. The interplay between global NER and TCR in repairing the polycyclic aromatic hydrocarbon-derived DNA adducts (+)-trans-anti-B[a]P-N6-dA, which is subject to NER and blocks transcription in vitro, and (+)-trans-anti-B[c]Ph-N6-dA, which is a poor substrate for NER but also blocks transcription in vitro, was tested. The results show that both adducts inhibit transcription in human cells that lack both NER and TCR. The (+)-trans-anti-B[a]P-N6-dA lesion exhibited no detectable effect on transcription in cells proficient in NER but lacking TCR, indicating that NER can remove the lesion in the absence of TCR, which is consistent with in vitro data. In primary human cells lacking NER, (+)-trans-anti-B[a]P-N6-dA exhibited a deleterious effect on transcription that was less severe than in cells lacking both pathways, suggesting that TCR can repair the adduct but not as effectively as global NER. In contrast, (+)-trans-anti-B[c]Ph-N6-dA dramatically reduces transcript production in cells proficient in global NER but lacking TCR, indicating that TCR is necessary for the removal of this adduct, which is consistent with in vitro data showing that it is a poor substrate for NER. Hence, both global NER and TCR enhance the recovery of gene expression following DNA damage, and TCR plays an important role in removing DNA damage that is refractory to NER. PMID:26559971

Coupling between nucleotide excision repair and gene expression.

PubMed

Cambindo Botto, Adrián E; Muñoz, Juan C; Muñoz, Manuel J

2018-05-17

Gene expression and DNA repair are fundamental processes for life. During the last decade, accumulating experimental evidence point towards different modes of coupling between these processes. Here we discuss the molecular mechanisms by which RNAPII-dependent transcription affects repair by the Nucleotide Excision Repair system (NER) and how NER activity, through the generation of single stranded DNA intermediates and activation of the DNA damage response kinase ATR, drives gene expression in a genotoxic scenario. Since NER-dependent repair is compromised in Xeroderma Pigmentosum (XP) patients, and having in mind that these patients present a high degree of clinical heterogeneity, we speculate that some of the clinical features of XP patients can be explained by misregulation of gene expression.

Interplay of DNA repair with transcription: from structures to mechanisms.

PubMed

Deaconescu, Alexandra M; Artsimovitch, Irina; Grigorieff, Nikolaus

2012-12-01

Many DNA transactions are crucial for maintaining genomic integrity and faithful transfer of genetic information but remain poorly understood. An example is the interplay between nucleotide excision repair (NER) and transcription, also known as transcription-coupled DNA repair (TCR). Discovered decades ago, the mechanisms for TCR have remained elusive, not in small part due to the scarcity of structural studies of key players. Here we summarize recent structural information on NER/TCR factors, focusing on bacterial systems, and integrate it with existing genetic, biochemical, and biophysical data to delineate the mechanisms at play. We also review emerging, alternative modalities for recruitment of NER proteins to DNA lesions. Copyright © 2012 Elsevier Ltd. All rights reserved.

Oxidative Damage to RPA Limits the Nucleotide Excision Repair Capacity of Human Cells.

PubMed

Guven, Melisa; Brem, Reto; Macpherson, Peter; Peacock, Matthew; Karran, Peter

2015-11-01

Nucleotide excision repair (NER) protects against sunlight-induced skin cancer. Defective NER is associated with photosensitivity and a high skin cancer incidence. Some clinical treatments that cause photosensitivity can also increase skin cancer risk. Among these, the immunosuppressant azathioprine and the fluoroquinolone antibiotics ciprofloxacin and ofloxacin interact with UVA radiation to generate reactive oxygen species that diminish NER capacity by causing protein damage. The replication protein A (RPA) DNA-binding protein has a pivotal role in DNA metabolism and is an essential component of NER. The relationship between protein oxidation and NER inhibition was investigated in cultured human cells expressing different levels of RPA. We show here that RPA is limiting for NER and that oxidative damage to RPA compromises NER capability. Our findings reveal that cellular RPA is surprisingly vulnerable to oxidation, and we identify oxidized forms of RPA that are associated with impaired NER. The vulnerability of NER to inhibition by oxidation provides a connection between cutaneous photosensitivity, protein damage, and increased skin cancer risk. Our findings emphasize that damage to DNA repair proteins, as well as to DNA itself, is likely to be an important contributor to skin cancer risk.

Implication of SUMO E3 ligases in nucleotide excision repair.

PubMed

Tsuge, Maasa; Kaneoka, Hidenori; Masuda, Yusuke; Ito, Hiroki; Miyake, Katsuhide; Iijima, Shinji

2015-08-01

Post-translational modifications alter protein function to mediate complex hierarchical regulatory processes that are crucial to eukaryotic cellular function. The small ubiquitin-like modifier (SUMO) is an important post-translational modification that affects transcriptional regulation, nuclear localization, and the maintenance of genome stability. Nucleotide excision repair (NER) is a very versatile DNA repair system that is essential for protection against ultraviolet (UV) irradiation. The deficiencies in NER function remarkably increase the risk of skin cancer. Recent studies have shown that several NER factors are SUMOylated, which influences repair efficiency. However, how SUMOylation modulates NER has not yet been elucidated. In the present study, we performed RNAi knockdown of SUMO E3 ligases and found that, in addition to PIASy, the polycomb protein Pc2 affected the repair of cyclobutane pyrimidine dimers. PIAS1 affected both the removal of 6-4 pyrimidine pyrimidone photoproducts and cyclobutane pyrimidine dimers, whereas other SUMO E3 ligases did not affect the removal of either UV lesion.

Inoculation of soil with an Isoproturon degrading microbial community reduced the pool of "real non-extractable" Isoproturon residues.

PubMed

Zhu, Xiaomin; Schroll, Reiner; Dörfler, Ulrike; Chen, Baoliang

2018-03-01

During pesticides degradation, biogenic non-extractable residues ("apparent NER") may not share the same environmental fate and risks with the "real NER" that are bound to soil matrix. It is not clear how microbial community (MC) inoculation for pesticides degradation would influence the NER composition. To investigate degradation efficiency of pesticides Isoproturon (IPU) and NER composition following MC inoculation, clay particles harboring MC that contains the IPU degrading strain, Sphingomonas sp., were inoculated into soil receiving 14 C-labeled IPU addition. Mineralization of IPU was greatly enhanced with MC inoculation that averagely 55.9% of the applied 14 C-IPU was consumed up into 14 CO 2 during 46 days soil incubation. Isoproturon degradation was more thorough with MC than that in the control: much less amount of metabolic products (4.6% of applied IPU) and NER (35.4%) formed in MC treatment, while the percentages were respectively 30.3% for metabolites and 49.8% for NER in the control. Composition of NER shifted with MC inoculation, that relatively larger amount of IPU was incorporated into the biogenic "apparent NER" in comparison with "real NER". Besides its well-recognized role on enhancing mineralization, MC inoculation with clay particles benefits soil pesticides remediation in term of reducing "real NER" formation, which has been previously underestimated. Copyright © 2017 Elsevier Inc. All rights reserved.

Nucleotide excision repair deficient mouse models and neurological disease

PubMed Central

Niedernhofer, Laura J.

2008-01-01

Nucleotide excision repair (NER) is a highly conserved mechanism to remove helix-distorting DNA base damage. A major substrate for NER is DNA damage caused by environmental genotoxins, most notably ultraviolet radiation. Xeroderma pigmentosum, Cockayne syndrome and trichothiodystrophy are three human diseases caused by inherited defects in NER. The symptoms and severity of these diseases vary dramatically, ranging from profound developmental delay to cancer predisposition and accelerated aging. All three syndromes include neurological disease, indicating an important role for NER in protecting against spontaneous DNA damage as well. To study the pathophysiology caused by DNA damage, numerous mouse models of NER deficiency were generated by knocking-out genes required for NER or knocking-in disease-causing human mutations. This review explores the utility of these mouse models to study neurological disease caused by NER deficiency. PMID:18272436

Pour Savoir ou vous en etes. Evaluez vous-meme vos connaissances (Knowing Where You Are. Evaluate Your Knowledge by Yourself).

ERIC Educational Resources Information Center

Aiello, Angelo; And Others

1986-01-01

A form is presented for language teacher self-evaluation concerning attitudes and knowledge about learning theories, general linguistics, sociolinguistics, pragmatics, discourse analysis, teaching methodology, the communicative approach, class activities, class management, instructional support, and evaluation. (MSE)

The endoperoxide ascaridol shows strong differential cytotoxicity in nucleotide excision repair-deficient cells

DOE Office of Scientific and Technical Information (OSTI.GOV)

Abbasi, Rashda; Efferth, Thomas; Kuhmann, Christine

2012-03-15

Targeting synthetic lethality in DNA repair pathways has become a promising anti-cancer strategy. However little is known about such interactions with regard to the nucleotide excision repair (NER) pathway. Therefore, cell lines with a defect in the NER genes ERCC6 or XPC and their normal counterparts were screened with 53 chemically defined phytochemicals isolated from plants used in traditional Chinese medicine for differential cytotoxic effects. The screening revealed 12 drugs that killed NER-deficient cells more efficiently than proficient cells. Five drugs were further analyzed for IC{sub 50} values, effects on cell cycle distribution, and induction of DNA damage. Ascaridol wasmore » the most effective compound with a difference of > 1000-fold in resistance between normal and NER-deficient cells (IC{sub 50} values for cells with deficiency in ERCC6: 0.15 μM, XPC: 0.18 μM, and normal cells: > 180 μM). NER-deficiency combined with ascaridol treatment led to G2/M-phase arrest, an increased percentage of subG1 cells, and a substantially higher DNA damage induction. These results were confirmed in a second set of NER-deficient and -proficient cell lines with isogenic background. Finally, ascaridol was characterized for its ability to generate oxidative DNA damage. The drug led to a dose-dependent increase in intracellular levels of reactive oxygen species at cytotoxic concentrations, but only NER-deficient cells showed a strongly induced amount of 8-oxodG sites. In summary, ascaridol is a cytotoxic and DNA-damaging compound which generates intracellular reactive oxidative intermediates and which selectively affects NER-deficient cells. This could provide a new therapeutic option to treat cancer cells with mutations in NER genes. -- Highlights: ► Thousand-fold higher Ascaridol activity in NER-deficient versus proficient cells. ► Impaired repair of Ascaridol-induced oxidative DNA damage in NER-deficient cells. ► Selective activity of Ascaridol opens new therapy options in NER-deficient tumors.« less

Tutoiement et Vouvoiement chez les Lyceens Francais (French Pupils' Use of the Personal Pronouns "Tu" and "Vous")

ERIC Educational Resources Information Center

Bustin-Lekeu, Francine

1973-01-01

Surveys conducted among secondary school students in Toulon, France in choice of personal pronouns indicate more prevalent use of tu''. Students consider widespread use of tu'' to be more democratic and thought employment of vous'' on certain occasions is a hypocritical and bourgeois habit. (DS)

Disruption of nucleotide excision repair by the human T-cell leukemia virus type 1 Tax protein.

PubMed

Kao, S Y; Marriott, S J

1999-05-01

The Tax protein of human T-cell leukemia virus type 1 (HTLV-1) is a transcriptional transactivator and viral oncogene. Since cellular transformation has been frequently linked to alterations in genome stability, we investigated the effect of Tax on nucleotide excision repair (NER), a prominent cellular DNA repair pathway. Cells expressing Tax exhibited a reduced capacity for NER as measured by unscheduled DNA synthesis and host cell reactivation assays. The cellular proliferating cell nuclear antigen (PCNA) gene product regulates DNA replication and repair pathways, including NER. Since Tax activates transcription of the PCNA promoter, we investigated whether this activity contributes to the reduction of NER. Tax increased endogenous PCNA protein expression, and analysis of Tax mutant proteins demonstrated that the reduction in NER correlated with Tax transactivation of PCNA gene expression. Direct overexpression of PCNA also reduced NER. We propose that overexpression of PCNA, and disruption of NER induced by Tax, predisposes cells to accumulate DNA damage and contributes to HTLV-1 transformation.

Nuclear organization of nucleotide excision repair is mediated by RING1B dependent H2A-ubiquitylation

PubMed Central

Chitale, Shalaka; Richly, Holger

2017-01-01

One of the major cellular DNA repair pathways is nucleotide excision repair (NER). It is the primary pathway for repair of various DNA lesions caused by exposure to ultraviolet (UV) light, such as cyclobutane pyrimidine dimers (CPDs) and 6-4 photoproducts. Although lesion-containing DNA associates with the nuclear matrix after UV irradiation it is still not understood how nuclear organization affects NER. Analyzing unscheduled DNA synthesis (UDS) indicates that NER preferentially occurs in specific nuclear areas, viz the nucleolus. Upon inducing localized damage, we observe migration of damaged DNA towards the nucleolus. Employing a LacR-based tethering system we demonstrate that H2A-ubiquitylation via the UV-RING1B complex localizes chromatin close to the nucleolus. We further show that the H2A-ubiquitin binding protein ZRF1 resides in the nucleolus, and that it anchors ubiquitylated chromatin along with XPC. Our data thus provide insight into the sub-nuclear organization of NER and reveal a novel role for histone H2A-ubiquitylation. PMID:28416769

Functional Analysis of Nuclear Estrogen Receptors in Zebrafish Reproduction by Genome Editing Approach.

PubMed

Lu, Huijie; Cui, Yong; Jiang, Liwen; Ge, Wei

2017-07-01

Estrogens signal through both nuclear and membrane receptors with most reported effects being mediated via the nuclear estrogen receptors (nERs). Although much work has been reported on nERs in the zebrafish, there is a lack of direct genetic evidence for their functional roles and importance in reproduction. To address this issue, we undertook this study to disrupt all three nERs in the zebrafish, namely esr1 (ERα), esr2a (ERβII), and esr2b (ERβI), by the genome-editing technology clustered regularly interspaced short palindromic repeats and its associated nuclease (CRISPR/Cas9). Using this loss-of-function genetic approach, we successfully created three mutant zebrafish lines with each nER knocked out. In addition, we also generated all possible double and triple knockouts of the three nERs. The phenotypes of these mutants in reproduction were analyzed in all single, double, and triple nER knockouts in both females and males. Surprisingly, all three single nER mutant fish lines display normal reproductive development and function in both females and males, suggesting functional redundancy among these nERs. Further analysis of double and triple knockouts showed that nERs, especially Esr2a and Esr2b, were essential for female reproduction, and loss of these two nERs led to an arrest of folliculogenesis at previtellogenic stage II followed by sex reversal from female to male. In addition, the current study also revealed a unique role for Esr2a in follicle cell proliferation and transdifferentiation, follicle growth, and chorion formation. Taken together, this study provides the most comprehensive genetic analysis for differential functions of esr1, esr2a, and esr2b in fish reproduction. Copyright © 2017 Endocrine Society.

NDR1 modulates the UV-induced DNA-damage checkpoint and nucleotide excision repair

DOE Office of Scientific and Technical Information (OSTI.GOV)

Park, Jeong-Min; Choi, Ji Ye; Yi, Joo Mi

2015-06-05

Nucleotide excision repair (NER) is the sole mechanism of UV-induced DNA lesion repair in mammals. A single round of NER requires multiple components including seven core NER factors, xeroderma pigmentosum A–G (XPA–XPG), and many auxiliary effector proteins including ATR serine/threonine kinase. The XPA protein helps to verify DNA damage and thus plays a rate-limiting role in NER. Hence, the regulation of XPA is important for the entire NER kinetic. We found that NDR1, a novel XPA-interacting protein, modulates NER by modulating the UV-induced DNA-damage checkpoint. In quiescent cells, NDR1 localized mainly in the cytoplasm. After UV irradiation, NDR1 accumulated inmore » the nucleus. The siRNA knockdown of NDR1 delayed the repair of UV-induced cyclobutane pyrimidine dimers in both normal cells and cancer cells. It did not, however, alter the expression levels or the chromatin association levels of the core NER factors following UV irradiation. Instead, the NDR1-depleted cells displayed reduced activity of ATR for some set of its substrates including CHK1 and p53, suggesting that NDR1 modulates NER indirectly via the ATR pathway. - Highlights: • NDR1 is a novel XPA-interacting protein. • NDR1 accumulates in the nucleus in response to UV irradiation. • NDR1 modulates NER (nucleotide excision repair) by modulating the UV-induced DNA-damage checkpoint response.« less

Classification and modelling of non-extractable residue (NER) formation from xenobiotics in soil - a synthesis

NASA Astrophysics Data System (ADS)

Kaestner, Matthias; Nowak, Karolina; Miltner, Anja; Trapp, Stefan; Schaeffer, Andreas

2014-05-01

This presentation provides a comprehensive overview about the formation of non-extractable residues (NER) from organic pesticides and contaminants in soil and tries classifying the different types. Anthropogenic organic chemicals are deliberately (e.g. pesticides) or unintentionally (e.g. polyaromatic hydrocarbons [PAH], chlorinated solvents, pharmaceuticals) released in major amounts to nearly all compartments of the environment. Soils and sediments as complex matrices provide a wide variety of binding sites and are the major sinks for these compounds. Many of the xenobiotics entering soil undergo turnover processes and can be volatilised, leached to the groundwater, degraded by microorganisms or taken up and enriched by living organisms. Xenobiotic NER may be derived from parent compounds and primary metabolites that are sequestered (sorbed or entrapped) within the soil organic matter (type I NER) or can be covalently bound (type II NER). Especially type I NER may pose a considerably environmental risk of potential release. However, NER resulting from productive biodegradation, which means the conversion of carbon (or nitrogen) from the compounds into microbial biomass molecules during microbial degradation (type III, bioNER), do not pose any risk. Experimental and analytical approaches to clearly distinguish between the types are provided and a model to prospectively estimate their fate in soil is proposed.

"Vous" or "tu"? Native and Non-Native Speakers of French on a Sociolinguistic Tightrope

ERIC Educational Resources Information Center

Dewaele, Jean-Marc

2004-01-01

Sociolinguistic rules governing choice of pronouns of address are notoriously difficult in French, despite the fact that the number of variants is rather limited: the more formal "vous" versus the more informal "tu." Children with French as L1 learn to use pronouns of address appropriately as part of their socialization process. The learning curve…

Optimality and self-organization in river deltas

NASA Astrophysics Data System (ADS)

Tejedor, A.; Longjas, A.; Edmonds, D. A.; Zaliapin, I. V.; Georgiou, T. T.; Rinaldo, A.; Foufoula-Georgiou, E.

2017-12-01

Deltas are nourished by channel networks, whose connectivity constrains, if not drives, the evolution, functionality and resilience of these systems. Understanding the coevolution of deltaic channels and their flux organization is crucial for guiding maintenance strategies of these highly stressed systems from a range of anthropogenic activities. However, in contrast to tributary channel networks, to date, no theory has been proposed to explain how deltas self-organize to distribute water and sediment to the delta top and the shoreline. Here, we hypothesize the existence of an optimality principle underlying the self-organized partition of fluxes in delta channel networks. Specifically, we hypothesize that deltas distribute water and sediment fluxes on a given delta topology such as to maximize the diversity of flux delivery to the shoreline. By introducing the concept of nonlocal Entropy Rate (nER) and analyzing ten field deltas in diverse environments, we present evidence that supports our hypothesis, suggesting that delta networks achieve dynamically accessible maxima of their nER. Furthermore, by analyzing six simulated deltas using the Delf3D model and following their topologic and flux re-organization before and after major avulsions, we further study the evolution of nER and confirm our hypothesis. We discuss how optimal flux distributions in terms of nER, when interpreted in terms of resilience, are configurations that reflect an increased ability to withstand perturbations.

"Anything "You" Can Do, "Tu" Can Do Better": "Tu" and "Vous" as Substitutes for Indefinite "On" in French.

ERIC Educational Resources Information Center

Coveney, Aidan

2003-01-01

Presents a survey of the French indefinite "tu/vous" in in earlier periods and in a range of varieties. Draws on a corpus of French spoken in Picardy in Northern France to investigate the extent to which this use of second person pronouns helps to avoid ambiguity and co-occurs with another grammatical variable. (Author/VWL)

Spatial variations in isostatic compensation mechanisms of the Ninetyeast Ridge and their tectonic significance

NASA Astrophysics Data System (ADS)

Sreejith, K. M.; Krishna, K. S.

2013-10-01

Ninetyeast Ridge (NER), one of the longest linear volcanic features on the Earth, offers an excellent opportunity of understanding the isostatic response to the interactions of mantle plume with the migrating mid-ocean ridge. Bathymetry, geoid, and gravity (shipborne and satellite) data along 72 closely spaced transects and 17 overlapping grids on the NER are analyzed and modeled to determine the effective elastic thickness (Te) beneath the entire ridge. The results of 2-D and 3-D flexural modeling of the NER show large spatial variations in Te values ranging from 4 to 35 km, suggesting that the ridge was compensated along its length by different isostatic mechanisms. The southern (south of 22°S latitude) and northern (north of 2°N latitude) parts of the NER have Te values of >10 and >23 km, respectively, revealing that the southern part was emplaced on a lithosphere of intermediate strength possibly on flank of the Indian plate, whereas the northern part was emplaced in an intraplate setting. In contrast, in the central part of the NER (between latitudes 22°S and 2°N), highly variable Te values (4-22 km) are estimated. The scattered Te values in the central NER suggest that this part may have evolved due to the occurrence of frequent ridge jumps caused by the interaction of Kerguelen hot spot with rapid northward migration of the Wharton spreading ridge. Residual Mantle Bouguer Anomaly (RMBA) map of the NER and adjacent basins reveals that the entire length of the NER is associated with a significant negative anomaly up to 200 mGal, indicating the presence of thickened crust or less dense mantle beneath the ridge. 3-D crustal thickness map of the NER, generated by inversion of the RMBA data, shows a thick crust ranging from 15 to 19 km. The present study clearly shows that NER possesses a highly segmented isostatic pattern with the occurrence of subcrustal underplating or subsurface loading.

True Lies: The Double Life of the Nucleotide Excision Repair Factors in Transcription and DNA Repair

PubMed Central

Le May, Nicolas; Egly, Jean-Marc; Coin, Frédéric

2010-01-01

Nucleotide excision repair (NER) is a major DNA repair pathway in eukaryotic cells. NER removes structurally diverse lesions such as pyrimidine dimers, arising upon UV irradiation or bulky chemical adducts, arising upon exposure to carcinogens and some chemotherapeutic drugs. NER defects lead to three genetic disorders that result in predisposition to cancers, accelerated aging, neurological and developmental defects. During NER, more than 30 polypeptides cooperate to recognize, incise, and excise a damaged oligonucleotide from the genomic DNA. Recent papers reveal an additional and unexpected role for the NER factors. In the absence of a genotoxic attack, the promoters of RNA polymerases I- and II-dependent genes recruit XPA, XPC, XPG, and XPF to initiate gene expression. A model that includes the growth arrest and DNA damage 45α protein (Gadd45α) and the NER factors, in order to maintain the promoter of active genes under a hypomethylated state, has been proposed but remains controversial. This paper focuses on the double life of the NER factors in DNA repair and transcription and describes the possible roles of these factors in the RNA synthesis process. PMID:20725631

Nucleotide excision repair is a potential therapeutic target in multiple myeloma

PubMed Central

Szalat, R; Samur, M K; Fulciniti, M; Lopez, M; Nanjappa, P; Cleynen, A; Wen, K; Kumar, S; Perini, T; Calkins, A S; Reznichenko, E; Chauhan, D; Tai, Y-T; Shammas, M A; Anderson, K C; Fermand, J-P; Arnulf, B; Avet-Loiseau, H; Lazaro, J-B; Munshi, N C

2018-01-01

Despite the development of novel drugs, alkylating agents remain an important component of therapy in multiple myeloma (MM). DNA repair processes contribute towards sensitivity to alkylating agents and therefore we here evaluate the role of nucleotide excision repair (NER), which is involved in the removal of bulky adducts and DNA crosslinks in MM. We first evaluated NER activity using a novel functional assay and observed a heterogeneous NER efficiency in MM cell lines and patient samples. Using next-generation sequencing data, we identified that expression of the canonical NER gene, excision repair cross-complementation group 3 (ERCC3), significantly impacted the outcome in newly diagnosed MM patients treated with alkylating agents. Next, using small RNA interference, stable knockdown and overexpression, and small-molecule inhibitors targeting xeroderma pigmentosum complementation group B (XPB), the DNA helicase encoded by ERCC3, we demonstrate that NER inhibition significantly increases sensitivity and overcomes resistance to alkylating agents in MM. Moreover, inhibiting XPB leads to the dual inhibition of NER and transcription and is particularly efficient in myeloma cells. Altogether, we show that NER impacts alkylating agents sensitivity in myeloma cells and identify ERCC3 as a potential therapeutic target in MM. PMID:28588253

Phosphorylation of XPB helicase regulates TFIIH nucleotide excision repair activity

PubMed Central

Coin, Frédéric; Auriol, Jérome; Tapias, Angel; Clivio, Pascale; Vermeulen, Wim; Egly, Jean-Marc

2004-01-01

Nucleotide excision repair (NER) removes damage from DNA in a tightly regulated multiprotein process. The xeroderma pigmentosum group B (XPB) helicase subunit of TFIIH functions in NER and transcription. The serine 751 (S751) residue of XPB was found to be phosphorylated in vivo. This phosphorylation inhibits NER and the microinjection of a phosphomimicking XPB-S751E mutant is unable to correct the NER defect of XP-B cells. Conversely, XPB-S751 dephosphorylation or its substitution with alanine (S751A) restores NER both in vivo and in vitro. Surprisingly, phospho/dephosphorylation of S751 spares TFIIH-dependent transcription. Finally, the phosphorylation of XPB-S751 does not impair the TFIIH unwinding of the DNA around the lesion, but rather prevents the 5′ incision triggered by the ERCC1-XPF endonuclease. These data support an additional role for XPB in promoting the incision of the damaged fragment and reveal a point of NER regulation on TFIIH without interference in its transcription activity. PMID:15549133

Overview of xeroderma pigmentosum proteins architecture, mutations and post-translational modifications.

PubMed

Feltes, Bruno César; Bonatto, Diego

2015-01-01

The xeroderma pigmentosum complementation group proteins (XPs), which include XPA through XPG, play a critical role in coordinating and promoting global genome and transcription-coupled nucleotide excision repair (GG-NER and TC-NER, respectively) pathways in eukaryotic cells. GG-NER and TC-NER are both required for the repair of bulky DNA lesions, such as those induced by UV radiation. Mutations in genes that encode XPs lead to the clinical condition xeroderma pigmentosum (XP). Although the roles of XPs in the GG-NER/TC-NER subpathways have been extensively studied, complete knowledge of their three-dimensional structure is only beginning to emerge. Hence, this review aims to summarize the current knowledge of mapped mutations and other structural information on XP proteins that influence their function and protein-protein interactions. We also review the possible post-translational modifications for each protein and the impact of these modifications on XP protein functions. Copyright © 2014 Elsevier B.V. All rights reserved.

Cockayne syndrome pathogenesis: lessons from mouse models.

PubMed

Jaarsma, Dick; van der Pluijm, Ingrid; van der Horst, Gijsbertus T J; Hoeijmakers, Jan H J

2013-01-01

Cockayne syndrome (CS) is a rare multisystem disorder characterized by cachectic dwarfism, nervous system abnormalities and features of premature aging. CS symptoms are associated with mutations in 5 genes, CSA, CSB, XPB, XPD and XPG encoding for proteins involved in the transcription-coupled subpathway of nucleotide excision DNA repair (NER). Mutant mice have been generated for all CS-associated genes and provide tools to examine how the cellular defects translate into CS symptoms. Mice deficient for Csa or Csb genetically mimic CS in man, and develop mild CS symptoms including reduced fat tissue, photoreceptor cell loss, and mild, but characteristic, nervous system pathology. These mild CS models are converted into severe CS models with short life span, progressive nervous system degeneration and cachectic dwarfism after simultaneous complete inactivation of global genome NER. A spectrum of mild-to-severe CS-like symptoms occurs in Xpb, Xpd, and Xpg mice that genetically mimic patients with a disorder that combines CS symptoms with another NER syndrome, xeroderma pigmentosum. In conclusion, CS mouse models mice develop a range of CS phenotypes and open promising perspectives for testing interventional approaches. Copyright © 2013 Elsevier Ireland Ltd. All rights reserved.

Cloning of a human homolog of the yeast nucleotide excision repair gene MMS19 and interaction with transcription repair factor TFIIH via the XPB and XPD helicases.

PubMed

Seroz, T; Winkler, G S; Auriol, J; Verhage, R A; Vermeulen, W; Smit, B; Brouwer, J; Eker, A P; Weeda, G; Egly, J M; Hoeijmakers, J H

2000-11-15

Nucleotide excision repair (NER) removes UV-induced photoproducts and numerous other DNA lesions in a highly conserved 'cut-and-paste' reaction that involves approximately 25 core components. In addition, several other proteins have been identified which are dispensable for NER in vitro but have an undefined role in vivo and may act at the interface of NER and other cellular processes. An intriguing example is the Saccharomyces cerevisiae Mms19 protein that has an unknown dual function in NER and RNA polymerase II transcription. Here we report the cloning and characterization of a human homolog, designated hMMS19, that encodes a 1030 amino acid protein with 26% identity and 51% similarity to S.cerevisiae Mms19p and with a strikingly similar size. The expression profile and nuclear location are consistent with a repair function. Co-immunoprecipitation experiments revealed that hMMS19 directly interacts with the XPB and XPD subunits of NER-transcription factor TFIIH. These findings extend the conservation of the NER apparatus and the link between NER and basal transcription and suggest that hMMS19 exerts its function in repair and transcription by interacting with the XPB and XPD helicases.

Fate of phenanthrene and mineralization of its non-extractable residues in an oxic soil.

PubMed

Wang, Yongfeng; Xu, Jun; Shan, Jun; Ma, Yini; Ji, Rong

2017-05-01

The fate of organic pollutants in the environment, especially the formation and stability of non-extractable (i.e., bound) residues (NERs) determines their environmental risk. Using 14 C-tracers, we studied the fate of the carcinogen phenanthrene in active or sterilized oxic loamy soil in the absence and presence of the geophagous earthworm Metaphire guillelmi and characterized the NERs derived from phenanthrene. After incubation of 14 C-phenanthrene in active soil for 28 days, 40 ± 3.1% of the initial amount was mineralized and 70.1 ± 1.9% was converted to NERs. Most of the NERs (>92%) were bound to soil humin. Silylation of the humin-bound residues released 45.3 ± 5.3% of these residues, which indicated that they were physically entrapped, whereas the remainder of the residues were chemically bound or biogenic. By contrast, in sterilized soil, only 43.4 ± 12.6% of the phenanthrene was converted to NERs and all of these residues were completely released upon silylation, which underlines the essential role of microbial activity in NER formation. The presence of M. guillelmi in active soil significantly inhibited phenanthrene mineralization (24.4 ± 2.6% mineralized), but NER formation was not significantly affected. Only a small amount of phenanthrene-derived residues (1.9-5.3% of the initial amount) accumulated in the earthworm body. When humin-bound residues were mixed with fresh soil, 33.9% (humin recovered from active soils) and 12.4% (humin recovered from sterilized soils) of the residues were mineralized after 75 days of incubation, respectively, which indicated a high bioavailability of NERs, albeit lower than the initial addition of phenanthrene. Our results indicated that many phenanthrene-derived NERs, especially those physically entrapped, are still bioavailable and may pose a toxic threat to soil organisms. Copyright © 2017 Elsevier Ltd. All rights reserved.

Metal binding mediated conformational change of XPA protein: a potential cytotoxic mechanism of nickel in the nucleotide excision repair

PubMed Central

Hu, Jianping; Hu, Ziheng; Zhang, Yan; Gou, Xiaojun; Mu, Ying; Wang, Lirong; Xie, Xiang-Qun

2017-01-01

Nucleotide excision repair (NER) is a pivotal life process for repairing DNA nucleotide mismatch caused by chemicals, metal ions, radiation, and other factors. As the initiation step of NER, the xeroderma pigmentosum complementation group A protein (XPA) recognizes damaged DNA molecules, and recruits the replication protein A (RPA), another important player in the NER process. The stability of the Zn2+-chelated Zn-finger domain of XPA center core portion (i.e., XPA98–210) is the foundation of its biological functionality, while the displacement of the Zn2+ by toxic metal ions (such as Ni2+, a known human carcinogen and allergen) may impair the effectiveness of NER and hence elevate the chance of carcinogenesis. In this study, we first calculated the force field parameters for the bonded model in the metal center of the XPA98–210 system, showing that the calculated results, including charges, bonds, angles etc., are congruent with previously reported results measured by spectrometry experiments and quantum chemistry computation. Then, comparative molecular dynamics simulations using these parameters revealed the changes in the conformation and motion mode of XPA98–210 Zn-finger after the substitution of Zn2+ by Ni2+. The results showed that Ni2+ dramatically disrupted the relative positions of the four Cys residues in the Zn-finger structure, forcing them to collapse from a tetrahedron into an almost planar structure. Finally, we acquired the binding mode of XPA98–210 with its ligands RPA70N and DNA based on molecular docking and structural alignment. We found that XPA98–210’s Zn-finger domain primarily binds to a V-shaped cleft in RPA70N, while the cationic band in its C-terminal subdomain participates in the recognition of damaged DNA. In addition, this article sheds light on the multi-component interaction pattern among XPA, DNA, and other NER-related proteins (i.e., RPA70N, RPA70A, RPA70B, RPA70C, RPA32, and RPA14) based on previously reported structural biology information. Thus, we derived a putative cytotoxic mechanism associated with the nickel ion, where the Ni2+ disrupts the conformation of the XPA Zn-finger, directly weakening its interaction with RPA70N, and thus lowering the effectiveness of the NER process. In sum, this work not only provides a theoretical insight into the multi-protein interactions involved in the NER process and potential cytotoxic mechanism associated with Ni2+ binding in XPA, but may also facilitate rational anti-cancer drug design based on the NER mechanism. PMID:27307058

Nucleotide excision repair and human syndromes.

PubMed

de Boer, J; Hoeijmakers, J H

2000-03-01

DNA damage is implicated in cancer and aging, and several DNA repair mechanisms exist that safeguard the genome from these deleterious consequences. Nucleotide excision repair (NER) removes a wide diversity of lesions, the main of which include UV-induced lesions, bulky chemical adducts and some forms of oxidative damage. The NER process involves the action of at least 30 proteins in a 'cut-and-paste'-like mechanism. The consequences of a defect in one of the NER proteins are apparent from three rare recessive syndromes: xeroderma pigmentosum (XP), Cockayne syndrome (CS) and the photosensitive form of the brittle hair disorder trichothiodystrophy (TTD). Sun-sensitive skin is associated with skin cancer predisposition in the case of XP, but remarkably not in CS and TTD. Moreover, the spectrum of clinical symptoms differs considerably between the three syndromes. CS and TTD patients exhibit a spectrum of neurodevelopmental abnormalities and, in addition, TTD is associated with ichthyosis and brittle hair. These typical CS and TTD abnormalities are difficult to comprehend as a consequence of defective NER. This review briefly describes the biochemistry of the NER process, summarizes the clinical features of the NER disorders and speculates on the molecular basis underlying these pleitropic syndromes.

A rule-based named-entity recognition method for knowledge extraction of evidence-based dietary recommendations

PubMed Central

2017-01-01

Evidence-based dietary information represented as unstructured text is a crucial information that needs to be accessed in order to help dietitians follow the new knowledge arrives daily with newly published scientific reports. Different named-entity recognition (NER) methods have been introduced previously to extract useful information from the biomedical literature. They are focused on, for example extracting gene mentions, proteins mentions, relationships between genes and proteins, chemical concepts and relationships between drugs and diseases. In this paper, we present a novel NER method, called drNER, for knowledge extraction of evidence-based dietary information. To the best of our knowledge this is the first attempt at extracting dietary concepts. DrNER is a rule-based NER that consists of two phases. The first one involves the detection and determination of the entities mention, and the second one involves the selection and extraction of the entities. We evaluate the method by using text corpora from heterogeneous sources, including text from several scientifically validated web sites and text from scientific publications. Evaluation of the method showed that drNER gives good results and can be used for knowledge extraction of evidence-based dietary recommendations. PMID:28644863

The Nucleotide Excision Repair Pathway Limits L1 Retrotransposition

PubMed Central

Servant, Geraldine; Streva, Vincent A.; Derbes, Rebecca S.; Wijetunge, Madushani I.; Neeland, Marc; White, Travis B.; Belancio, Victoria P.; Roy-Engel, Astrid M.; Deininger, Prescott L.

2017-01-01

Long interspersed elements 1 (L1) are active mobile elements that constitute almost 17% of the human genome. They amplify through a “copy-and-paste” mechanism termed retrotransposition, and de novo insertions related to these elements have been reported to cause 0.2% of genetic diseases. Our previous data demonstrated that the endonuclease complex ERCC1-XPF, which cleaves a 3′ DNA flap structure, limits L1 retrotransposition. Although the ERCC1-XPF endonuclease participates in several different DNA repair pathways, such as single-strand annealing, or in telomere maintenance, its recruitment to DNA lesions is best characterized in the nucleotide excision repair (NER) pathway. To determine if the NER pathway prevents the insertion of retroelements in the genome, we monitored the retrotransposition efficiencies of engineered L1 elements in NER-deficient cells and in their complemented versions. Core proteins of the NER pathway, XPD and XPA, and the lesion binding protein, XPC, are involved in limiting L1 retrotransposition. In addition, sequence analysis of recovered de novo L1 inserts and their genomic locations in NER-deficient cells demonstrated the presence of abnormally large duplications at the site of insertion, suggesting that NER proteins may also play a role in the normal L1 insertion process. Here, we propose new functions for the NER pathway in the maintenance of genome integrity: limitation of insertional mutations caused by retrotransposons and the prevention of potentially mutagenic large genomic duplications at the site of retrotransposon insertion events. PMID:28049704

NERBio: using selected word conjunctions, term normalization, and global patterns to improve biomedical named entity recognition.

PubMed

Tsai, Richard Tzong-Han; Sung, Cheng-Lung; Dai, Hong-Jie; Hung, Hsieh-Chuan; Sung, Ting-Yi; Hsu, Wen-Lian

2006-12-18

Biomedical named entity recognition (Bio-NER) is a challenging problem because, in general, biomedical named entities of the same category (e.g., proteins and genes) do not follow one standard nomenclature. They have many irregularities and sometimes appear in ambiguous contexts. In recent years, machine-learning (ML) approaches have become increasingly common and now represent the cutting edge of Bio-NER technology. This paper addresses three problems faced by ML-based Bio-NER systems. First, most ML approaches usually employ singleton features that comprise one linguistic property (e.g., the current word is capitalized) and at least one class tag (e.g., B-protein, the beginning of a protein name). However, such features may be insufficient in cases where multiple properties must be considered. Adding conjunction features that contain multiple properties can be beneficial, but it would be infeasible to include all conjunction features in an NER model since memory resources are limited and some features are ineffective. To resolve the problem, we use a sequential forward search algorithm to select an effective set of features. Second, variations in the numerical parts of biomedical terms (e.g., "2" in the biomedical term IL2) cause data sparseness and generate many redundant features. In this case, we apply numerical normalization, which solves the problem by replacing all numerals in a term with one representative numeral to help classify named entities. Third, the assignment of NE tags does not depend solely on the target word's closest neighbors, but may depend on words outside the context window (e.g., a context window of five consists of the current word plus two preceding and two subsequent words). We use global patterns generated by the Smith-Waterman local alignment algorithm to identify such structures and modify the results of our ML-based tagger. This is called pattern-based post-processing. To develop our ML-based Bio-NER system, we employ conditional random fields, which have performed effectively in several well-known tasks, as our underlying ML model. Adding selected conjunction features, applying numerical normalization, and employing pattern-based post-processing improve the F-scores by 1.67%, 1.04%, and 0.57%, respectively. The combined increase of 3.28% yields a total score of 72.98%, which is better than the baseline system that only uses singleton features. We demonstrate the benefits of using the sequential forward search algorithm to select effective conjunction feature groups. In addition, we show that numerical normalization can effectively reduce the number of redundant and unseen features. Furthermore, the Smith-Waterman local alignment algorithm can help ML-based Bio-NER deal with difficult cases that need longer context windows.

Conservation of the Nucleotide Excision Repair Pathway: Characterization of Hydra Xeroderma Pigmentosum Group F Homolog

PubMed Central

Barve, Apurva; Ghaskadbi, Saroj; Ghaskadbi, Surendra

2013-01-01

Hydra, one of the earliest metazoans with tissue grade organization and nervous system, is an animal with a remarkable regeneration capacity and shows no signs of organismal aging. We have for the first time identified genes of the nucleotide excision repair (NER) pathway from hydra. Here we report cloning and characterization of hydra homolog of xeroderma pigmentosum group F (XPF) gene that encodes a structure-specific 5′ endonuclease which is a crucial component of NER. In silico analysis shows that hydra XPF amino acid sequence is very similar to its counterparts from other animals, especially vertebrates, and shows all features essential for its function. By in situ hybridization, we show that hydra XPF is expressed prominently in the multipotent stem cell niche in the central region of the body column. Ectoderm of the diploblastic hydra was shown to express higher levels of XPF as compared to the endoderm by semi-quantitative RT-PCR. Semi-quantitative RT-PCR analysis also demonstrated that interstitial cells, a multipotent and rapidly cycling stem cell lineage of hydra, express higher levels of XPF mRNA than other cell types. Our data show that XPF and by extension, the NER pathway is highly conserved during evolution. The prominent expression of an NER gene in interstitial cells may have implications for the lack of senescence in hydra. PMID:23577191

Conservation of the nucleotide excision repair pathway: characterization of hydra Xeroderma Pigmentosum group F homolog.

PubMed

Barve, Apurva; Ghaskadbi, Saroj; Ghaskadbi, Surendra

2013-01-01

Hydra, one of the earliest metazoans with tissue grade organization and nervous system, is an animal with a remarkable regeneration capacity and shows no signs of organismal aging. We have for the first time identified genes of the nucleotide excision repair (NER) pathway from hydra. Here we report cloning and characterization of hydra homolog of xeroderma pigmentosum group F (XPF) gene that encodes a structure-specific 5' endonuclease which is a crucial component of NER. In silico analysis shows that hydra XPF amino acid sequence is very similar to its counterparts from other animals, especially vertebrates, and shows all features essential for its function. By in situ hybridization, we show that hydra XPF is expressed prominently in the multipotent stem cell niche in the central region of the body column. Ectoderm of the diploblastic hydra was shown to express higher levels of XPF as compared to the endoderm by semi-quantitative RT-PCR. Semi-quantitative RT-PCR analysis also demonstrated that interstitial cells, a multipotent and rapidly cycling stem cell lineage of hydra, express higher levels of XPF mRNA than other cell types. Our data show that XPF and by extension, the NER pathway is highly conserved during evolution. The prominent expression of an NER gene in interstitial cells may have implications for the lack of senescence in hydra.

Nucleotide excision repair-dependent DNA double-strand break formation and ATM signaling activation in mammalian quiescent cells.

PubMed

Wakasugi, Mitsuo; Sasaki, Takuma; Matsumoto, Megumi; Nagaoka, Miyuki; Inoue, Keiko; Inobe, Manabu; Horibata, Katsuyoshi; Tanaka, Kiyoji; Matsunaga, Tsukasa

2014-10-10

Histone H2A variant H2AX is phosphorylated at Ser(139) in response to DNA double-strand break (DSB) and single-stranded DNA (ssDNA) formation. UV light dominantly induces pyrimidine photodimers, which are removed from the mammalian genome by nucleotide excision repair (NER). We previously reported that in quiescent G0 phase cells, UV induces ATR-mediated H2AX phosphorylation plausibly caused by persistent ssDNA gap intermediates during NER. In this study, we have found that DSB is also generated following UV irradiation in an NER-dependent manner and contributes to an earlier fraction of UV-induced H2AX phosphorylation. The NER-dependent DSB formation activates ATM kinase and triggers the accumulation of its downstream factors, MRE11, NBS1, and MDC1, at UV-damaged sites. Importantly, ATM-deficient cells exhibited enhanced UV sensitivity under quiescent conditions compared with asynchronously growing conditions. Finally, we show that the NER-dependent H2AX phosphorylation is also observed in murine peripheral T lymphocytes, typical nonproliferating quiescent cells in vivo. These results suggest that in vivo quiescent cells may suffer from NER-mediated secondary DNA damage including ssDNA and DSB. © 2014 by The American Society for Biochemistry and Molecular Biology, Inc.

Cyclosporin A inhibits nucleotide excision repair via downregulation of the xeroderma pigmentosum group A and G proteins, which is mediated by calcineurin inhibition.

PubMed

Kuschal, Christiane; Thoms, Kai-Martin; Boeckmann, Lars; Laspe, Petra; Apel, Antje; Schön, Michael P; Emmert, Steffen

2011-10-01

Cyclosporin A (CsA) inhibits nucleotide excision repair (NER) in human cells, a process that contributes to the skin cancer proneness in organ transplant patients. We investigated the mechanisms of CsA-induced NER reduction by assessing all xeroderma pigmentosum (XP) genes (XPA-XPG). Western blot analyses revealed that XPA and XPG protein expression was reduced in normal human GM00637 fibroblasts exposed to 0.1 and 0.5 μm CsA. Interestingly, the CsA treatment reduced XPG, but not XPA, mRNA expression. Calcineurin knockdown in GM00637 fibroblasts using RNAi led to similar results suggesting that calcineurin-dependent signalling is involved in XPA and XPG protein regulation. CsA-induced reduction in NER could be complemented by the overexpression of either XPA or XPG protein. Likewise, XPA-deficient fibroblasts with stable overexpression of XPA (XP2OS-pCAH19WS) did not show the inhibitory effect of CsA on NER. In contrast, XPC-deficient fibroblasts overexpressing XPC showed CsA-reduced NER. Our data indicate that the CsA-induced inhibition of NER is a result of downregulation of XPA and XPG protein in a calcineurin-dependent manner. © 2011 John Wiley & Sons A/S.

XERODERMA PIGMENTOSUM, TRICHOTHIODYSTROPHY AND COCKAYNE SYNDROME: A COMPLEX GENOTYPE-PHENOTYPE RELATIONSHIP

PubMed Central

Kraemer, Kenneth H.; Patronas, Nicholas J.; Schiffmann, Raphael; Brooks, Brian P.; Tamura, Deborah; DiGiovanna, John J.

2008-01-01

Patients with the rare genetic disorders, xeroderma pigmentosum (XP), trichothiodystrophy (TTD) and Cockayne syndrome (CS) have defects in DNA nucleotide excision repair (NER). The NER pathway involves at least 28 genes. Three NER genes are also part of the basal transcription factor, TFIIH. Mutations in 11 NER genes have been associated with clinical diseases with at least 8 overlapping phenotypes. The clinical features of these patients have some similarities and but also have marked differences. NER is involved in protection against sunlight induced DNA damage. While XP patients have 1000-fold increase in susceptibility to skin cancer, TTD and CS patients have normal skin cancer risk. Several of the genes involved in NER also affect somatic growth and development. Some patients have short stature and immature sexual development. TTD patients have sulfur deficient brittle hair. Progressive sensorineural deafness is an early feature of XP and CS. Many of these clinical diseases are associated with developmental delay and progressive neurological degeneration. The main neuropathology of XP is a primary neuronal degeneration. In contrast, CS and TTD patients have reduced myelination of the brain. These complex neurological abnormalities are not related to sunlight exposure but may be caused by developmental defects as well as faulty repair of DNA damage to neuronal cells induced by oxidative metabolism or other endogenous processes. PMID:17276014

Oxidative stress-induced protein damage inhibits DNA repair and determines mutation risk and anticancer drug effectiveness

PubMed Central

McAdam, Elizabeth; Brem, Reto; Karran, Peter

2016-01-01

The relationship between sun exposure and non-melanoma skin cancer risk is well established. Solar ultraviolet radiation (UV; wavelengths 280-400 nm) is firmly implicated in skin cancer development. Nucleotide excision repair (NER) protects against cancer by removing potentially mutagenic DNA lesions induced by UVB (280-320 nm). How the 20-fold more abundant UVA (320-400 mn) component of solar UV radiation increases skin cancer risk is not understood. We demonstrate here that the contribution of UVA to the effects of UV radiation on cultured human cells is largely independent of its ability to damage DNA. Instead, the effects of UVA reflect the induction of oxidative stress that causes extensive protein oxidation. Because NER proteins are among those damaged, UVA irradiation inhibits NER and increases the cells’ susceptibility to mutation by UVB. NER inhibition is a common consequence of oxidative stress. Exposure to chemical oxidants, treatment with drugs that deplete cellular antioxidants, and interventions that interfere with glucose metabolism to disrupt the supply of cellular reducing power all inhibit NER. Tumor cells are often in a condition of oxidative stress and one effect of the NER inhibition that results from stress-induced protein oxidation is an increased sensitivity to the anticancer drug cisplatin. Statement of implication: Since NER is both a defence against cancer a significant determinant of cell survival after treatment with anticancer drugs, its attenuation by protein damage under conditions of oxidative-stress has implications for both cancer risk and for the effectiveness of anticancer therapy. PMID:27106867

Mutations in Replicative Stress Response Pathways Are Associated with S Phase-specific Defects in Nucleotide Excision Repair*

PubMed Central

Bélanger, François; Angers, Jean-Philippe; Fortier, Émile; Hammond-Martel, Ian; Costantino, Santiago; Drobetsky, Elliot; Wurtele, Hugo

2016-01-01

Nucleotide excision repair (NER) is a highly conserved pathway that removes helix-distorting DNA lesions induced by a plethora of mutagens, including UV light. Our laboratory previously demonstrated that human cells deficient in either ATM and Rad3-related (ATR) kinase or translesion DNA polymerase η (i.e. key proteins that promote the completion of DNA replication in response to UV-induced replicative stress) are characterized by profound inhibition of NER exclusively during S phase. Toward elucidating the mechanistic basis of this phenomenon, we developed a novel assay to quantify NER kinetics as a function of cell cycle in the model organism Saccharomyces cerevisiae. Using this assay, we demonstrate that in yeast, deficiency of the ATR homologue Mec1 or of any among several other proteins involved in the cellular response to replicative stress significantly abrogates NER uniquely during S phase. Moreover, initiation of DNA replication is required for manifestation of this defect, and S phase NER proficiency is correlated with the capacity of individual mutants to respond to replicative stress. Importantly, we demonstrate that partial depletion of Rfa1 recapitulates defective S phase-specific NER in wild type yeast; moreover, ectopic RPA1–3 overexpression rescues such deficiency in either ATR- or polymerase η-deficient human cells. Our results strongly suggest that reduction of NER capacity during periods of enhanced replicative stress, ostensibly caused by inordinate sequestration of RPA at stalled DNA replication forks, represents a conserved feature of the multifaceted eukaryotic DNA damage response. PMID:26578521

ToNER: A tool for identifying nucleotide enrichment signals in feature-enriched RNA-seq data.

PubMed

Promworn, Yuttachon; Kaewprommal, Pavita; Shaw, Philip J; Intarapanich, Apichart; Tongsima, Sissades; Piriyapongsa, Jittima

2017-01-01

Biochemical methods are available for enriching 5' ends of RNAs in prokaryotes, which are employed in the differential RNA-seq (dRNA-seq) and the more recent Cappable-seq protocols. Computational methods are needed to locate RNA 5' ends from these data by statistical analysis of the enrichment. Although statistical-based analysis methods have been developed for dRNA-seq, they may not be suitable for Cappable-seq data. The more efficient enrichment method employed in Cappable-seq compared with dRNA-seq could affect data distribution and thus algorithm performance. We present Transformation of Nucleotide Enrichment Ratios (ToNER), a tool for statistical modeling of enrichment from RNA-seq data obtained from enriched and unenriched libraries. The tool calculates nucleotide enrichment scores and determines the global transformation for fitting to the normal distribution using the Box-Cox procedure. From the transformed distribution, sites of significant enrichment are identified. To increase power of detection, meta-analysis across experimental replicates is offered. We tested the tool on Cappable-seq and dRNA-seq data for identifying Escherichia coli transcript 5' ends and compared the results with those from the TSSAR tool, which is designed for analyzing dRNA-seq data. When combining results across Cappable-seq replicates, ToNER detects more known transcript 5' ends than TSSAR. In general, the transcript 5' ends detected by ToNER but not TSSAR occur in regions which cannot be locally modeled by TSSAR. ToNER uses a simple yet robust statistical modeling approach, which can be used for detecting RNA 5'ends from Cappable-seq data, in particular when combining information from experimental replicates. The ToNER tool could potentially be applied for analyzing other RNA-seq datasets in which enrichment for other structural features of RNA is employed. The program is freely available for download at ToNER webpage (http://www4a.biotec.or.th/GI/tools/toner) and GitHub repository (https://github.com/PavitaKae/ToNER).

Restricting night-time eating reduces daily energy intake in healthy young men: a short-term cross-over study.

PubMed

LeCheminant, James D; Christenson, Ed; Bailey, Bruce W; Tucker, Larry A

2013-12-14

Few experimental data are available to support the notion that reducing night-time eating changes total daily energy intake (EI) or body weight in healthy adults. The present study primarily examined the short-term effect of night eating restriction (NER) on daily EI in healthy young men. It secondarily examined body weight and moods associated with NER. Using a cross-over design, twenty-nine men (20·9 (sd 2·5) years; 24·4 (sd 2·5) kg/m²) initiated a 2-week NER intervention (elimination of EI from 19.00 to 06.00 hours) and a 2-week control condition, counterbalanced and separated by a 1-week washout period. EI and macronutrient intake were assessed using computerised, multiple-pass 24 h food recalls, body weight via a digital scale and mood using the Profile of Mood States survey. Of the twenty-nine participants, twenty-seven (93 %) completed all aspects of the study. During the NER condition, the participants consumed less total energy per d than during the control condition (10 125 v. 11 146 kJ/d; F= 6·41; P= 0·018). During the NER condition, no energy was reported consumed between 19.00 and 06.00 hours; however, during the control condition, the energy intake of participants was 2920 (sd 1347) kJ/d between 19.00 and 06.00 hours. There was a significant difference in weight change between the NER (-0·4 (sd 1·1) kg) and control (+0·6 (sd 0·9) kg) conditions (F= 22·68; P< 0·001). Differences in total mood score or mood subscales between the NER and control conditions were not apparent (P>0·05). These findings provide support for NER decreasing short-term EI in healthy young men.

Identifying non-elliptical entity mentions in a coordinated NP with ellipses.

PubMed

Chae, Jeongmin; Jung, Younghee; Lee, Taemin; Jung, Soonyoung; Huh, Chan; Kim, Gilhan; Kim, Hyeoncheol; Oh, Heungbum

2014-02-01

Named entities in the biomedical domain are often written using a Noun Phrase (NP) along with a coordinating conjunction such as 'and' and 'or'. In addition, repeated words among named entity mentions are frequently omitted. It is often difficult to identify named entities. Although various Named Entity Recognition (NER) methods have tried to solve this problem, these methods can only deal with relatively simple elliptical patterns in coordinated NPs. We propose a new NER method for identifying non-elliptical entity mentions with simple or complex ellipses using linguistic rules and an entity mention dictionary. The GENIA and CRAFT corpora were used to evaluate the performance of the proposed system. The GENIA corpus was used to evaluate the performance of the system according to the quality of the dictionary. The GENIA corpus comprises 3434 non-elliptical entity mentions in 1585 coordinated NPs with ellipses. The system achieves 92.11% precision, 95.20% recall, and 93.63% F-score in identification of non-elliptical entity mentions in coordinated NPs. The accuracy of the system in resolving simple and complex ellipses is 94.54% and 91.95%, respectively. The CRAFT corpus was used to evaluate the performance of the system under realistic conditions. The system achieved 78.47% precision, 67.10% recall, and 72.34% F-score in coordinated NPs. The performance evaluations of the system show that it efficiently solves the problem caused by ellipses, and improves NER performance. The algorithm is implemented in PHP and the code can be downloaded from https://code.google.com/p/medtextmining/. Copyright © 2013. Published by Elsevier Inc.

The impact of trauma on the psyche of the individual using the film Belleville Rendez-vous as an illustrative vehicle.

PubMed

Waldron, Sharn

2008-09-01

Using the film Belleville Rendez-vous as a vehicle for discussion, this paper argues that whilst a traumatic complex may bring about dissociation of the psyche, this is not the only possibility, nor is dissociation necessarily to be seen solely as a difficulty to be overcome. If trauma is experienced within the context of support and validation, the experience of trauma may generate integration not only of the trauma but also of the growth potential that the trauma has previously inhibited.

Extraction of CYP chemical interactions from biomedical literature using natural language processing methods.

PubMed

Jiao, Dazhi; Wild, David J

2009-02-01

This paper proposes a system that automatically extracts CYP protein and chemical interactions from journal article abstracts, using natural language processing (NLP) and text mining methods. In our system, we employ a maximum entropy based learning method, using results from syntactic, semantic, and lexical analysis of texts. We first present our system architecture and then discuss the data set for training our machine learning based models and the methods in building components in our system, such as part of speech (POS) tagging, Named Entity Recognition (NER), dependency parsing, and relation extraction. An evaluation of the system is conducted at the end, yielding very promising results: The POS, dependency parsing, and NER components in our system have achieved a very high level of accuracy as measured by precision, ranging from 85.9% to 98.5%, and the precision and the recall of the interaction extraction component are 76.0% and 82.6%, and for the overall system are 68.4% and 72.2%, respectively.

GRAM-CNN: a deep learning approach with local context for named entity recognition in biomedical text.

PubMed

Zhu, Qile; Li, Xiaolin; Conesa, Ana; Pereira, Cécile

2018-05-01

Best performing named entity recognition (NER) methods for biomedical literature are based on hand-crafted features or task-specific rules, which are costly to produce and difficult to generalize to other corpora. End-to-end neural networks achieve state-of-the-art performance without hand-crafted features and task-specific knowledge in non-biomedical NER tasks. However, in the biomedical domain, using the same architecture does not yield competitive performance compared with conventional machine learning models. We propose a novel end-to-end deep learning approach for biomedical NER tasks that leverages the local contexts based on n-gram character and word embeddings via Convolutional Neural Network (CNN). We call this approach GRAM-CNN. To automatically label a word, this method uses the local information around a word. Therefore, the GRAM-CNN method does not require any specific knowledge or feature engineering and can be theoretically applied to a wide range of existing NER problems. The GRAM-CNN approach was evaluated on three well-known biomedical datasets containing different BioNER entities. It obtained an F1-score of 87.26% on the Biocreative II dataset, 87.26% on the NCBI dataset and 72.57% on the JNLPBA dataset. Those results put GRAM-CNN in the lead of the biological NER methods. To the best of our knowledge, we are the first to apply CNN based structures to BioNER problems. The GRAM-CNN source code, datasets and pre-trained model are available online at: https://github.com/valdersoul/GRAM-CNN. andyli@ece.ufl.edu or aconesa@ufl.edu. Supplementary data are available at Bioinformatics online.

GRAM-CNN: a deep learning approach with local context for named entity recognition in biomedical text

PubMed Central

Zhu, Qile; Li, Xiaolin; Conesa, Ana; Pereira, Cécile

2018-01-01

Abstract Motivation Best performing named entity recognition (NER) methods for biomedical literature are based on hand-crafted features or task-specific rules, which are costly to produce and difficult to generalize to other corpora. End-to-end neural networks achieve state-of-the-art performance without hand-crafted features and task-specific knowledge in non-biomedical NER tasks. However, in the biomedical domain, using the same architecture does not yield competitive performance compared with conventional machine learning models. Results We propose a novel end-to-end deep learning approach for biomedical NER tasks that leverages the local contexts based on n-gram character and word embeddings via Convolutional Neural Network (CNN). We call this approach GRAM-CNN. To automatically label a word, this method uses the local information around a word. Therefore, the GRAM-CNN method does not require any specific knowledge or feature engineering and can be theoretically applied to a wide range of existing NER problems. The GRAM-CNN approach was evaluated on three well-known biomedical datasets containing different BioNER entities. It obtained an F1-score of 87.26% on the Biocreative II dataset, 87.26% on the NCBI dataset and 72.57% on the JNLPBA dataset. Those results put GRAM-CNN in the lead of the biological NER methods. To the best of our knowledge, we are the first to apply CNN based structures to BioNER problems. Availability and implementation The GRAM-CNN source code, datasets and pre-trained model are available online at: https://github.com/valdersoul/GRAM-CNN. Contact andyli@ece.ufl.edu or aconesa@ufl.edu Supplementary information Supplementary data are available at Bioinformatics online. PMID:29272325

Mutagenesis and repair induced by the DNA advanced glycation end product N2-1-(carboxyethyl)-2'-deoxyguanosine in human cells.

PubMed

Tamae, Daniel; Lim, Punnajit; Wuenschell, Gerald E; Termini, John

2011-03-29

Glycation of biopolymers by glucose-derived α-oxo-aldehydes such as methylglyoxal (MG) is believed to play a major role in the complex pathologies associated with diabetes and metabolic disease. In contrast to the extensive literature detailing the formation and physiological consequences of protein glycation, there is little information about the corresponding phenomenon for DNA. To assess the potential contribution of DNA glycation to genetic instability, we prepared shuttle vectors containing defined levels of the DNA glycation adduct N(2)-(1-carboxyethyl)-2'-deoxyguanosine (CEdG) and transfected them into isogenic human fibroblasts that differed solely in the capacity to conduct nucleotide excision repair (NER). In the NER-compromised fibroblasts, the induced mutation frequencies increased up to 18-fold relative to background over a range of ∼10-1400 CEdG adducts/10(5) dG, whereas the same substrates transfected into NER-competent cells induced a response that was 5-fold over background at the highest adduct density. The positive linear correlation (R(2) = 0.998) of mutation frequency with increasing CEdG level in NER-defective cells suggested that NER was the primary if not exclusive mechanism for repair of this adduct in human fibroblasts. Consistent with predictions from biochemical studies using CEdG-substituted oligonucleotides, guanine transversions were the predominant mutation resulting from replication of MG-modified plasmids. At high CEdG levels, significant increases in the number of AT → GC transitions were observed exclusively in NER-competent cells (P < 0.0001). This suggested the involvement of an NER-dependent mutagenic process in response to critical levels of DNA damage, possibly mediated by error-prone Y-family polymerases.

DNA damage mediated transcription arrest: Step back to go forward.

PubMed

Mullenders, Leon

2015-12-01

The disturbance of DNA helix conformation by bulky DNA damage poses hindrance to transcription elongating due to stalling of RNA polymerase at transcription blocking lesions. Stalling of RNA polymerase provokes the formation of R-loops, i.e. the formation of a DNA-RNA hybrid and a displaced single stranded DNA strand as well as displacement of spliceosomes. R-loops are processed into DNA single and double strand breaks by NER factors depending on TC-NER factors leading to genome instability. Moreover, stalling of RNA polymerase induces a strong signal for cell cycle arrest and apoptosis. These toxic and mutagenic effects are counteracted by a rapid recruitment of DNA repair proteins to perform transcription coupled nucleotide excision repair (TC-NER) to remove the blocking DNA lesions and to restore transcription. Recent studies have highlighted the role of backtracking of RNA polymerase to facilitate TC-NER and identified novel factors that play key roles in TC-NER and in restoration of transcription. On the molecular level these factors facilitate stability of the repair complex by promotion and regulation of various post-translational modifications of NER factors and chromatin substrate. In addition, the continuous flow of new factors that emerge from screening assays hints to several regulatory levels to safeguard the integrity of transcription elongation after disturbance by DNA damage that have yet to be explored. Copyright © 2015 Elsevier B.V. All rights reserved.

Attenuated XPC Expression Is Not Associated with Impaired DNA Repair in Bladder Cancer

PubMed Central

Naipal, Kishan A. T.; Raams, Anja; Bruens, Serena T.; Brandsma, Inger; Verkaik, Nicole S.; Jaspers, Nicolaas G. J.; Hoeijmakers, Jan H. J.; van Leenders, Geert J. L. H.; Pothof, Joris; Kanaar, Roland; Boormans, Joost; van Gent, Dik C.

2015-01-01

Bladder cancer has a high incidence with significant morbidity and mortality. Attenuated expression of the DNA damage response protein Xeroderma Pigmentosum complementation group C (XPC) has been described in bladder cancer. XPC plays an essential role as the main initiator and damage-detector in global genome nucleotide excision repair (NER) of UV-induced lesions, bulky DNA adducts and intrastrand crosslinks, such as those made by the chemotherapeutic agent Cisplatin. Hence, XPC protein might be an informative biomarker to guide personalized therapy strategies in a subset of bladder cancer cases. Therefore, we measured the XPC protein expression level and functional NER activity of 36 bladder tumors in a standardized manner. We optimized conditions for dissociation and in vitro culture of primary bladder cancer cells and confirmed attenuated XPC expression in approximately 40% of the tumors. However, NER activity was similar to co-cultured wild type cells in all but one of 36 bladder tumors. We conclude, that (i) functional NER deficiency is a relatively rare phenomenon in bladder cancer and (ii) XPC protein levels are not useful as biomarker for NER activity in these tumors. PMID:25927440

Sequential and ordered assembly of a large DNA repair complex on undamaged chromatin

PubMed Central

Ziani, Salim; Nagy, Zita; Alekseev, Sergey; Soutoglou, Evi; Egly, Jean-Marc

2014-01-01

In nucleotide excision repair (NER), damage recognition by XPC-hHR23b is described as a critical step in the formation of the preincision complex (PInC) further composed of TFIIH, XPA, RPA, XPG, and ERCC1-XPF. To obtain new molecular insights into the assembly of the PInC, we analyzed its formation independently of DNA damage by using the lactose operator/repressor reporter system. We observed a sequential and ordered self-assembly of the PInC operating upon immobilization of individual NER factors on undamaged chromatin and mimicking that functioning on a bona fide NER substrate. We also revealed that the recruitment of the TFIIH subunit TTDA, involved in trichothiodystrophy group A disorder (TTD-A), was key in the completion of the PInC. TTDA recruits XPA through its first 15 amino acids, depleted in some TTD-A patients. More generally, these results show that proteins forming large nuclear complexes can be recruited sequentially on chromatin in the absence of their natural DNA target and with no reciprocity in their recruitment. PMID:25154395

Boosting drug named entity recognition using an aggregate classifier.

PubMed

Korkontzelos, Ioannis; Piliouras, Dimitrios; Dowsey, Andrew W; Ananiadou, Sophia

2015-10-01

Drug named entity recognition (NER) is a critical step for complex biomedical NLP tasks such as the extraction of pharmacogenomic, pharmacodynamic and pharmacokinetic parameters. Large quantities of high quality training data are almost always a prerequisite for employing supervised machine-learning techniques to achieve high classification performance. However, the human labour needed to produce and maintain such resources is a significant limitation. In this study, we improve the performance of drug NER without relying exclusively on manual annotations. We perform drug NER using either a small gold-standard corpus (120 abstracts) or no corpus at all. In our approach, we develop a voting system to combine a number of heterogeneous models, based on dictionary knowledge, gold-standard corpora and silver annotations, to enhance performance. To improve recall, we employed genetic programming to evolve 11 regular-expression patterns that capture common drug suffixes and used them as an extra means for recognition. Our approach uses a dictionary of drug names, i.e. DrugBank, a small manually annotated corpus, i.e. the pharmacokinetic corpus, and a part of the UKPMC database, as raw biomedical text. Gold-standard and silver annotated data are used to train maximum entropy and multinomial logistic regression classifiers. Aggregating drug NER methods, based on gold-standard annotations, dictionary knowledge and patterns, improved the performance on models trained on gold-standard annotations, only, achieving a maximum F-score of 95%. In addition, combining models trained on silver annotations, dictionary knowledge and patterns are shown to achieve comparable performance to models trained exclusively on gold-standard data. The main reason appears to be the morphological similarities shared among drug names. We conclude that gold-standard data are not a hard requirement for drug NER. Combining heterogeneous models build on dictionary knowledge can achieve similar or comparable classification performance with that of the best performing model trained on gold-standard annotations. Copyright © 2015 The Authors. Published by Elsevier B.V. All rights reserved.

ToNER: A tool for identifying nucleotide enrichment signals in feature-enriched RNA-seq data

PubMed Central

Promworn, Yuttachon; Kaewprommal, Pavita; Shaw, Philip J.; Intarapanich, Apichart; Tongsima, Sissades

2017-01-01

Background Biochemical methods are available for enriching 5′ ends of RNAs in prokaryotes, which are employed in the differential RNA-seq (dRNA-seq) and the more recent Cappable-seq protocols. Computational methods are needed to locate RNA 5′ ends from these data by statistical analysis of the enrichment. Although statistical-based analysis methods have been developed for dRNA-seq, they may not be suitable for Cappable-seq data. The more efficient enrichment method employed in Cappable-seq compared with dRNA-seq could affect data distribution and thus algorithm performance. Results We present Transformation of Nucleotide Enrichment Ratios (ToNER), a tool for statistical modeling of enrichment from RNA-seq data obtained from enriched and unenriched libraries. The tool calculates nucleotide enrichment scores and determines the global transformation for fitting to the normal distribution using the Box-Cox procedure. From the transformed distribution, sites of significant enrichment are identified. To increase power of detection, meta-analysis across experimental replicates is offered. We tested the tool on Cappable-seq and dRNA-seq data for identifying Escherichia coli transcript 5′ ends and compared the results with those from the TSSAR tool, which is designed for analyzing dRNA-seq data. When combining results across Cappable-seq replicates, ToNER detects more known transcript 5′ ends than TSSAR. In general, the transcript 5′ ends detected by ToNER but not TSSAR occur in regions which cannot be locally modeled by TSSAR. Conclusion ToNER uses a simple yet robust statistical modeling approach, which can be used for detecting RNA 5′ends from Cappable-seq data, in particular when combining information from experimental replicates. The ToNER tool could potentially be applied for analyzing other RNA-seq datasets in which enrichment for other structural features of RNA is employed. The program is freely available for download at ToNER webpage (http://www4a.biotec.or.th/GI/tools/toner) and GitHub repository (https://github.com/PavitaKae/ToNER). PMID:28542466

A study of active learning methods for named entity recognition in clinical text.

PubMed

Chen, Yukun; Lasko, Thomas A; Mei, Qiaozhu; Denny, Joshua C; Xu, Hua

2015-12-01

Named entity recognition (NER), a sequential labeling task, is one of the fundamental tasks for building clinical natural language processing (NLP) systems. Machine learning (ML) based approaches can achieve good performance, but they often require large amounts of annotated samples, which are expensive to build due to the requirement of domain experts in annotation. Active learning (AL), a sample selection approach integrated with supervised ML, aims to minimize the annotation cost while maximizing the performance of ML-based models. In this study, our goal was to develop and evaluate both existing and new AL methods for a clinical NER task to identify concepts of medical problems, treatments, and lab tests from the clinical notes. Using the annotated NER corpus from the 2010 i2b2/VA NLP challenge that contained 349 clinical documents with 20,423 unique sentences, we simulated AL experiments using a number of existing and novel algorithms in three different categories including uncertainty-based, diversity-based, and baseline sampling strategies. They were compared with the passive learning that uses random sampling. Learning curves that plot performance of the NER model against the estimated annotation cost (based on number of sentences or words in the training set) were generated to evaluate different active learning and the passive learning methods and the area under the learning curve (ALC) score was computed. Based on the learning curves of F-measure vs. number of sentences, uncertainty sampling algorithms outperformed all other methods in ALC. Most diversity-based methods also performed better than random sampling in ALC. To achieve an F-measure of 0.80, the best method based on uncertainty sampling could save 66% annotations in sentences, as compared to random sampling. For the learning curves of F-measure vs. number of words, uncertainty sampling methods again outperformed all other methods in ALC. To achieve 0.80 in F-measure, in comparison to random sampling, the best uncertainty based method saved 42% annotations in words. But the best diversity based method reduced only 7% annotation effort. In the simulated setting, AL methods, particularly uncertainty-sampling based approaches, seemed to significantly save annotation cost for the clinical NER task. The actual benefit of active learning in clinical NER should be further evaluated in a real-time setting. Copyright © 2015 Elsevier Inc. All rights reserved.

Geothermal projects funded under the NER 300 programme - current state of development and knowledge gained

NASA Astrophysics Data System (ADS)

Shortall, Ruth; Uihlein, Andreas

2017-04-01

Introduction The NER 300 programme, managed by the European Commission is one of the largest funding programmes for innovative low-carbon energy demonstration projects. NER 300 is so called because it is funded from the sale of 300 million emission allowances from the new entrants' reserve (NER) set up for the third phase of the EU emissions trading system (ETS). The programme aims to successfully demonstrate environmentally safe carbon capture and storage (CCS) and innovative renewable energy (RES) technologies on a commercial scale with a view to scaling up production of low-carbon technologies in the EU. Consequently, it supports a wide range of CCS and RES technologies (bioenergy, concentrated solar power, photovoltaics, geothermal, wind, ocean, hydropower, and smart grids). Funded projects and the role of geothermal projects for the programme In total, about EUR 2.1 billion have been awarded through the programme's 2 calls for proposals (the first awarded in December 2012, the second in July 2014). The programme has awarded around EUR 70 million funding to 3 geothermal projects in Hungary, Croatia and France. The Croatian geothermal project will enter into operation during 2017 the Hungarian in 2018, and the French in 2020. Knowledge Sharing Knowledge sharing requirements are built into the legal basis of the programme as a critical tool to lower risks in bridging the transition to large-scale production of innovative renewable energy and CCS deployment. Projects have to submit annually to the European Commission relevant knowledge gained during that year in the implementation of their project. The relevant knowledge is aggregated and disseminated by the European Commission to industry, research, government, NGO and other interest groups and associations in order to provide a better understanding of the practical challenges that arise in the important step of scaling up technologies and operating them at commercial scale. The knowledge sharing of the NER 300 programme should lead to better planning and faster introduction of low carbon technologies in the future. Content of the presentation The presentation will introduce the geothermal projects that have been awarded funding (see Annex), including their state-of-play. Insights and knowledge gained from the projects that have entered into operation will be shown and discussed. Furthermore, the presentation will provide an overview of the NER 300 programme.

Dynamic Interaction of TTDA with TFIIH Is Stabilized by Nucleotide Excision Repair in Living Cells

PubMed Central

Theil, Arjan F; Mari, Pierre-Olivier; Hoogstraten, Deborah; Ng, Jessica M. Y; Dinant, Christoffel; Hoeijmakers, Jan H. J

2006-01-01

Transcription/repair factor IIH (TFIIH) is essential for RNA polymerase II transcription and nucleotide excision repair (NER). This multi-subunit complex consists of ten polypeptides, including the recently identified small 8-kDa trichothiodystrophy group A (TTDA)/ hTFB5 protein. Patients belonging to the rare neurodevelopmental repair syndrome TTD-A carry inactivating mutations in the TTDA/hTFB5 gene. One of these mutations completely inactivates the protein, whereas other TFIIH genes only tolerate point mutations that do not compromise the essential role in transcription. Nevertheless, the severe NER-deficiency in TTD-A suggests that the TTDA protein is critical for repair. Using a fluorescently tagged and biologically active version of TTDA, we have investigated the involvement of TTDA in repair and transcription in living cells. Under non-challenging conditions, TTDA is present in two distinct kinetic pools: one bound to TFIIH, and a free fraction that shuttles between the cytoplasm and nucleus. After induction of NER-specific DNA lesions, the equilibrium between these two pools dramatically shifts towards a more stable association of TTDA to TFIIH. Modulating transcriptional activity in cells did not induce a similar shift in this equilibrium. Surprisingly, DNA conformations that only provoke an abortive-type of NER reaction do not result into a more stable incorporation of TTDA into TFIIH. These findings identify TTDA as the first TFIIH subunit with a primarily NER-dedicated role in vivo and indicate that its interaction with TFIIH reflects productive NER. PMID:16669699

Redundancy checking algorithms based on parallel novel extension rule

NASA Astrophysics Data System (ADS)

Liu, Lei; Yang, Yang; Li, Guangli; Wang, Qi; Lü, Shuai

2017-05-01

Redundancy checking (RC) is a key knowledge reduction technology. Extension rule (ER) is a new reasoning method, first presented in 2003 and well received by experts at home and abroad. Novel extension rule (NER) is an improved ER-based reasoning method, presented in 2009. In this paper, we first analyse the characteristics of the extension rule, and then present a simple algorithm for redundancy checking based on extension rule (RCER). In addition, we introduce MIMF, a type of heuristic strategy. Using the aforementioned rule and strategy, we design and implement RCHER algorithm, which relies on MIMF. Next we design and implement an RCNER (redundancy checking based on NER) algorithm based on NER. Parallel computing greatly accelerates the NER algorithm, which has weak dependence among tasks when executed. Considering this, we present PNER (parallel NER) and apply it to redundancy checking and necessity checking. Furthermore, we design and implement the RCPNER (redundancy checking based on PNER) and NCPPNER (necessary clause partition based on PNER) algorithms as well. The experimental results show that MIMF significantly influences the acceleration of algorithm RCER in formulae on a large scale and high redundancy. Comparing PNER with NER and RCPNER with RCNER, the average speedup can reach up to the number of task decompositions when executed. Comparing NCPNER with the RCNER-based algorithm on separating redundant formulae, speedup increases steadily as the scale of the formulae is incrementing. Finally, we describe the challenges that the extension rule will be faced with and suggest possible solutions.

Priority data on marine and estuarine resources within northeastern National Parks: Inventory and acquisition needs

USGS Publications Warehouse

Hart, Tracy E.; Neckles, Hilary A.; Kopp, Blaine S.

2013-01-01

The purpose of this project was to guide development of a strategy for the inventory and mapping of submerged natural resources associated within 10 coastal parks of the National Park Service (NPS) Northeast Region (NER; see Table 1). Priority data needs were identified by the NER Ocean Stewardship Task Force. The majority of the NER priority data needs involve the biotic, chemical, and geological characterization of the seabed. Taken collectively, this demands a consistent and unified approach to habitat classification. The Coastal and Marine Ecological Classification Standard (CMECS) is endorsed by the Federal Geographic Data Committee (FGDC-STD-018) for classifying ecological units in coastal and marine environments, and is recommended as a framework for acquiring and organizing NER data. We prepared an inventory of existing data on priority marine and estuarine natural resources within the ten NER coastal parks. This report describes the data and information sources relevant to each park and identifies gaps in available data. Overwhelmingly and uniformly across all parks, the most pressing needs are consistent, high-resolution bathymetry and seafloor characterization data. Approaches for acquiring these data using an integrated, multi-resolution sampling framework are recommended.

Enhancement of UV-induced nucleotide excision repair activity upon forskolin treatment is cell growth-dependent.

PubMed

Lee, Jeong-Min; Park, Jeong-Min; Kang, Tae-Hong

2016-10-01

Forskolin (FSK), an adenylyl cyclase activator, has recently been shown to enhance nucleotide excision repair (NER) upon UV exposure. However, our study revealed that this effect was detected in human skin epithelial ARPE19 cells only in growing cells, but not in non-cycling cells. When the cells were grown at low density (70% confluence), FSK was capable of stimulating cAMP responsive element binding (CREB) phosphorylation, a marker for FSK-stimulated PKA activation, and resulted in a significant increase of NER activity compared to control treatment. However, cells grown under 100% confluent conditions showed neither FSK-induced CREB phosphorylation nor the resulting NER enhancement. These findings indicate that cellular growth is critical for FSK-induced NER enhancement and suggest that cellular growth conditions should be considered as a variable while evaluating a reagent's pharmacotherapeutic efficacy. [BMB Reports 2016; 49(10): 566-571].

A C. elegans homolog for the UV-hypersensitivity syndrome disease gene UVSSA.

