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Sample records for aib1 predicts resistance

  1. AIB1 is required for the acquisition of epithelial growth factor receptor-mediated tamoxifen resistance in breast cancer cells

    SciTech Connect

    Zhao Wenhui; Zhang Qingyuan Kang Xinmei; Jin Shi; Lou Changjie

    2009-03-13

    Acquired resistance to tamoxifen has become a serious obstacle in breast cancer treatment. The underlying mechanism responsible for this condition has not been completely elucidated. In this study, a tamoxifen-resistant (Tam-R) MCF-7 breast cancer cell line was developed to mimic the occurrence of acquired tamoxifen resistance as seen in clinical practice. Increased expression levels of HER1, HER2 and the estrogen receptor (ER)-AIB1 complex were found in tamoxifen-resistant cells. EGF stimulation and gefitinib inhibition experiments further demonstrated that HER1/HER2 signaling and AIB1 were involved in the proliferation of cells that had acquired Tam resistance. However, when AIB1 was silenced with AIB1-siRNA in Tam-R cells, the cell growth stimulated by the HER1/HER2 signaling pathway was significantly reduced, and the cells were again found to be inhibited by tamoxifen. These results suggest that the AIB1 protein could be a limiting factor in the HER1/HER2-mediated hormone-independent growth of Tam-R cells. Thus, AIB1 may be a new therapeutic target, and the removal of AIB1 may decrease the crosstalk between ER and the HER1/HER2 pathway, resulting in the restoration of tamoxifen sensitivity in tamoxifen-resistant cells.

  2. Altered AIB1 or AIB1Δ3 Expression Impacts ERα Effects on Mammary Gland Stromal and Epithelial Content

    PubMed Central

    Nakles, Rebecca E.; Shiffert, Maddalena Tilli; Díaz-Cruz, Edgar S.; Cabrera, M. Carla; Alotaiby, Maram; Miermont, Anne M.; Riegel, Anna T.

    2011-01-01

    Amplified in breast cancer 1 (AIB1) (also known as steroid receptor coactivator-3) is a nuclear receptor coactivator enhancing estrogen receptor (ER)α and progesterone receptor (PR)-dependent transcription in breast cancer. The splice variant AIB1Δ3 demonstrates increased ability to promote ERα and PR-dependent transcription. Both are implicated in breast cancer risk and antihormone resistance. Conditional transgenic mice tested the in vivo impact of AIB1Δ3 overexpression compared with AIB1 on histological features of increased breast cancer risk and growth response to estrogen and progesterone in the mammary gland. Combining expression of either AIB1 or AIB1Δ3 with ERα overexpression, we investigated in vivo cooperativity. AIB1 and AIB1Δ3 overexpression equivalently increased the prevalence of hyperplastic alveolar nodules but not ductal hyperplasia or collagen content. When AIB1 or AIB1Δ3 overexpression was combined with ERα, both stromal collagen content and ductal hyperplasia prevalence were significantly increased and adenocarcinomas appeared. Overexpression of AIB1Δ3, especially combined with overexpressed ERα, led to an abnormal response to estrogen and progesterone with significant increases in stromal collagen content and development of a multilayered mammary epithelium. AIB1Δ3 overexpression was associated with a significant increase in PR expression and PR downstream signaling genes. AIB1 overexpression produced less marked growth abnormalities and no significant change in PR expression. In summary, AIB1Δ3 overexpression was more potent than AIB1 overexpression in increasing stromal collagen content, inducing abnormal mammary epithelial growth, altering PR expression levels, and mediating the response to estrogen and progesterone. Combining ERα overexpression with either AIB1 or AIB1Δ3 overexpression augmented abnormal growth responses in both epithelial and stromal compartments. PMID:21292825

  3. AIB1 gene amplification and the instability of polyQ encoding sequence in breast cancer cell lines

    PubMed Central

    Wong, Lee-Jun C; Dai, Pu; Lu, Jyh-Feng; Lou, Mary Ann; Clarke, Robert; Nazarov, Viktor

    2006-01-01

    Background The poly Q polymorphism in AIB1 (amplified in breast cancer) gene is usually assessed by fragment length analysis which does not reveal the actual sequence variation. The purpose of this study is to investigate the sequence variation of poly Q encoding region in breast cancer cell lines at single molecule level, and to determine if the sequence variation is related to AIB1 gene amplification. Methods The polymorphic poly Q encoding region of AIB1 gene was investigated at the single molecule level by PCR cloning/sequencing. The amplification of AIB1 gene in various breast cancer cell lines were studied by real-time quantitative PCR. Results Significant amplifications (5–23 folds) of AIB1 gene were found in 2 out of 9 (22%) ER positive cell lines (in BT-474 and MCF-7 but not in BT-20, ZR-75-1, T47D, BT483, MDA-MB-361, MDA-MB-468 and MDA-MB-330). The AIB1 gene was not amplified in any of the ER negative cell lines. Different passages of MCF-7 cell lines and their derivatives maintained the feature of AIB1 amplification. When the cells were selected for hormone independence (LCC1) and resistance to 4-hydroxy tamoxifen (4-OH TAM) (LCC2 and R27), ICI 182,780 (LCC9) or 4-OH TAM, KEO and LY 117018 (LY-2), AIB1 copy number decreased but still remained highly amplified. Sequencing analysis of poly Q encoding region of AIB1 gene did not reveal specific patterns that could be correlated with AIB1 gene amplification. However, about 72% of the breast cancer cell lines had at least one under represented (<20%) extra poly Q encoding sequence patterns that were derived from the original allele, presumably due to somatic instability. Although all MCF-7 cells and their variants had the same predominant poly Q encoding sequence pattern of (CAG)3CAA(CAG)9(CAACAG)3(CAACAGCAG)2CAA of the original cell line, a number of altered poly Q encoding sequences were found in the derivatives of MCF-7 cell lines. Conclusion These data suggest that poly Q encoding region of AIB1 gene is

  4. Overexpression of transcriptional coactivator AIB1 promotes hepatocellular carcinoma progression by enhancing cell proliferation and invasiveness.

    PubMed

    Xu, Y; Chen, Q; Li, W; Su, X; Chen, T; Liu, Y; Zhao, Y; Yu, C

    2010-06-10

    Amplified in breast cancer 1 (AIB1) is a transcriptional coactivator for nuclear receptors and other transcription factors. AIB1 has an important role in malignancy of several cancers such as breast and prostate cancers. However, its involvement in human hepatocellular carcinoma (HCC) progression remains unclear. Here, we found that AIB1 protein was overexpressed in 23 of 34 human HCC specimens (68%). Down-regulation of AIB1 reduced HCC cell proliferation, migration, invasion, colony formation ability and tumorigenic potential in nude mice. These phenotypic changes caused by AIB1 knockdown correlated with increased expression of the cell cycle inhibitor p21(Cip1/Waf1) and decreased Akt activation and the expression of proliferating cell nuclear antigen (PCNA) and matrix metallopeptidase MMP-9. In agreement with these findings, clinical AIB1-positive HCC expressed higher levels of PCNA than AIB1-negative HCC. A positive correlation was established between the levels of AIB1 protein and PCNA protein in HCC, suggesting that AIB1 may contribute to HCC cell proliferation. In addition, MMP-9 expression in AIB1-postive HCC was significantly higher than that in AIB1-negative HCC, suggesting that AIB1-postive HCC may be more invasive. Collectively, our results show that overexpression of AIB1 promotes human HCC progression by enhancing cell proliferation and invasiveness. Therefore, AIB1 is a master regulator of human HCC growth and might be a useful molecular target for HCC prognosis and treatment.

  5. Acetylation Enhances the Promoting Role of AIB1 in Breast Cancer Cell Proliferation

    PubMed Central

    You, Dingyun; Zhao, Hongbo; Wang, Yan; Jiao, Yang; Lu, Minnan; Yan, Shan

    2016-01-01

    The oncogene nuclear receptor coactivator amplified in breast cancer 1 (AIB1) is a transcriptional coactivator, which is overexpressed in various types of human cancers, including breast cancer. However, the molecular mechanisms regulating AIB1 function remain largely unknown. In this study, we present evidence demonstrating that AIB1 is acetylated by MOF in human breast cancer cells. Moreover, we also found that the acetylation of AIB1 enhances its function in promoting breast cancer cell proliferation. We further showed that the acetylation of AIB1 is required for its recruitment to E2F1 target genes by E2F1. More importantly, we found that the acetylation levels of AIB1 are greatly elevated in human breast cancer cells compared with that in non-cancerous cells. Collectively, our results shed light on the molecular mechanisms that regulate AIB1 function in breast cancer. PMID:27665502

  6. Prior Adjuvant Tamoxifen Treatment in Breast Cancer Is Linked to Increased AIB1 and HER2 Expression in Metachronous Contralateral Breast Cancer

    PubMed Central

    Alkner, Sara; Bendahl, Pär-Ola; Ehinger, Anna; Lövgren, Kristina; Rydén, Lisa; Fernö, Mårten

    2016-01-01

    Aim The estrogen receptor coactivator Amplified in Breast Cancer 1 (AIB1) has been associated with an improved response to adjuvant tamoxifen in breast cancer, but also with endocrine treatment resistance. We hereby use metachronous contralateral breast cancer (CBC) developed despite prior adjuvant tamoxifen for the first tumor as an “in vivo”-model for tamoxifen resistance. AIB1-expression in the presumable resistant (CBC after prior tamoxifen) and naïve setting (CBC without prior tamoxifen) is compared and correlated to prognosis after CBC. Methods From a well-defined population-based cohort of CBC-patients we have constructed a unique tissue-microarray including >700 patients. Results CBC developed after adjuvant tamoxifen more often had a HER2-positive/triple negative-subtype and a high AIB1-expression (37% vs. 23%, p = 0.009), than if no prior endocrine treatment had been administered. In patients with an estrogen receptor (ER) positive CBC, a high AIB1-expression correlated to an inferior prognosis. However, these patients seemed to respond to tamoxifen, but only if endocrine therapy had not been administered for BC1. Conclusions Metachronous CBC developed after prior endocrine treatment has a decreased ER-expression and an increased HER2-expression. This is consistent with endocrine treatment escape mechanisms previously suggested, and indicates metachronous CBC to be a putative model for studies of treatment resistance “in vivo”. The increased AIB1-expression in CBC developed after prior tamoxifen suggests a role of AIB1 in endocrine treatment resistance. In addition, we found indications that the response to tamoxifen in CBC with a high AIB1-expression seem to differ depending on previous exposure to this drug. A different function for AIB1 in the tamoxifen treatment naïve vs. resistant setting is suggested, and may explain previously conflicting results where a high AIB1-expression has been correlated to both a good response to adjuvant

  7. Phosphorylation of AIB1 at Mitosis Is Regulated by CDK1/CYCLIN B

    PubMed Central

    Ferrero, Macarena; Ferragud, Juan; Orlando, Leonardo; Valero, Luz; Sánchez del Pino, Manuel; Farràs, Rosa; Font de Mora, Jaime

    2011-01-01

    Background Although the AIB1 oncogene has an important role during the early phase of the cell cycle as a coactivator of E2F1, little is known about its function during mitosis. Methodology/Principal Findings Mitotic cells isolated by nocodazole treatment as well as by shake-off revealed a post-translational modification occurring in AIB1 specifically during mitosis. This modification was sensitive to the treatment with phosphatase, suggesting its modification by phosphorylation. Using specific inhibitors and in vitro kinase assays we demonstrate that AIB1 is phosphorylated on Ser728 and Ser867 by Cdk1/cyclin B at the onset of mitosis and remains phosphorylated until exit from M phase. Differences in the sensitivity to phosphatase inhibitors suggest that PP1 mediates dephosphorylation of AIB1 at the end of mitosis. The phosphorylation of AIB1 during mitosis was not associated with ubiquitylation or degradation, as confirmed by western blotting and flow cytometry analysis. In addition, luciferase reporter assays showed that this phosphorylation did not alter the transcriptional properties of AIB1. Importantly, fluorescence microscopy and sub-cellular fractionation showed that AIB1 phosphorylation correlated with the exclusion from the condensed chromatin, thus preventing access to the promoters of AIB1-dependent genes. Phospho-specific antibodies developed against Ser728 further demonstrated the presence of phosphorylated AIB1 only in mitotic cells where it was localized preferentially in the periphery of the cell. Conclusions Collectively, our results describe a new mechanism for the regulation of AIB1 during mitosis, whereby phosphorylation of AIB1 by Cdk1 correlates with the subcellular redistribution of AIB1 from a chromatin-associated state in interphase to a more peripheral localization during mitosis. At the exit of mitosis, AIB1 is dephosphorylated, presumably by PP1. This exclusion from chromatin during mitosis may represent a mechanism for governing the

  8. The expression of AIB1 correlates with cellular proliferation in human prolactinomas.

    PubMed

    Carretero, José; Blanco, Enrique J; Carretero, Manuel; Carretero-Hernández, Marta; García-Barrado, Ma José; Iglesias-Osma, Ma Carmen; Burks, Deborah Jane; Font de Mora, Jaime

    2013-05-01

    Estrogens as well as certain growth factors strongly influence the development and growth of prolactinomas. However, the molecular mechanisms by which extracellular factors trigger prolactinomas are not well known. Amplified in breast cancer 1 (AIB1), also known as steroid receptor co-activator 3 (SRC-3), belongs to the p160/SRC family of nuclear receptor co-activators and is a major co-activator of the estrogen receptor. Here, we report that the estrogen receptor coactivator AIB1 is overexpressed in human prolactinomas and correlates with the detection of aromatase and estrogen receptor α (ERα). Of the 87 pituitary tumors evaluated in women, 56%, corresponding to hyperoprolactinemic women, contained an enriched population of prolactin-positive cells and hence were further classified as prolactinomas. All prolactinomas stained positive for both ERα and AIB1. Moreover, AIB1 sub-cellular distribution was indicative of the cell-cycle status of tumors; the nuclear expression of AIB1 was correlated with proliferative markers whereas the cytoplasmic localization of AIB1 coincided with active caspase-3. Thus, our results demonstrate for the first time that AIB1 is expressed in prolactinomas and suggest its participation in the regulation of proliferation and apoptosis of tumoral cells. Because aromatase expression is also enhanced in these prolactinomas and it is involved in the local production of estradiol, both mechanisms, ER-AIB1 and aromatase could be related.

  9. Role of the nuclear receptor coactivator AIB1/SRC-3 in angiogenesis and wound healing.

    PubMed

    Al-Otaiby, Maram; Tassi, Elena; Schmidt, Marcel O; Chien, Chris D; Baker, Tabari; Salas, Armando Ganoza; Xu, Jianming; Furlong, Mary; Schlegel, Richard; Riegel, Anna T; Wellstein, Anton

    2012-04-01

    The nuclear receptor coactivator amplified in breast cancer 1 (AIB1/SRC-3) has a well-defined role in steroid and growth factor signaling in cancer and normal epithelial cells. Less is known about its function in stromal cells, although AIB1/SRC-3 is up-regulated in tumor stroma and may, thus, contribute to tumor angiogenesis. Herein, we show that AIB1/SRC-3 depletion from cultured endothelial cells reduces their proliferation and motility in response to growth factors and prevents the formation of intact monolayers with tight junctions and of endothelial tubes. In AIB1/SRC-3(+/-) and (-/-) mice, the angiogenic responses to subcutaneous Matrigel implants was reduced by two-thirds, and exogenously added fibroblast growth factor (FGF) 2 did not overcome this deficiency. Furthermore, AIB1/SRC-3(+/-) and (-/-) mice showed similarly delayed healing of full-thickness excisional skin wounds, indicating that both alleles were required for proper tissue repair. Analysis of this defective wound healing showed reduced recruitment of inflammatory cells and macrophages, cytokine induction, and metalloprotease activity. Skin grafts from animals with different AIB1 genotypes and subsequent wounding of the grafts revealed that the defective healing was attributable to local factors and not to defective bone marrow responses. Indeed, wounds in AIB1(+/-) mice showed reduced expression of FGF10, FGFBP3, FGFR1, FGFR2b, and FGFR3, major local drivers of angiogenesis. We conclude that AIB1/SRC-3 modulates stromal cell responses via cross-talk with the FGF signaling pathway. PMID:22342158

  10. Chaperonin CCT-mediated AIB1 folding promotes the growth of ERα-positive breast cancer cells on hard substrates.

    PubMed

    Chen, Li; Zhang, Ze; Qiu, Juhui; Zhang, Lingling; Luo, Xiangdong; Jang, Jun

    2014-01-01

    Clinical observations have revealed a strong association between estrogen receptor alpha (ERα)-positive tumors and the development of bone metastases, however, the mechanism underlying this association remains unknown. We cultured MCF-7 (ERα-positive) on different rigidity substrates. Compared with cells grown on more rigid substrates (100 kPa), cells grown on soft substrates (10 kPa) exhibited reduced spreading ability, a lower ratio of cells in the S and G2/M cell cycle phases, and a decreased proliferation rate. Using stable isotope labeling by amino acids (SILAC), we further compared the whole proteome of MCF-7 cells grown on substrates of different rigidity (10 and 100 kPa), and found that the expression of eight members of chaperonin CCT increased by at least 2-fold in the harder substrate. CCT folding activity was increased in the hard substrate compared with the soft substrates. Amplified in breast cancer 1 (AIB1), was identified in CCT immunoprecipitates. CCT folding ability of AIB1 increased on 100-kPa substrate compared with 10- and 30-kPa substrates. Moreover, using mammalian two-hybrid protein-protein interaction assays, we found that the polyglutamine repeat sequence of the AIB1 protein was essential for interaction between CCTζ and AIB1. CCTζ-mediated AIB1 folding affects the cell area spreading, growth rate, and cell cycle. The expressions of the c-myc, cyclin D1, and PgR genes were higher on hard substrates than on soft substrate in both MCF-7 and T47D cells. ERα and AIB1 could up-regulate the mRNA and protein expression levels of the c-myc, cyclin D1, and PgR genes, and that 17 β-estradiol could enhance this effects. Conversely, 4-hydroxytamoxifen, could inhibit these effects. Taken together, our studies demonstrate that some ERα-positive breast cancer cells preferentially grow on more rigid substrates. CCT-mediated AIB1 folding appears to be involved in the rigidity response of breast cancer cells, which provides novel insight into the

  11. Progestin and antiprogestin responsiveness in breast cancer is driven by the PRA/PRB ratio via AIB1 or SMRT recruitment to the CCND1 and MYC promoters.

    PubMed

    Wargon, Victoria; Riggio, Marina; Giulianelli, Sebastián; Sequeira, Gonzalo R; Rojas, Paola; May, María; Polo, María L; Gorostiaga, María A; Jacobsen, Britta; Molinolo, Alfredo; Novaro, Virginia; Lanari, Claudia

    2015-06-01

    There is emerging interest in understanding the role of progesterone receptors (PRs) in breast cancer. The aim of this study was to investigate the proliferative effect of progestins and antiprogestins depending on the relative expression of the A (PRA) and B (PRB) isoforms of PR. In mifepristone (MFP)-resistant murine carcinomas antiprogestin responsiveness was restored by re-expressing PRA using demethylating agents and histone deacetylase inhibitors. Consistently, in two human breast cancer xenograft models, one manipulated to overexpress PRA or PRB (IBH-6 cells), and the other expressing only PRA (T47D-YA) or PRB (T47D-YB), MFP selectively inhibited the growth of PRA-overexpressing tumors and stimulated IBH-6-PRB xenograft growth. Furthermore, in cells with high or equimolar PRA/PRB ratios, which are stimulated to proliferate in vitro by progestins, and are inhibited by MFP, MPA increased the interaction between PR and the coactivator AIB1, and MFP favored the interaction between PR and the corepressor SMRT. In a PRB-dominant context in which MFP stimulates and MPA inhibits cell proliferation, the opposite interactions were observed. Chromatin immunoprecipitation assays in T47D cells in the presence of MPA or MFP confirmed the interactions between PR and the coregulators at the CCND1 and MYC promoters. SMRT downregulation by siRNA abolished the inhibitory effect of MFP on MYC expression and cell proliferation. Our results indicate that antiprogestins are therapeutic tools that selectively inhibit PRA-overexpressing tumors by increasing the SMRT/AIB1 balance at the CCND1 and MYC promoters.

  12. Identification of SRC3/AIB1 as a Preferred Coactivator for Hormone-activated Androgen Receptor

    SciTech Connect

    Zhou, X. Edward; Suino-Powell, Kelly M.; Li, Jun; He, Yuanzheng; MacKeigan, Jeffrey P.; Melcher, Karsten; Yong, Eu-Leong; Xu, H.Eric

    2010-09-17

    Transcription activation by androgen receptor (AR), which depends on recruitment of coactivators, is required for the initiation and progression of prostate cancer, yet the mechanisms of how hormone-activated AR interacts with coactivators remain unclear. This is because AR, unlike any other nuclear receptor, prefers its own N-terminal FXXLF motif to the canonical LXXLL motifs of coactivators. Through biochemical and crystallographic studies, we identify that steroid receptor coactivator-3 (SRC3) (also named as amplified in breast cancer-1 or AIB1) interacts strongly with AR via synergistic binding of its first and third LXXLL motifs. Mutagenesis and functional studies confirm that SRC3 is a preferred coactivator for hormone-activated AR. Importantly, AR mutations found in prostate cancer patients correlate with their binding potency to SRC3, corroborating with the emerging role of SRC3 as a prostate cancer oncogene. These results provide a molecular mechanism for the selective utilization of SRC3 by hormone-activated AR, and they link the functional relationship between AR and SRC3 to the development and growth of prostate cancer.

  13. The nuclear cofactor RAC3/AIB1/SRC-3 enhances Nrf2 signaling by interacting with transactivation domains

    PubMed Central

    Kim, Jung-Hwan; Yu, Siwang; Chen, J. Don; Kong, A.-N. Tony

    2012-01-01

    Nuclear factor erythroid 2-related factor 2 (Nrf2, NM 006164, 605 AA) is essential for the antioxidant responsive element (ARE)-mediated expression of a group of detoxifying antioxidant genes that detoxify carcinogens and protect against oxidative stress. Several proteins have been identified as Nrf2-interacting molecules. In this study, we found that the overexpression of RAC3/AIB-1/SRC-3, a nuclear co-regulator and oncogene frequently amplified in human breast cancers, induced heme oxygenase-1 (HO-1) through Nrf2 transactivation in HeLa cells. Next, we determined the interaction between RAC3 and Nrf2 proteins using a co-immunoprecipitation assay (co-IP) and fluorescence resonance energy transfer (FRET) analysis. The results showed that RAC3 bound directly to the Nrf2 protein in the nucleus. Subsequently, we identified the interacting domains of Nrf2 and RAC3 using a GST pull-down assay. The results showed that both the N-terminal RAC3-pasB and C-terminal RAC3-R3B3 domains were tightly bound to the Neh4 and Neh5 transactivation domains. Furthermore, chromatin immunoprecipitation (ChIP) showed that RAC3 bound tightly to the ARE enhancer region of the HO-1 promoter via Nrf2 binding. These data suggest that Nrf2 activation is modulated and directly controlled through interactions with the RAC3 protein in HeLa cells. PMID:22370642

  14. Pattern prediction in EUV resists

    NASA Astrophysics Data System (ADS)

    Biafore, John J.; Smith, Mark D.; Wallow, Tom; Nalleau, Patrick; Blankenship, David; Deng, Yunfei

    2009-12-01

    Accurate and flexible simulation methods may be used to further a researcher's understanding of how complex resist effects influence the patterning of critical structures. In this work, we attempt to gain insight into the behavior of a state-of-the-art EUV resist through the use of stochastic resist modeling. The statistics of photon and molecule counting are discussed. The acid generation mechanism at EUV is discussed. At lambda = 13.5 nm, the acid generation mechanism may be similar to that found in electron beam resists: acid generators are hypothesized to be activated by secondary electrons yielded by ionization of the resist matrix by high-energy EUV photons, suggesting that acid generators may be activated some distance from the absorption site. A discrete, probabilistic ionization and electron scattering model for PAG conversion at EUV is discussed. The simulated effect of resist absorbance at EUV upon doseto- size and line-width roughness is shown. The model's parameterized fit to experimental data from a resist irradiated EUV are shown. Predictions of statistical resist responses such as CD distribution and line-width roughness are compared with experimental data.

  15. Predicting Resistance Mutations Using Protein Design Algorithms

    SciTech Connect

    Frey, K.; Georgiev, I; Donald, B; Anderson, A

    2010-01-01

    Drug resistance resulting from mutations to the target is an unfortunate common phenomenon that limits the lifetime of many of the most successful drugs. In contrast to the investigation of mutations after clinical exposure, it would be powerful to be able to incorporate strategies early in the development process to predict and overcome the effects of possible resistance mutations. Here we present a unique prospective application of an ensemble-based protein design algorithm, K*, to predict potential resistance mutations in dihydrofolate reductase from Staphylococcus aureus using positive design to maintain catalytic function and negative design to interfere with binding of a lead inhibitor. Enzyme inhibition assays show that three of the four highly-ranked predicted mutants are active yet display lower affinity (18-, 9-, and 13-fold) for the inhibitor. A crystal structure of the top-ranked mutant enzyme validates the predicted conformations of the mutated residues and the structural basis of the loss of potency. The use of protein design algorithms to predict resistance mutations could be incorporated in a lead design strategy against any target that is susceptible to mutational resistance.

  16. Antimicrobial Resistance Prediction in PATRIC and RAST.

    PubMed

    Davis, James J; Boisvert, Sébastien; Brettin, Thomas; Kenyon, Ronald W; Mao, Chunhong; Olson, Robert; Overbeek, Ross; Santerre, John; Shukla, Maulik; Wattam, Alice R; Will, Rebecca; Xia, Fangfang; Stevens, Rick

    2016-01-01

    The emergence and spread of antimicrobial resistance (AMR) mechanisms in bacterial pathogens, coupled with the dwindling number of effective antibiotics, has created a global health crisis. Being able to identify the genetic mechanisms of AMR and predict the resistance phenotypes of bacterial pathogens prior to culturing could inform clinical decision-making and improve reaction time. At PATRIC (http://patricbrc.org/), we have been collecting bacterial genomes with AMR metadata for several years. In order to advance phenotype prediction and the identification of genomic regions relating to AMR, we have updated the PATRIC FTP server to enable access to genomes that are binned by their AMR phenotypes, as well as metadata including minimum inhibitory concentrations. Using this infrastructure, we custom built AdaBoost (adaptive boosting) machine learning classifiers for identifying carbapenem resistance in Acinetobacter baumannii, methicillin resistance in Staphylococcus aureus, and beta-lactam and co-trimoxazole resistance in Streptococcus pneumoniae with accuracies ranging from 88-99%. We also did this for isoniazid, kanamycin, ofloxacin, rifampicin, and streptomycin resistance in Mycobacterium tuberculosis, achieving accuracies ranging from 71-88%. This set of classifiers has been used to provide an initial framework for species-specific AMR phenotype and genomic feature prediction in the RAST and PATRIC annotation services. PMID:27297683

  17. Antimicrobial resistance prediction in PATRIC and RAST

    DOE PAGES

    Davis, James J.; Boisvert, Sebastien; Brettin, Thomas; Kenyon, Ronald W.; Mao, Chunhong; Olson, Robert; Overbeek, Ross; Santerre, John; Shukla, Maulik; Wattam, Alice R.; et al

    2016-06-14

    The emergence and spread of antimicrobial resistance (AMR) mechanisms in bacterial pathogens, coupled with the dwindling number of effective antibiotics, has created a global health crisis. Being able to identify the genetic mechanisms of AMR and predict the resistance phenotypes of bacterial pathogens prior to culturing could inform clinical decision-making and improve reaction time. At PATRIC (http://patricbrc.org/), we have been collecting bacterial genomes with AMR metadata for several years. In order to advance phenotype prediction and the identification of genomic regions relating to AMR, we have updated the PATRIC FTP server to enable access to genomes that are binned bymore » their AMR phenotypes, as well as metadata including minimum inhibitory concentrations. Using this infrastructure, we custom built AdaBoost (adaptive boosting) machine learning classifiers for identifying carbapenem resistance in Acinetobacter baumannii, methicillin resistance in Staphylococcus aureus, and beta-lactam and co-trimoxazole resistance in Streptococcus pneumoniae with accuracies ranging from 88–99%. We also did this for isoniazid, kanamycin, ofloxacin, rifampicin, and streptomycin resistance in Mycobacterium tuberculosis, achieving accuracies ranging from 71–88%. Lastly, this set of classifiers has been used to provide an initial framework for species-specific AMR phenotype and genomic feature prediction in the RAST and PATRIC annotation services.« less

  18. Antimicrobial Resistance Prediction in PATRIC and RAST

    PubMed Central

    Davis, James J.; Boisvert, Sébastien; Brettin, Thomas; Kenyon, Ronald W.; Mao, Chunhong; Olson, Robert; Overbeek, Ross; Santerre, John; Shukla, Maulik; Wattam, Alice R.; Will, Rebecca; Xia, Fangfang; Stevens, Rick

    2016-01-01

    The emergence and spread of antimicrobial resistance (AMR) mechanisms in bacterial pathogens, coupled with the dwindling number of effective antibiotics, has created a global health crisis. Being able to identify the genetic mechanisms of AMR and predict the resistance phenotypes of bacterial pathogens prior to culturing could inform clinical decision-making and improve reaction time. At PATRIC (http://patricbrc.org/), we have been collecting bacterial genomes with AMR metadata for several years. In order to advance phenotype prediction and the identification of genomic regions relating to AMR, we have updated the PATRIC FTP server to enable access to genomes that are binned by their AMR phenotypes, as well as metadata including minimum inhibitory concentrations. Using this infrastructure, we custom built AdaBoost (adaptive boosting) machine learning classifiers for identifying carbapenem resistance in Acinetobacter baumannii, methicillin resistance in Staphylococcus aureus, and beta-lactam and co-trimoxazole resistance in Streptococcus pneumoniae with accuracies ranging from 88–99%. We also did this for isoniazid, kanamycin, ofloxacin, rifampicin, and streptomycin resistance in Mycobacterium tuberculosis, achieving accuracies ranging from 71–88%. This set of classifiers has been used to provide an initial framework for species-specific AMR phenotype and genomic feature prediction in the RAST and PATRIC annotation services. PMID:27297683

  19. Predicted wear resistances of binary carbide coatings

    SciTech Connect

    Kramer, B.M.

    1986-11-01

    A mechanistic model of the tool wear process has been presented (B. M. Kramer and P. K. Judd, J. Vac. Sci. Technol. A 3, 2439 (1985)) that includes the effects of both the abrasion of the tool material by inclusions within the workpiece and the chemical dissolution of the tool material into the matrix of the workpiece. Machining tests have been run on steel with titanium carbide coated tooling and the resulting test data have been employed to produce a rough calibration of the proposed model. This model has been used to predict the wear resistances of the other group IV B carbides and of the (Ti,Hf)C system in the machining of steel.

  20. Prediction of Cancer Drug Resistance and Implications for Personalized Medicine

    PubMed Central

    Volm, Manfred; Efferth, Thomas

    2015-01-01

    Drug resistance still impedes successful cancer chemotherapy. A major goal of early concepts in individualized therapy was to develop in vitro tests to predict tumors’ drug responsiveness. We have developed an in vitro short-term test based on nucleic acid precursor incorporation to determine clinical drug resistance. This test detects inherent and acquired resistance in vitro and transplantable syngeneic and xenografted tumors in vivo. In several clinical trials, clinical resistance was predictable with more than 90% accuracy, while drug sensitivity was detected with less accuracy (~60%). Remarkably, clinical cross-resistance to numerous drugs (multidrug resistance, broad spectrum resistance) was detectable by a single compound, doxorubicin, due to its multifactorial modes of action. The results of this predictive test were in good agreement with predictive assays of other authors. As no predictive test has been established as yet for clinical diagnostics, the identification of sensitive drugs may not reach sufficiently high reliability for clinical routine. A meta-analysis of the literature published during the past four decades considering test results of more than 15,000 tumor patients unambiguously demonstrated that, in the majority of studies, resistance was correctly predicted with an accuracy between 80 and 100%, while drug sensitivity could only be predicted with an accuracy of 50–80%. This synopsis of the published literature impressively illustrates that prediction of drug resistance could be validated. The determination of drug resistance was reliable independent of tumor type, test assay, and drug used in these in vitro tests. By contrast, chemosensitivity could not be predicted with high reliability. Therefore, we propose a rethinking of the “chemosensitivity” concept. Instead, predictive in vitro tests may reliably identify drug-resistant tumors. The clinical consequence imply to subject resistant tumors not to chemotherapy, but to other new

  1. Resist develop prediction by Monte Carlo simulation

    NASA Astrophysics Data System (ADS)

    Sohn, Dong-Soo; Jeon, Kyoung-Ah; Sohn, Young-Soo; Oh, Hye-Keun

    2002-07-01

    Various resist develop models have been suggested to express the phenomena from the pioneering work of Dill's model in 1975 to the recent Shipley's enhanced notch model. The statistical Monte Carlo method can be applied to the process such as development and post exposure bake. The motions of developer during development process were traced by using this method. We have considered that the surface edge roughness of the resist depends on the weight percentage of protected and de-protected polymer in the resist. The results are well agreed with other papers. This study can be helpful for the developing of new photoresist and developer that can be used to pattern the device features smaller than 100 nm.

  2. BEM Prediction of TBC Fracture Resistance

    NASA Astrophysics Data System (ADS)

    Keppas, Loukas K.; Anifantis, Nick K.

    The present study investigates the transient behavior of interfacial cracks in thermal barrier coatings (TBC). It is assumed that these material systems withstand thermal shock in the presence of external operating pressure load acting on the coating surface. Partial of full crack closure takes place and the thermal contact resistance as well the friction between the crack faces is considered. The dependence of the thermal resistance on the contact pressure leads to a coupled the thermal-mechanical analysis. An appropriate boundary element formulation based on two-dimensional time-dependent thermoelasticity, implemented in a verified computer code, is utilized for the numerical solution. A series of parametric analyses examines the impact of coefficient of friction and the level of loading and thermal contact resistance on crack severity.

  3. Prediction of antibiotic resistance by gene expression profiles

    PubMed Central

    Suzuki, Shingo; Horinouchi, Takaaki; Furusawa, Chikara

    2014-01-01

    Although many mutations contributing to antibiotic resistance have been identified, the relationship between the mutations and the related phenotypic changes responsible for the resistance has yet to be fully elucidated. To better characterize phenotype–genotype mapping for drug resistance, here we analyse phenotypic and genotypic changes of antibiotic-resistant Escherichia coli strains obtained by laboratory evolution. We demonstrate that the resistances can be quantitatively predicted by the expression changes of a small number of genes. Several candidate mutations contributing to the resistances are identified, while phenotype–genotype mapping is suggested to be complex and includes various mutations that cause similar phenotypic changes. The integration of transcriptome and genome data enables us to extract essential phenotypic changes for drug resistances. PMID:25517437

  4. Biophysical principles predict fitness landscapes of drug resistance.

    PubMed

    Rodrigues, João V; Bershtein, Shimon; Li, Anna; Lozovsky, Elena R; Hartl, Daniel L; Shakhnovich, Eugene I

    2016-03-15

    Fitness landscapes of drug resistance constitute powerful tools to elucidate mutational pathways of antibiotic escape. Here, we developed a predictive biophysics-based fitness landscape of trimethoprim (TMP) resistance for Escherichia coli dihydrofolate reductase (DHFR). We investigated the activity, binding, folding stability, and intracellular abundance for a complete set of combinatorial DHFR mutants made out of three key resistance mutations and extended this analysis to DHFR originated from Chlamydia muridarum and Listeria grayi We found that the acquisition of TMP resistance via decreased drug affinity is limited by a trade-off in catalytic efficiency. Protein stability is concurrently affected by the resistant mutants, which precludes a precise description of fitness from a single molecular trait. Application of the kinetic flux theory provided an accurate model to predict resistance phenotypes (IC50) quantitatively from a unique combination of the in vitro protein molecular properties. Further, we found that a controlled modulation of the GroEL/ES chaperonins and Lon protease levels affects the intracellular steady-state concentration of DHFR in a mutation-specific manner, whereas IC50 is changed proportionally, as indeed predicted by the model. This unveils a molecular rationale for the pleiotropic role of the protein quality control machinery on the evolution of antibiotic resistance, which, as we illustrate here, may drastically confound the evolutionary outcome. These results provide a comprehensive quantitative genotype-phenotype map for the essential enzyme that serves as an important target of antibiotic and anticancer therapies.

  5. Biophysical principles predict fitness landscapes of drug resistance.

    PubMed

    Rodrigues, João V; Bershtein, Shimon; Li, Anna; Lozovsky, Elena R; Hartl, Daniel L; Shakhnovich, Eugene I

    2016-03-15

    Fitness landscapes of drug resistance constitute powerful tools to elucidate mutational pathways of antibiotic escape. Here, we developed a predictive biophysics-based fitness landscape of trimethoprim (TMP) resistance for Escherichia coli dihydrofolate reductase (DHFR). We investigated the activity, binding, folding stability, and intracellular abundance for a complete set of combinatorial DHFR mutants made out of three key resistance mutations and extended this analysis to DHFR originated from Chlamydia muridarum and Listeria grayi We found that the acquisition of TMP resistance via decreased drug affinity is limited by a trade-off in catalytic efficiency. Protein stability is concurrently affected by the resistant mutants, which precludes a precise description of fitness from a single molecular trait. Application of the kinetic flux theory provided an accurate model to predict resistance phenotypes (IC50) quantitatively from a unique combination of the in vitro protein molecular properties. Further, we found that a controlled modulation of the GroEL/ES chaperonins and Lon protease levels affects the intracellular steady-state concentration of DHFR in a mutation-specific manner, whereas IC50 is changed proportionally, as indeed predicted by the model. This unveils a molecular rationale for the pleiotropic role of the protein quality control machinery on the evolution of antibiotic resistance, which, as we illustrate here, may drastically confound the evolutionary outcome. These results provide a comprehensive quantitative genotype-phenotype map for the essential enzyme that serves as an important target of antibiotic and anticancer therapies. PMID:26929328

  6. Cooperative Bacterial Growth Dynamics Predict the Evolution of Antibiotic Resistance

    NASA Astrophysics Data System (ADS)

    Artemova, Tatiana; Gerardin, Ylaine; Hsin-Jung Li, Sophia; Gore, Jeff

    2011-03-01

    Since the discovery of penicillin, antibiotics have been our primary weapon against bacterial infections. Unfortunately, bacteria can gain resistance to penicillin by acquiring the gene that encodes beta-lactamase, which inactivates the antibiotic. However, mutations in this gene are necessary to degrade the modern antibiotic cefotaxime. Understanding the conditions that favor the spread of these mutations is a challenge. Here we show that bacterial growth in beta-lactam antibiotics is cooperative and that the nature of this growth determines the conditions in which resistance evolves. Quantitative analysis of the growth dynamics predicts a peak in selection at very low antibiotic concentrations; competition between strains confirms this prediction. We also find significant selection at higher antibiotic concentrations, close to the minimum inhibitory concentrations of the strains. Our results argue that an understanding of the evolutionary forces that lead to antibiotic resistance requires a quantitative understanding of the evolution of cooperation in bacteria.

  7. Development of a protocol for predicting bacterial resistance to microbicides.

    PubMed

    Knapp, Laura; Amézquita, Alejandro; McClure, Peter; Stewart, Sara; Maillard, Jean-Yves

    2015-04-01

    Regulations dealing with microbicides in Europe and the United States are evolving and now require data on the risk of the development of resistance in organisms targeted by microbicidal products. There is no standard protocol to assess the risk of the development of resistance to microbicidal formulations. This study aimed to validate the use of changes in microbicide and antibiotic susceptibility as initial markers for predicting microbicide resistance and cross-resistance to antibiotics. Three industrial isolates (Pseudomonas aeruginosa, Burkholderia cepacia, and Klebsiella pneumoniae) and two Salmonella enterica serovar Typhimurium strains (SL1344 and 14028S) were exposed to a shampoo, a mouthwash, eye makeup remover, and the microbicides contained within these formulations (chlorhexidine digluconate [CHG] and benzalkonium chloride [BZC]) under realistic, in-use conditions. Baseline and postexposure data were compared. No significant increases in the MIC or the minimum bactericidal concentration (MBC) were observed for any strain after exposure to the three formulations. Increases as high as 100-fold in the MICs and MBCs of CHG and BZC for SL1344 and 14028S were observed but were unstable. Changes in antibiotic susceptibility were not clinically significant. The use of MICs and MBCs combined with antibiotic susceptibility profiling and stability testing generated reproducible data that allowed for an initial prediction of the development of resistance to microbicides. These approaches measure characteristics that are directly relevant to the concern over resistance and cross-resistance development following the use of microbicides. These are low-cost, high-throughput techniques, allowing manufacturers to provide to regulatory bodies, promptly and efficiently, data supporting an early assessment of the risk of resistance development. PMID:25636848

  8. Personalized Cancer Medicine: Molecular Diagnostics, Predictive biomarkers, and Drug Resistance

    PubMed Central

    Gonzalez de Castro, D; Clarke, P A; Al-Lazikani, B; Workman, P

    2013-01-01

    The progressive elucidation of the molecular pathogenesis of cancer has fueled the rational development of targeted drugs for patient populations stratified by genetic characteristics. Here we discuss general challenges relating to molecular diagnostics and describe predictive biomarkers for personalized cancer medicine. We also highlight resistance mechanisms for epidermal growth factor receptor (EGFR) kinase inhibitors in lung cancer. We envisage a future requiring the use of longitudinal genome sequencing and other omics technologies alongside combinatorial treatment to overcome cellular and molecular heterogeneity and prevent resistance caused by clonal evolution. PMID:23361103

  9. Modelling proteins' hidden conformations to predict antibiotic resistance

    NASA Astrophysics Data System (ADS)

    Hart, Kathryn M.; Ho, Chris M. W.; Dutta, Supratik; Gross, Michael L.; Bowman, Gregory R.