PubMed

Babu, Vipin; Schumacher, Björn

2016-05-01

The transcription-coupled repair pathway (TC-NER) plays a vital role in removing transcription-blocking DNA lesions, particularly UV-induced damage. Clinical symptoms of the two TC-NER-deficiency syndromes, Cockayne syndrome (CS) and UV-hypersensitivity syndrome (UVSS) are dissimilar and the underlying molecular mechanism causing this difference in disease pathology is not yet clearly understood. UV-stimulated scaffold protein A (UVSSA) has been identified recently as a new causal gene for UVSS. Here we describe a functional homolog of the human UVSSA gene in the nematode Caenorhabditis elegans, uvs-1 (UVSSA-like-1). Mutations in uvs-1 render the animals hypersensitive to UV-B irradiation and transcription-blocking lesion-inducing illudin-M, similar to mutations in TC-NER deficient mutants. Moreover, we demonstrate that TC-NER factors including UVS-1 are required for the survival of the adult animals after UV-treatment. Copyright © 2016 Elsevier B.V. All rights reserved.

DNA repair factor XPC is modified by SUMO-1 and ubiquitin following UV irradiation

PubMed Central

Wang, Qi-En; Zhu, Qianzheng; Wani, Gulzar; El-Mahdy, Mohamed A.; Li, Jinyou; Wani, Altaf A.

2005-01-01

Nucleotide excision repair (NER) is the major DNA repair process that removes diverse DNA lesions including UV-induced photoproducts. There are more than 20 proteins involved in NER. Among them, XPC is thought to be one of the first proteins to recognize DNA damage during global genomic repair (GGR), a sub-pathway of NER. In order to study the mechanism through which XPC participates in GGR, we investigated the possible modifications of XPC protein upon UV irradiation in mammalian cells. Western blot analysis of cell lysates from UV-irradiated normal human fibroblast, prepared by direct boiling in an SDS lysis buffer, showed several anti-XPC antibody-reactive bands with molecular weight higher than the original XPC protein. The reciprocal immunoprecipitation and siRNA transfection analysis demonstrated that XPC protein is modified by SUMO-1 and ubiquitin. By using several NER-deficient cell lines, we found that DDB2 and XPA are required for UV-induced XPC modifications. Interestingly, both the inactivation of ubiquitylation and the treatment of proteasome inhibitors quantitatively inhibited the UV-induced XPC modifications. Furthermore, XPC protein is degraded significantly following UV irradiation in XP-A cells in which sumoylation of XPC does not occur. Taken together, we conclude that XPC protein is modified by SUMO-1 and ubiquitin following UV irradiation and these modifications require the functions of DDB2 and XPA, as well as the ubiquitin–proteasome system. Our results also suggest that at least one function of UV-induced XPC sumoylation is related to the stabilization of XPC protein. PMID:16030353

Xeroderma Pigmentosum Group A Suppresses Mutagenesis Caused by Clustered Oxidative DNA Adducts in the Human Genome.

PubMed

Sassa, Akira; Kamoshita, Nagisa; Kanemaru, Yuki; Honma, Masamitsu; Yasui, Manabu

2015-01-01

Clustered DNA damage is defined as multiple sites of DNA damage within one or two helical turns of the duplex DNA. This complex damage is often formed by exposure of the genome to ionizing radiation and is difficult to repair. The mutagenic potential and repair mechanisms of clustered DNA damage in human cells remain to be elucidated. In this study, we investigated the involvement of nucleotide excision repair (NER) in clustered oxidative DNA adducts. To identify the in vivo protective roles of NER, we established a human cell line lacking the NER gene xeroderma pigmentosum group A (XPA). XPA knockout (KO) cells were generated from TSCER122 cells derived from the human lymphoblastoid TK6 cell line. To analyze the mutagenic events in DNA adducts in vivo, we previously employed a system of tracing DNA adducts in the targeted mutagenesis (TATAM), in which DNA adducts were site-specifically introduced into intron 4 of thymidine kinase genes. Using the TATAM system, one or two tandem 7,8-dihydro-8-oxoguanine (8-oxoG) adducts were introduced into the genomes of TSCER122 or XPA KO cells. In XPA KO cells, the proportion of mutants induced by a single 8-oxoG (7.6%) was comparable with that in TSCER122 cells (8.1%). In contrast, the lack of XPA significantly enhanced the mutant proportion of tandem 8-oxoG in the transcribed strand (12%) compared with that in TSCER122 cells (7.4%) but not in the non-transcribed strand (12% and 11% in XPA KO and TSCER122 cells, respectively). By sequencing the tandem 8-oxoG-integrated loci in the transcribed strand, we found that the proportion of tandem mutations was markedly increased in XPA KO cells. These results indicate that NER is involved in repairing clustered DNA adducts in the transcribed strand in vivo.

Xeroderma Pigmentosum Group A Suppresses Mutagenesis Caused by Clustered Oxidative DNA Adducts in the Human Genome

PubMed Central

Sassa, Akira; Kamoshita, Nagisa; Kanemaru, Yuki; Honma, Masamitsu; Yasui, Manabu

2015-01-01

Clustered DNA damage is defined as multiple sites of DNA damage within one or two helical turns of the duplex DNA. This complex damage is often formed by exposure of the genome to ionizing radiation and is difficult to repair. The mutagenic potential and repair mechanisms of clustered DNA damage in human cells remain to be elucidated. In this study, we investigated the involvement of nucleotide excision repair (NER) in clustered oxidative DNA adducts. To identify the in vivo protective roles of NER, we established a human cell line lacking the NER gene xeroderma pigmentosum group A (XPA). XPA knockout (KO) cells were generated from TSCER122 cells derived from the human lymphoblastoid TK6 cell line. To analyze the mutagenic events in DNA adducts in vivo, we previously employed a system of tracing DNA adducts in the targeted mutagenesis (TATAM), in which DNA adducts were site-specifically introduced into intron 4 of thymidine kinase genes. Using the TATAM system, one or two tandem 7,8-dihydro-8-oxoguanine (8-oxoG) adducts were introduced into the genomes of TSCER122 or XPA KO cells. In XPA KO cells, the proportion of mutants induced by a single 8-oxoG (7.6%) was comparable with that in TSCER122 cells (8.1%). In contrast, the lack of XPA significantly enhanced the mutant proportion of tandem 8-oxoG in the transcribed strand (12%) compared with that in TSCER122 cells (7.4%) but not in the non-transcribed strand (12% and 11% in XPA KO and TSCER122 cells, respectively). By sequencing the tandem 8-oxoG-integrated loci in the transcribed strand, we found that the proportion of tandem mutations was markedly increased in XPA KO cells. These results indicate that NER is involved in repairing clustered DNA adducts in the transcribed strand in vivo. PMID:26559182

Lifecycle assessment of microalgae to biofuel: Comparison of thermochemical processing pathways

DOE PAGES

Bennion, Edward P.; Ginosar, Daniel M.; Moses, John; ...

2015-01-16

Microalgae are currently being investigated as a renewable transportation fuel feedstock based on various advantages that include high annual yields, utilization of poor quality land, does not compete with food, and can be integrated with various waste streams. This study focuses on directly assessing the impact of two different thermochemical conversion technologies on the microalgae to biofuel process through life cycle assessment. A system boundary of a “well to pump” (WTP) is defined and includes sub-process models of the growth, dewatering, thermochemical bio-oil recovery, bio-oil stabilization, conversion to renewable diesel, and transport to the pump. Models were validated with experimentalmore » and literature data and are representative of an industrial-scale microalgae to biofuel process. Two different thermochemical bio-oil conversion systems are modeled and compared on a systems level, hydrothermal liquefaction (HTL) and pyrolysis. The environmental impact of the two pathways were quantified on the metrics of net energy ratio (NER), defined here as energy consumed over energy produced, and greenhouse gas (GHG) emissions. Results for WTP biofuel production through the HTL pathway were determined to be 1.23 for the NER and GHG emissions of -11.4 g CO 2-eq (MJ renewable diesel) -1. WTP biofuel production through the pyrolysis pathway results in a NER of 2.27 and GHG emissions of 210 g CO2 eq (MJ renewable diesel)-1. The large environmental impact associated with the pyrolysis pathway is attributed to feedstock drying requirements and combustion of co-products to improve system energetics. Discussion focuses on a detailed breakdown of the overall process energetics and GHGs, impact of modeling at laboratory- scale compared to industrial-scale, environmental impact sensitivity to engineering systems input parameters for future focused research and development and a comparison of results to literature.« less

Life cycle assessment of microalgae to biofuel: Thermochemical processing through hydrothermal liquefaction or pyrolysis

NASA Astrophysics Data System (ADS)

Bennion, Edward P.

Microalgae are currently being investigated as a renewable transportation fuel feedstock based on various advantages that include high annual yields, utilization of poor quality land, does not compete with food, and can be integrated with various waste streams. This study focuses on directly assessing the impact of two different thermochemical conversion technologies on the microalgae-to-biofuel process through life cycle assessment. A system boundary of a "well to pump" (WTP) is defined and includes sub-process models of the growth, dewatering, thermochemical bio-oil recovery, bio-oil stabilization, conversion to renewable diesel, and transport to the pump. Models were validated with experimental and literature data and are representative of an industrial-scale microalgae-to-biofuel process. Two different thermochemical bio-oil conversion systems are modeled and compared on a systems level, hydrothermal liquefaction (HTL) and pyrolysis. The environmental impact of the two pathways were quantified on the metrics of net energy ratio (NER), defined here as energy consumed over energy produced, and greenhouse gas (GHG) emissions. Results for WTP biofuel production through the HTL pathway were determined to be 1.23 for the NER and GHG emissions of -11.4 g CO2 eq (MJ renewable diesel)-1. WTP biofuel production through the pyrolysis pathway results in a NER of 2.27 and GHG emissions of 210 g CO2 eq (MJ renewable diesel)-1. The large environmental impact associated with the pyrolysis pathway is attributed to feedstock drying requirements and combustion of co-products to improve system energetics. Discussion focuses on a detailed breakdown of the overall process energetics and GHGs, impact of modeling at laboratory-scale compared to industrial-scale, environmental impact sensitivity to engineering systems input parameters for future focused research and development, and a comparison of results to literature.

PET Quantification of the Norepinephrine Transporter in Human Brain with (S,S)-18F-FMeNER-D2.

PubMed

Moriguchi, Sho; Kimura, Yasuyuki; Ichise, Masanori; Arakawa, Ryosuke; Takano, Harumasa; Seki, Chie; Ikoma, Yoko; Takahata, Keisuke; Nagashima, Tomohisa; Yamada, Makiko; Mimura, Masaru; Suhara, Tetsuya

2017-07-01

Norepinephrine transporter (NET) in the brain plays important roles in human cognition and the pathophysiology of psychiatric disorders. Two radioligands, ( S , S )- 11 C-MRB and ( S , S )- 18 F-FMeNER-D 2 , have been used for imaging NETs in the thalamus and midbrain (including locus coeruleus) using PET in humans. However, NET density in the equally important cerebral cortex has not been well quantified because of unfavorable kinetics with ( S , S )- 11 C-MRB and defluorination with ( S , S )- 18 F-FMeNER-D 2 , which can complicate NET quantification in the cerebral cortex adjacent to the skull containing defluorinated 18 F radioactivity. In this study, we have established analysis methods of quantification of NET density in the brain including the cerebral cortex using ( S , S )- 18 F-FMeNER-D 2 PET. Methods: We analyzed our previous ( S , S )- 18 F-FMeNER-D 2 PET data of 10 healthy volunteers dynamically acquired for 240 min with arterial blood sampling. The effects of defluorination on the NET quantification in the superficial cerebral cortex was evaluated by establishing a time stability of NET density estimations with an arterial input 2-tissue-compartment model, which guided the less-invasive reference tissue model and area under the time-activity curve methods to accurately quantify NET density in all brain regions including the cerebral cortex. Results: Defluorination of ( S , S )- 18 F-FMeNER-D 2 became prominent toward the latter half of the 240-min scan. Total distribution volumes in the superficial cerebral cortex increased with the scan duration beyond 120 min. We verified that 90-min dynamic scans provided a sufficient amount of data for quantification of NET density unaffected by defluorination. Reference tissue model binding potential values from the 90-min scan data and area under the time-activity curve ratios of 70- to 90-min data allowed for the accurate quantification of NET density in the cerebral cortex. Conclusion: We have established methods of quantification of NET densities in the brain including the cerebral cortex unaffected by defluorination using ( S , S )- 18 F-FMeNER-D 2 These results suggest that we can accurately quantify NET density with a 90-min ( S , S )- 18 F-FMeNER-D 2 scan in broad brain areas. © 2017 by the Society of Nuclear Medicine and Molecular Imaging.

Outcome prediction in patients with glioblastoma by using imaging, clinical, and genomic biomarkers: focus on the nonenhancing component of the tumor.

PubMed

Jain, Rajan; Poisson, Laila M; Gutman, David; Scarpace, Lisa; Hwang, Scott N; Holder, Chad A; Wintermark, Max; Rao, Arvind; Colen, Rivka R; Kirby, Justin; Freymann, John; Jaffe, C Carl; Mikkelsen, Tom; Flanders, Adam

2014-08-01

To correlate patient survival with morphologic imaging features and hemodynamic parameters obtained from the nonenhancing region (NER) of glioblastoma (GBM), along with clinical and genomic markers. An institutional review board waiver was obtained for this HIPAA-compliant retrospective study. Forty-five patients with GBM underwent baseline imaging with contrast material-enhanced magnetic resonance (MR) imaging and dynamic susceptibility contrast-enhanced T2*-weighted perfusion MR imaging. Molecular and clinical predictors of survival were obtained. Single and multivariable models of overall survival (OS) and progression-free survival (PFS) were explored with Kaplan-Meier estimates, Cox regression, and random survival forests. Worsening OS (log-rank test, P = .0103) and PFS (log-rank test, P = .0223) were associated with increasing relative cerebral blood volume of NER (rCBVNER), which was higher with deep white matter involvement (t test, P = .0482) and poor NER margin definition (t test, P = .0147). NER crossing the midline was the only morphologic feature of NER associated with poor survival (log-rank test, P = .0125). Preoperative Karnofsky performance score (KPS) and resection extent (n = 30) were clinically significant OS predictors (log-rank test, P = .0176 and P = .0038, respectively). No genomic alterations were associated with survival, except patients with high rCBVNER and wild-type epidermal growth factor receptor (EGFR) mutation had significantly poor survival (log-rank test, P = .0306; area under the receiver operating characteristic curve = 0.62). Combining resection extent with rCBVNER marginally improved prognostic ability (permutation, P = .084). Random forest models of presurgical predictors indicated rCBVNER as the top predictor; also important were KPS, age at diagnosis, and NER crossing the midline. A multivariable model containing rCBVNER, age at diagnosis, and KPS can be used to group patients with more than 1 year of difference in observed median survival (0.49-1.79 years). Patients with high rCBVNER and NER crossing the midline and those with high rCBVNER and wild-type EGFR mutation showed poor survival. In multivariable survival models, however, rCBVNER provided unique prognostic information that went above and beyond the assessment of all NER imaging features, as well as clinical and genomic features.

Outcome Prediction in Patients with Glioblastoma by Using Imaging, Clinical, and Genomic Biomarkers: Focus on the Nonenhancing Component of the Tumor

PubMed Central

Poisson, Laila M.; Gutman, David; Scarpace, Lisa; Hwang, Scott N.; Holder, Chad A.; Wintermark, Max; Rao, Arvind; Colen, Rivka R.; Kirby, Justin; Freymann, John; Jaffe, C. Carl; Mikkelsen, Tom; Flanders, Adam

2014-01-01

Purpose To correlate patient survival with morphologic imaging features and hemodynamic parameters obtained from the nonenhancing region (NER) of glioblastoma (GBM), along with clinical and genomic markers. Materials and Methods An institutional review board waiver was obtained for this HIPAA-compliant retrospective study. Forty-five patients with GBM underwent baseline imaging with contrast material–enhanced magnetic resonance (MR) imaging and dynamic susceptibility contrast-enhanced T2*-weighted perfusion MR imaging. Molecular and clinical predictors of survival were obtained. Single and multivariable models of overall survival (OS) and progression-free survival (PFS) were explored with Kaplan-Meier estimates, Cox regression, and random survival forests. Results Worsening OS (log-rank test, P = .0103) and PFS (log-rank test, P = .0223) were associated with increasing relative cerebral blood volume of NER (rCBVNER), which was higher with deep white matter involvement (t test, P = .0482) and poor NER margin definition (t test, P = .0147). NER crossing the midline was the only morphologic feature of NER associated with poor survival (log-rank test, P = .0125). Preoperative Karnofsky performance score (KPS) and resection extent (n = 30) were clinically significant OS predictors (log-rank test, P = .0176 and P = .0038, respectively). No genomic alterations were associated with survival, except patients with high rCBVNER and wild-type epidermal growth factor receptor (EGFR) mutation had significantly poor survival (log-rank test, P = .0306; area under the receiver operating characteristic curve = 0.62). Combining resection extent with rCBVNER marginally improved prognostic ability (permutation, P = .084). Random forest models of presurgical predictors indicated rCBVNER as the top predictor; also important were KPS, age at diagnosis, and NER crossing the midline. A multivariable model containing rCBVNER, age at diagnosis, and KPS can be used to group patients with more than 1 year of difference in observed median survival (0.49–1.79 years). Conclusion Patients with high rCBVNER and NER crossing the midline and those with high rCBVNER and wild-type EGFR mutation showed poor survival. In multivariable survival models, however, rCBVNER provided unique prognostic information that went above and beyond the assessment of all NER imaging features, as well as clinical and genomic features. © RSNA, 2014 Online supplemental material is available for this article. PMID:24646147

Helicopter Maritime Environment Trainer: Software Product Specification

DTIC Science & Technology

2011-06-01

d’entraîner les pilotes d’hélicoptère à l’atterrissage sur le pont d’envol d’une frégate canadienne de patrouille dans un environnement virtuel. Le...d’entraîner les pilotes d’hélicoptère à l’atterrissage sur le pont d’envol d’une frégate canadienne de patrouille dans un environnement virtuel. Le...d’entraîner les pilotes d’hélicoptère à l’atterrissage sur le pont d’envol d’une frégate canadienne de patrouille dans un environnement virtuel. Le système

Evaluation of Biomonitoring Data from the CDC National ...

EPA Pesticide Factsheets

BACKGROUND: Biomonitoring data reported in the National Report on Human Exposure to Environmental Chemicals (NER) provide information on the presence and concentrations of more than 400 chemicals in human blood and urine. Biomonitoring Equivalents (BEs) and other risk assessment-based values now allow interpretation of these biomonitoring data in a public health risk context. OBJECTIVES: Compare the measured biomarker concentrations in the NER with BEs and similar risk assessment values to provide an across-chemical risk assessment perspective on the measured levels for approximately 130 analytes in the NER. METHODS: Available risk assessment-based biomarker screening values, including BEs and Human Biomonitoring-I (HBM-I) values from the German Human Biomonitoring Commission, were identified. Geometric mean and 95th percentile population biomarker concentrations from the NER were compared to the available screening values to generate chemical-specific hazard quotients (HQ) or cancer risk estimates. CONCLUSIONS: Several analytes in the NER approach or exceed HQ values of 1 or cancer risks greater than 1x 10-4 at the geometric mean or 95th percentile, suggesting exposure levels exceed what is considered safe in a large fraction of the population. Analytes of concern include acrylamide, dioxin-like chemicals, benzene, xylene, several metals, di-2(ethylhexyl)phthalate, and some legacy organochlorine pesticides. This analysis provides for the first time a mean

Geothermal projects funded under the NER 300 programme - current state of development and knowledge gained

NASA Astrophysics Data System (ADS)

Uihlein, Andreas; Salto Saura, Lourdes; Sigfusson, Bergur; Lichtenvort, Kerstin; Gagliardi, Filippo

2015-04-01

Introduction The NER 300 programme, managed by the European Commission is one of the largest funding programmes for innovative low-carbon energy demonstration projects. NER 300 is so called because it is funded from the sale of 300 million emission allowances from the new entrants' reserve (NER) set up for the third phase of the EU emissions trading system (ETS). The programme aims to successfully demonstrate environmentally safe carbon capture and storage (CCS) and innovative renewable energy (RES) technologies on a commercial scale with a view to scaling up production of low-carbon technologies in the EU. Consequently, it supports a wide range of CCS and RES technologies (bioenergy, concentrated solar power, photovoltaics, geothermal, wind, ocean, hydropower, and smart grids). Funded projects and the role of geothermal projects for the programme In total, about EUR 2.1 billion have been awarded to 39 projects through the programme's 2 calls for proposals (the first awarded in December 2012, the second in July 2014). The programme has awarded around 70 mEUR funding to 3 geothermal projects in Hungary, Croatia and France (see Annex). The Hungarian geothermal project awarded funding under the first call will enter into operation at the end of 2015 and the rest are expected to start in 2016 (HR) and in 2018 (FR), respectively. Knowledge Sharing Knowledge sharing requirements are built into the legal basis of the programme as a critical tool to lower risks in bridging the transition to large-scale production of innovative renewable energy and CCS deployment. Projects have to submit annually to the European Commission relevant knowledge gained during that year in the implementation of their project. The relevant knowledge is aggregated and disseminated by the European Commission to industry, research, government, NGO and other interest groups and associations in order to provide a better understanding of the practical challenges that arise in the important step of scaling up technologies and operating them at commercial scale. The knowledge sharing of the NER 300 programme should lead to better planning and faster introduction of low carbon technologies in the future. Content of the presentation The presentation will introduce the geothermal projects that have been awarded funding, including their state-of-play. Insights and knowledge gained from the projects that have entered into operation will be shown and discussed. Furthermore, the presentation will provide an overview of the NER 300 programme.

Evolution of NASA's Near-Earth Tracking and Data Relay Satellite System (TDRSS)

NASA Technical Reports Server (NTRS)

Flaherty, Roger; Stocklin, Frank; Weinberg, Aaron

2006-01-01

NASA's Tracking and Data Relay Satellite System (TDRSS) is now in its 23rd year of operations and its spacecraft fleet includes three second-generation spacecraft launched since the year 2000; a figure illustrates the first generation TDRSS spacecraft. During this time frame the TDRSS has provided communications relay support to a broad range of missions, with emphasis on low-earth-orbiting (LEO) spacecraft that include unmanned science spacecraft (e.g., Hubble Space Telescope), and human spaceflight (Space Shuttle and Space Station). Furthermore, the TDRSS has consistently demonstrated its uniqueness and adaptability in several ways. First, its S- and K-band services, combined with its multi-band/steerable single-access (SA) antennas and ground-based configuration flexibility, have permitted the mission set to expand to unique users such as scientific balloons and launch vehicles. Second, the bent-pipe nature of the system has enabled the introduction of new/improved services via technology insertion and upgrades at each of the ground terminals; a specific example here is the Demand Access Service (DAS), which, for example, is currently providing science-alert support to NASA science missions Third, the bent-pipe nature of the system, combined with the flexible ground-terminal signal processing architecture has permitted the demonstration/vaIidation of new techniques/services/technologies via a real satellite channel; over the past 10+ years these have, for example, included demonstrations/evaluations of emerging modulation/coding techniques. Given NASA's emerging Exploration plans, with missions beginning later this decade and expanding for decades to come, NASA is currently planning the development of a seamless, NASA-wide architecture that must accommodate missions from near-earth to deep space. Near-earth elements include Ground-Network (GN) and Near-Earth Relay (NER) components and both must efficiently and seamlessly support missions that encompass: earth orbit, including dedicated science missions and lunar support/cargo vehicles; earth/moon transit; lunar in-situ operations; and other missions within approximately 2 million km of earth (e.g., at the sun/earth libration points). Given that the NER is an evolution of TDRSS, one element of this NASA-wide architecture development activity is a trade study of future NER architecture candidates. The present paper focuses on trade study aspects associated with the NER, highlights study elements, and provides representative interim results.

Atl1 regulates choice between global genome and transcription-coupled repair of O(6)-alkylguanines.

PubMed

Latypov, Vitaly F; Tubbs, Julie L; Watson, Amanda J; Marriott, Andrew S; McGown, Gail; Thorncroft, Mary; Wilkinson, Oliver J; Senthong, Pattama; Butt, Amna; Arvai, Andrew S; Millington, Christopher L; Povey, Andrew C; Williams, David M; Santibanez-Koref, Mauro F; Tainer, John A; Margison, Geoffrey P

2012-07-13

Nucleotide excision repair (NER) has long been known to remove DNA lesions induced by chemical carcinogens, and the molecular mechanism has been partially elucidated. Here we demonstrate that in Schizosaccharomyces pombe a DNA recognition protein, alkyltransferase-like 1 (Atl1), can play a pivotal role in selecting a specific NER pathway, depending on the nature of the DNA modification. The relative ease of dissociation of Atl1 from DNA containing small O(6)-alkylguanines allows accurate completion of global genome repair (GGR), whereas strong Atl1 binding to bulky O(6)-alkylguanines blocks GGR, stalls the transcription machinery, and diverts the damage to transcription-coupled repair. Our findings redraw the initial stages of the NER process in those organisms that express an alkyltransferase-like gene and raise the question of whether or not O(6)-alkylguanine lesions that are poor substrates for the alkyltransferase proteins in higher eukaryotes might, by analogy, signal such lesions for repair by NER. Copyright © 2012 Elsevier Inc. All rights reserved.

Structure and specificity of FEN-1 from Methanopyrus kandleri

DOE PAGES

Shah, Santosh; Dunten, Pete; Stiteler, Amanda; ...

2014-11-18

DNA repair is fundamental to genome stability and is found in all three domains of life. However, many archaeal species, such as Methanopyrus kandleri, contain only a subset of the eukaryotic nucleotide excision repair (NER) homologues, and those present often contain significant differences compared to their eukaryotic homologues. To clarify the role of the NER XPG-like protein Mk0566 from M. kandleri, its biochemical activity and three dimensional structure were investigated. Ultimately, we found both to be more similar to human FEN-1 than human XPG, suggesting a biological role in replication and long-patch base excision repair rather than in NER.

Generic Methodology for Verification and Validation (GM-VV) to Support Acceptance of Models, Simulations and Data (Methodologie generale de verification et de validation (GM-VV) visant a soutenir l acceptation des modeles, simulations et donnees)

DTIC Science & Technology

2015-01-01

RTO ou AGARD doivent comporter la dénomination « STO », « RTO » ou « AGARD » selon le cas, suivi du numéro de série. Des informations analogues...rapports de la STO au fur et à mesure de leur publication, vous pouvez consulter notre site Web (http://www.sto.nato.int/) et vous abonner à ce service...le cas, suivie du numéro de série (par exemple AGARD-AG-315). Des informations analogues, telles que le titre et la date de publication sont

The Case for 8, 5’-Cyclopurine-2’-Deoxynucleosides as Endogenous DNA Lesions That Cause Neurodegeneration in Xeroderma Pigmentosum

PubMed Central

Brooks, PJ

2007-01-01

Patients with the genetic disease xeroderma pigmentosum (XP) lack the capacity to carry out a specific type of DNA repair process called nucleotide excision repair (NER). The NER pathway plays a critical role in the repair of DNA damage resulting from UV radiation. A subset of XP patients develop a profound neurodegenerative condition known as XP neurological disease. Robbins and colleagues (PNAS 75:1984–88, 1978) hypothesized that since UV light cannot reach into the human brain, XP neurological disease results from some form of endogenous DNA damage that is normally repaired by the NER pathway. In the absence of NER, the damage accumulates, causing neuronal death by blocking transcription. In this manuscript, I consider the evidence that a particular class of oxidative DNA lesions, the 8, 5’-cyclopurine-2’-deoxynucleosides, fulfills many of the criteria expected of neurodegenerative DNA lesions in XP. Specifically, these lesions are chemically stable, endogenous DNA lesions that are repaired by the NER pathway but not by any other known process, and strongly block transcription by RNA polymerase II in cells from XP patients. A similar set of criteria might be used to evaluate other candidate DNA lesions responsible for neurological diseases resulting from defects in other DNA repair mechanisms as well. PMID:17184928

Disease named entity recognition from biomedical literature using a novel convolutional neural network.

PubMed

Zhao, Zhehuan; Yang, Zhihao; Luo, Ling; Wang, Lei; Zhang, Yin; Lin, Hongfei; Wang, Jian

2017-12-28

Automatic disease named entity recognition (DNER) is of utmost importance for development of more sophisticated BioNLP tools. However, most conventional CRF based DNER systems rely on well-designed features whose selection is labor intensive and time-consuming. Though most deep learning methods can solve NER problems with little feature engineering, they employ additional CRF layer to capture the correlation information between labels in neighborhoods which makes them much complicated. In this paper, we propose a novel multiple label convolutional neural network (MCNN) based disease NER approach. In this approach, instead of the CRF layer, a multiple label strategy (MLS) first introduced by us, is employed. First, the character-level embedding, word-level embedding and lexicon feature embedding are concatenated. Then several convolutional layers are stacked over the concatenated embedding. Finally, MLS strategy is applied to the output layer to capture the correlation information between neighboring labels. As shown by the experimental results, MCNN can achieve the state-of-the-art performance on both NCBI and CDR corpora. The proposed MCNN based disease NER method achieves the state-of-the-art performance with little feature engineering. And the experimental results show the MLS strategy's effectiveness of capturing the correlation information between labels in the neighborhood.

Techno-economic and life-cycle assessment of an attached growth algal biorefinery.

PubMed

Barlow, Jay; Sims, Ronald C; Quinn, Jason C

2016-11-01

This study examined the sustainability of generating renewable diesel via hydrothermal liquefaction (HTL) of biomass from a rotating algal biofilm reactor. Pilot-scale growth studies and laboratory-scale HTL experiments were used to validate an engineering system model. The engineering system model served as the foundation to evaluate the economic feasibility and environmental impact of the system at full scale. Techno-economic results indicate that biomass feedstock costs dominated the minimum fuel selling price (MFSP), with a base case of $104.31per gallon. Life-cycle assessment results show a base-case global warming potential (GWP) of 80gCO2-eMJ(-1) and net energy ratio (NER) of 1.65 based on a well-to-product system boundary. Optimization of the system reduces MFSP, GWP and NER to $11.90Gal(-1), -44gCO2-eMJ(-1), and 0.33, respectively. The systems-level impacts of integrating algae cultivation with wastewater treatment were found to significantly reduce environmental impact. Sensitivity analysis showed that algal productivity most significantly affected fuel selling price, emphasizing the importance of optimizing biomass productivity. Copyright © 2016 Elsevier Ltd. All rights reserved.

WITHDRAWN: Ivory vertebra and systemic mastocytosis. Comments on the article by Frenzel et al.

PubMed

Marhadour, Thierry; Saraux, Alain

2013-06-02

L'éditeur a le regret de vous informer que cet article ayant déjà été publié dans: , 80/5 (2013) 553-554, doi:10.1016/< S1297-319X(13)00186-3 >, cette seconde publication faite par erreur a été retirée. Copyright © 2013 Société française de rhumatologie. Published by Elsevier SAS. All rights reserved.

A novel regulation mechanism of DNA repair by damage-induced and RAD23-dependent stabilization of xeroderma pigmentosum group C protein

PubMed Central

Ng, Jessica M.Y.; Vermeulen, Wim; van der Horst, Gijsbertus T.J.; Bergink, Steven; Sugasawa, Kaoru; Vrieling, Harry; Hoeijmakers, Jan H.J.

2003-01-01

Primary DNA damage sensing in mammalian global genome nucleotide excision repair (GG-NER) is performed by the xeroderma pigmentosum group C (XPC)/HR23B protein complex. HR23B and HR23A are human homologs of the yeast ubiquitin-domain repair factor RAD23, the function of which is unknown. Knockout mice revealed that mHR23A and mHR23B have a fully redundant role in NER, and a partially redundant function in embryonic development. Inactivation of both genes causes embryonic lethality, but appeared still compatible with cellular viability. Analysis of mHR23A/B double-mutant cells showed that HR23 proteins function in NER by governing XPC stability via partial protection against proteasomal degradation. Interestingly, NER-type DNA damage further stabilizes XPC and thereby enhances repair. These findings resolve the primary function of RAD23 in repair and reveal a novel DNA-damage-dependent regulation mechanism of DNA repair in eukaryotes, which may be part of a more global damage-response circuitry. PMID:12815074

E2F1 interactions with hHR23A inhibit its degradation and promote DNA repair.

PubMed

Singh, Randeep K; Dagnino, Lina

2016-05-03

Nucleotide excision repair (NER) is a major mechanism for removal of DNA lesions induced by exposure to UV radiation in the epidermis. Recognition of damaged DNA sites is the initial step in their repair, and requires multiprotein complexes that contain XPC and hHR23 proteins, or their orthologues. A variety of transcription factors are also involved in NER, including E2F1. In epidermal keratinocytes, UV exposure induces E2F1 phosphorylation, which allows it to recruit various NER factors to sites of DNA damage. However, the relationship between E2F1 and hHR23 proteins vis-à-vis NER has remained unexplored. We now show that E2F1 and hHR23 proteins can interact, and this interaction stabilizes E2F1, inhibiting its proteasomal degradation. Reciprocally, E2F1 regulates hHR23A subcellular localization, recruiting it to sites of DNA photodamage. As a result, E2F1 and hHR23A enhance DNA repair following exposure to UV radiation, contributing to genomic stability in the epidermis.

Nucleotide excision repair modulates the cytotoxic and mutagenic effects of N-n-butyl-N-nitrosourea in cultured mammalian cells as well as in mouse splenocytes in vivo.

PubMed

Bol, S A; van Steeg, H; van Oostrom, C T; Tates, A D; Vrieling, H; de Groot, A J; Mullenders, L H; van Zeeland, A A; Jansen, J G

1999-05-01

The butylating agent N-n-butyl-N-nitrosourea (BNU) was employed to study the role of nucleotide excision repair (NER) in protecting mammalian cells against the genotoxic effects of monofunctional alkylating agents. The direct acting agent BNU was found to be mutagenic in normal and XPA mouse splenocytes after a single i.p. treatment in vivo. After 25 and 35 mg/kg BNU, but not after 75 mg/ kg, 2- to 3-fold more hprt mutants were detected in splenocytes from XPA mice than from normal mice. Using O6-alkylguanine-DNA alkyltransferase (AGT)-deficient hamster cells, it was found that NER-deficient CHO UV5 cells carrying a mutation in the ERCC-2 gene were 40% more mutable towards lesions induced by BNU when compared with parental NER-proficient CHO AA8 cells. UV5 cells were 1.4-fold more sensitive to the cytotoxic effects of BNU compared with AA8 cells. To investigate whether this increased sensitivity of NER-deficient cells is modulated by AGT activity, cell survival studies were performed in human and mouse primary fibroblasts as well. BNU was 2.7-fold more toxic for mouse XPA fibroblasts compared with normal mouse fibroblasts. Comparable results were found for human fibroblasts. Taken together these data indicate that the role of NER in protecting rodent cells against the mutagenic and cytotoxic effects of the alkylating agent BNU depends on AGT.

Operational Remote Sensing Services in North Eastern Region of India for Natural Resources Management, Early Warning for Disaster Risk Reduction and Dissemination of Information and Services

NASA Astrophysics Data System (ADS)

Raju, P. L. N.; Sarma, K. K.; Barman, D.; Handique, B. K.; Chutia, D.; Kundu, S. S.; Das, R. Kr.; Chakraborty, K.; Das, R.; Goswami, J.; Das, P.; Devi, H. S.; Nongkynrih, J. M.; Bhusan, K.; Singh, M. S.; Singh, P. S.; Saikhom, V.; Goswami, C.; Pebam, R.; Borgohain, A.; Gogoi, R. B.; Singh, N. R.; Bharali, A.; Sarma, D.; Lyngdoh, R. B.; Mandal, P. P.; Chabukdhara, M.

2016-06-01

North Eastern Region (NER) of India comprising of eight states considered to be most unique and one of the most challenging regions to govern due to its unique physiographic condition, rich biodiversity, disaster prone and diverse socio-economic characteristics. Operational Remote Sensing services increased manifolds in the region with the establishment of North Eastern Space Applications Centre (NESAC) in the year 2000. Since inception, NESAC has been providing remote sensing services in generating inventory, planning and developmental activities, and management of natural resources, disasters and dissemination of information and services through geo-web services for NER. The operational remote sensing services provided by NESAC can be broadly divided into three categories viz. natural resource planning and developmental services, disaster risk reduction and early warning services and information dissemination through geo-portal services. As a apart of natural resources planning and developmental services NESAC supports the state forest departments in preparing the forest working plans by providing geospatial inputs covering entire NER, identifying the suitable culturable wastelands for cultivation of silkworm food plants, mapping of natural resources such as land use/land cover, wastelands, land degradation etc. on temporal basis. In the area of disaster risk reduction, NESAC has initiated operational services for early warning and post disaster assessment inputs for flood early warning system (FLEWS) using satellite remote sensing, numerical weather prediction, hydrological modeling etc.; forest fire alert system with actionable attribute information; Japanese Encephalitis Early Warning System (JEWS) based on mosquito vector abundance, pig population and historical disease intensity and agriculture drought monitoring for the region. The large volumes of geo-spatial databases generated as part of operational services are made available to the administrators and local government bodies for better management, preparing prospective planning, and sustainable use of available resources. The knowledge dissemination is being done through online web portals wherever the internet access is available and as well as offline space based information kiosks, where the internet access is not available or having limited bandwidth availability. This paper presents a systematic and comprehensive study on the remote sensing services operational in NER of India for natural resources management, disaster risk reduction and dissemination of information and services, in addition to outlining future areas and direction of space applications for the region.

Comparative pharmacokinetic profiles of selected irreversible tyrosine kinase inhibitors, neratinib and pelitinib, with apigenin in rat plasma by UPLC-MS/MS.

PubMed

Maher, Hadir M; Alzoman, Nourah Z; Shehata, Shereen M; Abahussain, Ashwag O

2017-04-15

Neratinib (NER) and pelitinib (PEL) are irreversible tyrosine kinase inhibitors (TKIs) that have been recently employed in cancer treatment. Apigenin (API), among other flavonoids, is known to have antioxidant, anti-proliferative, and carcinogenic effect. API can potentiate the antitumor effect of chemotherapeutic agents and/or alleviate the side effects of many anticancer agents. Since TKIs are mostly metabolized by CYP3A4 enzymes and that API could alter the enzymatic activity, potential drug interactions could be expected following their co-aministration. In the present study, a bioanalytical UPLC-MS/MS method has been developed and validated for the quantification of NER and PEL in rat plasma, using domperidone (DOM) as an internal standard. Sample preparation was carried out using solid phase extraction (SPE) with C18 cartridges with good extraction recovery of not less than 92.42% (NER) and 89.73% (PEL). Chromatographic analysis was performed on a Waters BEH C18 column with a mobile phase composed of acetonitrile and water, (70:30, v/v), each with 0.1% formic acid. Quantitation was performed using multiple reaction monitoring (MRM) of the transitions from protonated precursor ions [M+H] + , at m/z 557.30 (NER), m/z 468.21 (PEL), and at m/z 426.27 (DOM), to selected product ions at m/z 112.05 (NER), m/z 395.22 (PEL), and at m/z 175.18 (DOM). The method was fully validated as per the FDA guidelines over the concentration range of 0.5-200ng/mL with very low lower limit of quantification (LLOQ) of 0.5ng/mL for both NER and PEL. The intra- and inter-day assay precision and accuracy were evaluated for both drugs and the calculated values of percentage relative standards deviations (%RSD) and relative errors (%E r ) were within the acceptable limits (<15%) for concentrations other than LLOQ and 20% for LLOQ. The applicability of the method was extended to study the possibility of drug interactions following the oral co-administration of NER/PEL with API. Thus, this study could be readily applied in therapeutic drug monitoring (TDM) of cancerous patients receiving such drug combinations. Copyright © 2017 Elsevier B.V. All rights reserved.

Cost-effectiveness of a national exercise referral programme for primary care patients in Wales: results of a randomised controlled trial

PubMed Central

2013-01-01

Background A recent HTA review concluded that there was a need for RCTs of exercise referral schemes (ERS) for people with a medical diagnosis who might benefit from exercise. Overall, there is still uncertainty as to the cost-effectiveness of ERS. Evaluation of public health interventions places challenges on conventional health economics approaches. This economic evaluation of a national public health intervention addresses this issue of where ERS may be most cost effective through subgroup analysis, particularly important at a time of financial constraint. Method This economic analysis included 798 individuals aged 16 and over (55% of the randomised controlled trial (RCT) sample) with coronary heart disease risk factors and/or mild to moderate anxiety, depression or stress. Individuals were referred by health professionals in a primary care setting to a 16 week national exercise referral scheme (NERS) delivered by qualified exercise professionals in local leisure centres in Wales, UK. Health-related quality of life, health care services use, costs per participant in NERS, and willingness to pay for NERS were measured at 6 and 12 months. Results The base case analysis assumed a participation cost of £385 per person per year, with a mean difference in QALYs between the two groups of 0.027. The incremental cost-effectiveness ratio was £12,111 per QALY gained. Probabilistic sensitivity analysis demonstrated an 89% probability of NERS being cost-effective at a payer threshold of £30,000 per QALY. When participant payments of £1 and £2 per session were considered, the cost per QALY fell from £12,111 (base case) to £10,926 and £9,741, respectively. Participants with a mental health risk factor alone or in combination with a risk of chronic heart disease generated a lower ICER (£10,276) compared to participants at risk of chronic heart disease only (£13,060). Conclusions Results of cost-effectiveness analyses suggest that NERS is cost saving in fully adherent participants. Though full adherence to NERS (62%) was higher for the economics sample than the main sample (44%), results still suggest that NERS can be cost-effective in Wales with respect to existing payer thresholds particularly for participants with mental health and CHD risk factors. Trial registration Current Controlled Trials ISRCTN47680448 PMID:24164697

Cost-effectiveness of a national exercise referral programme for primary care patients in Wales: results of a randomised controlled trial.

PubMed

Edwards, Rhiannon Tudor; Linck, Pat; Hounsome, Natalia; Raisanen, Larry; Williams, Nefyn; Moore, Laurence; Murphy, Simon

2013-10-29

A recent HTA review concluded that there was a need for RCTs of exercise referral schemes (ERS) for people with a medical diagnosis who might benefit from exercise. Overall, there is still uncertainty as to the cost-effectiveness of ERS. Evaluation of public health interventions places challenges on conventional health economics approaches. This economic evaluation of a national public health intervention addresses this issue of where ERS may be most cost effective through subgroup analysis, particularly important at a time of financial constraint. This economic analysis included 798 individuals aged 16 and over (55% of the randomised controlled trial (RCT) sample) with coronary heart disease risk factors and/or mild to moderate anxiety, depression or stress. Individuals were referred by health professionals in a primary care setting to a 16 week national exercise referral scheme (NERS) delivered by qualified exercise professionals in local leisure centres in Wales, UK. Health-related quality of life, health care services use, costs per participant in NERS, and willingness to pay for NERS were measured at 6 and 12 months. The base case analysis assumed a participation cost of £385 per person per year, with a mean difference in QALYs between the two groups of 0.027. The incremental cost-effectiveness ratio was £12,111 per QALY gained. Probabilistic sensitivity analysis demonstrated an 89% probability of NERS being cost-effective at a payer threshold of £30,000 per QALY. When participant payments of £1 and £2 per session were considered, the cost per QALY fell from £12,111 (base case) to £10,926 and £9,741, respectively. Participants with a mental health risk factor alone or in combination with a risk of chronic heart disease generated a lower ICER (£10,276) compared to participants at risk of chronic heart disease only (£13,060). Results of cost-effectiveness analyses suggest that NERS is cost saving in fully adherent participants. Though full adherence to NERS (62%) was higher for the economics sample than the main sample (44%), results still suggest that NERS can be cost-effective in Wales with respect to existing payer thresholds particularly for participants with mental health and CHD risk factors. Current Controlled Trials ISRCTN47680448.

Effects of the updated national emission regulation in China on circulating fluidized bed boilers and the solutions to meet them.

PubMed

Li, Jingji; Yang, Hairui; Wu, Yuxin; Lv, Junfu; Yue, Guangxi

2013-06-18

The advantage of circulating fluidized bed (CFB) boilers in China is their ability to utilize low rank coal with low cost emission control. However, the new National Emission Regulation (NER) issued in early 2012 brings much more stringent challenges on the CFB industries, which also causes much attention from other countries. Based on the principle of a CFB boiler and previous operating experience, it is possible for the CFB boilers to meet the new NER and maintain the advantage of low cost emission control, while, more influences should be considered in their design and operation. To meet the requirement of the new NER, the fly ash collector should adopt a bag house or combination of electrostatic precipitator and bag filter to ensure dust emissions of less than 30 mg · Nm(-3). For SO2 emission control, the bed temperature should be strictly lower than 900 °C to maintain high reactivity and pores. The limestone particle size distribution should be ranged within a special scope to optimize the residence time and gas-solid reaction. At the same time, the injecting point should be optimized to ensure fast contact of lime with oxygen. In such conditions, the desulfurization efficiency could be increased more than 90%. For lower sulfur content fuels (<1.5%, referred value based on the heating value of standard coal of China), increasing Ca/S enough could decrease SO2 emissions lower than that of the new NER, 100 mg · Nm(-3). For fuels with sulfur content higher than 1.5%, some simplified systems for flue gas desulfurization, such as flash dryer absorber (FDA), are needed. And the NOx emissions of a CFB can be controlled to less than 100 mg · Nm(-3) without any equipment at a bed temperature lower than 900 °C for fuels with low volatiles content (<12%), while for fuels with high volatiles, selective non-catalytic reduction (SNCR) should be considered. Due to the unique temperature in CFB as well as the circulating ash, the efficiency of SNCR could reach as high as 70%. The Hg emission of CFB is very low for the new NER due to its innate property.

An eco-friendly direct spectrofluorimetric method for the determination of irreversible tyrosine kinase inhibitors, neratinib and pelitinib: application to stability studies.

PubMed

Maher, H M; Alzoman, N Z; Shehata, S M

2017-03-01

A new rapid and simple stability-indicating spectrofluorimetric method has been developed for the determination of two irreversible tyrosine kinase inhibitors (TKIs), neratinib (NER) and pelitinib (PEL). The method is based upon measurement of the native fluorescence intensity of both drugs at λ ex 270 nm in aqueous borate buffer solutions (pH 10.5). The fluorescence intensity recorded at 545 nm (NER) and 465 nm (PEL) were rectilinear over the concentration range of 0.1-10 μg/mL for both drugs with a high correlation coefficient (r > 0.999). The proposed method provided low limits of detection and of quantitation of 0.07, 0.11 μg/mL (NER) and 0.02, 0.05 μg/mL (PEL), respectively. The method was successfully applied for the determination of NER and PEL in bulk powder. The proposed methods were fully validated as per the International Conference on Harmonisation (ICH) guidelines. The application of the method was extended to stability studies of both NER and PEL under different forced-degradation conditions (acidic-induced, base-induced, oxidative, wet heat, and photolytic degradation). Moreover, the kinetics of the base-induced and oxidative degradation of both drugs was investigated and the pseudo-first-order rate constants and half-lives were estimated at different temperatures. Also, an Arrhenius plot was applied to predict the stability behaviour of the two drugs at room temperature. Copyright © 2016 John Wiley & Sons, Ltd. Copyright © 2016 John Wiley & Sons, Ltd.

Nucleotide Excision Repair and Vitamin D--Relevance for Skin Cancer Therapy.

PubMed

Pawlowska, Elzbieta; Wysokinski, Daniel; Blasiak, Janusz

2016-04-06

Ultraviolet (UV) radiation is involved in almost all skin cancer cases, but on the other hand, it stimulates the production of pre-vitamin D3, whose active metabolite, 1,25-dihydroxyvitamin D3 (1,25VD3), plays important physiological functions on binding with its receptor (vitamin D receptor, VDR). UV-induced DNA damages in the form of cyclobutane pyrimidine dimers or (6-4)-pyrimidine-pyrimidone photoproducts are frequently found in skin cancer and its precursors. Therefore, removing these lesions is essential for the prevention of skin cancer. As UV-induced DNA damages are repaired by nucleotide excision repair (NER), the interaction of 1,25VD3 with NER components can be important for skin cancer transformation. Several studies show that 1,25VD3 protects DNA against damage induced by UV, but the exact mechanism of this protection is not completely clear. 1,25VD3 was also shown to affect cell cycle regulation and apoptosis in several signaling pathways, so it can be considered as a potential modulator of the cellular DNA damage response, which is crucial for mutagenesis and cancer transformation. 1,25VD3 was shown to affect DNA repair and potentially NER through decreasing nitrosylation of DNA repair enzymes by NO overproduction by UV, but other mechanisms of the interaction between 1,25VD3 and NER machinery also are suggested. Therefore, the array of NER gene functioning could be analyzed and an appropriate amount of 1.25VD3 could be recommended to decrease UV-induced DNA damage important for skin cancer transformation.

Mobile phone specific electromagnetic fields induce transient DNA damage and nucleotide excision repair in serum-deprived human glioblastoma cells.

PubMed

Al-Serori, Halh; Ferk, Franziska; Kundi, Michael; Bileck, Andrea; Gerner, Christopher; Mišík, Miroslav; Nersesyan, Armen; Waldherr, Monika; Murbach, Manuel; Lah, Tamara T; Herold-Mende, Christel; Collins, Andrew R; Knasmüller, Siegfried

2018-01-01

Some epidemiological studies indicate that the use of mobile phones causes cancer in humans (in particular glioblastomas). It is known that DNA damage plays a key role in malignant transformation; therefore, we investigated the impact of the UMTS signal which is widely used in mobile telecommunications, on DNA stability in ten different human cell lines (six brain derived cell lines, lymphocytes, fibroblasts, liver and buccal tissue derived cells) under conditions relevant for users (SAR 0.25 to 1.00 W/kg). We found no evidence for induction of damage in single cell gel electrophoresis assays when the cells were cultivated with serum. However, clear positive effects were seen in a p53 proficient glioblastoma line (U87) when the cells were grown under serum free conditions, while no effects were found in p53 deficient glioblastoma cells (U251). Further experiments showed that the damage disappears rapidly in U87 and that exposure induced nucleotide excision repair (NER) and does not cause double strand breaks (DSBs). The observation of NER induction is supported by results of a proteome analysis indicating that several proteins involved in NER are up-regulated after exposure to UMTS; additionally, we found limited evidence for the activation of the γ-interferon pathway. The present findings show that the signal causes transient genetic instability in glioma derived cells and activates cellular defense systems.

Radiation Effects in 3D Integrated SOl SRAM Circuits

DTIC Science & Technology

2011-08-23

Because of the front-to- hack capacitive coupling, significant device parametric shifts can be observed unless the BOX has been engineered to...8. - l.E-12 .,..--------------, .. J5 ;::.. 5 63-MeV Protons · Tier1 • ner2 ner3 -c a • ’i 1.E-13 ----·· -----·-- ~ . = . i§ • • g • f L_

An attention-based BiLSTM-CRF approach to document-level chemical named entity recognition.

PubMed

Luo, Ling; Yang, Zhihao; Yang, Pei; Zhang, Yin; Wang, Lei; Lin, Hongfei; Wang, Jian

2018-04-15

In biomedical research, chemical is an important class of entities, and chemical named entity recognition (NER) is an important task in the field of biomedical information extraction. However, most popular chemical NER methods are based on traditional machine learning and their performances are heavily dependent on the feature engineering. Moreover, these methods are sentence-level ones which have the tagging inconsistency problem. In this paper, we propose a neural network approach, i.e. attention-based bidirectional Long Short-Term Memory with a conditional random field layer (Att-BiLSTM-CRF), to document-level chemical NER. The approach leverages document-level global information obtained by attention mechanism to enforce tagging consistency across multiple instances of the same token in a document. It achieves better performances with little feature engineering than other state-of-the-art methods on the BioCreative IV chemical compound and drug name recognition (CHEMDNER) corpus and the BioCreative V chemical-disease relation (CDR) task corpus (the F-scores of 91.14 and 92.57%, respectively). Data and code are available at https://github.com/lingluodlut/Att-ChemdNER. yangzh@dlut.edu.cn or wangleibihami@gmail.com. Supplementary data are available at Bioinformatics online.

Disruption of TTDA Results in Complete Nucleotide Excision Repair Deficiency and Embryonic Lethality

PubMed Central

Theil, Arjan F.; Nonnekens, Julie; Steurer, Barbara; Mari, Pierre-Olivier; de Wit, Jan; Lemaitre, Charlène; Marteijn, Jurgen A.; Raams, Anja; Maas, Alex; Vermeij, Marcel; Essers, Jeroen; Hoeijmakers, Jan H. J.; Giglia-Mari, Giuseppina; Vermeulen, Wim

2013-01-01

The ten-subunit transcription factor IIH (TFIIH) plays a crucial role in transcription and nucleotide excision repair (NER). Inactivating mutations in the smallest 8-kDa TFB5/TTDA subunit cause the neurodevelopmental progeroid repair syndrome trichothiodystrophy A (TTD-A). Previous studies have shown that TTDA is the only TFIIH subunit that appears not to be essential for NER, transcription, or viability. We studied the consequences of TTDA inactivation by generating a Ttda knock-out (Ttda−/−) mouse-model resembling TTD-A patients. Unexpectedly, Ttda−/− mice were embryonic lethal. However, in contrast to full disruption of all other TFIIH subunits, viability of Ttda−/− cells was not affected. Surprisingly, Ttda−/− cells were completely NER deficient, contrary to the incomplete NER deficiency of TTD-A patient-derived cells. We further showed that TTD-A patient mutations only partially inactivate TTDA function, explaining the relatively mild repair phenotype of TTD-A cells. Moreover, Ttda−/− cells were also highly sensitive to oxidizing agents. These findings reveal an essential role of TTDA for life, nucleotide excision repair, and oxidative DNA damage repair and identify Ttda−/− cells as a unique class of TFIIH mutants. PMID:23637614

E2F1 interactions with hHR23A inhibit its degradation and promote DNA repair

PubMed Central

Singh, Randeep K.; Dagnino, Lina

2016-01-01

Nucleotide excision repair (NER) is a major mechanism for removal of DNA lesions induced by exposure to UV radiation in the epidermis. Recognition of damaged DNA sites is the initial step in their repair, and requires multiprotein complexes that contain XPC and hHR23 proteins, or their orthologues. A variety of transcription factors are also involved in NER, including E2F1. In epidermal keratinocytes, UV exposure induces E2F1 phosphorylation, which allows it to recruit various NER factors to sites of DNA damage. However, the relationship between E2F1 and hHR23 proteins vis-à-vis NER has remained unexplored. We now show that E2F1 and hHR23 proteins can interact, and this interaction stabilizes E2F1, inhibiting its proteasomal degradation. Reciprocally, E2F1 regulates hHR23A subcellular localization, recruiting it to sites of DNA photodamage. As a result, E2F1 and hHR23A enhance DNA repair following exposure to UV radiation, contributing to genomic stability in the epidermis. PMID:27028861

Mitotic regulator Nlp interacts with XPA/ERCC1 complexes and regulates nucleotide excision repair (NER) in response to UV radiation.

PubMed

Ma, Xiao-Juan; Shang, Li; Zhang, Wei-Min; Wang, Ming-Rong; Zhan, Qi-Min

2016-04-10

Cellular response to DNA damage, including ionizing radiation (IR) and UV radiation, is critical for the maintenance of genomic fidelity. Defects of DNA repair often result in genomic instability and malignant cell transformation. Centrosomal protein Nlp (ninein-like protein) has been characterized as an important cell cycle regulator that is required for proper mitotic progression. In this study, we demonstrate that Nlp is able to improve nucleotide excision repair (NER) activity and protects cells against UV radiation. Upon exposure of cells to UVC, Nlp is translocated into the nucleus. The C-terminus (1030-1382) of Nlp is necessary and sufficient for its nuclear import. Upon UVC radiation, Nlp interacts with XPA and ERCC1, and enhances their association. Interestingly, down-regulated expression of Nlp is found to be associated with human skin cancers, indicating that dysregulated Nlp might be related to the development of human skin cancers. Taken together, this study identifies mitotic protein Nlp as a new and important member of NER pathway and thus provides novel insights into understanding of regulatory machinery involved in NER. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

Chronic low-dose ultraviolet-induced mutagenesis in nucleotide excision repair-deficient cells.

PubMed

Haruta, Nami; Kubota, Yoshino; Hishida, Takashi

2012-09-01

UV radiation induces two major types of DNA lesions, cyclobutane pyrimidine dimers (CPDs) and 6-4 pyrimidine-pyrimidine photoproducts, which are both primarily repaired by nucleotide excision repair (NER). Here, we investigated how chronic low-dose UV (CLUV)-induced mutagenesis occurs in rad14Δ NER-deficient yeast cells, which lack the yeast orthologue of human xeroderma pigmentosum A (XPA). The results show that rad14Δ cells have a marked increase in CLUV-induced mutations, most of which are C→T transitions in the template strand for transcription. Unexpectedly, many of the CLUV-induced C→T mutations in rad14Δ cells are dependent on translesion synthesis (TLS) DNA polymerase η, encoded by RAD30, despite its previously established role in error-free TLS. Furthermore, we demonstrate that deamination of cytosine-containing CPDs contributes to CLUV-induced mutagenesis. Taken together, these results uncover a novel role for Polη in the induction of C→T transitions through deamination of cytosine-containing CPDs in CLUV-exposed NER deficient cells. More generally, our data suggest that Polη can act as both an error-free and a mutagenic DNA polymerase, depending on whether the NER pathway is available to efficiently repair damaged templates.

Effect of the anti-neoplastic drug doxorubicin on XPD-mutated DNA repair-deficient human cells.

PubMed

Saffi, Jenifer; Agnoletto, Mateus H; Guecheva, Temenouga N; Batista, Luís F Z; Carvalho, Helotonio; Henriques, João A P; Stary, Anne; Menck, Carlos F M; Sarasin, Alain

2010-01-02

Doxorubicin (DOX), a member of the anthracycline group, is a widely used drug in cancer therapy. The mechanisms of DOX action include topoisomerase II-poisoning, free radical release, DNA adducts and interstrand cross-link (ICL) formation. Nucleotide excision repair (NER) is involved in the removal of helix-distorting lesions and chemical adducts, however, little is known about the response of NER-deficient cell lines to anti-tumoral drugs like DOX. Wild type and XPD-mutated cells, harbouring mutations in different regions of this gene and leading to XP-D, XP/CS or TTD diseases, were treated with this drug and analyzed for cell cycle arrest and DNA damage by comet assay. The formation of DSBs was also investigated by determination of gammaH2AX foci. Our results indicate that all three NER-deficient cell lines tested are more sensitive to DOX treatment, when compared to wild type cells or XP cells complemented by the wild type XPD cDNA, suggesting that NER is involved in the removal of DOX-induced lesions. The cell cycle analysis showed the characteristic G2 arrest in repair-proficient MRC5 cell line after DOX treatment, whereas the repair-deficient cell lines presented significant increase in sub-G1 fraction. The NER-deficient cell lines do not show different patterns of DNA damage formation as assayed by comet assay and phosphorylated H2AX foci formation. Knock-down of topoisomerase IIalpha with siRNA leads to increased survival in both MRC5 and XP cells, however, XP cell line still remained significantly more sensitive to the treatment by DOX. Our study suggests that the enhanced sensitivity is due to DOX-induced DNA damage that is subject to NER, as we observed decreased unscheduled DNA synthesis in XP-deficient cells upon DOX treatment. Furthermore, the complementation of the XPD-function abolished the observed sensitivity at lower DOX concentrations, suggesting that the XPD helicase activity is involved in the repair of DOX-induced lesions. Copyright (c) 2009 Elsevier B.V. All rights reserved.

Historically Speaking, "Tu" or "Vocus"?

ERIC Educational Resources Information Center

Maley, Catherine A.

1972-01-01

Comments on the usage of the second person pronouns of address ( tu" and vous") in French, and traces the usage from the fifteenth century to present day, reflecting social, religious, and political attitudes. (DS)

Enhancements for a Dynamic Data Warehousing and Mining System for Large-scale HSCB Data

DTIC Science & Technology

2016-07-20

Intelligent Automation Incorporated Enhancements for a Dynamic Data Warehousing and Mining ...Page | 2 Intelligent Automation Incorporated Monthly Report No. 4 Enhancements for a Dynamic Data Warehousing and Mining System Large-Scale HSCB...including Top Videos, Top Users, Top Words, and Top Languages, and also applied NER to the text associated with YouTube posts. We have also developed UI for

Enhancements for a Dynamic Data Warehousing and Mining System for Large-Scale HSCB Data

DTIC Science & Technology

2016-07-20

Intelligent Automation Incorporated Enhancements for a Dynamic Data Warehousing and Mining ...Page | 2 Intelligent Automation Incorporated Monthly Report No. 4 Enhancements for a Dynamic Data Warehousing and Mining System Large-Scale HSCB...including Top Videos, Top Users, Top Words, and Top Languages, and also applied NER to the text associated with YouTube posts. We have also developed UI for

Cdt2-mediated XPG degradation promotes gap-filling DNA synthesis in nucleotide excision repair

PubMed Central

Han, Chunhua; Wani, Gulzar; Zhao, Ran; Qian, Jiang; Sharma, Nidhi; He, Jinshan; Zhu, Qianzheng; Wang, Qi-En; Wani, Altaf A

2015-01-01

Xeroderma pigmentosum group G (XPG) protein is a structure-specific repair endonuclease, which cleaves DNA strands on the 3′ side of the DNA damage during nucleotide excision repair (NER). XPG also plays a crucial role in initiating DNA repair synthesis through recruitment of PCNA to the repair sites. However, the fate of XPG protein subsequent to the excision of DNA damage has remained unresolved. Here, we show that XPG, following its action on bulky lesions resulting from exposures to UV irradiation and cisplatin, is subjected to proteasome-mediated proteolytic degradation. Productive NER processing is required for XPG degradation as both UV and cisplatin treatment-induced XPG degradation is compromised in NER-deficient XP-A, XP-B, XP-C, and XP-F cells. In addition, the NER-related XPG degradation requires Cdt2, a component of an E3 ubiquitin ligase, CRL4Cdt2. Micropore local UV irradiation and in situ Proximity Ligation assays demonstrated that Cdt2 is recruited to the UV-damage sites and interacts with XPG in the presence of PCNA. Importantly, Cdt2-mediated XPG degradation is crucial to the subsequent recruitment of DNA polymerase δ and DNA repair synthesis. Collectively, our data support the idea of PCNA recruitment to damage sites which occurs in conjunction with XPG, recognition of the PCNA-bound XPG by CRL4Cdt2 for specific ubiquitylation and finally the protein degradation. In essence, XPG elimination from DNA damage sites clears the chromatin space needed for the subsequent recruitment of DNA polymerase δ to the damage site and completion of gap-filling DNA synthesis during the final stage of NER. PMID:25483071

Polymerization by DNA polymerase eta is blocked by cis-diamminedichloroplatinum(II) 1,3-d(GpTpG) cross-link: implications for cytotoxic effects in nucleotide excision repair-negative tumor cells.

PubMed

Chijiwa, Shotaro; Masutani, Chikahide; Hanaoka, Fumio; Iwai, Shigenori; Kuraoka, Isao

2010-03-01

cis-Diamminedichloroplatinum(II) (cisplatin) forms DNA adducts that interfere with replication and transcription. The most common adducts formed in vivo are 1,2-intrastrand d(GpG) cross-links (Pt-GG) and d(ApG) cross-links (Pt-AG), with minor amounts of 1,3-d(GpNpG) cross-links (Pt-GNG), interstrand cross-links and monoadducts. Although the relative contribution of these different adducts to toxicity is not known, literature implicates that Pt-GG and Pt-AG adducts block replication. Thus, nucleotide excision repair (NER), by which platinum adducts are excised, and translesion DNA synthesis (TLS), which permits adduct bypass, are thought to be associated with cisplatin resistance. Recent studies have reported that the clinical benefit from platinum-based chemotherapy is high if tumor cells express low levels of NER factors. To investigate the role of platinum-DNA adducts in mediating tumor cell survival by TLS, we examined whether 1,3-intrastrand d(GpTpG) platinum cross-links (Pt-GTG), which probably exist in NER-negative tumor cells but not in NER-positive tumor cells, are bypassed by the translesion DNA polymerase eta (pol eta), which is known to bypass Pt-GG. We show that pol eta can incorporate the correct deoxycytidine triphosphate opposite the first 3'-cross-linked G of Pt-GTG but cannot insert any nucleotides opposite the second intact T or the third 5'-cross-linked G of the adducts, thereby suggesting that TLS does not facilitate replication past Pt-GTG adducts. Thus, our findings implicate Pt-GNG adducts as mediating the cytotoxicity of platinum-DNA adducts in NER-negative tumors in vivo.

COMPREHENSIVE ANALYSES OF DNA REPAIR PATHWAYS, SMOKING, AND BLADDER CANCER RISK IN LOS ANGELES AND SHANGHAI

PubMed Central

Corral, Roman; Lewinger, Juan Pablo; Berg, David Van Den; Joshi, Amit D.; Yuan, Jian-Min; Gago-Dominguez, Manuela; Cortessis, Victoria K.; Pike, Malcolm C.; Conti, David V.; Thomas, Duncan C.; Edlund, Christopher K.; Gao, Yu-Tang; Xiang, Yong-Bing; Zhang, Wei; Su, Yu-Chen; Stern, Mariana C.

2014-01-01

Tobacco smoking is a bladder cancer risk factor and a source of carcinogens that induce DNA damage to urothelial cells. Using data and samples from 988 cases and 1,004 controls enrolled in the Los Angeles County Bladder Cancer Study and the Shanghai Bladder Cancer Study we investigated associations between bladder cancer risk and 632 tagSNPs that comprehensively capture genetic variation in 28 DNA repair genes from four DNA repair pathways: base excision repai, nucleotide excision repair (NER), non-homologous end-joining (NHEJ), and homologous recombination repair (HHR). Odds ratios (ORs) and 95% confidence intervals (CIs) for each tagSNP were corrected for multiple testing for all SNPs within each gene using pACT, and for genes within each pathway and across pathways with Bonferroni. Gene and pathway summary estimates were obtained using ARTP. We observed an association between bladder cancer and POLB rs7832529 (BER) (pACT = 0.003; ppathway = 0.021) among all, and SNPs in XPC (NER) and OGG1 (BER) among Chinese men and women, respectively. The NER pathway showed an overall association with risk among Chinese males (ARTP NER p = 0.034). The XRCC6 SNP rs2284082 (NHEJ), also in LD with SREBF2, showed an interaction with smoking (Smoking status interaction pgene = 0.001, ppathway = 0.008, poverall = 0.034). Our findings support a role in bladder carcinogenesis for regions that map close to or within BER (POLB, OGG1) and NER genes (XPC). A SNP that tags both the XRCC6 and SREBF2 genes strongly modifies the association between bladder cancer risk and smoking. PMID:24382701

The response of mammalian cells to UV-light reveals Rad54-dependent and independent pathways of homologous recombination.

PubMed

Eppink, Berina; Tafel, Agnieszka A; Hanada, Katsuhiro; van Drunen, Ellen; Hickson, Ian D; Essers, Jeroen; Kanaar, Roland

2011-11-10

Ultraviolet (UV) radiation-induced DNA lesions can be efficiently repaired by nucleotide excision repair (NER). However, NER is less effective during replication of UV-damaged chromosomes. In contrast, translesion DNA synthesis (TLS) and homologous recombination (HR) are capable of dealing with lesions in replicating DNA. The core HR protein in mammalian cells is the strand exchange protein RAD51, which is aided by numerous proteins, including RAD54. We used RAD54 as a cellular marker for HR to study the response of mammalian embryonic stem (ES) cells to UV irradiation. In contrast to yeast, ES cells lacking RAD54 are not UV sensitive. Here we show that the requirement for mammalian RAD54 is masked by active NER. By genetically inactivating NER and HR through disruption of the Xpa and Rad54 genes, respectively, we demonstrate the contribution of HR to chromosomal integrity upon UV irradiation. We demonstrate using chromosome fiber analysis at the individual replication fork level, that HR activity is important for the restart of DNA replication after induction of DNA damage by UV-light in NER-deficient cells. Furthermore, our data reveal RAD54-dependent and -independent contributions of HR to the cellular sensitivity to UV-light, and they uncover that RAD54 can compensate for the loss of TLS polymerase η with regard to UV-light sensitivity. In conclusion, we show that HR is important for the progression of UV-stalled replication forks in ES cells, and that protection of the fork is an interplay between HR and TLS. Copyright © 2011 Elsevier B.V. All rights reserved.

The versatile DNA nucleotide excision repair (NER) and its medical significance.

PubMed

Falik-Zaccai, Tzipora C; Keren, Zohar; Slor, Hanoch

2009-12-01

Two of DNA's worst enemies, ultraviolet light and chemical carcinogens, can cause damage to the molecule by mutating individual nucleotides or changing its physical structure. In most cases, genomic integrity is restored by specialized suites of proteins dedicated to repairing specific types of injuries. One restoration mechanism, called nucleotide excision repair (NER), recruits and coordinates the services of 20-30 proteins to recognize and remove structure-impairing lesions, including those induced by ultraviolet (UV) light. Mutations in a gene that encodes a protein from the NER machinery might cause a wide variety of rare inherited human disorders. Sun sensitivity, cancer, developmental retardation, neurodegeneration and premature aging characterize these syndromes. Identification of the causative genes and proteins in affected families in Israel allowed us to establish accurate molecular diagnosis of couples at risk, and provide them with better genetic counseling.

Chromosomal microarray in clinical diagnosis: a study of 337 patients with congenital anomalies and developmental delays or intellectual disability.

PubMed

Sansović, Ivona; Ivankov, Ana-Maria; Bobinec, Adriana; Kero, Mijana; Barišić, Ingeborg

2017-06-14

To determine the diagnostic yield and criteria that could help to classify and interpret the copy number variations (CNVs) detected by chromosomal microarray (CMA) technique in patients with congenital and developmental abnormalities including dysmorphia, developmental delay (DD) or intellectual disability (ID), autism spectrum disorders (ASD) and congenital anomalies (CA). CMA analysis was performed in 337 patients with DD/ID with or without dysmorphism, ASD, and/or CA. In 30 of 337 patients, chromosomal imbalances had previously been detected by classical cytogenetic and molecular cytogenetic methods. In 73 of 337 patients, clinically relevant variants were detected and better characterized. Most of them were >1 Mb. Variants of unknown clinical significance (VOUS) were discovered in 35 patients. The most common VOUS size category was <300 kb (40.5%). Deletions and de novo imbalances were more frequent in pathogenic CNV than in VOUS category. CMA had a high diagnostic yield of 43/307, excluding patients previously detected by other methods. CMA was valuable in establishing the diagnosis in a high proportion of patients. Criteria for classification and interpretation of CNVs include CNV size and type, mode of inheritance, and genotype-phenotype correlation. Agilent ISCA v2 Human Genome 8x60 K oligonucleotide microarray format proved to be reasonable resolution for clinical use, particularly in the regions that are recommended by the International Standard Cytogenomic Array (ISCA) Consortium and associated with well-established syndromes.

77 FR 71612 - Minor Boundary Revision of Saratoga National Historical Park

Federal Register 2010, 2011, 2012, 2013, 2014

2012-12-03

..., owned respectively by Open Space Conservancy, Inc., and the State of New York, will be donated to the... DEPARTMENT OF THE INTERIOR National Park Service [NPS-NER-SARA-11235; 4901-726] Minor Boundary... make minor boundary revisions to areas of the National Park System. The Committees have been so...

Science and Technology Issues Relating to Data Quality in C2 Systems

DTIC Science & Technology

2011-01-01

domains. 2 Various investigators have given different definitions of the terms “information” and “data,” depending on the context. For this paper ...in a formalized man- ner suitable for communication, interpretation or processing [2]. In the context of this paper , data includes both raw and...operate faster. Modern C2 systems, especially in a coalition environment, are among the most complex systems imaginable. In this paper , we examine

Rare Disease Biospecimens and Patient Registries: Interoperability for Research Promotion, a European Example: EuroBioBank and SpainRDR-BioNER.

PubMed

Rubinstein, Yaffa R; Posada de la Paz, Manuel; Mora, Marina

2017-01-01

Well-annotated and properly preserved specimens are crucial both for diagnostic purposes and for use in basic and pre-clinical research, and are especially important for rare disease (RD) studies. Several consortia have been established in the recent years in order to facilitate research and to maximise access to rare biological samples and data stored in rare disease biobanks and registries, among them the EuroBioBank network and the Spain National Rare Disease Registry (RDR) and Biobank (BioNER).EuroBioBank, established in 2001, was the first network of RD biobanks to operate in Europe as a service distributing human DNA, cells, and tissue to the scientific community conducting research on rare diseases.The Spanish RDR and BioNER were created for facilitating rare disease research and health-related matters. The coordination of these two bodies represents an example of great scientific value as biological samples donated by patients at BioNER are linked to clinical information collected in the RDR.Rare disease biobanks and registries will need for the future to increase their effort to improve interconnection so to enable investigators to better locate samples and associated data, while protecting security of the data and privacy of the participants and adhering to international ethical and legal requirements.

Contribution of microorganisms to non-extractable residue formation during biodegradation of ibuprofen in soil.

PubMed

Nowak, Karolina M; Girardi, Cristobal; Miltner, Anja; Gehre, Matthias; Schäffer, Andreas; Kästner, Matthias

2013-02-15

Non-extractable residues (NER) formed during biodegradation of organic contaminants in soil are considered to be mainly composed of parent compounds or their primary metabolites with hazardous potential. However, in the case of biodegradable organic compounds, the soil NER may also contain microbial biomass components, for example fatty acids (FA) and amino acids (AA). After cell death, these biomolecules are subsequently incorporated into non-living soil organic matter (SOM) and are stabilised ultimately forming hardly extractable residues of biogenic origin. We investigated biodegradation of (13)C(6)-ibuprofen, in particular the metabolic incorporation of the (13)C-label into FA and AA and their fate in soil over 90 days. (13)C-FA and (13)C-AA amounts in the living microbial biomass fraction initially increased, then decreased over time and were continuously incorporated into the non-living SOM pool. The (13)C-FA in the non-living SOM remained stable from day 59 whereas the contents of (13)C-AA slightly increased until the end. After 90 days, nearly all NER were biogenic as they were made up almost completely by natural biomass compounds. The presented data demonstrated that the potential environmental risks related to the ibuprofen-derived NER are overestimated. Copyright © 2012 Elsevier B.V. All rights reserved.

Strand-specific Recognition of DNA Damages by XPD Provides Insights into Nucleotide Excision Repair Substrate Versatility*

PubMed Central

Buechner, Claudia N.; Heil, Korbinian; Michels, Gudrun; Carell, Thomas; Kisker, Caroline; Tessmer, Ingrid

2014-01-01

Recognition and removal of DNA damages is essential for cellular and organismal viability. Nucleotide excision repair (NER) is the sole mechanism in humans for the repair of carcinogenic UV irradiation-induced photoproducts in the DNA, such as cyclobutane pyrimidine dimers. The broad substrate versatility of NER further includes, among others, various bulky DNA adducts. It has been proposed that the 5′-3′ helicase XPD (xeroderma pigmentosum group D) protein plays a decisive role in damage verification. However, despite recent advances such as the identification of a DNA-binding channel and central pore in the protein, through which the DNA is threaded, as well as a dedicated lesion recognition pocket near the pore, the exact process of target site recognition and verification in eukaryotic NER still remained elusive. Our single molecule analysis by atomic force microscopy reveals for the first time that XPD utilizes different recognition strategies to verify structurally diverse lesions. Bulky fluorescein damage is preferentially detected on the translocated strand, whereas the opposite strand preference is observed for a cyclobutane pyrimidine dimer lesion. Both states, however, lead to similar conformational changes in the resulting specific complexes, indicating a merge to a “final” verification state, which may then trigger the recruitment of further NER proteins. PMID:24338567

Xeroderma pigmentosum complementation group C protein (XPC) serves as a general sensor of damaged DNA

PubMed Central

Shell, Steven M.; Hawkins, Edward K.; Tsai, Miaw-Sheue; Hlaing, Aye Su; Rizzo, Carmelo J.; Chazin, Walter J.

2013-01-01

The xeroderma pigmentosum complementation group C protein (XPC) serves as the primary initiating factor in the global genome nucleotide excision repair pathway (GG-NER). Recent reports suggest XPC also stimulates repair of oxidative lesions by base excision repair. However, whether XPC distinguishes among various types of DNA lesions remains unclear. Although the DNA binding properties of XPC have been studied by several groups, there is a lack of consensus over whether XPC discriminates between DNA damaged by lesions associated with NER activity versus those that are not. In this study we report a high-throughput fluorescence anisotropy assay used to measure the DNA binding affinity of XPC for a panel of DNA substrates containing a range of chemical lesions in a common sequence. Our results demonstrate that while XPC displays a preference for binding damaged DNA, the identity of the lesion has little effect on the binding affinity of XPC. Moreover, XPC was equally capable of binding to DNA substrates containing lesions not repaired by GG-NER. Our results support an indirect read-out model for sensing the presence of lesions by human XPC and suggest XPC may act as a general sensor of damaged DNA capable of recognizing DNA containing lesions not repaired by NER. PMID:24051049

Linking intended visitation to regional economic impact models of bison and elk management

USGS Publications Warehouse

Loomis, J.; Caughlan, L.

2004-01-01

This article links intended National Park visitation estimates to regional economic models to calculate the employment impacts of alternative bison and elk management strategies. The survey described alternative National Elk Refuge (NER) management actions and the effects on elk and bison populations at the NER and adjacent Grand Teton National Park (GTNP). Park visitors were then asked if they would change their number of visits with each potential management action. Results indicate there would be a 10% decrease in visitation if bison populations were reduced from 600 to 400 animals and elk populations were reduced in GTNP and the NER. The related decrease in jobs in Teton counties of Wyoming and Idaho is estimated at 5.5%. Adopting a “no active management” option of never feeding elk and bison on the NER yields about one-third the current bison population (200 bison) and about half the elk population. Visitors surveyed about this management option would take about 20% fewer trips, resulting in an 11.3% decrease in employment. Linking intended visitation surveys and regional economic models represents a useful tool for natural resource planners who must present the consequences of potential actions in Environmental Impact Statements and plans to the public and decision makers prior to any action being implemented.

Recognizing chemicals in patents: a comparative analysis.

PubMed

Habibi, Maryam; Wiegandt, David Luis; Schmedding, Florian; Leser, Ulf

2016-01-01

Recently, methods for Chemical Named Entity Recognition (NER) have gained substantial interest, driven by the need for automatically analyzing todays ever growing collections of biomedical text. Chemical NER for patents is particularly essential due to the high economic importance of pharmaceutical findings. However, NER on patents has essentially been neglected by the research community for long, mostly because of the lack of enough annotated corpora. A recent international competition specifically targeted this task, but evaluated tools only on gold standard patent abstracts instead of full patents; furthermore, results from such competitions are often difficult to extrapolate to real-life settings due to the relatively high homogeneity of training and test data. Here, we evaluate the two state-of-the-art chemical NER tools, tmChem and ChemSpot, on four different annotated patent corpora, two of which consist of full texts. We study the overall performance of the tools, compare their results at the instance level, report on high-recall and high-precision ensembles, and perform cross-corpus and intra-corpus evaluations. Our findings indicate that full patents are considerably harder to analyze than patent abstracts and clearly confirm the common wisdom that using the same text genre (patent vs. scientific) and text type (abstract vs. full text) for training and testing is a pre-requisite for achieving high quality text mining results.