    2016-10-01

    TEM β-lactamase confers bacteria with resistance to many antibiotics and rapidly evolves activity against new drugs. However, functional changes are not easily explained by differences in crystal structures. We employ Markov state models to identify hidden conformations and explore their role in determining TEM's specificity. We integrate these models with existing drug-design tools to create a new technique, called Boltzmann docking, which better predicts TEM specificity by accounting for conformational heterogeneity. Using our MSMs, we identify hidden states whose populations correlate with activity against cefotaxime. To experimentally detect our predicted hidden states, we use rapid mass spectrometric footprinting and confirm our models' prediction that increased cefotaxime activity correlates with reduced Ω-loop flexibility. Finally, we design novel variants to stabilize the hidden cefotaximase states, and find their populations predict activity against cefotaxime in vitro and in vivo. Therefore, we expect this framework to have numerous applications in drug and protein design.

  10. Assist feature printability prediction by 3-D resist profile reconstruction

    NASA Astrophysics Data System (ADS)

    Zheng, Xin; Huang, Jensheng; Chin, Fook; Kazarian, Aram; Kuo, Chun-Chieh

    2012-06-01

    properties may then be used to optimize the printability vs. efficacy of an SRAF either prior to or during an Optical Proximity Correction (OPC) run. The process models that are used during OPC have never been able to reliably predict which SRAFs will print. This appears to be due to the fact that OPC process models are generally created using data that does not include printed subresolution patterns. An enhancement to compact modeling capability to predict Assist Features (AF) printability is developed and discussed. A hypsometric map representing 3-D resist profile was built by applying a first principle approximation to estimate the "energy loss" from the resist top to bottom. Such a 3-D resist profile is an extrapolation of a well calibrated traditional OPC model without any additional information. Assist features are detected at either top of resist (dark field) or bottom of resist (bright field). Such detection can be done by just extracting top or bottom resist models from our 3-D resist model. There is no measurement of assist features needed when we build AF but it can be included if interested but focusing on resist calibration to account for both exposure dosage and focus change sensitivities. This approach significantly increases resist model's capability for predicting printed SRAF accuracy. And we don't need to calibrate an SRAF model in addition to the OPC model. Without increase in computation time, this compact model can draw assist feature contour with real placement and size at any vertical plane. The result is compared and validated with 3-D rigorous modeling as well as SEM images. Since this method does not change any form of compact modeling, it can be integrated into current MBAF solutions without any additional work.

  11. Genomic prediction for tick resistance in Braford and Hereford cattle.

    PubMed

    Cardoso, F F; Gomes, C C G; Sollero, B P; Oliveira, M M; Roso, V M; Piccoli, M L; Higa, R H; Yokoo, M J; Caetano, A R; Aguilar, I

    2015-06-01

    One of the main animal health problems in tropical and subtropical cattle production is the bovine tick, which causes decreased performance, hide devaluation, increased production costs with acaricide treatments, and transmission of infectious diseases. This study investigated the utility of genomic prediction as a tool to select Braford (BO) and Hereford (HH) cattle resistant to ticks. The accuracy and bias of different methods for direct and blended genomic prediction was assessed using 10,673 tick counts obtained from 3,435 BO and 928 HH cattle belonging to the Delta G Connection breeding program. A subset of 2,803 BO and 652 HH samples were genotyped and 41,045 markers remained after quality control. Log transformed records were adjusted by a pedigree repeatability model to estimate variance components, genetic parameters, and breeding values (EBV) and subsequently used to obtain deregressed EBV. Estimated heritability and repeatability for tick counts were 0.19 ± 0.03 and 0.29 ± 0.01, respectively. Data were split into 5 subsets using k-means and random clustering for cross-validation of genomic predictions. Depending on the method, direct genomic value (DGV) prediction accuracies ranged from 0.35 with Bayes least absolute shrinkage and selection operator (LASSO) to 0.39 with BayesB for k-means clustering and between 0.42 with BayesLASSO and 0.45 with BayesC for random clustering. All genomic methods were superior to pedigree BLUP (PBLUP) accuracies of 0.26 for k-means and 0.29 for random groups, with highest accuracy gains obtained with BayesB (39%) for k-means and BayesC (55%) for random groups. Blending of historical phenotypic and pedigree information by different methods further increased DGV accuracies by values between 0.03 and 0.05 for direct prediction methods. However, highest accuracy was observed with single-step genomic BLUP with values of 0.48 for -means and 0.56, which represent, respectively, 84 and 93% improvement over PBLUP. Observed random

  12. Widespread convergence in toxin resistance by predictable molecular evolution.

    PubMed

    Ujvari, Beata; Casewell, Nicholas R; Sunagar, Kartik; Arbuckle, Kevin; Wüster, Wolfgang; Lo, Nathan; O'Meally, Denis; Beckmann, Christa; King, Glenn F; Deplazes, Evelyne; Madsen, Thomas

    2015-09-22

    The question about whether evolution is unpredictable and stochastic or intermittently constrained along predictable pathways is the subject of a fundamental debate in biology, in which understanding convergent evolution plays a central role. At the molecular level, documented examples of convergence are rare and limited to occurring within specific taxonomic groups. Here we provide evidence of constrained convergent molecular evolution across the metazoan tree of life. We show that resistance to toxic cardiac glycosides produced by plants and bufonid toads is mediated by similar molecular changes to the sodium-potassium-pump (Na(+)/K(+)-ATPase) in insects, amphibians, reptiles, and mammals. In toad-feeding reptiles, resistance is conferred by two point mutations that have evolved convergently on four occasions, whereas evidence of a molecular reversal back to the susceptible state in varanid lizards migrating to toad-free areas suggests that toxin resistance is maladaptive in the absence of selection. Importantly, resistance in all taxa is mediated by replacements of 2 of the 12 amino acids comprising the Na(+)/K(+)-ATPase H1-H2 extracellular domain that constitutes a core part of the cardiac glycoside binding site. We provide mechanistic insight into the basis of resistance by showing that these alterations perturb the interaction between the cardiac glycoside bufalin and the Na(+)/K(+)-ATPase. Thus, similar selection pressures have resulted in convergent evolution of the same molecular solution across the breadth of the animal kingdom, demonstrating how a scarcity of possible solutions to a selective challenge can lead to highly predictable evolutionary responses. PMID:26372961

  13. Widespread convergence in toxin resistance by predictable molecular evolution

    PubMed Central

    Ujvari, Beata; Casewell, Nicholas R.; Sunagar, Kartik; Arbuckle, Kevin; Wüster, Wolfgang; Lo, Nathan; O’Meally, Denis; Beckmann, Christa; King, Glenn F.; Deplazes, Evelyne; Madsen, Thomas

    2015-01-01

    The question about whether evolution is unpredictable and stochastic or intermittently constrained along predictable pathways is the subject of a fundamental debate in biology, in which understanding convergent evolution plays a central role. At the molecular level, documented examples of convergence are rare and limited to occurring within specific taxonomic groups. Here we provide evidence of constrained convergent molecular evolution across the metazoan tree of life. We show that resistance to toxic cardiac glycosides produced by plants and bufonid toads is mediated by similar molecular changes to the sodium-potassium-pump (Na+/K+-ATPase) in insects, amphibians, reptiles, and mammals. In toad-feeding reptiles, resistance is conferred by two point mutations that have evolved convergently on four occasions, whereas evidence of a molecular reversal back to the susceptible state in varanid lizards migrating to toad-free areas suggests that toxin resistance is maladaptive in the absence of selection. Importantly, resistance in all taxa is mediated by replacements of 2 of the 12 amino acids comprising the Na+/K+-ATPase H1–H2 extracellular domain that constitutes a core part of the cardiac glycoside binding site. We provide mechanistic insight into the basis of resistance by showing that these alterations perturb the interaction between the cardiac glycoside bufalin and the Na+/K+-ATPase. Thus, similar selection pressures have resulted in convergent evolution of the same molecular solution across the breadth of the animal kingdom, demonstrating how a scarcity of possible solutions to a selective challenge can lead to highly predictable evolutionary responses. PMID:26372961

  14. Programs For Predicting Fatigue And Creep-Fatigue Resistances

    NASA Technical Reports Server (NTRS)

    Saltsman, J. F.

    1994-01-01

    TS-SRP/PACK set of computer programs for characterizing and predicting fatigue and creep-fatigue resistances of metallic materials under isothermal and nonisothermal fatigue conditions in high-temperature, long-life regime. Programs implement total-strain version of strainrange-partitioning (TS-SRP) method. User should be thoroughly familiar with TS-SRP method before attempting to use any of these programs. Five programs included along with alloy data base. Four programs written in FORTRAN 77. One written in BASIC version 3.0.

  15. Predicting and tracking spatiotemporal moments in electrical resistivity tomography

    NASA Astrophysics Data System (ADS)

    Ward, W. O. C.; Wilkinson, P. B.; Chambers, J.; Bai, L.

    2015-12-01

    Visualisation is an invaluable tool in the study of near sub-surface processes, whether by mathematical modelling or by geophysical imaging. Quantitative analysis can further assist interpretation of the ongoing physical processes, and it is clear that any reliable model should take direct observations into account. Using electrical resistivity tomography (ERT), localised areas can be surveyed to produce 2-D and 3-D time-lapse images. This study investigates combining quantitative results obtained via ERT with spatio-temporal motion models in tracer experiments to interpret and predict fluid flow. As with any indirect imaging technique, ERT suffers specific issues with resolution and smoothness as a result of its inversion process. In addition, artefacts are typical in the resulting volumes. Mathematical models are also a source of uncertainty - and in combining these with ERT images, a trade-off must be made between the theoretical and the observed. Using computational imaging, distinct regions of stable resistivity can be directly extracted from a time-slice of an ERT volume. The automated nature, as well the potential for more than one region-of-interest, means that multiple regions can be detected. Using Kalman filters, it is possible to convert the detections into a process state, taking into account pre-defined models and predicting progression. In consecutive time-steps, newly detected features are assigned, where possible, to existing predictions to create tracks that match the tracer model. Preliminary studies looked at a simple motion model, tracking the centre of mass of a tracer plume with assumed constant velocity and mean resistivity. Extending the model to factor in spatial distribution of the plume, an oriented semi-axis is used to represent the centralised second-order moment, with an increasing factor of magnitude to represent the plume dispersion. Initial results demonstrate the efficacy of the approach, significantly improving reliability as the

  16. Prediction of Putative Resistance Islands in a Carbapenem-Resistant Acinetobacter baumannii Global Clone 2 Clinical Isolate

    PubMed Central

    Lee, Yangsoon; D'Souza, Roshan; Lee, Kyungwon

    2016-01-01

    Background We investigated the whole genome sequence (WGS) of a carbapenem-resistant Acinetobacter baumannii isolate belonging to the global clone 2 (GC2) and predicted resistance islands using a software tool. Methods A. baumannii strain YU-R612 was isolated from the sputum of a 61-yr-old man with sepsis. The WGS of the YU-R612 strain was obtained by using the PacBio RS II Sequencing System (Pacific Biosciences Inc., USA). Antimicrobial resistance genes and resistance islands were analyzed by using ResFinder and Genomic Island Prediction software (GIPSy), respectively. Results The YU-R612 genome consisted of a circular chromosome (ca. 4,075 kb) and two plasmids (ca. 74 kb and 5 kb). Its sequence type (ST) under the Oxford scheme was ST191, consistent with assignment to GC2. ResFinder analysis showed that YU-R612 possessed the following resistance genes: four β-lactamase genes blaADC-30, blaOXA-66, blaOXA-23, and blaTEM-1; armA, aadA1, and aacA4 as aminoglycoside resistance-encoding genes; aac(6')Ib-cr for fluoroquinolone resistance; msr(E) for macrolide, lincosamide, and streptogramin B resistance; catB8 for phenicol resistance; and sul1 for sulfonamide resistance. By GIPSy analysis, six putative resistant islands (PRIs) were determined on the YU-R612 chromosome. Among them, PRI1 possessed two copies of Tn2009 carrying blaOXA-23, and PRI5 carried two copies of a class I integron carrying sul1 and armA genes. Conclusions By prediction of resistance islands in the carbapenem-resistant A. baumannii YU-R612 GC2 strain isolated in Korea, PRIs were detected on the chromosome that possessed Tn2009 and class I integrons. The prediction of resistance islands using software tools was useful for analysis of the WGS. PMID:27139604

  17. Anhedonia Predicts Poorer Recovery among Youth with Selective Serotonin Reuptake Inhibitor Treatment-Resistant Depression

    ERIC Educational Resources Information Center

    McMakin, Dana L.; Olino, Thomas M.; Porta, Giovanna; Dietz, Laura J.; Emslie, Graham; Clarke, Gregory; Wagner, Karen Dineen; Asarnow, Joan R.; Ryan, Neal D.; Birmaher, Boris; Shamseddeen, Wael; Mayes, Taryn; Kennard, Betsy; Spirito, Anthony; Keller, Martin; Lynch, Frances L.; Dickerson, John F.; Brent, David A.

    2012-01-01

    Objective: To identify symptom dimensions of depression that predict recovery among selective serotonin reuptake inhibitor (SSRI) treatment-resistant adolescents undergoing second-step treatment. Method: The Treatment of Resistant Depression in Adolescents (TORDIA) trial included 334 SSRI treatment-resistant youth randomized to a medication…

  18. WGS accurately predicts antimicrobial resistance in Escherichia coli

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Objectives: To determine the effectiveness of whole-genome sequencing (WGS) in identifying resistance genotypes of multidrug-resistant Escherichia coli (E. coli) and whether these correlate with observed phenotypes. Methods: Seventy-six E. coli strains were isolated from farm cattle and measured f...

  19. Beyond serial passages: new methods for predicting the emergence of resistance to novel antibiotics.

    PubMed

    Martínez, José Luis; Baquero, Fernando; Andersson, Dan I

    2011-10-01

    Market launching of a new antibiotic requires knowing in advance its benefits and possible risks, and among them how rapidly resistance will emerge and spread among bacterial pathogens. This information is not only useful from a public health point of view, but also for pharmaceutical industry, in order to reduce potential waste of resources in the development of a compound that might be discontinued at the short term because of resistance development. Most assays currently used for predicting the emergence of resistance are based on culturing the target bacteria by serial passages in the presence of increasing concentrations of antibiotics. Whereas these assays may be valuable for identifying mutations that might cause resistance, they are not useful to establish how fast resistance might appear, neither to address the risk of spread of resistance genes by horizontal gene transfer. In this article, we review recent information pertinent for a more accurate prediction on the emergence and dispersal of antibiotic resistance.

  20. Microstructure of frontoparietal connections predicts individual resistance to sleep deprivation.

    PubMed

    Cui, Jiaolong; Tkachenko, Olga; Gogel, Hannah; Kipman, Maia; Preer, Lily A; Weber, Mareen; Divatia, Shreya C; Demers, Lauren A; Olson, Elizabeth A; Buchholz, Jennifer L; Bark, John S; Rosso, Isabelle M; Rauch, Scott L; Killgore, William D S

    2015-02-01

    Sleep deprivation (SD) can degrade cognitive functioning, but growing evidence suggests that there are large individual differences in the vulnerability to this effect. Some evidence suggests that baseline differences in the responsiveness of a fronto-parietal attention system that is activated during working memory (WM) tasks may be associated with the ability to sustain vigilance during sleep deprivation. However, the neurocircuitry underlying this network remains virtually unexplored. In this study, we employed diffusion tensor imaging (DTI) to investigate the association between the microstructure of the axonal pathway connecting the frontal and parietal regions--i.e., the superior longitudinal fasciculus (SLF)--and individual resistance to SD. Thirty healthy participants (15 males) aged 20-43 years underwent functional magnetic resonance imaging (fMRI) and diffusion tensor imaging (DTI) at rested wakefulness prior to a 28-hour period of SD. Task-related fronto-parietal fMRI activation clusters during a Sternberg WM Task were localized and used as seed regions for probabilistic fiber tractography. DTI metrics, including fractional anisotropy, mean diffusivity, axial and radial diffusivity were measured in the SLF. The psychomotor vigilance test (PVT) was used to evaluate resistance to SD. We found that activation in the left inferior parietal lobule (IPL) and dorsolateral prefrontal cortex (DLPFC) positively correlated with resistance. Higher fractional anisotropy of the left SLF comprising the primary axons connecting IPL and DLPFC was also associated with better resistance. These findings suggest that individual differences in resistance to SD are associated with the functional responsiveness of a fronto-parietal attention system and the microstructural properties of the axonal interconnections.

  1. Monitoring Central Venous Catheter Resistance to Predict Imminent Occlusion: A Prospective Pilot Study

    PubMed Central

    Wolf, Joshua; Tang, Li; Rubnitz, Jeffrey E.; Brennan, Rachel C.; Shook, David R.; Stokes, Dennis C.; Monagle, Paul; Curtis, Nigel; Worth, Leon J.; Allison, Kim; Sun, Yilun; Flynn, Patricia M.

    2015-01-01

    Background Long-term central venous catheters are essential for the management of chronic medical conditions, including childhood cancer. Catheter occlusion is associated with an increased risk of subsequent complications, including bloodstream infection, venous thrombosis, and catheter fracture. Therefore, predicting and pre-emptively treating occlusions should prevent complications, but no method for predicting such occlusions has been developed. Methods We conducted a prospective trial to determine the feasibility, acceptability, and efficacy of catheter-resistance monitoring, a novel approach to predicting central venous catheter occlusion in pediatric patients. Participants who had tunneled catheters and were receiving treatment for cancer or undergoing hematopoietic stem cell transplantation underwent weekly catheter-resistance monitoring for up to 12 weeks. Resistance was assessed by measuring the inline pressure at multiple flow-rates via a syringe pump system fitted with a pressure-sensing transducer. When turbulent flow through the device was evident, resistance was not estimated, and the result was noted as “non-laminar.” Results Ten patients attended 113 catheter-resistance monitoring visits. Elevated catheter resistance (>8.8% increase) was strongly associated with the subsequent development of acute catheter occlusion within 10 days (odds ratio = 6.2; 95% confidence interval, 1.8–21.5; p <0.01; sensitivity, 75%; specificity, 67%). A combined prediction model comprising either change in resistance greater than 8.8% or a non-laminar result predicted subsequent occlusion (odds ratio = 6.8; 95% confidence interval, 2.0–22.8; p = 0.002; sensitivity, 80%; specificity, 63%). Participants rated catheter-resistance monitoring as highly acceptable. Conclusions In this pediatric hematology and oncology population, catheter-resistance monitoring is feasible, acceptable, and predicts imminent catheter occlusion. Larger studies are required to validate

  2. Large Size Cells in the Visceral Adipose Depot Predict Insulin Resistance in the Canine Model

    PubMed Central

    Kabir, Morvarid; Stefanovski, Darko; Hsu, Isabel R.; Iyer, Malini; Woolcott, Orison O.; Zheng, Dan; Catalano, Karyn J.; Chiu, Jenny D.; Kim, Stella P.; Harrison, Lisa N.; Ionut, Viorica; Lottati, Maya; Bergman, Richard N.; Richey, Joyce M.

    2015-01-01

    Adipocyte size plays a key role in the development of insulin resistance. We examined longitudinal changes in adipocyte size and distribution in visceral (VIS) and subcutaneous (SQ) fat during obesity-induced insulin resistance and after treatment with CB-1 receptor antagonist, rimonabant (RIM) in canines. We also examined whether adipocyte size and/or distribution is predictive of insulin resistance. Adipocyte morphology was assessed by direct microscopy and analysis of digital images in previously studied animals 6 weeks after high-fat diet (HFD) and 16 weeks of HFD + placebo (PL; n = 8) or HFD + RIM (1.25 mg/kg/day; n = 11). At 6 weeks, mean adipocyte diameter increased in both depots with a bimodal pattern only in VIS. Sixteen weeks of HFD+PL resulted in four normally distributed cell populations in VIS and a bimodal pattern in SQ. Multilevel mixed-effects linear regression with random-effects model of repeated measures showed that size combined with share of adipocytes >75 µm in VIS only was related to hepatic insulin resistance. VIS adipocytes >75 µm were predictive of whole body and hepatic insulin resistance. In contrast, there was no predictive power of SQ adipocytes >75 µm regarding insulin resistance. RIM prevented the formation of large cells, normalizing to pre-fat status in both depots. The appearance of hypertrophic adipocytes in VIS is a critical predictor of insulin resistance, supporting the deleterious effects of increased VIS adiposity in the pathogenesis of insulin resistance. PMID:21836643

  3. Testing Taxonomic Predictivity of Foliar and Tuber Resistance to Phytophthora infestans in Wild Relatives of Potato.

    PubMed

    Khiutti, A; Spooner, D M; Jansky, S H; Halterman, D A

    2015-09-01

    Potato late blight, caused by the oomycete phytopathogen Phytophthora infestans, is a devastating disease found in potato-growing regions worldwide. Long-term management strategies to control late blight include the incorporation of host resistance to predominant strains. However, due to rapid genetic changes within pathogen populations, rapid and recurring identification and integration of novel host resistance traits is necessary. Wild relatives of potato offer a rich source of desirable traits, including late blight resistance, but screening methods can be time intensive. We tested the ability of taxonomy, ploidy, crossing group, breeding system, and geography to predict the presence of foliar and tuber late blight resistance in wild Solanum spp. Significant variation for resistance to both tuber and foliar late blight was found within and among species but there was no discernable predictive power based on taxonomic series, clade, ploidy, breeding system, elevation, or geographic location. We observed a moderate but significant correlation between tuber and foliar resistance within species. Although previously uncharacterized sources of both foliar and tuber resistance were identified, our study does not support an assumption that taxonomic or geographic data can be used to predict sources of late blight resistance in wild Solanum spp.

  4. Absence of RIPK3 predicts necroptosis resistance in malignant melanoma

    PubMed Central

    Geserick, P; Wang, J; Schilling, R; Horn, S; Harris, P A; Bertin, J; Gough, P J; Feoktistova, M; Leverkus, M

    2015-01-01

    Acquired or intrinsic resistance to apoptotic and necroptotic stimuli is considered a major hindrance of therapeutic success in malignant melanoma. Inhibitor of apoptosis proteins (IAPs) are important regulators of apoptotic and necroptotic cell death mediated by numerous cell death signalling platforms. In this report we investigated the impact of IAPs for cell death regulation in malignant melanoma. Suppression of IAPs strongly sensitized a panel of melanoma cells to death ligand-induced cell death, which, surprisingly, was largely mediated by apoptosis, as it was completely rescued by addition of caspase inhibitors. Interestingly, the absence of necroptosis signalling correlated with a lack of receptor-interacting protein kinase-3 (RIPK3) mRNA and protein expression in all cell lines, whereas primary melanocytes and cultured nevus cells strongly expressed RIPK3. Reconstitution of RIPK3, but not a RIPK3-kinase dead mutant in a set of melanoma cell lines overcame CD95L/IAP antagonist-induced necroptosis resistance independent of autocrine tumour necrosis factor secretion. Using specific inhibitors, functional studies revealed that RIPK3-mediated mixed-lineage kinase domain-like protein (MLKL) phosphorylation and necroptosis induction critically required receptor-interacting protein kinase-1 signalling. Furthermore, the inhibitor of mutant BRAF Dabrafenib, but not Vemurafenib, inhibited necroptosis in melanoma cells whenever RIPK3 is present. Our data suggest that loss of RIPK3 in melanoma and selective inhibition of the RIPK3/MLKL axis by BRAF inhibitor Dabrafenib, but not Vemurafenib, is critical to protect from necroptosis. Strategies that allow RIPK3 expression may allow unmasking the necroptotic signalling machinery in melanoma and points to reactivation of this pathway as a treatment option for metastatic melanoma. PMID:26355347

  5. Prediction of HIV drug resistance from genotype with encoded three-dimensional protein structure

    PubMed Central

    2014-01-01

    Background Drug resistance has become a severe challenge for treatment of HIV infections. Mutations accumulate in the HIV genome and make certain drugs ineffective. Prediction of resistance from genotype data is a valuable guide in choice of drugs for effective therapy. Results In order to improve the computational prediction of resistance from genotype data we have developed a unified encoding of the protein sequence and three-dimensional protein structure of the drug target for classification and regression analysis. The method was tested on genotype-resistance data for mutants of HIV protease and reverse transcriptase. Our graph based sequence-structure approach gives high accuracy with a new sparse dictionary classification method, as well as support vector machine and artificial neural networks classifiers. Cross-validated regression analysis with the sparse dictionary gave excellent correlation between predicted and observed resistance. Conclusion The approach of encoding the protein structure and sequence as a 210-dimensional vector, based on Delaunay triangulation, has promise as an accurate method for predicting resistance from sequence for drugs inhibiting HIV protease and reverse transcriptase. PMID:25081370

  6. Using the functional response of a consumer to predict biotic resistance to invasive prey.

    PubMed

    Twardochleb, Laura A; Novak, Mark; Moore, Jonathan W

    2012-06-01

    Predators sometimes provide biotic resistance against invasions by nonnative prey. Understanding and predicting the strength of biotic resistance remains a key challenge in invasion biology. A predator's functional response to nonnative prey may predict whether a predator can provide biotic resistance against nonnative prey at different prey densities. Surprisingly, functional responses have not been used to make quantitative predictions about biotic resistance. We parameterized the functional response of signal crayfish (Pacifastacus leniusculus) to invasive New Zealand mud snails (Potamopyrgus antipodarum; NZMS) and used this functional response and a simple model of NZMS population growth to predict the probability of biotic resistance at different predator and prey densities. Signal crayfish were effective predators of NZMS, consuming more than 900 NZMS per predator in a 12-h period, and Bayesian model fitting indicated their consumption rate followed a type 3 functional response to NZMS density. Based on this functional response and associated parameter uncertainty, we predict that NZMS will be able to invade new systems at low crayfish densities (< 0.2 crayfish/m2) regardless of NZMS density. At intermediate to high crayfish densities (> 0.2 crayfish/m2), we predict that low densities of NZMS will be able to establish in new communities; however, once NZMS reach a threshold density of -2000 NZMS/m2, predation by crayfish will drive negative NZMS population growth. Further, at very high densities, NZMS overwhelm predation by crayfish and invade. Thus, interacting thresholds of propagule pressure and predator densities define the probability of biotic resistance. Quantifying the shape and uncertainty of predator functional responses to nonnative prey may help predict the outcomes of invasions.

  7. Mycobacterial Interspersed Repetitive Unit Can Predict Drug Resistance of Mycobacterium tuberculosis in China

    PubMed Central

    Cheng, Xian-feng; Jiang, Chao; Zhang, Min; Xia, Dan; Chu, Li-li; Wen, Yu-feng; Zhu, Ming; Jiang, Yue-gen

    2016-01-01

    Background: Recently, Mycobacterial Interspersed Repetitive Unit (MIRU) was supposed to be associated with drug resistance in Mycobacterium tuberculosis (M. tuberculosis), but whether the association exists actually in local strains in China was still unknown. This research was conducted to explore that association and the predictability of MIRU to drug resistance of Tuberculosis (TB). Methods: The clinical isolates were collected and the susceptibility test were conducted with Lowenstein–Jensen (LJ) medium for five anti-TB drug. Based on PCR of MIRU-VNTR (Variable Number of Tandem Repeat) genotyping, we tested the number of the repeat unite of MIRU. Then, we used logistic regression to evaluate the association between 15 MIRU and drug resistance. In addition, we explored the most suitable MIRU locus of identified MIRU loci for drug resistance by multivariate logistic regression. Results: Of the 102 strains, one isolate was resistant to rifampicin and one isolate was resistant to streptomycin. Among these fifteen MIRU, there was a association between MIRU loci polymorphism and anti-tuberculosis drug resistance, ETRB (P = 0.03, OR = 0.19, 95% CI 0.05–0.81) and ETRC (P = 0.01, OR = 0.14, 95% CI 0.03–0.64) were negatively related to isoniazid resistance; MIRU20 (P = 0.05, OR = 2.87, 95% CI 1.01–8.12) was positively associated with ethambutol resistance; and QUB11a (P = 0.02, OR = 0.79, 95% CI 0.65–0.96) was a negative association factor of p-aminosalicylic acid resistance. Conclusion: Our research showed that MIRU loci may predict drug resistance of tuberculosis in China. However, the mechanism still needs further exploration. PMID:27047485

  8. Resistance to sunitinib in renal cell carcinoma: From molecular mechanisms to predictive markers and future perspectives.

    PubMed

    Joosten, S C; Hamming, L; Soetekouw, P M; Aarts, M J; Veeck, J; van Engeland, M; Tjan-Heijnen, V C

    2015-01-01

    The introduction of agents that inhibit tumor angiogenesis by targeting vascular endothelial growth factor (VEGF) signaling has made a significant impact on the survival of patients with metastasized renal cell carcinoma (RCC). Sunitinib, a tyrosine kinase inhibitor of the VEGF receptor, has become the mainstay of treatment for these patients. Although treatment with sunitinib substantially improved patient outcome, the initial success is overshadowed by the occurrence of resistance. The mechanisms of resistance are poorly understood. Insight into the molecular mechanisms of resistance will help to better understand the biology of RCC and can ultimately aid the development of more effective therapies for patients with this infaust disease. In this review we comprehensively discuss molecular mechanisms of resistance to sunitinib and the involved biological processes, summarize potential biomarkers that predict response and resistance to treatment with sunitinib, and elaborate on future perspectives in the treatment of metastasized RCC. PMID:25446042

  9. Electrical Resistance of Ceramic Matrix Composites for Damage Detection and Life-Prediction

    NASA Technical Reports Server (NTRS)

    Smith, Craig; Morscher, Gregory N.; Xia, Zhenhai

    2008-01-01

    The electric resistance of woven SiC fiber reinforced SiC matrix composites were measured under tensile loading conditions. The results show that the electrical resistance is closely related to damage and that real-time information about the damage state can be obtained through monitoring of the resistance. Such self-sensing capability provides the possibility of on-board/in-situ damage detection or inspection of a component during "down time". The correlation of damage with appropriate failure mechanism can then be applied to accurate life prediction for high-temperature ceramic matrix composites.

  10. Prediction of ship resistance in head waves using RANS based solver

    NASA Astrophysics Data System (ADS)

    Islam, Hafizul; Akimoto, Hiromichi

    2016-07-01

    Maneuverability prediction of ships using CFD has gained high popularity over the years because of its improving accuracy and economics. This paper discusses the estimation of calm water and added resistance properties of a KVLCC2 model using a light and economical RaNS based solver, called SHIP_Motion. The solver solves overset structured mesh using finite volume method. In the calm water test, total drag coefficient, sinkage and trim values were predicted together with mesh dependency analysis and compared with experimental data. For added resistance in head sea, short wave cases were simulated and compared with experimental and other simulation data. Overall the results were well predicted and showed good agreement with comparative data. The paper concludes that it is well possible to predict ship maneuverability characteristics using the present solver, with reasonable accuracy utilizing minimum computational resources and within acceptable time.

  11. Modeling bulk canopy resistance from climatic variables for predicting hourly evapotranspiration of maize and buckwheat

    NASA Astrophysics Data System (ADS)

    Yan, Haofang; Shi, Haibin; Hiroki, Oue; Zhang, Chuan; Xue, Zhu; Cai, Bin; Wang, Guoqing

    2015-06-01

    This study presents models for predicting hourly canopy resistance ( r c) and evapotranspiration (ETc) based on Penman-Monteith approach. The micrometeorological data and ET c were observed during maize and buckwheat growing seasons in 2006 and 2009 in China and Japan, respectively. The proposed models of r c were developed by a climatic resistance ( r *) that depends on climatic variables. Non-linear relationships between r c and r * were applied. The measured ETc using Bowen ratio energy balance method was applied for model validation. The statistical analysis showed that there were no significant differences between predicted ETc by proposed models and measured ETc for both maize and buckwheat crops. The model for predicting ETc at maize field showed better performance than predicting ETc at buckwheat field, the coefficients of determination were 0.92 and 0.84, respectively. The study provided an easy way for the application of Penman-Monteith equation with only general available meteorological database.

  12. Relative Prolongation of Inspiratory Time Predicts High versus Low Resistance Categorization of Hypopneas

    PubMed Central

    Mooney, Anne M.; Abounasr, Khader K.; Rapoport, David M.; Ayappa, Indu

    2012-01-01

    Study Objectives: Sleep disordered breathing events conceptually separate into “obstructive” and “central” events. Esophageal manometry is the definitive but invasive means of classifying hypopneas. The purpose of this project was to identify noninvasive markers for discriminating high vs. low resistance hypopneas. Methods: Forty subjects with obstructive or central sleep apnea underwent diagnostic polysomnography with nasal cannula airflow and esophageal manometry; 200% resistance relative to reference breaths was used to define “high” resistance. Noninvasive parameters from 292 randomly selected hypopneas in 20 subjects were analyzed and correlated to resistance. The best parameter and cutoff for predicting high relative resistance was determined and tested prospectively in 2 test sets in the 20 remaining subjects. Test Set A: 15 randomly selected hypopneas in each subject; Test Set B: all hypopneas in 7 subjects. Results: In the development set, prolongation of inspiratory time during the 2 smallest breaths of a hypopnea (Ti) relative to baseline had the best correlation to high relative resistance. In the Test Set A, relative Ti > 110% classified obstructive events with sensitivity = 72%, specificity = 77%, PPV = 64%, NPV = 83%. Similar numbers were obtained for classification of hypopneas based on presence of flow limitation (FL) alone. When either relative Ti or presence of FL were used to define high resistance, sensitivity = 84%, specificity = 74%, PPV = 65%, NPV = 89%. Similar results were obtained for Test Set B. Conclusions: Relative prolongation of Ti is a good noninvasive predictor of high/low resistance in a dataset with both FL and NFL hypopneas. Combination of FL and relative Ti improves this classification. The use of Ti to separate obstructive and central hypopneas needs to be further tested for clinical utility (outcomes and treatment effects). Citation: Mooney AM; Abounasr KK; Rapoport DM; Ayappa I. Relative prolongation of

  13. Prediction of clothing thermal insulation and moisture vapour resistance of the clothed body walking in wind.

    PubMed

    Qian, Xiaoming; Fan, Jintu

    2006-11-01

    Clothing thermal insulation and moisture vapour resistance are the two most important parameters in thermal environmental engineering, functional clothing design and end use of clothing ensembles. In this study, clothing thermal insulation and moisture vapour resistance of various types of clothing ensembles were measured using the walking-able sweating manikin, Walter, under various environmental conditions and walking speeds. Based on an extensive experimental investigation and an improved understanding of the effects of body activities and environmental conditions, a simple but effective direct regression model has been established, for predicting the clothing thermal insulation and moisture vapour resistance under wind and walking motion, from those when the manikin was standing in still air. The model has been validated by using experimental data reported in the previous literature. It has shown that the new models have advantages and provide very accurate prediction.

  14. Low MITF/AXL ratio predicts early resistance to multiple targeted drugs in melanoma.

    PubMed

    Müller, Judith; Krijgsman, Oscar; Tsoi, Jennifer; Robert, Lidia; Hugo, Willy; Song, Chunying; Kong, Xiangju; Possik, Patricia A; Cornelissen-Steijger, Paulien D M; Geukes Foppen, Marnix H; Kemper, Kristel; Goding, Colin R; McDermott, Ultan; Blank, Christian; Haanen, John; Graeber, Thomas G; Ribas, Antoni; Lo, Roger S; Peeper, Daniel S

    2014-12-15

    Increased expression of the Microphthalmia-associated transcription factor (MITF) contributes to melanoma progression and resistance to BRAF pathway inhibition. Here we show that the lack of MITF is associated with more severe resistance to a range of inhibitors, while its presence is required for robust drug responses. Both in primary and acquired resistance, MITF levels inversely correlate with the expression of several activated receptor tyrosine kinases, most frequently AXL. The MITF-low/AXL-high/drug-resistance phenotype is common among mutant BRAF and NRAS melanoma cell lines. The dichotomous behaviour of MITF in drug response is corroborated in vemurafenib-resistant biopsies, including MITF-high and -low clones in a relapsed patient. Furthermore, drug cocktails containing AXL inhibitor enhance melanoma cell elimination by BRAF or ERK inhibition. Our results demonstrate that a low MITF/AXL ratio predicts early resistance to multiple targeted drugs, and warrant clinical validation of AXL inhibitors to combat resistance of BRAF and NRAS mutant MITF-low melanomas.

  15. Low MITF/AXL ratio predicts early resistance to multiple targeted drugs in melanoma

    PubMed Central

    Müller, Judith; Krijgsman, Oscar; Tsoi, Jennifer; Robert, Lidia; Hugo, Willy; Song, Chunying; Kong, Xiangju; Possik, Patricia A.; Cornelissen-Steijger, Paulien D.M.; Foppen, Marnix H. Geukes; Kemper, Kristel; Goding, Colin R.; McDermott, Ultan; Blank, Christian; Haanen, John; Graeber, Thomas G.; Ribas, Antoni; Lo, Roger S.; Peeper, Daniel S.

    2015-01-01

    Increased expression of the Microphthalmia-associated transcription factor (MITF) contributes to melanoma progression and resistance to BRAF pathway inhibition. Here we show that the lack of MITF is associated with more severe resistance to a range of inhibitors, while its presence is required for robust drug responses. Both in primary and acquired resistance, MITF levels inversely correlate with the expression of several activated receptor tyrosine kinases, most frequently AXL. The MITF-low/AXL-high/drug-resistance phenotype is common among mutant BRAF and NRAS melanoma cell lines. The dichotomous behaviour of MITF in drug response is corroborated in vemurafenib-resistant biopsies, including MITF-high and -low clones in a relapsed patient. Furthermore, drug cocktails containing AXL inhibitor enhance melanoma cell elimination by BRAF or ERK inhibition. Our results demonstrate that a low MITF/AXL ratio predicts early resistance to multiple targeted drugs, and warrant clinical validation of AXL inhibitors to combat resistance of BRAF and NRAS mutant MITF-low melanomas. PMID:25502142

  16. pncA gene expression and prediction factors on pyrazinamide resistance in Mycobacterium tuberculosis.

    PubMed

    Sheen, Patricia; Lozano, Katherine; Gilman, Robert H; Valencia, Hugo J; Loli, Sebastian; Fuentes, Patricia; Grandjean, Louis; Zimic, Mirko

    2013-09-01

    Mutations in the pyrazinamidase (PZAse) coding gene, pncA, have been considered as the main cause of pyrazinamide (PZA) resistance in Mycobacterium tuberculosis. However, recent studies suggest there is no single mechanism of resistance to PZA. The pyrazinoic acid (POA) efflux rate is the basis of the PZA susceptibility Wayne test, and its quantitative measurement has been found to be a highly sensitive and specific predictor of PZA resistance. Based on biological considerations, the POA efflux rate is directly determined by the PZAse activity, the level of pncA expression, and the efficiency of the POA efflux pump system. This study analyzes the individual and the adjusted contribution of PZAse activity, pncA expression and POA efflux rate on PZA resistance. Thirty M. tuberculosis strains with known microbiological PZA susceptibility or resistance were analyzed. For each strain, PZAse was recombinantly produced and its enzymatic activity measured. The level of pncA mRNA was estimated by quantitative RT-PCR, and the POA efflux rate was determined. Mutations in the pncA promoter were detected by DNA sequencing. All factors were evaluated by multiple regression analysis to determine their adjusted effects on the level of PZA resistance. Low level of pncA expression associated to mutations in the pncA promoter region was observed in pncA wild type resistant strains. POA efflux rate was the best predictor after adjusting for the other factors, followed by PZAse activity. These results suggest that tests which rely on pncA mutations or PZAse activity are likely to be less predictive of real PZA resistance than tests which measure the rate of POA efflux. This should be further analyzed in light of the development of alternate assays to determine PZA resistance. PMID:23867321

  17. pncA gene expression and prediction factors on pyrazinamide resistance in Mycobacterium tuberculosis.