Angular dependence of etch rates in the etching of poly-Si and fluorocarbon polymer using SF6, C4F8, and O2 plasmas

NASA Astrophysics Data System (ADS)

Min, Jae-Ho; Lee, Gyeo-Re; Lee, Jin-Kwan; Moon, Sang Heup; Kim, Chang-Koo

2004-05-01

The dependences of etch rates on the angle of ions incident on the substrate surface in four plasma/substrate systems that constitute the advanced Bosch process were investigated using a Faraday cage designed for the accurate control of the ion-incident angle. The four systems, established by combining discharge gases and substrates, were a SF6/poly-Si, a SF6/fluorocarbon polymer, an O2/fluorocarbon polymer, and a C4F8/Si. In the case of SF6/poly-Si, the normalized etch rates (NERs), defined as the etch rates normalized by the rate on the horizontal surface, were higher at all angles than values predicted from the cosine of the ion-incident angle. This characteristic curve shape was independent of changes in process variables including the source power and bias voltage. Contrary to the earlier case, the NERs for the O2/polymer decreased and eventually reached much lower values than the cosine values at angles between 30° and 70° when the source power was increased and the bias voltage was decreased. On the other hand, the NERs for the SF6/polymer showed a weak dependence on the process variables. In the case of C4F8/Si, which is used in the Bosch process for depositing a fluorocarbon layer on the substrate surface, the deposition rate varied with the ion incident angle, showing an S-shaped curve. These characteristic deposition rate curves, which were highly dependent on the process conditions, could be divided into four distinct regions: a Si sputtering region, an ion-suppressed polymer deposition region, an ion-enhanced polymer deposition region, and an ion-free polymer deposition region. Based on the earlier characteristic angular dependences of the etch (or deposition) rates in the individual systems, ideal process conditions for obtaining an anisotropic etch profile in the advanced Bosch process are proposed. .

Resolving anaphoras for the extraction of drug-drug interactions in pharmacological documents

PubMed Central

2010-01-01

Background Drug-drug interactions are frequently reported in the increasing amount of biomedical literature. Information Extraction (IE) techniques have been devised as a useful instrument to manage this knowledge. Nevertheless, IE at the sentence level has a limited effect because of the frequent references to previous entities in the discourse, a phenomenon known as 'anaphora'. DrugNerAR, a drug anaphora resolution system is presented to address the problem of co-referring expressions in pharmacological literature. This development is part of a larger and innovative study about automatic drug-drug interaction extraction. Methods The system uses a set of linguistic rules drawn by Centering Theory over the analysis provided by a biomedical syntactic parser. Semantic information provided by the Unified Medical Language System (UMLS) is also integrated in order to improve the recognition and the resolution of nominal drug anaphors. Besides, a corpus has been developed in order to analyze the phenomena and evaluate the current approach. Each possible case of anaphoric expression was looked into to determine the most effective way of resolution. Results An F-score of 0.76 in anaphora resolution was achieved, outperforming significantly the baseline by almost 73%. This ad-hoc reference line was developed to check the results as there is no previous work on anaphora resolution in pharmalogical documents. The obtained results resemble those found in related-semantic domains. Conclusions The present approach shows very promising results in the challenge of accounting for anaphoric expressions in pharmacological texts. DrugNerAr obtains similar results to other approaches dealing with anaphora resolution in the biomedical domain, but, unlike these approaches, it focuses on documents reflecting drug interactions. The Centering Theory has proved being effective at the selection of antecedents in anaphora resolution. A key component in the success of this framework is the analysis provided by the MMTx program and the DrugNer system that allows to deal with the complexity of the pharmacological language. It is expected that the positive results of the resolver increases performance of our future drug-drug interaction extraction system. PMID:20406499

Vous avez dit "immersion?" (You Said "Immersion?").

ERIC Educational Resources Information Center

Gajo, Laurent, Ed.

1998-01-01

Articles on immersion and bilingual education include these: "Terminological Considerations Regarding Content and Language Integrated Learning" (Tarja Nikula, David Marsh); "Educazione bilingue e multiculturale, istruzione bilingue, immersione totale: quattro nozioni da definire" ("Bilingual and Multicultural Education,…

[Combined G-banded karyotyping and multiplex ligation-dependent probe amplification for the detection of chromosomal abnormalities in fetuses with congenital heart defects].

PubMed

Liu, Yang; Xie, Jiansheng; Geng, Qian; Xu, Zhiyong; Wu, Weiqin; Luo, Fuwei; Li, Suli; Wang, Qin; Chen, Wubin; Tan, Hongxi; Zhang, Hu

2017-02-10

To assess the value of G-banded karyotyping in combination with multiplex ligation-dependent probe amplification (MLPA) as a tool for the detection of chromosomal abnormalities in fetuses with congenital heart defects. The combined method was used to analyze 104 fetuses with heart malformations identified by ultrasonography. Abnormal findings were confirmed with chromosomal microarray analysis (CMA). Nineteen (18%) fetuses were found to harbor chromosomal aberrations by G-banded karyotyping and MLPA. For 93 cases, CMA has detected abnormalities in 14 cases including 10 pathogenic copy number variations (CNVs) and 4 CNVs of uncertain significance (VOUS). MLPA was able to detect all of the pathogenic CNVs and 1 VOUS CNV. Combined use of G-banded karyotyping and MLPA is a rapid, low-cost and effective method to detect chromosomal abnormalities in fetuses with various heart malformations.

The role of microalgae as biodiesel feedstock in a tropical setting: Economics, agro-energy competitiveness, and potential impacts on regional agricultural feedstock production

NASA Astrophysics Data System (ADS)

Boll, Matias G.

The objective of this study is to obtain a realistic evaluation of the potential role of microalgae as a biodiesel feedstock in a tropical setting. First, microalgae economics are estimated, including the detailed design of a 400 ha microalgae open pond production farm together with the microalgae biomass and crude oil production costs calculations. Sensitivity analysis and a stochastic evaluation of the microalgae venture chances for profit are also included. Next, microalgae potential for biodiesel production is compared to traditional oil crops such as soybeans and African palm. This comparison is performed using the Northeast Region (NER) of Brazil as background. Six potential biodiesel feedstock sources produced in the NER and microalgae are compared considering selected environmental, economic and social sustainability indicators. Finally, in the third chapter, the study proposes a cropland allocation model for the NER. The model aims to offer insights to the decision maker concerning biofuel development strategies and their impact on regional agricultural feedstock production. In the model, cropland allocation among three agriculture feedstock sectors, namely staple food, commodity export and biofuel is optimized through the use of the multiple objective technique referred to as compromise programming (CP). Our results indicate a projected microalgae total production cost of R 78,359 ha-1 (US43,533), which has a breakdown as follows: R 34,133 ha-1 (US18,963) for operating costs and R 44,226 ha-1 (US24,570) for overhead (ownership) costs. Our stochastic analysis indicates that microalgae production under the conditions assumed in the baseline scenario of this study has a 0% chance to present a positive NPV for a microalgae crude oil price of R 1.86. This price corresponds to an international oil price around US 77 bbl-1. To obtain a reasonable investment return (IRR = 12%) from the microalgae farm, an international oil price as high as US 461 bbl-1 is required. Despite the advantage of using about 14 times less cropland area (0.13 ha boe-1 ), microalgae presented significant disadvantages as compared to some of the traditional oil crops. Among these is the significant amount of N fertilizer and water demanded by microalgae production, namely 205 kg and 4,990 boe -1, about 132% and 30% higher than the second highest value among the crops compared in this study, respectively. Optimized CP scenarios expanded annual cropland allocation to 14.58 million ha in the NER, year 2017, compared to 11.04 and 12.81 million ha in current (2007) and baseline (2017) scenarios, respectively. In comparison to the baseline scenario, cropland expansions allied to the shift of the commodities export dedicated cropland to the biofuel production sector in CP scenarios significantly increased the NER fuel autonomy (95%) and reduced its R 5,126 million reais deficit baseline comprehensive feedstock trade balance by 79%. Contrary to the concerns usually referred to biofuel development, our model indicates that in the NER case, it is the commodity export, rather than the staple food agriculture feedstock production sector, that is mostly affected by the biofuel cropland allocation demand. When compared to traditional oil crops, microalgae-based biodiesel scenarios could not significantly improve regional staple food autonomy, increasing this objective by 1% only. The NER fuel autonomy, in its turn, is positively impacted in the microalgae scenarios, but the increment as compared to the traditional oil crops is rather small, namely 2% and 7% in the B5 and B10 levels, respectively. These results indicate that the potential advantages expected for the microalgae-based biodiesel introduction did not materialize for the NER. It is concluded that the adoption of microalgae-based biodiesel is not an interesting biofuel alternative for the NER of Brazil for the next ten years.

Both base excision repair and nucleotide excision repair in humans are influenced by nutritional factors.

PubMed

Brevik, Asgeir; Karlsen, Anette; Azqueta, Amaya; Tirado, Anna Estaban; Blomhoff, Rune; Collins, Andrew

2011-01-01

Lack of reliable assays for DNA repair has largely prevented measurements of DNA repair from being included in human biomonitoring studies. Using newly developed modifications of the comet assay we tested whether a fruit- and antioxidant-rich plant-based intervention could affect base excision repair (BER) and nucleotide excision repair (NER) in a group of 102 male volunteers. BER and NER repair capacities were measured in lymphocytes before and after a dietary intervention lasting 8 weeks. The study had one control group, one group consuming three kiwifruits per day and one group consuming a variety of antioxidant-rich fruits and plant products in addition to their normal diet. DNA strand breaks were reduced following consumption of both kiwifruits (13%, p = 0.05) and antioxidant-rich plant products (20%, p = 0.02). Increased BER (55%, p = 0.01) and reduced NER (-39%, p < 0.01) were observed in the group consuming a wide variety of plant products. Reduced NER was also observed in the kiwifruit group (-38%, p = 0.05), but BER was not affected in this group. Here we have demonstrated that DNA repair is affected by diet and that modified versions of the comet assay can be used to assess activity of different DNA repair pathways in human biomonitoring studies. Copyright © 2010 John Wiley & Sons, Ltd.

PTEN positively regulates UVB-induced DNA damage repair

PubMed Central

Ming, Mei; Feng, Li; Shea, Christopher R.; Soltani, Keyoumars; Zhao, Baozhong; Han, Weinong; Smart, Robert C.; Trempus, Carol S.; He, Yu-Ying

2011-01-01

Non-melanoma skin cancer is the most common cancer in the U.S., where DNA-damaging UVB radiation from the sun remains the major environmental risk factor. However, the critical genetic targets of UVB radiation are undefined. Here we show that attenuating PTEN in epidermal keratinocytes is a predisposing factor for UVB-induced skin carcinogenesis in mice. In skin papilloma and squamous cell carcinoma (SCC), levels of PTEN were reduced compared to skin lacking these lesions. Likewise, there was a reduction in PTEN levels in human premalignant actinic keratosis and malignant SCC, supporting a key role for PTEN in human skin cancer formation and progression. PTEN downregulation impaired the capacity of global genomic nucleotide excision repair (GG-NER), a critical mechanism for removing UVB-induced mutagenic DNA lesions. In contrast to the response to ionizing radiation, PTEN downregulation prolonged UVB-induced growth arrest and increased the activation of the Chk1 DNA damage pathway in an AKT-independent manner, likely due to reduced DNA repair. PTEN loss also suppressed expression of the key GG-NER protein xeroderma pigmentosum C (XPC) through the AKT/p38 signaling axis. Reconstitution of XPC levels in PTEN-inhibited cells restored GG-NER capacity. Taken together, our findings define PTEN as an essential genomic gatekeeper in the skin, through its ability to positively regulate XPC-dependent GG-NER following DNA damage. PMID:21771908

Assessment of regional downscaling simulations for long term mean, excess and deficit Indian Summer Monsoons

NASA Astrophysics Data System (ADS)

Varikoden, Hamza; Mujumdar, M.; Revadekar, J. V.; Sooraj, K. P.; Ramarao, M. V. S.; Sanjay, J.; Krishnan, R.

2018-03-01

This study undertakes a comprehensive assessment of dynamical downscaling of summer monsoon (June-September; JJAS) rainfall over heterogeneous regions namely the Western Ghats (WG), Central India (CI) and North-Eastern Region (NER) for long term mean, excess and deficit episodes for the historical period from 1951 to 2005. This downscaling assessment is based on six Coordinated Regional Climate Downscaling Experiments (CORDEX) for South Asia (SAS) region, their five driving Global Climate Models (GCM) simulations along with observations from India Meteorological Department (IMD) and Asian Precipitation Highly Resolved Observational Integrated Towards Evaluation for Water Resources (APHRODITE). The analysis reveals an overall reduction of dry bias in rainfall across the regions of Indian sub-continent in most of the downscaled CORDEX-SAS models and in their ensemble mean as compared to that of driving GCMs. The interannual variabilities during historical period are reasonably captured by the ensemble means of CORDEX-SAS simulations with an underestimation of 0.43%, 38% and 52% for the WG, CI and NER, respectively. Upon careful examination of the CORDEX-SAS models and their driving GCMs revealed considerable improvement in the regionally downscaled rainfall. The value addition of dynamical downscaling is apparent over the WG in Regional Climate Model (RCM) simulations with an improvement of more than 30% for the long term mean, excess and deficit episodes from their driving GCMs. In the case of NER, the improvement in the downscaled rainfall product is more than 10% for all the episodes. However, the value addition in the CORDEX-SAS simulations for CI region, dominantly influenced by synoptic scale processes, is not clear. Nevertheless, the reduction of dry bias in the complex topographical regions is remarkable. The relative performance of dynamical downscaling of rainfall over complex topography in response to local forcing and orographic lifting depict the value addition (30% over WG and 10% over NER, with a statistical significance of more than 5% level), when compared with the synoptic scale system induced rainfall over the plains of central-India.

Enhancements for a Dynamic Data Warehousing and Mining System for Large-Scale Human Social Cultural Behavioral (HSBC) Data

DTIC Science & Technology

2016-09-26

Intelligent Automation Incorporated Enhancements for a Dynamic Data Warehousing and Mining ...Enhancements for a Dynamic Data Warehousing and Mining System for N00014-16-P-3014 Large-Scale Human Social Cultural Behavioral (HSBC) Data 5b. GRANT NUMBER...Representative Media Gallery View. We perform Scraawl’s NER algorithm to the text associated with YouTube post, which classifies the named entities into

Structural dynamics and interactions of Xeroderma pigmentosum complementation group A (XPA98-210) with damaged DNA.

PubMed

Pradhan, Sushmita; Mattaparthi, Venkata Satish Kumar

2017-10-25

Nucleotide excision repair (NER) in higher organisms repair massive DNA abrasions caused by ultraviolet rays, and various mutagens, where Xeroderma pigmentosum group A (XPA) protein is known to be involved in damage recognition step. Any mutations in XPA cause classical Xeroderma pigmentosum disease. The extent to which XPA is required in the NER is still unclear. Here, we present the comparative study on the structural and conformational changes in globular DNA binding domain of XPA 98-210 in DNA bound and DNA free state. Atomistic molecular dynamics simulation was carried out for both XPA 98-210 systems using AMBER force fields. We observed that XPA 98-210 in presence of damaged DNA exhibited more structural changes compared to XPA 98-210 in its free form. When XPA is in contact with DNA, we found marked stability of the complex due to the formation of characteristic longer antiparallel β-sheets consisting mainly lysine residues.

Inefficient DNA Repair Is an Aging-Related Modifier of Parkinson's Disease.

PubMed

Sepe, Sara; Milanese, Chiara; Gabriels, Sylvia; Derks, Kasper W J; Payan-Gomez, Cesar; van IJcken, Wilfred F J; Rijksen, Yvonne M A; Nigg, Alex L; Moreno, Sandra; Cerri, Silvia; Blandini, Fabio; Hoeijmakers, Jan H J; Mastroberardino, Pier G

2016-05-31

The underlying relation between Parkinson's disease (PD) etiopathology and its major risk factor, aging, is largely unknown. In light of the causative link between genome stability and aging, we investigate a possible nexus between DNA damage accumulation, aging, and PD by assessing aging-related DNA repair pathways in laboratory animal models and humans. We demonstrate that dermal fibroblasts from PD patients display flawed nucleotide excision repair (NER) capacity and that Ercc1 mutant mice with mildly compromised NER exhibit typical PD-like pathological alterations, including decreased striatal dopaminergic innervation, increased phospho-synuclein levels, and defects in mitochondrial respiration. Ercc1 mouse mutants are also more sensitive to the prototypical PD toxin MPTP, and their transcriptomic landscape shares important similarities with that of PD patients. Our results demonstrate that specific defects in DNA repair impact the dopaminergic system and are associated with human PD pathology and might therefore constitute an age-related risk factor for PD. Copyright © 2016 The Author(s). Published by Elsevier Inc. All rights reserved.

DNA Damage Induced by Alkylating Agents and Repair Pathways

PubMed Central

Kondo, Natsuko; Takahashi, Akihisa; Ono, Koji; Ohnishi, Takeo

2010-01-01

The cytotoxic effects of alkylating agents are strongly attenuated by cellular DNA repair processes, necessitating a clear understanding of the repair mechanisms. Simple methylating agents form adducts at N- and O-atoms. N-methylations are removed by base excision repair, AlkB homologues, or nucleotide excision repair (NER). O6-methylguanine (MeG), which can eventually become cytotoxic and mutagenic, is repaired by O6-methylguanine-DNA methyltransferase, and O6MeG:T mispairs are recognized by the mismatch repair system (MMR). MMR cannot repair the O6MeG/T mispairs, which eventually lead to double-strand breaks. Bifunctional alkylating agents form interstrand cross-links (ICLs) which are more complex and highly cytotoxic. ICLs are repaired by complex of NER factors (e.g., endnuclease xeroderma pigmentosum complementation group F-excision repair cross-complementing rodent repair deficiency complementation group 1), Fanconi anemia repair, and homologous recombination. A detailed understanding of how cells cope with DNA damage caused by alkylating agents is therefore potentially useful in clinical medicine. PMID:21113301

Uncommon nucleotide excision repair phenotypes revealed by targeted high-throughput sequencing.

PubMed

Calmels, Nadège; Greff, Géraldine; Obringer, Cathy; Kempf, Nadine; Gasnier, Claire; Tarabeux, Julien; Miguet, Marguerite; Baujat, Geneviève; Bessis, Didier; Bretones, Patricia; Cavau, Anne; Digeon, Béatrice; Doco-Fenzy, Martine; Doray, Bérénice; Feillet, François; Gardeazabal, Jesus; Gener, Blanca; Julia, Sophie; Llano-Rivas, Isabel; Mazur, Artur; Michot, Caroline; Renaldo-Robin, Florence; Rossi, Massimiliano; Sabouraud, Pascal; Keren, Boris; Depienne, Christel; Muller, Jean; Mandel, Jean-Louis; Laugel, Vincent

2016-03-22

Deficient nucleotide excision repair (NER) activity causes a variety of autosomal recessive diseases including xeroderma pigmentosum (XP) a disorder which pre-disposes to skin cancer, and the severe multisystem condition known as Cockayne syndrome (CS). In view of the clinical overlap between NER-related disorders, as well as the existence of multiple phenotypes and the numerous genes involved, we developed a new diagnostic approach based on the enrichment of 16 NER-related genes by multiplex amplification coupled with next-generation sequencing (NGS). Our test cohort consisted of 11 DNA samples, all with known mutations and/or non pathogenic SNPs in two of the tested genes. We then used the same technique to analyse samples from a prospective cohort of 40 patients. Multiplex amplification and sequencing were performed using AmpliSeq protocol on the Ion Torrent PGM (Life Technologies). We identified causative mutations in 17 out of the 40 patients (43%). Four patients showed biallelic mutations in the ERCC6(CSB) gene, five in the ERCC8(CSA) gene: most of them had classical CS features but some had very mild and incomplete phenotypes. A small cohort of 4 unrelated classic XP patients from the Basque country (Northern Spain) revealed a common splicing mutation in POLH (XP-variant), demonstrating a new founder effect in this population. Interestingly, our results also found ERCC2(XPD), ERCC3(XPB) or ERCC5(XPG) mutations in two cases of UV-sensitive syndrome and in two cases with mixed XP/CS phenotypes. Our study confirms that NGS is an efficient technique for the analysis of NER-related disorders on a molecular level. It is particularly useful for phenotypes with combined features or unusually mild symptoms. Targeted NGS used in conjunction with DNA repair functional tests and precise clinical evaluation permits rapid and cost-effective diagnosis in patients with NER-defects.

Unusual ruby-sapphire transition in alluvial megacrysts, Cenozoic basaltic gem field, New England, New South Wales, Australia

NASA Astrophysics Data System (ADS)

Sutherland, Frederick L.; Graham, Ian T.; Harris, Stephen J.; Coldham, Terry; Powell, William; Belousova, Elena A.; Martin, Laure

2017-05-01

Rare ruby crystals appear among prevailing sapphire crystals mined from placers within basaltic areas in the New England gem-field, New South Wales, Australia. New England ruby (NER) has distinctive trace element features compared to those from ruby elsewhere in Australia and indeed most ruby from across the world. The NER suite includes ruby (up to 3370 ppm Cr), pink sapphire (up to 1520 ppm Cr), white sapphire (up to 910 ppm) and violet, mauve, purple, or bluish sapphire (up to 1410 ppm Cr). Some crystals show outward growth banding in this respective colour sequence. All four colour zones are notably high in Ga (up to 310 ppm) and Si (up to 1820 ppm). High Ga and Ga/Mg values are unusual in ruby and its trace element plots (laser ablation-inductively coupled plasma-mass spectrometry) and suggests that magmatic-metasomatic inputs were involved in the NER suite genesis. In situ oxygen isotope analyses (secondary ion mass spectrometry) across the NER suite colour range showed little variation (n = 22; δ18O = 4.4 ± 0.4, 2σ error), and are values typical for corundum associated with ultramafic/mafic rocks. The isolated NER xenocryst suite, corroded by basalt transport and with few internal inclusions, presents a challenge in deciphering its exact origin. Detailed consideration of its high Ga chemistry in relation to the known geology of the surrounding region was used to narrow down potential sources. These include Late Palaeozoic-Triassic fractionated I-type granitoid magmas or Mesozoic-Cenozoic felsic fractionates from basaltic magmas that interacted with early Palaeozoic Cr-bearing ophiolite bodies in the New England Orogen. Other potential sources may lie deeper within lower crust-mantle metamorphic assemblages, but need to match the anomalous high-Ga geochemistry of the New England ruby suite.

Silymarin Protects Epidermal Keratinocytes from Ultraviolet Radiation-Induced Apoptosis and DNA Damage by Nucleotide Excision Repair Mechanism

PubMed Central

Katiyar, Santosh K.; Mantena, Sudheer K.; Meeran, Syed M.

2011-01-01

Solar ultraviolet (UV) radiation is a well recognized epidemiologic risk factor for melanoma and non-melanoma skin cancers. This observation has been linked to the accumulation of UVB radiation-induced DNA lesions in cells, and that finally lead to the development of skin cancers. Earlier, we have shown that topical treatment of skin with silymarin, a plant flavanoid from milk thistle (Silybum marianum), inhibits photocarcinogenesis in mice; however it is less understood whether chemopreventive effect of silymarin is mediated through the repair of DNA lesions in skin cells and that protect the cells from apoptosis. Here, we show that treatment of normal human epidermal keratinocytes (NHEK) with silymarin blocks UVB-induced apoptosis of NHEK in vitro. Silymarin reduces the amount of UVB radiation-induced DNA damage as demonstrated by reduced amounts of cyclobutane pyrimidine dimers (CPDs) and as measured by comet assay, and that ultimately may lead to reduced apoptosis of NHEK. The reduction of UV radiation-induced DNA damage by silymarin appears to be related with induction of nucleotide excision repair (NER) genes, because UV radiation-induced apoptosis was not blocked by silymarin in NER-deficient human fibroblasts. Cytostaining and dot-blot analysis revealed that silymarin repaired UV-induced CPDs in NER-proficient fibroblasts from a healthy individual but did not repair UV-induced CPD-positive cells in NER-deficient fibroblasts from patients suffering from xeroderma pigmentosum complementation-A disease. Similarly, immunohistochemical analysis revealed that silymarin did not reduce the number of UVB-induced sunburn/apoptotic cells in the skin of NER-deficient mice, but reduced the number of sunburn cells in their wild-type counterparts. Together, these results suggest that silymarin exert the capacity to reduce UV radiation-induced DNA damage and, thus, prevent the harmful effects of UV radiation on the genomic stability of epidermal cells. PMID:21731736

ATR- and ATM-Mediated DNA Damage Response Is Dependent on Excision Repair Assembly during G1 but Not in S Phase of Cell Cycle.

PubMed

Ray, Alo; Blevins, Chessica; Wani, Gulzar; Wani, Altaf A

2016-01-01

Cell cycle checkpoint is mediated by ATR and ATM kinases, as a prompt early response to a variety of DNA insults, and culminates in a highly orchestrated signal transduction cascade. Previously, we defined the regulatory role of nucleotide excision repair (NER) factors, DDB2 and XPC, in checkpoint and ATR/ATM-dependent repair pathway via ATR and ATM phosphorylation and recruitment to ultraviolet radiation (UVR)-induced damage sites. Here, we have dissected the molecular mechanisms of DDB2- and XPC- mediated regulation of ATR and ATM recruitment and activation upon UVR exposures. We show that the ATR and ATM activation and accumulation to UVR-induced damage not only depends on DDB2 and XPC, but also on the NER protein XPA, suggesting that the assembly of an active NER complex is essential for ATR and ATM recruitment. ATR and ATM localization and H2AX phosphorylation at the lesion sites occur as early as ten minutes in asynchronous as well as G1 arrested cells, showing that repair and checkpoint-mediated by ATR and ATM starts early upon UV irradiation. Moreover, our results demonstrated that ATR and ATM recruitment and H2AX phosphorylation are dependent on NER proteins in G1 phase, but not in S phase. We reasoned that in G1 the UVR-induced ssDNA gaps or processed ssDNA, and the bound NER complex promote ATR and ATM recruitment. In S phase, when the UV lesions result in stalled replication forks with long single-stranded DNA, ATR and ATM recruitment to these sites is regulated by different sets of proteins. Taken together, these results provide evidence that UVR-induced ATR and ATM recruitment and activation differ in G1 and S phases due to the existence of distinct types of DNA lesions, which promote assembly of different proteins involved in the process of DNA repair and checkpoint activation.

The Mechanism of Nucleotide Excision Repair-Mediated UV-Induced Mutagenesis in Nonproliferating Cells

PubMed Central

Kozmin, Stanislav G.; Jinks-Robertson, Sue

2013-01-01

Following the irradiation of nondividing yeast cells with ultraviolet (UV) light, most induced mutations are inherited by both daughter cells, indicating that complementary changes are introduced into both strands of duplex DNA prior to replication. Early analyses demonstrated that such two-strand mutations depend on functional nucleotide excision repair (NER), but the molecular mechanism of this unique type of mutagenesis has not been further explored. In the experiments reported here, an ade2 adeX colony-color system was used to examine the genetic control of UV-induced mutagenesis in nondividing cultures of Saccharomyces cerevisiae. We confirmed a strong suppression of two-strand mutagenesis in NER-deficient backgrounds and demonstrated that neither mismatch repair nor interstrand crosslink repair affects the production of these mutations. By contrast, proteins involved in the error-prone bypass of DNA damage (Rev3, Rev1, PCNA, Rad18, Pol32, and Rad5) and in the early steps of the DNA-damage checkpoint response (Rad17, Mec3, Ddc1, Mec1, and Rad9) were required for the production of two-strand mutations. There was no involvement, however, for the Pol η translesion synthesis DNA polymerase, the Mms2-Ubc13 postreplication repair complex, downstream DNA-damage checkpoint factors (Rad53, Chk1, and Dun1), or the Exo1 exonuclease. Our data support models in which UV-induced mutagenesis in nondividing cells occurs during the Pol ζ-dependent filling of lesion-containing, NER-generated gaps. The requirement for specific DNA-damage checkpoint proteins suggests roles in recruiting and/or activating factors required to fill such gaps. PMID:23307894

Genome-wide map of Apn1 binding sites under oxidative stress in Saccharomyces cerevisiae.

PubMed

Morris, Lydia P; Conley, Andrew B; Degtyareva, Natalya; Jordan, I King; Doetsch, Paul W

2017-11-01

The DNA is cells is continuously exposed to reactive oxygen species resulting in toxic and mutagenic DNA damage. Although the repair of oxidative DNA damage occurs primarily through the base excision repair (BER) pathway, the nucleotide excision repair (NER) pathway processes some of the same lesions. In addition, damage tolerance mechanisms, such as recombination and translesion synthesis, enable cells to tolerate oxidative DNA damage, especially when BER and NER capacities are exceeded. Thus, disruption of BER alone or disruption of BER and NER in Saccharomyces cerevisiae leads to increased mutations as well as large-scale genomic rearrangements. Previous studies demonstrated that a particular region of chromosome II is susceptible to chronic oxidative stress-induced chromosomal rearrangements, suggesting the existence of DNA damage and/or DNA repair hotspots. Here we investigated the relationship between oxidative damage and genomic instability utilizing chromatin immunoprecipitation combined with DNA microarray technology to profile DNA repair sites along yeast chromosomes under different oxidative stress conditions. We targeted the major yeast AP endonuclease Apn1 as a representative BER protein. Our results indicate that Apn1 target sequences are enriched for cytosine and guanine nucleotides. We predict that BER protects these sites in the genome because guanines and cytosines are thought to be especially susceptible to oxidative attack, thereby preventing large-scale genome destabilization from chronic accumulation of DNA damage. Information from our studies should provide insight into how regional deployment of oxidative DNA damage management systems along chromosomes protects against large-scale rearrangements. Copyright © 2017 John Wiley & Sons, Ltd. Copyright © 2017 John Wiley & Sons, Ltd.

A unified model for the molecular basis of Xeroderma pigmentosum-Cockayne Syndrome

PubMed Central

Moriel-Carretero, María; Herrera-Moyano, Emilia; Aguilera, Andrés

2015-01-01

Nucleotide Excision Repair (NER) is a pathway that removes lesions distorting the DNA helix. The molecular basis of the rare diseases Xeroderma pigmentosum (XP) and Cockayne Syndrome (CS) are explained based on the defects happening in 2 NER branches: Global-Genome Repair and Transcription-Coupled Repair, respectively. Nevertheless, both afflictions sporadically occur together, giving rise to XP/CS; however, the molecular basis of XP/CS is not understood very well. Many efforts have been made to clarify why mutations in only 4 NER genes, namely XPB, XPD, XPF and XPG, are the basis of this disease. Effort has also been made to unravel why mutations within these genes lead to XP, XP/CS, or other pathologies. We have recently contributed to the disclosure of this puzzle by characterizing Rad3/XPD mutations in Saccharomyces cerevisiae and human cells. Based on our, and others', observations, we propose a model compatible with all XP/CS cases and the current bibliography. PMID:26460500

Structure and mechanism of the UvrA-UvrB DNA damage sensor

DOE Office of Scientific and Technical Information (OSTI.GOV)

Pakotiprapha, Danaya; Samuels, Martin; Shen, Koning

2012-04-17

Nucleotide excision repair (NER) is used by all organisms to eliminate DNA lesions. We determined the structure of the Geobacillus stearothermophilus UvrA-UvrB complex, the damage-sensor in bacterial NER and a new structure of UvrA. We observe that the DNA binding surface of UvrA, previously found in an open shape that binds damaged DNA, also exists in a closed groove shape compatible with native DNA only. The sensor contains two UvrB molecules that flank the UvrA dimer along the predicted path for DNA, ~80 Å from the lesion. We show that the conserved signature domain II of UvrA mediates a nexusmore » of contacts among UvrA, UvrB and DNA. Further, in our new structure of UvrA, this domain adopts an altered conformation while an adjacent nucleotide binding site is vacant. Our findings raise unanticipated questions about NER and also suggest a revised picture of its early stages.« less

Neurodegeneration as the presenting symptom in 2 adults with xeroderma pigmentosum complementation group F

PubMed Central

Shanbhag, Niraj M.; Geschwind, Michael D.; DiGiovanna, John J.; Groden, Catherine; Godfrey, Rena; Yousefzadeh, Matthew J.; Wade, Erin A.; Niedernhofer, Laura J.; Malicdan, May Christine V.; Kraemer, Kenneth H.; Gahl, William A.

2018-01-01

Objective To describe the features of 2 unrelated adults with xeroderma pigmentosum complementation group F (XP-F) ascertained in a neurology care setting. Methods We report the clinical, imaging, molecular, and nucleotide excision repair (NER) capacity of 2 middle-aged women with progressive neurodegeneration ultimately diagnosed with XP-F. Results Both patients presented with adult-onset progressive neurologic deterioration involving chorea, ataxia, hearing loss, cognitive deficits, profound brain atrophy, and a history of skin photosensitivity, skin freckling, and/or skin neoplasms. We identified compound heterozygous pathogenic mutations in ERCC4 and confirmed deficient NER capacity in skin fibroblasts from both patients. Conclusions These cases illustrate the role of NER dysfunction in neurodegeneration and how adult-onset neurodegeneration could be the major symptom bringing XP-F patients to clinical attention. XP-F should be considered by neurologists in the differential diagnosis of patients with adult-onset progressive neurodegeneration accompanied by global brain atrophy and a history of heightened sun sensitivity, excessive freckling, and skin malignancies. PMID:29892709

Causes of childhood blindness in the northeastern states of India.

PubMed

Bhattacharjee, Harsha; Das, Kalyan; Borah, Rishi Raj; Guha, Kamalesh; Gogate, Parikshit; Purukayastha, S; Gilbert, Clare

2008-01-01

The northeastern region (NER) of India is geographically isolated and ethno-culturally different from the rest of the country. There is lacuna regarding the data on causes of blindness and severe visual impairment in children from this region. To determine the causes of severe visual impairment and blindness amongst children from schools for the blind in the four states of NER of India. Survey of children attending special education schools for the blind in the NER. Blind and severely visually impaired children (best corrected visual acuity < 20/200 in the better eye, aged up to 16 years) underwent visual acuity estimation, external ocular examination, retinoscopy and fundoscopy. Refraction and low vision workup was done where indicated. World Health Organization's reporting form was used to code anatomical and etiological causes of visual loss. Microsoft Excel Windows software with SPSS. A total of 376 students were examined of whom 258 fulfilled the eligibility criteria. The major anatomical causes of visual loss amongst the 258 were congenital anomalies (anophthalmos, microphthalmos) 93 (36.1%); corneal conditions (scarring, vitamin A deficiency) 94 (36.7%); cataract or aphakia 28 (10.9%), retinal disorders 15 (5.8%) and optic atrophy 14 (5.3%). Nearly half of the children were blind from conditions which were either preventable or treatable (48.5%). Nearly half the childhood blindness in the NER states of India is avoidable and Vitamin A deficiency forms an important component unlike other Indian states. More research and multisectorial effort is needed to tackle congenital anomalies.

Poly(ADP-ribose) Contributes to an Association between Poly(ADP-ribose) Polymerase-1 and Xeroderma Pigmentosum Complementation Group A in Nucleotide Excision Repair*

PubMed Central

King, Brenee S.; Cooper, Karen L.; Liu, Ke Jian; Hudson, Laurie G.

2012-01-01

Exposure to ultraviolet radiation (UVR) promotes the formation of UVR-induced, DNA helix distorting photolesions such as (6-4) pyrimidine-pyrimidone photoproducts and cyclobutane pyrimidine dimers. Effective repair of such lesions by the nucleotide excision repair (NER) pathway is required to prevent DNA mutations and chromosome aberrations. Poly(ADP-ribose) polymerase-1 (PARP-1) is a zinc finger protein with well documented involvement in base excision repair. PARP-1 is activated in response to DNA damage and catalyzes the formation of poly(ADP-ribose) subunits that assist in the assembly of DNA repair proteins at sites of damage. In this study, we present evidence for PARP-1 contributions to NER, extending the knowledge of PARP-1 function in DNA repair beyond the established role in base excision repair. Silencing the PARP-1 protein or inhibiting PARP activity leads to retention of UVR-induced photolesions. PARP activation following UVR exposure promotes association between PARP-1 and XPA, a central protein in NER. Administration of PARP inhibitors confirms that poly(ADP-ribose) facilitates PARP-1 association with XPA in whole cell extracts, in isolated chromatin complexes, and in vitro. Furthermore, inhibition of PARP activity decreases UVR-stimulated XPA chromatin association, illustrating that these relationships occur in a meaningful context for NER. These results provide a mechanistic link for PARP activity in the repair of UVR-induced photoproducts. PMID:23038248

Expression of domains for protein-protein interaction of nucleotide excision repair proteins modifies cancer cell sensitivity to platinum derivatives and genomic stability.

PubMed

Jordheim, Lars Petter; Cros-Perrial, Emeline; Matera, Eva-Laure; Bouledrak, Karima; Dumontet, Charles

2014-10-01

Nucleotide excision repair (NER) is involved in the repair of DNA damage caused by platinum derivatives and has been shown to decrease the cytotoxic activity of these drugs. Because protein-protein interactions are essential for NER activity, we transfected human cancer cell lines (A549 and HCT116) with plasmids coding the amino acid sequences corresponding to the interacting domains between excision repair cross-complementation group 1 (ERCC1) and xeroderma pigmentosum, complementation group A (XPA), as well as ERCC1 and xeroderma pigmentosum, complementation group F (XPF), all NER proteins. Using the 3-(4,5-dimethyl-2 thiazoyl)-2,5-diphenyl-2H-tetrazolium bromide (MTT) assay and annexin V staining, we showed that transfected A549 cells were sensitized 1.2-2.2-fold to carboplatin and that transfected HCT116 cells were sensitized 1.4-5.4-fold to oxaliplatin in vitro. In addition, transfected cells exhibited modified in vivo sensitivity to the same drugs. Finally, in particular cell models of the interaction between ERCC1 and XPF, DNA repair was decreased, as evidenced by increased phosphorylation of the histone 2AX after exposure to mitomycin C, and genomic instability was increased, as determined by comparative genomic hybridization studies. The results indicate that the interacting peptides act as dominant negatives and decrease NER activity through inhibition of protein-protein interactions. © 2014 Wiley Publishing Asia Pty Ltd.

Deep learning with word embeddings improves biomedical named entity recognition.

PubMed

Habibi, Maryam; Weber, Leon; Neves, Mariana; Wiegandt, David Luis; Leser, Ulf

2017-07-15

Text mining has become an important tool for biomedical research. The most fundamental text-mining task is the recognition of biomedical named entities (NER), such as genes, chemicals and diseases. Current NER methods rely on pre-defined features which try to capture the specific surface properties of entity types, properties of the typical local context, background knowledge, and linguistic information. State-of-the-art tools are entity-specific, as dictionaries and empirically optimal feature sets differ between entity types, which makes their development costly. Furthermore, features are often optimized for a specific gold standard corpus, which makes extrapolation of quality measures difficult. We show that a completely generic method based on deep learning and statistical word embeddings [called long short-term memory network-conditional random field (LSTM-CRF)] outperforms state-of-the-art entity-specific NER tools, and often by a large margin. To this end, we compared the performance of LSTM-CRF on 33 data sets covering five different entity classes with that of best-of-class NER tools and an entity-agnostic CRF implementation. On average, F1-score of LSTM-CRF is 5% above that of the baselines, mostly due to a sharp increase in recall. The source code for LSTM-CRF is available at https://github.com/glample/tagger and the links to the corpora are available at https://corposaurus.github.io/corpora/ . habibima@informatik.hu-berlin.de. © The Author 2017. Published by Oxford University Press. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com

Deep learning with word embeddings improves biomedical named entity recognition

PubMed Central

Habibi, Maryam; Weber, Leon; Neves, Mariana; Wiegandt, David Luis; Leser, Ulf

2017-01-01

Abstract Motivation: Text mining has become an important tool for biomedical research. The most fundamental text-mining task is the recognition of biomedical named entities (NER), such as genes, chemicals and diseases. Current NER methods rely on pre-defined features which try to capture the specific surface properties of entity types, properties of the typical local context, background knowledge, and linguistic information. State-of-the-art tools are entity-specific, as dictionaries and empirically optimal feature sets differ between entity types, which makes their development costly. Furthermore, features are often optimized for a specific gold standard corpus, which makes extrapolation of quality measures difficult. Results: We show that a completely generic method based on deep learning and statistical word embeddings [called long short-term memory network-conditional random field (LSTM-CRF)] outperforms state-of-the-art entity-specific NER tools, and often by a large margin. To this end, we compared the performance of LSTM-CRF on 33 data sets covering five different entity classes with that of best-of-class NER tools and an entity-agnostic CRF implementation. On average, F1-score of LSTM-CRF is 5% above that of the baselines, mostly due to a sharp increase in recall. Availability and implementation: The source code for LSTM-CRF is available at https://github.com/glample/tagger and the links to the corpora are available at https://corposaurus.github.io/corpora/. Contact: habibima@informatik.hu-berlin.de PMID:28881963

Assessing the feasibility of using uniaxial accelerometers with an online support platform in the delivery of a community-based exercise referral scheme.

PubMed

Hawkins, Jemma L; Oliver, Emily J; Wyatt-Williams, Jeannie; Scale, Elaine; van Woerden, Hugo C

2014-10-01

Exercise referral schemes are established within community-based health care; however, they have been criticized for failing to evidence long-term behavior change relative to usual care. As such, recent reviews have called for refinement of their delivery with a focus on embedded strategies targeting client motivation. This research letter presents findings from an initial pilot trial conducted within Wales' National Exercise Referral Scheme (NERS), examining the feasibility of using validated physical activity monitoring devices and an accompanying online platform within standard scheme delivery. 30 individuals referred to generic or cardiovascular pathways were offered the system; of these 17 agreed to participate. Common reasons for declining were clustered into lack of technology literacy or access, condition severity, or fear of costs associated with losing the device. Analysis of follow-up interviews after 4 weeks of use indicated that while participants found the monitoring devices practical and informative, only a minority (n = 4) were using the system in full. Crucially, the system element most aligned with contemporary theories of motivation (the online portal) was not used as expected. In addition, feedback from exercise referral professionals indicated that there were demands for support from clients, which might be mitigated by more effective independent system use. Recommendations for larger scale trials using similar systems include consideration of targeted patient groups, equity of access, and providing adequate technological support that is currently beyond the capacity of the NERS system. © The Author(s) 2014.

Detailed structure and tectonics of the Ninetyeast Ridge near Site ODP 758 (on new geophysical data from KNOX06RR cruise of R/V Roger Revelle)

NASA Astrophysics Data System (ADS)

Levchenko, O.; Eisin, A. E.; Ivanenko, A. N.; Marinova, J. G.; Paul, C. F.; Sborshchikov, I. M.; Sager, W. W.

2008-12-01

Detailed geophysical survey was carried out during the NSF-funded KNOX06RR cruise of R/V Roger Revelle in July 2007 over the ~70×70 km area near ODP Site 758, the northern Ninetyeast Ridge (NER). In addition to multibeam echo-sounder bathymetry, 3.5 kHz echo-sounder profiles, magnetic, and gravity data, high-resolution multichannel seismic reflection data were collected on eight orthogonal profiles of total length ~270 km. Large NE-trending depressions with complicated horst and graben morphology dominate the whole detailed survey area. The numerous basement faults extend upward into overlying sediments filling out these depressions. Thickness of the sedimentary fill is highly variable due to very rough basement topography, and is up to 800 m maximum. This fill is divided in two clear sedimentary layers: transparent pelagic sediments above and stratified shallow-water ones below. Two high ~400-450 m isometric seamounts extend from the surrounding NER seafloor. High-resolution seismic records show that these igneous basement highs are covered by thin transparent pelagic sediments which hamper the dredging of volcanic rocks. Seismic stratigraphy analyses for sedimentary cover over the seamounts buried slopes suggest that they seem to be recent volcanoes superimposed on the main NER edifice. Both volcanoes are clearly delineated in the constructed map of total anomaly magnetic field. Since water depths are ~2.5 km above these seamounts, the lower edge of the magnetic body in these volcanoes is situated deep at ~7 km under sea level. That appears to represent deep roots of the volcanoes. Preliminary magnetic modeling shows that they were generated during negative chron of the geomagnetic scale rather not long ago and not far from their present location, seeming to confirm the inference that these volcanoes are recent in origin. In general, one may assume a secondary phase of magmatic activity on the NER. It is important to reveal, any recent phase of tectonic and magnetic activity occurred over the northern NER during the same time of well-known intense intraplate deformation in the Central Indian Basin which was initiated ~8 Ma in response to growing regional compression due to continental collision Hindustan and Eurasia. It appears to be nonrandom that this NER segment is located in an anomalous zone of high oceanic intraplate seismicity. Seismic stratigraphy analyses of high-resolution seismic records over the fault features simultaneously with careful study of reflectors on the buried slopes of the recent volcanoes will allow us to examine this problem.

Involvement of noradrenergic and corticoid receptors in the consolidation of the lasting anxiogenic effects of predator stress.

PubMed

Adamec, R; Muir, C; Grimes, M; Pearcey, K

2007-05-16

The roles of beta-NER (beta-noradrenergic receptor), GR (glucocorticoid) and mineral corticoid receptors (MR) in the consolidation of anxiogenic effects of predator stress were studied. One minute after predator stress, different groups of rats were injected (ip) with vehicle, propranolol (beta-NER blocker, 5 and 10 mg/kg), mifepristone (RU486, GR blocker, 20 mg/kg), spironolactone (MR blocker, 50 mg/kg), propranolol (5 mg/kg) plus RU486 (20 mg/kg) or the anxiolytic, chloradiazepoxide (CPZ, 10 mg/kg). One week later, rodent anxiety was assessed in elevated plus maze, hole board, light/dark box, social interaction and acoustic startle. Considering all tests except startle, propranolol dose dependently blocked consolidation of lasting anxiogenic effects of predator stress in all tests. GR receptor block alone was ineffective. However, GR block in combination with an ineffective dose of propranolol did blocked consolidation of predator stress effects in all tests, suggesting a synergism between beta-NER and GR. Surprisingly, MR block prevented consolidation of anxiogenic effects in all tests except the light/dark box. CPZ post stress was ineffective against the anxiogenic impact of predator stress. Study of startle was complicated by the fact that anxiogenic effects of stress on startle amplitude manifested as both an increase and a decrease in startle amplitude. Suppression of startle occurred in stressed plus vehicle injected groups handled three times prior to predator stress. In contrast, stressed plus vehicle rats handled five times prior to predator stress showed increases in startle, as did all predator stressed only groups. Mechanisms of consolidation of the different startle responses appear to differ. CPZ post stress blocked startle suppression but not enhancement of startle. Propranolol post stress had no effect on either suppression or enhancement of startle. GR block alone post stress prevented suppression of startle, but not enhancement. In contrast blocking GR and beta-NER together prevented startle enhancement. MR block also prevented startle enhancement. Effects of MR block on startle suppression were not tested. Delay of habituation to startle was found in all stressed rats. Consolidation of delay of habituation was blocked or attenuated by post stress MR block, GR plus beta-NER block and CPZ but not by post stress GR or beta-NER block alone. Taken together, present findings suggest consolidation of lasting anxiogenic effects of predator stress may share some of the same neurochemical mechanisms implicated in some forms of fear memory consolidation. Implications of these findings for the study of stress-induced changes in affect including posttraumatic stress disorder (PTSD) are discussed.

Optimizing Segmental Bone Regeneration Using Functionally Graded Scaffolds

DTIC Science & Technology

2012-10-01

Such a model system would allow more realistic assessment of different clinical treatment options in a rapid, cost -efficient, and safe man- ner...along with MichealiseMenten kinetics. Genetic algorithm [37] was adopted to minimize the cost function in Equation (14). Fig. 3 shows that simulated...associated with autografts, such as high cost , requirement of additional surgeries, donor-site morbidity, and limiting autographs for the treatment

More French, s'il vous plait!

ERIC Educational Resources Information Center

McGillivray, W. Russ, Ed.

The collection of essays on French second language instruction in Canada, directed to parents, includes: "Our Brave New World" (Andrew Kniewasser); "French in Your School: Identifying and Achieving the Right Program" (Carolyn Hodych, Jos Scott); "So, You're Worried About Becoming an Immersion Parent" (Judy Gibson);…

Collaborative biocuration--text-mining development task for document prioritization for curation.

PubMed

Wiegers, Thomas C; Davis, Allan Peter; Mattingly, Carolyn J

2012-01-01

The Critical Assessment of Information Extraction systems in Biology (BioCreAtIvE) challenge evaluation is a community-wide effort for evaluating text mining and information extraction systems for the biological domain. The 'BioCreative Workshop 2012' subcommittee identified three areas, or tracks, that comprised independent, but complementary aspects of data curation in which they sought community input: literature triage (Track I); curation workflow (Track II) and text mining/natural language processing (NLP) systems (Track III). Track I participants were invited to develop tools or systems that would effectively triage and prioritize articles for curation and present results in a prototype web interface. Training and test datasets were derived from the Comparative Toxicogenomics Database (CTD; http://ctdbase.org) and consisted of manuscripts from which chemical-gene-disease data were manually curated. A total of seven groups participated in Track I. For the triage component, the effectiveness of participant systems was measured by aggregate gene, disease and chemical 'named-entity recognition' (NER) across articles; the effectiveness of 'information retrieval' (IR) was also measured based on 'mean average precision' (MAP). Top recall scores for gene, disease and chemical NER were 49, 65 and 82%, respectively; the top MAP score was 80%. Each participating group also developed a prototype web interface; these interfaces were evaluated based on functionality and ease-of-use by CTD's biocuration project manager. In this article, we present a detailed description of the challenge and a summary of the results.

Cross domains Arabic named entity recognition system

NASA Astrophysics Data System (ADS)

Al-Ahmari, S. Saad; Abdullatif Al-Johar, B.

2016-07-01

Named Entity Recognition (NER) plays an important role in many Natural Language Processing (NLP) applications such as; Information Extraction (IE), Question Answering (QA), Text Clustering, Text Summarization and Word Sense Disambiguation. This paper presents the development and implementation of domain independent system to recognize three types of Arabic named entities. The system works based on a set of domain independent grammar-rules along with Arabic part of speech tagger in addition to gazetteers and lists of trigger words. The experimental results shown, that the system performed as good as other systems with better results in some cases of cross-domains corpora.

Evidence for a repair enzyme complex involving ERCC1 and complementing activities of ERCC4, ERCC11 and xeroderma pigmentosum group F.

PubMed Central

van Vuuren, A J; Appeldoorn, E; Odijk, H; Yasui, A; Jaspers, N G; Bootsma, D; Hoeijmakers, J H

1993-01-01

Nucleotide excision repair (NER), one of the major cellular DNA repair systems, removes a wide range of lesions in a multi-enzyme reaction. In man, a NER defect due to a mutation in one of at least 11 distinct genes, can give rise to the inherited repair disorders xeroderma pigmentosum (XP), Cockayne's syndrome or PIBIDS, a photosensitive form of the brittle hair disease trichothiodystrophy. Laboratory-induced NER-deficient mutants of cultured rodent cells have been classified into 11 complementation groups (CGs). Some of these have been shown to correspond with human disorders. In cell-free extracts prepared from rodent CGs 1-5 and 11, but not in a mutant from CG6, we find an impaired repair of damage induced in plasmids by UV light and N-acetoxy-acetylaminofluorene. Complementation analysis in vitro of rodent CGs is accomplished by pairwise mixing of mutant extracts. The results show that mutants from groups 2, 3, 5 and XP-A can complement all other CGs tested. However, selective non-complementation in vitro was observed in mutual mixtures of groups 1, 4, 11 and XP-F, suggesting that the complementing activities involved somehow affect each other. Depletion of wild-type human extracts from ERCC1 protein using specific anti-ERCC1 antibodies concomitantly removed the correcting activities for groups 4, 11 and XP-F, but not those for the other CGs. Furthermore, we find that 33 kDa ERCC1 protein sediments as a high mol. wt species of approximately 120 kDa in a native glycerol gradient.(ABSTRACT TRUNCATED AT 250 WORDS) Images PMID:8253091

Incision of trivalent chromium [Cr(III)]-induced DNA damage by Bacillus caldotenax UvrABC endonuclease.

PubMed

O'Brien, Travis J; Jiang, Guohui; Chun, Gina; Mandel, H George; Westphal, Craig S; Kahen, Kaveh; Montaser, Akbar; States, J Christopher; Patierno, Steven R

2006-11-07

Some hexavalent chromium [Cr(VI)]-containing compounds are lung carcinogens. Once within cells, Cr(VI) is reduced to trivalent chromium [Cr(III)] which displays an affinity for both DNA bases and the phosphate backbone. A diverse array of genetic lesions is produced by Cr including Cr-DNA monoadducts, DNA interstrand crosslinks (ICLs), DNA-Cr-protein crosslinks (DPCs), abasic sites, DNA strand breaks and oxidized bases. Despite the large amount of information available on the genotoxicity of Cr, little is known regarding the molecular mechanisms involved in the removal of these lesions from damaged DNA. Recent work indicates that nucleotide excision repair (NER) is involved in the processing of Cr-DNA adducts in human and rodent cells. In order to better understand this process at the molecular level and begin to identify the Cr-DNA adducts processed by NER, the incision of CrCl(3) [Cr(III)]-damaged plasmid DNA was studied using a thermal-resistant UvrABC NER endonuclease from Bacillus caldotenax (Bca). Treatment of plasmid DNA with Cr(III) (as CrCl(3)) increased DNA binding as a function of dose. For example, at a Cr(III) concentration of 1 microM we observed approximately 2 Cr(III)-DNA adducts per plasmid. At this same concentration of Cr(III) we found that approximately 17% of the plasmid DNA contained ICLs ( approximately 0.2 ICLs/plasmid). When plasmid DNA treated with Cr(III) (1 microM) was incubated with Bca UvrABC we observed approximately 0.8 incisions/plasmid. The formation of endonuclease IV-sensitive abasic lesions or Fpg-sensitive oxidized DNA bases was not detected suggesting that the incision of Cr(III)-damaged plasmid DNA by UvrABC was not related to the generation of oxidized DNA damage. Taken together, our data suggest that a sub-fraction of Cr(III)-DNA adducts is recognized and processed by the prokaryotic NER machinery and that ICLs are not necessarily the sole lesions generated by Cr(III) that are substrates for NER.

Nucleotide Excision Repair Lesion-Recognition Protein Rad4 Captures a Pre-Flipped Partner Base in a Benzo[a]pyrene-Derived DNA Lesion: How Structure Impacts the Binding Pathway.

PubMed

Mu, Hong; Geacintov, Nicholas E; Min, Jung-Hyun; Zhang, Yingkai; Broyde, Suse

2017-06-19

The xeroderma pigmentosum C protein complex (XPC) recognizes a variety of environmentally induced DNA lesions and is the key in initiating their repair by the nucleotide excision repair (NER) pathway. When bound to a lesion, XPC flips two nucleotide pairs that include the lesion out of the DNA duplex, yielding a productively bound complex that can lead to successful lesion excision. Interestingly, the efficiencies of NER vary greatly among different lesions, influencing their toxicity and mutagenicity in cells. Though differences in XPC binding may influence NER efficiency, it is not understood whether XPC utilizes different mechanisms to achieve productive binding with different lesions. Here, we investigated the well-repaired 10R-(+)-cis-anti-benzo[a]pyrene-N 2 -dG (cis-B[a]P-dG) DNA adduct in a duplex containing normal partner C opposite the lesion. This adduct is derived from the environmental pro-carcinogen benzo[a]pyrene and is likely to be encountered by NER in the cell. We have extensively investigated its binding to the yeast XPC orthologue, Rad4, using umbrella sampling with restrained molecular dynamics simulations and free energy calculations. The NMR solution structure of this lesion in duplex DNA has shown that the dC complementary to the adducted dG is flipped out of the DNA duplex in the absence of XPC. However, it is not known whether the "pre-flipped" base would play a role in its recognition by XPC. Our results show that Rad4 first captures the displaced dC, which is followed by a tightly coupled lesion-extruding pathway for productive binding. This binding path differs significantly from the one deduced for the small cis-syn cyclobutane pyrimidine dimer lesion opposite mismatched thymines [ Mu , H. , ( 2015 ) Biochemistry , 54 ( 34 ), 5263 - 7 ]. The possibility of multiple paths that lead to productive binding to XPC is consistent with the versatile lesion recognition by XPC that is required for successful NER.

Nucleotide Excision Repair Lesion-Recognition Protein Rad4 Captures a Pre-Flipped Partner Base in a Benzo[a]pyrene-Derived DNA Lesion: How Structure Impacts the Binding Pathway

PubMed Central

2017-01-01

The xeroderma pigmentosum C protein complex (XPC) recognizes a variety of environmentally induced DNA lesions and is the key in initiating their repair by the nucleotide excision repair (NER) pathway. When bound to a lesion, XPC flips two nucleotide pairs that include the lesion out of the DNA duplex, yielding a productively bound complex that can lead to successful lesion excision. Interestingly, the efficiencies of NER vary greatly among different lesions, influencing their toxicity and mutagenicity in cells. Though differences in XPC binding may influence NER efficiency, it is not understood whether XPC utilizes different mechanisms to achieve productive binding with different lesions. Here, we investigated the well-repaired 10R-(+)-cis-anti-benzo[a]pyrene-N2-dG (cis-B[a]P-dG) DNA adduct in a duplex containing normal partner C opposite the lesion. This adduct is derived from the environmental pro-carcinogen benzo[a]pyrene and is likely to be encountered by NER in the cell. We have extensively investigated its binding to the yeast XPC orthologue, Rad4, using umbrella sampling with restrained molecular dynamics simulations and free energy calculations. The NMR solution structure of this lesion in duplex DNA has shown that the dC complementary to the adducted dG is flipped out of the DNA duplex in the absence of XPC. However, it is not known whether the “pre-flipped” base would play a role in its recognition by XPC. Our results show that Rad4 first captures the displaced dC, which is followed by a tightly coupled lesion-extruding pathway for productive binding. This binding path differs significantly from the one deduced for the small cis-syn cyclobutane pyrimidine dimer lesion opposite mismatched thymines [MuH., (2015) Biochemistry, 54(34), 5263−726270861]. The possibility of multiple paths that lead to productive binding to XPC is consistent with the versatile lesion recognition by XPC that is required for successful NER. PMID:28460163

"Parlez-Vous Bien Francais?" No Comment!

ERIC Educational Resources Information Center

Dale, Mark; Liss, Mimi

1996-01-01

Describes an experience of introducing a "Records of Achievement" scheme in university extramural language courses. The article discusses the effectiveness of existing teaching/learning styles and examines the way in which records of achievement could foster autonomous learning. Student reaction to recording progress as a means of sustaining…

Distant neighbor base sequence context effects in human nucleotide excision repair of a benzo[a]pyrene-derived DNA lesion

PubMed Central

Cai, Yuqin; Kropachev, Konstantin; Xu, Rong; Tang, Yijin; Kolbanovskii, Marina; Kolbanovskii, Alexander; Amin, Shantu; Patel, Dinshaw J.; Broyde, Suse; Geacintov, Nicholas E.

2010-01-01

Summary The effects of non-nearest base sequences, beyond the nucleotides flanking a DNA lesion on either side, on nucleotide excision repair (NER) in extracts from human cells were investigated. We constructed two duplexes containing the same minor groove-aligned 10S (+)-trans-anti-B[a]P-N2-dG (G*) DNA adduct, derived from the environmental carcinogen benzo[a]pyrene (B[a]P): 5′-C-C-A-T-C-G*-C-T-A-C-C-3′ (CG*C-I), and 5′-C-A-C3-A4-C5-G*-C-A-C-A-C-3′ (CG*C-II). We utilized gel electrophoresis to compare the extent of DNA bending, and molecular dynamics (MD) simulations to analyze the structural characteristics of these two DNA duplexes. The NER efficiencies are 1.6 ± 0.2 times greater in the case of the CG*C-II than the CG*C-I sequence context in 135-mer duplexes. Gel electrophoresis and self-ligation circularization experiments revealed that the CG*C-II duplex is more bent than the CG*C-I duplex, while MD simulations showed that the unique -C3-A4-C5- segment in the CG*C-II duplex plays a key role. The presence of a minor groove-positioned guanine amino group, namely, the Watson-Crick partner to C3, acts as a wedge; facilitated by a highly deformable local -C3-A4- base step, this amino group allows the B[a]P ring system to produce a more enlarged minor groove in CG*C-II than in CG*C-I, as well as a local untwisting and enlarged and flexible Roll only in the CG*C-II sequence. These structural properties fit well with our prior findings that in the case of the family of minor groove 10S (+)-trans-anti-B[a]P-N2-dG lesions, flexible bends and enlarged minor groove widths (Cai et al. (2009) J. Mol. Biol., 385: 30–44) constitute NER recognition signals, and extend our understanding of sequence context effects on NER to the neighbors that are distant to the lesion. PMID:20399214

Impact of Aerosols on Shortwave and Photosynthetically Active Radiation Balance over Sub-tropical Region in South Asia: Observational and Modeling Approach

NASA Astrophysics Data System (ADS)

Subba, T.; Pathak, B.

2016-12-01

The North-East Indian Region (NER) (22-30ºN, 89-98ºE) in south Asia sandwiched between two global biodiversity hotspots namely, Himalaya and Indo-Burma, assumes significance owing to its unique topography with mountains in the north, east and south and densely populated Indo Gangetic plains (IGP) towards the west resulting in complex aerosol system. Multi-year (2010-2014) concurrent measurements of aerosol properties and the shortwave radiation budget are examined over four geographically distinct stations of NER operational under Indian Space Research organization's ARFINET (Aerosol Radiative Forcing over India NETwork). An attempt has been made to lessen the ambiguity of forcing estimation by validating the radiative transfer modelled ARF with the CNR4 net radiometer measured values (r2 0.98). The Normalized Difference Vegetation Index and its dependence on the extinction of the photosynthetically active radiation (PAR) due to aerosol are assessed. The spring time enhancement of aerosols in the column has shown significant surface cooling (ARF = -48 ± 5 Wm-2) over the region, while the very high Black Carbon (BC) mass concentrations near the surface (SSA > 0.8) leads to significant atmospheric warming (ARF = +41 ± 7 Wm-2) in the shortwave range. Radiative forcing estimates reveal that the atmospheric forcing by BC could be as high as +30Wm-2 over the western part, which are significantly higher than the eastern part with a consequent heating rate of 1.5 K day-1 revealing an east-west asymmetry over NER. The impact of BC aerosols on the photosynthetic rate varies among different locations ranging from -5±2 Wm-2 to -25±3 Wm-2. Almost 70% of the total atmospheric shortwave radiative absorption is attributed to just 10% contribution of Black Carbon (BC) to total mass concentration and causes a reduction of more than 30% of PAR reaching the surface over Brahmaputra valley due to direct radiative effect. Comparison of previous and the present study shows highest surface dimming is observed in west-Asia followed by IGP and west-India. Surface radiative reduction over NER is comparable to south-India standing on the third place which is still higher than that of the Himalayan and Oceanic regions.

Nutritional Quality of Preparations Based on Döner Kebab Sold in Two Towns of Veneto Region, Italy: Preliminary Results

PubMed Central

Panozzo, Monica; Magro, Luciano; Erle, Ilario; Ferrarini, Stefano; Murari, Riccardo; Masaro, Simone

2015-01-01

The sampling activity for this study was performed between September and October 2012. It involved seven shops in Verona, eleven in Vicenza and two in its province (Bassano del Grappa), northern Italy. The scope was to measure the values of energy and nutritional components and to identify the profile of fatty acids in a serving of ready to eat Döner Kebab. The samples were collected according to the usual proportions of this preparation, keeping all the components (bread, meat, vegetables and sauces) separated in different bags. In the laboratory, each component was weighed and, after pooling, processed for the analytical determination of humidity, crude protein, lipid content and fatty acid profile, ashes, sodium (salt), carbohydrate, collagen (measured only in meat) and fibre. The results showed a highly standardized recipe, while the comparison between the two towns showed a significant difference in carbohydrate concentration (mainly due to the quantity of bread used). By observing data on the serving sizes sampled (274 to 618 g) and the nutritional values obtained, Döner Kebab can be seen as a ready to eat dish providing much energy: on average a serving size covers 45 and 36% of the recommended daily intake of energy, 95.7 and 82.1% of protein, 42.5 and 33.4% of saturated fatty acids for females and males, respectively, and 85.5% of salt regardless of gender. Döner Kebab can be considered as an occasional substitute to one of the two main meals of the day. PMID:27800390

Causes of childhood blindness in the northeastern states of India

PubMed Central

Bhattacharjee, Harsha; Das, Kalyan; Borah, Rishi Raj; Guha, Kamalesh; Purukayastha, S; Gilbert, Clare

2008-01-01

Background: The northeastern region (NER) of India is geographically isolated and ethno-culturally different from the rest of the country. There is lacuna regarding the data on causes of blindness and severe visual impairment in children from this region. Aim: To determine the causes of severe visual impairment and blindness amongst children from schools for the blind in the four states of NER of India. Design and Setting: Survey of children attending special education schools for the blind in the NER. Materials and Methods: Blind and severely visually impaired children (best corrected visual acuity <20/200 in the better eye, aged up to 16 years) underwent visual acuity estimation, external ocular examination, retinoscopy and fundoscopy. Refraction and low vision workup was done where indicated. World Health Organization′s reporting form was used to code anatomical and etiological causes of visual loss. Statistical Analysis: Microsoft Excel Windows software with SPSS. Results: A total of 376 students were examined of whom 258 fulfilled the eligibility criteria. The major anatomical causes of visual loss amongst the 258 were congenital anomalies (anophthalmos, microphthalmos) 93 (36.1%); corneal conditions (scarring, vitamin A deficiency) 94 (36.7%); cataract or aphakia 28 (10.9%), retinal disorders 15 (5.8%) and optic atrophy 14 (5.3%). Nearly half of the children were blind from conditions which were either preventable or treatable (48.5%). Conclusion: Nearly half the childhood blindness in the NER states of India is avoidable and Vitamin A deficiency forms an important component unlike other Indian states. More research and multisectorial effort is needed to tackle congenital anomalies. PMID:18974521

Occupancy of Norepinephrine Transporter by Duloxetine in Human Brains Measured by Positron Emission Tomography with (S,S)-[18F]FMeNER-D2.

PubMed

Moriguchi, Sho; Takano, Harumasa; Kimura, Yasuyuki; Nagashima, Tomohisa; Takahata, Keisuke; Kubota, Manabu; Kitamura, Soichiro; Ishii, Tatsuya; Ichise, Masanori; Zhang, Ming-Rong; Shimada, Hitoshi; Mimura, Masaru; Meyer, Jeffrey H; Higuchi, Makoto; Suhara, Tetsuya

2017-12-01

The norepinephrine transporter in the brain has been targeted in the treatment of psychiatric disorders. Duloxetine is a serotonin and norepinephrine reuptake inhibitor that has been widely used for the treatment of depression. However, the relationship between dose and plasma concentration of duloxetine and norepinephrine transporter occupancy in the human brain has not been determined. In this study, we examined norepinephrine transporter occupancy by different doses of duloxetine. We calculated norepinephrine transporter occupancies from 2 positron emission tomography scans using (S,S)-[18F]FMeNER-D2 before and after a single oral dose of duloxetine (20 mg, n = 3; 40 mg, n = 3; 60 mg, n =2). Positron emission tomography scans were performed from 120 to 180 minutes after an i.v. bolus injection of (S,S)-[18F]FMeNER-D2. Venous blood samples were taken to measure the plasma concentration of duloxetine just before and after the second positron emission tomography scan. Norepinephrine transporter occupancy by duloxetine was 29.7% at 20 mg, 30.5% at 40 mg, and 40.0% at 60 mg. The estimated dose of duloxetine inducing 50% norepinephrine transporter occupancy was 76.8 mg, and the estimated plasma drug concentration inducing 50% norepinephrine transporter occupancy was 58.0 ng/mL. Norepinephrine transporter occupancy by clinical doses of duloxetine was approximately 30% to 40% in human brain as estimated using positron emission tomography with (S,S)-[18F]FMeNER-D2. © The Author 2017. Published by Oxford University Press on behalf of CINP.

Moderating effects of childhood maltreatment on associations between social information processing and adult aggression

PubMed Central

Chen, P.; Coccaro, E. F.; Lee, R.; Jacobson, K. C.

2014-01-01

Background Associations between early life maltreatment, social information processing (SIP) and aggression in childhood and adolescence have been widely documented. Few studies have examined the importance of childhood maltreatment independent of SIP in the etiology of adult aggression. Furthermore, moderating effects of childhood maltreatment on the SIP–aggression links have not been explored. Method Hierarchical, multi-level models were fitted to data from n=2752 twins aged 20–55 years from the PennTwins Cohort. Adult aggression was assessed with the Life History of Aggression questionnaire. Childhood maltreatment was measured using the Childhood Trauma Questionnaire. Two aspects of SIP were examined : hostile attribution biases (HAB) ; negative emotional responses (NER). Results Childhood maltreatment was positively correlated with adult aggression, independently of HAB and NER. In addition, childhood maltreatment moderated the relationships between both aspects of SIP and adult aggression. Specifically, the relationship between NER and aggression was stronger among individuals with higher levels of childhood maltreatment and NER was not associated with aggression for adults who experienced low levels of childhood maltreatment. Moderating effects of childhood maltreatment on the NER–aggression link were supported for total childhood maltreatment, emotional neglect and emotional abuse. In contrast, HAB was more strongly associated with adult aggression at lower levels of emotional abuse and physical neglect. Conclusions The current study provides insight into the mechanisms by which early life experiences influence adult aggression. Our findings suggest that childhood maltreatment may not only lead to increased levels of aggression in adulthood but may also modify the associations between SIP and adult aggression. PMID:22008562

Identification of a Plastid-Localized Bifunctional Nerolidol/Linalool Synthase in Relation to Linalool Biosynthesis in Young Grape Berries

PubMed Central

Zhu, Bao-Qing; Cai, Jian; Wang, Zhi-Qun; Xu, Xiao-Qing; Duan, Chang-Qing; Pan, Qiu-Hong

2014-01-01

Monoterpenoids are a diverse class of natural products and contribute to the important varietal aroma of certain Vitis vinifera grape cultivars. Among the typical monoterpenoids, linalool exists in almost all grape varieties. A gene coding for a nerolidol/linalool (NES/LINS) synthase was evaluated in the role of linalool biosynthesis in grape berries. Enzyme activity assay of this recombinant protein revealed that it could convert geranyl diphosphate and farnesyl diphosphate into linalool and nerolidol in vitro, respectively, and thus it was named VvRILinNer. However, localization experiment showed that this enzyme was only localized to chloroplasts, which indicates that VvRILinNer functions in the linalool production in vivo. The patterns of gene expression and linalool accumulation were analyzed in the berries of three grape cultivars (“Riesling”, “Cabernet Sauvignon”, “Gewurztraminer”) with significantly different levels of monoterpenoids. The VvRILinNer was considered to be mainly responsible for the synthesis of linalool at the early developmental stage. This finding has provided us with new knowledge to uncover the complex monoterpene biosynthesis in grapes. PMID:25470020

Ordered Conformational Changes in Damaged DNA Induced by Nucleotide Excision Repair Factors*

PubMed Central

Tapias, Angels; Auriol, Jerome; Forget, Diane; Enzlin, Jacqueline H.; Schärer, Orlando D; Coin, Frederic; Coulombe, Benoit; Egly, Jean-Marc

2015-01-01

In response to genotoxic attacks, cells activate sophisticated DNA repair pathways such as nucleotide excision repair (NER), which consists of damage removal via dual incision and DNA resynthesis. Using permanganate footprinting as well as highly purified factors, we show that NER is a dynamic process that takes place in a number of successive steps during which the DNA is remodeled around the lesion in response to the various NER factors. XPC/HR23B first recognizes the damaged structure and initiates the opening of the helix from position −3 to +6. TFIIH is then recruited and, in the presence of ATP, extends the opening from position −6 to +6; it also displaces XPC downstream from the lesion, thereby providing the topological structure for recruiting XPA and RPA, which will enlarge the opening. Once targeted by XPG, the damaged DNA is further melted from position −19 to +8. XPG and XPF/ERCC1 endo-nucleases then cut the damaged DNA at the limit of the opened structure that was previously “labeled” by the positioning of XPC/HR23B and TFIIH. PMID:14981083

Nucleotide Excision Repair Proteins Rapidly Accumulate but Fail to Persist in Human XP-E (DDB2 Mutant) Cells

PubMed Central

Oh, Kyu-Seon; Imoto, Kyoko; Emmert, Steffen; Tamura, Deborah; DiGiovanna, John J.; Kraemer, Kenneth. H.

2011-01-01

The XP-E DNA damage binding protein (DDB2) is involved in early recognition of global genome DNA damage during DNA nucleotide excision repair (NER). We found that skin fibroblasts from 4 newly reported XP-E patients with numerous skin cancers and DDB2 mutations had slow repair of 6-4 photoproducts (6-4PP) and markedly reduced repair of cyclobutane pyrimidine dimers (CPD). NER proteins (XPC, XPB, XPG, XPA, and XPF) co-localized to CPD and 6-4PP positive regions immediately (< 0.1h) after localized UV irradiation in cells from the XP-E patients and normal controls. While these proteins persist in normal cells, surprisingly, within 0.5h these repair proteins were no longer detectable at the sites of DNA damage in XP-E cells. Our results indicate that DDB2 is not required for the rapid recruitment of NER proteins to sites of UV photoproducts or for partial repair of 6-4PP but is essential for normal persistence of these proteins for CPD photoproduct removal. PMID:21388382

Stimulation of ribosomal RNA gene promoter by transcription factor Sp1 involves active DNA demethylation by Gadd45-NER pathway.

PubMed

Rajput, Pallavi; Pandey, Vijaya; Kumar, Vijay

2016-08-01

The well-studied Pol II transcription factor Sp1 has not been investigated for its regulatory role in rDNA transcription. Here, we show that Sp1 bound to specific sites on rDNA and localized into the nucleoli during the G1 phase of cell cycle to activate rDNA transcription. It facilitated the recruitment of Pol I pre-initiation complex and impeded the binding of nucleolar remodeling complex (NoRC) to rDNA resulting in the formation of euchromatin active state. More importantly, Sp1 also orchestrated the site-specific binding of Gadd45a-nucleotide excision repair (NER) complex resulting in active demethylation and transcriptional activation of rDNA. Interestingly, knockdown of Sp1 impaired rDNA transcription due to reduced engagement of the Gadd45a-NER complex and hypermethylation of rDNA. Thus, the present study unveils a novel role of Sp1 in rDNA transcription involving promoter demethylation. Copyright © 2016 Elsevier B.V. All rights reserved.

A rapid non-radioactive technique for measurement of repair synthesis in primary human fibroblasts by incorporation of ethynyl deoxyuridine (EdU).

PubMed

Limsirichaikul, Siripan; Niimi, Atsuko; Fawcett, Heather; Lehmann, Alan; Yamashita, Shunichi; Ogi, Tomoo

2009-03-01

Xeroderma pigmentosum (XP) is an autosomal recessive genetic disorder. Afflicted patients show extreme sun-sensitivity and skin cancer predisposition. XP is in most cases associated with deficient nucleotide excision repair (NER), which is the process responsible for removing photolesions from DNA. Measuring NER activity by nucleotide incorporation into repair patches, termed 'unscheduled DNA synthesis (UDS)', is one of the most commonly used assays for XP-diagnosis and NER research. We have established a rapid and accurate procedure for measuring UDS by replacement of thymidine with 5-ethynyl-2'-deoxyuridine (EdU). EdU incorporated into repair patches can be directly conjugated to fluorescent azide derivatives, thereby obviating the need for either radiolabeled thymidine or denaturation and antibody detection of incorporated bromodeoxyuridine (BrdU). We demonstrate that the EdU incorporation assay is compatible with conventional techniques such as immunofluorescent staining and labeling of cells with micro-latex beads. Importantly, we can complete the entire UDS assay within half a day from preparation of the assay coverslips; this technique may prove useful as a method for XP diagnosis.

DNA damage leads to progressive replicative decline but extends the life span of long-lived mutant animals.

PubMed

Lans, H; Lindvall, J M; Thijssen, K; Karambelas, A E; Cupac, D; Fensgård, O; Jansen, G; Hoeijmakers, J H J; Nilsen, H; Vermeulen, W

2013-12-01

Human-nucleotide-excision repair (NER) deficiency leads to different developmental and segmental progeroid symptoms of which the pathogenesis is only partially understood. To understand the biological impact of accumulating spontaneous DNA damage, we studied the phenotypic consequences of DNA-repair deficiency in Caenorhabditis elegans. We find that DNA damage accumulation does not decrease the adult life span of post-mitotic tissue. Surprisingly, loss of functional ERCC-1/XPF even further extends the life span of long-lived daf-2 mutants, likely through an adaptive activation of stress signaling. Contrariwise, NER deficiency leads to a striking transgenerational decline in replicative capacity and viability of proliferating cells. DNA damage accumulation induces severe, stochastic impairment of development and growth, which is most pronounced in NER mutants that are also impaired in their response to ionizing radiation and inter-strand crosslinks. These results suggest that multiple DNA-repair pathways can protect against replicative decline and indicate that there might be a direct link between the severity of symptoms and the level of DNA-repair deficiency in patients.

Cultural Representations in Foreign Language Teaching: A Critique of Four BBC Courses.

ERIC Educational Resources Information Center

Mar-Molinero, Clare

1992-01-01

Examines four well-known BBC language courses, "Deutsch Direkt!""A Vous la France!""Viva Espana," and "Buongiorno Italia!" It is suggested that these courses focus on tourism, stereotyping both learners and the target culture and that the presentation of the cultural materials is unrealistic. (VWL)

A Vous de Parler. French Trainee Book.

ERIC Educational Resources Information Center

Cole, Richard

A set of instructional materials for French is designed for Peace Corps volunteer language instruction and geared to the daily language needs of volunteers in Morocco. It consists of 38 units containing mini-dialogues, related grammatical and cultural information, vocabulary, and exercises. Unit topics include introductions, information giving and…

Cles: Etes-vous bon detective?; Enigmes grammaticales; Problemes policiers; Kidnapping (Keys: Are You a Good Detective?; Grammatical Puzzles; Detective Mysteries; Kidnapping).

ERIC Educational Resources Information Center

Debyser, Francis; And Others

1984-01-01

Four sets of French classroom activities are presented: a mystery whose clues include two postcard messages; three puzzles with grammar-related clues; a mystery contained in three comic strip frames; and the solving of a kidnapping mystery. (MSE)

E-mail et Web: Pour une Navigation Sans Risque

DOE Office of Scientific and Technical Information (OSTI.GOV)

Dellabella, Sebastien

2010-06-28

Présentation orale en français, support visuel en anglais. À travers des exemples concrets, vous consoliderez vos connaissances et pourrez ainsi réajuster vos habitudes concernant l’utilisation sécurisée de votre boîte e-mail et de votre navigateur Web.

Some Recent French Courses: Kindergarten to Grade 3.

ERIC Educational Resources Information Center

Weinrib, Alice

1976-01-01

The following courses of study in French at the primary level are described and evaluated: (1) "En Avant" (E. J. Arnold, 1966), (2) "Repondez s'il vous plait" (Copp Clark, 1975), (3) "Pour les Tous Petits" (Carleton Board of Education, 1974), (4) "Dansons la Capucine (Clarke Irwin, 1973), and (5) "Le…

Vous Desirez? (What Would You Like?).

ERIC Educational Resources Information Center

Carlile, Jan

This self-instructional unit about cafes in France is intended for beginning students of French. The introduction to the teacher specifies the general goals, specific learner objectives, evaluation process, and equipment needed. The student's learning activities are divided into four parts, three of which are followed by a written self-quiz and…

Controls on ferromanganese crust composition and reconnaissance resource potential, Ninetyeast Ridge, Indian Ocean

USGS Publications Warehouse

Hein, James; Conrad, Tracey A.; Mizell, Kira; Banakar, Virupaxa K.; Frey, Frederick A.; Sager, William W.

2016-01-01

The southern third of NER has Fe-Mn crusts with the highest Co (0.91%), Ni (0.43%), ΣREY (0.33%), Cu (0.22%), Te (146 ppm), Pt (1.5 ppm), Ru (52 ppb), and Rh (99 ppb) contents. These are among the highest Pt, Ru, and Rh concentrations measured in marine Fe-Mn deposits. Because of these high metal concentrations, exploration is warranted for the southern sector of the NER, especially at shallower-water sites where the platinum group elements (PGE) and Co are likely to be even more enriched.

Adam, Eve and the reflux enigma: age and sex differences across the gastro-oesophageal reflux spectrum.