    PubMed

    Sheen, Patricia; Lozano, Katherine; Gilman, Robert H; Valencia, Hugo J; Loli, Sebastian; Fuentes, Patricia; Grandjean, Louis; Zimic, Mirko

    2013-09-01

    Mutations in the pyrazinamidase (PZAse) coding gene, pncA, have been considered as the main cause of pyrazinamide (PZA) resistance in Mycobacterium tuberculosis. However, recent studies suggest there is no single mechanism of resistance to PZA. The pyrazinoic acid (POA) efflux rate is the basis of the PZA susceptibility Wayne test, and its quantitative measurement has been found to be a highly sensitive and specific predictor of PZA resistance. Based on biological considerations, the POA efflux rate is directly determined by the PZAse activity, the level of pncA expression, and the efficiency of the POA efflux pump system. This study analyzes the individual and the adjusted contribution of PZAse activity, pncA expression and POA efflux rate on PZA resistance. Thirty M. tuberculosis strains with known microbiological PZA susceptibility or resistance were analyzed. For each strain, PZAse was recombinantly produced and its enzymatic activity measured. The level of pncA mRNA was estimated by quantitative RT-PCR, and the POA efflux rate was determined. Mutations in the pncA promoter were detected by DNA sequencing. All factors were evaluated by multiple regression analysis to determine their adjusted effects on the level of PZA resistance. Low level of pncA expression associated to mutations in the pncA promoter region was observed in pncA wild type resistant strains. POA efflux rate was the best predictor after adjusting for the other factors, followed by PZAse activity. These results suggest that tests which rely on pncA mutations or PZAse activity are likely to be less predictive of real PZA resistance than tests which measure the rate of POA efflux. This should be further analyzed in light of the development of alternate assays to determine PZA resistance.

  18. pncA gene expression and prediction factors on pyrazinamide resistance in Mycobacterium tuberculosis

    PubMed Central

    Sheen, Patricia; Lozano, Katherine; Gilman, Robert H.; Valencia, Hugo J.; Loli, Sebastian; Fuentes, Patricia; Grandjean, Louis; Zimic, Mirko

    2013-01-01

    Summary Background Mutations in the pyrazinamidase (PZAse) coding gene, pncA, have been considered as the main cause of pyrazinamide (PZA) resistance in Mycobacterium tuberculosis. However, recent studies suggest there is no single mechanism of resistance to PZA. The pyrazinoic acid (POA) efflux rate is the basis of the PZA susceptibility Wayne test, and its quantitative measurement has been found to be a highly sensitive and specific predictor of PZA resistance. Based on biological considerations, the POA efflux rate is directly determined by the PZAse activity, the level of pncA expression, and the efficiency of the POA efflux pump system. Objective This study analyzes the individual and the adjusted contribution of PZAse activity, pncA expression and POA efflux rate on PZA resistance. Methods Thirty M. tuberculosis strains with known microbiological PZA susceptibility or resistance were analyzed. For each strain, PZAse was recombinantly produced and its enzymatic activity measured. The level of pncA mRNA was estimated by quantitative RT-PCR, and the POA efflux rate was determined. Mutations in the pncA promoter were detected by DNA sequencing. All factors were evaluated by multiple regression analysis to determine their adjusted effects on the level of PZA resistance. Findings Low level of pncA expression associated to mutations in the pncA promoter region was observed in pncA wild type resistant strains. POA efflux rate was the best predictor after adjusting for the other factors, followed by PZAse activity. These results suggest that tests which rely on pncA mutations or PZAse activity are likely to be less predictive of real PZA resistance than tests which measure the rate of POA efflux. This should be further analyzed in light of the development of alternate assays to determine PZA resistance. PMID:23867321

  19. Ecological resistance surfaces predict fine-scale genetic differentiation in a terrestrial woodland salamander.

    PubMed

    Peterman, William E; Connette, Grant M; Semlitsch, Raymond D; Eggert, Lori S

    2014-05-01

    Landscape genetics has seen tremendous advances since its introduction, but parameterization and optimization of resistance surfaces still poses significant challenges. Despite increased availability and resolution of spatial data, few studies have integrated empirical data to directly represent ecological processes as genetic resistance surfaces. In our study, we determine the landscape and ecological factors affecting gene flow in the western slimy salamander (Plethodon albagula). We used field data to derive resistance surfaces representing salamander abundance and rate of water loss through combinations of canopy cover, topographic wetness, topographic position, solar exposure and distance from ravine. These ecologically explicit composite surfaces directly represent an ecological process or physiological limitation of our organism. Using generalized linear mixed-effects models, we optimized resistance surfaces using a nonlinear optimization algorithm to minimize model AIC. We found clear support for the resistance surface representing the rate of water loss experienced by adult salamanders in the summer. Resistance was lowest at intermediate levels of water loss and higher when the rate of water loss was predicted to be low or high. This pattern may arise from the compensatory movement behaviour of salamanders through suboptimal habitat, but also reflects the physiological limitations of salamanders and their sensitivity to extreme environmental conditions. Our study demonstrates that composite representations of ecologically explicit processes can provide novel insight and can better explain genetic differentiation than ecologically implicit landscape resistance surfaces. Additionally, our study underscores the fact that spatial estimates of habitat suitability or abundance may not serve as adequate proxies for describing gene flow, as predicted abundance was a poor predictor of genetic differentiation.

  20. Prediction of multi-drug resistance transporters using a novel sequence analysis method

    PubMed Central

    McDermott, Jason E.; Bruillard, Paul; Overall, Christopher C.; Gosink, Luke; Lindemann, Stephen R.

    2015-01-01

    There are many examples of groups of proteins that have similar function, but the determinants of functional specificity may be hidden by lack of sequence similarity, or by large groups of similar sequences with different functions. Transporters are one such protein group in that the general function, transport, can be easily inferred from the sequence, but the substrate specificity can be impossible to predict from sequence with current methods. In this paper we describe a linguistic-based approach to identify functional patterns from groups of unaligned protein sequences and its application to predict multi-drug resistance transporters (MDRs) from bacteria. We first show that our method can recreate known patterns from PROSITE for several motifs from unaligned sequences. We then show that the method, MDRpred, can predict MDRs with greater accuracy and positive predictive value than a collection of currently available family-based models from the Pfam database. Finally, we apply MDRpred to a large collection of protein sequences from an environmental microbiome study to make novel predictions about drug resistance in a potential environmental reservoir. PMID:26913187

  1. Neural Network-Based Resistance Spot Welding Control and Quality Prediction

    SciTech Connect

    Allen, J.D., Jr.; Ivezic, N.D.; Zacharia, T.

    1999-07-10

    This paper describes the development and evaluation of neural network-based systems for industrial resistance spot welding process control and weld quality assessment. The developed systems utilize recurrent neural networks for process control and both recurrent networks and static networks for quality prediction. The first section describes a system capable of both welding process control and real-time weld quality assessment, The second describes the development and evaluation of a static neural network-based weld quality assessment system that relied on experimental design to limit the influence of environmental variability. Relevant data analysis methods are also discussed. The weld classifier resulting from the analysis successfldly balances predictive power and simplicity of interpretation. The results presented for both systems demonstrate clearly that neural networks can be employed to address two significant problems common to the resistance spot welding industry, control of the process itself, and non-destructive determination of resulting weld quality.

  2. Prediction of Corrosion Resistance of Some Dental Metallic Materials with an Adaptive Regression Model

    NASA Astrophysics Data System (ADS)

    Chelariu, Romeu; Suditu, Gabriel Dan; Mareci, Daniel; Bolat, Georgiana; Cimpoesu, Nicanor; Leon, Florin; Curteanu, Silvia

    2015-04-01

    The aim of this study is to investigate the electrochemical behavior of some dental metallic materials in artificial saliva for different pH (5.6 and 3.4), NaF content (500 ppm, 1000 ppm, and 2000 ppm), and with albumin protein addition (0.6 wt.%) for pH 3.4. The corrosion resistance of the alloys was quantitatively evaluated by polarization resistance, estimated by electrochemical impedance spectroscopy method. An adaptive k-nearest-neighbor regression method was applied for evaluating the corrosion resistance of the alloys by simulation, depending on the operation conditions. The predictions provided by the model are useful for experimental practice, as they can replace or, at least, help to plan the experiments. The accurate results obtained prove that the developed model is reliable and efficient.

  3. ABCG2 expression in colorectal adenocarcinomas may predict resistance to irinotecan

    PubMed Central

    Tuy, Hoang Dinh; Shiomi, Hisanori; Mukaisho, Ken Ichi; Naka, Shigeyuki; Shimizu, Tomoharu; Sonoda, Hiromichi; Mekata, Eiji; Endo, Yoshihiro; Kurumi, Yoshimasa; Sugihara, Hiroyuki; Tani, Masaji; Tani, Tohru

    2016-01-01

    Irinotecan is a key drug for patients with advanced and recurrent colorectal carcinoma. However, the efficacy of irinotecan is not sufficient; partly, as there is no useful marker to predict chemosensitivity to the drug. The aim of the present study was to evaluate whether the expression levels of adenosine triphosphate-binding cassette sub-family G (WHITE) member 2 (Junior blood group) (ABCG2) in primary colorectal tumors predict chemoresistance to irinotecan. Using the resected primary tumor specimens of 189 patients with colorectal cancer, the association between the immunohistochemical expression of ABCG2 protein and the results of the collagen gel droplet embedded culture drug sensitivity test, performed to evaluate the chemosensitivity to SN-38 (an active metabolite of irinotecan), was investigated. Among the 189 patients, 17 received irinotecan-based chemotherapy, and their responses and progression-free survival (PFS) were analyzed. The tumors of patients with increased ABCG2 expression accounted for 60% of the tumors examined, and were significantly more resistant to SN-38, compared with patients with low ABCG2 expression (P<0.001). In a multivariate logistic regression analysis, increased expression of ABCG2 protein was an independent and significant predictor of resistance to SN-38, increasing the risk of resistance by 12-fold. Increased expression of ABCG2 and a low sensitivity to SN-38 was significantly associated with resistance to irinotecan-based chemotherapy (P=0.01 and 0.028, respectively). The median PFS of patients with increased expression of ABCG2 was significantly shorter, compared with patients with low expression levels of ABCG2 (104 vs. 242 days; P=0.047). The increased immunohistochemical expression of ABCG2 in primary tumors may be a useful predictive biomarker of resistance to irinotecan-based chemotherapy for patients with recurrent or metastatic colorectal cancer.

  4. Concentrations of antibiotics predicted to select for resistant bacteria: Proposed limits for environmental regulation.

    PubMed

    Bengtsson-Palme, Johan; Larsson, D G Joakim

    2016-01-01

    There are concerns that selection pressure from antibiotics in the environment may accelerate the evolution and dissemination of antibiotic-resistant pathogens. Nevertheless, there is currently no regulatory system that takes such risks into account. In part, this is due to limited knowledge of environmental concentrations that might exert selection for resistant bacteria. To experimentally determine minimal selective concentrations in complex microbial ecosystems for all antibiotics would involve considerable effort. In this work, our aim was to estimate upper boundaries for selective concentrations for all common antibiotics, based on the assumption that selective concentrations a priori need to be lower than those completely inhibiting growth. Data on Minimal Inhibitory Concentrations (MICs) were obtained for 111 antibiotics from the public EUCAST database. The 1% lowest observed MICs were identified, and to compensate for limited species coverage, predicted lowest MICs adjusted for the number of tested species were extrapolated through modeling. Predicted No Effect Concentrations (PNECs) for resistance selection were then assessed using an assessment factor of 10 to account for differences between MICs and minimal selective concentrations. The resulting PNECs ranged from 8 ng/L to 64 μg/L. Furthermore, the link between taxonomic similarity between species and lowest MIC was weak. This work provides estimated upper boundaries for selective concentrations (lowest MICs) and PNECs for resistance selection for all common antibiotics. In most cases, PNECs for selection of resistance were below available PNECs for ecotoxicological effects. The generated PNECs can guide implementation of compound-specific emission limits that take into account risks for resistance promotion.

  5. Rapid antibiotic-resistance predictions from genome sequence data for Staphylococcus aureus and Mycobacterium tuberculosis

    PubMed Central

    Bradley, Phelim; Gordon, N. Claire; Walker, Timothy M.; Dunn, Laura; Heys, Simon; Huang, Bill; Earle, Sarah; Pankhurst, Louise J.; Anson, Luke; de Cesare, Mariateresa; Piazza, Paolo; Votintseva, Antonina A.; Golubchik, Tanya; Wilson, Daniel J.; Wyllie, David H.; Diel, Roland; Niemann, Stefan; Feuerriegel, Silke; Kohl, Thomas A.; Ismail, Nazir; Omar, Shaheed V.; Smith, E. Grace; Buck, David; McVean, Gil; Walker, A. Sarah; Peto, Tim E. A.; Crook, Derrick W.; Iqbal, Zamin

    2015-01-01

    The rise of antibiotic-resistant bacteria has led to an urgent need for rapid detection of drug resistance in clinical samples, and improvements in global surveillance. Here we show how de Bruijn graph representation of bacterial diversity can be used to identify species and resistance profiles of clinical isolates. We implement this method for Staphylococcus aureus and Mycobacterium tuberculosis in a software package (‘Mykrobe predictor') that takes raw sequence data as input, and generates a clinician-friendly report within 3 minutes on a laptop. For S. aureus, the error rates of our method are comparable to gold-standard phenotypic methods, with sensitivity/specificity of 99.1%/99.6% across 12 antibiotics (using an independent validation set, n=470). For M. tuberculosis, our method predicts resistance with sensitivity/specificity of 82.6%/98.5% (independent validation set, n=1,609); sensitivity is lower here, probably because of limited understanding of the underlying genetic mechanisms. We give evidence that minor alleles improve detection of extremely drug-resistant strains, and demonstrate feasibility of the use of emerging single-molecule nanopore sequencing techniques for these purposes. PMID:26686880

  6. Rapid antibiotic-resistance predictions from genome sequence data for Staphylococcus aureus and Mycobacterium tuberculosis.

    PubMed

    Bradley, Phelim; Gordon, N Claire; Walker, Timothy M; Dunn, Laura; Heys, Simon; Huang, Bill; Earle, Sarah; Pankhurst, Louise J; Anson, Luke; de Cesare, Mariateresa; Piazza, Paolo; Votintseva, Antonina A; Golubchik, Tanya; Wilson, Daniel J; Wyllie, David H; Diel, Roland; Niemann, Stefan; Feuerriegel, Silke; Kohl, Thomas A; Ismail, Nazir; Omar, Shaheed V; Smith, E Grace; Buck, David; McVean, Gil; Walker, A Sarah; Peto, Tim E A; Crook, Derrick W; Iqbal, Zamin

    2015-01-01

    The rise of antibiotic-resistant bacteria has led to an urgent need for rapid detection of drug resistance in clinical samples, and improvements in global surveillance. Here we show how de Bruijn graph representation of bacterial diversity can be used to identify species and resistance profiles of clinical isolates. We implement this method for Staphylococcus aureus and Mycobacterium tuberculosis in a software package ('Mykrobe predictor') that takes raw sequence data as input, and generates a clinician-friendly report within 3 minutes on a laptop. For S. aureus, the error rates of our method are comparable to gold-standard phenotypic methods, with sensitivity/specificity of 99.1%/99.6% across 12 antibiotics (using an independent validation set, n=470). For M. tuberculosis, our method predicts resistance with sensitivity/specificity of 82.6%/98.5% (independent validation set, n=1,609); sensitivity is lower here, probably because of limited understanding of the underlying genetic mechanisms. We give evidence that minor alleles improve detection of extremely drug-resistant strains, and demonstrate feasibility of the use of emerging single-molecule nanopore sequencing techniques for these purposes. PMID:26686880

  7. Rapid antibiotic-resistance predictions from genome sequence data for Staphylococcus aureus and Mycobacterium tuberculosis.

    PubMed

    Bradley, Phelim; Gordon, N Claire; Walker, Timothy M; Dunn, Laura; Heys, Simon; Huang, Bill; Earle, Sarah; Pankhurst, Louise J; Anson, Luke; de Cesare, Mariateresa; Piazza, Paolo; Votintseva, Antonina A; Golubchik, Tanya; Wilson, Daniel J; Wyllie, David H; Diel, Roland; Niemann, Stefan; Feuerriegel, Silke; Kohl, Thomas A; Ismail, Nazir; Omar, Shaheed V; Smith, E Grace; Buck, David; McVean, Gil; Walker, A Sarah; Peto, Tim E A; Crook, Derrick W; Iqbal, Zamin

    2015-01-01

    The rise of antibiotic-resistant bacteria has led to an urgent need for rapid detection of drug resistance in clinical samples, and improvements in global surveillance. Here we show how de Bruijn graph representation of bacterial diversity can be used to identify species and resistance profiles of clinical isolates. We implement this method for Staphylococcus aureus and Mycobacterium tuberculosis in a software package ('Mykrobe predictor') that takes raw sequence data as input, and generates a clinician-friendly report within 3 minutes on a laptop. For S. aureus, the error rates of our method are comparable to gold-standard phenotypic methods, with sensitivity/specificity of 99.1%/99.6% across 12 antibiotics (using an independent validation set, n=470). For M. tuberculosis, our method predicts resistance with sensitivity/specificity of 82.6%/98.5% (independent validation set, n=1,609); sensitivity is lower here, probably because of limited understanding of the underlying genetic mechanisms. We give evidence that minor alleles improve detection of extremely drug-resistant strains, and demonstrate feasibility of the use of emerging single-molecule nanopore sequencing techniques for these purposes.

  8. Evaluation of candidate biomarkers to predict cancer cell sensitivity or resistance to PARP-1 inhibitor treatment

    PubMed Central

    Oplustilova, Lenka; Wolanin, Kamila; Mistrik, Martin; Korinkova, Gabriela; Simkova, Dana; Bouchal, Jan; Lenobel, Rene; Bartkova, Jirina; Lau, Alan; O’Connor, Mark J.; Lukas, Jiri; Bartek, Jiri

    2012-01-01

    Impaired DNA damage response pathways may create vulnerabilities of cancer cells that can be exploited therapeutically. One such selective vulnerability is the sensitivity of BRCA1- or BRCA2-defective tumors (hence defective in DNA repair by homologous recombination, HR) to inhibitors of the poly(ADP-ribose) polymerase-1 (PARP-1), an enzyme critical for repair pathways alternative to HR. While promising, treatment with PARP-1 inhibitors (PARP-1i) faces some hurdles, including (1) acquired resistance, (2) search for other sensitizing, non-BRCA1/2 cancer defects and (3) lack of biomarkers to predict response to PARP-1i. Here we addressed these issues using PARP-1i on 20 human cell lines from carcinomas of the breast, prostate, colon, pancreas and ovary. Aberrations of the Mre11-Rad50-Nbs1 (MRN) complex sensitized cancer cells to PARP-1i, while p53 status was less predictive, even in response to PARP-1i combinations with camptothecin or ionizing radiation. Furthermore, monitoring PARsylation and Rad51 foci formation as surrogate markers for PARP activity and HR, respectively, supported their candidacy for biomarkers of PARP-1i responses. As to resistance mechanisms, we confirmed the role of the multidrug resistance efflux transporters and its reversibility. More importantly, we demonstrated that shRNA lentivirus-mediated depletion of 53BP1 in human BRCA1-mutant breast cancer cells increased their resistance to PARP-1i. Given the preferential loss of 53BP1 in BRCA-defective and triple-negative breast carcinomas, our findings warrant assessment of 53BP1 among candidate predictive biomarkers of response to PARPi. Overall, this study helps characterize genetic and functional determinants of cellular responses to PARP-1i and contributes to the search for biomarkers to exploit PARP inhibitors in cancer therapy. PMID:22983061

  9. Establishing a predictive model for aspirin resistance in elderly Chinese patients with chronic cardiovascular disease

    PubMed Central

    Cao, Jian; Hao, Wei-Jun; Gao, Ling-Gen; Chen, Tian-Meng; Liu, Lin; Sun, Yu-Fa; Hu, Guo-Liang; Hu, Yi-Xin; Fan, Li

    2016-01-01

    Background Resistance to anti-platelet therapy is detrimental to patients. Our aim was to establish a predictive model for aspirin resistance to identify high-risk patients and to propose appropriate intervention. Methods Elderly patients (n = 1130) with stable chronic coronary heart disease who were taking aspirin (75 mg) for > 2 months were included. Details of their basic characteristics, laboratory test results, and medications were collected. Logistic regression analysis was performed to establish a predictive model for aspirin resistance. Risk score was finally established according to coefficient B and type of variables in logistic regression. The Hosmer–Lemeshow (HL) test and receiver operating characteristic curves were performed to respectively test the calibration and discrimination of the model. Results Seven risk factors were included in our risk score. They were serum creatinine (> 110 μmol/L, score of 1); fasting blood glucose (> 7.0 mmol/L, score of 1); hyperlipidemia (score of 1); number of coronary arteries (2 branches, score of 2; ≥ 3 branches, score of 4); body mass index (20–25 kg/m2, score of 2; > 25 kg/m2, score of 4); percutaneous coronary intervention (score of 2); and smoking (score of 3). The HL test showed P ≥ 0.05 and area under the receiver operating characteristic curve ≥ 0.70. Conclusions We explored and quantified the risk factors for aspirin resistance. Our predictive model showed good calibration and discriminative power and therefore a good foundation for the further study of patients undergoing anti-platelet therapy. PMID:27594876

  10. A quasi-physical model for predicting the thermal insulation and moisture vapour resistance of clothing.

    PubMed

    Qian, Xiaoming; Fan, Jintu

    2009-07-01

    Based on the improved understanding of the effects of wind and walking motion on the thermal insulation and moisture vapour resistance of clothing induced by air ventilation in the clothing system, a new model has been derived based on fundamental mechanisms of heat and mass transfer, which include conduction, diffusion, radiation and natural convection, wind penetration and air ventilation. The model predicts thermal insulation of clothing under body movement and windy conditions from the thermal insulation of clothing measured when the person is standing in the still air. The effects of clothing characteristics such as fabric air permeability, garment style, garment fitting and construction have been considered in the model through the key prediction parameters. With the new model, an improved prediction accuracy is achieved with a percentage of fit being as high as 0.96.