PubMed

Royston, Christine; Bardhan, Karna D

2017-06-01

We present demographic differences across the gastro-oesophageal reflux disease (GORD) spectrum in a UK District General Hospital. Data were prospectively collected over 37 years. At endoscopy patients were categorized as: erosive oesophagitis (EO), Barrett's oesophagus (BO) or nonerosive reflux disease (NER). Analysis 1: comparison of EO, BO and NER 1977-2001 when the database for GORD without BO closed. Analysis 2: demographic differences in oesophageal adenocarcinoma (OAC) in total BO population diagnosed 1977-2011. GORD 1977-2001 (n=11 944): sex, male predominance in EO and BO but not NER; male : female ratios, 1.81, 1.65, 0.87, respectively (P<0.0001); mean age at presentation, EO 54 years, BO 62 years, NER 50 years; women were older than men by 10, 7 and 6 years, respectively.BO 1977-2011: prevalent OAC, 87/1468 (6%); male : female ratio, 4.1 (P<0.0001); incident OAC, 54/1381 (3.9%); male : female ratio, 3.5 (P<0.0001). Among all BO, more men developed OAC (3 vs. 0.9%). Within each sex, proportion of OAC higher among men (4.9 vs. 2.3%); at OAC diagnosis women were slightly but not significantly older (69.9 vs. 72.3 years, P=0.322). Two views may explain our findings. First, women have either milder reflux, or reduced mucosal sensitivity hence reflux remains silent for longer. Alternatively, women genuinely develop reflux later, that is, are more protected and for longer from developing GORD and its complications. Early evidence is emerging that female sex hormones may indeed have a protective role in GORD during the reproductive period. We suggest reflux and its consequences may be an example of 'protection' conferred on Eve.

Nuclear and membrane estrogen receptor antagonists induce similar mTORC2 activation-reversible changes in synaptic protein expression and actin polymerization in the mouse hippocampus.

PubMed

Xing, Fang-Zhou; Zhao, Yan-Gang; Zhang, Yuan-Yuan; He, Li; Zhao, Ji-Kai; Liu, Meng-Ying; Liu, Yan; Zhang, Ji-Qiang

2018-06-01

Estrogens play pivotal roles in hippocampal synaptic plasticity through nuclear receptors (nERs; including ERα and ERβ) and the membrane receptor (mER; also called GPR30), but the underlying mechanism and the contributions of nERs and mER remain unclear. Mammalian target of rapamycin complex 2 (mTORC2) is involved in actin cytoskeleton polymerization and long-term memory, but whether mTORC2 is involved in the regulation of hippocampal synaptic plasticity by ERs is unclear. We treated animals with nER antagonists (MPP/PHTPP) or the mER antagonist (G15) alone or in combination with A-443654, an activator of mTORC2. Then, we examined the changes in hippocampal SRC-1 expression, mTORC2 signaling (rictor and phospho-AKTSer473), actin polymerization (phospho-cofilin and profilin-1), synaptic protein expression (GluR1, PSD95, spinophilin, and synaptophysin), CA1 spine density, and synapse density. All of the examined parameters except synaptophysin expression were significantly decreased by MPP/PHTPP and G15 treatment. MPP/PHTPP and G15 induced a similar decrease in most parameters except p-cofilin, GluR1, and spinophilin expression. The ER antagonist-induced decreases in these parameters were significantly reversed by mTORC2 activation, except for the change in SRC-1, rictor, and synaptophysin expression. nERs and mER contribute similarly to the changes in proteins and structures associated with synaptic plasticity, and mTORC2 may be a novel target of hippocampal-dependent dementia such as Alzheimer's disease as proposed by previous studies. © 2018 John Wiley & Sons Ltd.

Ubiquitin-specific Protease 7 Regulates Nucleotide Excision Repair through Deubiquitinating XPC Protein and Preventing XPC Protein from Undergoing Ultraviolet Light-induced and VCP/p97 Protein-regulated Proteolysis*

PubMed Central

He, Jinshan; Zhu, Qianzheng; Wani, Gulzar; Sharma, Nidhi; Han, Chunhua; Qian, Jiang; Pentz, Kyle; Wang, Qi-en; Wani, Altaf A.

2014-01-01

Ubiquitin specific protease 7 (USP7) is a known deubiquitinating enzyme for tumor suppressor p53 and its downstream regulator, E3 ubiquitin ligase Mdm2. Here we report that USP7 regulates nucleotide excision repair (NER) via deubiquitinating xeroderma pigmentosum complementation group C (XPC) protein, a critical damage recognition factor that binds to helix-distorting DNA lesions and initiates NER. XPC is ubiquitinated during the early stage of NER of UV light-induced DNA lesions. We demonstrate that transiently compromising cellular USP7 by siRNA and chemical inhibition leads to accumulation of ubiquitinated forms of XPC, whereas complete USP7 deficiency leads to rapid ubiquitin-mediated XPC degradation upon UV irradiation. We show that USP7 physically interacts with XPC in vitro and in vivo. Overexpression of wild-type USP7, but not its catalytically inactive or interaction-defective mutants, reduces the ubiquitinated forms of XPC. Importantly, USP7 efficiently deubiquitinates XPC-ubiquitin conjugates in deubiquitination assays in vitro. We further show that valosin-containing protein (VCP)/p97 is involved in UV light-induced XPC degradation in USP7-deficient cells. VCP/p97 is readily recruited to DNA damage sites and colocalizes with XPC. Chemical inhibition of the activity of VCP/p97 ATPase causes an increase in ubiquitinated XPC on DNA-damaged chromatin. Moreover, USP7 deficiency severely impairs the repair of cyclobutane pyrimidine dimers and, to a lesser extent, affects the repair of 6-4 photoproducts. Taken together, our findings uncovered an important role of USP7 in regulating NER via deubiquitinating XPC and by preventing its VCP/p97-regulated proteolysis. PMID:25118285

Silibinin enhances the repair of ultraviolet B-induced DNA damage by activating p53-dependent nucleotide excision repair mechanism in human dermal fibroblasts

PubMed Central

Guillermo-Lagae, Ruth; Deep, Gagan; Ting, Harold; Agarwal, Chapla; Agarwal, Rajesh

2015-01-01

Ultraviolet radiation B (UVB) is the main cause of DNA damage in epidermal cells; and if not repaired, this DNA damage leads to skin cancer. In earlier studies, we have reported that natural flavonolignan silibinin exerts strong chemopreventive efficacy against UVB-induced skin damage and carcinogenesis; however mechanistic studies are still being actively pursued. Here, we investigated the role of nucleotide excision repair (NER) pathway in silibinin's efficacy to repair UVB-induced DNA damage. Normal human dermal fibroblasts (NHDFs) were exposed to UVB (1 mJ/cm2) with pre- or post- silibinin (100 μM) treatment, and cyclobutane pyrimidine dimers (CPDs) formation/repair was measured. Results showed that post-UVB silibinin treatment accelerates DNA repair via activating the NER pathway including the expression of XPA (xeroderma pigmentosum complementation group A), XPB, XPC, and XPG. In UVB exposed fibroblasts, silibinin treatment also increased p53 and GADD45α expression; the key regulators of the NER pathway and DNA repair. Consistently, post-UVB silibinin treatment increased the mRNA transcripts of XPA and GADD45α. Importantly, silibinin showed no effect on UVB-induced DNA damage repair in XPA- and XPB-deficient human dermal fibroblasts suggesting their key role in silibinin-mediated DNA damage repair. Moreover, in the presence of pifithrin-α, an inhibitor of p53, the DNA repair efficacy of silibinin was compromised associated with a reduction in XPA and GADD45α transcripts. Together, these findings suggest that silibinin's efficacy against UVB-induced photodamage is primarily by inhibiting NER and p53; and these findings further support silibinin's usage as a potential inexpensive, effective, and non-toxic agent for skin cancer chemoprevention. PMID:26447614

Silibinin enhances the repair of ultraviolet B-induced DNA damage by activating p53-dependent nucleotide excision repair mechanism in human dermal fibroblasts.

PubMed

Guillermo-Lagae, Ruth; Deep, Gagan; Ting, Harold; Agarwal, Chapla; Agarwal, Rajesh

2015-11-24

Ultraviolet radiation B (UVB) is the main cause of DNA damage in epidermal cells; and if not repaired, this DNA damage leads to skin cancer. In earlier studies, we have reported that natural flavonolignan silibinin exerts strong chemopreventive efficacy against UVB-induced skin damage and carcinogenesis; however mechanistic studies are still being actively pursued. Here, we investigated the role of nucleotide excision repair (NER) pathway in silibinin's efficacy to repair UVB-induced DNA damage. Normal human dermal fibroblasts (NHDFs) were exposed to UVB (1 mJ/cm2) with pre- or post- silibinin (100 μM) treatment, and cyclobutane pyrimidine dimers (CPDs) formation/repair was measured. Results showed that post-UVB silibinin treatment accelerates DNA repair via activating the NER pathway including the expression of XPA (xeroderma pigmentosum complementation group A), XPB, XPC, and XPG. In UVB exposed fibroblasts, silibinin treatment also increased p53 and GADD45α expression; the key regulators of the NER pathway and DNA repair. Consistently, post-UVB silibinin treatment increased the mRNA transcripts of XPA and GADD45α. Importantly, silibinin showed no effect on UVB-induced DNA damage repair in XPA- and XPB-deficient human dermal fibroblasts suggesting their key role in silibinin-mediated DNA damage repair. Moreover, in the presence of pifithrin-α, an inhibitor of p53, the DNA repair efficacy of silibinin was compromised associated with a reduction in XPA and GADD45α transcripts. Together, these findings suggest that silibinin's efficacy against UVB-induced photodamage is primarily by inhibiting NER and p53; and these findings further support silibinin's usage as a potential inexpensive, effective, and non-toxic agent for skin cancer chemoprevention.

Elevated Urinary Levels of 8-Hydroxy-2'-deoxyguanosine in a Japanese Child of Xeroderma Pigmentosum/Cockayne Syndrome Complex with Infantile Onset of Nephrotic Syndrome.

PubMed

Kondo, Daiki; Noguchi, Atsuko; Tamura, Hiroaki; Tsuchida, Satoko; Takahashi, Ikuko; Kubota, Hiroki; Yano, Tamami; Oyama, Chikako; Sawaishi, Yukio; Moriwaki, Shinichi; Takahashi, Tsutomu

2016-07-01

Nucleotide excision repair (NER) is an essential biological pathway protecting against ultraviolet light-induced DNA damage. Deficient NER causes a group of rare genetic disorders including two autosomal recessive diseases, xeroderma pigmentosum (XP) and Cockayne syndrome (CS). In addition to the cutaneous photosensitivity shared in XP and CS, CS is featured by growth failure, neurological deterioration, microcephaly, and deep sunken eyes. XP/CS complex is an extremely rare type of NER disorder with a distinct phenotype that is characterized by the skin and eye pathology of XP and the somatic and neurological abnormalities of CS. Some of CS cases have been reported to be complicated with renal failure, but the genetic background or the etiology of the renal failure has not been reported. We herein report a 1-year-old Japanese boy with XP/CS complex, complicated by nephrotic syndrome. Diagnosis was confirmed by the presence of compound heterozygous mutations, G47R (c.139G>A) and R616G (c.1846C>G), in the excision repair cross-complementation group 2 (ERCC2) gene. The kidney biopsies, performed at the age of 1 year and 2 months, revealed diffuse expansion of the mesangial matrix and segmental glomerulosclerosis under light microscopy, and diffused thin capillary walls with partially lamellated regions under electron microscopy. Notably, high levels of urinary 8-hydroxy-2'-deoxyguanosin, known as an oxidative stress marker, were observed during the clinical course. The patient died at the age of 1 year and 11 months because of renal failure. We suggest the involvement of oxidative stress in the pathogenesis of nephrotic syndrome in NER disorders.

Clinical heterogeneity within xeroderma pigmentosum associated with mutations in the DNA repair and transcription gene ERCC3

DOE Office of Scientific and Technical Information (OSTI.GOV)

Vermeulen, W.; Kleijer, W.J.; Bootsma, D.

1994-02-01

The human DNA excision repair gene ERCC3 specifically corrects the nucleotide excision repair (NER) defect of xeroderma pigmentosum (XP) complementation group B. In addition to its function in NER, the ERCC3 DNA helicase was recently identified as one of the components of the human BTF2/TFIIH transcription factor complex, which is required for initiation of transcription of class II genes. To date, a single patient (XP11BE) has been assigned to this XP group B (XP-B), with the remarkable conjunction of two autosomal recessive DNA repair deficiency disorders: XP and Cockayne syndrome (CS). The intriguing involvement of the ERCC3 protein in themore » vital process of transcription may provide an explanation for the rarity, severity, and wide spectrum of clinical features in this complementation group. Here the authors report the identification of two new XP-B patients: XPCS1BA and XPCS2BA (siblings), by microneedle injection of the cloned ERCC3 repair gene as well as by cell hybridization. Molecular analysis of the ERCC3 gene in both patients revealed a single base substitution causing a missense mutation in a region that is completely conserved in yeast, Drosophila, mouse, and human ERCC3. As in patient XP11BE, the expression of only one allele (paternal) is detected. The mutation causes a virtually complete inactivation of the NER function of the protein. Despite this severe NER defect, both patients display a late onset of neurologic impairment, mild cutaneous symptoms, and a striking absence of skin tumors even at an age of >40 years. Analysis of the frequency of hprt[sup [minus

Persistence of Repair Proteins at Unrepaired DNA Damage Distinguishes Diseases with ERCC2 (XPD) Mutations: Cancer-Prone Xeroderma Pigmentosum vs. Non-Cancer-Prone Trichothiodystrophy

PubMed Central

Boyle, Jennifer; Ueda, Takahiro; Oh, Kyu-Seon; Imoto, Kyoko; Tamura, Deborah; Jagdeo, Jared; Khan, Sikandar G.; Nadem, Carine; DiGiovanna, John J.; Kraemer, Kenneth H.

2012-01-01

Patients with xeroderma pigmentosum (XP) have a 1,000-fold increase in ultraviolet (UV)-induced skin cancers while trichothiodystrophy (TTD) patients, despite mutations in the same genes, ERCC2 (XPD) or ERCC3 (XPB), are cancer-free. Unlike XP cells, TTD cells have a nearly normal rate of removal of UV-induced 6-4 photoproducts (6-4PP) in their DNA and low levels of the basal transcription factor, TFIIH. We examined seven XP, TTD, and XP/TTD complex patients and identified mutations in the XPD gene. We discovered large differences in nucleotide excision repair (NER) protein recruitment to sites of localized UV damage in TTD cells compared to XP or normal cells. XPC protein was rapidly localized in all cells. XPC was redistributed in TTD, and normal cells by 3 hr postirradiation, but remained localized in XP cells at 24-hr postirradiation. In XP cells recruitment of other NER proteins (XPB, XPD, XPG, XPA, and XPF) was also delayed and persisted at 24 hr (p < 0.001). In TTD cells with defects in the XPD, XPB, or GTF2H5 (TTDA) genes, in contrast, recruitment of these NER proteins was reduced compared to normals at early time points (p < 0.001) and remained low at 24 hr postirradiation. These data indicate that in XP persistence of NER proteins at sites of unrepaired DNA damage is associated with greatly increased skin cancer risk possibly by blockage of translesion DNA synthesis. In contrast, in TTD, low levels of unstable TFIIH proteins do not accumulate at sites of unrepaired photoproducts and may permit normal translesion DNA synthesis without increased skin cancer. PMID:18470933

Avez-vous vu la meme chose que les Francais? Stereotypes et documents authentiques video. (Did You See the Same Thing as the French? Stereotypes and Authentic Video Documents).

ERIC Educational Resources Information Center

Wilczynska, Weronika

1990-01-01

This discussion treats cultural stereotypes as a significant issue in second-language instruction, and examines the role of video documents from the mass media in helping students perceive and understand such stereotypes. (MSE)

Towards a Sociolinguistically Responsive Pedagogy: Teaching Second-Person Address Forms in French

ERIC Educational Resources Information Center

van Compernolle, Remi A.

2010-01-01

This article presents a sociolinguistically responsive model of pedagogy situated within existing sociocultural and communicative approaches to language learning and teaching. The specific focus of the discussion is on the French pronouns of address, "tu" and "vous". The article reviews previous research on second-person address in educational and…

Developing standards for chromosomal microarray testing counselling in paediatrics.

PubMed

Godfrey, Emma; Clark, Phillipa

2014-06-01

Chromosomal microarray testing (CMA) generally aids paediatric genetic diagnosis. However, pre-CMA counselling is important as results can be ambiguous, generate uncertainty and raise ethical issues. We developed standards for counselling and giving families results; using these we evaluated practice for children seen by the Auckland Developmental Paediatric team in 2011. Pretest discussion was documented in 14 of 28 subjects and potential outcomes in 4of 28. 8 of 28 received information leaflets, 1 of 28 gave signed consent. 3 of 3 with abnormal results and 4 of 5 with variants of unknown significance (VOUS) were offered clinical genetics referral. 8 of 20 families with normal results were written to; two with abnormal results were informed face-to-face and one in writing; most VOUS were communicated by phone, voicemail or letter. CMA testing requires clear patient information sheets and in-depth pretest discussion for informed consent, timely feedback of results and genetics referral as appropriate. Authoritative guidelines and training are needed to strengthen CMA counselling. ©2014 Foundation Acta Paediatrica. Published by John Wiley & Sons Ltd.

The Cerebro-oculo-facio-skeletal Syndrome Point Mutation F231L in the ERCC1 DNA Repair Protein Causes Dissociation of the ERCC1-XPF Complex*

PubMed Central

Faridounnia, Maryam; Wienk, Hans; Kovačič, Lidija; Folkers, Gert E.; Jaspers, Nicolaas G. J.; Kaptein, Robert; Hoeijmakers, Jan H. J.; Boelens, Rolf

2015-01-01

The ERCC1-XPF heterodimer, a structure-specific DNA endonuclease, is best known for its function in the nucleotide excision repair (NER) pathway. The ERCC1 point mutation F231L, located at the hydrophobic interaction interface of ERCC1 (excision repair cross-complementation group 1) and XPF (xeroderma pigmentosum complementation group F), leads to severe NER pathway deficiencies. Here, we analyze biophysical properties and report the NMR structure of the complex of the C-terminal tandem helix-hairpin-helix domains of ERCC1-XPF that contains this mutation. The structures of wild type and the F231L mutant are very similar. The F231L mutation results in only a small disturbance of the ERCC1-XPF interface, where, in contrast to Phe231, Leu231 lacks interactions stabilizing the ERCC1-XPF complex. One of the two anchor points is severely distorted, and this results in a more dynamic complex, causing reduced stability and an increased dissociation rate of the mutant complex as compared with wild type. These data provide a biophysical explanation for the severe NER deficiencies caused by this mutation. PMID:26085086

Generation of DNA single-strand displacement by compromised nucleotide excision repair

PubMed Central

Godon, Camille; Mourgues, Sophie; Nonnekens, Julie; Mourcet, Amandine; Coin, Fréderic; Vermeulen, Wim; Mari, Pierre-Olivier; Giglia-Mari, Giuseppina

2012-01-01

Nucleotide excision repair (NER) is a precisely coordinated process essential to avoid DNA damage-induced cellular malfunction and mutagenesis. Here, we investigate the mechanistic details and effects of the NER machinery when it is compromised by a pathologically significant mutation in a subunit of the repair/transcription factor TFIIH, namely XPD. In contrast to previous studies, we find that no single- or double-strand DNA breaks are produced at early time points after UV irradiation of cells bearing a specific XPD mutation, despite the presence of a clear histone H2AX phosphorylation (γH2AX) signal in the UV-exposed areas. We show that the observed γH2AX signal can be explained by the presence of longer single-strand gaps possibly generated by strand displacement. Our in vivo measurements also indicate a strongly reduced TFIIH-XPG binding that could promote single-strand displacement at the site of UV lesions. This finding not only highlights the crucial role of XPG's interactions with TFIIH for proper NER, but also sheds new light on how a faulty DNA repair process can induce extreme genomic instability in human patients. PMID:22863773

RPA and XPA interaction with DNA structures mimicking intermediates of the late stages in nucleotide excision repair

PubMed Central

Maltseva, Ekaterina A.

2018-01-01

Replication protein A (RPA) and the xeroderma pigmentosum group A (XPA) protein are indispensable for both pathways of nucleotide excision repair (NER). Here we analyze the interaction of RPA and XPA with DNA containing a flap and different size gaps that imitate intermediates of the late NER stages. Using gel mobility shift assays, we found that RPA affinity for DNA decreased when DNA contained both extended gap and similar sized flap in comparison with gapped-DNA structure. Moreover, crosslinking experiments with the flap-gap DNA revealed that RPA interacts mainly with the ssDNA platform within the long gap and contacts flap in DNA with a short gap. XPA exhibits higher affinity for bubble-DNA structures than to flap-gap-containing DNA. Protein titration analysis showed that formation of the RPA-XPA-DNA ternary complex depends on the protein concentration ratio and these proteins can function as independent players or in tandem. Using fluorescently-labelled RPA, direct interaction of this protein with XPA was detected and characterized quantitatively. The data obtained allow us to suggest that XPA can be involved in the post-incision NER stages via its interaction with RPA. PMID:29320546

Preclinical Corrective Gene Transfer in Xeroderma Pigmentosum Human Skin Stem Cells

PubMed Central

Warrick, Emilie; Garcia, Marta; Chagnoleau, Corinne; Chevallier, Odile; Bergoglio, Valérie; Sartori, Daniela; Mavilio, Fulvio; Angulo, Jaime F; Avril, Marie-Françoise; Sarasin, Alain; Larcher, Fernando; Del Rio, Marcela; Bernerd, Françoise; Magnaldo, Thierry

2012-01-01

Xeroderma pigmentosum (XP) is a devastating disease associated with dramatic skin cancer proneness. XP cells are deficient in nucleotide excision repair (NER) of bulky DNA adducts including ultraviolet (UV)-induced mutagenic lesions. Approaches of corrective gene transfer in NER-deficient keratinocyte stem cells hold great hope for the long-term treatment of XP patients. To face this challenge, we developed a retrovirus-based strategy to safely transduce the wild-type XPC gene into clonogenic human primary XP-C keratinocytes. De novo expression of XPC was maintained in both mass population and derived independent candidate stem cells (holoclones) after more than 130 population doublings (PD) in culture upon serial propagation (>1040 cells). Analyses of retrovirus integration sequences in isolated keratinocyte stem cells suggested the absence of adverse effects such as oncogenic activation or clonal expansion. Furthermore, corrected XP-C keratinocytes exhibited full NER capacity as well as normal features of epidermal differentiation in both organotypic skin cultures and in a preclinical murine model of human skin regeneration in vivo. The achievement of a long-term genetic correction of XP-C epidermal stem cells constitutes the first preclinical model of ex vivo gene therapy for XP-C patients. PMID:22068429

Transcription-coupled repair of UV damage in the halophilic archaea.

PubMed

Stantial, Nicole; Dumpe, Jarrod; Pietrosimone, Kathryn; Baltazar, Felicia; Crowley, David J

2016-05-01

Transcription-coupled repair (TCR) is a subpathway of nucleotide excision repair (NER) in which excision repair proteins are targeted to RNA polymerase-arresting lesions located in the transcribed strand of active genes. TCR has been documented in a variety of bacterial and eukaryotic organisms but has yet to be observed in the Archaea. We used Halobacterium sp. NRC-1 and Haloferax volcanii to determine if TCR occurs in the halophilic archaea. Following UV irradiation of exponentially growing cultures, we quantified the rate of repair of cyclobutane pyrimidine dimers in the two strands of the rpoB2B1A1A2 and the trpDFEG operons of Halobacterium sp. NRC-1 and the pts operon of H. volcanii through the use of a Southern blot assay and strand-specific probes. TCR was observed in all three operons and was dependent on the NER gene uvrA in Halobacterium sp. NRC-1, but not in H. volcanii. The halophilic archaea likely employ a novel mechanism for TCR in which an as yet unknown coupling factor recognizes the arrested archaeal RNA polymerase complex and recruits certain NER proteins to complete the process. Copyright © 2016 Elsevier B.V. All rights reserved.

RPA and XPA interaction with DNA structures mimicking intermediates of the late stages in nucleotide excision repair.

PubMed

Krasikova, Yuliya S; Rechkunova, Nadejda I; Maltseva, Ekaterina A; Lavrik, Olga I

2018-01-01

Replication protein A (RPA) and the xeroderma pigmentosum group A (XPA) protein are indispensable for both pathways of nucleotide excision repair (NER). Here we analyze the interaction of RPA and XPA with DNA containing a flap and different size gaps that imitate intermediates of the late NER stages. Using gel mobility shift assays, we found that RPA affinity for DNA decreased when DNA contained both extended gap and similar sized flap in comparison with gapped-DNA structure. Moreover, crosslinking experiments with the flap-gap DNA revealed that RPA interacts mainly with the ssDNA platform within the long gap and contacts flap in DNA with a short gap. XPA exhibits higher affinity for bubble-DNA structures than to flap-gap-containing DNA. Protein titration analysis showed that formation of the RPA-XPA-DNA ternary complex depends on the protein concentration ratio and these proteins can function as independent players or in tandem. Using fluorescently-labelled RPA, direct interaction of this protein with XPA was detected and characterized quantitatively. The data obtained allow us to suggest that XPA can be involved in the post-incision NER stages via its interaction with RPA.

A New Paradigm for African American Breast Cancer Involving Stem Cell Differentiation in a Novel Cell Culture System

DTIC Science & Technology

2006-10-01

hereditary xeroderma pigmentosum (XP) [19], a disease with a 1200-fold increase in incidence of skin cancer [20]. The signal for activation of the NER...repair replication of DNA in xeroderma pigmentosum . Nature 1968, 218:652-656. 20. Luddy RE, Sweren RJ: Skin cancer. In Malignant Diseases of...the DNA repair defective genodermatoses xeroderma pigmentosum , Cockayne’s syndrome, and trichothiodystrophy. J Invest Dermatol 1990, 94:94-100. 41

Entropy and optimality in river deltas

NASA Astrophysics Data System (ADS)

Tejedor, Alejandro; Longjas, Anthony; Edmonds, Douglas A.; Zaliapin, Ilya; Georgiou, Tryphon T.; Rinaldo, Andrea; Foufoula-Georgiou, Efi

2017-10-01

The form and function of river deltas is intricately linked to the evolving structure of their channel networks, which controls how effectively deltas are nourished with sediments and nutrients. Understanding the coevolution of deltaic channels and their flux organization is crucial for guiding maintenance strategies of these highly stressed systems from a range of anthropogenic activities. To date, however, a unified theory explaining how deltas self-organize to distribute water and sediment up to the shoreline remains elusive. Here, we provide evidence for an optimality principle underlying the self-organized partition of fluxes in delta channel networks. By introducing a suitable nonlocal entropy rate (nER) and by analyzing field and simulated deltas, we suggest that delta networks achieve configurations that maximize the diversity of water and sediment flux delivery to the shoreline. We thus suggest that prograding deltas attain dynamically accessible optima of flux distributions on their channel network topologies, thus effectively decoupling evolutionary time scales of geomorphology and hydrology. When interpreted in terms of delta resilience, high nER configurations reflect an increased ability to withstand perturbations. However, the distributive mechanism responsible for both diversifying flux delivery to the shoreline and dampening possible perturbations might lead to catastrophic events when those perturbations exceed certain intensity thresholds.

Developing Communication Skills: General Considerations and Specific Techniques.

ERIC Educational Resources Information Center

Joiner, Elizabeth Garner; Westphal, Patricia Barney, Ed.

This practical book is designed for the classroom teacher of a second or foreign language at any level. The articles are grouped into two distinct but interdependent sections on general considerations and specific techniques. The contents of the first section are as follows: "Moi Tarzan, Vous Jane?: A Study of Communicative Competence" by P.B.…

[From Algebra as art to School Algebra : The textbooks written by Pierre de La Ramée, Bernard Salignac and Lazare Schöner].

PubMed

Loget, François

2011-01-01

Bernard Salignac and Lazare Schöner both published a treatise based on La Ramée's Algebra. Why did they endeavour to republish a book that their master had abandoned ? What changes did they make in the original ? They turned algebra into apedagogical discipline at a time when Ramism was making its presence felt in some Northern European educational establishments. Salignac took La Ramée's thoughts concerning the language of mathematics further and offered an original and precocious contribution to what I call the "scriptural turn" of mathematics at the end of the 16(th) century.

p21 differentially regulates DNA replication and DNA-repair-associated processes after UV irradiation.

PubMed

Soria, Gaston; Speroni, Juliana; Podhajcer, Osvaldo L; Prives, Carol; Gottifredi, Vanesa

2008-10-01

Although p21 upregulation is required to block cell-cycle progression following many types of genotoxic insult, UV irradiation triggers p21 proteolysis. The significance of the increased p21 turnover is unclear and might be associated with DNA repair. While the role of p21 in nucleotide excision repair (NER) remains controversial, recent reports have explored its effect on translesion DNA synthesis (TLS), a process that avoids replication blockage during S phase. Herein, we analyze the effect of p21 on different PCNA-driven processes including DNA replication, NER and TLS. Whereas only the CDK-binding domain of p21 is required for cell-cycle arrest in unstressed cells, neither the CDK-binding nor the PCNA-binding domain of p21 is able to block early and late steps of NER. Intriguingly, through its PCNA-binding domain, p21 inhibits the interaction of the TLS polymerase, pol eta (pol eta), with PCNA and impairs the assembly of pol eta foci after UV. Moreover, this obstruction correlates with accumulation of phosphorylated H2AX and increased apoptosis. By showing that p21 is a negative regulator of PCNA-pol eta interaction, our data unveil a link between efficient TLS and UV-induced degradation of p21.

Delineating the requirements for spontaneous DNA damage resistance pathways in genome maintenance and viability in Saccharomyces cerevisiae.

PubMed

Morey, Natalie J; Doetsch, Paul W; Jinks-Robertson, Sue

2003-06-01

Cellular metabolic processes constantly generate reactive species that damage DNA. To counteract this relentless assault, cells have developed multiple pathways to resist damage. The base excision repair (BER) and nucleotide excision repair (NER) pathways remove damage whereas the recombination (REC) and postreplication repair (PRR) pathways bypass the damage, allowing deferred removal. Genetic studies in yeast indicate that these pathways can process a common spontaneous lesion(s), with mutational inactivation of any pathway increasing the burden on the remaining pathways. In this study, we examine the consequences of simultaneously compromising three or more of these pathways. Although the presence of a functional BER pathway alone is able to support haploid growth, retention of the NER, REC, or PRR pathway alone is not, indicating that BER is the key damage resistance pathway in yeast and may be responsible for the removal of the majority of either spontaneous DNA damage or specifically those lesions that are potentially lethal. In the diploid state, functional BER, NER, or REC alone can support growth, while PRR alone is insufficient for growth. In diploids, the presence of PRR alone may confer a lethal mutation load or, alternatively, PRR alone may be insufficient to deal with potentially lethal, replication-blocking lesions.

Processing closely spaced lesions during Nucleotide Excision Repair triggers mutagenesis in E. coli

PubMed Central

Isogawa, Asako; Fujii, Shingo

2017-01-01

It is generally assumed that most point mutations are fixed when damage containing template DNA undergoes replication, either right at the fork or behind the fork during gap filling. Here we provide genetic evidence for a pathway, dependent on Nucleotide Excision Repair, that induces mutations when processing closely spaced lesions. This pathway, referred to as Nucleotide Excision Repair-induced Mutagenesis (NERiM), exhibits several characteristics distinct from mutations that occur within the course of replication: i) following UV irradiation, NER-induced mutations are fixed much more rapidly (t ½ ≈ 30 min) than replication dependent mutations (t ½ ≈ 80–100 min) ii) NERiM specifically requires DNA Pol IV in addition to Pol V iii) NERiM exhibits a two-hit dose-response curve that suggests processing of closely spaced lesions. A mathematical model let us define the geometry (infer the structure) of the toxic intermediate as being formed when NER incises a lesion that resides in close proximity of another lesion in the complementary strand. This critical NER intermediate requires Pol IV / Pol II for repair, it is either lethal if left unrepaired or mutation-prone when repaired. Finally, NERiM is found to operate in stationary phase cells providing an intriguing possibility for ongoing evolution in the absence of replication. PMID:28686598

TFIIH Subunit Alterations Causing Xeroderma Pigmentosum and Trichothiodystrophy Specifically Disturb Several Steps during Transcription

PubMed Central

Singh, Amita; Compe, Emanuel; Le May, Nicolas; Egly, Jean-Marc

2015-01-01

Mutations in genes encoding the ERCC3 (XPB), ERCC2 (XPD), and GTF2H5 (p8 or TTD-A) subunits of the transcription and DNA-repair factor TFIIH lead to three autosomal-recessive disorders: xeroderma pigmentosum (XP), XP associated with Cockayne syndrome (XP/CS), and trichothiodystrophy (TTD). Although these diseases were originally associated with defects in DNA repair, transcription deficiencies might be also implicated. By using retinoic acid receptor beta isoform 2 (RARB2) as a model in several cells bearing mutations in genes encoding TFIIH subunits, we observed that (1) the recruitment of the TFIIH complex was altered at the activated RARB2 promoter, (2) TFIIH participated in the recruitment of nucleotide excision repair (NER) factors during transcription in a manner different from that observed during NER, and (3) the different TFIIH variants disturbed transcription by having distinct consequences on post-translational modifications of histones, DNA-break induction, DNA demethylation, and gene-loop formation. The transition from heterochromatin to euchromatin was disrupted depending on the variant, illustrating the fact that TFIIH, by contributing to NER factor recruitment, orchestrates chromatin remodeling. The subtle transcriptional differences found between various TFIIH variants thus participate in the phenotypic variability observed among XP, XP/CS, and TTD individuals. PMID:25620205

The rem mutations in the ATP-binding groove of the Rad3/XPD helicase lead to Xeroderma pigmentosum-Cockayne syndrome-like phenotypes.

PubMed

Herrera-Moyano, Emilia; Moriel-Carretero, María; Montelone, Beth A; Aguilera, Andrés

2014-12-01

The eukaryotic TFIIH complex is involved in Nucleotide Excision Repair and transcription initiation. We analyzed three yeast mutations of the Rad3/XPD helicase of TFIIH known as rem (recombination and mutation phenotypes). We found that, in these mutants, incomplete NER reactions lead to replication fork breaking and the subsequent engagement of the homologous recombination machinery to restore them. Nevertheless, the penetrance varies among mutants, giving rise to a phenotype gradient. Interestingly, the mutations analyzed reside at the ATP-binding groove of Rad3 and in vivo experiments reveal a gain of DNA affinity upon damage of the mutant Rad3 proteins. Since mutations at the ATP-binding groove of XPD in humans are present in the Xeroderma pigmentosum-Cockayne Syndrome (XP-CS), we recreated rem mutations in human cells, and found that these are XP-CS-like. We propose that the balance between the loss of helicase activity and the gain of DNA affinity controls the capacity of TFIIH to open DNA during NER, and its persistence at both DNA lesions and promoters. This conditions NER efficiency and transcription resumption after damage, which in human cells would explain the XP-CS phenotype, opening new perspectives to understand the molecular basis of the role of XPD in human disease.

Chromosomal localization of three repair genes: The xeroderma pigmentosum group C gene and two human homologs of yeast RAD23

DOE Office of Scientific and Technical Information (OSTI.GOV)

Spek, P.J. van der; Smit, E.M.E.; Beverloo, H.B.

1994-10-01

The nucleotide excision repair (NER) disorder xeroderma pigmentosum (XP) is characterized by sun (UV) sensitivity, predisposition to skin cancer, and extensive genetic heterogeneity. Recently, we reported the cloning and analysis of three human NER genes, XPC, HHR23A, and HHR23B. The previously cloned XPC gene is involved in the common XP complementation group C, which is defective in excision repair of nontranscribed sequences in the genome. The XPC protein was found to be complexed with the product of HHR23B, one of the two human homologs of the Saccharomyes cerevisiae NER gene RAD23. Here we present the chromosomal localization by in situmore » hybridization using haptenized probes of all three genes. The HHR23A gene was assigned to chromosome 19p13.2. Interestingly, the HHR23B and XPC genes, the product of which forms a tight complex, were found to colocalize on band 3p25.1. Pulsed-field gel electrophoresis revealed that the HHR23B and XPC genes possibly share a MluI restriction fragment of about 625 kb. Potential involvement of the HHR23 genes in human genetic disorders is discussed. 53 refs., 4 figs., 2 tabs.« less

Xeroderma pigmentosum in Ghanaians: a report of three cases and review of literature.

PubMed

Adu, E J

2014-01-01

Xeroderma pigmentosum is an autosomal recessive disease with sun sensitivity, photophobia, early onset of freckling, and subsequent neoplastic changes on sun-exposed surfaces. There is cellular hypersensitivity to UV radiation and to certain chemicals in association with abnormal DNA repair. Patients with defective DNA nucleotide excision repair (NER) have defects in one of seven NER genes; xeroderma pigmentosum variants have normal NER and a defect in a polymerase gene. This is a case presentation of three patients with the features of xeroderma pigmentosum, aged 48, 15, and 14 years. The latter two patients were females. Each presented with areas of hyper-and hypo-pigmentation over sun exposed body surfaces. Each patient had a minimum of two cutaneous malignancies, distributed on the upper chest, face or scalp. The first and third patients had their lesions surgically excised and the defects were skin grafted. The second patient was treated with radiotherapy. All the lesions presented were confirmed histologically as squamous cell carcinoma. No recurrence of the malignancies has been noticed. Xeroderma pigmentosum is not rare in Ghana. Early recognition of the disease is necessary to avoid morbidity and mortality from malignant complications. The use of other treatment modalities such as sunscreens, oral retinoids, and chemical therapy with 5-fluorouracil is discussed.

The Cerebro-oculo-facio-skeletal Syndrome Point Mutation F231L in the ERCC1 DNA Repair Protein Causes Dissociation of the ERCC1-XPF Complex.

PubMed

Faridounnia, Maryam; Wienk, Hans; Kovačič, Lidija; Folkers, Gert E; Jaspers, Nicolaas G J; Kaptein, Robert; Hoeijmakers, Jan H J; Boelens, Rolf

2015-08-14

The ERCC1-XPF heterodimer, a structure-specific DNA endonuclease, is best known for its function in the nucleotide excision repair (NER) pathway. The ERCC1 point mutation F231L, located at the hydrophobic interaction interface of ERCC1 (excision repair cross-complementation group 1) and XPF (xeroderma pigmentosum complementation group F), leads to severe NER pathway deficiencies. Here, we analyze biophysical properties and report the NMR structure of the complex of the C-terminal tandem helix-hairpin-helix domains of ERCC1-XPF that contains this mutation. The structures of wild type and the F231L mutant are very similar. The F231L mutation results in only a small disturbance of the ERCC1-XPF interface, where, in contrast to Phe(231), Leu(231) lacks interactions stabilizing the ERCC1-XPF complex. One of the two anchor points is severely distorted, and this results in a more dynamic complex, causing reduced stability and an increased dissociation rate of the mutant complex as compared with wild type. These data provide a biophysical explanation for the severe NER deficiencies caused by this mutation. © 2015 by The American Society for Biochemistry and Molecular Biology, Inc.

Algae biodiesel life cycle assessment using current commercial data.

PubMed

Passell, Howard; Dhaliwal, Harnoor; Reno, Marissa; Wu, Ben; Ben Amotz, Ami; Ivry, Etai; Gay, Marcus; Czartoski, Tom; Laurin, Lise; Ayer, Nathan

2013-11-15

Autotrophic microalgae represent a potential feedstock for transportation fuels, but life cycle assessment (LCA) studies based on laboratory-scale or theoretical data have shown mixed results. We attempt to bridge the gap between laboratory-scale and larger scale biodiesel production by using cultivation and harvesting data from a commercial algae producer with ∼1000 m(2) production area (the base case), and compare that with a hypothetical scaled up facility of 101,000 m(2) (the future case). Extraction and separation data are from Solution Recovery Services, Inc. Conversion and combustion data are from the Greenhouse Gases, Regulated Emissions, and Energy Use in Transportation Model (GREET). The LCA boundaries are defined as "pond-to-wheels". Environmental impacts are quantified as NER (energy in/energy out), global warming potential, photochemical oxidation potential, water depletion, particulate matter, and total NOx and SOx. The functional unit is 1 MJ of energy produced in a passenger car. Results for the base case and the future case show an NER of 33.4 and 1.37, respectively and GWP of 2.9 and 0.18 kg CO2-equivalent, respectively. In comparison, petroleum diesel and soy diesel show an NER of 0.18 and 0.80, respectively and GWP of 0.12 and 0.025, respectively. A critical feature in this work is the low algal productivity (3 g/m(2)/day) reported by the commercial producer, relative to the much higher productivities (20-30 g/m(2)/day) reported by other sources. Notable results include a sensitivity analysis showing that algae with an oil yield of 0.75 kg oil/kg dry biomass in the future case can bring the NER down to 0.64, more comparable with petroleum diesel and soy biodiesel. An important assumption in this work is that all processes are fully co-located and that no transport of intermediate or final products from processing stage to stage is required. Copyright © 2013 Elsevier Ltd. All rights reserved.

Newly identified CHO ERCC3/XPB mutations and phenotype characterization

PubMed Central

Rybanská, Ivana; Gurský, Ján; Fašková, Miriam; Salazar, Edmund P.; Kimlíčková-Polakovičová, Erika; Kleibl, Karol; Thompson, Larry H.; Piršel, Miroslav

2010-01-01

Nucleotide excision repair (NER) is a complex multistage process involving many interacting gene products to repair a wide range of DNA lesions. Genetic defects in NER cause human hereditary diseases including xeroderma pigmentosum (XP), Cockayne syndrome (CS), trichothiodystrophy and a combined XP/CS overlapping symptom. One key gene product associated with all these disorders is the excision repair cross-complementing 3/xeroderma pigmentosum B (ERCC3/XPB) DNA helicase, a subunit of the transcription factor IIH complex. ERCC3 is involved in initiation of basal transcription and global genome repair as well as in transcription-coupled repair (TCR). The hamster ERCC3 gene shows high degree of homology with the human ERCC3/XPB gene. We identified new mutations in the Chinese hamster ovary cell ERCC3 gene and characterized the role of hamster ERCC3 protein in DNA repair of ultraviolet (UV)-induced and oxidative DNA damage. All but one newly described mutations are located in the protein C-terminal region around the last intron–exon boundary. Due to protein truncations or frameshifts, they lack amino acid Ser751, phosphorylation of which prevents the 5′ incision of the UV-induced lesion during NER. Thus, despite the various locations of the mutations, their phenotypes are similar. All ercc3 mutants are extremely sensitive to UV-C light and lack recovery of RNA synthesis (RRS), confirming a defect in TCR of UV-induced damage. Their limited global genome NER capacity averages ∼8%. We detected modest sensitivity of ercc3 mutants to the photosensitizer Ro19-8022, which primarily introduces 8-oxoguanine lesions into DNA. Ro19-8022-induced damage interfered with RRS, and some of the ercc3 mutants had delayed kinetics. All ercc3 mutants showed efficient base excision repair (BER). Thus, the positions of the mutations have no effect on the sensitivity to, and repair of, Ro19-8022-induced DNA damage, suggesting that the ERCC3 protein is not involved in BER. PMID:19942596

Nucleotide Excision Repair Gene Polymorphisms, Meat Intake and Colon Cancer Risk

PubMed Central

Steck, Susan E.; Butler, Lesley M.; Keku, Temitope; Antwi, Samuel; Galanko, Joseph; Sandler, Robert S.; Hu, Jennifer J.

2014-01-01

Purpose Much of the DNA damage from colon cancer-related carcinogens, including heterocyclic amines (HCA) and polycyclic aromatic hydrocarbons (PAH) from red meat cooked at high temperature, are repaired by the nucleotide excision repair (NER) pathway. Thus, we examined whether NER non-synonymous single nucleotide polymorphisms (nsSNPs) modified the association between red meat intake and colon cancer risk. Methods The study consists of 244 African-American and 311 white colon cancer cases and population-based controls (331 African Americans and 544 whites) recruited from 33 counties in North Carolina from 1996 to 2000. Information collected by food frequency questionnaire on meat intake and preparation methods were used to estimate HCA and benzo(a)pyrene (BaP, a PAH) intake. We tested 7 nsSNPs in 5 NER genes: XPC A499V and K939Q, XPD D312N and K751Q, XPF R415Q, XPG D1104H, and RAD23B A249V. Adjusted odds ratios (OR) and 95% confidence intervals (CI) were calculated using unconditional logistic regression. Results Among African Americans, we observed a statistically significant positive association between colon cancer risk and XPC 499 AV+VV genotype (OR=1.7, 95% CI: 1.1, 2.7, AA as referent), and an inverse association with XPC 939 QQ (OR=0.3, 95%CI: 0.2, 0.8, KK as referent). These associations were not observed among whites. For both races combined, there was interaction between the XPC 939 genotype, well-done red meat intake and colon cancer risk (OR=1.5, 95% CI=1.0, 2.2 for high well-done red meat and KK genotype as compared to low well-done red meat and KK genotype, pinteraction =0.05). Conclusions Our data suggest that NER nsSNPs are associated with colon cancer risk and may modify the association between well-done red meat intake and colon cancer risk. PMID:24607854

Family Incomes: Will Your Children Be as Well Off as Your? = Les revenue familiaux: vos enfants s'en tireront-ils aussi bien que vous?

ERIC Educational Resources Information Center

Theilheimer, Ish, Ed.

1993-01-01

Against the background of recent radical changes in the Canadian economy, this issue of the Canadian journal "Transition" examines the question of parents' concerns for their children's economic futures. "Changes in Family Incomes and Labour Market Participation in Post-War Canada" (David Ross and Clarence Lochhead) charts…

E-mail et Web: Pour une Navigation Sans Risque

ScienceCinema

Dellabella, Sebastien

2018-04-27

Présentation orale en français, support visuel en anglais. À travers des exemples concrets, vous consoliderez vos connaissances et pourrez ainsi réajuster vos habitudes concernant l’utilisation sécurisée de votre boîte e-mail et de votre navigateur Web.

"Cascades, Torrents & Drowning" in Information: Seeking Help in the Contemporary General Practitioner Practice in the UK

ERIC Educational Resources Information Center

Holley, Debbie; Santos, Patricia; Cook, John; Kerr, Micky

2016-01-01

This paper responds to the Alpine Rendez-Vous "crisis" in technology-enhanced learning. It takes a contested area of policy as well as a rapid change in the National Health Service, and documents the responses to "information overload" by a group of general practitioners practices in the North of England. Located between the…

Effects of physical activity on systemic oxidative/DNA status in breast cancer survivors.

PubMed

Tomasello, Barbara; Malfa, Giuseppe Antonio; Strazzanti, Angela; Gangi, Santi; Di Giacomo, Claudia; Basile, Francesco; Renis, Marcella

2017-01-01

Physical activity offers a paradoxical hormetic effect and a health benefit to cancer survivors; however, the biochemical mechanisms have not been entirely elucidated. Despite the well-documented evidence implicating oxidative stress in breast cancer, the association between health benefits and redox status has not been investigated in survivors who participate in dragon boating. The present study investigated the plasmatic systemic oxidative status (SOS) in breast cancer survivors involved in two distinct physical training exercises. A total of 75 breast cancer survivors were allocated to one of three groups: Control (resting), dragon boat racing and walking group; the latter is a type of aerobic conditioning exercise often advised to cancer patients. Various biochemical oxidative stress markers were examined, including oxidant status (hydroperoxide levels, lipid oxidation) and antioxidant status (enzymatic activities of superoxide dismutase and glutathione peroxidase, reduced glutathione levels and antioxidant capability). In addition, the individual DNA fragmentation and DNA repair capability of nucleotide excision repair (NER) systems were examined by comet assays. According to the results, all patients exhibited high levels of oxidative stress. Physical activity maintained this oxidative stress condition but simultaneously had a positive influence on the antioxidant component of the SOS, particularly in the dragon boat racing group. DNA fragmentation, according to the levels of single- and double-strand breaks, were within the normal range in the two survivor groups that were involved in training activities. Radiation-induced damage was not completely recognised or repaired by NER systems in any of the patients, probably leading to radiosensitivity and/or susceptibility of patients to cancer. These findings suggest that physical activity, particularly dragon boat racing, that modulates SOS and DNA repair capability could represent a strategy for enhancing the quality of life and improving the long-term health benefits for breast cancer survivors.

Effects of physical activity on systemic oxidative/DNA status in breast cancer survivors

PubMed Central

Tomasello, Barbara; Malfa, Giuseppe Antonio; Strazzanti, Angela; Gangi, Santi; Di Giacomo, Claudia; Basile, Francesco; Renis, Marcella

2017-01-01

Physical activity offers a paradoxical hormetic effect and a health benefit to cancer survivors; however, the biochemical mechanisms have not been entirely elucidated. Despite the well-documented evidence implicating oxidative stress in breast cancer, the association between health benefits and redox status has not been investigated in survivors who participate in dragon boating. The present study investigated the plasmatic systemic oxidative status (SOS) in breast cancer survivors involved in two distinct physical training exercises. A total of 75 breast cancer survivors were allocated to one of three groups: Control (resting), dragon boat racing and walking group; the latter is a type of aerobic conditioning exercise often advised to cancer patients. Various biochemical oxidative stress markers were examined, including oxidant status (hydroperoxide levels, lipid oxidation) and antioxidant status (enzymatic activities of superoxide dismutase and glutathione peroxidase, reduced glutathione levels and antioxidant capability). In addition, the individual DNA fragmentation and DNA repair capability of nucleotide excision repair (NER) systems were examined by comet assays. According to the results, all patients exhibited high levels of oxidative stress. Physical activity maintained this oxidative stress condition but simultaneously had a positive influence on the antioxidant component of the SOS, particularly in the dragon boat racing group. DNA fragmentation, according to the levels of single- and double-strand breaks, were within the normal range in the two survivor groups that were involved in training activities. Radiation-induced damage was not completely recognised or repaired by NER systems in any of the patients, probably leading to radiosensitivity and/or susceptibility of patients to cancer. These findings suggest that physical activity, particularly dragon boat racing, that modulates SOS and DNA repair capability could represent a strategy for enhancing the quality of life and improving the long-term health benefits for breast cancer survivors. PMID:28123580

Nuclear Magnetic Resonance Studies of an N2-Guanine Adduct Derived from the Tumorigen Dibenzo[a,l]pyrene in DNA: Impact of Adduct Stereochemistry, Size, and Local DNA Sequence on Solution Conformations

PubMed Central

2015-01-01

The dimensions and arrangements of aromatic rings (topology) in adducts derived from the reactions of polycyclic aromatic hydrocarbon (PAH) diol epoxide metabolites with DNA influence the distortions and stabilities of double-stranded DNA, and hence their recognition and processing by the human nucleotide excision repair (NER) system. Dibenzo[a,l]pyrene (DB[a,l]P) is a highly tumorigenic six-ring PAH, which contains a nonplanar and aromatic fjord region that is absent in the structurally related bay region five-ring PAH benzo[a]pyrene (B[a]P). The PAH diol epoxide–DNA adducts formed include the stereoisomeric 14S and 14Rtrans-anti-DB[a,l]P-N2-dG and the stereochemically analogous 10S- and 10R-B[a]P-N2-dG (B[a]P-dG) guanine adducts. However, nuclear magnetic resonance (NMR) solution studies of the 14S-DB[a,l]P-N2-dG adduct in DNA have not yet been presented. Here we have investigated the 14S-DB[a,l]P-N2-dG adduct in two different sequence contexts using NMR methods with distance-restrained molecular dynamics simulations. In duplexes with dC opposite the adduct deleted, a well-resolved base-displaced intercalative adduct conformation can be observed. In full duplexes, in contrast to the intercalated 14R stereoisomeric adduct, the bulky DB[a,l]P residue in the 14S adduct is positioned in a greatly widened and distorted minor groove, with significant disruptions and distortions of base pairing at the lesion site and two 5′-side adjacent base pairs. These unique structural features are significantly different from those of the stereochemically analogous but smaller B[a]P-dG adduct. The greater size and different topology of the DB[a,l]P aromatic ring system lead to greater structurally destabilizing DNA distortions that are partially compensated by stabilizing DB[a,l]P-DNA van der Waals interactions, whose combined effects impact the NER response to the adduct. These structural results broaden our understanding of the structure–function relationship in NER. PMID:24617538

From "La Plume de Ma Tante" to "Parlez-Vous Francais?" The Making of French Language Policy in British Columbia, 1945-1982

ERIC Educational Resources Information Center

Raptis, Helen; Fleming, Thomas

2004-01-01

During the first half of the twentieth century in British Columbia, French language was considered a school subject to be taught as any other using formal classical approaches. Generally, no specific provincial or local policies existed to guide how French was taught and learned. By 1981, however, British Columbia had developed explicit language…

Flore et menagerie phonetiques; Collages; Tirez a vous la couverture; A propos d'un quiproquo (Phonetic Flora and Fauna; Collages; Take the Covers; A Propos of a Quid Pro Quo).

ERIC Educational Resources Information Center

Francais dans le Monde, 1987

1987-01-01

Four suggestions for classroom language-learning activities include a series of dot-to-dot phonetics games, small group collage making and presentation, use of magazine covers to stimulate class discussion and introduction of vocabulary, and student-written sketches based on misunderstandings. (MSE)

Spermatogenesis is not impaired in a nucleotide excision repair-deficient min mouse model with or without neonatal mutagen treatment.

PubMed

Andreassen, Ashild; Steffensen, Inger-Lise; Olsen, Ann-Karin; Tanaka, Kiyoji; Wiger, Richard

2011-01-01

Mice deficient in the xeroderma pigmentosum group A gene (Xpa) exhibit impaired nucleotide excision repair (NER) and are expected to accumulate bulky DNA adducts when subjected to certain compounds (eg, heterocyclic amines). Multiple intestinal neoplasia (Min) mice (B6(Min)(/+)) are particularly sensitive to low concentrations of mutagenic compounds in food. They develop intestinal tumors spontaneously, and the number and size of the tumors increase following exposure to 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP), which humans are exposed to via fried food. We previously reported that NER is inefficient in adult testicular cells. Reduced NER (genetic deficiency; Xpa(-/-)) is expected to represent risk factors for PhIP-induced genotoxicity and could possibly disturb spermatogenesis, particularly in B6(Min)(/+) mice. We therefore studied spermatogenesis in mice with combinations of Xpa and Min or wild-type genotypes 11 weeks after exposure to PhIP on days 3 to 6. Fewer offspring were obtained from B6(Min)(/+)Xpa(-/-) than from B6(Min)(/+)Xpa(+/+) or B6(Min)(/+)Xpa(+/-). Distributions of the different testicular cell types, indicative of normal spermatogenesis and relative testes weights, did not differ significantly in PhIP-exposed or unexposed mice regardless of their genotypes. We conclude that the removal of bulky DNA adducts does not seem to be essential for normal spermatogenesis.

Active transcriptomic and proteomic reprogramming in the C. elegans nucleotide excision repair mutant xpa-1.

PubMed

Arczewska, Katarzyna D; Tomazella, Gisele G; Lindvall, Jessica M; Kassahun, Henok; Maglioni, Silvia; Torgovnick, Alessandro; Henriksson, Johan; Matilainen, Olli; Marquis, Bryce J; Nelson, Bryant C; Jaruga, Pawel; Babaie, Eshrat; Holmberg, Carina I; Bürglin, Thomas R; Ventura, Natascia; Thiede, Bernd; Nilsen, Hilde

2013-05-01

Transcription-blocking oxidative DNA damage is believed to contribute to aging and to underlie activation of oxidative stress responses and down-regulation of insulin-like signaling (ILS) in Nucleotide Excision Repair (NER) deficient mice. Here, we present the first quantitative proteomic description of the Caenorhabditis elegans NER-defective xpa-1 mutant and compare the proteome and transcriptome signatures. Both methods indicated activation of oxidative stress responses, which was substantiated biochemically by a bioenergetic shift involving increased steady-state reactive oxygen species (ROS) and Adenosine triphosphate (ATP) levels. We identify the lesion-detection enzymes of Base Excision Repair (NTH-1) and global genome NER (XPC-1 and DDB-1) as upstream requirements for transcriptomic reprogramming as RNA-interference mediated depletion of these enzymes prevented up-regulation of genes over-expressed in the xpa-1 mutant. The transcription factors SKN-1 and SLR-2, but not DAF-16, were identified as effectors of reprogramming. As shown in human XPA cells, the levels of transcription-blocking 8,5'-cyclo-2'-deoxyadenosine lesions were reduced in the xpa-1 mutant compared to the wild type. Hence, accumulation of cyclopurines is unlikely to be sufficient for reprogramming. Instead, our data support a model where the lesion-detection enzymes NTH-1, XPC-1 and DDB-1 play active roles to generate a genomic stress signal sufficiently strong to result in transcriptomic reprogramming in the xpa-1 mutant.

The rem Mutations in the ATP-Binding Groove of the Rad3/XPD Helicase Lead to Xeroderma pigmentosum-Cockayne Syndrome-Like Phenotypes

PubMed Central

Montelone, Beth A.; Aguilera, Andrés

2014-01-01

The eukaryotic TFIIH complex is involved in Nucleotide Excision Repair and transcription initiation. We analyzed three yeast mutations of the Rad3/XPD helicase of TFIIH known as rem (recombination and mutation phenotypes). We found that, in these mutants, incomplete NER reactions lead to replication fork breaking and the subsequent engagement of the homologous recombination machinery to restore them. Nevertheless, the penetrance varies among mutants, giving rise to a phenotype gradient. Interestingly, the mutations analyzed reside at the ATP-binding groove of Rad3 and in vivo experiments reveal a gain of DNA affinity upon damage of the mutant Rad3 proteins. Since mutations at the ATP-binding groove of XPD in humans are present in the Xeroderma pigmentosum-Cockayne Syndrome (XP-CS), we recreated rem mutations in human cells, and found that these are XP-CS-like. We propose that the balance between the loss of helicase activity and the gain of DNA affinity controls the capacity of TFIIH to open DNA during NER, and its persistence at both DNA lesions and promoters. This conditions NER efficiency and transcription resumption after damage, which in human cells would explain the XP-CS phenotype, opening new perspectives to understand the molecular basis of the role of XPD in human disease. PMID:25500814

Binding of RDX to Cell Wall Components of Pinus sylvestris and Picea glauca and Three-Year Mineralisation Study of Tissue-Associated RDX Residues.

PubMed

Schoenmuth, Bernd; Schenke, Detlef; Scharnhorst, Tanja; Combrinck, Sandra; McCrindle, Robert I; Mueller, Jakob O; Büttner, Carmen; Pestemer, Wilfried

2015-01-01

Contamination of soils with the explosive hexahydro-1,3,5-trinitro-1,3,5-triazine (RDX, Research Department Explosive) as a result of military applications is a large-area problem globally. Since coniferous trees dominate the vegetation of large areas of military land in Central Europe, particularly in Germany, the long-term fate of (14)C-RDX in the conifers Scots pine and Dwarf Alberta spruce was studied. Acetic acid was the most effective solvent for the removal of extractable RDX residues from homogenates of RDX-laden tree material (85%, 80-90% and 64-80% for roots, wood and needles, respectively). On average, only a fifth of RDX-derived (14)C was bound in non-extractable residues (NER). Within the main cell wall compartments, lignin was the dominant binding site for NER (needles: 32-62%; roots: 38-42%). Hemicellulose (needles: 11-18%; roots: 6-11%) and cellulose (needles: 12-24%; roots: 1-2%) were less involved in binding and a considerable proportion of NER (needles: 15-24%; roots: 59-51%) was indigestible. After three-year incubation in rot chambers, mineralisation of tree-associated (14)C-RDX to (14)CO2 clearly dominated the mass balance in both tree species with 48-83%. 13-33% of (14)C-RDX-derived radioactivity remained in an unleachable form and the remobilisation by water leaching was negligible (< 2%).

Applying Suffix Rules to Organization Name Recognition

NASA Astrophysics Data System (ADS)

Inui, Takashi; Murakami, Koji; Hashimoto, Taiichi; Utsumi, Kazuo; Ishikawa, Masamichi

This paper presents a method for boosting the performance of the organization name recognition, which is a part of named entity recognition (NER). Although gazetteers (lists of the NEs) have been known as one of the effective features for supervised machine learning approaches on the NER task, the previous methods which have applied the gazetteers to the NER were very simple. The gazetteers have been used just for searching the exact matches between input text and NEs included in them. The proposed method generates regular expression rules from gazetteers, and, with these rules, it can realize a high-coverage searches based on looser matches between input text and NEs. To generate these rules, we focus on the two well-known characteristics of NE expressions; 1) most of NE expressions can be divided into two parts, class-reference part and instance-reference part, 2) for most of NE expressions the class-reference parts are located at the suffix position of them. A pattern mining algorithm runs on the set of NEs in the gazetteers, and some frequent word sequences from which NEs are constructed are found. Then, we employ only word sequences which have the class-reference part at the suffix position as suffix rules. Experimental results showed that our proposed method improved the performance of the organization name recognition, and achieved the 84.58 F-value for evaluation data.

TFIIH subunit alterations causing xeroderma pigmentosum and trichothiodystrophy specifically disturb several steps during transcription.

PubMed

Singh, Amita; Compe, Emanuel; Le May, Nicolas; Egly, Jean-Marc

2015-02-05

Mutations in genes encoding the ERCC3 (XPB), ERCC2 (XPD), and GTF2H5 (p8 or TTD-A) subunits of the transcription and DNA-repair factor TFIIH lead to three autosomal-recessive disorders: xeroderma pigmentosum (XP), XP associated with Cockayne syndrome (XP/CS), and trichothiodystrophy (TTD). Although these diseases were originally associated with defects in DNA repair, transcription deficiencies might be also implicated. By using retinoic acid receptor beta isoform 2 (RARB2) as a model in several cells bearing mutations in genes encoding TFIIH subunits, we observed that (1) the recruitment of the TFIIH complex was altered at the activated RARB2 promoter, (2) TFIIH participated in the recruitment of nucleotide excision repair (NER) factors during transcription in a manner different from that observed during NER, and (3) the different TFIIH variants disturbed transcription by having distinct consequences on post-translational modifications of histones, DNA-break induction, DNA demethylation, and gene-loop formation. The transition from heterochromatin to euchromatin was disrupted depending on the variant, illustrating the fact that TFIIH, by contributing to NER factor recruitment, orchestrates chromatin remodeling. The subtle transcriptional differences found between various TFIIH variants thus participate in the phenotypic variability observed among XP, XP/CS, and TTD individuals. Copyright © 2015 The American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.

FANCJ localization by mismatch repair is vital to maintain genomic integrity after UV irradiation.

PubMed

Guillemette, Shawna; Branagan, Amy; Peng, Min; Dhruva, Aashana; Schärer, Orlando D; Cantor, Sharon B

2014-02-01

Nucleotide excision repair (NER) is critical for the repair of DNA lesions induced by UV radiation, but its contribution in replicating cells is less clear. Here, we show that dual incision by NER endonucleases, including XPF and XPG, promotes the S-phase accumulation of the BRCA1 and Fanconi anemia-associated DNA helicase FANCJ to sites of UV-induced damage. FANCJ promotes replication protein A phosphorylation and the arrest of DNA synthesis following UV irradiation. Interaction defective mutants of FANCJ reveal that BRCA1 binding is not required for FANCJ localization, whereas interaction with the mismatch repair (MMR) protein MLH1 is essential. Correspondingly, we find that FANCJ, its direct interaction with MLH1, and the MMR protein MSH2 function in a common pathway in response to UV irradiation. FANCJ-deficient cells are not sensitive to killing by UV irradiation, yet we find that DNA mutations are significantly enhanced. Thus, we considered that FANCJ deficiency could be associated with skin cancer. Along these lines, in melanoma we found several somatic mutations in FANCJ, some of which were previously identified in hereditary breast cancer and Fanconi anemia. Given that, mutations in XPF can also lead to Fanconi anemia, we propose collaborations between Fanconi anemia, NER, and MMR are necessary to initiate checkpoint activation in replicating human cells to limit genomic instability.

ATTIRE (analytical tools for thermal infrared engineering): A sensor simulation and modeling package

NASA Astrophysics Data System (ADS)

Jaggi, S.

1993-02-01

The Advanced Sensor Development Laboratory (ASDL) at the Stennis Space Center develops, maintains and calibrates remote sensing instruments for the National Aeronautics & Space Administration (NASA). To perform system design trade-offs, analysis, and establish system parameters, ASDL has developed a software package for analytical simulation of sensor systems. This package called 'Analytical Tools for Thermal InfraRed Engineering' - ATTIRE, simulates the various components of a sensor system. The software allows each subsystem of the sensor to be analyzed independently for its performance. These performance parameters are then integrated to obtain system level information such as Signal-to-Noise Ratio (SNR), Noise Equivalent Radiance (NER), Noise Equivalent Temperature Difference (NETD) etc. This paper describes the uses of the package and the physics that were used to derive the performance parameters.

Cell type-specific hypersensitivity to oxidative damage in CSB and XPA mice.

PubMed

de Waard, Harm; de Wit, Jan; Gorgels, Theo G M F; van den Aardweg, Gerard; Andressoo, Jaan Olle; Vermeij, Marcel; van Steeg, Harry; Hoeijmakers, Jan H J; van der Horst, Gijsbertus T J

2003-01-02

Mutations in the CSB gene cause Cockayne syndrome (CS), a rare inherited disorder, characterized by UV-sensitivity, severe neurodevelopmental and progeroid symptoms. CSB functions in the transcription-coupled repair (TCR) sub-pathway of nucleotide excision repair (NER), responsible for the removal of UV-induced and other helix-distorting lesions from the transcribed strand of active genes. Several lines of evidence support the notion that the CSB TCR defect extends to other non-NER type transcription-blocking lesions, notably various kinds of oxidative damage, which may provide an explanation for part of the severe CS phenotype. We used genetically defined mouse models to examine the relationship between the CSB defect and sensitivity to oxidative damage in different cell types and at the level of the intact organism. The main conclusions are: (1) CSB(-/-) mouse embryo fibroblasts (MEFs) exhibit a clear hypersensitivity to ionizing radiation, extending the findings in genetically heterogeneous human CSB fibroblasts to another species. (2) CSB(-/-) MEFs are highly sensitive to paraquat, strongly indicating that the increased cytotoxicity is due to oxidative damage. (3) The hypersenstivity is independent of genetic background and directly related to the CSB defect and is not observed in totally NER-deficient XPA MEFs. (4) Wild type embryonic stem (ES) cells display an increased sensitivity to ionizing radiation compared to fibroblasts. Surprisingly, the CSB deficiency has only a very minor additional effect on ES cell sensitivity to oxidative damage and is comparable to that of an XPA defect, indicating cell type-specific differences in the contribution of TCR and NER to cellular survival. (5) Similar to ES cells, CSB and XPA mice both display a minor sensitivity to whole-body X-ray exposure. This suggests that the response of an intact organism to radiation is largely determined by the sensitivity of stem cells, rather than differentiated cells. These findings establish the role of transcription-coupled repair in resistance to oxidative damage and reveal a cell- and organ-specific impact of this repair pathway to the clinical phenotype of CS and XP.

bioNerDS: exploring bioinformatics’ database and software use through literature mining

PubMed Central

2013-01-01

Background Biology-focused databases and software define bioinformatics and their use is central to computational biology. In such a complex and dynamic field, it is of interest to understand what resources are available, which are used, how much they are used, and for what they are used. While scholarly literature surveys can provide some insights, large-scale computer-based approaches to identify mentions of bioinformatics databases and software from primary literature would automate systematic cataloguing, facilitate the monitoring of usage, and provide the foundations for the recovery of computational methods for analysing biological data, with the long-term aim of identifying best/common practice in different areas of biology. Results We have developed bioNerDS, a named entity recogniser for the recovery of bioinformatics databases and software from primary literature. We identify such entities with an F-measure ranging from 63% to 91% at the mention level and 63-78% at the document level, depending on corpus. Not attaining a higher F-measure is mostly due to high ambiguity in resource naming, which is compounded by the on-going introduction of new resources. To demonstrate the software, we applied bioNerDS to full-text articles from BMC Bioinformatics and Genome Biology. General mention patterns reflect the remit of these journals, highlighting BMC Bioinformatics’s emphasis on new tools and Genome Biology’s greater emphasis on data analysis. The data also illustrates some shifts in resource usage: for example, the past decade has seen R and the Gene Ontology join BLAST and GenBank as the main components in bioinformatics processing. Abstract Conclusions We demonstrate the feasibility of automatically identifying resource names on a large-scale from the scientific literature and show that the generated data can be used for exploration of bioinformatics database and software usage. For example, our results help to investigate the rate of change in resource usage and corroborate the suspicion that a vast majority of resources are created, but rarely (if ever) used thereafter. bioNerDS is available at http://bionerds.sourceforge.net/. PMID:23768135

Quantifying uncertainty in future floods and drought conditions in the Northeastern United States using regionally downscaled climate projections

NASA Astrophysics Data System (ADS)

Siddique, R.; Wu, C.; Karmalkar, A.; Bradley, R. S.; Palmer, R. N.

2017-12-01

Northeastern region (NER) of the United States (US) has been projected to be a place where climate change can have the most severe impacts. These impacts include, but are not limited to, increases in the following: extreme precipitation events, temperature, flood magnitudes, flood frequencies, droughts, and sea level rise. In this study, we estimate the frequency of hydrological extremes under different climate change scenarios using regionally downscaled climate projections from a limited number of selected models from the fifth phase of Coupled Model Intercomparison Project (CMIP5). The models are chosen to minimize the loss of key climate information relevant to the NER. Precipitation and temperature from the selected models are forced into a distributed hydrological model called Hydrology Laboratory - Research Distributed Hydrological Model (HL-RDHM) to obtain streamflows for two different time regimes, near-term (20-50 years out) and long-term (50-80 years out). For this, two climate emission scenarios will be considered: RCP 4.5 and RCP 8.5. The impacts of the climate projections on the streamflows are then evaluated across different watershed scales in the NER. Among different metrics, we employ: 1) Flood Events - return period of 1 year, 10 year, 20 year, 50 year, and 100 year flood events and 2) Drought Events -low flow events associated with the 7-day 10 year low flow, number of days per month that will be below the historic monthly average, number of days per month that will be below the 25 percentile monthly historic average, changes in the 30-day and 60-day cumulative summer flows, and the timing and magnitude of spring run-off. For estimates of the climate impacts on low and high flows, only the unregulated watersheds are taken into consideration. Ensembles of streamflows obtained by forcing different climate projections are used to quantify and account for the associated uncertainties. Thus, the outcomes of this study are expected to guide regional decision makers on potential impacts of climate change on hydrological extreme events and water resources across different spatial scales within NER of the US.

Analysis of repair and PCNA complex formation induced by ionizing radiation in human fibroblast cell lines.

PubMed

Karmakar, P; Balajee, A S; Natarajan, A T

2001-05-01

Proliferating cell nuclear antigen (PCNA), an auxiliary factor for DNA polymerase delta and epsilon, is involved in both DNA replication and repair. Previous studies in vitro have demonstrated the requirement of PCNA in the resynthesis step of nucleotide excision repair (NER) and base excision repair (BER). Using a native chromatin template isolated under near physiological conditions, we have analysed the involvement of PCNA in the BER pathway in different NER defective human cell lines. The repair sites and PCNA were visualized by indirect immunolabelling followed by fluorescence microscopy. The results indicate that exposure to X-rays triggers the induction of PCNA in all the three human fibroblast cell lines studied, namely normal, xeroderma pigmentosum group A (XP-A) and Cockayne syndrome group B (CS-B). In all the cell lines, induction of PCNA and repair patches occurred in a dose- and time-dependent fashion. Induction of repair patches in NER-deficient XP-A cells suggests that the X-ray-induced lesions are largely repaired via the BER pathway involving PCNA as one of the key components of this pathway. X-ray-induced repair synthesis was greatly inhibited by treatment of cells with DNA polymerase inhibitors aphidicolin and cytosine arabinoside. Interestingly, inhibition of repair resynthesis did not affect the intensity of PCNA staining in X-irradiated cells indicating that the PCNA may be required for the BER pathway at a step preceding the resynthesis step.

GTF2E2 Mutations Destabilize the General Transcription Factor Complex TFIIE in Individuals with DNA Repair-Proficient Trichothiodystrophy

PubMed Central

Kuschal, Christiane; Botta, Elena; Orioli, Donata; Digiovanna, John J.; Seneca, Sara; Keymolen, Kathelijn; Tamura, Deborah; Heller, Elizabeth; Khan, Sikandar G.; Caligiuri, Giuseppina; Lanzafame, Manuela; Nardo, Tiziana; Ricotti, Roberta; Peverali, Fiorenzo A.; Stephens, Robert; Zhao, Yongmei; Lehmann, Alan R.; Baranello, Laura; Levens, David; Kraemer, Kenneth H.; Stefanini, Miria

2016-01-01

The general transcription factor IIE (TFIIE) is essential for transcription initiation by RNA polymerase II (RNA pol II) via direct interaction with the basal transcription/DNA repair factor IIH (TFIIH). TFIIH harbors mutations in two rare genetic disorders, the cancer-prone xeroderma pigmentosum (XP) and the cancer-free, multisystem developmental disorder trichothiodystrophy (TTD). The phenotypic complexity resulting from mutations affecting TFIIH has been attributed to the nucleotide excision repair (NER) defect as well as to impaired transcription. Here, we report two unrelated children showing clinical features typical of TTD who harbor different homozygous missense mutations in GTF2E2 (c.448G>C [p.Ala150Pro] and c.559G>T [p.Asp187Tyr]) encoding the beta subunit of transcription factor IIE (TFIIEβ). Repair of ultraviolet-induced DNA damage was normal in the GTF2E2 mutated cells, indicating that TFIIE was not involved in NER. We found decreased protein levels of the two TFIIE subunits (TFIIEα and TFIIEβ) as well as decreased phosphorylation of TFIIEα in cells from both children. Interestingly, decreased phosphorylation of TFIIEα was also seen in TTD cells with mutations in ERCC2, which encodes the XPD subunit of TFIIH, but not in XP cells with ERCC2 mutations. Our findings support the theory that TTD is caused by transcriptional impairments that are distinct from the NER disorder XP. PMID:26996949

Binding Pattern Elucidation of NNK and NNAL Cigarette Smoke Carcinogens with NER Pathway Enzymes: an Onco- Informatics Study.

PubMed

Jamal, Qazi Mohammad Sajid; Dhasmana, Anupam; Lohani, Mohtashim; Firdaus, Sumbul; Ansari, Md Yousuf; Sahoo, Ganesh Chandra; Haque, Shafiul

2015-01-01

Cigarette smoke derivatives like NNK (4-(Methylnitrosamino)-1-(3-pyridyl)-1-butanone) and NNAL (4-(methylnitrosamino)-1-(3-pyridyl)-1-butan-1-ol) are well-known carcinogens. We analyzed the interaction of enzymes involved in the NER (nucleotide excision repair) pathway with ligands (NNK and NNAL). Binding was characterized for the enzymes sharing equivalent or better interaction as compared to +Ve control. The highest obtained docking energy between NNK and enzymes RAD23A, CCNH, CDK7, and CETN2 were -7.13 kcal/mol, -7.27 kcal/mol, -8.05 kcal/mol and -7.58 kcal/mol respectively. Similarly the highest obtained docking energy between NNAL and enzymes RAD23A, CCNH, CDK7, and CETN2 were -7.46 kcal/mol, -7.94 kcal/mol, -7.83 kcal/mol and -7.67 kcal/mol respectively. In order to find out the effect of NNK and NNAL on enzymes involved in the NER pathway applying protein-protein interaction and protein-complex (i.e. enzymes docked with NNK/NNAL) interaction analysis. It was found that carcinogens are well capable to reduce the normal functioning of genes like RAD23A (HR23A), CCNH, CDK7 and CETN2. In silico analysis indicated loss of functions of these genes and their corresponding enzymes, which possibly might be a cause for alteration of DNA repair pathways leading to damage buildup and finally contributing to cancer formation.

A multistep damage recognition mechanism for global genomic nucleotide excision repair

PubMed Central

Sugasawa, Kaoru; Okamoto, Tomoko; Shimizu, Yuichiro; Masutani, Chikahide; Iwai, Shigenori; Hanaoka, Fumio

2001-01-01

A mammalian nucleotide excision repair (NER) factor, the XPC–HR23B complex, can specifically bind to certain DNA lesions and initiate the cell-free repair reaction. Here we describe a detailed analysis of its binding specificity using various DNA substrates, each containing a single defined lesion. A highly sensitive gel mobility shift assay revealed that XPC–HR23B specifically binds a small bubble structure with or without damaged bases, whereas dual incision takes place only when damage is present in the bubble. This is evidence that damage recognition for NER is accomplished through at least two steps; XPC–HR23B first binds to a site that has a DNA helix distortion, and then the presence of injured bases is verified prior to dual incision. Cyclobutane pyrimidine dimers (CPDs) were hardly recognized by XPC–HR23B, suggesting that additional factors may be required for CPD recognition. Although the presence of mismatched bases opposite a CPD potentiated XPC–HR23B binding, probably due to enhancement of the helix distortion, cell-free excision of such compound lesions was much more efficient than expected from the observed affinity for XPC–HR23B. This also suggests that additional factors and steps are required for the recognition of some types of lesions. A multistep mechanism of this sort may provide a molecular basis for ensuring the high level of damage discrimination that is required for global genomic NER. PMID:11238373

A multistep damage recognition mechanism for global genomic nucleotide excision repair.

PubMed

Sugasawa, K; Okamoto, T; Shimizu, Y; Masutani, C; Iwai, S; Hanaoka, F

2001-03-01

A mammalian nucleotide excision repair (NER) factor, the XPC-HR23B complex, can specifically bind to certain DNA lesions and initiate the cell-free repair reaction. Here we describe a detailed analysis of its binding specificity using various DNA substrates, each containing a single defined lesion. A highly sensitive gel mobility shift assay revealed that XPC-HR23B specifically binds a small bubble structure with or without damaged bases, whereas dual incision takes place only when damage is present in the bubble. This is evidence that damage recognition for NER is accomplished through at least two steps; XPC-HR23B first binds to a site that has a DNA helix distortion, and then the presence of injured bases is verified prior to dual incision. Cyclobutane pyrimidine dimers (CPDs) were hardly recognized by XPC-HR23B, suggesting that additional factors may be required for CPD recognition. Although the presence of mismatched bases opposite a CPD potentiated XPC-HR23B binding, probably due to enhancement of the helix distortion, cell-free excision of such compound lesions was much more efficient than expected from the observed affinity for XPC-HR23B. This also suggests that additional factors and steps are required for the recognition of some types of lesions. A multistep mechanism of this sort may provide a molecular basis for ensuring the high level of damage discrimination that is required for global genomic NER.

Xeroderma Pigmentosum-Trichothiodystrophy overlap patient with novel XPD/ERCC2 mutation

PubMed Central

Kralund, Henrik H.; Ousager, Lilian; Jaspers, Nicolaas G.; Raams, Anja; Pedersen, Erling B.; Gade, Else; Bygum, Anette

2013-01-01

Xeroderma Pigmentosum (XP), Trichothiodystrophy (TTD) and Cockayne Syndrome (CS) are rare, recessive disorders caused by mutational defects in the Nucleotide Excision Repair (NER) pathway and/or disruption of basic cellular DNA transcription. To date, a multitude of mutations in the XPD/ERCC2 gene have been described, many of which give rise to NER- and DNA transcription related diseases, which share certain diagnostic features and few overlap patients have been described. Despite increasing understanding of the roles of XPD/ERCC2 in mammalian cells, there is still weak predictability of somatic outcome from many of these mutations. We demonstrate a patient, believed to represent an overlap between XP and TTD/CS. In addition to other organ dysfunctions, the young man presented with Photosensitivity, Ichthyosis, Brittle hair, Impaired physical and mental development, Decreased fertility and Short stature (PIBIDS) suggestive of TTD, but lacking the almost patognomonic “tiger tail” banding of the hair under polarized light. Additionally, he developed basal cell carcinoma aged 28, as well as adult onset kidney failure, features normally not associated with TTD but rather XP/CS. His freckled appearance also suggested XP, but fibroblast cultures only demonstrated x2 UV-sensitivity with expected NER and TFIIH-activity decrease. Genetic sequencing of the XPD/ERCC2 gene established the patient as heterozygote compound with a novel, N-terminal Y18H mutation and a known C-terminal (TTD) mutation, A725P. The possible interplay between gene products and the patient phenotype is discussed. PMID:25002996

Predicting isoproturon long-term mineralization from short-term experiment: Can this be a suitable approach?

PubMed

Wang, Fang; Dörfler, Ulrike; Jiang, Xin; Schroll, Reiner

2016-02-01

A worldwide used pesticide - isoproturon (IPU) - was selected to test whether short-term experiments can be used to predict long-term mineralization of IPU in soil. IPU-mineralization was measured for 39 and 265 days in four different agricultural soils with a low mineralization dynamic. Additionally, in one soil IPU dissipation, formation and dissipation of metabolites, formation of non-extractable residues (NER) and (14)C-microbial biomass from (14)C-IPU were monitored for 39 and 265 days. The data from short-term and long-term experiments were used for model fitting. The long-term dynamics of IPU mineralization were considerably overestimated by the short-term experiments in two soils with neutral pH, while in two other soils with low pH and lower mineralization, the long-term mineralization of IPU could be sufficiently predicted. Additional investigations in one of the soils with neutral pH showed that dissipation of IPU and metabolites could be correctly predicted by the short-term experiment. However, the formation of NER and (14)C-microbial biomass were remarkably overestimated by the short-term experiment. Further, it could be shown that the released NER and (14)C-microbial biomass were the main contributors of (14)CO2 formation at later incubation stages. Taken together, our results indicate that in soils with neutral pH short-term experiments were inadequate to predict the long-term mineralization of IPU. Copyright © 2015 Elsevier Ltd. All rights reserved.

Multiple repair pathways mediate tolerance to chemotherapeutic cross-linking agents in vertebrate cells.

PubMed

Nojima, Kuniharu; Hochegger, Helfrid; Saberi, Alihossein; Fukushima, Toru; Kikuchi, Koji; Yoshimura, Michio; Orelli, Brian J; Bishop, Douglas K; Hirano, Seiki; Ohzeki, Mioko; Ishiai, Masamichi; Yamamoto, Kazuhiko; Takata, Minoru; Arakawa, Hiroshi; Buerstedde, Jean-Marie; Yamazoe, Mitsuyoshi; Kawamoto, Takuo; Araki, Kasumi; Takahashi, Jun A; Hashimoto, Nobuo; Takeda, Shunichi; Sonoda, Eiichiro

2005-12-15

Cross-linking agents that induce DNA interstrand cross-links (ICL) are widely used in anticancer chemotherapy. Yeast genetic studies show that nucleotide excision repair (NER), Rad6/Rad18-dependent postreplication repair, homologous recombination, and cell cycle checkpoint pathway are involved in ICL repair. To study the contribution of DNA damage response pathways in tolerance to cross-linking agents in vertebrates, we made a panel of gene-disrupted clones from chicken DT40 cells, each defective in a particular DNA repair or checkpoint pathway, and measured the sensitivities to cross-linking agents, including cis-diamminedichloroplatinum (II) (cisplatin), mitomycin C, and melphalan. We found that cells harboring defects in translesion DNA synthesis (TLS), Fanconi anemia complementation groups (FANC), or homologous recombination displayed marked hypersensitivity to all the cross-linking agents, whereas NER seemed to play only a minor role. This effect of replication-dependent repair pathways is distinctively different from the situation in yeast, where NER seems to play a major role in dealing with ICL. Cells deficient in Rev3, the catalytic subunit of TLS polymerase Polzeta, showed the highest sensitivity to cisplatin followed by fanc-c. Furthermore, epistasis analysis revealed that these two mutants work in the same pathway. Our genetic comprehensive study reveals a critical role for DNA repair pathways that release DNA replication block at ICLs in cellular tolerance to cross-linking agents and could be directly exploited in designing an effective chemotherapy.

Telomere attrition and genomic instability in xeroderma pigmentosum type-b deficient fibroblasts under oxidative stress

PubMed Central

Ting, Aloysius Poh Leong; Low, Grace Kah Mun; Gopalakrishnan, Kalpana; Hande, M Prakash

2010-01-01

Abstract Xeroderma pigmentosum B (XPB/ERCC3/p89) is an ATP-dependent 3′→5′ directed DNA helicase involved in basal RNA transcription and the nucleotide excision repair (NER) pathway. While the role of NER in alleviating oxidative DNA damage has been acknowledged it remains poorly understood. To study the involvement of XPB in repair of oxidative DNA damage, we utilized primary fibroblasts from a patient suffering from XP with Cockayne syndrome and hydrogen peroxide (H2O2) to induce oxidative stress. Mutant cells retained higher viability and cell cycle dysfunction after H2O2 exposure. Cytokinesis blocked micronucleus assay revealed increased genome instability induced by H2O2. Single cell gel electrophoresis (comet) assay showed that the missense mutation caused a reduced repair capacity for oxidative DNA damage. Mutant fibroblasts also displayed decreased population doubling rate, increased telomere attrition rate and early emergence of senescent characteristics under chronic low dose exposure to H2O2. Fibroblasts from a heterozygous individual displayed intermediate traits in some assays and normal traits in others, indicating possible copy number dependence. The results show that a deficiency in functional XPB paradoxically renders cells more sensitive to the genotoxic effects of oxidative stress while reducing the cytotoxic effects. These findings have implications in the mechanisms of DNA repair, mutagenesis and carcinogenesis and ageing in normal physiological systems. PMID:19840190

Fiches pratiques: Geographie, coup d'envoi; Face a l'epargne; L'Europe; Gerez vous-meme une societe! (Practical Ideas: Geography Kick-Off; Looking at Savings; Europe; Run a Company Yourself!).

ERIC Educational Resources Information Center

Barnaba, Enzo; And Others

1990-01-01

Four language classroom activities are described, including a geography unit focusing on the Paris/province contrast and use of maps as authentic documents; a reading exercise teaching comprehension of an article on French family economics; an oral communication activity about European countries; and a year-long project on business administration…

40 CFR 1051.137 - What are the consumer labeling requirements?

Code of Federal Regulations, 2011 CFR

2011-07-01

... final deteriorated emission level. Round the resulting normalized emission rate for your vehicle to one... name, vehicle model name, engine description (500 cc two-stroke with DFI), the NER, and a brief...

40 CFR 1051.137 - What are the consumer labeling requirements?

Code of Federal Regulations, 2012 CFR

2012-07-01

... final deteriorated emission level. Round the resulting normalized emission rate for your vehicle to one... name, vehicle model name, engine description (500 cc two-stroke with DFI), the NER, and a brief...

40 CFR 1051.137 - What are the consumer labeling requirements?

Code of Federal Regulations, 2014 CFR

2014-07-01

... final deteriorated emission level. Round the resulting normalized emission rate for your vehicle to one... name, vehicle model name, engine description (500 cc two-stroke with DFI), the NER, and a brief...

40 CFR 1051.137 - What are the consumer labeling requirements?

Code of Federal Regulations, 2013 CFR

2013-07-01

... final deteriorated emission level. Round the resulting normalized emission rate for your vehicle to one... name, vehicle model name, engine description (500 cc two-stroke with DFI), the NER, and a brief...

A System for Identifying Named Entities in Biomedical Text: how Results From two Evaluations Reflect on Both the System and the Evaluations

PubMed Central

Dingare, Shipra; Nissim, Malvina; Finkel, Jenny; Grover, Claire

2005-01-01

We present a maximum entropy-based system for identifying named entities (NEs) in biomedical abstracts and present its performance in the only two biomedical named entity recognition (NER) comparative evaluations that have been held to date, namely BioCreative and Coling BioNLP. Our system obtained an exact match F-score of 83.2% in the BioCreative evaluation and 70.1% in the BioNLP evaluation. We discuss our system in detail, including its rich use of local features, attention to correct boundary identification, innovative use of external knowledge resources, including parsing and web searches, and rapid adaptation to new NE sets. We also discuss in depth problems with data annotation in the evaluations which caused the final performance to be lower than optimal. PMID:18629295

Xeroderma Pigmentosum - Facts and Perspectives.

PubMed

Lehmann, Janin; Seebode, Christina; Martens, Marie Christine; Emmert, Steffen

2018-02-01

Ultraviolet (UV)-induced DNA lesions are almost exclusively removed by the nucleotide excision repair (NER) pathway, which is essential for prevention of skin cancer development. Patients with xeroderma pigmentosum (XP) are extremely sun sensitive due to a genetic defect in components of the NER cascade. They present with first signs of premature skin aging at an early age, with a considerably increased risk of developing UV-induced skin cancer. XP belongs to the group of DNA repair defective disorders that are mainly diagnosed in the clinic and in hindsight confirmed at the molecular level. Unfortunately, there are no causative treatment options for this rare, autosomal-recessive disorder, emphasizing the importance of an early diagnosis. Subsequently, UV-protective measures such as the reduction of exposure to environmental UV and regular skin cancer screenings should be undertaken to substantially improve prognosis as well as the disease course. Copyright© 2018, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.

Fiches pratiques: Si on jouait a la famille Dubois...; Pic et pic...et phonetique; Les rendez-vous des souvenirs; A l'ami (Practical Ideas: Let's Play House; Tick and Tick...and Phonetic; Rendezvous with Memories; To My Friend).

ERIC Educational Resources Information Center

Bravo, Maria Antonia Lavandera; And Others

1991-01-01

Four activities for French language classroom use are presented, including a simulation of the relationships and communication within a family; pronunciation instruction through phonetic transcription; cultural awareness through students' analysis of their own and their parents' specific memories; and analysis and comparison of a literary text and…

Patents - An Information Resource.

DTIC Science & Technology

1980-09-01

11 vs sans dire que ces aspects de description at de divulqation interviennent en plus des trois critbrea classiques de nouveautd, de hauteur...la divulgation doit, nous 1’ avons vu, aux termes de Ia loi , permettre b l’homme de l’art de reconstituer 1’invention. Or on sait bien que lea d...je vous en donnerai confirmation au mayen de r~sultats dletudea conduites au cours de ceo dernibres annies dans diff~rents pays et secteurs

Fiches pratiques: Vous et vos conversations; Lire le journal autrement; Detourner les titres; Entre Brel et Rimbaud (Practical Ideas: You and Your Conversations; Reading the Newspaper Differently; Deviating Titles; and Between Brel and Rimbaud).

ERIC Educational Resources Information Center

Bertrand, Denis; And Others

1990-01-01

Four ideas for language classroom activities are presented, including an exercise in oral discourse analysis, a newspaper-reading activity using the holistic approach, the use of slight phonological changes to turn a title into a joke or play on words, and an exercise looking at varieties of language style. (MSE)

Reproductive Endocrinologists’ Utilization of Genetic Counselors for Oncofertility and Preimplantation Genetic Diagnosis (PGD) Treatment of BRCA1/2 Mutation Carriers

PubMed Central

Goetsch, Allison L.; Wicklund, Catherine; Clayman, Marla L.; Woodruff, Teresa K.

2016-01-01

Genetic counselors believe fertility preservation and preimplantation genetic diagnosis (PGD) discussions to be a part of their role when counseling BRCA1/2 mutation-positive patients. This study is the first to explore reproductive endocrinologists’ (REI) practices and attitudes regarding involvement of genetic counselors in the care of BRCA1/2 mutation carriers seeking fertility preservation and PGD. A survey was mailed to 1000 REIs from Reproductive Endocrinology & Infertility (SREI), an American Society for Reproductive Medicine (ASRM) affiliate group. A 14.5 % response rate was achieved; data was analyzed using SPSS software. The majority of participating REIs were found to recommend genetic counseling to cancer patients considering fertility preservation (82 %) and consult with a genetic counselor regarding PGD for hereditary cancer syndromes (92 %). Additionally, REIs consult genetic counselors regarding PGD patient counseling (88 %), genetic testing (78 %), and general genetics questions (66 %). Two areas genetic counselors may further aid REIs are: elicitation of family history, which is useful to determine fertility preservation and PGD intervention timing (32 % of REIs utilize a cancer family history to determine intervention timing); and, interpretation of variants of uncertain significance (VOUS) as cancer panel genetic testing becomes more common (36 % of REIs are unfamiliar with VOUS). Given our findings, the Oncofertility Consortium® created an online resource for genetic counselors focused on fertility preservation education and communication strategies. PMID:26567039

XPC and human homologs of RAD23: intracellular localization and relationship to other nucleotide excision repair complexes.

PubMed Central

van der Spek, P J; Eker, A; Rademakers, S; Visser, C; Sugasawa, K; Masutani, C; Hanaoka, F; Bootsma, D; Hoeijmakers, J H

1996-01-01

The xeroderma pigmentosum syndrome complementation group C (XP-C) is due to a defect in the global genome repair subpathway of nucleotide excision repair (NER). The XPC protein is complexed with HHR23B, one of the two human homologs of the yeast NER protein, RAD23 (Masutani at al. (1994) EMBO J. 8, 1831-1843). Using heparin chromatography, gel filtration and native gel electrophoresis we demonstrate that the majority of HHR23B is in a free, non-complexed form, and that a minor fraction is tightly associated with XPC. In contrast, we cannot detect any bound HHR23A. Thus the HHR23 proteins may have an additional function independent of XPC. The fractionation behaviour suggests that the non-bound forms of the HHR23 proteins are not necessary for the core of the NER reaction. Although both HHR23 proteins share a high level of overall homology, they migrate very differently on native gels, pointing to a difference in conformation. Gel filtration suggests the XPC-HHR23B heterodimer resides in a high MW complex. However, immunodepletion studies starting from repair-competent Manley extracts fall to reveal a stable association of a significant fraction of the HHR23 proteins or the XPC-HHR23B complex with the basal transcription/repair factor TFIIH, or with the ERCC1 repair complex. Consistent with a function in repair or DNA/chromatin metabolism, immunofluorescence studies show all XPC, HHR23B and (the free) HHR23A to reside in the nucleus. PMID:8692695

Xeroderma pigmentosum complementation group G associated with Cockayne syndrome

DOE Office of Scientific and Technical Information (OSTI.GOV)

Vermeulen, W.; Jaspers, N.G.J.; Bootsma, D.

1993-07-01

Xeroderma pigmentosum (XP) and Cockayne syndrome (CS) are two rare inherited disorders with a clinical and cellular hypersensitivity to the UV component of the sunlight spectrum. Although the two traits are generally considered as clinically and genetically distinct entities, on the biochemical level a defect in the nucleotide excision-repair (NER) pathway is involved in both. Classical CS patients are primarily deficient in the preferential repair of DNA damage in actively transcribed genes, whereas in most XP patients the genetic defect affects both [open quotes]preferential[close quotes] and [open quotes]overall[close quotes] NER modalities. Here the authors report a genetic study of twomore » unrelated, severely affected patients with the clinical characteristics of CS but with a biochemical defect typical of XP. By complementation analysis, using somatic cell fusion and nuclear microinjection of cloned repair genes, they assign these two patients to XP complementation group G, which previously was not associated with CS. This observation extends the earlier identification of two patients with a rare combined XP/CS phenotype within XP complementation groups B and D, respectively. It indicates that some mutations in at least three of the seven genes known to be involved in XP also can result in a picture of partial or even full-blown CS. It is concluded that the syndromes XP and CS are biochemically closely related and may be part of a broader clinical disease spectrum. The authors suggest, as a possible molecular mechanism underlying this relation, that the XPGC repair gene has an additional vital function, as shown for some other NER genes. 33 refs., 5 tabs.« less

Effect of point substitutions within the minimal DNA-binding domain of xeroderma pigmentosum group A protein on interaction with DNA intermediates of nucleotide excision repair.

PubMed

Maltseva, E A; Krasikova, Y S; Naegeli, H; Lavrik, O I; Rechkunova, N I

2014-06-01

Xeroderma pigmentosum factor A (XPA) is one of the key proteins in the nucleotide excision repair (NER) process. The effects of point substitutions in the DNA-binding domain of XPA (positively charged lysine residues replaced by negatively charged glutamate residues: XPA K204E, K179E, K141E, and tandem mutant K141E/K179E) on the interaction of the protein with DNA structures modeling intermediates of the damage recognition and pre-incision stages in NER were analyzed. All these mutations decreased the affinity of the protein to DNA, the effect depending on the substitution and the DNA structure. The mutant as well as wild-type proteins bind with highest efficiency partly open damaged DNA duplex, and the affinity of the mutants to this DNA is reduced in the order: K204E > K179E > K141E = K141/179E. For all the mutants, decrease in DNA binding efficiency was more pronounced in the case of full duplex and single-stranded DNA than with bubble-DNA structure, the difference between protein affinities to different DNA structures increasing as DNA binding activity of the mutant decreased. No effect of the studied XPA mutations on the location of the protein on the partially open DNA duplex was observed using photoinduced crosslinking with 5-I-dUMP in different positions of the damaged DNA strand. These results combined with earlier published data suggest no direct correlation between DNA binding and activity in NER for these XPA mutants.

Polychlorinated biphenyl quinone induces oxidative DNA damage and repair responses: The activations of NHEJ, BER and NER via ATM-p53 signaling axis

DOE Office of Scientific and Technical Information (OSTI.GOV)

Dong, Hui; Shi, Qiong; Song, Xiufang

2015-07-01

Our previous studies demonstrated that polychlorinated biphenyl (PCB) quinone induced oxidative DNA damage in HepG2 cells. To promote genomic integrity, DNA damage response (DDR) coordinates cell-cycle transitions, DNA repair and apoptosis. PCB quinone-induced cell cycle arrest and apoptosis have been documented, however, whether PCB quinone insult induce DNA repair signaling is still unknown. In this study, we identified the activation of DDR and corresponding signaling events in HepG2 cells upon the exposure to a synthetic PCB quinone, PCB29-pQ. Our data illustrated that PCB29-pQ induces the phosphorylation of p53, which was mediated by ataxia telangiectasia mutated (ATM) protein kinase. The observedmore » phosphorylated histone H2AX (γ-H2AX) foci and the elevation of 8-hydroxy-2′-deoxyguanosine (8-OHdG) indicated that DDR was stimulated by PCB29-pQ treatment. Additionally, we found PCB29-pQ activates non-homologous end joining (NHEJ), base excision repair (BER) and nucleotide excision repair (NER) signalings. However, these repair pathways are not error-free processes and aberrant repair of DNA damage may cause the potential risk of carcinogenesis and mutagenesis. - Highlights: • Polychlorinated biphenyl quinone induces oxidative DNA damage in HepG2 cells. • The elevation of γ-H2AX and 8-OHdG indicates the activation of DNA damage response. • ATM-p53 signaling acts as the DNA damage sensor and effector. • Polychlorinated biphenyl quinone activates NHEJ, BER and NER signalings.« less

Associations between expression levels of nucleotide excision repair proteins in lymphoblastoid cells and risk of squamous cell carcinoma of the head and neck.

PubMed

Han, Peng; Liu, Hongliang; Shi, Qiong; Liu, Zhensheng; Troy, Jesse D; Lee, Walter T; Zevallos, Jose P; Li, Guojun; Sturgis, Erich M; Wei, Qingyi

2018-06-01

Squamous cell carcinoma of head and neck (SCCHN) is one of the most common malignancies worldwide, and nucleotide excision repair (NER) is involved in SCCHN susceptibility. In this analysis of 349 newly diagnosed SCCHN patients and 295 cancer-free controls, we investigated whether expression levels of eight core NER proteins were associated with risk of SCCHN. We quantified NER protein expression levels in cultured peripheral lymphocytes using a reverse-phase protein microarray. Compared with the controls, SCCHN patients had statistically significantly lower expression levels of ERCC3 and XPA (P = 0.001 and 0.001, respectively). After dividing the subjects by controls' median values of expression levels, we found a dose-dependent association between an increased risk of SCCHN and low expression levels of ERCC3 (adjusted OR, 1.75, and 95% CI: 1.26-2.42; P trend  = 0.008) and XPA (adjusted OR, 1.88; 95% CI, 1.35-2.60; P trend  = 0.001). We also identified a significant multiplicative interaction between smoking status and ERCC3 expression levels (P = 0.014). Finally, after integrating demographic and clinical variables, we found that the addition of ERCC3 and XPA expression levels to the model significantly improved the sensitivity of the expanded model on SCCHN risk. In conclusion, reduced protein expression levels of ERCC3 and XPA were associated with an increased risk of SCCHN. However, these results need to be confirmed in additional large studies. © 2018 Wiley Periodicals, Inc.

Effect of Amalaki rasayana on DNA damage and repair in randomized aged human individuals.

PubMed

Vishwanatha, Udupi; Guruprasad, Kanive P; Gopinath, Puthiya M; Acharya, Raviraj V; Prasanna, Bokkasa V; Nayak, Jayakrishna; Ganesh, Rajeshwari; Rao, Jayalaxmi; Shree, Rashmi; Anchan, Suchitra; Raghu, Kothanahalli S; Joshi, Manjunath B; Paladhi, Puspendu; Varier, Panniampilly M; Muraleedharan, Kollath; Muraleedharan, Thrikovil S; Satyamoorthy, Kapaettu

2016-09-15

Preparations from Phyllanthus emblica called Amalaki rasayana is used in the Indian traditional medicinal system of Ayurveda for healthy living in elderly. The biological effects and its mechanisms are not fully understood. Since the diminishing DNA repair is the hallmark of ageing, we tested the influence of Amalaki rasayana on recognized DNA repair activities in healthy aged individuals. Amalaki rasayana was prepared fresh and healthy aged randomized human volunteers were administrated with either rasayana or placebo for 45 days strictly as per the traditional text. The DNA repair was analyzed in peripheral blood mononuclear cells before and after rasayana administration and after 45 days post-rasayana treatment regimen. UVC-induced DNA strand break repair (DSBR) based on extent of DNA unwinding by fluorometric analysis, nucleotide excision repair (NER) by flow cytometry and constitutive base excision repair (BER) by gap filling method were analyzed. Amalaki rasayana administration stably maintained/enhanced the DSBR in aged individuals. There were no adverse side effects. Further, subjects with different body mass index showed differential DNA strand break repair capacity. No change in unscheduled DNA synthesis during NER and BER was observed between the groups. Intake of Amalaki rasayana by aged individuals showed stable maintenance of DNA strand break repair without toxic effects. However, there was no change in nucleotide and base excision repair activities. Results warrant further studies on the effects of Amalaki rasayana on DSBR activities. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

Standardisation for C2-Simulation Interoperation

DTIC Science & Technology

2015-11-01

la continuité du MSG-048 a permis, grâce notamment à la contribution de la communauté opérationnelle, de consolider le besoin et d’approfondir un...demandes de documents STO, RTO ou AGARD doivent comporter la dénomination « STO », « RTO » ou « AGARD » selon le cas, suivi du numéro de série. Des ...disponibilité des rapports de la STO au fur et à mesure de leur publication, vous pouvez consulter notre site Web

V2010 Security Planning and Operations: A Social Network Study of Key Information Sharing Relationships

DTIC Science & Technology

2011-05-01

la scurit. Je vous remercie de votre temps et de votre contribution. Susan G. McIntyre Knowledge Management/ Gestion du savoir...National Defence, 2011 © Sa Majesté la Reine (en droit du Canada), telle que représentée par le ministre de la Défense nationale, 2011 DRDC CSS TR 2011...avantages du renforcement de la communication horizontale au sein du gouvernement fédéral, surtout en présence d’organismes de

Information Tailoring Enhancements for Large-Scale Social Data

DTIC Science & Technology

2016-06-15

Intelligent Automation Incorporated Information Tailoring Enhancements for Large-Scale... Automation Incorporated Progress Report No. 3 Information Tailoring Enhancements for Large-Scale Social Data Submitted in accordance with...1 Work Performed within This Reporting Period .................................................... 2 1.1 Enhanced Named Entity Recognition (NER

Poly(ADP-ribose) polymerase 1 escorts XPC to UV-induced DNA lesions during nucleotide excision repair

PubMed Central

Robu, Mihaela; Shah, Rashmi G.; Purohit, Nupur K.; Zhou, Pengbo; Naegeli, Hanspeter

2017-01-01

Xeroderma pigmentosum C (XPC) protein initiates the global genomic subpathway of nucleotide excision repair (GG-NER) for removal of UV-induced direct photolesions from genomic DNA. The XPC has an inherent capacity to identify and stabilize at the DNA lesion sites, and this function is facilitated in the genomic context by UV-damaged DNA-binding protein 2 (DDB2), which is part of a multiprotein UV–DDB ubiquitin ligase complex. The nuclear enzyme poly(ADP-ribose) polymerase 1 (PARP1) has been shown to facilitate the lesion recognition step of GG-NER via its interaction with DDB2 at the lesion site. Here, we show that PARP1 plays an additional DDB2-independent direct role in recruitment and stabilization of XPC at the UV-induced DNA lesions to promote GG-NER. It forms a stable complex with XPC in the nucleoplasm under steady-state conditions before irradiation and rapidly escorts it to the damaged DNA after UV irradiation in a DDB2-independent manner. The catalytic activity of PARP1 is not required for the initial complex formation with XPC in the nucleoplasm but it enhances the recruitment of XPC to the DNA lesion site after irradiation. Using purified proteins, we also show that the PARP1–XPC complex facilitates the handover of XPC to the UV-lesion site in the presence of the UV–DDB ligase complex. Thus, the lesion search function of XPC in the genomic context is controlled by XPC itself, DDB2, and PARP1. Our results reveal a paradigm that the known interaction of many proteins with PARP1 under steady-state conditions could have functional significance for these proteins. PMID:28760956

Poly(ADP-ribose) polymerase 1 escorts XPC to UV-induced DNA lesions during nucleotide excision repair.

PubMed

Robu, Mihaela; Shah, Rashmi G; Purohit, Nupur K; Zhou, Pengbo; Naegeli, Hanspeter; Shah, Girish M

2017-08-15

Xeroderma pigmentosum C (XPC) protein initiates the global genomic subpathway of nucleotide excision repair (GG-NER) for removal of UV-induced direct photolesions from genomic DNA. The XPC has an inherent capacity to identify and stabilize at the DNA lesion sites, and this function is facilitated in the genomic context by UV-damaged DNA-binding protein 2 (DDB2), which is part of a multiprotein UV-DDB ubiquitin ligase complex. The nuclear enzyme poly(ADP-ribose) polymerase 1 (PARP1) has been shown to facilitate the lesion recognition step of GG-NER via its interaction with DDB2 at the lesion site. Here, we show that PARP1 plays an additional DDB2-independent direct role in recruitment and stabilization of XPC at the UV-induced DNA lesions to promote GG-NER. It forms a stable complex with XPC in the nucleoplasm under steady-state conditions before irradiation and rapidly escorts it to the damaged DNA after UV irradiation in a DDB2-independent manner. The catalytic activity of PARP1 is not required for the initial complex formation with XPC in the nucleoplasm but it enhances the recruitment of XPC to the DNA lesion site after irradiation. Using purified proteins, we also show that the PARP1-XPC complex facilitates the handover of XPC to the UV-lesion site in the presence of the UV-DDB ligase complex. Thus, the lesion search function of XPC in the genomic context is controlled by XPC itself, DDB2, and PARP1. Our results reveal a paradigm that the known interaction of many proteins with PARP1 under steady-state conditions could have functional significance for these proteins.

Estimating decades-long trends in petroleum field energy return on investment (EROI) with an engineering-based model.

PubMed

Tripathi, Vinay S; Brandt, Adam R

2017-01-01

This paper estimates changes in the energy return on investment (EROI) for five large petroleum fields over time using the Oil Production Greenhouse Gas Emissions Estimator (OPGEE). The modeled fields include Cantarell (Mexico), Forties (U.K.), Midway-Sunset (U.S.), Prudhoe Bay (U.S.), and Wilmington (U.S.). Data on field properties and production/processing parameters were obtained from a combination of government and technical literature sources. Key areas of uncertainty include details of the oil and gas surface processing schemes. We aim to explore how long-term trends in depletion at major petroleum fields change the effective energetic productivity of petroleum extraction. Four EROI ratios are estimated for each field as follows: The net energy ratio (NER) and external energy ratio (EER) are calculated, each using two measures of energy outputs, (1) oil-only and (2) all energy outputs. In all cases, engineering estimates of inputs are used rather than expenditure-based estimates (including off-site indirect energy use and embodied energy). All fields display significant declines in NER over the modeling period driven by a combination of (1) reduced petroleum production and (2) increased energy expenditures on recovery methods such as the injection of water, steam, or gas. The fields studied had NER reductions ranging from 46% to 88% over the modeling periods (accounting for all energy outputs). The reasons for declines in EROI differ by field. Midway-Sunset experienced a 5-fold increase in steam injected per barrel of oil produced. In contrast, Prudhoe Bay has experienced nearly a 30-fold increase in amount of gas processed and reinjected per unit of oil produced. In contrast, EER estimates are subject to greater variability and uncertainty due to the relatively small magnitude of external energy investments in most cases.

Transcriptional consequences of XPA disruption in human cell lines

PubMed Central

Manandhar, Mandira; Lowery, Megan G.; Boulware, Karen S.; Lin, Kevin H.; Lu, Yue; Wood, Richard D.

2017-01-01

Nucleotide excision repair (NER) in mammalian cells requires the xeroderma pigmentosum group A protein (XPA) as a core factor. Remarkably, XPA and other NER proteins have been detected by chromatin immunoprecipitation at some active promoters, and NER deficiency is reported to influence the activated transcription of selected genes. However, the global influence of XPA on transcription in human cells has not been determined. We analyzed the human transcriptome by RNA sequencing (RNA-Seq). We first confirmed that XPA is confined to the cell nucleus even in the absence of external DNA damage, in contrast to previous reports that XPA is normally resident in the cytoplasm and is imported following DNA damage. We then analyzed four genetically matched human cell line pairs deficient or proficient in XPA. Of the ∼14,000 genes transcribed in each cell line, 325 genes (2%) had a significant XPA-dependent directional change in gene expression that was common to all four pairs (with a false discovery rate of 0.05). These genes were enriched in pathways for the maintenance of mitochondria. Only 27 common genes were different by more than 1.5-fold. The most significant hits were AKR1C1 and AKR1C2, involved in steroid hormone metabolism. AKR1C2 protein was lower in all of the immortalized XPA-deficient cells. Retinoic acid treatment led to modest XPA-dependent activation of some genes with transcription-related functions. We conclude that XPA status does not globally influence human gene transcription. However, XPA significantly influences expression of a small subset of genes important for mitochondrial functions and steroid hormone metabolism. The results may help explain defects in neurological function and sterility in individuals with xeroderma pigmentosum. PMID:28704716

Phosphorylation of Nucleotide Excision Repair Factor Xeroderma Pigmentosum Group A by Ataxia Telangiectasia Mutated and Rad3-Related-Dependent Checkpoint Pathway Promotes Cell Survival in Response to UV Irradiation

PubMed Central

Wu, Xiaoming; Shell, Steven M.; Yang, Zhengguan; Zou, Yue

2006-01-01

DNA damage triggers complex cellular responses in eukaryotic cells, including initiation of DNA repair and activation of cell cycle checkpoints. In addition to inducing cell cycle arrest, checkpoint also has been suggested to modulate a variety of other cellular processes in response to DNA damage. In this study, we present evidence showing that the cellular function of xeroderma pigmentosum group A (XPA), a major nucleotide excision repair (NER) factor, could be modulated by checkpoint kinase ataxia-telangiectasia mutated and Rad3-related (ATR) in response to UV irradiation. We observed the apparent interaction and colocalization of XPA with ATR in response to UV irradiation. We showed that XPA was a substrate for in vitro phosphorylation by phosphatidylinositol-3-kinase-related kinase family kinases whereas in cells XPA was phosphorylated in an ATR-dependent manner and stimulated by UV irradiation. The Ser196 of XPA was identified as a biologically significant residue to be phosphorylated in vivo. The XPA-deficient cells complemented with XPA-S196A mutant, in which Ser196 was substituted with an alanine, displayed significantly higher UV sensitivity compared with the XPA cells complemented with wild-type XPA. Moreover, substitution of Ser196 with aspartic acid for mimicking the phosphorylation of XPA increased the cell survival to UV irradiation. Taken together, our results revealed a potential physical and functional link between NER and the ATR-dependent checkpoint pathway in human cells and suggested that the ATR checkpoint pathway could modulate the cellular activity of NER through phosphorylation of XPA at Ser196 on UV irradiation. PMID:16540648

Estimating decades-long trends in petroleum field energy return on investment (EROI) with an engineering-based model

PubMed Central

Tripathi, Vinay S.

2017-01-01

This paper estimates changes in the energy return on investment (EROI) for five large petroleum fields over time using the Oil Production Greenhouse Gas Emissions Estimator (OPGEE). The modeled fields include Cantarell (Mexico), Forties (U.K.), Midway-Sunset (U.S.), Prudhoe Bay (U.S.), and Wilmington (U.S.). Data on field properties and production/processing parameters were obtained from a combination of government and technical literature sources. Key areas of uncertainty include details of the oil and gas surface processing schemes. We aim to explore how long-term trends in depletion at major petroleum fields change the effective energetic productivity of petroleum extraction. Four EROI ratios are estimated for each field as follows: The net energy ratio (NER) and external energy ratio (EER) are calculated, each using two measures of energy outputs, (1) oil-only and (2) all energy outputs. In all cases, engineering estimates of inputs are used rather than expenditure-based estimates (including off-site indirect energy use and embodied energy). All fields display significant declines in NER over the modeling period driven by a combination of (1) reduced petroleum production and (2) increased energy expenditures on recovery methods such as the injection of water, steam, or gas. The fields studied had NER reductions ranging from 46% to 88% over the modeling periods (accounting for all energy outputs). The reasons for declines in EROI differ by field. Midway-Sunset experienced a 5-fold increase in steam injected per barrel of oil produced. In contrast, Prudhoe Bay has experienced nearly a 30-fold increase in amount of gas processed and reinjected per unit of oil produced. In contrast, EER estimates are subject to greater variability and uncertainty due to the relatively small magnitude of external energy investments in most cases. PMID:28178318

A novel XPD mutation in a compound heterozygote; the mutation in the second allele is present in three homozygous patients with mild sun sensitivity.

PubMed

Falik-Zaccai, Tzipora C; Erel-Segal, Reut; Horev, Liran; Bitterman-Deutsch, Ora; Koka, Sivan; Chaim, Sara; Keren, Zohar; Kalfon, Limor; Gross, Bella; Segal, Zvi; Orgal, Shlomi; Shoval, Yishay; Slor, Hanoch; Spivak, Graciela; Hanawalt, Philip C

2012-08-01

The XPD protein plays a pivotal role in basal transcription and in nucleotide excision repair (NER) as one of the ten known components of the transcription factor TFIIH. Mutations in XPD can result in the DNA repair-deficient diseases xeroderma pigmentosum (XP), trichothiodystrophy (TTD), cerebro-oculo-facial-skeletal syndrome, and in combined phenotypes such as XP/Cockayne syndrome and XP/TTD. We describe here an 18-year-old individual with mild sun sensitivity, no neurological abnormalities and no tumors, who carries a p.R683Q mutation in one allele, and the novel p.R616Q mutation in the other allele of the XPD gene. We also describe four patients from one family, homozygous for the identical p.R683Q mutation in XPD, who exhibit mild skin pigmentation and loss of tendon reflexes. Three homozygous patients presented with late-onset skin tumors, and two with features of premature aging and moderate cognitive decline. Cells from the compound heterozygous individual and from one of the patients homozygous for p.R683Q exhibited similar responses to UV irradiation: reduced viability and defective overall removal of UV-induced cyclobutane pyrimidine dimers, implying deficient global genomic NER. Cells from the compound heterozygous subject also failed to recover RNA synthesis after UV, indicating defective transcription-coupled NER. Mutations affecting codon 616 in XPD generally result in functionally null proteins; we hypothesize that the phenotype of the heterozygous patient results solely from expression of the p.R683Q allele. This study illustrates the importance of detailed follow up with sun sensitive individuals, to ensure appropriate prophylaxis and to understand the mechanistic basis of the implicated hereditary disease. Copyright © 2012 Wiley Periodicals, Inc.

Effect of Crumb Rubber and Warm Mix Additives on Asphalt Aging, Rheological, and Failure Properties

NASA Astrophysics Data System (ADS)

Agrawal, Prashant

Asphalt-rubber mixtures have been shown to have useful properties with respect to distresses observed in asphalt concrete pavements. The most notable change in properties is a large increase in viscosity and improved low-temperature cracking resistance. Warm mix additives can lower production and compaction temperatures. Lower temperatures reduce harmful emissions and lower energy consumption, and thus provide environmental benefits and cut costs. In this study, the effects of crumb rubber modification on various asphalts such as California Valley, Boscan, Alaska North Slope, Laguna and Cold Lake were also studied. The materials used for warm mix modification were obtained from various commercial sources. The RAF binder was produced by Imperial Oil in their Nanticoke, Ontario, refinery on Lake Erie. A second commercial PG 52-34 (hereafter denoted as NER) was obtained/sampled during the construction of a northern Ontario MTO contract. Some regular tests such as Dynamic Shear Rheometer (DSR) and Bending Beam Rheometer (BBR), Multiple Stress Creep Recovery (MSCR) and some modified new protocols such as the extended BBR test (LS-308) and the Double-Edge Notched Tension (DENT) test (LS-299) are used to study, the effect of warm mix and a host of other additives on rheological, aging and failure properties. A comparison in the properties of RAF and NER asphalts has also been made as RAF is good quality asphalt and NER is bad quality asphalt. From the studies the effect of additives on chemical and physical hardening tendencies was found to be significant. The asphalt samples tested in this study showed a range of tendencies for chemical and physical hardening.

Xeroderma pigmentosum genes and melanoma risk.

PubMed

Paszkowska-Szczur, K; Scott, R J; Serrano-Fernandez, P; Mirecka, A; Gapska, P; Górski, B; Cybulski, C; Maleszka, R; Sulikowski, M; Nagay, L; Lubinski, J; Dębniak, T

2013-09-01

Xeroderma pigmentosum is a rare autosomal recessive disease that is associated with a severe deficiency in nucleotide excision repair. The presence of a distinct the nucleotide excision repair (NER) mutation signature in melanoma suggests that perturbations in this critical repair process are likely to be involved with disease risk. We hypothesized that persons with polymorphic NER gene(s) are likely to have reduced NER activity and are consequently at an increased risk of melanoma development. We assessed the association between 94 SNPs within seven XP genes (XPA-XPG) and the melanoma risk in the Polish population. We genotyped 714 unselected melanoma patients and 1,841 healthy adults to determine if there were any polymorphisms differentially represented in the disease group. We found that a significantly decreased risk of melanoma was associated with the Xeroderma pigmentosum complementation (XPC) rs2228000_CT genotype (odds ratio [OR] = 0.15; p < 0.001) and the rs2228000_TT genotype (OR = 0.11; p < 0.001) compared to the reference genotype. Haplotype analysis within XPC revealed the rs2228001_A + G1475A_G + G2061A_A + rs2228000_T + rs3731062_C haplotype (OR = 0.26; p < 0.05) was associated with a significantly decreased disease risk. The haplotype analysis within the Xeroderma pigmentosum group D (XPD) showed a modest association between two haplotypes and a decrease in melanoma risk. There were no major differences between the prevalence of the XP polymorphisms among young or older patients with melanoma. Linkage disequilibrium of XPC: rs2228001, G1475A, G2061A, rs2228000 and rs3731062 was found. The data from our study support the notion that only XPC and XPD genes are associated with melanoma susceptibility. Copyright © 2013 UICC.

Effect of pyrochar and hydrochar amendments on the mineralization of the herbicide isoproturon in an agricultural soil.

PubMed

Eibisch, Nina; Schroll, Reiner; Fuß, Roland

2015-09-01

Carbon (C)-rich, solid products from pyrolysis (pyrochars) and hydrothermal carbonization (HTC, hydrochars) are expected to reduce the bioavailability and bioaccessibility of pesticides as side effect of soil addition. To compare effects of different feedstocks (digestate, miscanthus, woodchips) and production processes (pyrolysis at 750°C, HTC at 200°C and 250°C), (14)C-labeled isoproturon (IPU) was applied at 0.75 kg ha(-)(1) to loamy sand amended either with 0.5% or 5% pyrochars or hydrochars, which was then incubated for 50d. Mineralization of IPU was measured as (14)C-CO2 released from soil-char composites. Pore-water and methanol extractable (14)C-IPU was quantified as well as non-extractable (14)C-residues (NER). Furthermore, C mineralization of pyrochars, hydrochars and feedstocks was studied to assess the relationship between IPU bioaccessibility and char decomposability. In pure soil, 8.1% of applied IPU was mineralized after 50d. This was reduced more strongly in pyrochar treatments (81 ± 6% reduction) than in hydrochar treatments (56 ± 25% reduction). Different feedstocks had no significantly different effect when 5% char was added, but their effect was significant and dependent on the production process in 0.5% amendments. Pesticide binding can occur by surface sorption as well as by diffusion and subsequent occlusion in micropores. The latter can be expected to result in high amounts of NER, as it was observed in the pyrochar treatments. Hydrochars were less stable than pyrochars and contained lower amounts of NER. Thus, in hydrochar amended soils, better accessibility of IPU to microbial degradation may be a result of full char decomposition within decades ensuring controlled pesticide degradation. Copyright © 2014 Elsevier Ltd. All rights reserved.

Laser ranging application to time transfer using geodetic satellite and to other Japanese space programs

NASA Technical Reports Server (NTRS)

Kunimori, Hiroo; Takahashi, Fujinobu; Itabe, Toshikazu; Yamamoto, Atsushi

1993-01-01

Communications Research Laboratory (CRL) has been developing a laser time transfer system using a satellite laser ranging (SLR) system. We propose Japanese geodetic satellite 'AJISAI', launched in 1986 as a target satellite. The surface is covered not only with corner cube reflectors but also with mirrors. The mirrors are originally designed for observation of flushing solar light reflected by the separate mirrors while the satellite is spinning. In the experiment, synchronized laser pulses are transferred via specified mirror from one station to another while the satellite is up on the horizon to both stations. The system is based on the epoch timing ranging system with 40 ps ranging precision, connected together with UTC(CRL). Simulation study indicates that two stations at thousands of km distance from each other can be linked with signal strength of more than 10 photons and the distributed images of laser beam from AJISAI mirrors give many chances for two stations to link each other during a single AJISAI pass. Retro-reflector In Space for Advanced Earth Observation Satellite (ADEOS) and RendDezVous docking mission of Experimental Technology Satellite-7 (ETS-7) are briefly presented.

Majestic C Team, LLC - Clean Water Act Public Notice

EPA Pesticide Factsheets

The EPA is providing notice of a proposed Administrative Penalty Assessment against Majestic C Team, LLC., which owns a residential construction site located at 168th St and State St in Omaha, NE for alleged violations of its NPDES permit (permit No. NER11

Melanocortin 1 Receptor: Structure, Function, and Regulation

PubMed Central

Wolf Horrell, Erin M.; Boulanger, Mary C.; D’Orazio, John A.

2016-01-01

The melanocortin 1 receptor (MC1R) is a melanocytic Gs protein coupled receptor that regulates skin pigmentation, UV responses, and melanoma risk. It is a highly polymorphic gene, and loss of function correlates with a fair, UV-sensitive, and melanoma-prone phenotype due to defective epidermal melanization and sub-optimal DNA repair. MC1R signaling, achieved through adenylyl cyclase activation and generation of the second messenger cAMP, is hormonally controlled by the positive agonist melanocortin, the negative agonist agouti signaling protein, and the neutral antagonist β-defensin 3. Activation of cAMP signaling up-regulates melanin production and deposition in the epidermis which functions to limit UV penetration into the skin and enhances nucleotide excision repair (NER), the genomic stability pathway responsible for clearing UV photolesions from DNA to avoid mutagenesis. Herein we review MC1R structure and function and summarize our laboratory’s findings on the molecular mechanisms by which MC1R signaling impacts NER. PMID:27303435

Lossless compression of AVIRIS data: Comparison of methods and instrument constraints

NASA Technical Reports Server (NTRS)

Roger, R. E.; Arnold, J. F.; Cavenor, M. C.; Richards, J. A.

1992-01-01

A family of lossless compression methods, allowing exact image reconstruction, are evaluated for compressing Airborne Visible/Infrared Imaging Spectrometers (AVIRIS) image data. The methods are used on Differential Pulse Code Modulation (DPCM). The compressed data have an entropy of order 6 bits/pixel. A theoretical model indicates that significantly better lossless compression is unlikely to be achieved because of limits caused by the noise in the AVIRIS channels. AVIRIS data differ from data produced by other visible/near-infrared sensors, such as LANDSAT-TM or SPOT, in several ways. Firstly, the data are recorded at a greater resolution (12 bits, though packed into 16-bit words). Secondly, the spectral channels are relatively narrow and provide continuous coverage of the spectrum so that the data in adjacent channels are generally highly correlated. Thirdly, the noise characteristics of the AVIRIS are defined by the channels' Noise Equivalent Radiances (NER's), and these NER's show that, at some wavelengths, the least significant 5 or 6 bits of data are essentially noise.

Xeroderma pigmentosum and other diseases of human premature aging and DNA repair: Molecules to patients

PubMed Central

Niedernhofer, Laura J.; Bohr, Vilhelm A.; Sander, Miriam; Kraemer, Kenneth H.

2012-01-01

A workshop1 to share, consider and discuss the latest developments in understanding xeroderma pigmentosum and other human diseases caused by defects in nucleotide excision repair (NER) of DNA damage was held on September 21–24, 2010 in Virginia. It was attended by approximately 100 researchers and clinicians, as well as several patients and representatives of patient support groups. This was the third in a series of workshops with similar design and goals: to emphasize discussion and interaction among participants as well as open exchange of information and ideas. The participation of patients, their parents and physicians was an important feature of this and the preceding two workshops. Topics discussed included the natural history and clinical features of the diseases, clinical and laboratory diagnosis of these rare diseases, therapeutic strategies, mouse models of neurodegeneration, molecular analysis of accelerated aging, impact of transcriptional defects and mitochondrial dysfunction on neurodegeneration, and biochemical insights into mechanisms of NER and base excision repair. PMID:21708183

Mediator MED23 Links Pigmentation and DNA Repair through the Transcription Factor MITF.

PubMed

Xia, Min; Chen, Kun; Yao, Xiao; Xu, Yichi; Yao, Jiaying; Yan, Jun; Shao, Zhen; Wang, Gang

2017-08-22

DNA repair is related to many physiological and pathological processes, including pigmentation. Little is known about the role of the transcriptional cofactor Mediator complex in DNA repair and pigmentation. Here, we demonstrate that Mediator MED23 plays an important role in coupling UV-induced DNA repair to pigmentation. The loss of Med23 specifically impairs the pigmentation process in melanocyte-lineage cells and in zebrafish. Med23 deficiency leads to enhanced nucleotide excision repair (NER) and less DNA damage following UV radiation because of the enhanced expression and recruitment of NER factors to chromatin for genomic stability. Integrative analyses of melanoma cells reveal that MED23 controls the expression of a melanocyte master regulator, Mitf, by modulating its distal enhancer activity, leading to opposing effects on pigmentation and DNA repair. Collectively, the Mediator MED23/MITF axis connects DNA repair to pigmentation, thus providing molecular insights into the DNA damage response and skin-related diseases. Copyright © 2017 The Author(s). Published by Elsevier Inc. All rights reserved.

[Clinical value of genome-wide high resolution chromosomal microarray analysis in etiological study of fetuses with congenital heart defects].

PubMed

Wu, Xiaoli; Fu, Fang; Li, Ru; Pan, Min; Han, Jin; Zhen, Li; Yang, Xin; Zhang, Yongling; Li, Fatao; Liao, Can

2014-12-01

To explore the clinical value of genome-wide high resolution chromosomal microarray analysis (CMA) in etiological study of fetuses with congenital heart disease (CHD) diagnosed by fetal echocardiography. A total of 176 fetuses diagnosed CHD by fetal echocardiography were analyzed, and invasive prenatal diagnosis was performed at Guangzhou Women and Children's Medical Center from January 2012 to January 2014. Among them, 158 fetuses were proved to have normal karyotype, and 88 fetuses (50.0%, 88/176) underwent CMA testing. The parental blood specimens were also collected for assisting the diagnosis of variants of uncertain clinical significance (VOUS). The 88 fetuses were divided into two groups: isolated CHD (n = 68) and CHD with extra-cardiac structural abnormalities (n = 20). The phenotypes of the two groups were subclassified. Copy number variations (CNV) were classified as benign CNV, pathogenic CNV (pCNV) or VOUS. (1) 58 fetuses (66%, 58/88) were with simple CHD and 30 fetuses were with complicated CHD (34%, 30/88). In the 45 fetuses with isolated and simple CHD, the pCNV detection rate was 11% (5/45). In the 23 fetuses with isolated and complicated CHD, the pCNV detection rate was 17% (4/23). In the 13 fetuses with simple CHD and extra-cardiac structural abnormalities, the pCNV detection rate was 5/13. In the 7 fetuses with complicated CHD and extra-cardiac structural abnormalities, the pCNV detection rate was 0. (2) The total detection rate for pCNV detection was 16% (14/88) in the 88 fetuses. The pCNV detection rates for isolated CHD and CHD with extra-cardiac structural abnormalities were 13% (9/68) and 25% (5/20), respectively (P > 0.05). The pCNV detection rates for simple and complicated CHD were 17% (10/58) and 13% (4/30), respectively (P > 0.05). (3) Eighteen fetuses (10.2%, 18/176) had abnormal karyotype results. (4) CMA test was performed in 88 fetuses. CNV detected in 8 fetuses were classified as VOUS initially. After parental microarray analysis, CNV in 5 fetuses were inherited and interpreted as benign. CNV in the other 3 fetuses (3%, 3/88) were remained unknown significance. CNV in 14 fetuses (16% ) were interpreted as pCNV. In fetuses with CHD and normal karyotype, the application of CMA could increase the detection rate of pCNV. Genome-wide CMA could be used as a regular tool in the prenatal diagnosis of fetuses with CHD and normal karyotype. This technology may benefit evaluation of fetal prognosis in prenatal genetic counselling.

HINDBRAIN AND CRANIAL NERVE DYSMORPHOGENESIS RESULT FROM ACUTE MATERNAL ETHANOL ADMINISTRATION

EPA Science Inventory

Acute exposure of mouse embryos to ethanol during stages of hindbrain segmentation results in excessive cell death in specific cell populations. This study details the ethanol-induced cell loss and defines the subsequent effects of this early insult on rhombomere and cranial ner...

The Role of Measurement Error in Familiar Statistics

DTIC Science & Technology

2006-06-01

Manual of Mental Disorders (3rd ed., revised; American Psychiatric Association, 1987) for the clinical conditions of anorexia nervosa and borderline...borderline personality disorder, anorexia ner’vosa, and a control group. Family Process, 39, 345-358. Hunter, J. E., & Schmidt, F. L. (1976). A critical

Up-regulation of nucleotide excision repair in mouse lung and liver following chronic exposure to aflatoxin B{sub 1} and its dependence on p53 genotype

DOE Office of Scientific and Technical Information (OSTI.GOV)

Mulder, Jeanne E.; Bondy, Genevieve S.; Mehta, Rekha

Aflatoxin B{sub 1} (AFB{sub 1}) is biotransformed in vivo into an epoxide metabolite that forms DNA adducts that may induce cancer if not repaired. p53 is a tumor suppressor gene implicated in the regulation of global nucleotide excision repair (NER). Male heterozygous p53 knockout (B6.129-Trp53{sup tm1Brd}N5, Taconic) and wild-type mice were exposed to 0, 0.2 or 1.0 ppm AFB{sub 1} for 26 weeks. NER activity was assessed with an in vitro assay, using AFB{sub 1}-epoxide adducted plasmid DNA as a substrate. For wild-type mice, repair of AFB{sub 1}–N7-Gua adducts was 124% and 96% greater in lung extracts from mice exposedmore » to 0.2 ppm and 1.0 ppm AFB{sub 1} respectively, and 224% greater in liver extracts from mice exposed to 0.2 ppm AFB{sub 1} (p < 0.05). In heterozygous p53 knockout mice, repair of AFB{sub 1}–N7-Gua was only 45% greater in lung extracts from mice exposed to 0.2 ppm AFB{sub 1} (p < 0.05), and no effect was observed in lung extracts from mice treated with 1.0 ppm AFB{sub 1} or in liver extracts from mice treated with either AFB{sub 1} concentration. p53 genotype did not affect basal levels of repair. AFB{sub 1} exposure did not alter repair of AFB{sub 1}-derived formamidopyrimidine adducts in lung or liver extracts of either mouse genotype nor did it affect XPA or XPB protein levels. In summary, chronic exposure to AFB{sub 1} increased NER activity in wild-type mice, and this response was diminished in heterozygous p53 knockout mice, indicating that loss of one allele of p53 limits the ability of NER to be up-regulated in response to DNA damage. - Highlights: • Mice are chronically exposed to low doses of the mycotoxin aflatoxin B{sub 1} (AFB{sub 1}). • The effects of AFB{sub 1} and p53 status on nucleotide excision repair are investigated. • AFB{sub 1} increases nucleotide excision repair in wild type mouse lung and liver. • This increase is attenuated in p53 heterozygous mouse lung and liver. • Results portray the role of p53 in nucleotide excision repair after AFB{sub 1} exposure.« less

Aerosol characteristics in north-east India using ARFINET spectral optical depth measurements

NASA Astrophysics Data System (ADS)

Pathak, B.; Subba, T.; Dahutia, P.; Bhuyan, P. K.; Moorthy, K. Krishna; Gogoi, M. M.; Babu, S. Suresh; Chutia, L.; Ajay, P.; Biswas, J.; Bharali, C.; Borgohain, A.; Dhar, P.; Guha, A.; De, B. K.; Banik, T.; Chakraborty, M.; Kundu, S. S.; Sudhakar, S.; Singh, S. B.

2016-01-01

Four years (2010-2014) of spectral aerosol optical depth (AOD) data from 4 Indian Space Research Organisation's ARFINET (Aerosol Radiative Forcing over India) stations (Shillong, Agartala, Imphal and Dibrugarh) in the North-Eastern Region (NER) of India (lying between 22-30°N and 89-98°E) are synthesized to evolve a regional aerosol representation, for the first time. Results show that the columnar AOD (an indicator of the column abundance of aerosols) is highest at Agartala (0.80 ± 0.24) in the west and lowest at Imphal (0.59 ± 0.23) in the east in the pre-monsoon season due to intense anthropogenic bio-mass burning in this region aided by long-range transport from the high aerosol laden regions of the Indo-Gangetic Plains (IGP), polluted Bangladesh and Bay of Bengal. In addition to local biogenic aerosols and pollutants emitted from brick kilns, oil/gas fields, household bio-fuel/fossil-fuel, vehicles, industries. Aerosol distribution and climatic impacts show a west to east gradient within the NER. For example, the climatological mean AODs are 0.67 ± 0.26, 0.52 ± 0.14, 0.40 ± 0.17 and 0.41 ± 0.23 respectively in Agartala, Shillong, Imphal and Dibrugarh which are geographically located from west to east within the NER. The average aerosol burden in NER ranks second highest with climatological mean AOD 0.49 ± 0.2 next to the Indo-Gangetic Plains where the climatological mean AOD is 0.64 ± 0.2 followed by the South and South-East Asia region. Elevated aerosol layers are observed over the eastern most stations Dibrugarh and Imphal, while at the western stations the concentrations are high near the surface. The climate implications of aerosols are evaluated in terms of aerosol radiative forcing (ARF) and consequent heating of the atmosphere in the region which follows AOD and exhibit high values in pre-monsoon season at all the locations except in Agartala. The highest ARF in the atmosphere occurs in the pre-monsoon season ranging from 48.6 Wm-2 in Agartala to 25.1 Wm-2 in Imphal. Winter radiative forcing follows that in pre-monsoon season at these locations. The heating rate is high at 1.2 K day-1 and 1.0 K day-1 over Shillong and Dibrugarh respectively in this season. However, Agartala experiences higher surface forcing (-56.5 Wm-2) and consequent larger heating of the atmosphere of 1.6 K day-1 in winter.

Fiches pratiques: "Oui, je viens de Taiwan"; L'habit ne fait pas le moine; Objets inanimes avez-vous donc une ame?; La Bourse et la voix (Practical Ideas: "Yes, I Come from Taiwan"; The Clothes Don't Make the Man; Inanimate Objects, Do You Have a Soul?; The Stock Exchange and the Voice).

ERIC Educational Resources Information Center

Durbant, Jean-Claude; And Others

1988-01-01

Four ideas for classroom instruction are presented, including an approach to teaching foreign nationals or immigrants, a lesson in clothing and its terminology, an explanation of the symbolism and language of the French Revolution, and a description of how to use radio programs about economics. (MSE)

L'Aventure du LHC

DOE Office of Scientific and Technical Information (OSTI.GOV)

None

2010-06-11

Cette présentation s’adressera principalement aux personnes qui ont construit le LHC. La construction du LHC fut longue et difficile. De nombreux problèmes sont apparus en cours de route. Tous ont été résolus grâce au dévouement et à l’engagement du personnel et des collaborateurs. Je reviendrai sur les coups durs et les réussites qui ont marqués ces 15 dernières années et je vous montrerai combien cette machine, le fruit de vos efforts, est extraordinaire.

The Vermont oxford neonatal encephalopathy registry: rationale, methods, and initial results

PubMed Central

2012-01-01

Background In 2006, the Vermont Oxford Network (VON) established the Neonatal Encephalopathy Registry (NER) to characterize infants born with neonatal encephalopathy, describe evaluations and medical treatments, monitor hypothermic therapy (HT) dissemination, define clinical research questions, and identify opportunities for improved care. Methods Eligible infants were ≥ 36 weeks with seizures, altered consciousness (stupor, coma) during the first 72 hours of life, a 5 minute Apgar score of ≤ 3, or receiving HT. Infants with central nervous system birth defects were excluded. Results From 2006–2010, 95 centers registered 4232 infants. Of those, 59% suffered a seizure, 50% had a 5 minute Apgar score of ≤ 3, 38% received HT, and 18% had stupor/coma documented on neurologic exam. Some infants experienced more than one eligibility criterion. Only 53% had a cord gas obtained and only 63% had a blood gas obtained within 24 hours of birth, important components for determining HT eligibility. Sixty-four percent received ventilator support, 65% received anticonvulsants, 66% had a head MRI, 23% had a cranial CT, 67% had a full channel encephalogram (EEG) and 33% amplitude integrated EEG. Of all infants, 87% survived. Conclusions The VON NER describes the heterogeneous population of infants with NE, the subset that received HT, their patterns of care, and outcomes. The optimal routine care of infants with neonatal encephalopathy is unknown. The registry method is well suited to identify opportunities for improvement in the care of infants affected by NE and study interventions such as HT as they are implemented in clinical practice. PMID:22726296

In silico characterization of a novel pathogenic deletion mutation identified in XPA gene in a Pakistani family with severe xeroderma pigmentosum.

PubMed

Nasir, Muhammad; Ahmad, Nafees; Sieber, Christian M K; Latif, Amir; Malik, Salman Akbar; Hameed, Abdul

2013-09-24

Xeroderma Pigmentosum (XP) is a rare skin disorder characterized by skin hypersensitivity to sunlight and abnormal pigmentation. The aim of this study was to investigate the genetic cause of a severe XP phenotype in a consanguineous Pakistani family and in silico characterization of any identified disease-associated mutation. The XP complementation group was assigned by genotyping of family for known XP loci. Genotyping data mapped the family to complementation group A locus, involving XPA gene. Mutation analysis of the candidate XP gene by DNA sequencing revealed a novel deletion mutation (c.654del A) in exon 5 of XPA gene. The c.654del A, causes frameshift, which pre-maturely terminates protein and result into a truncated product of 222 amino acid (aa) residues instead of 273 (p.Lys218AsnfsX5). In silico tools were applied to study the likelihood of changes in structural motifs and thus interaction of mutated protein with binding partners. In silico analysis of mutant protein sequence, predicted to affect the aa residue which attains coiled coil structure. The coiled coil structure has an important role in key cellular interactions, especially with DNA damage-binding protein 2 (DDB2), which has important role in DDB-mediated nucleotide excision repair (NER) system. Our findings support the fact of genetic and clinical heterogeneity in XP. The study also predicts the critical role of DDB2 binding region of XPA protein in NER pathway and opens an avenue for further research to study the functional role of the mutated protein domain.

Development of the dynamic motion simulator of 3D micro-gravity with a combined passive/active suspension system

NASA Technical Reports Server (NTRS)

Yoshida, Kazuya; Hirose, Shigeo; Ogawa, Tadashi

1994-01-01

The establishment of those in-orbit operations like 'Rendez-Vous/Docking' and 'Manipulator Berthing' with the assistance of robotics or autonomous control technology, is essential for the near future space programs. In order to study the control methods, develop the flight models, and verify how the system works, we need a tool or a testbed which enables us to simulate mechanically the micro-gravity environment. There have been many attempts to develop the micro-gravity testbeds, but once the simulation goes into the docking and berthing operation that involves mechanical contacts among multi bodies, the requirement becomes critical. A group at the Tokyo Institute of Technology has proposed a method that can simulate the 3D micro-gravity producing a smooth response to the impact phenomena with relatively simple apparatus. Recently the group carried out basic experiments successfully using a prototype hardware model of the testbed. This paper will present our idea of the 3D micro-gravity simulator and report the results of our initial experiments.

Loss of Nucleotide Excision Repair as a Source of Genomic Instability in Breast Cancer

DTIC Science & Technology

2006-06-01

requiring millions of cells and DNA extraction techniques. Therefore, this approach may prove useful for determining NER activity from clinical... grapefruit juice per day, as this has been shown to cause liver problems when people are also taking lovastatin. Drinking less than this amount (for

77 FR 49021 - Minor Boundary Revision at Theodore Roosevelt Inaugural National Historic Site

Federal Register 2010, 2011, 2012, 2013, 2014

2012-08-15

... DEPARTMENT OF THE INTERIOR National Park Service [NPS-NER-THRI-10649; 1960-726] Minor Boundary Revision at Theodore Roosevelt Inaugural National Historic Site AGENCY: National Park Service, Interior. ACTION: Notification of Boundary Revision. SUMMARY: Notice is hereby given that, pursuant to 16 U.S.C...

Evaluation of Biomonitoring Data from the CDC National Exposure Report in a Risk Assessment Context: Perspectives across Chemicals

EPA Science Inventory

BACKGROUND: Biomonitoring data reported in the National Report on Human Exposure to Environmental Chemicals (NER) provide information on the presence and concentrations of more than 400 chemicals in human blood and urine. Biomonitoring Equivalents (BEs) and other risk assessment...

"The Plan(ner) Is Always Changing": Self-Directed Funding for Children with Hearing Loss

ERIC Educational Resources Information Center

Simpson, Andrea; Stewart, Lauryn; Douglas, Jacinta

2016-01-01

This study investigated the experience of families with young children with hearing loss participating in a self-directed funding scheme in Australia. Eleven hearing caregivers, one male, participated in qualitative semi-structured interviews. Analysis was undertaken using a phenomenological inspired thematic analysis approach. Major themes…

Sequence stratigraphy of the lower Upper Cretaceous Elbtal Group (Saxony, Germany): new data from Middle Cenomanian-Upper Turonian outcrops and boreholes

NASA Astrophysics Data System (ADS)

Richardt, Nadine; Wilmsen, Markus

2013-04-01

The formations of the Saxonian Cretaceous have been combined in the so-called Elbtal Group. Their sedimentation took place in a terrestrial to neritic environment palaeogeographically located between the Mid-European Island (MEI) in the SW and the Lusatian Massif in the NE. The through extended from the narrow marine strait of Saxony into the broad Bohemian Cretaceous Basin (Czech Republic) further to the SE. Deposition has been dominated by marine siliciclastics that accumulated on a graded shelf with basically three main facies zones: the coarse-grained nearshore zone ("Küstensandsteinzone"), the transitional zone ("Faziesübergangszone") and the fine-grained marly offshore facies zone ("Plänerfazies"). In general, transgression proceeded in late Early Cenomanian times from the N. Relictic remains of these marine bioclastic conglomerates (Meißen Formation) only occur in the northwesternmost area of the basin around Meißen and are related to the highstand of the depositional sequence Cenomanian 3 (DS Ce 3). After a short stratigraphic gap, onlap continued in the Middle Cenomanian with the following Niederschöna Formation consisting of coarse-grained braided river deposits at the base grading via carbonaceous point-bar cycles of a meandering river system into bioturbated, partly cross-bedded estuarine sediments toward the top. These sediments record DS Ce 4 and are capped by a paleosol. Sedimentation of DS Ce 5 started with a renewed transgressional pulse initiating the Late Cenomanian. The strata consist of bioturbated, cross-bedded predominantly fine- to medium-grained quartz sandstones with some shell-rich horizons corresponding to the Oberhäslich Formation. The unconformably overlying DS Tu 1 comprises the uppermost Cenomanian Dölzschen Formation and the Lower Turonian part of the Schmilka Formation. The onset of this depositional sequence is marked by a major transgression ("plenus Transgression) drowning the remaining pre-transgression topography (onlap of Dölzschen Formation onto basement highs). The lowermost Turonian "Lohmgrund Marl" defines the base of the Schmilka Formation changing gradually into strongly bioturbated, silty Pläner and coarsening upward into moderately bioturbated, thick-bedded-massive, mainly fine-grained quartz sandstones with occasional clayey or silty layers, shell-rich horizons and sparse wood remains. After an interruption in sedimentation indicated by a root horizon or a conspicuous erosional surface, the Schmilka Formation continues with similar lithology into the early Middle Turonian. It is replaced up-section by the overlying Middle-Upper Turonian Postelwitz Formation, characterized by decreasing thickness of bedding and stronger sedimentary variability (grain size, bioturbation, glauconite and fossil content), including the intercalation of thick units of silty Pläner. The lithological variations of sandy and Pläner intervals nicely reflect the Middle-Late Turonian sea-level changes of DS Tu 2 (early Middle Turonian), DS Tu 3 (late Middle-earliest Late Turonian) and DS Tu 4 (early Late-mid-Late Turonian): Pläner units represent transgressive and highstand conditions, sand packages late highstand as well as falling and lowstand systems tracts. A major mid-Late Turonian sea-level fall is indicated in the upper Postelwitz Formation, initiating DS Tu 5 (Late Turonian) with a strongly basin-ward prograding unit of coarse-grained sandstone. The following transgression culminated in a prominent maximum flooding interval represented by the intercalation of a clayey-fine-grained regional marker bed, forming the base of the Schrammstein Formation (thick-bedded, unfossiliferous medium- to coarse-grained quartz sandstones). In conclusion, all depositional sequences of Middle Cenomanian-Late Turonian age and their bounding unconformities (sequence boundaries SB Ce 4 and 5, SB Tu 1-4) reported from coeval sections around the MEI (e. g., Münsterland Creatceous Basin, Lower Saxonian and Danubian Cretaceous) and other Cretaceous basins in the Tethyan region (e. g., Egypt) are also developed in the Saxonian Cretaceous, supporting eustatic sea-level changes as main triggers for the sequence stratigraphic architecture of the Elbtal Group.

Mutations in Cockayne Syndrome-Associated Genes (Csa and Csb) Predispose to Cisplatin-Induced Hearing Loss in Mice

PubMed Central

Rainey, Robert N.; Ng, Sum-yan; Llamas, Juan; van der Horst, Gijsbertus T. J.

2016-01-01

Cisplatin is a common and effective chemotherapeutic agent, yet it often causes permanent hearing loss as a result of sensory hair cell death. The causes of sensitivity to DNA-damaging agents in nondividing cell populations, such as cochlear hair and supporting cells, are poorly understood, as are the specific DNA repair pathways that protect these cells. Nucleotide excision repair (NER) is a conserved and versatile DNA repair pathway for many DNA-distorting lesions, including cisplatin-DNA adducts. Progressive sensorineural hearing loss is observed in a subset of NER-associated DNA repair disorders including Cockayne syndrome and some forms of xeroderma pigmentosum. We investigated whether either of the two overlapping branches that encompass NER, transcription-coupled repair or global genome repair, which are implicated in Cockayne syndrome and xeroderma pigmentosum group C, respectively, modulates cisplatin-induced hearing loss and cell death in the organ of Corti, the auditory sensory epithelium of mammals. We report that cochlear hair cells and supporting cells in transcription-coupled repair-deficient Cockayne syndrome group A (Csa−/−) and group B (Csb−/−) mice are hypersensitive to cisplatin, in contrast to global genome repair-deficient Xpc−/− mice, both in vitro and in vivo. We show that sensory hair cells in Csa−/− and Csb−/− mice fail to remove cisplatin-DNA adducts efficiently in vitro; and unlike Xpc−/− mice, Csa−/− and Csb−/− mice lose hearing and manifest outer hair cell degeneration after systemic cisplatin treatment. Our results demonstrate that Csa and Csb deficiencies predispose to cisplatin-induced hearing loss and hair/supporting cell damage in the mammalian organ of Corti, and emphasize the importance of transcription-coupled DNA repair in the protection against cisplatin ototoxicity. SIGNIFICANCE STATEMENT The utility of cisplatin in chemotherapy remains limited due to serious side effects, including sensorineural hearing loss. We show that mouse models of Cockayne syndrome, a progeroid disorder resulting from a defect in the transcription-coupled DNA repair (TCR) branch of nucleotide excision repair, are hypersensitive to cisplatin-induced hearing loss and sensory hair cell death in the organ of Corti, the mammalian auditory sensory epithelium. Our work indicates that Csa and Csb, two genes involved in TCR, are preferentially required to protect against cisplatin ototoxicity, relative to global genome repair-specific elements of nucleotide excision repair, and suggests that TCR is a major force maintaining DNA integrity in the cochlea. The Cockayne syndrome mice thus represent a model for testing the contribution of DNA repair mechanisms to cisplatin ototoxicity. PMID:27122034

Association studies of excision repair cross-complementation group 1 (ERCC1) haplotypes with lung and head and neck cancer risk in a Caucasian population.

PubMed

Jones, Nathan R; Spratt, Thomas E; Berg, Arthur S; Muscat, Joshua E; Lazarus, Philip; Gallagher, Carla J

2011-04-01

The formation of bulky DNA adducts caused by diol epoxide derivatives of polycyclic aromatic hydrocarbons has been associated with tobacco-induced cancers, and inefficient repair of such adducts by the nucleotide excision repair (NER) system has been linked to increased risk of tobacco-induced lung and head and neck (H&N) cancers. The human excision repair cross-complementation group 1 (ERCC1) protein is essential for a functional NER system and genetic variation in ERCC1 may contribute to impaired DNA repair capacity and increased lung and H&N cancer risk. In order to comprehensively capture common genetic variation in the ERCC1 gene, Caucasian data from the International HapMap project was used to assess linkage disequilibrium and choose four tagSNPs (rs1319052, rs3212955, rs3212948, and rs735482) in the ERCC1 gene to genotype 452 lung cancer cases, 175 H&N cancer cases, and 790 healthy controls. Haplotypes were estimated using expectation maximization (EM) algorithm, and haplotype association with cancer was investigated using Haplo.stats software adjusting for known covariates. The genotype and haplotype frequencies matched previous estimates from Caucasians. There was no significant difference in the prevalence of rs1319052, rs3212955, rs3212948, and rs735482 when comparing lung or H&N cancer cases with controls (p-values>0.05). Similarly, there was no association between ERCC1 haplotypes and lung or H&N cancer susceptibility in this Caucasian population (p-values>0.05). No associations were found when stratifying lung cancer cases by histology, sex, smoking status, or smoking intensity. This study suggests that ERCC1 polymorphisms and haplotypes do not play a role in lung and H&N cancer susceptibility in Caucasians. Copyright © 2010 Elsevier Ltd. All rights reserved.

78 FR 28619 - Boston Harbor Islands Advisory Council Meeting

Federal Register 2010, 2011, 2012, 2013, 2014

2013-05-15

... DEPARTMENT OF THE INTERIOR [NPS-NER-BOHA-12921: PPMPSPD1Z.YM0000: PPNEBOHAS1] Boston Harbor.... SUMMARY: This notice announces a meeting of the Boston Harbor Islands Advisory Council. The agenda... park update. DATES: Date/Time: June 5, 2013, 4:00 p.m. to 6:00 p.m. (EASTERN). Location: Boston Society...

Consequence Management Symposium

DTIC Science & Technology

2001-09-01

AND SUBTITLE Consequence Management Symposium 5a. CONTRACT NUMBER 5b. GRANT NUMBER 5c. PROGRAM ELEMENT NUMBER 6. AUTHOR(S) 5d. PROJECT NUMBER 5e...log i cal agents and their effects was deemed essen tial for “first respond ers,” includ ing emer gency medi cal and hospi tal prac ti tio ners

A dynamic neural field model of temporal order judgments.

PubMed

Hecht, Lauren N; Spencer, John P; Vecera, Shaun P

2015-12-01

Temporal ordering of events is biased, or influenced, by perceptual organization-figure-ground organization-and by spatial attention. For example, within a region assigned figural status or at an attended location, onset events are processed earlier (Lester, Hecht, & Vecera, 2009; Shore, Spence, & Klein, 2001), and offset events are processed for longer durations (Hecht & Vecera, 2011; Rolke, Ulrich, & Bausenhart, 2006). Here, we present an extension of a dynamic field model of change detection (Johnson, Spencer, Luck, & Schöner, 2009; Johnson, Spencer, & Schöner, 2009) that accounts for both the onset and offset performance for figural and attended regions. The model posits that neural populations processing the figure are more active, resulting in a peak of activation that quickly builds toward a detection threshold when the onset of a target is presented. This same enhanced activation for some neural populations is maintained when a present target is removed, creating delays in the perception of the target's offset. We discuss the broader implications of this model, including insights regarding how neural activation can be generated in response to the disappearance of information. (c) 2015 APA, all rights reserved).

XPD Helicase Structures And Activities: Insights Into the Cancer And Aging Phenotypes From XPD Mutations

DOE Office of Scientific and Technical Information (OSTI.GOV)

Fan, L.; Fuss, J.O.; Cheng, Q.J.

2009-05-18

Mutations in XPD helicase, required for nucleotide excision repair (NER) as part of the transcription/repair complex TFIIH, cause three distinct phenotypes: cancer-prone xeroderma pigmentosum (XP), or aging disorders Cockayne syndrome (CS), and trichothiodystrophy (TTD). To clarify molecular differences underlying these diseases, we determined crystal structures of the XPD catalytic core from Sulfolobus acidocaldarius and measured mutant enzyme activities. Substrate-binding grooves separate adjacent Rad51/RecA-like helicase domains (HD1, HD2) and an arch formed by 4FeS and Arch domains. XP mutations map along the HD1 ATP-binding edge and HD2 DNA-binding channel and impair helicase activity essential for NER. XP/CS mutations both impair helicasemore » activity and likely affect HD2 functional movement. TTD mutants lose or retain helicase activity but map to sites in all four domains expected to cause framework defects impacting TFIIH integrity. These results provide a foundation for understanding disease consequences of mutations in XPD and related 4Fe-4S helicases including FancJ.« less

XPD Helicase Structures and Activities: Insights into the Cancer and Aging Phenotypes from XPD Mutations

DOE Office of Scientific and Technical Information (OSTI.GOV)

Tainer, John; Fan, Li; Fuss, Jill O.

2008-06-02

Mutations in XPD helicase, required for nucleotide excision repair (NER) as part of the transcription/repair complex TFIIH, cause three distinct phenotypes: cancer-prone xeroderma pigmentosum (XP), or aging disorders Cockayne syndrome (CS), and trichothiodystrophy (TTD). To clarify molecular differences underlying these diseases, we determined crystal structures of the XPD catalytic core from Sulfolobus acidocaldarius and measured mutant enzyme activities. Substrate-binding grooves separate adjacent Rad51/RecA-like helicase domains (HD1, HD2) and an arch formed by 4FeS and Arch domains. XP mutations map along the HD1 ATP-binding edge and HD2 DNA-binding channel and impair helicase activity essential for NER. XP/CS mutations both impair helicasemore » activity and likely affect HD2 functional movement. TTD mutants lose or retain helicase activity but map to sites in all four domains expected to cause framework defects impacting TFIIH integrity. These results provide a foundation for understanding disease consequences of mutations in XPD and related 4Fe-4S helicases including FancJ.« less

Replication-mediated disassociation of replication protein A-XPA complex upon DNA damage: implications for RPA handing off.

PubMed

Jiang, Gaofeng; Zou, Yue; Wu, Xiaoming

2012-08-01

RPA (replication protein A), the eukaryotic ssDNA (single-stranded DNA)-binding protein, participates in most cellular processes in response to genotoxic insults, such as NER (nucleotide excision repair), DNA, DSB (double-strand break) repair and activation of cell cycle checkpoint signalling. RPA interacts with XPA (xeroderma pigmentosum A) and functions in early stage of NER. We have shown that in cells the RPA-XPA complex disassociated upon exposure of cells to high dose of UV irradiation. The dissociation required replication stress and was partially attributed to tRPA hyperphosphorylation. Treatment of cells with CPT (camptothecin) and HU (hydroxyurea), which cause DSB DNA damage and replication fork collapse respectively and also leads to the disruption of RPA-XPA complex. Purified RPA and XPA were unable to form complex in vitro in the presence of ssDNA. We propose that the competition-based RPA switch among different DNA metabolic pathways regulates the dissociation of RPA with XPA in cells after DNA damage. The biological significances of RPA-XPA complex disruption in relation with checkpoint activation, DSB repair and RPA hyperphosphorylation are discussed.

Thomson scattering density calibration by Rayleigh and rotational Raman scattering on NSTX.

PubMed

LeBlanc, B P

2008-10-01

The multipoint Thomson scattering diagnostic measures the profiles of the electron temperature T(e)(R) and density n(e)(R) on the horizontal midplane of NSTX. Normal operation makes use of Rayleigh scattering in nitrogen or argon to derive the density profile. While the Rayleigh scattering n(e)(R) calibration has been validated by comparison to other density measurements and through its correlation with plasma phenomena, it does require dedicated detectors at the laser wavelength in this filter polychromator based diagnostic. The presence of dust and/or stray laser light precludes routine use of these dedicated spectral channels for Thomson scattering measurement. Hence it is of interest to investigate the use of Raman scattering in nitrogen for the purpose of density calibration since it could free up detection equipment, which could then be used for the instrumentation of additional radial channels. In this paper the viewing optics "geometrical factor" profiles obtained from Rayleigh and Raman scattering are compared. While both techniques agree nominally, residual effects on the order of 10% remain and will be discussed.

Landslide susceptibility assessment and validation in the framework of municipal planning in Portugal: the case of Loures Municipality.

PubMed

Guillard, Clemence; Zezere, Jose

2012-10-01

The legislation that demands the evaluation of landslide susceptibility in Portugal at the municipal level is the National Ecological Reserve (NER). A methodology for the evaluation of landslide susceptibility to be used in municipal planning is applied in Loures Municipality (169.3 km²) located north of Lisbon (Portugal). A landslide inventory was made for the whole area interpreting orthophoto maps and aerial photographs and using standard geomorphologic techniques in field work. It consists of 686 polygons, each polygon representing a rotational, a deep translational or a shallow translational slide, and is integrated into a GIS database. Landslide susceptibility is evaluated using algorithms based on statistical/probabilistic analysis (Information Value Method) over unique-condition terrain units in a raster basis. Three susceptibility models are elaborated independently according to the type of slide (rotational, deep translational, shallow translational). The landslide susceptibility maps are prepared by sorting all pixels according to the pixel susceptibility value in descending order. The robustness and accuracy of the landslide susceptibility models are evaluated by prediction-rate curves, which are used for the quantitative interpretation of the landslide susceptibility maps. Unstable slopes that have to be included into the National Ecological Reserve are extracted from the three susceptibility maps following the general rules to draw the NER that state that the area to be included in the NER should guarantee the inclusion of at least 70 % of the landslides identified in the landslide inventory. The obtained results allow us to conclude that 70 % of the future landslides should occur in these areas, classified as most susceptible to landslides corresponding to 20.3 % of the total area of Municipality. Thus, the consideration of these 20.3 % as regards prevention and protection of landslide risk could potentially reduce damage resulting from 70 % of future landslides in the Loures Municipality.