  11. Biomarkers of evasive resistance predict disease progression in cancer patients treated with antiangiogenic therapies.

    PubMed

    Pircher, Andreas; Jöhrer, Karin; Kocher, Florian; Steiner, Normann; Graziadei, Ivo; Heidegger, Isabel; Pichler, Renate; Leonhartsberger, Nicolai; Kremser, Christian; Kern, Johann; Untergasser, Gerold; Gunsilius, Eberhard; Hilbe, Wolfgang

    2016-04-12

    Numerous antiangiogenic agents are approved for the treatment of oncological diseases. However, almost all patients develop evasive resistance mechanisms against antiangiogenic therapies. Currently no predictive biomarker for therapy resistance or response has been established. Therefore, the aim of our study was to identify biomarkers predicting the development of therapy resistance in patients with hepatocellular cancer (n = 11), renal cell cancer (n = 7) and non-small cell lung cancer (n = 2). Thereby we measured levels of angiogenic growth factors, tumor perfusion, circulating endothelial cells (CEC), circulating endothelial progenitor cells (CEP) and tumor endothelial markers (TEM) in patients during the course of therapy with antiangiogenic agents, and correlated them with the time to antiangiogenic progression (aTTP). Importantly, at disease progression, we observed an increase of proangiogenic factors, upregulation of CEC/CEP levels and downregulation of TEMs, such as Robo4 and endothelial cell-specific chemotaxis regulator (ECSCR), reflecting the formation of torturous tumor vessels. Increased TEM expression levels tended to correlate with prolonged aTTP (ECSCR high = 275 days vs. ECSCR low = 92.5 days; p = 0.07 and for Robo4 high = 387 days vs. Robo4 low = 90.0 days; p = 0.08). This indicates that loss of vascular stabilization factors aggravates the development of antiangiogenic resistance. Thus, our observations confirm that CEP/CEC populations, proangiogenic cytokines and TEMs contribute to evasive resistance in antiangiogenic treated patients. Higher TEM expression during disease progression may have clinical and pathophysiological implications, however, validation of our results is warranted for further biomarker development.

  12. Biomarkers of evasive resistance predict disease progression in cancer patients treated with antiangiogenic therapies

    PubMed Central

    Pircher, Andreas; Jöhrer, Karin; Kocher, Florian; Steiner, Normann; Graziadei, Ivo; Heidegger, Isabel; Pichler, Renate; Leonhartsberger, Nicolai; Kremser, Christian; Kern, Johann; Untergasser, Gerold; Gunsilius, Eberhard; Hilbe, Wolfgang

    2016-01-01

    Numerous antiangiogenic agents are approved for the treatment of oncological diseases. However, almost all patients develop evasive resistance mechanisms against antiangiogenic therapies. Currently no predictive biomarker for therapy resistance or response has been established. Therefore, the aim of our study was to identify biomarkers predicting the development of therapy resistance in patients with hepatocellular cancer (n = 11), renal cell cancer (n = 7) and non-small cell lung cancer (n = 2). Thereby we measured levels of angiogenic growth factors, tumor perfusion, circulating endothelial cells (CEC), circulating endothelial progenitor cells (CEP) and tumor endothelial markers (TEM) in patients during the course of therapy with antiangiogenic agents, and correlated them with the time to antiangiogenic progression (aTTP). Importantly, at disease progression, we observed an increase of proangiogenic factors, upregulation of CEC/CEP levels and downregulation of TEMs, such as Robo4 and endothelial cell-specific chemotaxis regulator (ECSCR), reflecting the formation of torturous tumor vessels. Increased TEM expression levels tended to correlate with prolonged aTTP (ECSCR high = 275 days vs. ECSCR low = 92.5 days; p = 0.07 and for Robo4 high = 387 days vs. Robo4 low = 90.0 days; p = 0.08). This indicates that loss of vascular stabilization factors aggravates the development of antiangiogenic resistance. Thus, our observations confirm that CEP/CEC populations, proangiogenic cytokines and TEMs contribute to evasive resistance in antiangiogenic treated patients. Higher TEM expression during disease progression may have clinical and pathophysiological implications, however, validation of our results is warranted for further biomarker development. PMID:26956051

  13. TAK1-regulated expression of BIRC3 predicts resistance to preoperative chemoradiotherapy in oesophageal adenocarcinoma patients

    PubMed Central

    Piro, G; Giacopuzzi, S; Bencivenga, M; Carbone, C; Verlato, G; Frizziero, M; Zanotto, M; Mina, M M; Merz, V; Santoro, R; Zanoni, A; De Manzoni, G; Tortora, G; Melisi, D

    2015-01-01

    Background: About 20% of resectable oesophageal carcinoma is resistant to preoperative chemoradiotherapy. Here we hypothesised that the expression of the antiapoptotic gene Baculoviral inhibitor of apoptosis repeat containing (BIRC)3 induced by the transforming growth factor β activated kinase 1 (TAK1) might be responsible for the resistance to the proapoptotic effect of chemoradiotherapy in oesophageal carcinoma. Methods: TAK1 kinase activity was inhibited in FLO-1 and KYAE-1 oesophageal adenocarcinoma cells using (5Z)-7-oxozeaenol. The BIRC3 mRNA expression was measured by qRT–PCR in 65 pretreatment frozen biopsies from patients receiving preoperatively docetaxel, cisplatin, 5-fluorouracil, and concurrent radiotherapy. Receiver operator characteristic (ROC) analyses were performed to determine the performance of BIRC3 expression levels in distinguishing patients with sensitive or resistant carcinoma. Results: In vitro, (5Z)-7-oxozeaenol significantly reduced BIRC3 expression in FLO-1 and KYAE-1 cells. Exposure to chemotherapeutic agents or radiotherapy plus (5Z)-7-oxozeaenol resulted in a strong synergistic antiapoptotic effect. In patients, median expression of BIRC3 was significantly (P<0.0001) higher in adenocarcinoma than in the more sensitive squamous cell carcinoma subtype. The BIRC3 expression significantly discriminated patients with sensitive or resistant adenocarcinoma (AUC-ROC=0.7773 and 0.8074 by size-based pathological response or Mandard's tumour regression grade classifications, respectively). Conclusions: The BIRC3 expression might be a valid biomarker for predicting patients with oesophageal adenocarcinoma that could most likely benefit from preoperative chemoradiotherapy. PMID:26291056

  14. Finite-size effects on molecular dynamics interfacial thermal-resistance predictions

    NASA Astrophysics Data System (ADS)

    Liang, Zhi; Keblinski, Pawel

    2014-08-01

    Using molecular dynamics simulations, we study the role of finite size effects on the determination of interfacial thermal resistance between two solids characterized by high phonon mean free paths. In particular, we will show that a direct, heat source-sink method leads to strong size effect, associated with ballistic phonon transport to and from, and specular reflections at the simulation domain boundary. Lack of proper account for these effects can lead to incorrect predictions about the role of interfacial bonding and structure on interfacial thermal resistance. We also show that the finite size effect can be dramatically reduced by introduction of rough external boundaries leading to diffuse phonon scattering, as explicitly demonstrated by phonon wave-packet simulations. Finally, we demonstrate that when careful considerations are given to the effects associated with the finite heat capacity of the simulation domains and phonon scattering from the external surfaces, a size-independent interfacial resistance can be properly extracted from the time integral of the correlation function of heat power across the interface. Our work demonstrates that reliable and consistent values of the interfacial thermal resistance can be obtained by equilibrium and nonequilibrium methods with a relatively small computational cost.

  15. Carotenoid-based plumage coloration predicts resistance to a novel parasite in the house finch

    NASA Astrophysics Data System (ADS)

    Hill, Geoffrey E.; Farmer, Kristy L.

    2005-01-01

    The Hamilton-Zuk hypothesis proposes that the bright colours displayed by many species of birds serve as signals of individual resistance to parasites. Despite the popularity of this hypothesis, only one previous study has tested whether plumage coloration predicts how individuals respond to a disease challenge. We inoculated 24 male house finches (Carpodacus mexicanus) of variable plumage hue with a novel bacterial pathogen, Mycoplasma gallicepticum (MG). We found no relationship between plumage hue and time to first symptoms following inoculation, but we found a significant negative relationship between plumage hue and clearance of disease: males with redder plumage cleared MG infection significantly better than did males with yellower plumage. The hue of carotenoid-based plumage coloration has been shown to be a primary criterion in female mate choice in the house finch. These observations suggest that one benefit to females for choosing redder males is obtaining mates with better resistance to parasites.

  16. Carotenoid-based plumage coloration predicts resistance to a novel parasite in the house finch.

    PubMed

    Hill, Geoffrey E; Farmer, Kristy L

    2005-01-01

    The Hamilton-Zuk hypothesis proposes that the bright colours displayed by many species of birds serve as signals of individual resistance to parasites. Despite the popularity of this hypothesis, only one previous study has tested whether plumage coloration predicts how individuals respond to a disease challenge. We inoculated 24 male house finches (Carpodacus mexicanus) of variable plumage hue with a novel bacterial pathogen, Mycoplasma gallicepticum (MG). We found no relationship between plumage hue and time to first symptoms following inoculation, but we found a significant negative relationship between plumage hue and clearance of disease: males with redder plumage cleared MG infection significantly better than did males with yellower plumage. The hue of carotenoid-based plumage coloration has been shown to be a primary criterion in female mate choice in the house finch. These observations suggest that one benefit to females for choosing redder males is obtaining mates with better resistance to parasites. PMID:15558224

  17. Development and Life Prediction of Erosion Resistant Turbine Low Conductivity Thermal Barrier Coatings

    NASA Technical Reports Server (NTRS)

    Zhu, Dongming; Miller, Robert A.; Kuczmarski, Maria A.

    2010-01-01

    Future rotorcraft propulsion systems are required to operate under highly-loaded conditions and in harsh sand erosion environments, thereby imposing significant material design and durability issues. The incorporation of advanced thermal barrier coatings (TBC) in high pressure turbine systems enables engine designs with higher inlet temperatures, thus improving the engine efficiency, power density and reliability. The impact and erosion resistance of turbine thermal barrier coating systems are crucial to the turbine coating technology application, because a robust turbine blade TBC system is a prerequisite for fully utilizing the potential coating technology benefit in the rotorcraft propulsion. This paper describes the turbine blade TBC development in addressing the coating impact and erosion resistance. Advanced thermal barrier coating systems with improved performance have also been validated in laboratory simulated engine erosion and/or thermal gradient environments. A preliminary life prediction modeling approach to emphasize the turbine blade coating erosion is also presented.

  18. Predictive value of methicillin-resistant Staphylococcus aureus (MRSA) nasal swab PCR assay for MRSA pneumonia.

    PubMed

    Dangerfield, Benjamin; Chung, Andrew; Webb, Brandon; Seville, Maria Teresa

    2014-01-01

    Pneumonia due to methicillin-resistant Staphylococcus aureus (MRSA) is associated with poor outcomes and frequently merits empirical antibiotic consideration despite its relatively low incidence. Nasal colonization with MRSA is associated with clinical MRSA infection and can be reliably detected using the nasal swab PCR assay. In this study, we evaluated the performance of the nasal swab MRSA PCR in predicting MRSA pneumonia. A retrospective cohort study was performed in a tertiary care center from January 2009 to July 2011. All patients with confirmed pneumonia who had both a nasal swab MRSA PCR test and a bacterial culture within predefined time intervals were included in the study. These data were used to calculate sensitivity, specificity, positive predictive value, and negative predictive value for clinically confirmed MRSA pneumonia. Four hundred thirty-five patients met inclusion criteria. The majority of cases were classified as either health care-associated (HCAP) (54.7%) or community-acquired (CAP) (34%) pneumonia. MRSA nasal PCR was positive in 62 (14.3%) cases. MRSA pneumonia was confirmed by culture in 25 (5.7%) cases. The MRSA PCR assay demonstrated 88.0% sensitivity and 90.1% specificity, with a positive predictive value of 35.4% and a negative predictive value of 99.2%. In patients with pneumonia, the MRSA PCR nasal swab has a poor positive predictive value but an excellent negative predictive value for MRSA pneumonia in populations with low MRSA pneumonia incidence. In cases of culture-negative pneumonia where initial empirical antibiotics include an MRSA-active agent, a negative MRSA PCR swab can be reasonably used to guide antibiotic de-escalation.

  19. MEASUREMENT AND PREDICTION OF THE RESISTIVITY OF ASH/SORBENT MIXTURES PRODUCED BY SULFUR OXIDE CONTROL PROCESSES

    EPA Science Inventory

    The report describes the development of (1) a modified procedure for obtaining consistent and reproducible laboratory resistivity values for mixtures of coal fly ash and partially spent sorbent, and (2) an approach for predicting resistivity based on the chemical composition of t...

  20. ALDH-1 Expression Levels Predict Response or Resistance to Preoperative Chemoradiation in Resectable Esophageal Cancer Patients

    PubMed Central

    Ajani, J. A.; Wang, X.; Song, S.; Suzuki, A.; Taketa, T.; Sudo, K.; Wadhwa, R.; Hofstetter, W. L.; Komaki, R.; Maru, D. M.; Lee, J. H.; Bhutani, M. S.; Weston, B.; Baladandayuthapani, V.; Yao, Y.; Honjo, S.; Scott, A. W.; Skinner, H. D.; Johnson, R. L.; Berry, D.

    2013-01-01

    Purpose: Operable thoracic esophageal/gastroesophageal junction carcinoma (EC) is often treated with chemoradiation and surgery but tumor responses are unpredictable and heterogeneous. We hypothesized that aldehyde dehydrogenase-1 (ALDH-1) could be associated with response. Methods: The labeling indices (LIs) of ALDH-1 by immunohistochemistry in untreated tumor specimens were established in EC patients who had chemoradiation and surgery. Univariate logistic regression and 3-fold cross validation were carried out for the training (67% of patients) and validation (33%) sets. Non-clinical experiments in EC cells were performed to generate complimentary data. Results: Of 167 EC patients analyzed, 40 (24%) had a pathologic complete response (pathCR) and 27 (16%) had an extremely resistant (exCRTR) cancer. The median ALDH-1 LI was 0.2 (range, 0.01 to 0.85). There was a significant association between pathCR and low ALDH-1 LI (p=<0.001; odds-ratio [OR]=0.432). The 3-fold cross validation led to a concordance index (C-index) of 0.798 for the fitted model. There was a significant association between exCRTR and high ALDH-1 LI (p=<0.001; OR=3.782). The 3-fold cross validation led to the C-index of 0.960 for the fitted model. In several cell lines, higher ALDH-1 LIs correlated with resistant/aggressive phenotype. Cells with induced chemotherapy resistance upregulated ALDH-1 and resistance conferring genes (SOX9 and YAP1). Sorted ALDH-1+ cells were more resistant and had an aggressive phenotype in tumor spheres than ALDH-1− cells. Conclusions: Our clinical and non-clinical data demonstrate that ALDH-1 LIs are predictive of response to therapy and further research could lead to individualized therapeutic strategies and novel therapeutic targets for EC patients. PMID:24210755

  1. Predicting extensively drug-resistant Mycobacterium tuberculosis phenotypes with genetic mutations.

    PubMed

    Rodwell, Timothy C; Valafar, Faramarz; Douglas, James; Qian, Lishi; Garfein, Richard S; Chawla, Ashu; Torres, Jessica; Zadorozhny, Victoria; Kim, Min Soo; Hoshide, Matt; Catanzaro, Donald; Jackson, Lynn; Lin, Grace; Desmond, Edward; Rodrigues, Camilla; Eisenach, Kathy; Victor, Thomas C; Ismail, Nazir; Crudu, Valeru; Gler, Maria Tarcela; Catanzaro, Antonino

    2014-03-01

    Molecular diagnostic methods based on the detection of mutations conferring drug resistance are promising technologies for rapidly detecting multidrug-/extensively drug-resistant tuberculosis (M/XDR TB), but large studies of mutations as markers of resistance are rare. The Global Consortium for Drug-Resistant TB Diagnostics analyzed 417 Mycobacterium tuberculosis isolates from multinational sites with a high prevalence of drug resistance to determine the sensitivities and specificities of mutations associated with M/XDR TB to inform the development of rapid diagnostic methods. We collected M/XDR TB isolates from regions of high TB burden in India, Moldova, the Philippines, and South Africa. The isolates underwent standardized phenotypic drug susceptibility testing (DST) to isoniazid (INH), rifampin (RIF), moxifloxacin (MOX), ofloxacin (OFX), amikacin (AMK), kanamycin (KAN), and capreomycin (CAP) using MGIT 960 and WHO-recommended critical concentrations. Eight genes (katG, inhA, rpoB, gyrA, gyrB, rrs, eis, and tlyA) were sequenced using Sanger sequencing. Three hundred seventy isolates were INHr, 356 were RIFr, 292 were MOXr/OFXr, 230 were AMKr, 219 were CAPr, and 286 were KANr. Four single nucleotide polymorphisms (SNPs) in katG/inhA had a combined sensitivity of 96% and specificities of 97 to 100% for the detection of INHr. Eleven SNPs in rpoB had a combined sensitivity of 98% for RIFr. Eight SNPs in gyrA codons 88 to 94 had sensitivities of 90% for MOXr/OFXr. The rrs 1401/1484 SNPs had 89 to 90% sensitivity for detecting AMKr/CAPr but 71% sensitivity for KANr. Adding eis promoter SNPs increased the sensitivity to 93% for detecting AMKr and to 91% for detecting KANr. Approximately 30 SNPs in six genes predicted clinically relevant XDR-TB phenotypes with 90 to 98% sensitivity and almost 100% specificity.

  2. Genome-wide gene expression profiling to predict resistance to anthracyclines in breast cancer patients

    PubMed Central

    Haibe-Kains, B.; Desmedt, C.; Di Leo, A.; Azambuja, E.; Larsimont, D.; Selleslags, J.; Delaloge, S.; Duhem, C.; Kains, J.P.; Carly, B.; Maerevoet, M.; Vindevoghel, A.; Rouas, G.; Lallemand, F.; Durbecq, V.; Cardoso, F.; Salgado, R.; Rovere, R.; Bontempi, G.; Michiels, S.; Buyse, M.; Nogaret, J.M.; Qi, Y.; Symmans, F.; Pusztai, L.; D'Hondt, V.; Piccart-Gebhart, M.; Sotiriou, C.