Development and validation of a modified comet assay to phenotypically assess nucleotide excision repair.

PubMed

Langie, Sabine A S; Knaapen, Ad M; Brauers, Karen J J; van Berlo, Damien; van Schooten, Frederik-Jan; Godschalk, Roger W L

2006-03-01

There is an increasing need for simple and reliable approaches to phenotypically assess DNA repair capacities. Therefore, a modification of the alkaline comet assay was developed to determine the ability of human lymphocyte extracts to perform the initial steps of the nucleotide excision repair (NER) process, i.e. damage recognition and incision. Gel-embedded nucleoids from A549 cells, pre-exposed to 1 microM benzo[a]pyrene-diol-epoxide, were incubated with cell extracts from frozen or freshly isolated lymphocytes. The rate at which incisions are introduced and the subsequent increase in tail moment is indicative for the repair capacity of the extracts. Freshly prepared extracts from lymphocytes of human volunteers (n = 8) showed significant inter-individual variations in their DNA repair capacity, which correlated with the removal of bulky DNA lesions over a period of 48 h determined by (32)P-post-labelling (R(2) = 0.76, P = 0.005). Repeated measurements revealed a low inter-assay variation (11%). Storage of cell extracts for more than 3 weeks significantly reduced (up to 80%) the capacity to incise the damaged DNA as compared to freshly isolated extracts. This reduction was completely restored by addition of ATP to the extracts before use, as it is required for the incision step of NER. In contrast, extracts freshly prepared from frozen lymphocyte pellets can be used without loss of repair activity. DNA repair deficient XPA-/- and XPC-/- fibroblasts were used to further validate the assay. Although some residual capacity to incise the DNA was observed in these cells, the repair activity was restored to normal wild-type levels when a complementary mixture of both extracts (thereby restoring XPA and XPC deficiency) was used. These results demonstrate that this repair assay can be applied in molecular epidemiological studies to assess inter-individual differences in NER.

Coordination of Rad1-Rad10 interactions with Msh2-Msh3, Saw1 and RPA is essential for functional 3' non-homologous tail removal.

PubMed

Eichmiller, Robin; Medina-Rivera, Melisa; DeSanto, Rachel; Minca, Eugen; Kim, Christopher; Holland, Cory; Seol, Ja-Hwan; Schmit, Megan; Oramus, Diane; Smith, Jessica; Gallardo, Ignacio F; Finkelstein, Ilya J; Lee, Sang Eun; Surtees, Jennifer A

2018-06-01

Double strand DNA break repair (DSBR) comprises multiple pathways. A subset of DSBR pathways, including single strand annealing, involve intermediates with 3' non-homologous tails that must be removed to complete repair. In Saccharomyces cerevisiae, Rad1-Rad10 is the structure-specific endonuclease that cleaves the tails in 3' non-homologous tail removal (3' NHTR). Rad1-Rad10 is also an essential component of the nucleotide excision repair (NER) pathway. In both cases, Rad1-Rad10 requires protein partners for recruitment to the relevant DNA intermediate. Msh2-Msh3 and Saw1 recruit Rad1-Rad10 in 3' NHTR; Rad14 recruits Rad1-Rad10 in NER. We created two rad1 separation-of-function alleles, rad1R203A,K205A and rad1R218A; both are defective in 3' NHTR but functional in NER. In vitro, rad1R203A,K205A was impaired at multiple steps in 3' NHTR. The rad1R218A in vivo phenotype resembles that of msh2- or msh3-deleted cells; recruitment of rad1R218A-Rad10 to recombination intermediates is defective. Interactions among rad1R218A-Rad10 and Msh2-Msh3 and Saw1 are altered and rad1R218A-Rad10 interactions with RPA are compromised. We propose a model in which Rad1-Rad10 is recruited and positioned at the recombination intermediate through interactions, between Saw1 and DNA, Rad1-Rad10 and Msh2-Msh3, Saw1 and Msh2-Msh3 and Rad1-Rad10 and RPA. When any of these interactions is altered, 3' NHTR is impaired.

Analysis of DNA binding by human factor xeroderma pigmentosum complementation group A (XPA) provides insight into its interactions with nucleotide excision repair substrates.

PubMed

Sugitani, Norie; Voehler, Markus W; Roh, Michelle S; Topolska-Woś, Agnieszka M; Chazin, Walter J

2017-10-13

Xeroderma pigmentosum (XP) complementation group A (XPA) is an essential scaffolding protein in the multiprotein nucleotide excision repair (NER) machinery. The interaction of XPA with DNA is a core function of this protein; a number of mutations in the DNA-binding domain (DBD) are associated with XP disease. Although structures of the central globular domain of human XPA and data on binding of DNA substrates have been reported, the structural basis for XPA's DNA-binding activity remains unknown. X-ray crystal structures of the central globular domain of yeast XPA (Rad14) with lesion-containing DNA duplexes have provided valuable insights, but the DNA substrates used for this study do not correspond to the substrates of XPA as it functions within the NER machinery. To better understand the DNA-binding activity of human XPA in NER, we used NMR to investigate the interaction of its DBD with a range of DNA substrates. We found that XPA binds different single-stranded/double-stranded junction DNA substrates with a common surface. Comparisons of our NMR-based mapping of binding residues with the previously reported Rad14-DNA crystal structures revealed similarities and differences in substrate binding between XPA and Rad14. This includes direct evidence for DNA contacts to the residues extending C-terminally from the globular core, which are lacking in the Rad14 construct. Moreover, mutation of the XPA residue corresponding to Phe-262 in Rad14, previously reported as being critical for DNA binding, had only a moderate effect on the DNA-binding activity of XPA. The DNA-binding properties of several disease-associated mutations in the DBD were investigated. These results suggest that for XPA mutants exhibiting altered DNA-binding properties, a correlation exists between the extent of reduction in DNA-binding affinity and the severity of symptoms in XP patients. © 2017 by The American Society for Biochemistry and Molecular Biology, Inc.

Genetic polymorphisms in 19q13.3 genes associated with alteration of repair capacity to BPDE-DNA adducts in primary cultured lymphocytes.

PubMed

Xiao, Mingyang; Xiao, Sha; Straaten, Tahar van der; Xue, Ping; Zhang, Guopei; Zheng, Xiao; Zhang, Qianye; Cai, Yuan; Jin, Cuihong; Yang, Jinghua; Wu, Shengwen; Zhu, Guolian; Lu, Xiaobo

2016-12-01

Benzo[a]pyrene(B[a]P), and its ultimate metabolite Benzo[a]pyrene 7,8-diol 9,10-epoxide (BPDE), are classic DNA damaging carcinogens. DNA damage in cells caused by BPDE is normally repaired by Nucleotide Excision Repair (NER) and Base Excision Repair (BER). Genetic variations in NER and BER can change individual DNA repair capacity to DNA damage induced by BPDE. In the present study we determined the number of in vitro induced BPDE-DNA adducts in lymphocytes, to reflect individual susceptibility to Polycyclic aromatic hydrocarbons (PAHs)-induced carcinogenesis. The BPDE-DNA adduct level in lymphocytes were assessed by high performance liquid chromatography (HPLC) in 281 randomly selected participants. We genotyped for 9 single nucleotide polymorphisms (SNPs) in genes involved in NER (XPB rs4150441, XPC rs2228001, rs2279017 and XPF rs4781560), BER (XRCC1 rs25487, rs25489 and rs1799782) and genes located on chromosome 19q13.2-3 (PPP1R13L rs1005165 and CAST rs967591). We found that 3 polymorphisms in chromosome 19q13.2-3 were associated with lower levels of BPDE-DNA adducts (MinorT allele in XRCC1 rs1799782, minor T allele in PPP1R13L rs1005165 and minor A allele in CAST rs967571). In addition, a modified comet assay was performed to further confirm the above conclusions. We found both minor T allele in PPP1R13L rs1005165 and minor A allele in CAST rs967571 were associated with the lower levels of BPDE-adducts. Our data suggested that the variant genotypes of genes in chromosome 19q13.2-3 are associated with the alteration of repair efficiency to DNA damage caused by Benzo[a]pyrene, and may contribute to enhance predictive value for individual's DNA repair capacity in response to environmental carcinogens. Copyright © 2016 Elsevier B.V. All rights reserved.

The influence of DNA repair on neurological degeneration, cachexia, skin cancer and internal neoplasms: autopsy report of four xeroderma pigmentosum patients (XP-A, XP-C and XP-D)

PubMed Central

2013-01-01

Background To investigate the association of DNA nucleotide excision repair (NER) defects with neurological degeneration, cachexia and cancer, we performed autopsies on 4 adult xeroderma pigmentosum (XP) patients with different clinical features and defects in NER complementation groups XP-A, XP-C or XP-D. Results The XP-A (XP12BE) and XP-D (XP18BE) patients exhibited progressive neurological deterioration with sensorineural hearing loss. The clinical spectrum encompassed severe cachexia in the XP-A (XP12BE) patient, numerous skin cancers in the XP-A and two XP-C (XP24BE and XP1BE) patients and only few skin cancers in the XP-D patient. Two XP-C patients developed internal neoplasms including glioblastoma in XP24BE and uterine adenocarcinoma in XP1BE. At autopsy, the brains of the 44 yr XP-A and the 45 yr XP-D patients were profoundly atrophic and characterized microscopically by diffuse neuronal loss, myelin pallor and gliosis. Unlike the XP-A patient, the XP-D patient had a thickened calvarium, and the brain showed vacuolization of the neuropil in the cerebrum, cerebellum and brainstem, and patchy Purkinje cell loss. Axonal neuropathy and chronic denervation atrophy of the skeletal muscles were observed in the XP-A patient, but not in the XP-D patient. Conclusions These clinical manifestations and autopsy findings indicate advanced involvement of the central and peripheral nervous system. Despite similar defects in DNA repair, different clinicopathological phenotypes are seen in the four cases, and therefore distinct patterns of neurodegeneration characterize XP-D, XP-A and XP-C patients. PMID:24252196

In silico characterization of a novel pathogenic deletion mutation identified in XPA gene in a Pakistani family with severe xeroderma pigmentosum

PubMed Central

2013-01-01

Background Xeroderma Pigmentosum (XP) is a rare skin disorder characterized by skin hypersensitivity to sunlight and abnormal pigmentation. The aim of this study was to investigate the genetic cause of a severe XP phenotype in a consanguineous Pakistani family and in silico characterization of any identified disease-associated mutation. Results The XP complementation group was assigned by genotyping of family for known XP loci. Genotyping data mapped the family to complementation group A locus, involving XPA gene. Mutation analysis of the candidate XP gene by DNA sequencing revealed a novel deletion mutation (c.654del A) in exon 5 of XPA gene. The c.654del A, causes frameshift, which pre-maturely terminates protein and result into a truncated product of 222 amino acid (aa) residues instead of 273 (p.Lys218AsnfsX5). In silico tools were applied to study the likelihood of changes in structural motifs and thus interaction of mutated protein with binding partners. In silico analysis of mutant protein sequence, predicted to affect the aa residue which attains coiled coil structure. The coiled coil structure has an important role in key cellular interactions, especially with DNA damage-binding protein 2 (DDB2), which has important role in DDB-mediated nucleotide excision repair (NER) system. Conclusions Our findings support the fact of genetic and clinical heterogeneity in XP. The study also predicts the critical role of DDB2 binding region of XPA protein in NER pathway and opens an avenue for further research to study the functional role of the mutated protein domain. PMID:24063568

A method for detecting genetic toxicity using the RNA synthesis response to DNA damage.

PubMed

Morita, Yoko; Iwai, Shigenori; Kuraoka, Isao

2011-10-01

To date, biological risk assessment studies of chemicals that induce DNA lesions have been primarily based on the action of DNA polymerases during replication. However, DNA lesions interfere not only with replication but also with transcription. Therefore, detecting the damaging effects of DNA lesions during transcription might be important for estimating the safety of chemical mutagens and carcinogens. However, methods to address these effects have not been developed. Here, we report a simple, non-isotopic method for determining the toxicity of chemical agents by visualizing transcription in a mammalian cell system. The method is based on the measurement of the incorporation of bromouridine (as the uridine analogue) into the nascent RNA during RNA synthesis inhibition (RSI) induced by the stalling of RNA polymerases at DNA lesions on the transcribed DNA strand, which triggers transcription-coupled nucleotide excision repair (TC-NER). When we tested chemical agents (camptothecin, etoposide, 4-nitroquinoline-1-oxide, mitomycin C, methyl methanesulfonate, and cisplatin) in HeLa cells by the method, RSI indicative of genomic toxicity was observed in the nucleoli of the tested cells. This procedure provides the following advantages: 1) it uses common, affordable mammalian cells (HeLa cells, WI38VA13 cells, human dermal fibroblasts, or Chinese hamster ovary cells) rather than genetically modified microorganisms; 2) it can be completed within approximately 8 hr after the cells are prepared because RNA polymerase responses during TC-NER are faster than other DNA damage responses (replication, recombination, and apoptosis); and 3) it is safe because it uses non-radioactive bromouridine and antibodies to detect RNA synthesis on undamaged transcribed DNA strands.

Characterization of CDOM absorption of reservoirs with its linkage of regions and ages across China.

PubMed

Shang, Yingxin; Song, Kaishan; Wen, Zhidan; Lyu, Lili; Zhao, Ying; Fang, Chong; Zhang, Bai

2018-03-28

The absorption of chromophoric dissolved organic matter (CDOM) is an important part of light absorptions in aquatic systems. The increasing eutrophication of reservoirs and regional characteristics would affect the CDOM properties sensitively which would be important for the application of remote sensing monitoring. The highest (4.07 ± 2.31 m -1 ) and lowest (0.79 ± 0.67 m -1 ) CDOM concentrations of reservoirs were observed in the northeastern lake region (NER) and Tibetan Plateau lake region (TPR), respectively. The differences between S 275-295 among the five lake regions were significant (p < 0.05) in which the steepest S 275-295 (0.0173 ± 0.0026 nm -1 ) was observed in TPR and the shallowest (0.0326 ± 0.0152 nm -1 ) in Yungui Plateau lake region (YGR). The strong relationships between a CDOM (355) and DOC appeared in the NER (R 2  = 0.43), eastern lake region (EAR) (R 2  = 0.69), Mengxin lake region (MXR) (R 2  = 0.61), and YGR (R 2  = 0.79) which would be a good proxy for DOC in regional reservoirs. Most of all, the correlation between reservoir's establishing time and CDOM absorption under oligotrophic states was relatively strong in the EAR and MXR regions. It indicated that the establishing time of reservoirs affected the CDOM absorption to some extent under the oligotrophic states without much human disturbance. Our results indicate CDOM absorption varies with regions, and the relationships between CDOM and DOC are variable for different regions. Therefore, DOC estimation in reservoirs through CDOM absorption needs to be considered according to lake regions and trophic states.

Large-scale extraction of brain connectivity from the neuroscientific literature

PubMed Central

Richardet, Renaud; Chappelier, Jean-Cédric; Telefont, Martin; Hill, Sean

2015-01-01

Motivation: In neuroscience, as in many other scientific domains, the primary form of knowledge dissemination is through published articles. One challenge for modern neuroinformatics is finding methods to make the knowledge from the tremendous backlog of publications accessible for search, analysis and the integration of such data into computational models. A key example of this is metascale brain connectivity, where results are not reported in a normalized repository. Instead, these experimental results are published in natural language, scattered among individual scientific publications. This lack of normalization and centralization hinders the large-scale integration of brain connectivity results. In this article, we present text-mining models to extract and aggregate brain connectivity results from 13.2 million PubMed abstracts and 630 216 full-text publications related to neuroscience. The brain regions are identified with three different named entity recognizers (NERs) and then normalized against two atlases: the Allen Brain Atlas (ABA) and the atlas from the Brain Architecture Management System (BAMS). We then use three different extractors to assess inter-region connectivity. Results: NERs and connectivity extractors are evaluated against a manually annotated corpus. The complete in litero extraction models are also evaluated against in vivo connectivity data from ABA with an estimated precision of 78%. The resulting database contains over 4 million brain region mentions and over 100 000 (ABA) and 122 000 (BAMS) potential brain region connections. This database drastically accelerates connectivity literature review, by providing a centralized repository of connectivity data to neuroscientists. Availability and implementation: The resulting models are publicly available at github.com/BlueBrain/bluima. Contact: renaud.richardet@epfl.ch Supplementary information: Supplementary data are available at Bioinformatics online. PMID:25609795

Microplane Model for Fracture Analysis of Concrete Structures

DTIC Science & Technology

1983-05-01

Curves for Cot,- Proceadings, Intern. Sympositim cai Numevical crete io Tension," Mater ils ,tndI : Str ~tuiztres d.- Un R. /na~gr No I., an. o196.9...and 226. ivinsterwalder, K, , "Festigkeit und Verfor- mung van Bet an lniter- 7.oRsIannitgenl, Duo tsatho 8. Kr~ner, h. , Zur 2’lastischen Verformung

Chesapeake Bay Riparian Handbook: A Guide for Establishing and Maintaining Riparian Forest Buffers

Treesearch

Roxane Palone; Albert Todd

1998-01-01

The Purpose of This Handbook Riparian forest buffers have been identified as avaluable nutrient reduction tool when used inconjunction with other conservation practices. For this reason, the Chesapeake Bay Programhas targeted riparian forests as a key habitat for restoration. The purpose of this handbook is toprovide professional land managers and plan-ners with the...

Prediction of Supersonic Store Separation Characteristics Including Fuselage and Stores of Noncircular Cross Section. Volume II. Users Manual for the Computer Program.

DTIC Science & Technology

1980-11-01

CMACH $ FMACH) 132 TRJTRY STOP normal termination (test: TIME > TIMEF-0.00001 or NDIFEQ = 1) BDCOEF message warning - NAFLD exceeds blank common...BDCOEF**, NTAP7- , IUB= , NAFLD = . (Test: NAFLD > NADIM) CRFWBD STOP 001 (Test: NER > 1; equation solution singular) INVER2 STOP **Matrix is singular

A Compass in Need of Alignment: Does United States Air Force Fighter Doctrine Adequately Cover Contingency Operations?

DTIC Science & Technology

1989-12-13

New York: Harcourt Brace Jovancv’.ch, 1983. Ben-Porat, Yeshayahu, Haber , Eitan and Schiff, Zeev. Entebbe Rescue. Trans. Louis Williams. New York...Times 25 Sept.e:ner 1989: pp. 16-17, 22-24, 84. Barth, Fritz J., Captain, USMC. "Stemming Nuclear Terrorism.- U.S. Naval Institute Proceedings, December

Detection of PrP(Sc) in peripheral tissues of clinically affected cattle after oral challenge with bovine spongiform encephalopathy

USDA-ARS?s Scientific Manuscript database

Bovine spongiform encephalopathy (BSE) is a fatal neurodegenerative prion disease that affects cattle and can be transmitted to human beings as new variant Creutzfeldt-Jakob disease (vCJD). A protease-resistant, disease-associated isoform of the prion protein (PrP**Sc) accumulates in the central ner...

POLYMORPHISMS IN THE DNA BASE EXCISION REPAIR GENES APEX1 AND XRCC1 AND LUNG CANCER RISK IN XUAN WEI, CHINA

EPA Science Inventory

The lung cancer mortality rate in Xuan Wei County is among the highest in China and has been attributed to exposure to indoor smoky coal emissions that contain very high levels of polycyclic aromatic hydrocarbons (PAHs). Nucleotide excision repair (NER) plays a key role in revers...

Persistently Elevated Somatic Mutation as a Biomarker for Clinically Relevant Exposures in GWI

DTIC Science & Technology

2017-10-01

radiation and/or chemicals. However, since some, but not...microarray data in breast cancer and acute myelogenous leukemia, for this analysis. Figure 1. Expression of NER genes in 10 GWI patients (red...undergoing genotoxic radio- and/or chemotherapy and victims of radiation accidents and A-bomb survivors. Perhaps because the published

Molecular Determinants of Radio Resistance in Prostate Cancer

DTIC Science & Technology

2005-08-01

Pathway Gene Accession # Ratio H/N Ratio Hypoxia/Normoxla (Log,) NER ERCCt NM001983 1.3 BER APE,2 NM_014481 1.0 MMR PMS2 NM_000535 1.3 HR RAD51...cross-complementing group 1; APEX2, apurinic!apyrimidinic endonuclease/redox factor 2; PMS2 , postmeiotic segregation increased 2; RAD51, RAD51 homolog

BANNER: an executable survey of advances in biomedical named entity recognition.

PubMed

Leaman, Robert; Gonzalez, Graciela

2008-01-01

There has been an increasing amount of research on biomedical named entity recognition, the most basic text extraction problem, resulting in significant progress by different research teams around the world. This has created a need for a freely-available, open source system implementing the advances described in the literature. In this paper we present BANNER, an open-source, executable survey of advances in biomedical named entity recognition, intended to serve as a benchmark for the field. BANNER is implemented in Java as a machine-learning system based on conditional random fields and includes a wide survey of the best techniques recently described in the literature. It is designed to maximize domain independence by not employing brittle semantic features or rule-based processing steps, and achieves significantly better performance than existing baseline systems. It is therefore useful to developers as an extensible NER implementation, to researchers as a standard for comparing innovative techniques, and to biologists requiring the ability to find novel entities in large amounts of text.

40 CFR 1051.145 - What provisions apply only for a limited time?

Code of Federal Regulations, 2012 CFR

2012-07-01

... nitrogen in g/kW-hr. (ii) For engines below 225 cc, use the following equation: NER = 9.898 × log [(HC+NOX... oxides of nitrogen in g/kW-hr. (c) [Reserved] (d) Phase-in flexibility. For model years before 2014, if... model years, you may have a negative balance of emission credits relative to the permeation emission...

40 CFR 1051.145 - What provisions apply only for a limited time?

Code of Federal Regulations, 2013 CFR

2013-07-01

... nitrogen in g/kW-hr. (ii) For engines below 225 cc, use the following equation: NER = 9.898 × log [(HC+NOX... oxides of nitrogen in g/kW-hr. (c) [Reserved] (d) Phase-in flexibility. For model years before 2014, if... model years, you may have a negative balance of emission credits relative to the permeation emission...

40 CFR 1051.145 - What provisions apply only for a limited time?

Code of Federal Regulations, 2014 CFR

2014-07-01

... nitrogen in g/kW-hr. (ii) For engines below 225 cc, use the following equation: NER = 9.898 × log [(HC+NOX... oxides of nitrogen in g/kW-hr. (c) [Reserved] (d) Phase-in flexibility. For model years before 2014, if... model years, you may have a negative balance of emission credits relative to the permeation emission...

40 CFR 1051.145 - What provisions apply only for a limited time?

Code of Federal Regulations, 2011 CFR

2011-07-01

... nitrogen in g/kW-hr. (ii) For engines below 225 cc, use the following equation: NER = 9.898 × log [(HC+NOX... oxides of nitrogen in g/kW-hr. (c) [Reserved] (d) Phase-in flexibility. For model years before 2014, if... model years, you may have a negative balance of emission credits relative to the permeation emission...

40 CFR 1051.145 - What provisions apply only for a limited time?

Code of Federal Regulations, 2010 CFR

2010-07-01

... nitrogen in g/kW-hr. (ii) For engines below 225 cc, use the following equation: NER = 9.898 × log [(HC+NOX... oxides of nitrogen in g/kW-hr. (c) [Reserved] (d) Phase-in flexibility. For model years before 2014, if... model years, you may have a negative balance of emission credits relative to the permeation emission...

The United States Merchant Marine Academy Historic District: Nomination to the National Register of Historic Places

DTIC Science & Technology

2014-10-01

the determination of effect of federal... The USMMA is the nation’s only federally- owned educational facility for the advanced training of merchant mari- ners. This work determined the ...met through the design of the buildings that survive on the district’s grounds. The district was listed by the NRHP in August 2014 as

Open-Source Data Collection Techniques for Weapons Transfer Information

DTIC Science & Technology

2012-03-01

IR Infrared ISO International Organization for Standardization ITAR International Traffic in Arms Regulations NER Named Entity Recognition NLP ...Control Protocol UAE United Arab Emirates URI Uniform Resource Identifier URL Uniform Resource Locator USSR Union of Soviet Socialist Republics UTF...KOREA, DEMOCRATIC PEOPLE’S REPUBLIC OF North Korea KOREA, REPUBLIC OF South Korea LIBYAN ARAB JAMAHIRIYA Libya RUSSIAN FEDERATION Russia Table 3

A human XPC protein interactome--a resource.

PubMed

Lubin, Abigail; Zhang, Ling; Chen, Hua; White, Victoria M; Gong, Feng

2013-12-23

Global genome nucleotide excision repair (GG-NER) is responsible for identifying and removing bulky adducts from non-transcribed DNA that result from damaging agents such as UV radiation and cisplatin. Xeroderma pigmentosum complementation group C (XPC) is one of the essential damage recognition proteins of the GG-NER pathway and its dysfunction results in xeroderma pigmentosum (XP), a disorder involving photosensitivity and a predisposition to cancer. To better understand the identification of DNA damage by XPC in the context of chromatin and the role of XPC in the pathogenesis of XP, we characterized the interactome of XPC using a high throughput yeast two-hybrid screening. Our screening showed 49 novel interactors of XPC involved in DNA repair and replication, proteolysis and post-translational modifications, transcription regulation, signal transduction, and metabolism. Importantly, we validated the XPC-OTUD4 interaction by co-IP and provided evidence that OTUD4 knockdown in human cells indeed affects the levels of ubiquitinated XPC, supporting a hypothesis that the OTUD4 deubiquitinase is involved in XPC recycling by cleaving the ubiquitin moiety. This high-throughput characterization of the XPC interactome provides a resource for future exploration and suggests that XPC may have many uncharacterized cellular functions.

Photocarcinogenesis and Skin Cancer Prevention Strategies.

PubMed

Seebode, Christina; Lehmann, Janin; Emmert, Steffen

2016-03-01

In this review the basic principles of UV-induced carcinogenesis are summarized and the state of the art diagnosis and therapeutic strategies are discussed. The prevalent keratinocyte-derived neoplasms of the skin are basal cell and squamous cell carcinomas. Cutaneous melanoma is less frequent but associated with high mortality. Common risk factors for all three tumor entities include sun exposure and DNA-repair deficiencies. Photocarcinogenesis follows a multistep model of cancer development in which ultraviolet-induced DNA damage leads to mutations resulting in activation of oncogenes or silencing of tumor-suppressor genes. This ends in a cellular mutator phenotype even more prone to mutation acquisition. DNA repair, especially the nucleotide excision repair (NER) pathway, counteracts mutation formation and skin cancer development. This is vividly demonstrated by the NER-defective disorder xeroderma pigmentosum. Primary skin cancer preventative strategies, therefore, include reduction of DNA photodamage by protection from the sun. Secondary preventative strategies include skin cancer screening. This implies standard examination techniques with the naked eye, an epiluminescence microscope, or digital epiluminescence microscopy. More advanced techniques include confocal laser scan microscopy. Copyright© 2016 International Institute of Anticancer Research (Dr. John G. Delinassios), All rights reserved.

Physical chemistry of Nanogap-Enhanced Raman Scattering (NERS)

NASA Astrophysics Data System (ADS)

Suh, Yung Doug; Kim, Hyun Woo

2017-08-01

Plasmonically coupled electromagnetic field localization has generated a variety of new concepts and applications, and this has been one of the hottest topics in nanoscience, materials science, chemistry, physics and engineering and increasingly more important over the last decade. In particular, plasmonically coupled nanostructures with ultra-small gap ( 1-nm or smaller) gap have been of special interest due to their ultra-strong optical properties that can be useful for a variety of signal enhancements such surface-enhanced Raman scattering (SERS) and nanoantenna. These promising nanostructures with extraordinarily strong optical signal, however, have rendered a limited success in widespread use and commercialization largely due to the lack of designing principles, high-yield synthetic strategies with nm-level structural controllability and reproducibility and lack of systematic single-molecule and single-particle level studies. All these are extremely important challenges because even small changes ( 1 nm) of the coupled nanogap structures can significant affect plasmon mode and signal intensity and therefore structural and signal reproducibility and controllability can be in question. The plasmonic nanogap-enhanced Raman scattering (NERS) is defined as the plasmonic nanogap-based Raman signal enhancement within plasmonic nanogap particles with 1 nm gap and a Raman dye positioned inside the gap.

Towards an Obesity-Cancer Knowledge Base: Biomedical Entity Identification and Relation Detection

PubMed Central

Lossio-Ventura, Juan Antonio; Hogan, William; Modave, François; Hicks, Amanda; Hanna, Josh; Guo, Yi; He, Zhe; Bian, Jiang

2017-01-01

Obesity is associated with increased risks of various types of cancer, as well as a wide range of other chronic diseases. On the other hand, access to health information activates patient participation, and improve their health outcomes. However, existing online information on obesity and its relationship to cancer is heterogeneous ranging from pre-clinical models and case studies to mere hypothesis-based scientific arguments. A formal knowledge representation (i.e., a semantic knowledge base) would help better organizing and delivering quality health information related to obesity and cancer that consumers need. Nevertheless, current ontologies describing obesity, cancer and related entities are not designed to guide automatic knowledge base construction from heterogeneous information sources. Thus, in this paper, we present methods for named-entity recognition (NER) to extract biomedical entities from scholarly articles and for detecting if two biomedical entities are related, with the long term goal of building a obesity-cancer knowledge base. We leverage both linguistic and statistical approaches in the NER task, which supersedes the state-of-the-art results. Further, based on statistical features extracted from the sentences, our method for relation detection obtains an accuracy of 99.3% and a f-measure of 0.993. PMID:28503356

Survey of patient dosimetry for head and neck cancer patients undergoing external radiotherapy treatment: a study from northeastern hospitals of India.

PubMed

Sharma, Arunkumar B; Singh, Tomcha Th; Singh, Khelendra N; Gartia, R K

2009-01-01

To study dosimetry of patients during the external radiotherapy of head and neck cancers from different hospitals of the northeastern region (NER) of India. 35 confirmed cases of head and neck cancers reporting to three different hospitals in the NER of India who underwent radiation treatment were the materials for the study. Dosimetry was carried out at 8(eight) anatomical points to these patients, namely, target (entrance and exit points), forehead, chest, abdomen, gonad, arm, and leg respectively by thermoluminescence (TL) as well as optically stimulated luminescence (OSL) dosimeters. Unlike conventional appliances, we used common iodized salt as TL/OSL phosphor. Patient dosimetry was found to vary with an average of 1.17 +/- 0.39 Sv at forehead, 1.24 +/- 0.39 Sv at chest, 0.52 +/- 0.13 Sv at gonad to a minimum of 0.26 +/- 0.07 Sv at leg areas when exposed to a cumulative dose of 65 Sv at the target. Maximum dose received from a stray radiation is about 1.5 Sv at forehead/chest and dosimetry of patient among the three centers is not significantly different at the 5% level of probability.

Combined loss of three DNA damage response pathways renders C. elegans intolerant to light.

PubMed

van Bostelen, Ivo; Tijsterman, Marcel

2017-06-01

Infliction of DNA damage initiates a complex cellular reaction - the DNA damage response - that involves both signaling and DNA repair networks with many redundancies and parallel pathways. Here, we reveal the three strategies that the simple multicellular eukaryote, C. elegans, uses to deal with DNA damage induced by light. Separately inactivating repair or replicative bypass of photo-lesions results in cellular hypersensitivity towards UV-light, but impeding repair of replication associated DNA breaks does not. Yet, we observe an unprecedented synergistic relationship when these pathways are inactivated in combination. C. elegans mutants that lack nucleotide excision repair (NER), translesion synthesis (TLS) and alternative end joining (altEJ) grow undisturbed in the dark, but become sterile when grown in light. Even exposure to very low levels of normal daylight impedes animal growth. We show that NER and TLS operate to suppress the formation of lethal DNA breaks that require polymerase theta-mediated end joining (TMEJ) for their repair. Our data testifies to the enormous genotoxicity of light and to the demand of multiple layers of protection against an environmental threat that is so common. Copyright © 2017 Elsevier B.V. All rights reserved.

Replication-mediated disassociation of replication protein A–XPA complex upon DNA damage: implications for RPA handing off

PubMed Central

Jiang, Gaofeng; Zou, Yue; Wu, Xiaoming

2013-01-01

RPA (replication protein A), the eukaryotic ssDNA (single-stranded DNA)-binding protein, participates in most cellular processes in response to genotoxic insults, such as NER (nucleotide excision repair), DNA, DSB (double-strand break) repair and activation of cell cycle checkpoint signalling. RPA interacts with XPA (xeroderma pigmentosum A) and functions in early stage of NER. We have shown that in cells the RPA–XPA complex disassociated upon exposure of cells to high dose of UV irradiation. The dissociation required replication stress and was partially attributed to tRPA hyperphosphorylation. Treatment of cells with CPT (camptothecin) and HU (hydroxyurea), which cause DSB DNA damage and replication fork collapse respectively and also leads to the disruption of RPA–XPA complex. Purified RPA and XPA were unable to form complex in vitro in the presence of ssDNA. We propose that the competition-based RPA switch among different DNA metabolic pathways regulates the dissociation of RPA with XPA in cells after DNA damage. The biological significances of RPA–XPA complex disruption in relation with checkpoint activation, DSB repair and RPA hyperphosphorylation are discussed. PMID:22578086

A self-consistent density based embedding scheme applied to the adsorption of CO on Pd(111)

NASA Astrophysics Data System (ADS)

Lahav, D.; Klüner, T.

2007-06-01

We derive a variant of a density based embedded cluster approach as an improvement to a recently proposed embedding theory for metallic substrates (Govind et al 1999 J. Chem. Phys. 110 7677; Klüner et al 2001 Phys. Rev. Lett. 86 5954). In this scheme, a local region in space is represented by a small cluster which is treated by accurate quantum chemical methodology. The interaction of the cluster with the infinite solid is taken into account by an effective one-electron embedding operator representing the surrounding region. We propose a self-consistent embedding scheme which resolves intrinsic problems of the former theory, in particular a violation of strict density conservation. The proposed scheme is applied to the well-known benchmark system CO/Pd(111).

The rendez-vous of mobile sieve-element and abundant companion-cell proteins.

PubMed

De Marco, Federica; Le Hir, Rozenn; Dinant, Sylvie

2018-06-01

Thousands of sieve tube exudate proteins (STEP) have now been identified and predicted to fulfill a diversity of functions. However, most STEPs should be considered putative, since methods to collect sieve tube exudates have many technical drawbacks, and advanced functional characterization will be required to distinguish contaminant from bonafide proteins, and determine the latter's location and activity in sieve elements (SE). One major challenge is to develop new approaches to elucidate the function of these SE proteins, which in turn, is expected to shed light on intriguing aspects of SE cell biology. Copyright © 2018 Elsevier Ltd. All rights reserved.

L'Aventure du LHC

ScienceCinema

None

2018-05-16

Cette présentation s’adressera principalement aux personnes qui ont construit le LHC. La construction du LHC fut longue et difficile. De nombreux problèmes sont apparus en cours de route. Tous ont été résolus grâce au dévouement et à l’engagement du personnel et des collaborateurs. Je reviendrai sur les coups durs et les réussites qui ont marqués ces 15 dernières années et je vous montrerai combien cette machine, le fruit de vos efforts, est extraordinaire.

Repair Mechanism of UV-damaged DNA in Xeroderma Pigmentosum | Center for Cancer Research

Cancer.gov

Xeroderma pigmentosum (XP) is a rare, inherited disorder characterized by extreme skin sensitivity to ultraviolet (UV) rays from sunlight. XP is caused by mutations in genes involved in nucleotide excision repair (NER) of damaged DNA. Normal cells are usually able to fix this damage before it leads to problems; however, the DNA damage is not repaired normally in patients with

Country Reports on Terrorism 2004

DTIC Science & Technology

2005-04-01

designed to disrupt the ASEAN Summit in late November 2004. Malaysia The Malaysian Government continues to be a strong part- ner in the war on terrorism...lectures, and workshops. The Malaysian Government has worked to ensure that separatist violence in southern Thailand, which has wounded Malaysian tourists...primarily concentrated in the Muslim majority provinces of Pattani, Yala, and Narathiwat, which are located along the Thai- Malaysian border. Most

Distribution, fate and formation of non-extractable residues of a nonylphenol isomer in soil with special emphasis on soil derived organo-clay complexes.

PubMed

Riefer, Patrick; Klausmeyer, Timm; Schäffer, Andreas; Schwarzbauer, Jan; Schmidt, Burkhard

2011-01-01

Anthropogenic contaminants like nonylphenols (NP) are added to soil, for instance if sewage-sludge is used as fertilizer in agriculture. A commercial mixture of NP consists of more than 20 isomers. For our study, we used one of the predominate isomers of NP mixtures, 4-(3,5-dimethylhept-3-yl)phenol, as a representative compound. The aim was to investigate the fate and distribution of the isomer within soil and soil derived organo-clay complexes. Therefore, (14)C- and (13)C-labeled NP was added to soil samples and incubated up to 180 days. Mineralization was measured and soil samples were fractionated into sand, silt and clay; the clay fraction was further separated in humic acids, fulvic acids and humin. The organo-clay complexes pre-incubated for 90 or 180 days were re-incubated with fresh soil for 180 days, to study the potential of re-mobilization of incorporated residues. The predominate incorporation sites of the nonylphenol isomer in soil were the organo-clay complexes. After 180 days of incubation, 22 % of the applied (14)C was mineralized. The bioavailable, water extractable portion was low (9 % of applied (14)C) and remained constant during the entire incubation period, which could be explained by an incorporation/release equilibrium. Separation of organo-clay complexes, after extraction with solvents to release weakly incorporated, bioaccessible portions, showed that non-extractable residues (NER) were preferentially located in the humic acid fraction, which was regarded as an effect of the chemical composition of this fraction. Generally, 27 % of applied (14)C was incorporated into organo-clay complexes as NER, whereas 9 % of applied (14)C was bioaccessible after 180 days of incubation. The re-mobilization experiments showed on the one hand, a decrease of the bioavailability of the nonylphenol residues due to stronger incorporation, when the pre-incubation period was increased from 90 to 180 days. On the other hand, a shift of these residues from the clay fraction to other soil fractions was observed, implying a dynamic behavior of incorporated residues, which may result in bioaccessibility of the NER of nonylphenol.

Jealousy Graphs: Structure and Complexity of Decentralized Stable Matching

DTIC Science & Technology

2013-01-01

REPORT Jealousy Graphs: Structure and Complexity of Decentralized Stable Matching 14. ABSTRACT 16. SECURITY CLASSIFICATION OF: The stable matching...Franceschetti 858-822-2284 3. DATES COVERED (From - To) Standard Form 298 (Rev 8/98) Prescribed by ANSI Std. Z39.18 - Jealousy Graphs: Structure and...market. Using this structure, we are able to provide a ner analysis of the complexity of a subclass of decentralized matching markets. Jealousy

Mosquitoes of Middle America.

DTIC Science & Technology

1976-09-30

subtropical and tropical areas extending from the southern United States to the edge of the Amazon basin. The ultimate goal was to produce a monograph of...project in Argentina , Bolivia, Brazil , Chile, Paraguay~ Peru . Very valuable materia l not previously studied in detail was acquired for the project , pri...1965-1976. Gard ner , Clark , Department of Biology, University of Utah , Salt Lake City. —Collections in Colom- bia and Peru , 1975. Geijskes , D. C

Army Logistician. Volume 34, Issue 2, March-April 2002

DTIC Science & Technology

2002-04-01

potential coalition part- ners; and, • Leverage of U.S. resources through cost sharing and economies of scale.” DOD guidance focuses on the broad goals of...be funded privately through the Army Historical Foundation. • Operations research and operations management. • Engineering economy , life-cycle cost ...will be implemented this summer. A review of Army organizations below the headquarters level should be completed this spring. EDGEWOOD ENZYMATIC DECON

Abstracts of ARI Research Publications, FY 1978

DTIC Science & Technology

1980-09-01

initial item pool, 49 items were identified as having signifi- cant item-to-total-score correlations and were statistically determined to address a...failing. Differences among the three groups on main gun performance measures and the previous experience of gun- ners were not statistically significant...forms of the noncognitive cod- ing speed test; and (d) a second field administration to derive norms and other statistical characteristics of the new

Endogenous formation and repair of oxidatively induced G[8-5 m]T intrastrand cross-link lesion

PubMed Central

Wang, Jin; Cao, Huachuan; You, Changjun; Yuan, Bifeng; Bahde, Ralf; Gupta, Sanjeev; Nishigori, Chikako; Niedernhofer, Laura J.; Brooks, Philip J.; Wang, Yinsheng

2012-01-01

Exposure to reactive oxygen species (ROS) can give rise to the formation of various DNA damage products. Among them, d(G[8-5 m]T) can be induced in isolated DNA treated with Fenton reagents and in cultured human cells exposed to γ-rays, d(G[8-5m]T) can be recognized and incised by purified Escherichia coli UvrABC nuclease. However, it remains unexplored whether d(G[8-5 m]T) accumulates in mammalian tissues and whether it is a substrate for nucleotide excision repair (NER) in vivo. Here, we found that d(G[8-5 m]T) could be detected in DNA isolated from tissues of healthy humans and animals, and elevated endogenous ROS generation enhanced the accumulation of this lesion in tissues of a rat model of Wilson’s disease. Additionally, XPA-deficient human brain and mouse liver as well as various types of tissues of ERCC1-deficient mice contained higher levels of d(G[8-5 m]T) but not ROS-induced single-nucleobase lesions than the corresponding normal controls. Together, our studies established that d(G[8-5 m]T) can be induced endogenously in mammalian tissues and constitutes a substrate for NER in vivo. PMID:22581771

A damaged DNA binding protein 2 mutation disrupting interaction with proliferating-cell nuclear antigen affects DNA repair and confers proliferation advantage.

PubMed

Perucca, Paola; Mocchi, Roberto; Guardamagna, Isabella; Bassi, Elisabetta; Sommatis, Sabrina; Nardo, Tiziana; Prosperi, Ennio; Stivala, Lucia Anna; Cazzalini, Ornella

2018-06-01

In mammalian cells, Nucleotide Excision Repair (NER) plays a role in removing DNA damage induced by UV radiation. In Global Genome-NER subpathway, DDB2 protein forms a complex with DDB1 (UV-DDB), recognizing photolesions. During DNA repair, DDB2 interacts directly with PCNA through a conserved region in N-terminal tail and this interaction is important for DDB2 degradation. In this work, we sought to investigate the role of DDB2-PCNA association in DNA repair and cell proliferation after UV-induced DNA damage. To this end, stable clones expressing DDB2 Wt and DDB2 PCNA- were used. We have found that cells expressing a mutant DDB2 show inefficient photolesions removal, and a concomitant lack of binding to damaged DNA in vitro. Unexpected cellular behaviour after DNA damage, such as UV-resistance, increased cell growth and motility were found in DDB2 PCNA- stable cell clones, in which the most significant defects in cell cycle checkpoint were observed, suggesting a role in the new cellular phenotype. Based on these findings, we propose that DDB2-PCNA interaction may contribute to a correct DNA damage response for maintaining genome integrity. Copyright © 2018 Elsevier B.V. All rights reserved.

Mutational analysis of the human nucleotide excision repair gene ERCC1.

PubMed Central

Sijbers, A M; van der Spek, P J; Odijk, H; van den Berg, J; van Duin, M; Westerveld, A; Jaspers, N G; Bootsma, D; Hoeijmakers, J H

1996-01-01

The human DNA repair protein ERCC1 resides in a complex together with the ERCC4, ERCC11 and XP-F correcting activities, thought to perform the 5' strand incision during nucleotide excision repair (NER). Its yeast counterpart, RAD1-RAD10, has an additional engagement in a mitotic recombination pathway, probably required for repair of DNA cross-links. Mutational analysis revealed that the poorly conserved N-terminal 91 amino acids of ERCC1 are dispensable for both repair functions, in contrast to a deletion of only four residues from the C-terminus. A database search revealed a strongly conserved motif in this C-terminus sharing sequence homology with many DNA break processing proteins, indicating that this part is primarily required for the presumed structure-specific endonuclease activity of ERCC1. Most missense mutations in the central region give rise to an unstable protein (complex). Accordingly, we found that free ERCC1 is very rapidly degraded, suggesting that protein-protein interactions provide stability. Survival experiments show that the removal of cross-links requires less ERCC1 than UV repair. This suggests that the ERCC1-dependent step in cross-link repair occurs outside the context of NER and provides an explanation for the phenotype of the human repair syndrome xeroderma pigmentosum group F. PMID:8811092

Mutagenic cost of ribonucleotides in bacterial DNA

PubMed Central

Schroeder, Jeremy W.; Randall, Justin R.; Hirst, William G.; O’Donnell, Michael E.; Simmons, Lyle A.

2017-01-01

Replicative DNA polymerases misincorporate ribonucleoside triphosphates (rNTPs) into DNA approximately once every 2,000 base pairs synthesized. Ribonucleotide excision repair (RER) removes ribonucleoside monophosphates (rNMPs) from genomic DNA, replacing the error with the appropriate deoxyribonucleoside triphosphate (dNTP). Ribonucleotides represent a major threat to genome integrity with the potential to cause strand breaks. Furthermore, it has been shown in the bacterium Bacillus subtilis that loss of RER increases spontaneous mutagenesis. Despite the high rNTP error rate and the effect on genome integrity, the mechanism underlying mutagenesis in RER-deficient bacterial cells remains unknown. We performed mutation accumulation lines and genome-wide mutational profiling of B. subtilis lacking RNase HII, the enzyme that incises at single rNMP residues initiating RER. We show that loss of RER in B. subtilis causes strand- and sequence-context–dependent GC → AT transitions. Using purified proteins, we show that the replicative polymerase DnaE is mutagenic within the sequence context identified in RER-deficient cells. We also found that DnaE does not perform strand displacement synthesis. Given the use of nucleotide excision repair (NER) as a backup pathway for RER in RNase HII-deficient cells and the known mutagenic profile of DnaE, we propose that misincorporated ribonucleotides are removed by NER followed by error-prone resynthesis with DnaE. PMID:29078353

Polymorphisms in nucleotide excision repair genes and risk of primary prostate cancer in Chinese Han populations.

PubMed

Wang, Mengyun; Li, Qiaoxin; Gu, Chengyuan; Zhu, Yao; Yang, Yajun; Wang, Jiucun; Jin, Li; He, Jing; Ye, Dingwei; Wei, Qingyi

2017-04-11

Genetic variants of nucleotide excision repair (NER) genes have been extensively investigated for their roles in the development of prostate cancer (PCa); however, the published results have been inconsistent. In a hospital-based case-control study of 1,004 PCa cases and 1,055 cancer-free controls, we genotyped eight potentially functional single nucleotide polymorphisms (SNPs) of NER genes (i.e., XPC, rs2228001 T>G and rs1870134 G>C; XPD, rs13181 T>G and rs238406 G>T; XPG, rs1047768 T>C, rs751402 C>T, and rs17655 G>C; and XPF, rs2276464 G>C) and assessed their associations with risk of PCa by using logistic regression analysis. Among these eight SNPs investigated, only XPC rs1870134 CG/CC variant genotypes were associated with a decreased risk of prostate cancer under a dominant genetic model (adjusted odds ratio [OR] = 0.77, 95% confidence interval [CI] = 0.64-1.91, P = 0.003). Phenotype-genotype analysis also suggested that the XPC rs1870134 CG/CC variant genotypes were associated with significantly decreased expression levels of XPC mRNA in a mix population of different ethnicities. These findings suggested that XPC SNPs may contribute to risk of PCa in Eastern Chinese men.

Circadian Rhythms of Oxidative Stress Markers and Melatonin Metabolite in Patients with Xeroderma Pigmentosum Group A.

PubMed

Miyata, Rie; Tanuma, Naoyuki; Sakuma, Hiroshi; Hayashi, Masaharu

2016-01-01

Xeroderma pigmentosum group A (XPA) is a genetic disorder in DNA nucleotide excision repair (NER) with severe neurological disorders, in which oxidative stress and disturbed melatonin metabolism may be involved. Herein we confirmed the diurnal variation of melatonin metabolites, oxidative stress markers, and antioxidant power in urine of patients with XPA and age-matched controls, using enzyme-linked immunosorbent assay (ELISA). The peak of 6-sulfatoxymelatonin, a metabolite of melatonin, was seen at 6:00 in both the XPA patients and controls, though the peak value is lower, specifically in the younger age group of XPA patients. The older XPA patients demonstrated an increase in the urinary levels of 8-hydroxy-2'-deoxyguanosine and hexanoyl-lysine, a marker of oxidative DNA damage and lipid peroxidation, having a robust peak at 6:00 and 18:00, respectively. In addition, the urinary level of total antioxidant power was decreased in the older XPA patients. Recently, it is speculated that oxidative stress and antioxidant properties may have a diurnal variation, and the circadian rhythm is likely to influence the NER itself. We believe that the administration of melatonin has the possibility of ameliorating the augmented oxidative stress in neurodegeneration, especially in the older XPA patients, modulating the melatonin metabolism and the circadian rhythm.

Circadian Rhythms of Oxidative Stress Markers and Melatonin Metabolite in Patients with Xeroderma Pigmentosum Group A

PubMed Central

Sakuma, Hiroshi

2016-01-01

Xeroderma pigmentosum group A (XPA) is a genetic disorder in DNA nucleotide excision repair (NER) with severe neurological disorders, in which oxidative stress and disturbed melatonin metabolism may be involved. Herein we confirmed the diurnal variation of melatonin metabolites, oxidative stress markers, and antioxidant power in urine of patients with XPA and age-matched controls, using enzyme-linked immunosorbent assay (ELISA). The peak of 6-sulfatoxymelatonin, a metabolite of melatonin, was seen at 6:00 in both the XPA patients and controls, though the peak value is lower, specifically in the younger age group of XPA patients. The older XPA patients demonstrated an increase in the urinary levels of 8-hydroxy-2′-deoxyguanosine and hexanoyl-lysine, a marker of oxidative DNA damage and lipid peroxidation, having a robust peak at 6:00 and 18:00, respectively. In addition, the urinary level of total antioxidant power was decreased in the older XPA patients. Recently, it is speculated that oxidative stress and antioxidant properties may have a diurnal variation, and the circadian rhythm is likely to influence the NER itself. We believe that the administration of melatonin has the possibility of ameliorating the augmented oxidative stress in neurodegeneration, especially in the older XPA patients, modulating the melatonin metabolism and the circadian rhythm. PMID:27213030

SELF-CANCELLATION OF EPHEMERAL REGIONS IN THE QUIET SUN

DOE Office of Scientific and Technical Information (OSTI.GOV)

Yang, Shuhong; Zhang, Jun; Li, Ting

2012-06-20

With the observations from the Helioseismic and Magnetic Imager aboard the Solar Dynamics Observatory, we statistically investigate the ephemeral regions (ERs) in the quiet Sun. We find that there are two types of ERs: normal ERs (NERs) and self-canceled ERs (SERs). Each NER emerges and grows with separation of its opposite polarity patches which will cancel or coalesce with other surrounding magnetic flux. Each SER also emerges and grows and its dipolar patches separate at first, but a part of the magnetic flux of the SER will move together and cancel gradually, which is described with the term 'self-cancellation' bymore » us. We identify 2988 ERs, among which there are 190 SERs, about 6.4% of the ERs. The mean value of self-cancellation fraction of SERs is 62.5%, and the total self-canceled flux of SERs is 9.8% of the total ER flux. Our results also reveal that the higher the ER magnetic flux is, (1) the easier the performance of ER self-cancellation is, (2) the smaller the self-cancellation fraction is, and (3) the more the self-canceled flux is. We think that the self-cancellation of SERs is caused by the submergence of magnetic loops connecting the dipolar patches, without magnetic energy release.« less

A method for named entity normalization in biomedical articles: application to diseases and plants.

PubMed

Cho, Hyejin; Choi, Wonjun; Lee, Hyunju

2017-10-13

In biomedical articles, a named entity recognition (NER) technique that identifies entity names from texts is an important element for extracting biological knowledge from articles. After NER is applied to articles, the next step is to normalize the identified names into standard concepts (i.e., disease names are mapped to the National Library of Medicine's Medical Subject Headings disease terms). In biomedical articles, many entity normalization methods rely on domain-specific dictionaries for resolving synonyms and abbreviations. However, the dictionaries are not comprehensive except for some entities such as genes. In recent years, biomedical articles have accumulated rapidly, and neural network-based algorithms that incorporate a large amount of unlabeled data have shown considerable success in several natural language processing problems. In this study, we propose an approach for normalizing biological entities, such as disease names and plant names, by using word embeddings to represent semantic spaces. For diseases, training data from the National Center for Biotechnology Information (NCBI) disease corpus and unlabeled data from PubMed abstracts were used to construct word representations. For plants, a training corpus that we manually constructed and unlabeled PubMed abstracts were used to represent word vectors. We showed that the proposed approach performed better than the use of only the training corpus or only the unlabeled data and showed that the normalization accuracy was improved by using our model even when the dictionaries were not comprehensive. We obtained F-scores of 0.808 and 0.690 for normalizing the NCBI disease corpus and manually constructed plant corpus, respectively. We further evaluated our approach using a data set in the disease normalization task of the BioCreative V challenge. When only the disease corpus was used as a dictionary, our approach significantly outperformed the best system of the task. The proposed approach shows robust performance for normalizing biological entities. The manually constructed plant corpus and the proposed model are available at http://gcancer.org/plant and http://gcancer.org/normalization , respectively.

CRASHWORTHY HELICOPTER GUNNER’S SEAT INVESTIGATION

DTIC Science & Technology

1975-01-01

less restrict- ing to gun motion than a fully armored bucket seat. The problem remains in getting the gunners to wear body armor, and this can be... motions . The adjustable seat back accommodates a gun- ner with or without body armor and troops with or without combat packs and equipment. A back flap...Developmental Retractable Monkey Harness Restraint for UH-l 1 1.9 10 Gunner Survival Vest With Body Armor (ISVESTA) Side View . . . . . . . . *. . ... .. 22

Gender, Equity, and Job Satisfaction

DTIC Science & Technology

1992-02-01

Kahn, Nelson, and Gaeddert ers. Among married personnel, breadwinner (1980, p. 748) argued that "much of the research status (i.e., whether or not the...a lack of clarity on this issue and that not ners. Non- breadwinners , on whose income the all relevant variables have been identified. As family does...Sauser, W. I., & York, M. (1978). Sex dif- and female means to a just end. Basic and ferences in job satisfaction: A re-examination. Applied Social

A Calculus of Macro-Events: Progress Report

DTIC Science & Technology

2000-01-01

1410, USA iliano@itd.nrl.navy.mil Angelo Montanari Dipartimento di Matematica e Informatica Universita di Udine Via delle Scienze, 206 { 33100 Udine...and process iteration. This proposal builds on work by Chittaro and Montanari [10] on mod- eling discrete processes. The set of constructors of the...situations, in many cases the occurrence of an event happens over a period of time [24]. Capturing this possibility enables ner mod- els , as we can now

Checkpoint Kinase-Dependent Regulation of DNA Repair and Genome Instability in Breast Cancer

DTIC Science & Technology

2007-06-01

cells reduces radiosensitivity. Cancer J 9:277-85. 15. Lehmann, A. R. 2003. DNA repair-deficient diseases, xeroderma pigmentosum , Cockayne syndrome...in NER give rise to the autosomal recessive disorder xeroderma pigmentosum (XP), which is characterized by ex- treme sun sensitivity, premature aging...mediated ubiquitination and deg- radation. J. Biol. Chem. 276:48175–48182. 14. Chu, G., and E. Chang. 1988. Xeroderma pigmentosum group E cells lack a

Daily Magnetograms for 1979 from the AFGL Network.

DTIC Science & Technology

1985-02-22

produced the edited data shown in these plots and who lost his life in October 1982 while the work was under way. Many other persons have also...S317g 42919 24 OCT 79 (LAY 79.297) UIVERSAL TlrE AFGL r’bETt’ETER NErUcwa 304 5 NO.. ’.e> FLLA jTE X CiUtFffT40i’EL.Sr 1c I’III 161127 p C

HR Public meeting

DOE Office of Scientific and Technical Information (OSTI.GOV)

Heuer, Rolf; Catherin, Anne-Sylvie; Vuillemin, Vin

2010-06-25

Cher(e)s collègues, En collaboration avec le Département HR, le Directeur général a le plaisir de vous convier à une réunion publique qui se tiendra le vendredi 25 juin 2010 à 9h30 dans l’Amphithéâtre principal (Bâtiment 500)*. Un café d’accueil y sera servi à partir de 9h. Cette réunion abordera les thèmes suivants : • Valeurs de l’Organisation (Directeur général) • Code de Conduite (Directeur général / Anne-Sylvie Catherin) • Création du nouveau rôle d’Ombudsperson (Vincent Vuillemin); Ces présentations seront suivies d’une séance de questions-réponses. Nous espérons vous retrouver nombreux le 25 juin ! Meilleures salutations, Anne-Sylvie Catherin Chef du Départementmore » des Ressources humaines *Cette réunion sera retransmise simultanément dans l’Amphithéâtre BE de Prévessin (Bâtiment 864) et également disponible à l’adresse suivante : http://webcast.cern.ch. Dear colleagues, In collaboration with HR Department, the Director-General would like to invite you to an information meeting which will be held on Friday 25 June 2010 at 9:30 am in the Main Auditorium (Building 500)*. A welcome coffee will be available from 9:00 am. During this meeting, information will be given about: • Organization’s values (Director-General) • Code of Conduct (Director-General / Anne-Sylvie Catherin) • New Ombudsperson role (Vincent Vuillemin) These presentations will be followed by a questions & answers session. We look forward to seeing you all on 25 June! Best regards, Anne-Sylvie Catherin Head, Human Resources Department. This meeting will be simultaneously retransmitted in BE Auditorium (Building 864) and available at the following address: http://webcast.cern.ch.« less

HR Public meeting

DOE Office of Scientific and Technical Information (OSTI.GOV)

None

2010-10-12

Cher(e)s collègues, En collaboration avec le Département HR, le Directeur général a le plaisir de vous convier à une réunion publique qui se tiendra le vendredi 25 juin 2010 à 9h30 dans l’Amphithéâtre principal (Bâtiment 500)*. Un café d’accueil y sera servi à partir de 9h. Cette réunion abordera les thèmes suivants : Valeurs de l’Organisation (Directeur général); Code de Conduite (Directeur général / Anne-Sylvie Catherin); Création du nouveau rôle d’Ombudsperson (Vincent Vuillemin) Ces présentations seront suivies d’une séance de questions-réponses. Nous espérons vous retrouver nombreux le 25 juin ! Meilleures salutations, Anne-Sylvie Catherin Chef du Département des Ressources humainesmore » *Cette réunion sera retransmise simultanément dans l’Amphithéâtre BE de Prévessin (Bâtiment 864) et également disponible à l’adresse suivante : http://webcast.cern.ch [Dear colleagues, In collaboration with HR Department, the Director-General would like to invite you to an information meeting which will be held on Friday 25 June 2010 at 9:30 am in the Main Auditorium (Building 500)*. A welcome coffee will be available from 9:00 am. During this meeting, information will be given about: Organization’s values (Director-General); Code of Conduct (Director-General / Anne-Sylvie Catherin); New Ombudsperson role (Vincent Vuillemin); These presentations will be followed by a questions & answers session. We look forward to seeing you all on 25 June! Best regards, Anne-Sylvie Catherin Head, Human Resources Department *This meeting will be simultaneously retransmitted in BE Auditorium (Building 864) and available at the following address: http://webcast.cern.ch.« less

Prematurity, ventricular septal defect and dysmorphisms are independent predictors of pathogenic copy number variants: a retrospective study on array-CGH results and phenotypical features of 293 children with neurodevelopmental disorders and/or multiple congenital anomalies.

PubMed

Maini, I; Ivanovski, I; Djuric, O; Caraffi, S G; Errichiello, E; Marinelli, M; Franchi, F; Bizzarri, V; Rosato, S; Pollazzon, M; Gelmini, C; Malacarne, M; Fusco, C; Gargano, G; Bernasconi, S; Zuffardi, O; Garavelli, L

2018-03-09

Since 2010, array-CGH (aCGH) has been the first-tier test in the diagnostic approach of children with neurodevelopmental disorders (NDD) or multiple congenital anomalies (MCA) of unknown origin. Its broad application led to the detection of numerous variants of uncertain clinical significance (VOUS). How to appropriately interpret aCGH results represents a challenge for the clinician. We present a retrospective study on 293 patients with age range 1 month - 29 years (median 7 years) with NDD and/or MCA and/or dysmorphisms, investigated through aCGH between 2005 and 2016. The aim of the study was to analyze clinical and molecular cytogenetic data in order to identify what elements could be useful to interpret unknown or poorly described aberrations. Comparison of phenotype and cytogenetic characteristics through univariate analysis and multivariate logistic regression was performed. Copy number variations (CNVs) with a frequency < 1% were detected in 225 patients of the total sample, while 68 patients presented only variants with higher frequency (heterozygous deletions or amplification) and were considered to have negative aCGH. Proved pathogenic CNVs were detected in 70 patients (20.6%). Delayed psychomotor development, intellectual disability, intrauterine growth retardation (IUGR), prematurity, congenital heart disease, cerebral malformations and dysmorphisms correlated to reported pathogenic CNVs. Prematurity, ventricular septal defect and dysmorphisms remained significant predictors of pathogenic CNVs in the multivariate logistic model whereas abnormal EEG and limb dysmorphisms were mainly detected in the group with likely pathogenic VOUS. A flow-chart regarding the care for patients with NDD and/or MCA and/or dysmorphisms and the interpretation of aCGH has been made on the basis of the data inferred from this study and literature. Our work contributes to make the investigative process of CNVs more informative and suggests possible directions in aCGH interpretation and phenotype correlation.

Telescope-optical system performance analysis for the Cryogenic Limb Array Etalon Spectrometer (CLAES) on the Upper Atmospheric Research Satellite

NASA Technical Reports Server (NTRS)

Roche, A. E.; Forney, P. B.; Morrow, H. E.; Anapol, M.

1983-01-01

A first-order performance analysis of the CLAES telescope-optical system is presented. The experiment involves the passive measurement of earth-limb radiance over a 10-60 km tangent altitude range, and is based on a solid Fabry-Perot spectrometer which provides spectral resolution of 0.25/cm for atmospheric emission spectroscopy over the 3.5-12 micron IR range. The optical system is required to provide a high degree of off-axis rejection and stray-light control, primarily to suppress intense emission from the earth surface. The astigmatism and other geometric aberrations are corrected by a secondary mirror which produces an excellent image of the primary one, allowing for location of a diffraction control or Lyot stop. The off-axis scattering performance of the telescope is examined in terms of the mirror scatter coefficient and point source rejection ratio. A mirror bidirectional reflectance distribution function of 0.0001 at 1 deg with a 1/theta-squared roll-off between 1 and 0.2 deg is realizable based on recent measurements. This results in an off-axis radiance term that is generally small in comparison with the system-limiting NER.

Atypical radiation response of SCID cells

NASA Astrophysics Data System (ADS)

Chawapun, Nisa

Murine SCID (severe combined immune deficiency) cells are well known for their defect in DNA double-strand break repair and in variable(diversity)joining [V(D)J] recombination due to a mutation in a catalytic subunit of DNA-dependent protein kinase (DNA-PKcs). As a consequence, scid cells are hypersensitive to ionizing radiation. The present study showed that asynchronous populations of scid cells were about two-fold more sensitive than Balb/c with respect to cell killing and the defect in scid cells was corrected by complementation with human chromosome 8. Analysis of the survival of synchronized populations as a function of the cell cycle revealed that while scid cells were hypersensitive in all cell cycle phases compared to wild-type cells, this hypersensitivity is even more pronounced in G1 phase. The hypersensitivity reduced as the cells progressed into S phase suggested that homologous recombination repair plays a role. The results imply that there are at least two pathways for the repair of DSB DNA, consistent with a model previously proposed by others. The scid cells were also more sensitive to UVC light (254 nm) killing as compared to wild type cells by clonogenic survival. Using a host cell reactivation (HCR) assay to study the nucleotide excision repair (NER) which is the major repair pathway for UV-photoproducts, the results showed that NER in scid cells was not as efficient as CB- 17. This suggests that DNA-PK is involved in NER as well as non-homologous end-joining (NHEJ) DSB repair which is responsible for ionizing radiation sensitivity in scid cells. Repair in scid cells was not totally absent as shown by low dose rate sparing of cell killing after exposure to 137Cs γ-rays at dose rate of 0.6 cGy/h, 1.36 cGy/h, 6 cGy/h as compared to high dose rate at 171 cGy/min, although this phenomenon could be explained partly by proliferation. However, for radiation induced transformation, no significant dose rate effect was seen. A plot of transformation versus survival revealed that the transformation induction was inversely proportional to radiation dose rate. Lower dose rates were more effective in inducing transformation in scid cells. This finding could lead to the influence of cancer risk estimation in an irradiated population consisting of a subpopulation(s) with genetic disorders predisposing those individuals to cancer.

Final Independent External Peer Review Report, Cache la Poudre at Greeley, Colorado General Investigation Feasibility Study

DTIC Science & Technology

2014-06-06

Adaptive Management Plan NED national economic development NEPA National Environmental Policy Act NER National Ecosystem Restoration NFIP... management and flow maintenance (e.g., flood water height, channel and culvert sizing) are based on high water events (i.e., FEMA base flood – 1% or 100...Minimum 15 years of experience in economics X Minimum 15 years of experience in flood risk management analysis and benefits calculations X Direct

A history of the DNA repair and mutagenesis field: The discovery of base excision repair.

PubMed

Friedberg, Errol C

2016-01-01

This article reviews the early history of the discovery of an DNA repair pathway designated as base excision repair (BER), since in contrast to the enzyme-catalyzed removal of damaged bases from DNA as nucleotides [called nucleotide excision repair (NER)], BER involves the removal of damaged or inappropriate bases, such as the presence of uracil instead of thymine, from DNA as free bases. Copyright © 2015. Published by Elsevier B.V.

Corrosion and Passivity Studies with Titanium

DTIC Science & Technology

1955-09-30

the (00.1) Face of a Titanium Single Crystal . - Part 3 Secondary Electron Emission from the Titanium Crystal , and from the Copper-Covered Titanium...ner upon the (00.1) face of a titaniuT single crystal . Low- energy electron diffraction is used to investigate the struc- ture of the deposit. Before...cathode emisaion is strongly dependent on the work function k. 8ince varies with crystal faces and the tip is generally so small that it is a single

Non-Military Activities in Japan and Korea for the Months of September - October 1945

DTIC Science & Technology

1945-10-01

institutions, general elec- tions, woman suffrage, reorganization of government bureaus and pun- - 29 - ishment of high policy makers who engineered the war...which he was persecuted - 30 - during the war. This new Liberal Party has a women’s section and favors woman suffrage, lowering the voting age, and...textile goods. Spin - ners are inquiring as to the possibilities of importing raw cotton, yarn and other basic necessities inasmuch as cotton stocks on

TNT Degradation by Natural Microbial Assemblages at Frontal Boundaries Between Water Masses in Coastal Ecosystems (ER-2124)

DTIC Science & Technology

2017-06-20

that would pose an unacceptable ecological or human health risk. Recent work by our group and others has focused on determining energetic degradation...Eastern North Carolina, USA). J. Water Health 6:473-482. 59 Derrien, D., Plain, C., Courty, P.E., Gelhaye, L., Moerdijk-Poortvliet, T.C., Thomas, F...sediment enrichments. Biodegradation 24(2):179-190. Fenner, K., Canonica, S., Wackett, L.P., and M.Els ner. 2013. Evaluating pesticide

IRS Could Better Protect U.S. Tax Interests in Determining the Income of Multinational Corporations.

DTIC Science & Technology

1981-09-30

together by ties of common ownership and responsive to a common management strat- egy. 2/ Unlike a corporation which conducts business in only one...multinational corporate tax returns. The Assistant Commissi3ner carries out this responsibility through the IRS Examination Divi- sion and Office of...information return would not place an added burden on the corporations be- cause the corporations are currently providing similar data in response to

Both XPD alleles contribute to the phenotype of compound heterozygote xeroderma pigmentosum patients

PubMed Central

Ueda, Takahiro; Compe, Emmanuel; Catez, Philippe; Kraemer, Kenneth H.

2009-01-01

Mutations in the XPD subunit of the DNA repair/transcription factor TFIIH result in the rare recessive genetic disorder xeroderma pigmentosum (XP). Many XP patients are compound heterozygotes with a “causative” XPD point mutation R683W and different second mutant alleles, considered “null alleles.” However, there is marked clinical heterogeneity (including presence or absence of skin cancers or neurological degeneration) in these XPD/R683W patients, thus suggesting a contribution of the second allele. Here, we report XP patients carrying XPD/R683W and a second XPD allele either XPD/Q452X, /I455del, or /199insPP. We performed a systematic study of the effect of these XPD mutations on several enzymatic functions of TFIIH and found that each mutation exhibited unique biochemical properties. Although all the mutations inhibited the nucleotide excision repair (NER) by disturbing the XPD helicase function, each of them disrupted specific molecular steps during transcription: XPD/Q452X hindered the transactivation process, XPD/I455del disturbed RNA polymerase II phosphorylation, and XPD/199insPP inhibited kinase activity of the cdk7 subunit of TFIIH. The broad range and severity of clinical features in XP patients arise from a broad set of deficiencies in NER and transcription that result from the combination of mutations found on both XPD alleles. PMID:19934020

Anatomical Entity Recognition with a Hierarchical Framework Augmented by External Resources

PubMed Central

Xu, Yan; Hua, Ji; Ni, Zhaoheng; Chen, Qinlang; Fan, Yubo; Ananiadou, Sophia; Chang, Eric I-Chao; Tsujii, Junichi

2014-01-01

References to anatomical entities in medical records consist not only of explicit references to anatomical locations, but also other diverse types of expressions, such as specific diseases, clinical tests, clinical treatments, which constitute implicit references to anatomical entities. In order to identify these implicit anatomical entities, we propose a hierarchical framework, in which two layers of named entity recognizers (NERs) work in a cooperative manner. Each of the NERs is implemented using the Conditional Random Fields (CRF) model, which use a range of external resources to generate features. We constructed a dictionary of anatomical entity expressions by exploiting four existing resources, i.e., UMLS, MeSH, RadLex and BodyPart3D, and supplemented information from two external knowledge bases, i.e., Wikipedia and WordNet, to improve inference of anatomical entities from implicit expressions. Experiments conducted on 300 discharge summaries showed a micro-averaged performance of 0.8509 Precision, 0.7796 Recall and 0.8137 F1 for explicit anatomical entity recognition, and 0.8695 Precision, 0.6893 Recall and 0.7690 F1 for implicit anatomical entity recognition. The use of the hierarchical framework, which combines the recognition of named entities of various types (diseases, clinical tests, treatments) with information embedded in external knowledge bases, resulted in a 5.08% increment in F1. The resources constructed for this research will be made publicly available. PMID:25343498

Understanding Xeroderma Pigmentosum Complementation Groups Using Gene Expression Profiling after UV-Light Exposure.

PubMed

Bowden, Nikola A; Beveridge, Natalie J; Ashton, Katie A; Baines, Katherine J; Scott, Rodney J

2015-07-14

Children with the recessive genetic disorder Xeroderma Pigmentosum (XP) have extreme sensitivity to UV-light, a 10,000-fold increase in skin cancers from age 2 and rarely live beyond 30 years. There are seven genetic subgroups of XP, which are all resultant of pathogenic mutations in genes in the nucleotide excision repair (NER) pathway and a XP variant resultant of a mutation in translesion synthesis, POLH. The clinical symptoms and severity of the disease is varied across the subgroups, which does not correlate with the functional position of the affected protein in the NER pathway. The aim of this study was to further understand the biology of XP subgroups, particularly those that manifest with neurological symptoms. Whole genome gene expression profiling of fibroblasts from each XP complementation group was assessed before and after UV-light exposure. The biological pathways with altered gene expression after UV-light exposure were distinct for each subtype and contained oncogenic related functions such as perturbation of cell cycle, apoptosis, proliferation and differentiation. Patients from the subgroups XP-B and XP-F were the only subgroups to have transcripts associated with neuronal activity altered after UV-light exposure. This study will assist in furthering our understanding of the different subtypes of XP which will lead to better diagnosis, treatment and management of the disease.

Understanding Xeroderma Pigmentosum Complementation Groups Using Gene Expression Profiling after UV-Light Exposure

PubMed Central

Bowden, Nikola A.; Beveridge, Natalie J.; Ashton, Katie A.; Baines, Katherine J.; Scott, Rodney J.

2015-01-01

Children with the recessive genetic disorder Xeroderma Pigmentosum (XP) have extreme sensitivity to UV-light, a 10,000-fold increase in skin cancers from age 2 and rarely live beyond 30 years. There are seven genetic subgroups of XP, which are all resultant of pathogenic mutations in genes in the nucleotide excision repair (NER) pathway and a XP variant resultant of a mutation in translesion synthesis, POLH. The clinical symptoms and severity of the disease is varied across the subgroups, which does not correlate with the functional position of the affected protein in the NER pathway. The aim of this study was to further understand the biology of XP subgroups, particularly those that manifest with neurological symptoms. Whole genome gene expression profiling of fibroblasts from each XP complementation group was assessed before and after UV-light exposure. The biological pathways with altered gene expression after UV-light exposure were distinct for each subtype and contained oncogenic related functions such as perturbation of cell cycle, apoptosis, proliferation and differentiation. Patients from the subgroups XP-B and XP-F were the only subgroups to have transcripts associated with neuronal activity altered after UV-light exposure. This study will assist in furthering our understanding of the different subtypes of XP which will lead to better diagnosis, treatment and management of the disease. PMID:26184184

Synergistic Exposure of Rice Seeds to Different Doses of γ-Ray and Salinity Stress Resulted in Increased Antioxidant Enzyme Activities and Gene-Specific Modulation of TC-NER Pathway

PubMed Central

Macovei, Anca; Garg, Bharti; Raikwar, Shailendra; Carbonera, Daniela; Bremont, Juan Francisco Jiménez; Gill, Sarvajeet Singh; Tuteja, Narendra

2014-01-01

Recent reports have underlined the potential of gamma (γ)-rays as tools for seed priming, a process used in seed industry to increase seed vigor and to enhance plant tolerance to biotic/abiotic stresses. However, the impact of γ-rays on key aspects of plant metabolism still needs to be carefully evaluated. In the present study, rice seeds were challenged with different doses of γ-rays and grown in absence/presence of NaCl to assess the impact of these treatments on the early stages of plant life. Enhanced germination efficiency associated with increase in radicle and hypocotyl length was observed, while at later stages no increase in plant tolerance to salinity stress was evident. APX, CAT, and GR were enhanced at transcriptional level and in terms of enzyme activity, indicating the activation of antioxidant defence. The profiles of DNA damage accumulation were obtained using SCGE and the implication of TC-NER pathway in DNA damage sensing and repair mechanisms is discussed. OsXPB2, OsXPD, OsTFIIS, and OsTFIIS-like genes showed differential modulation in seedlings and plantlets in response to γ-irradiation and salinity stress. Altogether, the synergistic exposure to γ-rays and NaCl resulted in enhanced oxidative stress and proper activation of antioxidant mechanisms, thus being compatible with plant survival. PMID:24551849

Entity-based Stochastic Analysis of Search Results for Query Expansion and Results Re-Ranking

DTIC Science & Technology

2015-11-20

pages) and struc- tured data (e.g. Linked Open Data ( LOD ) [8]) coexist in var- ious forms. An important observation is that entity names (like names of...the top-L (e.g. L = 1, 000) results are retrieved. Then, Named Entity Recognition (NER) is applied in these results for identifying LOD entities. In...the next (optional) step, more semantic information about the identified entities is retrieved from the LOD (like properties and related entities). A

Military Standard. Marking Technical Data Prepared by or for the Department of Defense

DTIC Science & Technology

1990-02-01

Regulations f. ECCN - Export Commodity Control Number g. ED - Executive Order h. FOIA - Freedom of Information Act i. IEP - International Exchange...critical are explicitly covered in the CCL, ",, the Export Commodity Control Number ( ECCN ) reference is provided. In o~ner cases where the ECCN statement...controlling mechanism is in supplement three of the EAR. 3,7 MIL-STD-1806 APPENDIX B A listing such as " ECCN 1355A" means the technology is specifically

Effects of C1 Inhibitor on Tissue Damage in a Porcine Model of Controlled Hemorrhage

DTIC Science & Technology

2012-07-01

and cytokine release and improves metabolic acidosis in a porcine model of hemorrhagic shock. Male Yorkshire swine were assigned to experimental groups...damage in a dose-dependent man- ner (100 and 250 IU/kg). In addition, rhC1-INH (250 IU/kg) markedly improved hemorrhage-induced metabolic acidosis ... acidosis , reduced circulating tumor necrosis factor !, and attenuated tissue damage in this model. The observed beneficial effects of rhC1-INH treatment on

An Analysis of the Effectiveness of First Article Testing and Approval Requirements

DTIC Science & Technology

1976-12-01

EFFECTIVENESS OF FIRST ARTICLE TESTING AND ^APPROVAL REQUIREMENTS •>’r\\ a /’ j/’? by Harold F./fandy J / " / Robert Äaüner^jwifc II d ’^au...covered by design specifications. c - ASPR Criteria. Finally, there are several additional cir- cumstances cited in ASPR 1-1902 when the Government’s...select the alternate provision contained in ASPR 7-104.55( c ) which authorizes the contractor, upon written approval by the contracting officer, to

Computation of the Hydrodynamic Forces and Moments on a Body of Revolution with and without Appendages

DTIC Science & Technology

1991-08-01

SUPPLEMENTARY NOTATION 1 COSA. CODES 18 SUBJECT TERMS (,ontnuo 0 ner of necessary Atdi, block n" mbr ) FIELD GROUP SUB.GROUP Submarine ’hyoroaynamic ’~ aDS...hydrodynamic forces and moments developed on the hull and appendages of a submerged vehicle is required for determining its stability, control, and...an approximate method has been developed to compute the hydrodynamic forces and moments for a submerged vehicle. As discussed in Reference 1, the

Civilian Health and Medical Program of the Uniformed Services (CHAMPUS)

DTIC Science & Technology

1991-07-01

lenses, or other optical devices. 4-31c a. Exception to general exclusion. 4-31c b. Limitations. 4-32 7. Transsexualism or hermaphroditism. 4-32 8...psychological reasons. 4-48 26. Electrolysis. 4-49 27. Dental care. 4-49 28. Obesity, weight red iction. 4-49 29. Transsexualism or hermaphroditism. 4-4’ 30...subject to specific medical review. 7. Transsexualism or such other conditions as eýner dyssphoria. All services and supplies directly or indirectly

Algorithmic and user study of an autocompletion algorithm on a large medical vocabulary.

PubMed

Sevenster, Merlijn; van Ommering, Rob; Qian, Yuechen

2012-02-01

Autocompletion supports human-computer interaction in software applications that let users enter textual data. We will be inspired by the use case in which medical professionals enter ontology concepts, catering the ongoing demand for structured and standardized data in medicine. Goal is to give an algorithmic analysis of one particular autocompletion algorithm, called multi-prefix matching algorithm, which suggests terms whose words' prefixes contain all words in the string typed by the user, e.g., in this sense, opt ner me matches optic nerve meningioma. Second we aim to investigate how well it supports users entering concepts from a large and comprehensive medical vocabulary (snomed ct). We give a concise description of the multi-prefix algorithm, and sketch how it can be optimized to meet required response time. Performance will be compared to a baseline algorithm, which gives suggestions that extend the string typed by the user to the right, e.g. optic nerve m gives optic nerve meningioma, but opt ner me does not. We conduct a user experiment in which 12 participants are invited to complete 40 snomed ct terms with the baseline algorithm and another set of 40 snomed ct terms with the multi-prefix algorithm. Our results show that users need significantly fewer keystrokes when supported by the multi-prefix algorithm than when supported by the baseline algorithm. The proposed algorithm is a competitive candidate for searching and retrieving terms from a large medical ontology. Copyright © 2011 Elsevier Inc. All rights reserved.