    2013-01-01

    Validated biomarkers predictive of response/resistance to anthracyclines in breast cancer are currently lacking. The neoadjuvant Trial of Principle (TOP) study, in which patients with estrogen receptor (ER)–negative tumors were treated with anthracycline (epirubicin) monotherapy, was specifically designed to evaluate the predictive value of topoisomerase II-alpha (TOP2A) and develop a gene expression signature to identify those patients who do not benefit from anthracyclines. Here we describe in details the contents and quality controls for the gene expression and clinical data associated with the study published by Desmedt and colleagues in the Journal of Clinical Oncology in 2011 (Desmedt et al., 2011). We also provide R code to easily access the data and perform the quality controls and basic analyses relevant to this dataset. PMID:26484051

  3. Implementation of model predictive control for resistive wall mode stabilization on EXTRAP T2R

    NASA Astrophysics Data System (ADS)

    Setiadi, A. C.; Brunsell, P. R.; Frassinetti, L.

    2015-10-01

    A model predictive control (MPC) method for stabilization of the resistive wall mode (RWM) in the EXTRAP T2R reversed-field pinch is presented. The system identification technique is used to obtain a linearized empirical model of EXTRAP T2R. MPC employs the model for prediction and computes optimal control inputs that satisfy performance criterion. The use of a linearized form of the model allows for compact formulation of MPC, implemented on a millisecond timescale, that can be used for real-time control. The design allows the user to arbitrarily suppress any selected Fourier mode. The experimental results from EXTRAP T2R show that the designed and implemented MPC successfully stabilizes the RWM.

  4. Genome-wide gene expression profiling to predict resistance to anthracyclines in breast cancer patients.

    PubMed

    Haibe-Kains, B; Desmedt, C; Di Leo, A; Azambuja, E; Larsimont, D; Selleslags, J; Delaloge, S; Duhem, C; Kains, J P; Carly, B; Maerevoet, M; Vindevoghel, A; Rouas, G; Lallemand, F; Durbecq, V; Cardoso, F; Salgado, R; Rovere, R; Bontempi, G; Michiels, S; Buyse, M; Nogaret, J M; Qi, Y; Symmans, F; Pusztai, L; D'Hondt, V; Piccart-Gebhart, M; Sotiriou, C

    2013-12-01

    Validated biomarkers predictive of response/resistance to anthracyclines in breast cancer are currently lacking. The neoadjuvant Trial of Principle (TOP) study, in which patients with estrogen receptor (ER)-negative tumors were treated with anthracycline (epirubicin) monotherapy, was specifically designed to evaluate the predictive value of topoisomerase II-alpha (TOP2A) and develop a gene expression signature to identify those patients who do not benefit from anthracyclines. Here we describe in details the contents and quality controls for the gene expression and clinical data associated with the study published by Desmedt and colleagues in the Journal of Clinical Oncology in 2011 (Desmedt et al., 2011). We also provide R code to easily access the data and perform the quality controls and basic analyses relevant to this dataset. PMID:26484051

  5. In Silico Prediction of Inhibition of Promiscuous Breast Cancer Resistance Protein (BCRP/ABCG2)

    PubMed Central

    Ding, Yi-Lung; Shih, Yu-Hsuan; Tsai, Fu-Yuan; Leong, Max K.

    2014-01-01

    Background Breast cancer resistant protein has an essential role in active transport of endogenous substances and xenobiotics across extracellular and intracellular membranes along with P-glycoprotein. It also plays a major role in multiple drug resistance and permeation of blood-brain barrier. Therefore, it is of great importance to derive theoretical models to predict the inhibition of both transporters in the process of drug discovery and development. Hitherto, very limited BCRP inhibition predictive models have been proposed as compared with its P-gp counterpart. Methodology/Principal Findings An in silico BCRP inhibition model was developed in this study using the pharmacophore ensemble/support vector machine scheme to take into account the promiscuous nature of BCRP. The predictions by the PhE/SVM model were found to be in good agreement with the observed values for those molecules in the training set (n = 22, r2 = 0.82,  = 0.73, RMSE  =  0.40, s = 0.24), test set (n = 97, q2 = 0.75–0.89, RMSE  = 0.31, s = 0.21), and outlier set (n = 16, q2 = 0.72–0.91, RMSE  =  0.29, s = 0.17). When subjected to a variety of statistical validations, the developed PhE/SVM model consistently met the most stringent criteria. A mock test by HIV protease inhibitors also asserted its predictivity. Conclusions/Significance It was found that this accurate, fast, and robust PhE/SVM model can be employed to predict the BCRP inhibition of structurally diverse molecules that otherwise cannot be carried out by any other methods in a high-throughput fashion to design therapeutic agents with insignificant drug toxicity and unfavorable drug–drug interactions mediated by BCRP to enhance clinical efficacy and/or circumvent drug resistance. PMID:24614353

  6. An experimental and computational investigation of electrical resistivity imaging for prediction ahead of tunnel boring machines

    NASA Astrophysics Data System (ADS)

    Schaeffer, Kevin P.

    Tunnel boring machines (TBMs) are routinely used for the excavation of tunnels across a range of ground conditions, from hard rock to soft ground. In complex ground conditions and in urban environments, the TBM susceptible to damage due to uncertainty of what lies ahead of the tunnel face. The research presented here explores the application of electrical resistivity theory for use in the TBM tunneling environment to detect changing conditions ahead of the machine. Electrical resistivity offers a real-time and continuous imaging solution to increase the resolution of information along the tunnel alignment and may even unveil previously unknown geologic or man-made features ahead of the TBM. The studies presented herein, break down the tunneling environment and the electrical system to understand how its fundamental parameters can be isolated and tested, identifying how they influence the ability to predict changes ahead of the tunnel face. A proof-of-concept, scaled experimental model was constructed in order assess the ability of the model to predict a metal pipe (or rod) ahead of face as the TBM excavates through a saturated sand. The model shows that a prediction of up to three tunnel diameters could be achieved, but the unique presence of the pipe (or rod) could not be concluded with certainty. Full scale finite element models were developed in order evaluate the various influences on the ability to detect changing conditions ahead of the face. Results show that TBM/tunnel geometry, TBM type, and electrode geometry can drastically influence prediction ahead of the face by tens of meters. In certain conditions (i.e., small TBM diameter, low cover depth, large material contrasts), changes can be detected over 100 meters in front of the TBM. Various electrode arrays were considered and show that in order to better detect more finite differences (e.g., boulder, lens, pipe), the use of individual cutting tools as electrodes is highly advantageous to increase spatial

  7. Prediction of ligand binding site by insilico approach in cold resistant protein isolated from cold resistant mutant of Pseudomonas fluorescens.

    PubMed

    Kumar, Amit; Khan, Mahejibin

    2012-09-01

    Cold shock proteins perform vital functions, such as mRNA masking, coupling of transcription to translation and developmental timing and regulation, which aids in survival of microbes in cold stress. Pseudomonas fluorescens is an ecologically important bacterium which helps in plant growth promotion. Since the cold tolerant mutant of the bacterium is able to grow at the temperature ranges from 30 to 4°C, it is of interest to study the process of its survival in the extreme temperatures. Therefore, this study is focused on the three dimensional structure and molecular modeling of cold resistant protein (CRP) from P. fluorescens to predict its molecular mechanism. Investigating the structure of CRP confirmed the presence of a conserved domain characteristic of the cold shock domain (CSD) family and a single nucleotide binding domain. When 3D structure of CRP was compared with the existing cold shock proteins, major deviations were found in the loop regions connecting the β2-β3, β3-β4 and β4-β5 sheets. Docking studies showed that CRP forms a significant clamp like structure at the substrate binding cleft which stabilizes the ligand. Therefore, it can be concluded that CRP has a strong affinity for the poly thymidine (poly T) stretch and can be considered a candidate for transcription regulation. PMID:23099776

  8. A model for predicting nosocomial carbapenem-resistant Klebsiella pneumoniae infection

    PubMed Central

    Yang, Duo; Xie, Zeqiang; Xin, Xuli; Xue, Wenying; Zhang, Man

    2016-01-01

    Mortality associated with infections due to carbapenem-resistant Klebsiella pneumoniae (CR-KP) is high and the infections need to be predicted early. The risk factors for CR-KP infection are heterogeneous. The aim of the present study was to construct a model allowing for the early prediction of CR-KP infection. Nosocomial infections due to K. pneumoniae were evaluated retrospectively over a 2-year period. The case cohort consisted of 370 inpatients with CR-KP infection. For each case enrolled, two matched controls with no CR-KP infection during their hospitalization were randomly selected. Matching involved month of admission, ward, as well as interval days. The Vitek 2 system was used for identification of isolates and antimicrobial susceptibility testing. General linear model with logistic regression was used to identify possible risk factors. The predicted power of the model was expressed as the area under the receiver-operating characteristic curve. Age, male gender, with cardiovascular disease, hospital stay, recent admission to intensive care unit, indwelling urinary catheter, mechanical ventilation, recent β-lactam-β-lactamase inhibitors, fourth-generation cephalosporins and/or carbapenems therapy were independent risk factors for CR-KP infection. Models predicting CR-KP infection developed by cumulative risk factors exhibited good power, with areas under the receiver-operating characteristic curves of 0.902 [95% confidence interval (CI), 0.883–0.920; P<0.001] and 0.899 (95% CI, 0.877–0.921; P<0.001) after filtering by age (≥70 years). The Yonden index was at the maximum when the cumulative risk factors were ≥3 in the two prediction models. The results show that the prediction model developed in the present study might be useful for controlling infections caused by CR-KP strains.

  9. Microstructural Abnormality in Left Nucleus Accumbens Predicts Dysfunctional Beliefs in Treatment-Resistant Obsessive-Compulsive Disorder

    PubMed Central

    Li, Zhongchun; Ji, Weidong; Li, Deqiang; Li, Xujuan; Feng, Wei

    2014-01-01

    Background The aim of this study was to determine whether dysfunctional beliefs might predict treatment-resistance and to examine the relationship between fractional anisotropy (FA) in diffusion tensor imaging (DTI) and cognitive biases for optimal treatment choice. Material/Methods We recruited 11 non-resistant obsessive-compulsive disorder (OCD) patients, 11 resistant OCD patients, and 11 healthy subjects. Results OCD patients had higher Obsessive Beliefs Questionnaire (OBQ-87) subscale scores than subjects in non-resistant and resistant groups. A significant difference was found between non-resistant and resistant OCD patients in R-Scale and I-Scale. A significant decrease in FA was found in left dorsal frontal gyrus and left inferior parietal lobule in the non-resistant group as compared to the control group. FA also decreased significantly in left anterior cingulate cortex, putamen, and nucleus accumbens in the resistant group as compared to the control group. There was a significant decrease in FA in nucleus accumbens in the resistant group as compared to the non-resistant group. Reduced FA in left nucleus accumbens was negatively associated with OBQ-87 factor R and I and the total Yale-Brown Obsessive-Compulsive Scale (Y-BOCS). Conclusions Abnormalities in cortical-striatal white matter networks may contribute to the dysfunctional beliefs in patients with treatment-resistant OCD, and the left nucleus accumbens may be an important and promising target for the treatment of OCD. PMID:25393961

  10. On the TRAIL to successful cancer therapy? Predicting and counteracting resistance against TRAIL-based therapeutics.

    PubMed

    Dimberg, L Y; Anderson, C K; Camidge, R; Behbakht, K; Thorburn, A; Ford, H L

    2013-03-14

    Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) and agonistic antibodies against TRAIL death receptors (DR) kill tumor cells while causing virtually no damage to normal cells. Several novel drugs targeting TRAIL receptors are currently in clinical trials. However, TRAIL resistance is a common obstacle in TRAIL-based therapy and limits the efficiency of these drugs. In this review article we discuss different mechanisms of TRAIL resistance, and how they can be predicted and therapeutically circumvented. In addition, we provide a brief overview of all TRAIL-based clinical trials conducted so far. It is apparent that although the effects of TRAIL therapy are disappointingly modest overall, a small subset of patients responds very well to TRAIL. We argue that the true potential of targeting TRAIL DRs in cancer can only be reached when we find efficient ways to select for those patients that are most likely to benefit from the treatment. To achieve this, it is crucial to identify biomarkers that can help us predict TRAIL sensitivity.

  11. Prediction of Corrosion Resistance of Concrete Containing Natural Pozzolan from Compressive Strength

    NASA Astrophysics Data System (ADS)

    al-Swaidani, A. M.; Ismat, R.; Diyab, M. E.; Aliyan, S. D.

    2015-11-01

    A lot of Reinforced Concrete (RC) structures in Syria have suffered from reinforcement corrosion which shortened significantly their service lives. Probably, one of the most effective approaches to make concrete structures more durable and concrete industry on the whole - more sustainable is to substitute pozzolan for a portion of Portland cement (PC). Syria is relatively rich in natural pozzolan. In the study, in order to predict the corrosion resistance from compressive strength, concrete specimens were produced with seven cement types: one plain Portland cement (control) and six natural pozzolan-based cements with replacement levels ranging from 10 to 35%. The development of the compressive strengths of concrete cube specimens with curing time has been investigated. Chloride penetrability has also been evaluated for all concrete mixes after three curing times of 7, 28 and 90 days. The effect on resistance of concrete against damage caused by corrosion of the embedded reinforcing steel has been investigated using an accelerated corrosion test by impressing a constant anodic potential for 7, 28 and 90 days curing. Test results have been statistically analysed and correlation equations relating compressive strength and corrosion performance have been developed. Significant correlations have been noted between the compressive strength and both rapid chloride penetrability and corrosion initiation times. So, this prediction could be reliable in concrete mix design when using natural pozzolan as cement replacement.

  12. Whole-genome sequencing for prediction of Mycobacterium tuberculosis drug susceptibility and resistance: a retrospective cohort study

    PubMed Central

    Walker, Timothy M; Kohl, Thomas A; Omar, Shaheed V; Hedge, Jessica; Del Ojo Elias, Carlos; Bradley, Phelim; Iqbal, Zamin; Feuerriegel, Silke; Niehaus, Katherine E; Wilson, Daniel J; Clifton, David A; Kapatai, Georgia; Ip, Camilla L C; Bowden, Rory; Drobniewski, Francis A; Allix-Béguec, Caroline; Gaudin, Cyril; Parkhill, Julian; Diel, Roland; Supply, Philip; Crook, Derrick W; Smith, E Grace; Walker, A Sarah; Ismail, Nazir; Niemann, Stefan; Peto, Tim E A

    2015-01-01

    Summary Background Diagnosing drug-resistance remains an obstacle to the elimination of tuberculosis. Phenotypic drug-susceptibility testing is slow and expensive, and commercial genotypic assays screen only common resistance-determining mutations. We used whole-genome sequencing to characterise common and rare mutations predicting drug resistance, or consistency with susceptibility, for all first-line and second-line drugs for tuberculosis. Methods Between Sept 1, 2010, and Dec 1, 2013, we sequenced a training set of 2099 Mycobacterium tuberculosis genomes. For 23 candidate genes identified from the drug-resistance scientific literature, we algorithmically characterised genetic mutations as not conferring resistance (benign), resistance determinants, or uncharacterised. We then assessed the ability of these characterisations to predict phenotypic drug-susceptibility testing for an independent validation set of 1552 genomes. We sought mutations under similar selection pressure to those characterised as resistance determinants outside candidate genes to account for residual phenotypic resistance. Findings We characterised 120 training-set mutations as resistance determining, and 772 as benign. With these mutations, we could predict 89·2% of the validation-set phenotypes with a mean 92·3% sensitivity (95% CI 90·7–93·7) and 98·4% specificity (98·1–98·7). 10·8% of validation-set phenotypes could not be predicted because uncharacterised mutations were present. With an in-silico comparison, characterised resistance determinants had higher sensitivity than the mutations from three line-probe assays (85·1% vs 81·6%). No additional resistance determinants were identified among mutations under selection pressure in non-candidate genes. Interpretation A broad catalogue of genetic mutations enable data from whole-genome sequencing to be used clinically to predict drug resistance, drug susceptibility, or to identify drug phenotypes that cannot yet be genetically

  13. Predictive Power of ETRE Polymorphism and Katg463 Mutation to INH-Resistance of M.tuberculosis

    PubMed Central

    WEN, Yu-feng; JIANG, Chao; CHENG, Xian-feng; ZHANG, Zhi-ping; Chen, Bai-feng; ZHU, Yu

    2015-01-01

    Background: The MIRU-VNTR polymorphism and katG463 mutation are used to genotype the mycobacterium tuberculosis, but the correlation between them and INH-resistance were unknown. This study was aimed to explore whether ETRE polymorphism and katG463 mutation could predict the INH-resistance, and the relationship between ETRE polymorphism and katG463 mutation. Methods: The ETRE, katG463 mutation and drug resistance information of 109 M. tuberculosis strains were collected from online public database. We constructed the predictive diagnostic tool of ETRE polymorphism and katG463 mutation. Chi-square test was used to analyze the relationship between ETRE polymorphism, katG463 mutation and INH-resistance. ROC curve analysis and Z-test were used to evaluate the predictive ability of ETRE and katG463. The relationship between ETRE polymorphism and katG463 mutation was analyzed with Spearman correlation analysis. Results: The mutation rate of katG463 was 27.50%, and the h value of ETRE polymorphism was 0.67. KatG463 mutation was associated with INH resistance (OR=3.72). The INH drug resistance rate in VNTR≧5 group was 3.43 times higher than that in VNTR≦3 group (χ2=24.77, P<0.01), and there was no significant difference of INH resistance between the VNTR=4 group and VNTR≦3 group. The areas under the ROC curve of two loci prediction diagnostic tools were 0.64 and 0.70 respectively. The katG463 mutation was significantly related to the ETRE polymorphism (r=0.79, P<0.01). Conclusion: Both katG463 mutation and the ETRE polymorphism can predict the INH-resistance of tuberculosis. The katG463 mutation was associated with ETRE VNTR polymorphism. PMID:25905061

  14. Gene signatures of drug resistance predict patient survival in colorectal cancer

    PubMed Central

    Zheng, Y; Zhou, J; Tong, Y

    2015-01-01

    Different combinations of 5-fluorouracil (5-FU), oxaliplatin, irinotecan and other newly developed agents have been used to treat colorectal cancer. Despite the advent of new treatment regimens, the 5-year survival rate for metastatic colorectal cancer remains low (~10%). Knowing the drug sensitivity of a given tumor for a particular agent could significantly impact decision making and treatment planning. Biomarkers are proven to be successful in characterizing patients into different response groups. Using survival prediction analysis, we have identified three independent gene signatures, which are associated with sensitivity of colorectal cancer cells to 5-FU, oxaliplatin or irinotecan. On the basis of the three gene signatures, three score systems were developed to stratify patients from sensitive to resistance. These score systems exhibited robustness in stratify patients in two independent clinical studies. Patients with high scores in all three drugs exhibited the lowest survival. PMID:25179828

  15. Validation of the predictive power of a calibrated physical stochastic resist model

    NASA Astrophysics Data System (ADS)

    Robertson, Stewart A.; Biafore, John J.; Smith, Mark D.; Reilly, Michael T.; Wandell, Jerome

    2009-12-01

    A newly developed stochastic resist model, implemented in a prototype version of the PROLITH lithography simulation software is fitted to experimental data for a commercially available immersion ArF photoresist, EPIC 2013 (Dow Electronic Materials). Calibration is performed only considering the mean CD value through focus and dose for three line/space features of varying pitch (dense, semi-dense and isolated). An unweighted Root Mean Squared Error (RMSE) of approximately 2.0 nm is observed when the calibrated model is compared to the experimental data. Although the model is calibrated only to mean CD values, it is able to accurately predict LER through focus to better than 1.5 nm RMSE and highly accurate CDU distributions at fixed focus and dose conditions. It is also shown how a stochastic model can be used to the describe the bridging behavior often observed at marginal focus and exposure conditions.

  16. Bifurcation of resistive wall mode dynamics predicted by magnetohydrodynamic-kinetic hybrid theory

    SciTech Connect

    Yang, S. X.; Wang, Z. X.; Wang, S.; Hao, G. Z. Song, X. M.; Wang, A. K.; Liu, Y. Q.

    2015-09-15

    The magnetohydrodynamic-kinetic hybrid theory has been extensively and successfully applied for interpreting experimental observations of macroscopic, low frequency instabilities, such as the resistive wall mode, in fusion plasmas. In this work, it is discovered that an analytic version of the hybrid formulation predicts a bifurcation of the mode dynamics while varying certain physical parameters of the plasma, such as the thermal particle collisionality or the ratio of the thermal ion to electron temperatures. This bifurcation can robustly occur under reasonably large parameter spaces as well as with different assumptions, for instance, on the particle collision model. Qualitatively similar bifurcation features are also observed in full toroidal computations presented in this work, based on a non-perturbative hybrid formulation.