Differential DNA lesion formation and repair in heterochromatin and euchromatin

PubMed Central

Han, Chunhua; Srivastava, Amit Kumar; Cui, Tiantian; Wang, Qi-En; Wani, Altaf A.

2016-01-01

Discretely orchestrated chromatin condensation is important for chromosome protection from DNA damage. However, it is still unclear how different chromatin states affect the formation and repair of nucleotide excision repair (NER) substrates, e.g. ultraviolet (UV)-induced cyclobutane pyrimidine dimers (CPD) and the pyrimidine (6-4) pyrimidone photoproducts (6-4PP), as well as cisplatin-induced intrastrand crosslinks (Pt-GG). Here, by using immunofluorescence and chromatin immunoprecipitation assays, we have demonstrated that CPD, which cause minor distortion of DNA double helix, can be detected in both euchromatic and heterochromatic regions, while 6-4PP and Pt-GG, which cause major distortion of DNA helix, can exclusively be detected in euchromatin, indicating that the condensed chromatin environment specifically interferes with the formation of these DNA lesions. Mechanistic investigation revealed that the class III histone deacetylase SIRT1 is responsible for restricting the formation of 6-4PP and Pt-GG in cells, probably by facilitating the maintenance of highly condensed heterochromatin. In addition, we also showed that the repair of CPD in heterochromatin is slower than that in euchromatin, and DNA damage binding protein 2 (DDB2) can promote the removal of CPD from heterochromatic region. In summary, our data provide evidence for differential formation and repair of DNA lesions that are substrates of NER. Both the sensitivity of DNA to damage and the kinetics of repair can be affected by the underlying level of chromatin compaction. PMID:26717995

Energy assessment of second generation (2G) ethanol production from wheat straw in Indian scenario.

PubMed

Mishra, Archana; Kumar, Akash; Ghosh, Sanjoy

2018-03-01

Impact of second-generation ethanol (2G) use in transportation sector mainly depends upon energy efficiency of entire production process. The objective of present study was to determine energy efficiency of a potential lignocellulosic feedstock; wheat straw and its conversion into cellulosic ethanol in Indian scenario. Energy efficiency was determined by calculating Net energy ratio (NER), i.e. ratio of output energy obtained by ethanol and input energy used in ethanol production. Energy consumption and generation at each step is calculated briefly (11,837.35 MJ/ha during Indian dwarf irrigated variety of wheat crop production and 7.1148 MJ/kg straw during ethanol production stage). Total energy consumption is calculated as 8.2988 MJ/kg straw whereas energy generation from ethanol is 15.082 MJ/kg straw; resulting into NER > 1. Major portion of agricultural energy input is contributed by diesel and fertilisers whereas refining process of wheat straw feedstock to ethanol and by-products require mainly in the form of steam and electricity. On an average, 1671.8 kg water free ethanol, 930 kg lignin rich biomass (for combustion), and 561 kg C5-molasses (for fodder) per hectare are produced. Findings of this study, net energy ratio (1.81) and figure of merit (14.8028 MJ/nil kg carbon) proves wheat straw as highest energy efficient lignocellulosic feedstock for the country.

Apigenin prevents ultraviolet-B radiation induced cyclobutane pyrimidine dimers formation in human dermal fibroblasts.

PubMed

Britto, S Mary; Shanthakumari, D; Agilan, B; Radhiga, T; Kanimozhi, G; Prasad, N Rajendra

2017-09-01

Exposure to solar ultraviolet-B (UVB) radiation leads to the formation of cyclobutane pyrimidine dimers (CPDs). We investigated the protective effect of apigenin against UVB-induced CPDs formation in human dermal fibroblasts cells (HDFa). For this purpose, HDFa cells were treated with apigenin (15μM) prior to UVB irradiation (20mJ/cm 2 ); DNA damage and subsequent molecular end points were observed. Exposure to UVB radiation increased significant CPDs formation in HDFa cells and the frequencies of CPDs were reduced by treatment with apigenin (15μM). UVB-induced CPDs downregulates the expression of nucleotide excision repair (NER) genes such as xeroderma pigmentosum complementation group C, B, G and F (XPC, XPB, XPG and XPF), transcription factor II human (TFIIH) and excision repair cross-complementation group 1 (ERCC1) in HDFa cells. Conversely, apigenin treatment restored UVB-induced loss of NER proteins in HDFa cells, which indicates its preventive effect against CPDs formation. Besides, single low dose UVB-exposure induced nuclear fragmentation, apoptotic frequency and apoptotic proteins expression (Bax and Caspase-3) have been prevented by the apigenin pretreatment. Furthermore, apigenin exhibits strong UV absorbance property and showed 10.08 SPF value. Thus, apigenin can protect skin cells against UVB-induced CPDs formation probably through its sunscreen effect. Hence, apigenin can be considered as an effective protective agent against UV induced skin damages. Copyright © 2017 Elsevier B.V. All rights reserved.

Binding of calcium and target peptide to calmodulin-like protein CML19, the centrin 2 of Arabidopsis thaliana.

PubMed

La Verde, Valentina; Trande, Matteo; D'Onofrio, Mariapina; Dominici, Paola; Astegno, Alessandra

2018-03-01

Calmodulin-like protein 19 (CML19) is an Arabidopsis centrin that modulates nucleotide excision repair (NER) by binding to RAD4 protein, the Arabidopsis homolog of human Xeroderma pigmentosum complementation group C protein. Although the necessity of CML19 as a part of the RAD4 plant recognition complex for functional NER is known at a cellular level, little is known at a molecular level. Herein, we used a combination of biophysical and biochemical approaches to investigate the structural and ion and target-peptide binding properties of CML19. We found that CML19 possesses four Ca 2+ -specific binding sites, two of high affinity in the N-terminal domain and two of low affinity in the C-terminal domain. Binding of Ca 2+ to CML19 increases its alpha-helix content, stabilizes the tertiary structure, and triggers a conformational change, resulting in the exposure of a hydrophobic patch instrumental for target protein recognition. Using bioinformatics tools we identified a CML19-binding site at the C-terminus of RAD4, and through in vitro binding experiments we analyzed the interaction between a 17-mer peptide representing this site and CML19. We found that the peptide shows a high affinity for CML19 in the presence of Ca 2+ (stoichiometry 1:1) and the interaction primarily involves the C-terminal half of CML19. Copyright © 2017 Elsevier B.V. All rights reserved.

Genomic Knockout of Endogenous Canine P-Glycoprotein in Wild-Type, Human P-Glycoprotein and Human BCRP Transfected MDCKII Cell Lines by Zinc Finger Nucleases.

PubMed

Gartzke, Dominik; Delzer, Jürgen; Laplanche, Loic; Uchida, Yasuo; Hoshi, Yutaro; Tachikawa, Masanori; Terasaki, Tetsuya; Sydor, Jens; Fricker, Gert

2015-06-01

To investigate whether it is possible to specifically suppress the expression and function of endogenous canine P-glycoprotein (cPgp) in Madin-Darby canine kidney type II cells (MDCKII) transfected with hPGP and breast cancer resistance protein (hBCRP) by zinc finger nuclease (ZFN) producing sequence specific DNA double strand breaks. Wild-type, hPGP-transfected, and hBCRP-transfected MDCKII cells were transfected with ZFN targeting for cPgp. Net efflux ratios (NER) of Pgp and Bcrp substrates were determined by dividing efflux ratios (basal-to-apical / apical-to-basal) in over-expressing cell monolayers by those in wild-type ones. From ZFN-transfected cells, cell populations (ko-cells) showing knockout of cPgp were selected based on genotyping by PCR. qRT-PCR analysis showed the significant knock-downs of cPgp and interestingly also cMrp2 expressions. Specific knock-downs of protein expression for cPgp were shown by western blotting and quantitative targeted absolute proteomics. Endogenous canine Bcrp proteins were not detected. For PGP-transfected cells, NERs of 5 Pgp substrates in ko-cells were significantly greater than those in parental cells not transfected with ZFN. Similar result was obtained for BCRP-transfected cells with a dual Pgp and Bcrp substrate. Specific efflux mediated by hPGP or hBCRP can be determined with MDCKII cells where cPgp has been knocked out by ZFN.

Bacterial consortia at different wine fermentation phases of two typical Central European grape varieties: Blaufränkisch (Frankovka modrá) and Grüner Veltliner (Veltlínske zelené).

PubMed

Godálová, Zuzana; Kraková, Lucia; Puškárová, Andrea; Bučková, Mária; Kuchta, Tomáš; Piknová, Ľubica; Pangallo, Domenico

2016-01-18

This is the first study focused to bacterial diversity and dynamic during the vinification of two important Central Europe grape vines: Blaufränkisch and Grüner Veltliner. The investigation strategy included culture-dependent and culture-independent approaches. Four different agar media were utilized for the isolation of various bacteria occurring in several fermentation stages. The isolates were clustered by fluorescent-ITS PCR and, one or more representatives of each cluster, were identified by 16 rRNA gene sequencing. The culture-independent approach, based on 16S rRNA gene amplification, combined the denaturing gradient gel electrophoresis (DGGE) method and the construction of bacterial clone library for each wine fermentation step. A complex bacterial community was identified, comprising different lactic acid bacteria and acetic acid bacteria, such as Leuconostoc spp., Lactobacillus spp. and Gluconobacter spp. Other OTUs and bacterial isolates embraced the Actinobacteria, Bacilli, Alpha-, Beta- and Gamma-proteobacteria classes. Different taxa already detected by recent studies, such as Sphingomonas, Variovorax, Pantoea, Enterobacter and Tatumella, were detected confirming the continuous occurrence of these kinds of bacteria in wine environment. Moreover, novel genera (Amycolatopsis, Hydrogenophilus, Snodgrassella, Telluria, Gilliamella, Lelliottia, and Lonsdale quercina) never detected before were recognized, too. The role of these, until now anonymous, bacteria during vinification deserves investigation, which could open a new research field in wine technology. Copyright © 2015 Elsevier B.V. All rights reserved.

Text mining of cancer-related information: review of current status and future directions.

PubMed

Spasić, Irena; Livsey, Jacqueline; Keane, John A; Nenadić, Goran

2014-09-01

This paper reviews the research literature on text mining (TM) with the aim to find out (1) which cancer domains have been the subject of TM efforts, (2) which knowledge resources can support TM of cancer-related information and (3) to what extent systems that rely on knowledge and computational methods can convert text data into useful clinical information. These questions were used to determine the current state of the art in this particular strand of TM and suggest future directions in TM development to support cancer research. A review of the research on TM of cancer-related information was carried out. A literature search was conducted on the Medline database as well as IEEE Xplore and ACM digital libraries to address the interdisciplinary nature of such research. The search results were supplemented with the literature identified through Google Scholar. A range of studies have proven the feasibility of TM for extracting structured information from clinical narratives such as those found in pathology or radiology reports. In this article, we provide a critical overview of the current state of the art for TM related to cancer. The review highlighted a strong bias towards symbolic methods, e.g. named entity recognition (NER) based on dictionary lookup and information extraction (IE) relying on pattern matching. The F-measure of NER ranges between 80% and 90%, while that of IE for simple tasks is in the high 90s. To further improve the performance, TM approaches need to deal effectively with idiosyncrasies of the clinical sublanguage such as non-standard abbreviations as well as a high degree of spelling and grammatical errors. This requires a shift from rule-based methods to machine learning following the success of similar trends in biological applications of TM. Machine learning approaches require large training datasets, but clinical narratives are not readily available for TM research due to privacy and confidentiality concerns. This issue remains the main bottleneck for progress in this area. In addition, there is a need for a comprehensive cancer ontology that would enable semantic representation of textual information found in narrative reports. Copyright © 2014 The Authors. Published by Elsevier Ireland Ltd.. All rights reserved.

Repair of 8-oxo-7,8-dihydroguanine in prokaryotic and eukaryotic cells: Properties and biological roles of the Fpg and OGG1 DNA N-glycosylases.

PubMed

Boiteux, Serge; Coste, Franck; Castaing, Bertrand

2017-06-01

Oxidatively damaged DNA results from the attack of sugar and base moieties by reactive oxygen species (ROS), which are formed as byproducts of normal cell metabolism and during exposure to endogenous or exogenous chemical or physical agents. Guanine, having the lowest redox potential, is the DNA base the most susceptible to oxidation, yielding products such as 8-oxo-7,8-dihydroguanine (8-oxoG) and 2-6-diamino-4-hydroxy-5-formamidopyrimidine (FapyG). In DNA, 8-oxoG was shown to be mutagenic yielding GC to TA transversions upon incorporation of dAMP opposite this lesion by replicative DNA polymerases. In prokaryotic and eukaryotic cells, 8-oxoG is primarily repaired by the base excision repair pathway (BER) initiated by a DNA N-glycosylase, Fpg and OGG1, respectively. In Escherichia coli, Fpg cooperates with MutY and MutT to prevent 8-oxoG-induced mutations, the "GO-repair system". In Saccharomyces cerevisiae, OGG1 cooperates with nucleotide excision repair (NER), mismatch repair (MMR), post-replication repair (PRR) and DNA polymerase η to prevent mutagenesis. Human and mouse cells mobilize all these pathways using OGG1, MUTYH (MutY-homolog also known as MYH), MTH1 (MutT-homolog also known as NUDT1), NER, MMR, NEILs and DNA polymerases η and λ, to prevent 8-oxoG-induced mutations. In fact, mice deficient in both OGG1 and MUTYH develop cancer in different organs at adult age, which points to the critical impact of 8-oxoG repair on genetic stability in mammals. In this review, we will focus on Fpg and OGG1 proteins, their biochemical and structural properties as well as their biological roles. Other DNA N-glycosylases able to release 8-oxoG from damaged DNA in various organisms will be discussed. Finally, we will report on the role of OGG1 in human disease and the possible use of 8-oxoG DNA N-glycosylases as therapeutic targets. Copyright © 2017 Elsevier Inc. All rights reserved.

HR Public meeting

ScienceCinema

None

2018-05-24

Cher(e)s collègues, En collaboration avec le Département HR, le Directeur général a le plaisir de vous convier à une réunion publique qui se tiendra le vendredi 25 juin 2010 à 9h30 dans l’Amphithéâtre principal (Bâtiment 500)*. Un café d’accueil y sera servi à partir de 9h. Cette réunion abordera les thèmes suivants : Valeurs de l’Organisation (Directeur général); Code de Conduite (Directeur général / Anne-Sylvie Catherin); Création du nouveau rôle d’Ombudsperson (Vincent Vuillemin) Ces présentations seront suivies d’une séance de questions-réponses. Nous espérons vous retrouver nombreux le 25 juin ! Meilleures salutations, Anne-Sylvie Catherin Chef du Département des Ressources humaines *Cette réunion sera retransmise simultanément dans l’Amphithéâtre BE de Prévessin (Bâtiment 864) et également disponible à l’adresse suivante : http://webcast.cern.ch [Dear colleagues, In collaboration with HR Department, the Director-General would like to invite you to an information meeting which will be held on Friday 25 June 2010 at 9:30 am in the Main Auditorium (Building 500)*. A welcome coffee will be available from 9:00 am. During this meeting, information will be given about: Organization’s values (Director-General); Code of Conduct (Director-General / Anne-Sylvie Catherin); New Ombudsperson role (Vincent Vuillemin); These presentations will be followed by a questions & answers session. We look forward to seeing you all on 25 June! Best regards, Anne-Sylvie Catherin Head, Human Resources Department *This meeting will be simultaneously retransmitted in BE Auditorium (Building 864) and available at the following address: http://webcast.cern.ch.

The Archaeology of Coralville Lake, Iowa. Volume 3. Sample Survey (Interim Report 1).

DTIC Science & Technology

1985-03-01

n t ho I aite 19 60 ’ s , Air ian Anderson di rectedl a se-r ies coI Li in a ner e I cd s c1. ooIs v It 1h s tude ntLs f r om the tini v-er’si ty of r...wash cap the surface (Figure 13). 7 0- ii NORTH PROFILE 13 JH 479- UNIT 2 SIL WY 3/ c(HISTOWiCAL ALLUVIUM) stl ~SILT WVITH MINk CLAY JOYN 3/3 SCALE I

Properties and Residual Stresses in Angle-Ply Polymer Matrix Composites

DTIC Science & Technology

1982-03-01

AMMRC TR 82-12 PROPERTIES AND RES l DUAL STRESSES IN ANGLE-PLY POLYMER MATR l X COMPOSITES March 1982 ABDEL A. FAHMY,, HARVEY A. WEST, and MARK...m D.e. Enl.r.d) PROPERTIES AND RESIDUAL STRESSES I N ANGLE-PLY F i n a l Report POLYMER MATRIX COMPOSITES REPORTDOCUMENTATlON PAGE I 7. AUTHOR...SUPPLEMENTARV NOTES L 19. KEY WORDS (Comclrm. m r.r.r. wd. 11 ner..sw and idenllfy by blocb nmb-r) Composites Thermal expansion Epoxy l a m i n a t e s

The Coast Artillery Journal. Volume 85, Number 4, July-August 1942

DTIC Science & Technology

1942-08-01

Panay and T olur rivers and in the mountains. The sap of this tree is so poisonous that its entry into the body of man or animal is fatal. The dalit is a...aroused: that is the famous king cobra of India and Luzon." Passing of the GIP’s The War Department is gradually replacing the Gun- ners’ Instruction...Scie~tists of the United Nations, especially in this country, Britain and India , have found new secrets of the behavior of steel and other metallic

Interactions of Human Nucleotide Excision Repair Protein XPA with DNA and RPA70 Delta c327: Chemical Shift Mapping and N-15 NMR Relaxation Studies

DOE Office of Scientific and Technical Information (OSTI.GOV)

Buchko, Garry W.; Daughdrill, Gary W.; De Lorimier, Robert

1999-12-28

Human XPA is an essential component in the multienzyme nucleotide excision repair (NER) pathway. The solution structure of the minimal DNA binding domain of XPA (XPA-MBD: M98-F219) was recently determined [Buchko et al. (1998) Nucleic Acids Res. 26, 2779-2788, Ikegami et al (1998) Nat. Struct. Biol. 5, 701-706] and shown to consist of a compact zinc-binding core and a loop-rich C-terminal subdomain connected by a linker sequence.

Cockayne syndrome: Clinical features, model systems and pathways

PubMed Central

Karikkineth, Ajoy C.; Scheibye-Knudsen, Morten; Fivenson, Elayne; Croteau, Deborah L.; Bohr, Vilhelm A.

2016-01-01

Cockayne syndrome (CS) is a disorder characterized by a variety of clinical features including cachectic dwarfism, severe neurological manifestations including microcephaly and cognitive deficits, pigmentary retinopathy, cataracts, sensorineural deafness, and ambulatory and feeding difficulties, leading to death by 12 years of age on average. It is an autosomal recessive disorder, with a prevalence of approximately 2.5 per million. There are several phenotypes (1, 2 and 3) and complementation groups (CSA and CSB), and overlaps with xeroderma pigmentosum (XP). It has been considered a progeria, and many of the clinical features resemble accelerated aging. As such, the study of CS affords an opportunity to better understand the underlying mechanisms of aging. The molecular basis of CS has traditionally been considered to be due to defects in transcription and transcription-coupled nucleotide excision repair (TC-NER). However, recent work suggests that defects in base excision DNA repair and mitochondrial functions may also play key roles. This opens up the possibility of molecular interventions in CS, and by extrapolation, possibly in aging. PMID:27507608

ERCC1-XPF Endonuclease Facilitates DNA Double-Strand Break Repair▿ †

PubMed Central

Ahmad, Anwaar; Robinson, Andria Rasile; Duensing, Anette; van Drunen, Ellen; Beverloo, H. Berna; Weisberg, David B.; Hasty, Paul; Hoeijmakers, Jan H. J.; Niedernhofer, Laura J.

2008-01-01

ERCC1-XPF endonuclease is required for nucleotide excision repair (NER) of helix-distorting DNA lesions. However, mutations in ERCC1 or XPF in humans or mice cause a more severe phenotype than absence of NER, prompting a search for novel repair activities of the nuclease. In Saccharomyces cerevisiae, orthologs of ERCC1-XPF (Rad10-Rad1) participate in the repair of double-strand breaks (DSBs). Rad10-Rad1 contributes to two error-prone DSB repair pathways: microhomology-mediated end joining (a Ku86-independent mechanism) and single-strand annealing. To determine if ERCC1-XPF participates in DSB repair in mammals, mutant cells and mice were screened for sensitivity to gamma irradiation. ERCC1-XPF-deficient fibroblasts were hypersensitive to gamma irradiation, and γH2AX foci, a marker of DSBs, persisted in irradiated mutant cells, consistent with a defect in DSB repair. Mutant mice were also hypersensitive to irradiation, establishing an essential role for ERCC1-XPF in protecting against DSBs in vivo. Mice defective in both ERCC1-XPF and Ku86 were not viable. However, Ercc1−/− Ku86−/− fibroblasts were hypersensitive to gamma irradiation compared to single mutants and accumulated significantly greater chromosomal aberrations. Finally, in vitro repair of DSBs with 3′ overhangs led to large deletions in the absence of ERCC1-XPF. These data support the conclusion that, as in yeast, ERCC1-XPF facilitates DSB repair via an end-joining mechanism that is Ku86 independent. PMID:18541667

Structural Basis for Eukaryotic Transcription-Coupled DNA Repair Initiation

PubMed Central

Xu, Jun; Lahiri, Indrajit; Wang, Wei; Wier, Adam; Cianfrocco, Michael A.; Chong, Jenny; Hare, Alissa A.; Dervan, Peter B.; DiMaio, Frank; Leschziner, Andres E.; Wang, Dong

2017-01-01

Eukaryotic transcription-coupled repair (TCR), or transcription-coupled nucleotide excision repair (TC-NER), is an important and well-conserved sub-pathway of nucleotide excision repair (NER) that preferentially removes DNA lesions from the template strand blocking RNA polymerase II (Pol II) translocation1,2. Cockayne syndrome group B protein in humans (CSB, or ERCC6), or its yeast orthologs (Rad26 in Saccharomyces cerevisiae and Rhp26 in Schizosaccharomyces pombe), is among the first proteins to be recruited to the lesion-arrested Pol II during initiation of eukaryotic TCR1,3–10. Mutations in CSB are associated with Cockayne syndrome, an autosomal-recessive neurologic disorder characterized by progeriod features, growth failure, and photosensitivity1. The molecular mechanism of eukaryotic TCR initiation remains elusive, with several long-standing questions unanswered: How do cells distinguish DNA lesion-arrested Pol II from other forms of arrested Pol II? How does CSB interact with the arrested Pol II complex? What is the role of CSB in TCR initiation? The lack of structures of CSB or the Pol II-CSB complex have hindered our ability to answer those questions. Here we report the first structure of S. cerevisiae Pol II-Rad26 complex solved by cryo-electron microscopy (cryo-EM). The structure reveals that Rad26 binds to the DNA upstream of Pol II where it dramatically alters its path. Our structural and functional data suggest that the conserved Swi2/Snf2-family core ATPase domain promotes forward movement of Pol II and elucidate key roles for Rad26/CSB in both TCR and transcription elongation. PMID:29168508

Unsupervised Extraction of Diagnosis Codes from EMRs Using Knowledge-Based and Extractive Text Summarization Techniques

PubMed Central

Kavuluru, Ramakanth; Han, Sifei; Harris, Daniel

2017-01-01

Diagnosis codes are extracted from medical records for billing and reimbursement and for secondary uses such as quality control and cohort identification. In the US, these codes come from the standard terminology ICD-9-CM derived from the international classification of diseases (ICD). ICD-9 codes are generally extracted by trained human coders by reading all artifacts available in a patient’s medical record following specific coding guidelines. To assist coders in this manual process, this paper proposes an unsupervised ensemble approach to automatically extract ICD-9 diagnosis codes from textual narratives included in electronic medical records (EMRs). Earlier attempts on automatic extraction focused on individual documents such as radiology reports and discharge summaries. Here we use a more realistic dataset and extract ICD-9 codes from EMRs of 1000 inpatient visits at the University of Kentucky Medical Center. Using named entity recognition (NER), graph-based concept-mapping of medical concepts, and extractive text summarization techniques, we achieve an example based average recall of 0.42 with average precision 0.47; compared with a baseline of using only NER, we notice a 12% improvement in recall with the graph-based approach and a 7% improvement in precision using the extractive text summarization approach. Although diagnosis codes are complex concepts often expressed in text with significant long range non-local dependencies, our present work shows the potential of unsupervised methods in extracting a portion of codes. As such, our findings are especially relevant for code extraction tasks where obtaining large amounts of training data is difficult. PMID:28748227

Relationship between polymorphisms of nucleotide excision repair genes and oral cancer risk in Taiwan: evidence for modification of smoking habit.

PubMed

Bau, Da-Tian; Tsai, Ming-Hsui; Huang, Chih-Yang; Lee, Cheng-Chun; Tseng, Hsien-Chang; Lo, Yen-Li; Tsai, Yuhsin; Tsai, Fuu-Jen

2007-12-31

Inherited polymorphisms in DNA repair genes may be associated with differences in the repair capacity and contribute to individual's susceptibility to smoking-related cancers. Both XPA and XPD encode proteins that are part of the nucleotide excision repair (NER) pathway. In a hospital-based case-control study, we have investigated the influence of XPA A-23G and XPD Lys751Gln polymorphisms on oral cancer risk in a Taiwanese population. In total, 154 patients with oral cancer, and 105 age-matched controls recruited from the Chinese Medical Hospital in Central Taiwan were genotyped. No significant association was found between the heterozygous variant allele (AG), the homozygous variant allele (AA) at XPA A-23G, the heterozygous variant allele (AC), the homozygous variant allele (CC) at XPD Lys751Gln, and oral cancer risk. There was no significant joint effect of XPA A-23G and XPD Lys751Gln on oral cancer risk either. Since XPA and XPD are both NER genes, which are very important in removing tobacco-induced DNA adducts, further stratified analyses of both genotype and smoking habit were performed. We found a synergistic effect of variant genotypes of both XPA and XPD, and smoking status on oral cancer risk. Our results suggest that the genetic polymorphisms are modified by environmental carcinogen exposure status, and combined analyses of both genotype and personal habit record are a better access to know the development of oral cancer and useful for primary prevention and early intervention.

Pyrochars and hydrochars differently alter the sorption of the herbicide isoproturon in an agricultural soil.

PubMed

Eibisch, Nina; Schroll, Reiner; Fuß, Roland; Mikutta, Robert; Helfrich, Mirjam; Flessa, Heinz

2015-01-01

Carbonaceous material from pyrolysis (pyrochars) and hydrothermal carbonization (hydrochars) are applied to soil to improve soil fertility and carbon sequestration. As a positive side effect, the mobility of pesticides and the risk of groundwater contamination can be minimized. However, the impact of various raw materials on the sorption capacity of different pyrochars and hydrochars is poorly understood. Thus, sorption experiments were performed with (14)C-labeled isoproturon (IPU, 0.75 kg ha(-1)) in a loamy sand soil amended with either pyrochar or hydrochar (0.5% and 5% dry weight, respectively). Carbonaceous materials were produced from three different raw materials: corn digestate, miscanthus, woodchips of willow and poplar. After 72 h of incubation, a sequential extraction procedure was conducted to quantify in situ IPU bioavailability, total amount of extractable IPU, and non-extractable pesticide residues (NER). Added char amount, carbonization type, and raw materials had statistically significant effects on the sorption of IPU. The amount of in situ available IPU was reduced by a factor of 10-2283 in treatments with pyrochar and by a factor of 3-13 in hydrochar treatments. The surface area of the charred material was the most predictive variable of IPU sorption to char amended soil. Some physical and chemical char properties tend to correlate with pore water-, methanol- or non-extractable IPU amounts. Due to a low micro-porosity and ash content, high water extractable carbon contents and O-functional groups of hydrochars, the proportion of NER in hydrochar amended soils was considerably lower than in soil amended with pyrochars. Copyright © 2014 Elsevier Ltd. All rights reserved.

XPC genotypes/diplotypes play no independent or interaction role with PAH-DNA adducts for breast cancer risk

PubMed Central

Shen, Jing; Gammon, Marilie D.; Terry, Mary Beth; Teitelbaum, Susan L.; Eng, Sybil M.; Neugut, Alfred I.; Santella, Regina M.

2008-01-01

Xeroderma pigmentosum complementation group C (XPC) is an important DNA nuclear excision repair (NER) gene that recognizes the damage caused by variety of bulky DNA adducts. We evaluated the association of two common non-synonymous polymorphisms in XPC (Ala499Val and Lys939Gln) with breast cancer risk in the Long Island Breast Cancer Study Project (LIBCSP), a population-based case-control study. Genotyping of 1,067 cases and 1,110 controls was performed by a high throughput assay with fluorescence polarization. There were no overall associations between XPC polymorphisms and breast cancer risk. A diplotype CC-CC was significantly associated with increased breast cancer risk compared with diplotype CA-CA (OR = 1.4, 95%CI: 1.0–1.9), but was not significant when compared with all other diplotypes combined (OR = 1.22, 95%CI: 0.97–1.53). No modification effects were observed for XPC genotypes by cigarette smoking status, smoking pack years or polycyclic aromatic hydrocarbons (PAH) DNA adducts. The increase in breast cancer risk was slightly more pronounced among women with detectable PAH-DNA adducts and carrying the diplotype CC-CC (OR = 1.6, 95%CI: 1.1–2.2) compared to women with non detectable PAH-DNA adducts carrying other diplotypes combined, but no statistically significant interaction was observed (P interaction = 0.69). These data suggest that XPC have neither independent effects nor interactions with cigarette smoking and PAH-DNA adducts for breast cancer risk. Further studies with multiple genetic polymorphisms in NER pathway are warranted. PMID:18053706

Pulsed Magnetic Field Driven Gas Core Reactors for Space Power & Propulsion Applications

NASA Technical Reports Server (NTRS)

Anghaie, Samim; Smith, Blair; Knight, Travis; Butler, Carey

2003-01-01

The present results indicated that: 1. A pulsed magnetic driven fission power concept, PMD-GCR is developed for closed (NER) and semi-open (NTR) operations. 2. In power mode, power is generated at alpha less than 1 for power levels of hundreds of KW or higher 3. IN semi open NTR mode, PMD-GCR generates thrust at I(sub sp) approx. 5,000 s and jet power approx. 5KW/Kg. 4. PMD-GCR is highly subcritical and is actively driven to critically. 5. Parallel path with fusion R&D needs in many areas including magnet and plasma.

Use of the World Model for Policy Analysis: Education and Labor Policy in the Mideast

DTIC Science & Technology

1977-03-01

most thorough analysis of the economic benefits of education which we have seen to date. They have indicated that the primary approaches in attempting...revealed by more detailed analysis of the economic and demographic data. Note that in Figure 15 economic growth in Iraq-Libya with restrictions on the...V. U S E O F TtRE WORLD -MODEL F R POLICY ANALYSIS : E•DUCATION AND LABOR POLICY IN T H E MI D EA S T Q 2 L ! • Qu ~ ~~-" "c’, • "" ". ’.-?c..’* ner

Role of Infection Due to Campylobacter jejuni in the Initiation of Guillain-Barre Syndrome

DTIC Science & Technology

1993-01-01

21 Mild 6th-ner.e palks at 3 mo England. 1984 127]: 16/M 10 Complete recoer, at 6 mo England. 1985 1411: 27/M 7 Complete recoery r with minor delicits...14 Canes required for walking at 6 mo 83/F 7 Bedridden at 3 y Japan. 1991 1321 7/M ? Complete recovery with minor deficits 9/M 6 Complete recovery...study. Acta Neuriil Scand 1986.73:394-4o2. China 1301l 32 41 LtISA 14. T rahelsi M. Mokrani R . Beninaceur B. Pok radiculon~vrites aigu6s de United

[Gene expression analyses of kidney biopsies: the European renal cDNA bank--Kröner-Fresenius biopsy bank].

PubMed

Cohen, C D; Kretzler, M

2009-03-01

Histological analysis of kidney biopsies is an essential part of our current diagnostic workup of patients with renal disease. Besides the already established diagnostic tools, new methods allow extensive analysis of the sample tissue's gene expression. Using results from a European multicenter study on gene expression analysis of renal biopsies, in this review we demonstrate that this novel approach not only expands the scope of so-called basic research but also might supplement future biopsy diagnostics. The goals are improved diagnosis and more specific therapy choice and prognosis estimates.

Text mining in livestock animal science: introducing the potential of text mining to animal sciences.

PubMed

Sahadevan, S; Hofmann-Apitius, M; Schellander, K; Tesfaye, D; Fluck, J; Friedrich, C M

2012-10-01

In biological research, establishing the prior art by searching and collecting information already present in the domain has equal importance as the experiments done. To obtain a complete overview about the relevant knowledge, researchers mainly rely on 2 major information sources: i) various biological databases and ii) scientific publications in the field. The major difference between the 2 information sources is that information from databases is available, typically well structured and condensed. The information content in scientific literature is vastly unstructured; that is, dispersed among the many different sections of scientific text. The traditional method of information extraction from scientific literature occurs by generating a list of relevant publications in the field of interest and manually scanning these texts for relevant information, which is very time consuming. It is more than likely that in using this "classical" approach the researcher misses some relevant information mentioned in the literature or has to go through biological databases to extract further information. Text mining and named entity recognition methods have already been used in human genomics and related fields as a solution to this problem. These methods can process and extract information from large volumes of scientific text. Text mining is defined as the automatic extraction of previously unknown and potentially useful information from text. Named entity recognition (NER) is defined as the method of identifying named entities (names of real world objects; for example, gene/protein names, drugs, enzymes) in text. In animal sciences, text mining and related methods have been briefly used in murine genomics and associated fields, leaving behind other fields of animal sciences, such as livestock genomics. The aim of this work was to develop an information retrieval platform in the livestock domain focusing on livestock publications and the recognition of relevant data from cattle and pigs. For this purpose, the rather noncomprehensive resources of pig and cattle gene and protein terminologies were enriched with orthologue synonyms, integrated in the NER platform, ProMiner, which is successfully used in human genomics domain. Based on the performance tests done, the present system achieved a fair performance with precision 0.64, recall 0.74, and F(1) measure of 0.69 in a test scenario based on cattle literature.

A Novel DDB2-ATM Feedback Loop Regulates Human Cytomegalovirus Replication

PubMed Central

E, Xiaofei; Savidis, George; Chin, Christopher R.; Wang, Shixia; Lu, Shan; Brass, Abraham L.

2014-01-01

Human cytomegalovirus (HCMV) genome replication requires host DNA damage responses (DDRs) and raises the possibility that DNA repair pathways may influence viral replication. We report here that a nucleotide excision repair (NER)-associated-factor is required for efficient HCMV DNA replication. Mutations in genes encoding NER factors are associated with xeroderma pigmentosum (XP). One of the XP complementation groups, XPE, involves mutation in ddb2, which encodes DNA damage binding protein 2 (DDB2). Infectious progeny virus production was reduced by >2 logs in XPE fibroblasts compared to levels in normal fibroblasts. The levels of immediate early (IE) (IE2), early (E) (pp65), and early/late (E/L) (gB55) proteins were decreased in XPE cells. These replication defects were rescued by infection with a retrovirus expressing DDB2 cDNA. Similar patterns of reduced viral gene expression and progeny virus production were also observed in normal fibroblasts that were depleted for DDB2 by RNA interference (RNAi). Mature replication compartments (RCs) were nearly absent in XPE cells, and there were 1.5- to 2.0-log reductions in viral DNA loads in infected XPE cells relative to those in normal fibroblasts. The expression of viral genes (UL122, UL44, UL54, UL55, and UL84) affected by DDB2 status was also sensitive to a viral DNA replication inhibitor, phosphonoacetic acid (PAA), suggesting that DDB2 affects gene expression upstream of or events associated with the initiation of DNA replication. Finally, a novel, infection-associated feedback loop between DDB2 and ataxia telangiectasia mutated (ATM) was observed in infected cells. Together, these results demonstrate that DDB2 and a DDB2-ATM feedback loop influence HCMV replication. PMID:24335308

AML outcome: role of nucleotide excision repair polymorphisms in intermediate risk patients

PubMed Central

Strom, Sara S; Estey, Elihu H; Outschoorn, Ubaldo Martinez; Guillermo, Garcia-Manero

2010-01-01

Purpose Acute Myeloid Leukemia (AML) is frequently associated with genetic abnormalities. Based on pre-treatment cytogenetics, patients are classified into favorable, intermediate and poor subgroups. Cytogenetics predicts treatment outcome for the favorable and poor subgroups but not for the intermediate subgroup. Polymorphisms within the nucleotide excision repair (NER) pathway may lead to inter-individual differences in DNA repair capacity (DRC) which could influence outcome. Methods We studied the role of 6 polymorphisms (ERCC1 Gln504Lys, XPD Lys751Gln, XPC Ala499Val, XPC Lys939Gln, XPG Asp1104His, and CCNH Val270Ala) within NER pathway on overall and disease-free survival among 170 adult de-novo AML patients with intermediate cytogenetics [diploid (n=117); non-diploid (n=53)], treated with induction chemotherapy. Kaplan-Meier methods and Cox proportional hazards models were performed. Results Diploid patients with the XPD AC/CC genotype survived shorter than those with the wild-type (AA) genotype (median survival 22 vs. 40 months, log-rank p = 0.03). Similarly diploid patients with XPC CT/TT genotype survived shorter than those with the wild-type (CC) genotype (median survival 15 vs. 30 months, log-rank p = 0.02). Among diploid patients, after adjusting for clinical and socio-demographic variables, patients carrying both XPD AC/CC and XPC CT/TT had a greater than two-fold increased risk of dying compared to those with the wild-type genotypes (HR=2.49; 95%CI: 1.06–5.85). No significant associations were observed for disease-free survival in AML patients. Conclusion By reduced DRC, this combined genotype may result in greater susceptibility to treatment effects decreasing overall survival. These findings could in the future help in selecting treatment strategies for patients with normal cytogenetics. PMID:20141440

DTMiner: identification of potential disease targets through biomedical literature mining

PubMed Central

Xu, Dong; Zhang, Meizhuo; Xie, Yanping; Wang, Fan; Chen, Ming; Zhu, Kenny Q.; Wei, Jia

2016-01-01

Motivation: Biomedical researchers often search through massive catalogues of literature to look for potential relationships between genes and diseases. Given the rapid growth of biomedical literature, automatic relation extraction, a crucial technology in biomedical literature mining, has shown great potential to support research of gene-related diseases. Existing work in this field has produced datasets that are limited both in scale and accuracy. Results: In this study, we propose a reliable and efficient framework that takes large biomedical literature repositories as inputs, identifies credible relationships between diseases and genes, and presents possible genes related to a given disease and possible diseases related to a given gene. The framework incorporates name entity recognition (NER), which identifies occurrences of genes and diseases in texts, association detection whereby we extract and evaluate features from gene–disease pairs, and ranking algorithms that estimate how closely the pairs are related. The F1-score of the NER phase is 0.87, which is higher than existing studies. The association detection phase takes drastically less time than previous work while maintaining a comparable F1-score of 0.86. The end-to-end result achieves a 0.259 F1-score for the top 50 genes associated with a disease, which performs better than previous work. In addition, we released a web service for public use of the dataset. Availability and Implementation: The implementation of the proposed algorithms is publicly available at http://gdr-web.rwebox.com/public_html/index.php?page=download.php. The web service is available at http://gdr-web.rwebox.com/public_html/index.php. Contact: jenny.wei@astrazeneca.com or kzhu@cs.sjtu.edu.cn Supplementary information: Supplementary data are available at Bioinformatics online. PMID:27506226

Functional characterization of polymorphisms in DNA repair genes using cytogenetic challenge assays.

PubMed

Au, William W; Salama, Salama A; Sierra-Torres, Carlos H

2003-11-01

A major barrier to understanding the role of polymorphic DNA repair genes for environmental cancer is that the functions of variant genotypes are largely unknown. Using our cytogenetic challenge assays, we conducted an investigation to address the deficiency. Using X-rays or ultraviolet (UV) light, we irradiated blood lymphocytes from 80 nonsmoking donors to challenge the cells to repair the induced DNA damage, and we analyzed expression of chromosome aberrations (CA) specific to the inducing agents. We have genotyped polymorphic DNA repair genes preferentially involved with base excision repair (BER) and nucleotide excision repair (NER) activities (XRCC1, XRCC3, APE1, XPD) corresponding to the repair of X-ray- and UV light-induced DNA damage, respectively. We expected that defects in specific DNA repair pathways due to polymorphisms would cause corresponding increases of specific CA. From our data, XRCC1 399Gln and XRCC3 241Met were associated with significant increases in chromosome deletions compared with the corresponding homozygous wild types (18.27 1.1 vs 14.79 1.2 and 18.22 0.99 vs 14.20 1.39, respectively); XPD 312Asn and XPD 751Gln were associated with significant increases in chromatid breaks compared with wild types (16.09 1.36 vs 11.41 0.98 and 16.87 1.27 vs 10.54 0.87, respectively), p < 0.05. The data indicate that XRCC1 399Gln and XRCC3 241Met are significantly defective in BER, and the XPD 312Asn and XPD 751Gln are significantly defective in NER. In addition, the variant genotypes interact significantly, with limited overlap of the two different repair pathways.

Psoralen interstrand cross-link repair is specifically altered by an adjacent triple-stranded structure

PubMed Central

Guillonneau, F.; Guieysse, A. L.; Nocentini, S.; Giovannangeli, C.; Praseuth, D.

2004-01-01

Targeting DNA-damaging agents to specific DNA sites by using sequence-specific DNA ligands has been successful in directing genomic modifications. The understanding of repair processing of such targeted damage and the influence of the adjacent complex is largely unknown. In this way, directed interstrand cross-links (ICLs) have already been generated by psoralen targeting. The mechanisms responsible for ICL removal are far from being understood in mammalian cells, with the proposed involvement of both mutagenic and recombinogenic pathways. Here, a unique ICL was introduced at a selected site by photoactivation of a psoralen moiety with the use of psoralen conjugates of triplex-forming oligonucleotides. The processing of psoralen ICL was evaluated in vitro and in cells for two types of cross-linked substrates, either containing a psoralen ICL alone or with an adjacent triple-stranded structure. We show that the presence of a neighbouring triplex structure interferes with different stages of psoralen ICL processing: (i) the ICL-induced DNA repair synthesis in HeLa cell extracts is inhibited by the triplex structure, as measured by the efficiency of ‘true’ and futile repair synthesis, stopping at the ICL site; (ii) in HeLa cells, the ICL removal via a nucleotide excision repair (NER) pathway is delayed in the presence of a neighbouring triplex; and (iii) the binding to ICL of recombinant xeroderma pigmentosum A protein, which is involved in pre-incision recruitment of NER factors is impaired by the presence of the third DNA strand. These data characterize triplex-induced modulation of ICL repair pathways at specific steps, which might have implications for the controlled induction of targeted genomic modifications and for the associated cellular responses. PMID:14966263

Mismatch repair proteins recruited to ultraviolet light-damaged sites lead to degradation of licensing factor Cdt1 in the G1 phase.

PubMed

Tanaka, Miyuki; Takahara, Michiyo; Nukina, Kohei; Hayashi, Akiyo; Sakai, Wataru; Sugasawa, Kaoru; Shiomi, Yasushi; Nishitani, Hideo

2017-04-03

Cdt1 is rapidly degraded by CRL4 Cdt2 E3 ubiquitin ligase after UV (UV) irradiation. Previous reports revealed that the nucleotide excision repair (NER) pathway is responsible for the rapid Cdt1-proteolysis. Here, we show that mismatch repair (MMR) proteins are also involved in the degradation of Cdt1 after UV irradiation in the G1 phase. First, compared with the rapid (within ∼15 min) degradation of Cdt1 in normal fibroblasts, Cdt1 remained stable for ∼30 min in NER-deficient XP-A cells, but was degraded within ∼60 min. The delayed degradation was also dependent on PCNA and CRL4 Cdt2 . The MMR proteins Msh2 and Msh6 were recruited to the UV-damaged sites of XP-A cells in the G1 phase. Depletion of these factors with small interfering RNAs prevented Cdt1 degradation in XP-A cells. Similar to the findings in XP-A cells, depletion of XPA delayed Cdt1 degradation in normal fibroblasts and U2OS cells, and co-depletion of Msh6 further prevented Cdt1 degradation. Furthermore, depletion of Msh6 alone delayed Cdt1 degradation in both cell types. When Cdt1 degradation was attenuated by high Cdt1 expression, repair synthesis at the damaged sites was inhibited. Our findings demonstrate that UV irradiation induces multiple repair pathways that activate CRL4 Cdt2 to degrade its target proteins in the G1 phase of the cell cycle, leading to efficient repair of DNA damage.

DTMiner: identification of potential disease targets through biomedical literature mining.

PubMed

Xu, Dong; Zhang, Meizhuo; Xie, Yanping; Wang, Fan; Chen, Ming; Zhu, Kenny Q; Wei, Jia

2016-12-01

Biomedical researchers often search through massive catalogues of literature to look for potential relationships between genes and diseases. Given the rapid growth of biomedical literature, automatic relation extraction, a crucial technology in biomedical literature mining, has shown great potential to support research of gene-related diseases. Existing work in this field has produced datasets that are limited both in scale and accuracy. In this study, we propose a reliable and efficient framework that takes large biomedical literature repositories as inputs, identifies credible relationships between diseases and genes, and presents possible genes related to a given disease and possible diseases related to a given gene. The framework incorporates name entity recognition (NER), which identifies occurrences of genes and diseases in texts, association detection whereby we extract and evaluate features from gene-disease pairs, and ranking algorithms that estimate how closely the pairs are related. The F1-score of the NER phase is 0.87, which is higher than existing studies. The association detection phase takes drastically less time than previous work while maintaining a comparable F1-score of 0.86. The end-to-end result achieves a 0.259 F1-score for the top 50 genes associated with a disease, which performs better than previous work. In addition, we released a web service for public use of the dataset. The implementation of the proposed algorithms is publicly available at http://gdr-web.rwebox.com/public_html/index.php?page=download.php The web service is available at http://gdr-web.rwebox.com/public_html/index.php CONTACT: jenny.wei@astrazeneca.com or kzhu@cs.sjtu.edu.cn Supplementary information: Supplementary data are available at Bioinformatics online. © The Author 2016. Published by Oxford University Press.

Physiological and Molecular Characterization of Hydroxyphenylpyruvate Dioxygenase (HPPD)-inhibitor Resistance in Palmer Amaranth (Amaranthus palmeri S.Wats.)

PubMed Central

Nakka, Sridevi; Godar, Amar S.; Wani, Prashant S.; Thompson, Curtis R.; Peterson, Dallas E.; Roelofs, Jeroen; Jugulam, Mithila

2017-01-01

Herbicides that inhibit hydroxyphenylpyruvate dioxygenase (HPPD) such as mesotrione are widely used to control a broad spectrum of weeds in agriculture. Amaranthus palmeri is an economically troublesome weed throughout the United States. The first case of evolution of resistance to HPPD-inhibiting herbicides in A. palmeri was documented in Kansas (KS) and later in Nebraska (NE). The objective of this study was to investigate the mechansim of HPPD-inhibitor (mesotrione) resistance in A. palmeri. Dose response analysis revealed that this population (KSR) was 10–18 times more resistant than their sensitive counterparts (MSS or KSS). Absorbtion and translocation analysis of [14C] mesotrione suggested that these mechanisms were not involved in the resistance in A. palmeri. Importantly, mesotrione (>90%) was detoxified markedly faster in the resistant populations (KSR and NER), within 24 hours after treatment (HAT) compared to sensitive plants (MSS, KSS, or NER). However, at 48 HAT all populations metabolized the mesotrione, suggesting additional factors may contribute to this resistance. Further evaluation of mesotrione-resistant A. palmeri did not reveal any specific resistance-conferring mutations nor amplification of HPPD gene, the molecular target of mesotrione. However, the resistant populations showed 4- to 12-fold increase in HPPD gene expression. This increase in HPPD transcript levels was accompanied by increased HPPD protein expression. The significant aspects of this research include: the mesotrione resistance in A. palmeri is conferred primarily by rapid detoxification (non-target-site based) of mesotrione; additionally, increased HPPD gene expression (target-site based) also contributes to the resistance mechanism in the evolution of herbicide resistance in this naturally occurring weed species. PMID:28443128

Geoparsing text for characterizing urban operational environments through machine learning techniques

NASA Astrophysics Data System (ADS)

Garfinkle, Noah W.; Selig, Lucas; Perkins, Timothy K.; Calfas, George W.

2017-05-01

Increasing worldwide internet connectivity and access to sources of print and open social media has increased near realtime availability of textual information. Capabilities to structure and integrate textual data streams can contribute to more meaningful representations of operational environment factors (i.e., Political, Military, Economic, Social, Infrastructure, Information, Physical Environment, and Time [PMESII-PT]) and tactical civil considerations (i.e., Areas, Structures, Capabilities, Organizations, People and Events [ASCOPE]). However, relying upon human analysts to encode this information as it arrives quickly proves intractable. While human analysts possess an ability to comprehend context in unstructured text far beyond that of computers, automated geoparsing (the extraction of locations from unstructured text) can empower analysts to automate sifting through datasets for areas of interest. This research evaluates existing approaches to geoprocessing as well as initiating the research and development of locally-improved methods of tagging parts of text as possible locations, resolving possible locations into coordinates, and interfacing such results with human analysts. The objective of this ongoing research is to develop a more contextually-complete picture of an area of interest (AOI) including human-geographic context for events. In particular, our research is working to make improvements to geoparsing (i.e., the extraction of spatial context from documents), which requires development, integration, and validation of named-entity recognition (NER) tools, gazetteers, and entity-attribution. This paper provides an overview of NER models and methodologies as applied to geoparsing, explores several challenges encountered, presents preliminary results from the creation of a flexible geoparsing research pipeline, and introduces ongoing and future work with the intention of contributing to the efficient geocoding of information containing valuable insights into human activities in space.

Evidence for Gating Roles of Protein Kinase A and Protein Kinase C in Estradiol-Induced Luteinizing Hormone Receptor (lhcgr) Expression in Zebrafish Ovarian Follicle Cells

PubMed Central

Liu, Ka-Cheuk; Ge, Wei

2013-01-01

Estradiol (E2) stimulates luteinizing hormone receptor (lhcgr) expression in zebrafish follicle cells via nuclear estrogen receptors (nERs) that are likely expressed on the membrane, and lhcgr responds to E2 in a biphasic manner during 24-h treatment. These observations raise an interesting question on the signaling mechanism underlying E2 regulation, in particular the biphasic response of lhcgr expression. In the present study, we demonstrated that E2 regulation of lhcgr was significantly influenced by the activity of cAMP-PKA pathway. Activation of cAMP-PKA pathway by forskolin or db-cAMP suppressed E2-stimulated lhcgr expression in short-term (3 h) but enhanced its effect in long-term (24 h), suggesting differential roles of PKA at these two phases of lhcgr response. PKA inhibitor H89 showed reversed effects. In contrast, PKC pathway had consistent permissive effect on E2-induced lhcgr expression as evidenced by strong inhibition of E2 effect by PKC inhibitors GF109203X and Ro-31-8220 at both 3 and 24 h. One of the mechanisms by which PKA and PKC gated E2 effect might be through regulating nERs, particularly esr2a. Despite the strong influence of PKA and PKC, our data did not suggest direct mediating roles for these two pathways in E2 stimulation of lhcgr expression; yet they likely play critical gating roles in E2 signal transduction. As a follow-up study to our previous report on E2 regulation of gonadotropin receptors in the zebrafish ovary, the present study provides further evidence for the involvement of classical intracellular signal transduction pathways in E2 stimulation of lhcgr expression in the follicle cells. PMID:23658740

Delayed degradation in soil of foliar herbicides glyphosate and sulcotrione previously absorbed by plants: consequences on herbicide fate and risk assessment.

PubMed

Doublet, Jérémy; Mamy, Laure; Barriuso, Enrique

2009-10-01

Following application, pesticides can be intercepted and absorbed by weeds and/or crops. Plants containing pesticides residues may then reach the soil during the crop cycle or after harvest. However, the fate in soil of pesticides residues in plants is unknown. Two commonly used foliar herbicides, glyphosate and sulcotrione, (14)C-labeled, were applied on leaves of oilseed rape and/or maize, translocation was studied, and then soil incubations of aerial parts of plants containing herbicides residues were performed. Soil treated directly with herbicides was used as control. The effects of adjuvants on herbicide plant-absorption and subsequent soil-degradation were also investigated comparing herbicides application as active ingredients and as commercial formulations. The fate in soil of herbicides residues in plants was different from that of control, and different for glyphosate and sulcotrione. Mineralization in soil of glyphosate in crops decreased compared to control, and amounts of (14)C-extractable residues, mainly composed by the metabolite aminomethylphosphonic acid (AMPA), and non-extractable residues (NER) increased. In contrast, mineralization in soil of sulcotrione in maize increased compared to control, with a decrease in the (14)C-extractable residues and an increase in NER. The fate of both herbicides was influenced by the type of plant organ in which herbicide was incorporated, because of differences in herbicides bioavailability and organs biodegradability, but not by adjuvants. Absorption of both herbicides in plant delays their subsequent soil-degradation, and particularly, glyphosate persistence in soil could increase from two to six times. The modifications of herbicide degradation in soil due to interception by plants should be considered for environmental risks assessment.

Human XPA and RPA DNA repair proteins participate in specific recognition of triplex-induced helical distortions

NASA Astrophysics Data System (ADS)

Vasquez, Karen M.; Christensen, Jesper; Li, Lei; Finch, Rick A.; Glazer, Peter M.

2002-04-01

Nucleotide excision repair (NER) plays a central role in maintaining genomic integrity by detecting and repairing a wide variety of DNA lesions. Xeroderma pigmentosum complementation group A protein (XPA) is an essential component of the repair machinery, and it is thought to be involved in the initial step as a DNA damage recognition and/or confirmation factor. Human replication protein A (RPA) and XPA have been reported to interact to form a DNA damage recognition complex with greater specificity for damaged DNA than XPA alone. The mechanism by which these two proteins recognize such a wide array of structures resulting from different types of DNA damage is not known. One possibility is that they recognize a common feature of the lesions, such as distortions of the helical backbone. We have tested this idea by determining whether human XPA and RPA proteins can recognize the helical distortions induced by a DNA triple helix, a noncanonical DNA structure that has been shown to induce DNA repair, mutagenesis, and recombination. We measured binding of XPA and RPA, together or separately, to substrates containing triplexes with three, two, or no strands covalently linked by psoralen conjugation and photoaddition. We found that RPA alone recognizes all covalent triplex structures, but also forms multivalent nonspecific DNA aggregates at higher concentrations. XPA by itself does not recognize the substrates, but it binds them in the presence of RPA. Addition of XPA decreases the nonspecific DNA aggregate formation. These results support the hypothesis that the NER machinery is targeted to helical distortions and demonstrate that RPA can recognize damaged DNA even without XPA.

Comprehensive profiling of DNA repair defects in breast cancer identifies a novel class of endocrine therapy resistance drivers.

PubMed

Anurag, Meenakshi; Punturi, Nindo; Hoog, Jeremy; Bainbridge, Matthew N; Ellis, Matthew J; Haricharan, Svasti

2018-05-23

This study was undertaken to conduct a comprehensive investigation of the role of DNA damage repair (DDR) defects in poor outcome ER+ disease. Expression and mutational status of DDR genes in ER+ breast tumors were correlated with proliferative response in neoadjuvant aromatase inhibitor therapy trials (discovery data set), with outcomes in METABRIC, TCGA and Loi data sets (validation data sets), and in patient derived xenografts. A causal relationship between candidate DDR genes and endocrine treatment response, and the underlying mechanism, was then tested in ER+ breast cancer cell lines. Correlations between loss of expression of three genes: CETN2 (p<0.001) and ERCC1 (p=0.01) from the nucleotide excision repair (NER) and NEIL2 (p=0.04) from the base excision repair (BER) pathways were associated with endocrine treatment resistance in discovery data sets, and subsequently validated in independent patient cohorts. Complementary mutation analysis supported associations between mutations in NER and BER pathways and reduced endocrine treatment response. A causal role for CETN2, NEIL2 and ERCC1 loss in intrinsic endocrine resistance was experimentally validated in ER+ breast cancer cell lines, and in ER+ patient-derived xenograft models. Loss of CETN2, NEIL2 or ERCC1 induced endocrine treatment response by dysregulating G1/S transition, and therefore, increased sensitivity to CDK4/6 inhibitors. A combined DDR signature score was developed that predicted poor outcome in multiple patient cohorts. This report identifies DDR defects as a new class of endocrine treatment resistance drivers and indicates new avenues for predicting efficacy of CDK4/6 inhibition in the adjuvant treatment setting. Copyright ©2018, American Association for Cancer Research.

DOE Office of Scientific and Technical Information (OSTI.GOV)

Hang, Bo; Rodriguez, Ben; Yang, Yanu

Benzene, a ubiquitous human carcinogen, forms DNA adducts through its metabolites such as p-benzoquinone (p-BQ) and hydroquinone (HQ). N(2)-(4-Hydroxyphenyl)-2'-deoxyguanosine (N(2)-4-HOPh-dG) is the principal adduct identified in vivo by (32)P-postlabeling in cells or animals treated with p-BQ or HQ. To study its effect on repair specificity and replication fidelity, we recently synthesized defined oligonucleotides containing a site-specific adduct using phosphoramidite chemistry. We here report the repair of this adduct by Escherichia coli UvrABC complex, which performs the initial damage recognition and incision steps in the nucleotide excision repair (NER) pathway. We first showed that the p-BQ-treated plasmid was efficiently cleaved bymore » the complex, indicating the formation of DNA lesions that are substrates for NER. Using a 40-mer substrate, we found that UvrABC incises the DNA strand containing N(2)-4-HOPh-dG in a dose- and time-dependent manner. The specificity of such repair was also compared with that of DNA glycosylases and damage-specific endonucleases of E. coli, both of which were found to have no detectable activity toward N(2)-4-HOPh-dG. To understand why this adduct is specifically recognized and processed by UvrABC, molecular modeling studies were performed. Analysis of molecular dynamics trajectories showed that stable G:C-like hydrogen bonding patterns of all three Watson-Crick hydrogen bonds are present within the N(2)-4-HOPh-G:C base pair, with the hydroxyphenyl ring at an almost planar position. In addition, N(2)-4-HOPh-dG has a tendency to form more stable stacking interactions than a normal G in B-type DNA. These conformational properties may be critical in differential recognition of this adduct by specific repair enzymes.« less

Differential sensitivities of cellular XPA and PARP-1 to arsenite inhibition and zinc rescue.

PubMed

Ding, Xiaofeng; Zhou, Xixi; Cooper, Karen L; Huestis, Juliana; Hudson, Laurie G; Liu, Ke Jian

2017-09-15

Arsenite directly binds to the zinc finger domains of the DNA repair protein poly (ADP ribose) polymerase (PARP)-1, and inhibits PARP-1 activity in the base excision repair (BER) pathway. PARP inhibition by arsenite enhances ultraviolet radiation (UVR)-induced DNA damage in keratinocytes, and the increase in DNA damage is reduced by zinc supplementation. However, little is known about the effects of arsenite and zinc on the zinc finger nucleotide excision repair (NER) protein xeroderma pigmentosum group A (XPA). In this study, we investigated the difference in response to arsenite exposure between XPA and PARP-1, and the differential effectiveness of zinc supplementation in restoring protein DNA binding and DNA damage repair. Arsenite targeted both XPA and PARP-1 in human keratinocytes, resulting in zinc loss from each protein and a pronounced decrease in XPA and PARP-1 binding to chromatin as demonstrated by Chip-on-Western assays. Zinc effectively restored DNA binding of PARP-1 and XPA to chromatin when zinc concentrations were equal to those of arsenite. In contrast, zinc was more effective in rescuing arsenite-augmented direct UVR-induced DNA damage than oxidative DNA damage. Taken together, our findings indicate that arsenite interferes with PARP-1 and XPA binding to chromatin, and that zinc supplementation fully restores DNA binding activity to both proteins in the cellular context. Interestingly, rescue of arsenite-inhibited DNA damage repair by supplemental zinc was more sensitive for DNA damage repaired by the XPA-associated NER pathway than for the PARP-1-dependent BER pathway. This study expands our understanding of arsenite's role in DNA repair inhibition and co-carcinogenesis. Copyright © 2017 Elsevier Inc. All rights reserved.

HR Public meeting

ScienceCinema

Heuer, Rolf; Catherin, Anne-Sylvie; Vuillemin, Vin

2018-05-25

Cher(e)s collègues, En collaboration avec le Département HR, le Directeur général a le plaisir de vous convier à une réunion publique qui se tiendra le vendredi 25 juin 2010 à 9h30 dans l’Amphithéâtre principal (Bâtiment 500)*. Un café d’accueil y sera servi à partir de 9h. Cette réunion abordera les thèmes suivants : • Valeurs de l’Organisation (Directeur général) • Code de Conduite (Directeur général / Anne-Sylvie Catherin) • Création du nouveau rôle d’Ombudsperson (Vincent Vuillemin); Ces présentations seront suivies d’une séance de questions-réponses. Nous espérons vous retrouver nombreux le 25 juin ! Meilleures salutations, Anne-Sylvie Catherin Chef du Département des Ressources humaines *Cette réunion sera retransmise simultanément dans l’Amphithéâtre BE de Prévessin (Bâtiment 864) et également disponible à l’adresse suivante : http://webcast.cern.ch. Dear colleagues, In collaboration with HR Department, the Director-General would like to invite you to an information meeting which will be held on Friday 25 June 2010 at 9:30 am in the Main Auditorium (Building 500)*. A welcome coffee will be available from 9:00 am. During this meeting, information will be given about: • Organization’s values (Director-General) • Code of Conduct (Director-General / Anne-Sylvie Catherin) • New Ombudsperson role (Vincent Vuillemin) These presentations will be followed by a questions & answers session. We look forward to seeing you all on 25 June! Best regards, Anne-Sylvie Catherin Head, Human Resources Department. This meeting will be simultaneously retransmitted in BE Auditorium (Building 864) and available at the following address: http://webcast.cern.ch.

A Synergetic Approach to Describe the Stability and Variability of Motor Behavior

NASA Astrophysics Data System (ADS)

Witte, Kersttn; Bock, Holger; Storb, Ulrich; Blaser, Peter

At the beginning of the 20th century, the Russian physiologist and biomechanist Bernstein developed his cyclograms, in which he showed in the non-repetition of the same movement under constant conditions. We can also observe this phenomenon when we analyze several cyclic sports movements. For example, we investigated the trajectories of single joints and segments of the body in breaststroke, walking, and running. The problem of the stability and variability of movement, and the relation between the two, cannot be satisfactorily tackled by means of linear methods. Thus, several authors (Turvey, 1977; Kugler et al., 1980; Haken et al., 1985; Schöner et al., 1986; Mitra et al., 1997; Kay et al., 1991; Ganz et al., 1996; Schöllhorn, 1999) use nonlinear models to describe human movement. These models and approaches have shown that nonlinear theories of complex systems provide a new understanding of the stability and variability of motor control. The purpose of this chapter is a presentation of a common synergetic model of motor behavior and its application to foot tapping, walking, and running.

Molecular Mechanisms of Ultraviolet Radiation-Induced DNA Damage and Repair

PubMed Central

Rastogi, Rajesh P.; Richa; Kumar, Ashok; Tyagi, Madhu B.; Sinha, Rajeshwar P.

2010-01-01

DNA is one of the prime molecules, and its stability is of utmost importance for proper functioning and existence of all living systems. Genotoxic chemicals and radiations exert adverse effects on genome stability. Ultraviolet radiation (UVR) (mainly UV-B: 280–315 nm) is one of the powerful agents that can alter the normal state of life by inducing a variety of mutagenic and cytotoxic DNA lesions such as cyclobutane-pyrimidine dimers (CPDs), 6-4 photoproducts (6-4PPs), and their Dewar valence isomers as well as DNA strand breaks by interfering the genome integrity. To counteract these lesions, organisms have developed a number of highly conserved repair mechanisms such as photoreactivation, base excision repair (BER), nucleotide excision repair (NER), and mismatch repair (MMR). Additionally, double-strand break repair (by homologous recombination and nonhomologous end joining), SOS response, cell-cycle checkpoints, and programmed cell death (apoptosis) are also operative in various organisms with the expense of specific gene products. This review deals with UV-induced alterations in DNA and its maintenance by various repair mechanisms. PMID:21209706

Reduced nucleotide excision repair and GSTM1-null genotypes influence anti-B[a]PDE-DNA adduct levels in mononuclear white blood cells of highly PAH-exposed coke oven workers.

PubMed

Pavanello, Sofia; Pulliero, Alessandra; Siwinska, Ewa; Mielzynska, Danuta; Clonfero, Erminio

2005-01-01

It is important to identify the potential genetic-susceptible factors that are able to modulate individual responses to exposure to carcinogenic polycyclic aromatic hydrocarbons (PAHs). In the present study we evaluated the influence of four polymorphisms of nucleotide excision repair (NER) genes [xeroderma pigmentosum-C (XPC)-PAT +/-, xeroderma pigmentosum-A (XPA) 5' non-coding region-A23G, XPD-exon 23 A35931C Lys751Gln, xeroderma pigmentosum-D (XPD)-exon 10 G23591A Asp312Asn] and that of glutathione S-transferase mu1 (GSTM1-active or -null) on benzo[a]pyrene diol epoxide (B[a]PDE)-DNA adduct levels from the lympho-monocyte fraction (LMF) of highly PAH benzo[a]pyrene (B[a]P)-exposed Polish coke oven workers (n = 67, 67% current smokers) with individual urinary post-shift excretion of 1-pyrenol exceeding the proposed biological exposure index (BEI) (2.28 micromol/mol creatinine). The bulky (+/-)-r-7,t-8-dihydroxy-t-9,10-oxy-7,8,9,10-tetrahydrobenzo[a]pyrene (anti-B[a]PDE)-DNA adduct levels were detected by high-performance liquid chromatography (HPLC)/fluorescence analysis and genotypes by polymerase chain reaction. We found that workers with the low DNA repair capacity of XPC-PAT+/+ and XPA-A23A genotypes had significantly increased anti-B[a]PDE-DNA adduct levels (Mann-Whitney U-test, z = 2.24, P = 0.02 and z = 2.65, P = 0.01). Moreover, DNA adducts were also raised in workers without GSTM1 activity (GSTM1-null genotype) (Mann-Whitney U-test, z = 2.25, P = 0.0246). Workers with unfavourable XPC-PAT+/+ and XPA-A23A NER genotypes, alone (approximately 65% of workers) or combined with GSTM1-null genotype (approximately 75% of workers) were in the tertile with the highest adduct level, i.e. >4.11 adducts/10(8) nt (chi2 = 5.85, P = 0.0156 and chi2 = 5.40, P = 0.01). The increase in anti-B[a]PDE-DNA adduct levels (ln values) was significantly related in a multiple linear regression analysis to PAH exposure (i.e. urinary post-shift excretion of 1-pyrenol) (t = 2.61, P = 0.0115), lack of GSTM1 activity (t = 2.41, P = 0.0192) and to low DNA repair capacity of the XPC-PAT+/+ genotype (t = 2.34, P = 0.0226). The influence of the XPA-A23A genotype was not evident in this statistical analysis, and no associations with XPD polymorphisms, dietary habits or tobacco smoking were found. The modulation of anti-B[a]PDE-DNA adducts in the LMF by GSTM1-null and some low-activity NER genotypes may be considered as a potential genetic susceptibility factor capable of modulating individual responses to PAH (B[a]P) genotoxic exposure and the consequent risk of cancer in coke oven workers.

Spectroscopic Evidence for Covalent Binding of Sulfadiazine to Natural Soils via 1,4-nucleophilic addition (Michael Type Addition) studied by Spin Labeling ESR

NASA Astrophysics Data System (ADS)

Aleksandrova, Olga

2015-04-01

Among different classes of veterinary pharmaceuticals, Sulfadiazine (SDZ) is widely used in animal husbandry. Its residues were detected in different environmental compartments. However, soil is a hot spot for SDZ as it receives a large portion of excreted compounds through the application of manure during soil fertilization. Ample studies on the fate of SDZ in soils showed that a large portion forms nonextractable residues (NER) along with transformation products and a low mineralization (Mueller et al., 2013). A common observation was an initially fast formation of NER up to 10% of the applied amount promptly after the application of SDZ to soil, and this portion increased up to 50% within a few days (Mueller et al., 2013; Nowak et al., 2011). A common finding for SDZ, as for other sulfonamides, was biphasic kinetics of the formation of NER, which was attributed to the occurrence of two reaction processes: a rapid, often reversible process and a slower, irreversible process (Weber et al., 1996). A single-phase reaction process was also established under anaerobic treatment (Gulkowska et al., 2014). A major focus of this work is to elucidate a reaction mechanism of covalent binding of SDZ to soil that is currently required to estimate a risk of NER formed by SDZ in soils for human health. Taking into account a key role of the amine functional groups of SDZ on its reactivity in soil, nitroxide radicals with the sewed aromatic or aliphatic amines labeled soil samples and then, were investigated by means of ESR spectroscopy. 2,5,5-Trimethyl-2-(3-aminophenyl)pyrrolidin-1-yloxy and 4-amino-2,2,6,6-Tetramethylpiperidin-1-oxyl modeled decomposition products of SDZ with the aromatic and aliphatic amines, respectively. The application of the defined combination of both spin labels (SL) to different soils well simulated a change of a paramagnetic signal of soil organic radicals interacted with SDZ. After their application to soil, SL were found in soil sites characterized with different polarity. As shown by the spin labeling ESR experiment, molecules modeling SDZ were promptly bound to non-hydrolysable network of soil organic matter only via the aromatic amines that was accompanied by a prompt enlargement of humic particles binding aromatic amines, whereas binding of decomposition products of SDZ to humic acids of soil via the aliphatic amines was not observable. The ESR spectra obviously showed a single-phase process of covalent binding of the aromatic amines. Repeated washouts of labeled soil samples using distil water and ultrafiltration through the membrane of 5000 MWCO PES confirmed irreversible binding of the aromatic amines, and showed that via the aliphatic amines, binding of SDZ or decomposition products of SDZ to soil might also occur but reversibly and only to small soil molecules, which don't enter into the composition of non-hydrolysable part of soil organic matter. SL ESR experiments of different soils at the presence of Laccase highlighted that covalent binding of the aromatic amines to humic particles occurred in the specific hydrophobic areas of soil found as depleted in oxygen. All measured data evidenced that first, SDZ might be decomposed that allowed for measuring the same change of a paramagnetic signal of soil organic matter influenced by both aromatic and aliphatic amines as in the experiment of the interaction of soil with SDZ. Second, a decomposition product of SDZ with the aromatic amine might be bound to non-hydrolysable parts of soil organic matter under specific anaerobic conditions only via 1,4 - nucleophilic addition, Michael-type addition. Gulkowska, A., Thalmann, B., D., Hollender, J., & Krauss, M. (2014). Chemosphere, 107, 366 - 372. Müller, T., Rosendahl, I., Focks, A., Siemens, J., Klasmeier, J., & Matthies. (2013). Environmental Pollution, 172,180 - 185. Nowak, K.M., Miltner, A., Gehre, M., Schaeffer, A., & Kaestner, M. (2011). Environmental Science & Technology 45, 999 - 1006. Weber, E.J., Spidle, D.L., & Thron, K.A. (1996). Environmental Science & Technology, 30 (9), 2755-2763.

Challenges in transformation of the "traditional block rotation" medical student clinical education into a longitudinal integrated clerkship model.

PubMed

Heddle, William; Roberton, Gayle; Mahoney, Sarah; Walters, Lucie; Strasser, Sarah; Worley, Paul

2014-01-01

Longitudinal integrated clerkships (LIC) in the first major clinical year in medical student training have been demonstrated to be at least equivalent to and in some areas superior to the "traditional block rotation" (TBR). Flinders University School of Medicine is starting a pilot changing the traditional teaching at the major Academic Medical Centre from TBR to LIC (50% of students in other locations in the medical school already have a partial or full LIC programme). This paper summarises the expected challenges presented at the "Rendez-Vous" Conference in October 2012: (a) creating urgency, (b) training to be a clinician rather than imparting knowledge, (c) resistance to change. We discuss the unexpected challenges that have evolved since then: (a) difficulty finalising the precise schedule, (b) underestimating time requirements, (c) managing the change process inclusively. Transformation of a "block rotation" to "LIC" medical student education in a tertiary academic teaching hospital has many challenges, many of which can be anticipated, but some are unexpected.

Remedial Investigation/Feasibility Study, Operable Unit 5, Elmendorf AFB, Anchorage, Alaska. Volume 3. Appendices K - T

DTIC Science & Technology

1994-03-04

WalerQC METHOD BANK 30104 79-0146 TRHICLOROE1Ifl.BEE(TE) 0.j U11.01 WalerQC UShODSBAIN 301 04W 79-0146 TRIILMOROBHYLBEE (TCE) IU 1101.. alerQC METHOD...OOUL1!ANE -SS 89 %IC WSWeQC METHOD BANK 3020(1400 22M 0-Si-S 2*OOCLOROBUTANE -SI 902 sm WalerQC METHOD BLANK 8020(1400 22M 0-365 1.4003C2LOROSUfANE...SS 920 %wI WmerQC METHMOD BANK 0102(1400 CH 10-56-5 I.OX4-D01OOSUANE -SI IisBc WaNer C METHOD BLANK 8100(1400 22 10-5&5 2.40 EHOROSUTANE -SI 92 IC

Repair Mechanism of UV-damaged DNA in Xeroderma Pigmentosum | Center for Cancer Research

Cancer.gov

Xeroderma pigmentosum (XP) is a rare, inherited disorder characterized by extreme skin sensitivity to ultraviolet (UV) rays from sunlight. XP is caused by mutations in genes involved in nucleotide excision repair (NER) of damaged DNA. Normal cells are usually able to fix this damage before it leads to problems; however, the DNA damage is not repaired normally in patients with XP. As more abnormalities form in DNA, cells malfunction and eventually become cancerous or die. XP patients have more than a 10,000-fold increased risk of developing skin cancer. Kenneth Kraemer, M.D., in CCR’s Dermatology Branch, has been studying XP patients at the Clinical Center for more than 40 years.

Helicopter Maritime Environment Trainer: Operational Software CSCI Version Description Document (Simulateur D’Entrainement Virtuel pour Helicoptere Maritime: Logiciel Operationnel CSCI, Document de Description de la Version)

DTIC Science & Technology

2011-06-01

d’envol d’une frégate canadienne de patrouille dans un environnement virtuel. Le système HelMET a été installé à la 12e Escadre, Base des Forces...d’une frégate canadienne de patrouille dans un environnement virtuel. Le système HelMET a été installé à la 12e Escadre, Base des Forces canadiennes...afin d’entraîner les pilotes d’hélicoptère à l’atterrissage sur le pont d’envol d’une frégate canadienne de patrouille dans un environnement virtuel

PREFACE: The 27th IAHR Symposium on Hydraulic Machinery and Systems (IAHR 2014)

NASA Astrophysics Data System (ADS)

Désy, N.

2014-12-01

On behalf of the Organizing Committee and myself, it is my pleasure to welcome you to the 27th Symposium on Hydraulic Machinery and Systems. We are glad to welcome you in Montreal, Canada, in late September, just as the city welcomes the fall season and the trees start to show their nice colors. The Symposium will take place at the Hotel Omni Mont-Royal, located in the heart of the city. Participants will then have the opportunity to discover the many charms of Montreal, a rich blend between European and American cultures with diverse culinary offers and its legendary hospitality, nightlife and unique attractions. But other than the charm of Montreal, why are we holding it in Canada? · Canada is a world leader in hydropower production, with an installed capacity of over 70,000 megawatts (MW) and an annual average production of 350 terawatt-hours (TWh). · Thus, Canada is one of the world's largest producers of clean, renewable hydroelectric power. · Hydropower accounts for 97% of Canada's renewable electricity generation and nearly 13% of the world-wide production of hydropower, but with 0.5% of the world population. · Approximately 60% of the electricity generated in Canada in 2008 came from hydroelectric power plants. And there is the potential to more than double the hydroelectric capacity in Canada. Our Organizing Committee was formed in November 2011 and has undertaken a number of important steps to ensure that this event will be a success. We see this event as a very important one to help create personal networks and transfer knowledge to the younger generation of scientists. Bienvenue at our 2014 ''rendez-vous'' . Normand Désy Canadian Representative IAHR Executive Committee

Sieve-based coreference resolution enhances semi-supervised learning model for chemical-induced disease relation extraction.

PubMed

Le, Hoang-Quynh; Tran, Mai-Vu; Dang, Thanh Hai; Ha, Quang-Thuy; Collier, Nigel

2016-07-01

The BioCreative V chemical-disease relation (CDR) track was proposed to accelerate the progress of text mining in facilitating integrative understanding of chemicals, diseases and their relations. In this article, we describe an extension of our system (namely UET-CAM) that participated in the BioCreative V CDR. The original UET-CAM system's performance was ranked fourth among 18 participating systems by the BioCreative CDR track committee. In the Disease Named Entity Recognition and Normalization (DNER) phase, our system employed joint inference (decoding) with a perceptron-based named entity recognizer (NER) and a back-off model with Semantic Supervised Indexing and Skip-gram for named entity normalization. In the chemical-induced disease (CID) relation extraction phase, we proposed a pipeline that includes a coreference resolution module and a Support Vector Machine relation extraction model. The former module utilized a multi-pass sieve to extend entity recall. In this article, the UET-CAM system was improved by adding a 'silver' CID corpus to train the prediction model. This silver standard corpus of more than 50 thousand sentences was automatically built based on the Comparative Toxicogenomics Database (CTD) database. We evaluated our method on the CDR test set. Results showed that our system could reach the state of the art performance with F1 of 82.44 for the DNER task and 58.90 for the CID task. Analysis demonstrated substantial benefits of both the multi-pass sieve coreference resolution method (F1 + 4.13%) and the silver CID corpus (F1 +7.3%).Database URL: SilverCID-The silver-standard corpus for CID relation extraction is freely online available at: https://zenodo.org/record/34530 (doi:10.5281/zenodo.34530). © The Author(s) 2016. Published by Oxford University Press.

The Virtual Teacher (VT) Paradigm: Learning New Patterns of Interpersonal Coordination Using the Human Dynamic Clamp

PubMed Central

2015-01-01

The Virtual Teacher paradigm, a version of the Human Dynamic Clamp (HDC), is introduced into studies of learning patterns of inter-personal coordination. Combining mathematical modeling and experimentation, we investigate how the HDC may be used as a Virtual Teacher (VT) to help humans co-produce and internalize new inter-personal coordination pattern(s). Human learners produced rhythmic finger movements whilst observing a computer-driven avatar, animated by dynamic equations stemming from the well-established Haken-Kelso-Bunz (1985) and Schöner-Kelso (1988) models of coordination. We demonstrate that the VT is successful in shifting the pattern co-produced by the VT-human system toward any value (Experiment 1) and that the VT can help humans learn unstable relative phasing patterns (Experiment 2). Using transfer entropy, we find that information flow from one partner to the other increases when VT-human coordination loses stability. This suggests that variable joint performance may actually facilitate interaction, and in the long run learning. VT appears to be a promising tool for exploring basic learning processes involved in social interaction, unraveling the dynamics of information flow between interacting partners, and providing possible rehabilitation opportunities. PMID:26569608

General considerations on the nature of Zb(10610 ) and Zb(10650 ) from their pole positions

NASA Astrophysics Data System (ADS)

Kang, Xian-Wei; Guo, Zhi-Hui; Oller, J. A.

2016-07-01

The nature of the bottomonium-like states Zb(10610 ) and Zb(10650 ) is studied by calculating the B(*)B¯* compositeness (X ) in those resonances. We first consider uncoupled isovector S -wave scattering of B(*)B¯ * within the framework of effective-range expansion (ERE). Expressions for the scattering length (a ) and effective range (r ) are derived exclusively in terms of the masses and widths of the two Zb states. We then develop compositeness within ERE for the resonance case and deduce the expression X =1 /√{2 r /a -1 } , which is then applied to the systems of interest. Finally, the actual compositeness parameters are calculated in terms of resonance pole positions and their experimental branching ratios into B(*)B¯* by using the method of [U. G. Meißner and J. A. Oller, Phys. Lett. B 751, 59 (2015)]. We find the values X =0.66 ±0.11 and 0.51 ±0.10 for the Zb(10610 ) and Zb(10650 ), respectively. We also compare the ERE with Breit-Wigner and Flatté parametrizations to discuss the applicability of the last two for near-threshold resonances with explicit examples.

An annotated corpus with nanomedicine and pharmacokinetic parameters

PubMed Central

Lewinski, Nastassja A; Jimenez, Ivan; McInnes, Bridget T

2017-01-01

A vast amount of data on nanomedicines is being generated and published, and natural language processing (NLP) approaches can automate the extraction of unstructured text-based data. Annotated corpora are a key resource for NLP and information extraction methods which employ machine learning. Although corpora are available for pharmaceuticals, resources for nanomedicines and nanotechnology are still limited. To foster nanotechnology text mining (NanoNLP) efforts, we have constructed a corpus of annotated drug product inserts taken from the US Food and Drug Administration’s Drugs@FDA online database. In this work, we present the development of the Engineered Nanomedicine Database corpus to support the evaluation of nanomedicine entity extraction. The data were manually annotated for 21 entity mentions consisting of nanomedicine physicochemical characterization, exposure, and biologic response information of 41 Food and Drug Administration-approved nanomedicines. We evaluate the reliability of the manual annotations and demonstrate the use of the corpus by evaluating two state-of-the-art named entity extraction systems, OpenNLP and Stanford NER. The annotated corpus is available open source and, based on these results, guidelines and suggestions for future development of additional nanomedicine corpora are provided. PMID:29066897

The Virtual Teacher (VT) Paradigm: Learning New Patterns of Interpersonal Coordination Using the Human Dynamic Clamp.

PubMed

Kostrubiec, Viviane; Dumas, Guillaume; Zanone, Pier-Giorgio; Kelso, J A Scott

2015-01-01

The Virtual Teacher paradigm, a version of the Human Dynamic Clamp (HDC), is introduced into studies of learning patterns of inter-personal coordination. Combining mathematical modeling and experimentation, we investigate how the HDC may be used as a Virtual Teacher (VT) to help humans co-produce and internalize new inter-personal coordination pattern(s). Human learners produced rhythmic finger movements whilst observing a computer-driven avatar, animated by dynamic equations stemming from the well-established Haken-Kelso-Bunz (1985) and Schöner-Kelso (1988) models of coordination. We demonstrate that the VT is successful in shifting the pattern co-produced by the VT-human system toward any value (Experiment 1) and that the VT can help humans learn unstable relative phasing patterns (Experiment 2). Using transfer entropy, we find that information flow from one partner to the other increases when VT-human coordination loses stability. This suggests that variable joint performance may actually facilitate interaction, and in the long run learning. VT appears to be a promising tool for exploring basic learning processes involved in social interaction, unraveling the dynamics of information flow between interacting partners, and providing possible rehabilitation opportunities.

Practice guideline: joint CCMG-SOGC recommendations for the use of chromosomal microarray analysis for prenatal diagnosis and assessment of fetal loss in Canada

PubMed Central

Armour, Christine M; Dougan, Shelley Danielle; Brock, Jo-Ann; Chari, Radha; Chodirker, Bernie N; DeBie, Isabelle; Evans, Jane A; Gibson, William T; Kolomietz, Elena; Nelson, Tanya N; Tihy, Frédérique; Thomas, Mary Ann; Stavropoulos, Dimitri J

2018-01-01

Background The aim of this guideline is to provide updated recommendations for Canadian genetic counsellors, medical geneticists, maternal fetal medicine specialists, clinical laboratory geneticists and other practitioners regarding the use of chromosomal microarray analysis (CMA) for prenatal diagnosis. This guideline replaces the 2011 Society of Obstetricians and Gynaecologists of Canada (SOGC)-Canadian College of Medical Geneticists (CCMG) Joint Technical Update. Methods A multidisciplinary group consisting of medical geneticists, genetic counsellors, maternal fetal medicine specialists and clinical laboratory geneticists was assembled to review existing literature and guidelines for use of CMA in prenatal care and to make recommendations relevant to the Canadian context. The statement was circulated for comment to the CCMG membership-at-large for feedback and, following incorporation of feedback, was approved by the CCMG Board of Directors on 5 June 2017 and the SOGC Board of Directors on 19 June 2017. Results and conclusions Recommendations include but are not limited to: (1) CMA should be offered following a normal rapid aneuploidy screen when multiple fetal malformations are detected (II-1A) or for nuchal translucency (NT) ≥3.5 mm (II-2B) (recommendation 1); (2) a professional with expertise in prenatal chromosomal microarray analysis should provide genetic counselling to obtain informed consent, discuss the limitations of the methodology, obtain the parental decisions for return of incidental findings (II-2A) (recommendation 4) and provide post-test counselling for reporting of test results (III-A) (recommendation 9); (3) the resolution of chromosomal microarray analysis should be similar to postnatal microarray platforms to ensure small pathogenic variants are detected. To minimise the reporting of uncertain findings, it is recommended that variants of unknown significance (VOUS) smaller than 500 Kb deletion or 1 Mb duplication not be routinely reported in the prenatal context. Additionally, VOUS above these cut-offs should only be reported if there is significant supporting evidence that deletion or duplication of the region may be pathogenic (III-B) (recommendation 5); (4) secondary findings associated with a medically actionable disorder with childhood onset should be reported, whereas variants associated with adult-onset conditions should not be reported unless requested by the parents or disclosure can prevent serious harm to family members (III-A) (recommendation 8). The working group recognises that there is variability across Canada in delivery of prenatal testing, and these recommendations were developed to promote consistency and provide a minimum standard for all provinces and territories across the country (recommendation 9). PMID:29496978

A mutation in the XPB/ERCC3 DNA repair transcription gene, associated with trichothiodystrophy.

PubMed Central

Weeda, G; Eveno, E; Donker, I; Vermeulen, W; Chevallier-Lagente, O; Taïeb, A; Stary, A; Hoeijmakers, J H; Mezzina, M; Sarasin, A

1997-01-01

Trichothiodystrophy (TTD) is a rare, autosomal recessive disorder characterized by sulfur-deficient brittle hair and nails, mental retardation, impaired sexual development, and ichthyosis. Photosensitivity has been reported in approximately 50% of the cases, but no skin cancer is associated with TTD. Virtually all photosensitive TTD patients have a deficiency in the nucleotide excision repair (NER) of UV-induced DNA damage that is indistinguishable from that of xeroderma pigmentosum (XP) complementation group D (XP-D) patients. DNA repair defects in XP-D are associated with two additional, quite different diseases; XP, a sun-sensitive and cancer-prone repair disorder, and Cockayne syndrome (CS), a photosensitive condition characterized by physical and mental retardation and wizened facial appearance. One photosensitive TTD case constitutes a new repair-deficient complementation group, TTD-A. Remarkably, both TTD-A and XP-D defects are associated with subunits of TFIIH, a basal transcription factor with a second function in DNA repair. Thus, mutations in TFIIH components may, on top of a repair defect, also cause transcriptional insufficiency, which may explain part of the non-XP clinical features of TTD. Besides XPD and TTDA, the XPB gene product is also part of TFIIH. To date, three patients with the remarkable conjunction of XP and CS but not TTD have been assigned to XP complementation group B (XP-B). Here we present the characterization of the NER defect in two mild TTD patients (TTD6VI and TTD4VI) and confirm the assignment to X-PB. The causative mutation was found to be a single base substitution resulting in a missense mutation (T119P) in a region of the XPB protein completely conserved in yeast, Drosophila, mouse, and man. These findings define a third TTD complementation group, extend the clinical heterogeneity associated with XP-B, stress the exclusive relationship between TTD and mutations in subunits of repair/transcription factor TFIIH, and strongly support the concept of "transcription syndromes." Images Figure 6 PMID:9012405

Day and night variations in the repair of ionizing-radiation-induced DNA damage in mouse splenocytes.

PubMed

Palombo, Philipp; Moreno-Villanueva, Maria; Mangerich, Aswin

2015-04-01

In mammals, biological rhythms synchronize physiological and behavioral processes to the 24-h light-dark (LD) cycle. At the molecular level, self-sustaining processes, such as oscillations of transcription-translation feedback loops, control the circadian clock, which in turn regulates a wide variety of cellular processes, including gene expression and cell cycle progression. Furthermore, previous studies reported circadian oscillations in the repair capacity of DNA lesions specifically repaired by nucleotide excision repair (NER). However, it is so far only poorly understood if DNA repair pathways other than NER are under circadian control, in particular base excision and DNA strand break repair. In the present study, we analyzed potential day and night variations in the repair of DNA lesions induced by ionizing radiation (i.e., mainly oxidative damage and DNA strand breaks) in living mouse splenocytes using a modified protocol of the automated FADU assay. Our results reveal that splenocytes isolated from mice during the light phase (ZT06) displayed higher DNA repair activity than those of the dark phase (ZT18). As analyzed by highly sensitive and accurate qPCR arrays, these alterations were accompanied by significant differences in expression profiles of genes involved in the circadian clock and DNA repair. Notably, the majority of the DNA repair genes were expressed at higher levels during the light phase (ZT06). This included genes of all major DNA repair pathways with the strongest differences observed for genes of base excision and DNA double strand break repair. In conclusion, here we provide novel evidence that mouse splenocytes exhibit significant differences in the repair of IR-induced DNA damage during the LD cycle, both on a functional and on a gene expression level. It will be interesting to test if these findings could be exploited for therapeutic purposes, e.g. time-of-the-day-specific application of DNA-damaging treatments used against blood malignancies. Copyright © 2015 Elsevier B.V. All rights reserved.

Jasmonate-Mediated Induced Volatiles in the American Cranberry, Vaccinium macrocarpon: From Gene Expression to Organismal Interactions

PubMed Central

Rodriguez-Saona, Cesar R.; Polashock, James; Malo, Edi A.

2013-01-01

Jasmonates, i.e., jasmonic acid (JA) and methyl jasmonate (MeJA), are signaling hormones that regulate a large number of defense responses in plants which in turn affect the plants’ interactions with herbivores and their natural enemies. Here, we investigated the effect of jasmonates on the emission of volatiles in the American cranberry, Vaccinium macrocarpon, at different levels of biological organization from gene expression to organismal interactions. At the molecular level, four genes (BCS, LLS, NER1, and TPS21) responded significantly to gypsy moth larval feeding, MeJA, and mechanical wounding, but to different degrees. The most dramatic changes in expression of BCS and TPS21 (genes in the sesquiterpenoid pathway) were when treated with MeJA. Gypsy moth-damaged and MeJA-treated plants also had significantly elevated expression of LLS and NER1 (genes in the monoterpene and homoterpene biosynthesis pathways, respectively). At the biochemical level, MeJA induced a complex blend of monoterpene and sesquiterpene compounds that differed from gypsy moth and mechanical damage, and followed a diurnal pattern of emission. At the organismal level, numbers of Sparganothis sulfureana moths were lower while numbers of parasitic wasps were higher on sticky traps near MeJA-treated cranberry plants than those near untreated plants. Out of 11 leaf volatiles tested, (Z)-3-hexenyl acetate, linalool, and linalool oxide elicited strong antennal (EAG) responses from S. sulfureana, whereas sesquiterpenes elicited weak EAG responses. In addition, mortality of S. sulfureana larvae increased by about 43% in JA treated cranberry plants as compared with untreated plants, indicating a relationship among adult preference, antennal sensitivity to plant odors, and offspring performance. This study highlights the role of the jasmonate-dependent defensive pathway in the emissions of herbivore-induced volatiles in cranberries and its importance in multi-trophic level interactions. PMID:23641249

Jasmonate-Mediated Induced Volatiles in the American Cranberry, Vaccinium macrocarpon: From Gene Expression to Organismal Interactions.

PubMed

Rodriguez-Saona, Cesar R; Polashock, James; Malo, Edi A

2013-01-01

Jasmonates, i.e., jasmonic acid (JA) and methyl jasmonate (MeJA), are signaling hormones that regulate a large number of defense responses in plants which in turn affect the plants' interactions with herbivores and their natural enemies. Here, we investigated the effect of jasmonates on the emission of volatiles in the American cranberry, Vaccinium macrocarpon, at different levels of biological organization from gene expression to organismal interactions. At the molecular level, four genes (BCS, LLS, NER1, and TPS21) responded significantly to gypsy moth larval feeding, MeJA, and mechanical wounding, but to different degrees. The most dramatic changes in expression of BCS and TPS21 (genes in the sesquiterpenoid pathway) were when treated with MeJA. Gypsy moth-damaged and MeJA-treated plants also had significantly elevated expression of LLS and NER1 (genes in the monoterpene and homoterpene biosynthesis pathways, respectively). At the biochemical level, MeJA induced a complex blend of monoterpene and sesquiterpene compounds that differed from gypsy moth and mechanical damage, and followed a diurnal pattern of emission. At the organismal level, numbers of Sparganothis sulfureana moths were lower while numbers of parasitic wasps were higher on sticky traps near MeJA-treated cranberry plants than those near untreated plants. Out of 11 leaf volatiles tested, (Z)-3-hexenyl acetate, linalool, and linalool oxide elicited strong antennal (EAG) responses from S. sulfureana, whereas sesquiterpenes elicited weak EAG responses. In addition, mortality of S. sulfureana larvae increased by about 43% in JA treated cranberry plants as compared with untreated plants, indicating a relationship among adult preference, antennal sensitivity to plant odors, and offspring performance. This study highlights the role of the jasmonate-dependent defensive pathway in the emissions of herbivore-induced volatiles in cranberries and its importance in multi-trophic level interactions.

Histone deacetylases (HDACs) in XPC gene silencing and bladder cancer

PubMed Central

2011-01-01

Bladder cancer is one of the most common malignancies and causes hundreds of thousands of deaths worldwide each year. Bladder cancer is strongly associated with exposure to environmental carcinogens. It is believed that DNA damage generated by environmental carcinogens and their metabolites causes development of bladder cancer. Nucleotide excision repair (NER) is the major DNA repair pathway for repairing bulk DNA damage generated by most environmental carcinogens, and XPC is a DNA damage recognition protein required for initiation of the NER process. Recent studies demonstrate reduced levels of XPC protein in tumors for a majority of bladder cancer patients. In this work we investigated the role of histone deacetylases (HDACs) in XPC gene silencing and bladder cancer development. The results of our HDAC inhibition study revealed that the treatment of HTB4 and HTB9 bladder cancer cells with the HDAC inhibitor valproic acid (VPA) caused an increase in transcription of the XPC gene in these cells. The results of our chromatin immunoprecipitation (ChIP) studies indicated that the VPA treatment caused increased binding of both CREB1 and Sp1 transcription factors at the promoter region of the XPC gene for both HTB4 and HTB9 cells. The results of our immunohistochemistry (IHC) staining studies further revealed a strong correlation between the over-expression of HDAC4 and increased bladder cancer occurrence (p < 0.001) as well as a marginal significance of increasing incidence of HDAC4 positivity seen with an increase in severity of bladder cancer (p = 0.08). In addition, the results of our caspase 3 activation studies demonstrated that prior treatment with VPA increased the anticancer drug cisplatin-induced activation of caspase 3 in both HTB4 and HTB9 cells. All of these results suggest that the HDACs negatively regulate transcription of the XPC gene in bladder cancer cells and contribute to the severity of bladder tumors. PMID:21507255

Resistance to minor groove binders.

PubMed

Colmegna, Benedetta; Uboldi, Sarah; Erba, Eugenio; D'Incalci, Maurizio

2014-03-01

In this paper multiple resistance mechanisms to minor groove binders (MGBs) are overviewed. MGBs with antitumor properties are natural products or their derivatives and, as expected, they are all substrates of P-glycoprotein (P-gp). However, a moderate expression of P-gp does not appear to reduce the sensitivity to trabectedin, the only MGB so far approved for clinical use. Resistance to this drug is often related to transcriptional mechanisms and to DNA repair pathways, particularly defects in transcription-coupled nucleotide excision repair (TC-NER). Therefore tumors resistant to trabectedin may become hypersensitive to UV rays and other DNA damaging agents acting in the major groove, such as Platinum (Pt) complexes. If this is confirmed in clinic, that will provide the rationale to combine trabectedin sequentially with Pt derivates.

Consortium for Verification Technology Fellowship Report.

DOE Office of Scientific and Technical Information (OSTI.GOV)

Sadler, Lorraine E.

2017-06-01

As one recipient of the Consortium for Verification Technology (CVT) Fellowship, I spent eight days as a visiting scientist at the University of Michigan, Department of Nuclear Engineering and Radiological Sciences (NERS). During this time, I participated in multiple department and research group meetings and presentations, met with individual faculty and students, toured multiple laboratories, and taught one-half of a one-unit class on Risk Analysis in Nuclear Arms control (six 1.5 hour lectures). The following report describes some of the interactions that I had during my time as well as a brief discussion of the impact of this fellowship onmore » members of the consortium and on me/my laboratory’s technical knowledge and network.« less

Thermodynamic versus non-equilibrium stability of palmitic acid monolayers in calcium-enriched sea spray aerosol proxy systems.

PubMed

Wellen Rudd, Bethany A; Vidalis, Andrew S; Allen, Heather C

2018-04-16

Of the major cations in seawater (Na+, Mg2+, Ca2+, K+), Ca2+ is found to be the most enriched in fine sea spray aerosols (SSA). In this work, we investigate the binding of Ca2+ to the carboxylic acid headgroup of palmitic acid (PA), a marine-abundant fatty acid, and the impact such binding has on the stability of PA monolayers in both equilibrium and non-equilibrium systems. A range of Ca2+ conditions from 10 μM to 300 mM was utilized to represent the relative concentration of Ca2+ in high and low relative humidity aerosol environments. The CO2- stretching modes of PA detected by surface-sensitive infrared reflection-absorption spectroscopy (IRRAS) reveal ionic binding motifs of the Ca2+ ion to the carboxylate group with varying degrees of hydration. Surface tensiometry was used to determine the thermodynamic equilibrium spreading pressure (ESP) of PA on the various aqueous CaCl2 subphases. Up to concentrations of 1 mM Ca2+, each system reached equilibrium, and Ca2+:PA surface complexation gave rise to a lower energy state revealed by elevated surface pressures relative to water. We show that PA films are not thermodynamically stable at marine aerosol-relevant Ca2+ concentrations ([Ca2+] ≥ 10 mM). IRRAS and vibrational sum frequency generation (VSFG) spectroscopy were used to investigate the surface presence of PA on high concentration Ca2+ aqueous subphases. Non-equilibrium relaxation (NER) experiments were also conducted and monitored by Brewster angle microscopy (BAM) to determine the effect of the Ca2+ ions on PA stability. At high surface pressures, the relaxation mechanisms of PA varied among the systems and were dependent on Ca2+ concentration.

Folie à Trois à Lubumbashi: à propos d’un cas

PubMed Central

Bugeme, Marcellin; Mukuku, Olivier; Mobambo, Pitchou; Koba, Bora; Muyumba, Emmanuel

2013-01-01

Le trouble psychotique partagé est une entité psychiatrique rare caractérisée par la transmission des idées délirantes d’un patient dit “inducteur”, à un autre dit “induit”, tous vivant en association proche, dans un milieu clos et isolé, partageant des idées délirantes sur le même thème. Nous vous rapportons un cas clinique de “folie à trois” mettant en jeu un délire de persécution à mécanisme hallucinatoire et interprétatif par trois soeurs de même famille biologique, orphelines de père, vivant ensemble, ayant un niveau socio-économique bas après la mort de leur père. Elles ont des relations étroitement liéeset font leurs activités ensemble. L’aînée étant parvenue à partager ses idées délirantes avec ses soeurs et toutes troisse sont retrouvées dans un état d’excitation psychomotrice. PMID:23560130

Retrograde stapling of a free cervical jejunal interposition graft: a technical innovation and case report

PubMed Central

2014-01-01

Background Free jejunal interposition is a useful technique for reconstruction of the cervical esophagus. However, the distal anastomosis between the graft and the remaining thoracic esophagus or a gastric conduit can be technically challenging when located very low in the thoracic aperture. We here describe a modified technique for retrograde stapling of a jejunal graft to a failed gastric conduit using a circular stapler on a delivery system. Case presentation A 56 year-old patient had been referred for esophageal squamous cell carcinoma at 20 cm from the incisors. On day 8 after thoracoabdominal esophagectomy with gastric pull-up, an anastomotic leakage was diagnosed. A proximal-release stent was successfully placed by gastroscopy and the patient was discharged. Two weeks later, an esophagotracheal fistula occurred proximal to the esophageal stent. Cervical esophagostomy was performed with cranial closure of the gastric conduit, which was left in situ within the right hemithorax. Three months later, reconstruction was performed using a free jejunal interposition. The anvil of a circular stapler (Orvil®, Covidien) was placed transabdominally through an endoscopic rendez-vous procedure into the gastric conduit. A free jejunal graft was retrogradely stapled to the proximal end of the conduit. Microvascular anastomoses were performed subsequently. The proximal anastomosis of the conduit was completed manually after reperfusion. Conclusions This modified technique allows stapling of a jejunal interposition graft located deep in the thoracic aperture and is therefore a useful method that may help to avoid reconstruction by colonic pull-up and thoracotomy. PMID:25319372

Using Workflows to Explore and Optimise Named Entity Recognition for Chemistry

PubMed Central

Kolluru, BalaKrishna; Hawizy, Lezan; Murray-Rust, Peter; Tsujii, Junichi; Ananiadou, Sophia

2011-01-01

Chemistry text mining tools should be interoperable and adaptable regardless of system-level implementation, installation or even programming issues. We aim to abstract the functionality of these tools from the underlying implementation via reconfigurable workflows for automatically identifying chemical names. To achieve this, we refactored an established named entity recogniser (in the chemistry domain), OSCAR and studied the impact of each component on the net performance. We developed two reconfigurable workflows from OSCAR using an interoperable text mining framework, U-Compare. These workflows can be altered using the drag-&-drop mechanism of the graphical user interface of U-Compare. These workflows also provide a platform to study the relationship between text mining components such as tokenisation and named entity recognition (using maximum entropy Markov model (MEMM) and pattern recognition based classifiers). Results indicate that, for chemistry in particular, eliminating noise generated by tokenisation techniques lead to a slightly better performance than others, in terms of named entity recognition (NER) accuracy. Poor tokenisation translates into poorer input to the classifier components which in turn leads to an increase in Type I or Type II errors, thus, lowering the overall performance. On the Sciborg corpus, the workflow based system, which uses a new tokeniser whilst retaining the same MEMM component, increases the F-score from 82.35% to 84.44%. On the PubMed corpus, it recorded an F-score of 84.84% as against 84.23% by OSCAR. PMID:21633495

Using workflows to explore and optimise named entity recognition for chemistry.

PubMed

Kolluru, Balakrishna; Hawizy, Lezan; Murray-Rust, Peter; Tsujii, Junichi; Ananiadou, Sophia

2011-01-01

Chemistry text mining tools should be interoperable and adaptable regardless of system-level implementation, installation or even programming issues. We aim to abstract the functionality of these tools from the underlying implementation via reconfigurable workflows for automatically identifying chemical names. To achieve this, we refactored an established named entity recogniser (in the chemistry domain), OSCAR and studied the impact of each component on the net performance. We developed two reconfigurable workflows from OSCAR using an interoperable text mining framework, U-Compare. These workflows can be altered using the drag-&-drop mechanism of the graphical user interface of U-Compare. These workflows also provide a platform to study the relationship between text mining components such as tokenisation and named entity recognition (using maximum entropy Markov model (MEMM) and pattern recognition based classifiers). Results indicate that, for chemistry in particular, eliminating noise generated by tokenisation techniques lead to a slightly better performance than others, in terms of named entity recognition (NER) accuracy. Poor tokenisation translates into poorer input to the classifier components which in turn leads to an increase in Type I or Type II errors, thus, lowering the overall performance. On the Sciborg corpus, the workflow based system, which uses a new tokeniser whilst retaining the same MEMM component, increases the F-score from 82.35% to 84.44%. On the PubMed corpus, it recorded an F-score of 84.84% as against 84.23% by OSCAR.

Bauschinger Effect in an Austenitic Steel: Neutron Diffraction and a Multiscale Approach

NASA Astrophysics Data System (ADS)

Fajoui, Jamal; Gloaguen, David; Legrand, Vincent; Oum, Guy; Kelleher, Joe; Kockelmann, Winfried

2016-05-01

The generation of internal stresses/strains arising from mechanical deformations in single-phase engineering materials was studied. Neutron diffraction measurements were performed to study the evolution of intergranular strains in austenitic steel during sequential loadings. Intergranular strains expand due to incompatibilities between grains and also resulting from single-crystal elastic and plastic anisotropy. A two-level homogenization approach was adopted in order to predict the mechanical state of deformed polycrystals in relation to the microstructure during Bauschinger tests. A mechanical description of the grain was developed through a micro-meso transition based on the Kröner model. The meso-macro transition using a self-consistent approach was applied to deduce the global behavior. Mechanical tests and neutron diffraction measurements were used to validate and assess the model.

Image-Based Approach to Mapping, Charting, and Geodesy.

DTIC Science & Technology

1982-02-01

he..( reit- , st the .S Armyv I-npi ner Topographic Laboratories-, hll. Pi."ht inltete;(d inl de term ining the taipabil1i t ic e s nd 8 raotlhacho_...a.ve-ttor- bas-ed tipo I pi calIlIv t i l t ill-( I C I S) I (,r PiPC t; al p I( I i lt i ll (S fai-p i(%’ c t alI . , 1978’) , tr I F :TI, rt it I.,r...rt is to pr i de f 𔃻i : i t i t t he r in I ts of () Po r sei relit inidiui tic-d a t ,IllP. i n dir - ut t \\ Ii lisP Ordr l-P!U, Anit-odment Noe. 125

Radar correlated imaging for extended target by the combination of negative exponential restraint and total variation

NASA Astrophysics Data System (ADS)

Qian, Tingting; Wang, Lianlian; Lu, Guanghua

2017-07-01

Radar correlated imaging (RCI) introduces the optical correlated imaging technology to traditional microwave imaging, which has raised widespread concern recently. Conventional RCI methods neglect the structural information of complex extended target, which makes the quality of recovery result not really perfect, thus a novel combination of negative exponential restraint and total variation (NER-TV) algorithm for extended target imaging is proposed in this paper. The sparsity is measured by a sequential order one negative exponential function, then the 2D total variation technique is introduced to design a novel optimization problem for extended target imaging. And the proven alternating direction method of multipliers is applied to solve the new problem. Experimental results show that the proposed algorithm could realize high resolution imaging efficiently for extended target.

Practice guideline: joint CCMG-SOGC recommendations for the use of chromosomal microarray analysis for prenatal diagnosis and assessment of fetal loss in Canada.

PubMed

Armour, Christine M; Dougan, Shelley Danielle; Brock, Jo-Ann; Chari, Radha; Chodirker, Bernie N; DeBie, Isabelle; Evans, Jane A; Gibson, William T; Kolomietz, Elena; Nelson, Tanya N; Tihy, Frédérique; Thomas, Mary Ann; Stavropoulos, Dimitri J

2018-04-01

The aim of this guideline is to provide updated recommendations for Canadian genetic counsellors, medical geneticists, maternal fetal medicine specialists, clinical laboratory geneticists and other practitioners regarding the use of chromosomal microarray analysis (CMA) for prenatal diagnosis. This guideline replaces the 2011 Society of Obstetricians and Gynaecologists of Canada (SOGC)-Canadian College of Medical Geneticists (CCMG) Joint Technical Update. A multidisciplinary group consisting of medical geneticists, genetic counsellors, maternal fetal medicine specialists and clinical laboratory geneticists was assembled to review existing literature and guidelines for use of CMA in prenatal care and to make recommendations relevant to the Canadian context. The statement was circulated for comment to the CCMG membership-at-large for feedback and, following incorporation of feedback, was approved by the CCMG Board of Directors on 5 June 2017 and the SOGC Board of Directors on 19 June 2017. Recommendations include but are not limited to: (1) CMA should be offered following a normal rapid aneuploidy screen when multiple fetal malformations are detected (II-1A) or for nuchal translucency (NT) ≥3.5 mm (II-2B) (recommendation 1); (2) a professional with expertise in prenatal chromosomal microarray analysis should provide genetic counselling to obtain informed consent, discuss the limitations of the methodology, obtain the parental decisions for return of incidental findings (II-2A) (recommendation 4) and provide post-test counselling for reporting of test results (III-A) (recommendation 9); (3) the resolution of chromosomal microarray analysis should be similar to postnatal microarray platforms to ensure small pathogenic variants are detected. To minimise the reporting of uncertain findings, it is recommended that variants of unknown significance (VOUS) smaller than 500 Kb deletion or 1 Mb duplication not be routinely reported in the prenatal context. Additionally, VOUS above these cut-offs should only be reported if there is significant supporting evidence that deletion or duplication of the region may be pathogenic (III-B) (recommendation 5); (4) secondary findings associated with a medically actionable disorder with childhood onset should be reported, whereas variants associated with adult-onset conditions should not be reported unless requested by the parents or disclosure can prevent serious harm to family members (III-A) (recommendation 8).The working group recognises that there is variability across Canada in delivery of prenatal testing, and these recommendations were developed to promote consistency and provide a minimum standard for all provinces and territories across the country (recommendation 9). © Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2018. All rights reserved. No commercial use is permitted unless otherwise expressly granted.

Effects of methyl and inorganic mercury exposure on genome homeostasis and mitochondrial function in Caenorhabditis elegans.

PubMed

Wyatt, Lauren H; Luz, Anthony L; Cao, Xiou; Maurer, Laura L; Blawas, Ashley M; Aballay, Alejandro; Pan, William K Y; Meyer, Joel N

2017-04-01

Mercury toxicity mechanisms have the potential to induce DNA damage and disrupt cellular processes, like mitochondrial function. Proper mitochondrial function is important for cellular bioenergetics and immune signaling and function. Reported impacts of mercury on the nuclear genome (nDNA) are conflicting and inconclusive, and mitochondrial DNA (mtDNA) impacts are relatively unknown. In this study, we assessed genotoxic (mtDNA and nDNA), metabolic, and innate immune impacts of inorganic and organic mercury exposure in Caenorhabditis elegans. Genotoxic outcomes measured included DNA damage, DNA damage repair (nucleotide excision repair, NER; base excision repair, BER), and genomic copy number following MeHg and HgCl 2 exposure alone and in combination with known DNA damage-inducing agents ultraviolet C radiation (UVC) and hydrogen peroxide (H 2 O 2 ), which cause bulky DNA lesions and oxidative DNA damage, respectively. Following exposure to both MeHg and HgCl 2 , low-level DNA damage (∼0.25 lesions/10kb mtDNA and nDNA) was observed. Unexpectedly, a higher MeHg concentration reduced damage in both genomes compared to controls. However, this observation was likely the result of developmental delay. In co-exposure treatments, both mercury compounds increased initial DNA damage (mtDNA and nDNA) in combination with H 2 O 2 exposure, but had no impact in combination with UVC exposure. Mercury exposure both increased and decreased DNA damage removal via BER. DNA repair after H 2 O 2 exposure in mercury-exposed nematodes resulted in damage levels lower than measured in controls. Impacts to NER were not detected. mtDNA copy number was significantly decreased in the MeHg-UVC and MeHg-H 2 O 2 co-exposure treatments. Mercury exposure had metabolic impacts (steady-state ATP levels) that differed between the compounds; HgCl 2 exposure decreased these levels, while MeHg slightly increased levels or had no impact. Both mercury species reduced mRNA levels for immune signaling-related genes, but had mild or no effects on survival on pathogenic bacteria. Overall, mercury exposure disrupted mitochondrial endpoints in a mercury-compound dependent fashion. Copyright © 2017 Elsevier B.V. All rights reserved.

Effects of methyl and inorganic mercury exposure on genome homeostasis and mitochondrial function in Caenorhabditis elegans

PubMed Central

Wyatt, Lauren H.; Luz, Anthony L.; Cao, Xiou; Maurer, Laura L.; Blawas, Ashley M.; Aballay, Alejandro; Pan, William K.; Meyer, Joel N.

2017-01-01

Mercury toxicity mechanisms have the potential to induce DNA damage and disrupt cellular processes, like mitochondrial function. Proper mitochondrial function is important for cellular bioenergetics and immune signaling and function. Impacts of mercury on the nuclear genome (nDNA) are conflicting and inconclusive, and mitochondrial DNA (mtDNA) impacts are relatively unknown. In this study, we assessed genotoxic (mtDNA and nDNA), metabolic, and innate immune impacts of inorganic and organic mercury exposure in Caenorhabditis elegans. Genotoxic outcomes measured included DNA damage, DNA damage repair (nucleotide excision repair, NER; base excision repair, BER), and genomic copy number following MeHg and HgCl2 exposure alone and in combination with known DNA damage-inducing agents ultraviolet C radiation (UVC) and hydrogen peroxide (H2O2), which cause bulky DNA lesions and oxidative DNA damage, respectively. Following exposure to both MeHg and HgCl2, low-level DNA damage (~0.25 lesions/10 kb mtDNA and nDNA) was observed. Unexpectedly, a higher MeHg concentration reduced damage in both genomes compared to controls. However, this observation was likely the result of developmental delay. In co-exposure treatments, both mercury compounds increased initial DNA damage (mtDNA and nDNA) in combination with H2O2 exposure, but had no impact in combination with UVC exposure. Mercury exposure both increased and decreased DNA damage removal via BER. DNA repair after H2O2 exposure in mercury-exposed nematodes resulted in damage levels lower than measured in controls. Impacts to NER were not detected. mtDNA copy number was significantly decreased in the MeHg-UVC and MeHg-H2O2 co-exposure treatments. Mercury exposure had metabolic impacts (steady-state ATP levels) that differed between the compounds; HgCl2 exposure decreased these levels, while MeHg slightly increased levels or had no impact. Both mercury species reduced mRNA levels for immune signaling-related genes, but had mild or no effects on survival on pathogenic bacteria. Overall, mercury exposure disrupted mitochondrial endpoints in a mercury-compound dependent fashion. PMID:28242054

Analysis of Genetic Diversity and Population Structure of Rice Germplasm from North-Eastern Region of India and Development of a Core Germplasm Set

PubMed Central

Singh, Amit Kumar; Kumar, Sundeep; Srinivasan, Kalyani; Tyagi, R. K.; Ahmad, Altaf; Singh, N. K.; Singh, Rakesh

2014-01-01

The North-Eastern region (NER) of India, comprising of Arunachal Pradesh, Assam, Manipur, Meghalaya, Mizoram, Nagaland and Tripura, is a hot spot for genetic diversity and the most probable origin of rice. North-east rice collections are known to possess various agronomically important traits like biotic and abiotic stress tolerance, unique grain and cooking quality. The genetic diversity and associated population structure of 6,984 rice accessions, originating from NER, were assessed using 36 genome wide unlinked single nucleotide polymorphism (SNP) markers distributed across the 12 rice chromosomes. All of the 36 SNP loci were polymorphic and bi-allelic, contained five types of base substitutions and together produced nine types of alleles. The polymorphic information content (PIC) ranged from 0.004 for Tripura to 0.375 for Manipur and major allele frequency ranged from 0.50 for Assam to 0.99 for Tripura. Heterozygosity ranged from 0.002 in Nagaland to 0.42 in Mizoram and gene diversity ranged from 0.006 in Arunachal Pradesh to 0.50 in Manipur. The genetic relatedness among the rice accessions was evaluated using an unrooted phylogenetic tree analysis, which grouped all accessions into three major clusters. For determining population structure, populations K = 1 to K = 20 were tested and population K = 3 was present in all the states, with the exception of Meghalaya and Manipur where, K = 5 and K = 4 populations were present, respectively. Principal Coordinate Analysis (PCoA) showed that accessions were distributed according to their population structure. AMOVA analysis showed that, maximum diversity was partitioned at the individual accession level (73% for Nagaland, 58% for Arunachal Pradesh and 57% for Tripura). Using POWERCORE software, a core set of 701 accessions was obtained, which accounted for approximately 10% of the total NE India collections, representing 99.9% of the allelic diversity. The rice core set developed will be a valuable resource for future genomic studies and crop improvement strategies. PMID:25412256

Red meat and poultry intake, polymorphisms in the nucleotide excision repair and mismatch repair pathways and colorectal cancer risk

PubMed Central

Joshi, Amit D.; Corral, Román; Siegmund, Kimberly D.; Haile, Robert W.; Le Marchand, Loïc; Martínez, Maria Elena; Ahnen, Dennis J.; Sandler, Robert S.; Lance, Peter; Stern, Mariana C.

2009-01-01

Diets high in red meat have been consistently associated with colorectal cancer (CRC) risk and may result in exposure to carcinogens that cause DNA damage [i.e polycyclic aromatic hydrocarbons, heterocyclic amines (HCAs) and N-nitroso compounds]. Using a family-based study, we investigated whether polymorphisms in the nucleotide excision repair (NER) (ERCC1 3′ untranslated region (UTR) G/T, XPD Asp312Asn and Lys751Gln, XPC intron 11 C/A, XPA 5′ UTR C/T, XPF Arg415Gln and XPG Asp1104His) and mismatch repair (MLH1 Ile219Val and MSH2 Gly322Asp) pathways modified the association with red meat and poultry intake. We tested for gene–environment interactions using case-only analyses (n = 577) and compared the results using case-unaffected sibling comparisons (n = 307 sibships). Increased risk of CRC was observed for intake of more than or equal to three servings per week of red meat [odds ratio (OR) = 1.8, 95% confidence interval (CI) = 1.3–2.5)] or high-temperature cooked red meat (OR = 1.6, 95% CI = 1.1–2.2). Intake of red meat heavily brown on the outside or inside increased CRC risk only among subjects who carried the XPD codon 751 Lys/Lys genotype (case-only interaction P = 0.006 and P = 0.001, respectively, for doneness outside or inside) or the XPD codon 312 Asp/Asp genotype (case-only interaction P = 0.090 and P < 0.001, respectively). These interactions were stronger for rectal cancer cases (heterogeneity test P = 0.002 for XPD Asp312Asn and P = 0.03 for XPD Lys751Gln) and remained statistically significant after accounting for multiple testing. Case-unaffected sibling analyses were generally supportive of the case-only results. These findings highlight the possible contribution of diets high in red meat to the formation of lesions that elicit the NER pathway, such as carcinogen-induced bulky adducts. PMID:19029193

NMR structure of the DNA decamer duplex containing double T*G mismatches of cis-syn cyclobutane pyrimidine dimer: implications for DNA damage recognition by the XPC-hHR23B complex.

PubMed

Lee, Joon-Hwa; Park, Chin-Ju; Shin, Jae-Sun; Ikegami, Takahisa; Akutsu, Hideo; Choi, Byong-Seok

2004-01-01

The cis-syn cyclobutane pyrimidine dimer (CPD) is a cytotoxic, mutagenic and carcinogenic DNA photoproduct and is repaired by the nucleotide excision repair (NER) pathway in mammalian cells. The XPC-hHR23B complex as the initiator of global genomic NER binds to sites of certain kinds of DNA damage. Although CPDs are rarely recognized by the XPC-hHR23B complex, the presence of mismatched bases opposite a CPD significantly increased the binding affinity of the XPC-hHR23B complex to the CPD. In order to decipher the properties of the DNA structures that determine the binding affinity for XPC-hHR23B to DNA, we carried out structural analyses of the various types of CPDs by NMR spectroscopy. The DNA duplex which contains a single 3' T*G wobble pair in a CPD (CPD/GA duplex) induces little conformational distortion. However, severe distortion of the helical conformation occurs when a CPD contains double T*G wobble pairs (CPD/GG duplex) even though the T residues of the CPD form stable hydrogen bonds with the opposite G residues. The helical bending angle of the CPD/GG duplex was larger than those of the CPD/GA duplex and properly matched CPD/AA duplex. The fluctuation of the backbone conformation and significant changes in the widths of the major and minor grooves at the double T*G wobble paired site were also observed in the CPD/GG duplex. These structural features were also found in a duplex that contains the (6-4) adduct, which is efficiently recognized by the XPC-hHR23B complex. Thus, we suggest that the unique structural features of the DNA double helix (that is, helical bending, flexible backbone conformation, and significant changes of the major and/or minor grooves) might be important factors in determining the binding affinity of the XPC-hHR23B complex to DNA.

Psychosocial mediators of change in physical activity in the Welsh national exercise referral scheme: secondary analysis of a randomised controlled trial.

PubMed

Littlecott, Hannah J; Moore, Graham F; Moore, Laurence; Murphy, Simon

2014-08-27

While an increasing number of randomised controlled trials report impacts of exercise referral schemes (ERS) on physical activity, few have investigated the mechanisms through which increases in physical activity are produced. This study examines whether a National Exercise Referral Scheme (NERS) in Wales is associated with improvements in autonomous motivation, self-efficacy and social support, and whether change in physical activity is mediated by change in these psychosocial processes. A pragmatic randomised controlled trial of NERS across 12 LHBs in Wales. Questionnaires measured demographic data and physical activity at baseline. Participants (N = 2160) with depression, anxiety or CHD risk factors were referred by health professionals and randomly assigned to control or intervention. At six months psychological process measures were collected by questionnaire. At 12 months physical activity was assessed by 7 Day PAR telephone interview. Regressions tested intervention effects on psychosocial variables, physical activity before and after adjusting for mediators and socio demographic patterning. Significant intervention effects were found for autonomous motivation and social support for exercise at 6 months. No intervention effect was observed for self-efficacy. The data are consistent with a hypothesis of partial mediation of the intervention effect by autonomous motivation. Analysis of moderators showed significant improvements in relative autonomy in all subgroups. The greatest improvements in autonomous motivation were observed among patients who were least active at baseline. The present study offered key insights into psychosocial processes of change in an exercise referral scheme, with effects on physical activity mediated by autonomous motivation. Findings support the use of self-determination theory as a framework for ERS. Further research is required to explain socio-demographic patterning in responses to ERS, with changes in motivation occurring among all sub-groups of participants, though not always leading to higher adherence or behavioural change. This highlights the importance of socio-ecological approaches to developing and evaluating behaviour change interventions, which consider factors beyond the individual, including conditions in which improved motivation does or does not produce behavioural change. ISRCTN47680448.

MicroRNAs as Biomarkers for Acute Atrial Remodeling in Marathon Runners (The miRathon Study – A Sub-Study of the Munich Marathon Study)

PubMed Central

Hildebrand, Bianca; Kääb, Stefan; Hoster, Eva; Klier, Ina; Martens, Eimo; Hanley, Alan; Hanssen, Henner; Halle, Martin; Nickel, Thomas

2016-01-01

Introduction Physical activity is beneficial for individual health, but endurance sport is associated with the development of arrhythmias like atrial fibrillation. The underlying mechanisms leading to this increased risk are still not fully understood. MicroRNAs are important mediators of proarrhythmogenic remodeling and have potential value as biomarkers in cardiovascular diseases. Therefore, the objective of our study was to determine the value of circulating microRNAs as potential biomarkers for atrial remodeling in marathon runners (miRathon study). Methods 30 marathon runners were recruited into our study and were divided into two age-matched groups depending on the training status: elite (ER, ≥55 km/week, n = 15) and non-elite runners (NER, ≤40 km/week, n = 15). All runners participated in a 10 week training program before the marathon. MiRNA plasma levels were measured at 4 time points: at baseline (V1), after a 10 week training period (V2), immediately after the marathon (V3) and 24h later (V4). Additionally, we obtained clinical data including serum chemistry and echocardiography at each time point. Results MiRNA plasma levels were similar in both groups over time with more pronounced changes in ER. After the marathon miR-30a plasma levels increased significantly in both groups. MiR-1 and miR-133a plasma levels also increased but showed significant changes in ER only. 24h after the marathon plasma levels returned to baseline. MiR-26a decreased significantly after the marathon in elite runners only and miR-29b showed a non-significant decrease over time in both groups. In ER miRNA plasma levels showed a significant correlation with LA diameter, in NER miRNA plasma levels did not correlate with echocardiographic parameters. Conclusion MiRNAs were differentially expressed in the plasma of marathon runners with more pronounced changes in ER. Plasma levels in ER correlate with left atrial diameter suggesting that circulating miRNAs could potentially serve as biomarkers of atrial remodeling in athletes. PMID:26859843

Energy balances and greenhouse gas emissions of crude palm oil production system in Indonesia (Case study: Mill P, PT X, Sumatera Island)

NASA Astrophysics Data System (ADS)

Andarani, Pertiwi; Nugraha, Winardi Dwi; Wieddya

2017-03-01

Indonesia is one of the largest palm oil producers in the world. The total exported crude palm oil (CPO) and its derivatives in 2015 reached about 26.40 million tons or increase at 21% compared to the previous year (2014). However, the further expansion of the CPO production system could potentially have environmental impacts. The objective of this study is to analyze the energy balances and greenhouse gas emissions at mill P, PT X located in Sumatera Island. System analysis approaches was applied to this study and the assessment was focused on a CPO production system in PT XYZ located on the Sumatera Island. The system boundary was determined based on the field study. The data collection consisted of all the input and output energy which involving all input materials (including fertilizers, herbicides, pesticides, water, etc.) and energy consumption (consumption of diesel, electricity, etc.) starting from plantation activities (at the oil palm plantation) to the conversion process (at the palm oil mill). The energy output from biodiesel was 480.46 GJ/ha (2014) and decreased to 450.79 GJ/ha (2015). Surplus energy from biogas was 15.21 GJ/ha (2014) and 13.57 GJ/ha (2015). The NEP was 494.56 GJ/ha and decreased to 317.84 GJ/ha. Meanwhile, the NER decreased from 3.27 (2014) to 3.17 (2015). The NEP in this mill is significantly higher than other related studies of similar palm oil production system in other companies. The emission of the activities in the palm estate increased from 12.50 kgCO2eq/ton FFB to 22.057 kgCO2eq/ton FFB. In the palm oil mill, the emission decreased from 2,509.93 kgCO2eq/ton CPO to 2,057.14 kgCO2eq/ton CPO.

Cloning and characterization of p52, the fifth subunit of the core of the transcription/DNA repair factor TFIIH.

PubMed Central

Marinoni, J C; Roy, R; Vermeulen, W; Miniou, P; Lutz, Y; Weeda, G; Seroz, T; Gomez, D M; Hoeijmakers, J H; Egly, J M

1997-01-01

TFIIH is a multiprotein factor involved in transcription and DNA repair and is implicated in DNA repair/transcription deficiency disorders such as xeroderma pigmentosum, Cockayne syndrome and trichothiodystrophy. Eight out of the nine genes encoding the subunits forming TFIIH have already been cloned. We report here the identification, cDNA cloning and gene structure of the 52 kDa polypeptide and its homology with the yeast counterpart TFB2. This protein, along with p89/XPB, p62, p44 and p34, forms the core of TFIIH. Moreover, using in vitro reconstituted transcription and nucleotide excision repair (NER) assays and microinjection experiments, we demonstrate that p52 is directly involved in both transcription and DNA repair mechanisms in vitro and in vivo. PMID:9118947

Gimli: open source and high-performance biomedical name recognition

PubMed Central

2013-01-01

Background Automatic recognition of biomedical names is an essential task in biomedical information extraction, presenting several complex and unsolved challenges. In recent years, various solutions have been implemented to tackle this problem. However, limitations regarding system characteristics, customization and usability still hinder their wider application outside text mining research. Results We present Gimli, an open-source, state-of-the-art tool for automatic recognition of biomedical names. Gimli includes an extended set of implemented and user-selectable features, such as orthographic, morphological, linguistic-based, conjunctions and dictionary-based. A simple and fast method to combine different trained models is also provided. Gimli achieves an F-measure of 87.17% on GENETAG and 72.23% on JNLPBA corpus, significantly outperforming existing open-source solutions. Conclusions Gimli is an off-the-shelf, ready to use tool for named-entity recognition, providing trained and optimized models for recognition of biomedical entities from scientific text. It can be used as a command line tool, offering full functionality, including training of new models and customization of the feature set and model parameters through a configuration file. Advanced users can integrate Gimli in their text mining workflows through the provided library, and extend or adapt its functionalities. Based on the underlying system characteristics and functionality, both for final users and developers, and on the reported performance results, we believe that Gimli is a state-of-the-art solution for biomedical NER, contributing to faster and better research in the field. Gimli is freely available at http://bioinformatics.ua.pt/gimli. PMID:23413997

Laparoendoscopic management of concomitant gallbladder stones and common bile duct stones: what is the best technique?

PubMed

El-Geidie, Ahmed Abdel-Raouf

2011-08-01

The intraoperative use of endoscopic retrograde cholangiopancreatography (ERCP) during laparoscopic cholecystectomy (LC) is a safe, single-stage option for the management of concomitant gallstones (GS) and common bile duct stones (CBDS). This study aims to compare between 2 techniques of combined laparoendoscopic management, which are laparoendoscopic Rendez-vous (LC/LERV) technique and standard ERCP after the completion of LC intraoperative endoscopic sphincterotomy (IOES). Patients with GS and suspected CBDS were included. They were divided into 2 groups; LC/LERV and LC/IOES. Both groups were compared for failure of endoscopic sphincterotomy/stone extraction, operative time, conversion rate, mortality/morbidity, and length of hospital stay. Between October 2007 and February 2010, 98 patients with GS and CBDS were eligible for inclusion in the study. They were prospectively randomized into 2 groups; LC/LERV (N=45) and LC/IOES (N=53). There were no differences in preoperative parameters between both groups. There was a significant difference in operative time (shorter for LC/IOES). No difference was noted in success/failure rate, post-ERCP pancreatitis. Both Standard ERCP after the completion of LC and LC/LERV are valid single-session management for CBD stones, but LC-ERCP may be preferred.

Electronic mail, a new written-language register: a study with French-speaking adolescents.

PubMed

Volckaert-Legrier, Olga; Bernicot, Josie; Bert-Erboul, Alain

2009-03-01

The aim of this study was to determine the extent to which the linguistic forms used by adolescents in electronic mail (e-mail) differ from those used in standard written language. The study was conducted in French, a language with a deep orthography that has strict, addressee-dependent rules for using second person personal pronouns (unfamiliar and familiar forms). Data were collected from 80 adolescents ages 12 to 15 in a natural situation where they had to introduce themselves by e-mail to two addressees (peer/teacher). Participants were divided into two groups (skilled/unskilled in computer-mediated communication). Their emails contained a large number of orthographic deviations (the most frequent being neographic forms). Participants skilled in computer-mediated communication (CMC) deviated more than unskilled ones did. The number of orthographic deviations was not linked to the participants' standard writing ability. The personal-pronoun data clearly showed that adolescents used the familiar form of 'you' (tu) to address the peer and the unfamiliar form (vous) to address the teacher. We conclude that, for adolescents, e-mail constitutes a distinct written-language register. Nevertheless, the e-mail register seems to follow the pragmatic rules of standard spoken and written interaction.

Modelling of 67P cometary grains dynamic in the vicinity of the Rosetta spacecraft

NASA Astrophysics Data System (ADS)

Cipriani, F.; Altobelli, N.; Taylor, M.; Fulle, M.; Della Corte, V.; Rotundi, A.

2017-09-01

The interpretation of a number of Rosetta datasets (e.g. GIADA, COSIMA, MIDAS...), relies on the description of cometary grains dynamic in the close vicinity of the spacecraft. In particular the charged grains behaviour in the 3D spacecraft sheath open to the instrument entrances is complex and has not been described at such scales. The existence of a warm electrons population (a few 10eVs energy) in the cometary plasma as revealed during the Rendez-vous phase has been driving the spacecraft potential to negative values typically in the range -1 to -20V as inferred from RPC measurements [1]. Observation of cometary grains in the 10μm to mm range by GIADA and COSIMA[2] allowed to distinguish so called 'compact' grains of processed materials from the solar nebula from 'fluffy' aggregates of more primitive origin. When detected such grains have been observed to reach the instruments at m/s or less velocities. On particular it was inferred that fluffy aggregates are disrupted by electrostatic forces in the vicinity of the spacecraft due to the effects of local plasma hence resulting in particle showers observed by the instruments.

Structural and Sequence Similarities of Hydra Xeroderma Pigmentosum A Protein to Human Homolog Suggest Early Evolution and Conservation

PubMed Central

Ghaskadbi, Saroj

2013-01-01

Xeroderma pigmentosum group A (XPA) is a protein that binds to damaged DNA, verifies presence of a lesion, and recruits other proteins of the nucleotide excision repair (NER) pathway to the site. Though its homologs from yeast, Drosophila, humans, and so forth are well studied, XPA has not so far been reported from protozoa and lower animal phyla. Hydra is a fresh-water cnidarian with a remarkable capacity for regeneration and apparent lack of organismal ageing. Cnidarians are among the first metazoa with a defined body axis, tissue grade organisation, and nervous system. We report here for the first time presence of XPA gene in hydra. Putative protein sequence of hydra XPA contains nuclear localization signal and bears the zinc-finger motif. It contains two conserved Pfam domains and various characterized features of XPA proteins like regions for binding to excision repair cross-complementing protein-1 (ERCC1) and replication protein A 70 kDa subunit (RPA70) proteins. Hydra XPA shows a high degree of similarity with vertebrate homologs and clusters with deuterostomes in phylogenetic analysis. Homology modelling corroborates the very close similarity between hydra and human XPA. The protein thus most likely functions in hydra in the same manner as in other animals, indicating that it arose early in evolution and has been conserved across animal phyla. PMID:24083246

Structural and sequence similarities of hydra xeroderma pigmentosum A protein to human homolog suggest early evolution and conservation.

PubMed

Barve, Apurva; Ghaskadbi, Saroj; Ghaskadbi, Surendra

2013-01-01

Xeroderma pigmentosum group A (XPA) is a protein that binds to damaged DNA, verifies presence of a lesion, and recruits other proteins of the nucleotide excision repair (NER) pathway to the site. Though its homologs from yeast, Drosophila, humans, and so forth are well studied, XPA has not so far been reported from protozoa and lower animal phyla. Hydra is a fresh-water cnidarian with a remarkable capacity for regeneration and apparent lack of organismal ageing. Cnidarians are among the first metazoa with a defined body axis, tissue grade organisation, and nervous system. We report here for the first time presence of XPA gene in hydra. Putative protein sequence of hydra XPA contains nuclear localization signal and bears the zinc-finger motif. It contains two conserved Pfam domains and various characterized features of XPA proteins like regions for binding to excision repair cross-complementing protein-1 (ERCC1) and replication protein A 70 kDa subunit (RPA70) proteins. Hydra XPA shows a high degree of similarity with vertebrate homologs and clusters with deuterostomes in phylogenetic analysis. Homology modelling corroborates the very close similarity between hydra and human XPA. The protein thus most likely functions in hydra in the same manner as in other animals, indicating that it arose early in evolution and has been conserved across animal phyla.

John F. Kennedy Space Center's Chemochromic Hypergol Sensors

NASA Technical Reports Server (NTRS)

Nichols, James D.

2012-01-01

The National Aeronautics and Space Administration (NASA) seeks partne rs interested in the commercial application of the Chemochromic Hyper gol Sensors technology. NASA's Kennedy Space Center (KSC) is soliciti ng licensees for this innovative technology. The Chemochromic Hypergo l Sensors technology consists of chemochromic pigments incorporated i nto various matrices (e.g., tapes, sheets, injection molded parts, fi bers). When placed near strategic locations such as piping and contai ner valves, seams, and joints, these sensors provide an instantaneous , distinct color change from yellow to black indicating the presence of hypergols at the leak location. The chemochromic pigments can be incorporated into fibers used to make fabrics for personal protective equipment as well as into badge holders for use as a point leak detector. These affordable, easily replaceable sensors provide the capabil ity to visually monitor leak-prone locations and personnel working i n those areas on a continuous basis for the presence of dangerous hyp ergols.

ParaBTM: A Parallel Processing Framework for Biomedical Text Mining on Supercomputers.

PubMed

Xing, Yuting; Wu, Chengkun; Yang, Xi; Wang, Wei; Zhu, En; Yin, Jianping

2018-04-27

A prevailing way of extracting valuable information from biomedical literature is to apply text mining methods on unstructured texts. However, the massive amount of literature that needs to be analyzed poses a big data challenge to the processing efficiency of text mining. In this paper, we address this challenge by introducing parallel processing on a supercomputer. We developed paraBTM, a runnable framework that enables parallel text mining on the Tianhe-2 supercomputer. It employs a low-cost yet effective load balancing strategy to maximize the efficiency of parallel processing. We evaluated the performance of paraBTM on several datasets, utilizing three types of named entity recognition tasks as demonstration. Results show that, in most cases, the processing efficiency can be greatly improved with parallel processing, and the proposed load balancing strategy is simple and effective. In addition, our framework can be readily applied to other tasks of biomedical text mining besides NER.

Low-energy biomass pretreatment with deep eutectic solvents for bio-butanol production.

PubMed

Procentese, Alessandra; Raganati, Francesca; Olivieri, Giuseppe; Russo, Maria Elena; Rehmann, Lars; Marzocchella, Antonio

2017-11-01

Waste lettuce leaves - from the "fresh cut vegetable" industry - were pretreated with the deep eutectic solvent (DES) made of choline chloride - glycerol. Reaction time (3-16h) and the operation temperature (80-150°C) were investigated. Enzymatic glucose and xylose yields of 94.9% and 75.0%, respectively were obtained when the biomass was pretreated at 150°C for 16h. Sugars contained in the biomass hydrolysate were fermented in batch cultures of Clostridium acetobutylicum DSMZ 792. The energy consumption and the energy efficiency related to the DES pretreatment were calculated and compared to the most common lignocellulosic pretreatment processes reported in the literature. The DES pretreatment process was characterized by lower energy required (about 28% decrease and 72% decrease) than the NAOH pretreatment and steam explosion process respectively. The Net Energy Ratio (NER) value related to butanol production via DES biomass pretreatment was assessed. Copyright © 2017 Elsevier Ltd. All rights reserved.

Bayesian truncation errors in chiral effective field theory: model checking and accounting for correlations

NASA Astrophysics Data System (ADS)

Melendez, Jordan; Wesolowski, Sarah; Furnstahl, Dick

2017-09-01

Chiral effective field theory (EFT) predictions are necessarily truncated at some order in the EFT expansion, which induces an error that must be quantified for robust statistical comparisons to experiment. A Bayesian model yields posterior probability distribution functions for these errors based on expectations of naturalness encoded in Bayesian priors and the observed order-by-order convergence pattern of the EFT. As a general example of a statistical approach to truncation errors, the model was applied to chiral EFT for neutron-proton scattering using various semi-local potentials of Epelbaum, Krebs, and Meißner (EKM). Here we discuss how our model can learn correlation information from the data and how to perform Bayesian model checking to validate that the EFT is working as advertised. Supported in part by NSF PHY-1614460 and DOE NUCLEI SciDAC DE-SC0008533.

MAT1, cdk7 and cyclin H form a kinase complex which is UV light-sensitive upon association with TFIIH.

PubMed

Adamczewski, J P; Rossignol, M; Tassan, J P; Nigg, E A; Moncollin, V; Egly, J M

1996-04-15

MAT1, cyclin H and cdk7 are part of TFIIH, a class II transcription factor which possesses numerous subunits of which several have been shown to be involved in processes other than transcription. Two of them, XPD (ERCC2) and XPB (ERCC3), are helicases involved in nucleotide excision repair (NER), whereas cdk7, cyclin H and MAT1 are thought to participate in cell cycle regulation. MAT1, cyclin H and cdk7 exist as a ternary complex either free or associated with TFIIH from which the latter can be dissociated at high salt concentration. MAT1 is strongly associated with cdk7 and cyclin H. Although not strictly required for the formation and activity of the complex, it stimulates its kinase activity. The kinase activity of TFIIH, which is constant during the cell cycle, is reduced after UV light irradiation.

MAT1, cdk7 and cyclin H form a kinase complex which is UV light-sensitive upon association with TFIIH.

PubMed Central

Adamczewski, J P; Rossignol, M; Tassan, J P; Nigg, E A; Moncollin, V; Egly, J M

1996-01-01

MAT1, cyclin H and cdk7 are part of TFIIH, a class II transcription factor which possesses numerous subunits of which several have been shown to be involved in processes other than transcription. Two of them, XPD (ERCC2) and XPB (ERCC3), are helicases involved in nucleotide excision repair (NER), whereas cdk7, cyclin H and MAT1 are thought to participate in cell cycle regulation. MAT1, cyclin H and cdk7 exist as a ternary complex either free or associated with TFIIH from which the latter can be dissociated at high salt concentration. MAT1 is strongly associated with cdk7 and cyclin H. Although not strictly required for the formation and activity of the complex, it stimulates its kinase activity. The kinase activity of TFIIH, which is constant during the cell cycle, is reduced after UV light irradiation. Images PMID:8617234

Les enjuex éthiques entourant la recherche en santé sur les enfants

PubMed Central

2008-01-01

RÉSUMÉ La recherche en santé est un devoir moral parce qu’elle est la base des soins probants prodigués par tous les dispensateurs de soins. Des politiques et des règlements précis régissent la tenue des recherches sur des humains. Il faut procéder à une évaluation éthique d’un projet de recherche donné avant de pouvoir l’entreprendre. La recherche sur les enfants pose d’énormes défis en matière de consentement éclairé et d’assentiment, de vulnérabilité et de potentiel de conflit d’intérêts (CDI). Les chercheurs en santé pédiatrique devraient prôner la participation des enfants à la recherche, tout en se montrant attentifs à en limiter les risques.

KSC00pp0244

NASA Image and Video Library

2000-02-18

KENNEDY SPACE CENTER, FLA. -- Near a road at Kennedy Space Center, a red-shouldered hawk perches on a weathered tree stump. Red-shouldered hawks are large, long-winged, with rust-barred underparts, reddish shoulders, a narrowly banded tail, and a translucent area ner the tip of the wing. It ranges from Minnesota and New Brunswick south to the Gulf Coast, including Florida. It prefers deciduous woodlands, especially where there is standing water as in swampy woods and bogs. Kennedy Space Center shares a boundary with the Merritt Island National Wildlife Refuge that is a habitat for more than 331 species of birds, 31 mammals, 117 fishes, and 65 amphibians and reptiles. The marshes and open water of the refuge provide wintering areas for 23 species of migratory waterfowl, as well as a year-round home for great blue herons, great egrets, wood storks, cormorants, brown pelicans and other species of marsh and shore birds, as well as a variety of insects.

KSC-00pp0244

NASA Image and Video Library

2000-02-18

KENNEDY SPACE CENTER, FLA. -- Near a road at Kennedy Space Center, a red-shouldered hawk perches on a weathered tree stump. Red-shouldered hawks are large, long-winged, with rust-barred underparts, reddish shoulders, a narrowly banded tail, and a translucent area ner the tip of the wing. It ranges from Minnesota and New Brunswick south to the Gulf Coast, including Florida. It prefers deciduous woodlands, especially where there is standing water as in swampy woods and bogs. Kennedy Space Center shares a boundary with the Merritt Island National Wildlife Refuge that is a habitat for more than 331 species of birds, 31 mammals, 117 fishes, and 65 amphibians and reptiles. The marshes and open water of the refuge provide wintering areas for 23 species of migratory waterfowl, as well as a year-round home for great blue herons, great egrets, wood storks, cormorants, brown pelicans and other species of marsh and shore birds, as well as a variety of insects.

Tectonoestratigraphic and Thermal Models of the Tiburon and Wagner Basins, northern Gulf of California Rift System

NASA Astrophysics Data System (ADS)

Contreras, J.; Ramirez Zerpa, N. A.; Negrete-Aranda, R.

2014-12-01

The northern Gulf of California Rift System consist sofa series faults that accommodate both normal and strike-slip motion. The faults formed a series of half-greens filled with more than 7 km of siliciclastic suc­cessions. Here, we present tectonostratigraphic and heat flow models for the Tiburón basin, in the southern part of the system, and the Wag­ner basin in the north. The models are constrained by two-dimensional seis­mic lines and by two deep boreholes drilled by PEMEX­-PEP. Analysis of the seismic lines and models' results show that: (i) subsidence of the basins is controlled by high-angle normal faults and by flow of the lower crust, (ii) basins share a common history, and (iii) there are significant differences in the way brittle strain was partitioned in the basins, a feature frequently observed in rift basins. On one hand, the bounding faults of the Tiburón basin have a nested geometry and became active following a west-to-east sequence of activation. The Tiburon half-graben was formed by two pulses of fault activity. One took place during the protogulf extensional phase in the Miocene and the other during the opening of Gulf of California in the Pleistocene. On the other hand, the Wagner basin is the result of two fault generations. During the late-to middle Miocene, the west-dipping Cerro Prieto and San Felipe faults formed a domino array. Then, during the Pleistocene the Consag and Wagner faults dissected the hanging-wall of the Cerro Prieto fault forming the modern Wagner basin. Thermal modeling of the deep borehole temperatures suggests that the heat flow in these basins in the order of 110 mW/m2 which is in agreement with superficial heat flow measurements in the northern Gulf of California Rift System.

Bio-Oil Separation and Stabilization by Supercritical Fluid Fractionation. 2014 Final Report

DOE Office of Scientific and Technical Information (OSTI.GOV)

Agblevor, Foster; Petkovic, Lucia; Bennion, Edward

The objective of this project is to use supercritical fluids to separate and fractionate algal-based bio-oils into stable products that can be subsequently upgraded to produce drop-in renewable fuels. To accomplish this objective, algae was grown and thermochemically converted to bio-oils using hydrothermal liquefaction (HTL), pyrolysis, and catalytic pyrolysis. The bio-oils were separated into an extract and a raffinate using near-critical propane or carbon dioxide. The fractions were then subjected to thermal aging studies to determine if the extraction process had stabilized the products. It was found that the propane extract fraction was twice as stable as the parent catalyticmore » pyrolysis bio-oils as measured by the change in viscosity after two weeks of accelerated aging at 80°C. Further, in-situ NMR aging studies found that the propane extract was chemically more stable than the parent bio-oil. Thus the milestone of stabilizing the product was met. A preliminary design of the extraction plant was prepared. The design was based on a depot scale plant processing 20,000,000 gallons per year of bio-oil. It was estimated that the capital costs for such a plant would be $8,700,000 with an operating cost of $3,500,000 per year. On a per gallon of product cost and a 10% annual rate of return, capital costs would represent $0.06 per gallon and operating costs would amount to $0.20 per gallon. Further, it was found that the energy required to run the process represented 6.2% of the energy available in the bio-oil, meeting the milestone of less than 20%. Life cycle analysis and greenhouse gas (GHG) emission analysis found that the energy for running the critical fluid separation process and the GHG emissions were minor compared to all the inputs to the overall well to pump system. For the well to pump system boundary, energetics in biofuel conversion are typically dominated by energy demands in the growth, dewater, and thermochemical process. Bio-oil stabilization by near critical propane extraction had minimal impact in the overall energetics of the process with NER contributions of 0.03. Based on the LCA, the overall conversion pathways were found to be energy intensive with a NER of about 2.3 and 1.2 for catalytic pyrolysis and HTL, respectively. GHG emissions for the catalytic pyrolysis process were greater than that of petroleum diesel at 210 g CO2 eq compared to 18.9 g CO2 eq. Microalgae bio-oil based diesel with thermochemical conversion through HTL meets renewable fuel standards with favorable emission reductions of -10.8 g CO2 eq. The importance of the outcomes is that the critical fluid extraction and stabilization process improved product stability and did so with minimal energy inputs and processing costs. The LCA and GHG emission calculations point toward the HTL pathway as the more favorable thermochemical route towards upgrading algae to bio-fuels. Since the quality of the HTL oil was significantly lower than that of the catalytic pyrolysis bio-oil, the next steps point toward improving the quality of the HTL oils from algae biomass and focusing the critical fluid stabilization on that bio-oil product.« less

Protocol for a feasibility randomised controlled trial of the use of Physical ACtivity monitors in an Exercise Referral Setting: the PACERS study.

PubMed

Hawkins, Jemma; Edwards, Michelle; Charles, Joanna; Jago, Russell; Kelson, Mark; Morgan, Kelly; Murphy, Simon; Oliver, Emily; Simpson, Sharon; Edwards, Rhiannon Tudor; Moore, Graham

2017-01-01

Exercise referral schemes are recommended by the National Institute for Clinical Excellence (NICE) for physical activity promotion among inactive patients with health conditions or risk factors. Whilst there is evidence for the initial effectiveness and cost-effectiveness of such schemes for increasing physical activity, evidence of long-term effects is limited. Techniques such as goal setting, self-monitoring and personalised feedback may support motivation for physical activity. Technologies such as activity monitoring devices provide an opportunity to enhance delivery of motivational techniques. This paper describes the PACERS study protocol, which aims to assess the feasibility and acceptability of implementing an activity monitor within the existing Welsh National Exercise Referral Scheme (NERS) and proposed evaluation methodology for a full-scale randomised controlled trial. The PACERS study consists of a pilot randomised controlled trial, process evaluation and exploratory economic analyses. Participants will be recruited from the generic pathway of the Welsh NERS and will be randomly assigned to receive the intervention or usual practice. Usual practice is a 16-week structured exercise programme; the intervention consists of an accelerometry-based activity monitor (MyWellnessKey) and an associated web platform (MyWellnessCloud). The primary outcomes are predefined progression criteria assessing the acceptability and feasibility of the intervention and feasibility of the proposed evaluation methodology. Postal questionnaires will be completed at baseline (time 0: T0), 16 weeks after T0 (T1) and 12 months after T0 (T2). Routinely collected data will also be accessed at the same time points. A sub-sample of intervention participants and exercise referral staff will be interviewed following initiation of intervention delivery and at the end of the study. The PACERS study seeks to assess the feasibility of adding a novel motivational component to an existing effective intervention in order to enhance effects on physical activity and support longer-term maintenance. The study will provide insight into the acceptability of activity-monitoring technologies to an exercise referral population and delivery staff. Data from this study will be used to determine whether and how to proceed to a full-scale trial of effectiveness of the intervention, including any necessary refinements to intervention implementation or the proposed evaluation methodology. ISRCTN85785652.

Characteristics of intracranial aneurysms in the else kröner-fresenius registry of autosomal dominant polycystic kidney disease.

PubMed

Neumann, Hartmut P H; Malinoc, Angelica; Bacher, Janina; Nabulsi, Zinaida; Ivanovas, Vera; Bruechle, Nadine Ortiz; Mader, Irina; Hoffmann, Michael M; Riegler, Peter; Kraemer-Guth, Annette; Burchardi, Christian; Schaeffner, Elke; Martin, Rodolfo S; Azurmendi, Pablo J; Zerres, Klaus; Jilg, Cordula; Eng, Charis; Gläsker, Sven

2012-01-01

Patients who harbor intracranial aneurysms (IAs) run a risk for aneurysm rupture and subsequent subarachnoid hemorrhage which frequently results in permanent deficits or death. Prophylactic treatment of unruptured aneurysms is possible and recommended depending on the size and location of the aneurysm as well as patient age and condition. IAs are major manifestations of autosomal dominant polycystic kidney disease (ADPKD). Current guidelines do not suggest surveillance of IAs in ADPKD except in the setting of family history if IA was known in any relative with ADPKD. Management of IAs in ADPKD is problematic because limited data exist from large studies. We established the Else Kröner-Fresenius Registry for ADPKD in Germany. Clinical data were assessed for age at diagnosis of IAs, stage of renal insufficiency, and number, location and size of IAs as well as family history of cerebral events. Patients with symptomatic or asymptomatic IAs were included. All patients with ADPKD-related IAs were offered mutation scanning of the susceptibility genes for ADPKD, the PKD1 and PKD2 genes. Of 463 eligible ADPKD patients from the population base of Germany, 32 (7%) were found to have IAs, diagnosed at the age of 2-71 years, 19 females and 13 males. Twenty (63%) of these 32 patients were symptomatic, whereas IAs were detected in an asymptomatic stage in 12 patients. IAs were multifocal in 12 and unifocal in 20 patients. In 26 patients (81%), IAs were diagnosed before end-stage renal failure. Twenty-five out of 27 unrelated index cases (93%) had no IAs or cerebral events documented in their relatives with ADPKD. In 16 unrelated index patients and 3 relatives, we detected germline mutations. The mutations were randomly distributed across the PKD1 gene in 14 and the PKD2 gene in 2 index cases. Questionnaires answered for 320/441 ADPKD patients without IAs revealed that only 45/320 (14%) had MR angiography. In ADPKD, rupture of IAs occurs frequently before the start of dialysis, is only infrequently associated with a family history of IAs or subarachnoid hemorrhage, and is associated with mutations either of the PKD1 or the PKD2 gene of any type. Screening for IAs is widely insufficiently performed, should not be restricted to families with a history of cerebral events and should be started before end-stage renal failure.

Is there a self-organization principle of river deltas?

NASA Astrophysics Data System (ADS)

Tejedor, Alejandro; Longjas, Anthony; Foufoula-Georgiou, Efi

2017-04-01

River deltas are known to possess a complex topological and flux-partitioning structure which has recently been quantified using spectral graph theory [Tejedor et al., 2015a,b]. By analysis of real and simulated deltas it has also been shown that there is promise in formalizing relationships between this topo-dynamic delta structure and the underlying delta forming processes [e.g., Tejedor et al., 2016]. The question we pose here is whether there exists a first order organizational principle behind the self-organization of river deltas and whether this principle can be unraveled from the co-evolving topo-dynamic structure encoded in the delta planform. To answer this question, we introduce a new metric, the nonlocal Entropy Rate (nER) that captures the information content of a delta network in terms of the degree of uncertainty in delivering fluxes from any point of the network to the shoreline. We hypothesize that if the "guiding principle" of undisturbed deltas is to efficiently and robustly build land by increasing the diversity of their flux pathways over the delta plane, then they would exhibit maximum nonlocal Entropy Rate at states at which geometry and flux dynamics are at equilibrium. At the same time, their nER would be non-optimal at transient states, such as before and after major avulsions during which topology and dynamics adjust to each other to reach a new equilibrium state. We will present our results for field and simulated deltas, which confirm this hypothesis and open up new ways of thinking about self-organization, complexity and robustness in river deltas. One particular connection of interest might have important implications since entropy rate and resilience are related by the fluctuation theorem [Demetrius and Manke, 2005], and therefore our results suggest that deltas might in fact self-organize to maximize their resilience to structural and dynamic perturbations. References: Tejedor, A., A. Longjas, I. Zaliapin, and E. Foufoula­-Georgiou (2015), Water Resour. Res., 51, 3998-4018. Tejedor, A., A. Longjas, I. Zaliapin, and E. Foufoula-­Georgiou (2015), Water Resour. Res., 51, 4019-4045. Tejedor, A., A. Longjas, R. Caldwell, D. A. Edmonds, I. Zaliapin, and E. Foufoula­-Georgiou (2016), Geophys. Res. Lett., 43, 3280-3287. Demetrius, L., and T. Manke (2005), Phys. A Stat. Mech. Appl., 346, 682-696.

Ophthalmic Manifestations of Xeroderma Pigmentosum: A Perspective from the United Kingdom.

PubMed

Lim, Rongxuan; Sethi, Mieran; Morley, Ana M S

2017-11-01

To document the ocular manifestations of xeroderma pigmentosum (XP), presenting via the United Kingdom (UK) XP service, and to analyze the correlations between XP genotype and ophthalmic phenotype. Prospective observational case series. Eighty-nine patients seen by the UK Nationally Commissioned XP Service, from April 2010 to December 2014, with a genetically confirmed diagnosis of XP. Patients underwent a full ophthalmic examination at each visit. Clinical features from both eyes were recorded on a standard proforma. The most recent assessments were analyzed. A 2-tailed Fisher exact test was used to assess for differences in ocular features between patients in XP subgroups with impaired transcription coupled nucleotide excision repair (TC-NER) (category 1: XP-A, B, D, F, and G) and preserved TC-NER (category 2: XP-C, E, and V). Lid and periocular abnormalities, ocular surface pathologies, neuro-ophthalmologic abnormalities, lens and retinal abnormalities, and visual acuity (VA). Ninety-three percent of XP patients in our cohort had ocular involvement, with 65% describing photophobia. The most common abnormalities were in the periocular skin and ocular surface, including interpalpebral conjunctival melanosis (44%) and conjunctival injection (43%). Eleven percent of patients had required treatment for periocular cancers and 2% for ocular surface cancers. The most common neuro-ophthalmologic finding was minimal pupillary reaction to light (25%). Patients in category 2 had significantly more ocular surface abnormalities than patients in category 1, including a greater proportion of conjunctival injection (P = 0.003), conjunctival corkscrew vessels (P < 0.001), corneal scarring (P = 0.01) and pingueculae under the age of 50 (P = 0.02). Meanwhile, patients in category 1 had a higher proportion of poorly reactive pupils (P < 0.001) and abnormal ocular movements (P = 0.03) compared with those in category 2. Five patients (6%) presented to ophthalmologists with ocular surface signs related to XP, before any formal diagnosis of XP was made. A large proportion of XP patients have ocular involvement. Regular examination by an ophthalmologist is essential, especially in screening for eyelid and ocular surface tumors. The ocular phenotype-genotype segregation within XP patients suggests that XP is a heterogeneous and complex disease. With further study, we hope to offer these patients more individualized patient care. Copyright © 2017 American Academy of Ophthalmology. Published by Elsevier Inc. All rights reserved.

Understanding of the Regional Aerosol Characterization over the North-eastern part of the Indian Subcontinent: South-Asian Region

NASA Astrophysics Data System (ADS)

Dahutia, P.; Pathak, B.

2016-12-01

The north-eastern region (NER) of India is a part of Indian subcontinent owing a unique topography surrounded by three sides by high mountain and open in the west. The long-term characterization of aerosol and its effect on climate is carried out in 11 locations over NER of India along with two adjoining locations Dhaka (DAC) and Banmauk (BNK) (22-30°N and 88-98°E) using multiple satellite retrievals and model data. Quality assured monthly Level 3 Collection 6 data of MODerate Resolution Imaging Spectroradiometer (MODIS) data retrieved from both Aqua and Terra having 1°×1° resolution of columnar Aerosol Optical Depth (AOD) and its associated parameters for the period of 2001-2014. Investigation revealed a distinct spatio-temporal variation over all the locations with highest climatological mean AOD in Dhaka (0.66±0.19) and lowest in high altitude location Thimphu (0.17±0.1). The parameter Absorbing aerosols Index (AAI) from combine TOMS and OMI instrument is used to study absorbing aerosols during 1979-2014. The seasonal AOD and AAI are highest during pre-monsoon months while lowest in retreating monsoon in all the locations. The continuous wavelet transform (CWT) analysis of non-smoothen time-series of AOD revealed the strong annual oscillation (AO) of total columnar aerosol loading. The annual trend analysis of aerosol parameters shows a statistically significant (i.e., p<0.05) increasing trends of AOD ( 0.009-0.001year-1) as well as AAI ( 0.015-0.001year-1) over all locations. The simultaneous increase in Angtröm Exponent (AE) along with AOD and AAI indicates the enhancement of anthropogenic aerosols which might have a contribution to the climate change. The performed long-term (1979-2014) regression analysis of seasonal and annual mean of Net Surface Downward Shortwave Flux (NSDSF), Cloud Optical Depth (COD), rainfall and temperature shows a signature of climate change over this region. The opposite trend of COD (increasing) and NSDSF (decreasing) signifies the effect of clouds on reduction of surface reaching solar flux over the study locations. The increasing anthropogenic aerosols may have contributed to the decreasing trend of NSDSF directly or indirectly.