  17. Establishment and characterization of models of chemotherapy resistance in colorectal cancer: Towards a predictive signature of chemoresistance.

    PubMed

    Jensen, Niels F; Stenvang, Jan; Beck, Mette K; Hanáková, Barbora; Belling, Kirstine C; Do, Khoa N; Viuff, Birgitte; Nygård, Sune B; Gupta, Ramneek; Rasmussen, Mads H; Tarpgaard, Line S; Hansen, Tine P; Budinská, Eva; Pfeiffer, Per; Bosman, Fred; Tejpar, Sabine; Roth, Arnaud; Delorenzi, Mauro; Andersen, Claus L; Rømer, Maria U; Brünner, Nils; Moreira, José M A

    2015-06-01

    Current standard treatments for metastatic colorectal cancer (CRC) are based on combination regimens with one of the two chemotherapeutic drugs, irinotecan or oxaliplatin. However, drug resistance frequently limits the clinical efficacy of these therapies. In order to gain new insights into mechanisms associated with chemoresistance, and departing from three distinct CRC cell models, we generated a panel of human colorectal cancer cell lines with acquired resistance to either oxaliplatin or irinotecan. We characterized the resistant cell line variants with regards to their drug resistance profile and transcriptome, and matched our results with datasets generated from relevant clinical material to derive putative resistance biomarkers. We found that the chemoresistant cell line variants had distinctive irinotecan- or oxaliplatin-specific resistance profiles, with non-reciprocal cross-resistance. Furthermore, we could identify several new, as well as some previously described, drug resistance-associated genes for each resistant cell line variant. Each chemoresistant cell line variant acquired a unique set of changes that may represent distinct functional subtypes of chemotherapy resistance. In addition, and given the potential implications for selection of subsequent treatment, we also performed an exploratory analysis, in relevant patient cohorts, of the predictive value of each of the specific genes identified in our cellular models.

  18. Establishment and characterization of models of chemotherapy resistance in colorectal cancer: Towards a predictive signature of chemoresistance.

    PubMed

    Jensen, Niels F; Stenvang, Jan; Beck, Mette K; Hanáková, Barbora; Belling, Kirstine C; Do, Khoa N; Viuff, Birgitte; Nygård, Sune B; Gupta, Ramneek; Rasmussen, Mads H; Tarpgaard, Line S; Hansen, Tine P; Budinská, Eva; Pfeiffer, Per; Bosman, Fred; Tejpar, Sabine; Roth, Arnaud; Delorenzi, Mauro; Andersen, Claus L; Rømer, Maria U; Brünner, Nils; Moreira, José M A

    2015-06-01

    Current standard treatments for metastatic colorectal cancer (CRC) are based on combination regimens with one of the two chemotherapeutic drugs, irinotecan or oxaliplatin. However, drug resistance frequently limits the clinical efficacy of these therapies. In order to gain new insights into mechanisms associated with chemoresistance, and departing from three distinct CRC cell models, we generated a panel of human colorectal cancer cell lines with acquired resistance to either oxaliplatin or irinotecan. We characterized the resistant cell line variants with regards to their drug resistance profile and transcriptome, and matched our results with datasets generated from relevant clinical material to derive putative resistance biomarkers. We found that the chemoresistant cell line variants had distinctive irinotecan- or oxaliplatin-specific resistance profiles, with non-reciprocal cross-resistance. Furthermore, we could identify several new, as well as some previously described, drug resistance-associated genes for each resistant cell line variant. Each chemoresistant cell line variant acquired a unique set of changes that may represent distinct functional subtypes of chemotherapy resistance. In addition, and given the potential implications for selection of subsequent treatment, we also performed an exploratory analysis, in relevant patient cohorts, of the predictive value of each of the specific genes identified in our cellular models. PMID:25759163

  19. Transcriptional regulation prediction of antiestrogen resistance in breast cancer based on RNA polymerase II binding data

    PubMed Central

    2014-01-01

    Background Although endocrine therapy impedes estrogen-ER signaling pathway and thus reduces breast cancer mortality, patients remain at continued risk of relapse after tamoxifen or other endocrine therapies. Understanding the mechanisms of endocrine resistance, particularly the role of transcriptional regulation is very important and necessary. Methods We propose a two-step workflow based on linear model to investigate the significant differences between MCF7 and OHT cells stimulated by 17β-estradiol (E2) respect to regulatory transcription factors (TFs) and their interactions. We additionally compared predicted regulatory TFs based on RNA polymerase II (PolII) binding quantity data and gene expression data, which were taken from MCF7/MCF7+E2 and OHT/OHT+E2 cell lines following the same analysis workflow. Enrichment analysis concerning diseases and cell functions and regulatory pattern analysis of different motifs of the same TF also were performed. Results The results showed PolII data could provide more information and predict more recognizably important regulatory TFs. Large differences in TF regulatory mode were found between two cell lines. Through verified through GO annotation, enrichment analysis and related literature regarding these TFs, we found some regulatory TFs such as AP-1, C/EBP, FoxA1, GATA1, Oct-1 and NF-κB, maintained OHT cells through molecular interactions or signaling pathways that were different from the surviving MCF7 cells. From TF regulatory interaction network, we identified E2F, E2F-1 and AP-2 as hub-TFs in MCF7 cells; whereas, in addition to E2F and E2F-1, we identified C/EBP and Oct-1 as hub-TFs in OHT cells. Notably, we found the regulatory patterns of different motifs of the same TF were very different from one another sometimes. Conclusions We inferred some regulatory TFs, such as AP-1 and NF-κB, cooperated with ER through both genomic action and non-genomic action. The TFs that were involved in both protein

  20. Mutations of KRAS/NRAS/BRAF predict cetuximab resistance in metastatic colorectal cancer patients

    PubMed Central

    Hsu, Hung-Chih; Thiam, Tan Kien; Lu, Yen-Jung; Yeh, Chien Yuh; Tsai, Wen-Sy; You, Jeng Fu; Hung, Hsin Yuan; Tsai, Chi-Neu; Hsu, An; Chen, Hua-Chien; Chen, Shu-Jen; Yang, Tsai-Sheng

    2016-01-01

    Approximately 45% of metastatic colorectal cancer (mCRC) patients with wild-type KRAS exon 2 are resistant to cetuximab treatment. We set out to identify additional genetic markers that might predict the response to cetuximab treatment. Fifty-three wild-type KRAS exon 2 mCRC patients were treated with cetuximab/irinotecan-based chemotherapy as a first- or third-line therapy. The mutational statuses of 10 EGFR pathway genes were analyzed in primary tumors using next-generation sequencing. BRAF, PIK3CA, KRAS (exons 3 and 4), NRAS, PTEN, and AKT1 mutations were detected in 6, 6, 5, 4, 1, and 1 patient, respectively. Four of the BRAF mutations were non-V600 variants. Four tumors harbored multiple co-existing (complex) mutations. All patients with BRAF mutations or complex mutation patterns were cetuximab non-responders. All patients but one harboring KRAS, NRAS, or BRAF mutations were non-responders. Mutations in any one of these three genes were associated with a poor response rate (7.1%) and reduced survival (PFS = 8.0 months) compared to wild-type patients (74.4% and 11.6 months). Our data suggest that KRAS, NRAS, and BRAF mutations predict response to cetuximab treatment in mCRC patients. PMID:26989027

  1. TetAB(46), a predicted heterodimeric ABC transporter conferring tetracycline resistance in Streptococcus australis isolated from the oral cavity

    PubMed Central

    Warburton, Philip J.; Ciric, Lena; Lerner, Avigdor; Seville, Lorna A.; Roberts, Adam P.; Mullany, Peter; Allan, Elaine

    2013-01-01

    Objectives To identify the genes responsible for tetracycline resistance in a strain of Streptococcus australis isolated from pooled saliva from healthy volunteers in France. S. australis is a viridans Streptococcus, originally isolated from the oral cavity of children in Australia, and subsequently reported in the lungs of cystic fibrosis patients and as a cause of invasive disease in an elderly patient. Methods Agar containing 2 mg/L tetracycline was used for the isolation of tetracycline-resistant organisms. A genomic library in Escherichia coli was used to isolate the tetracycline resistance determinant. In-frame deletions and chromosomal repair were used to confirm function. Antibiotic susceptibility was determined by agar dilution and disc diffusion assay. Results The tetracycline resistance determinant from S. australis FRStet12 was isolated from a genomic library in E. coli and DNA sequencing showed two open reading frames predicted to encode proteins with similarity to multidrug resistance-type ABC transporters. Both genes were required for tetracycline resistance (to both the naturally occurring and semi-synthetic tetracyclines) and they were designated tetAB(46). Conclusions This is the first report of a predicted ABC transporter conferring tetracycline resistance in a member of the oral microbiota. PMID:22941900

  2. Neural network modeling and prediction of resistivity structures using VES Schlumberger data over a geothermal area

    NASA Astrophysics Data System (ADS)

    Singh, Upendra K.; Tiwari, R. K.; Singh, S. B.

    2013-03-01

    This paper presents the effects of several parameters on the artificial neural networks (ANN) inversion of vertical electrical sounding (VES) data. Sensitivity of ANN parameters was examined on the performance of adaptive backpropagation (ABP) and Levenberg-Marquardt algorithms (LMA) to test the robustness to noisy synthetic as well as field geophysical data and resolving capability of these methods for predicting the subsurface resistivity layers. We trained, tested and validated ANN using the synthetic VES data as input to the networks and layer parameters of the models as network output. ANN learning parameters are varied and corresponding observations are recorded. The sensitivity analysis of synthetic data and real model demonstrate that ANN algorithms applied in VES data inversion should be considered well not only in terms of accuracy but also in terms of high computational efforts. Also the analysis suggests that ANN model with its various controlling parameters are largely data dependent and hence no unique architecture can be designed for VES data analysis. ANN based methods are also applied to the actual VES field data obtained from the tectonically vital geothermal areas of Jammu and Kashmir, India. Analysis suggests that both the ABP and LMA are suitable methods for 1-D VES modeling. But the LMA method provides greater degree of robustness than the ABP in case of 2-D VES modeling. Comparison of the inversion results with known lithology correlates well and also reveals the additional significant feature of reconsolidated breccia of about 7.0 m thickness beneath the overburden in some cases like at sounding point RDC-5. We may therefore conclude that ANN based methods are significantly faster and efficient for detection of complex layered resistivity structures with a relatively greater degree of precision and resolution.

  3. Validation of airway resistance models for predicting pressure loss through anatomically realistic conducting airway replicas of adults and children.

    PubMed

    Borojeni, Azadeh A T; Noga, Michelle L; Martin, Andrew R; Finlay, Warren H

    2015-07-16

    This work describes in vitro measurement of the total pressure loss at varying flow rate through anatomically realistic conducting airway replicas of 10 children, 4 to 8 years old, and 5 adults. Experimental results were compared with analytical predictions made using published airway resistance models. For the adult replicas, the model proposed by van Ertbruggen et al. (2005. J. Appl. Physiol. 98, 970-980) most accurately predicted central conducting airway resistance for inspiratory flow rates ranging from 15 to 90 L/min. Models proposed by Pedley et al. (1970. J. Respir. Physiol. 9, 371-386) and by Katz et al. (2011. J. Biomech. 44, 1137-1143) also provided reasonable estimates, but with a tendency to over predict measured pressure loss for both models. For child replicas, the Pedley and Katz models both provided good estimation of measured pressure loss at flow rates representative of resting tidal breathing, but under predicted measured values at high inspiratory flow rate (60 L/min). The van Ertbruggen model, developed based on flow simulations performed in an adult airway model, tended to under predict measured pressure loss through the child replicas across the range of flow rates studied (2 to 60 L/min). These results are intended to provide guidance for selection of analytical pressure loss models for use in predicting airway resistance and ventilation distribution in adults and children.

  4. Low Adiponectin Concentration in Pregnancy Predicts Postpartum Insulin Resistance, Beta-cell Dysfunction, and Fasting Glycaemia

    PubMed Central

    Retnakaran, R; Qi, Y; Connelly, PW; Sermer, M; Hanley, AJ; Zinman, B

    2010-01-01

    Aims/Hypothesis The postpartum following gestational diabetes (GDM) is characterized by subtle metabolic defects, including beta-cell dysfunction that is believed to mediate the increased future risk of type 2 diabetes in this patient population. Recently, low circulating levels of adiponectin and increased leptin and C-reactive protein (CRP) have emerged as novel diabetic risk factors, although their relevance to GDM and subsequent diabetes has not been characterized. Thus, we sought to determine whether adiponectin, leptin and CRP in pregnancy relate to the postpartum metabolic defects linking GDM with type 2 diabetes. Methods 487 women underwent metabolic characterization, including oral glucose tolerance test (OGTT), in pregnancy and at 3-months postpartum. Based on the antepartum OGTT, there were 137 women with GDM, 91 with gestational impaired glucose tolerance, and 259 with normal glucose tolerance. Results Adiponectin levels were lowest (p<0.0001) and CRP levels highest (p=0.0008) in women with GDM. Leptin did not differ between the glucose tolerance groups (p=0.4483). Adiponectin (r=0.41,p<0.0001), leptin (r=−0.36,p<0.0001) and CRP (r=−0.30,p<0.0001) in pregnancy were all associated with postpartum insulin sensitivity (ISOGTT). Intriguingly, adiponectin was also related to postpartum beta-cell function (insulinogenic index/HOMA-IR) (r=0.16,p=0.0009). Indeed, on multiple linear regression analyses, adiponectin in pregnancy independently predicted both postpartum insulin sensitivity (t=3.97,p<0.0001) and beta-cell function (t=2.37,p=0.0181), even after adjustment for GDM. Furthermore, adiponectin emerged as a significant negative independent determinant of postpartum fasting glucose (t=−3.01,p=0.0027). Conclusions Hypoadiponectinemia in pregnancy predicts postpartum insulin resistance, beta-cell dysfunction, and fasting glycaemia, and hence may be relevant to the pathophysiology relating GDM with type 2 diabetes. PMID:19937225

  5. Accuracy of genomic prediction for BCWD resistance in rainbow trout using different genotyping platforms and genomic selection models

    Technology Transfer Automated Retrieval System (TEKTRAN)

    In this study, we aimed to (1) predict genomic estimated breeding value (GEBV) for bacterial cold water disease (BCWD) resistance by genotyping training (n=583) and validation samples (n=53) with two genotyping platforms (24K RAD-SNP and 49K SNP) and using different genomic selection (GS) models (Ba...

  6. Proteomics of Genetically Engineered Mouse Mammary Tumors Identifies Fatty Acid Metabolism Members as Potential Predictive Markers for Cisplatin Resistance*

    PubMed Central

    Warmoes, Marc; Jaspers, Janneke E.; Xu, Guotai; Sampadi, Bharath K.; Pham, Thang V.; Knol, Jaco C.; Piersma, Sander R.; Boven, Epie; Jonkers, Jos; Rottenberg, Sven; Jimenez, Connie R.

    2013-01-01

    In contrast to various signatures that predict the prognosis of breast cancer patients, markers that predict chemotherapy response are still elusive. To detect such predictive biomarkers, we investigated early changes in protein expression using two mouse models for distinct breast cancer subtypes who have a differential knock-out status for the breast cancer 1, early onset (Brca1) gene. The proteome of cisplatin-sensitive BRCA1-deficient mammary tumors was compared with that of cisplatin-resistant mammary tumors resembling pleomorphic invasive lobular carcinoma. The analyses were performed 24 h after administration of the maximum tolerable dose of cisplatin. At this time point, drug-sensitive BRCA1-deficient tumors showed DNA damage, but cells were largely viable. By applying paired statistics and quantitative filtering, we identified highly discriminatory markers for the sensitive and resistant model. Proteins up-regulated in the sensitive model are involved in centrosome organization, chromosome condensation, homology-directed DNA repair, and nucleotide metabolism. Major discriminatory markers that were up-regulated in the resistant model were predominantly involved in fatty acid metabolism, such as fatty-acid synthase. Specific inhibition of fatty-acid synthase sensitized resistant cells to cisplatin. Our data suggest that exploring the functional link between the DNA damage response and cancer metabolism shortly after the initial treatment may be a useful strategy to predict the efficacy of cisplatin. PMID:23397111

  7. Factors Predicting the Type of Tactics Used to Resist Sexual Assault: A Prospective Study of College Women

    ERIC Educational Resources Information Center

    Turchik, Jessica A.; Probst, Danielle R.; Chau, Minna; Nigoff, Amy; Gidycz, Christine A.

    2007-01-01

    The purpose of the current study was to examine how women's intentions, as well as psychological and situational factors, predicted the actual use of resistance tactics in response to a sexual assault situation over a 2-month follow-up period. Twenty-eight percent of the 378 undergraduate women who participated at the baseline assessment and…

  8. Electrical Resistance of SiC/SiC Ceramic Matrix Composites for Damage Detection and Life-Prediction

    NASA Technical Reports Server (NTRS)

    Smith, Craig; Morscher, Gregory; Xia, Zhenhai

    2009-01-01

    Ceramic matrix composites (CMC) are suitable for high temperature structural applications such as turbine airfoils and hypersonic thermal protection systems due to their low density high thermal conductivity. The employment of these materials in such applications is limited by the ability to accurately monitor and predict damage evolution. Current nondestructive methods such as ultrasound, x-ray, and thermal imaging are limited in their ability to quantify small scale, transverse, in-plane, matrix cracks developed over long-time creep and fatigue conditions. CMC is a multifunctional material in which the damage is coupled with the material s electrical resistance, providing the possibility of real-time information about the damage state through monitoring of resistance. Here, resistance measurement of SiC/SiC composites under mechanical load at both room temperature monotonic and high temperature creep conditions, coupled with a modal acoustic emission technique, can relate the effects of temperature, strain, matrix cracks, fiber breaks, and oxidation to the change in electrical resistance. A multiscale model can in turn be developed for life prediction of in-service composites, based on electrical resistance methods. Results of tensile mechanical testing of SiC/SiC composites at room and high temperatures will be discussed. Data relating electrical resistivity to composite constituent content, fiber architecture, temperature, matrix crack formation, and oxidation will be explained, along with progress in modeling such properties.

  9. Transmission of HIV Drug Resistance and the Predicted Effect on Current First-line Regimens in Europe

    PubMed Central

    Hofstra, L. Marije; Sauvageot, Nicolas; Albert, Jan; Alexiev, Ivailo; Garcia, Federico; Struck, Daniel; Van de Vijver, David A. M. C.; Åsjö, Birgitta; Beshkov, Danail; Coughlan, Suzie; Descamps, Diane; Griskevicius, Algirdas; Hamouda, Osamah; Horban, Andrzej; Van Kasteren, Marjo; Kolupajeva, Tatjana; Kostrikis, Leondios G.; Liitsola, Kirsi; Linka, Marek; Mor, Orna; Nielsen, Claus; Otelea, Dan; Paraskevis, Dimitrios; Paredes, Roger; Poljak, Mario; Puchhammer-Stöckl, Elisabeth; Sönnerborg, Anders; Staneková, Danica; Stanojevic, Maja; Van Laethem, Kristel; Zazzi, Maurizio; Zidovec Lepej, Snjezana; Boucher, Charles A. B.; Schmit, Jean-Claude; Wensing, Annemarie M. J.

    2016-01-01

    Background. Numerous studies have shown that baseline drug resistance patterns may influence the outcome of antiretroviral therapy. Therefore, guidelines recommend drug resistance testing to guide the choice of initial regimen. In addition to optimizing individual patient management, these baseline resistance data enable transmitted drug resistance (TDR) to be surveyed for public health purposes. The SPREAD program systematically collects data to gain insight into TDR occurring in Europe since 2001. Methods. Demographic, clinical, and virological data from 4140 antiretroviral-naive human immunodeficiency virus (HIV)–infected individuals from 26 countries who were newly diagnosed between 2008 and 2010 were analyzed. Evidence of TDR was defined using the WHO list for surveillance of drug resistance mutations. Prevalence of TDR was assessed over time by comparing the results to SPREAD data from 2002 to 2007. Baseline susceptibility to antiretroviral drugs was predicted using the Stanford HIVdb program version 7.0. Results. The overall prevalence of TDR did not change significantly over time and was 8.3% (95% confidence interval, 7.2%–9.5%) in 2008–2010. The most frequent indicators of TDR were nucleoside reverse transcriptase inhibitor (NRTI) mutations (4.5%), followed by nonnucleoside reverse transcriptase inhibitor (NNRTI) mutations (2.9%) and protease inhibitor mutations (2.0%). Baseline mutations were most predictive of reduced susceptibility to initial NNRTI-based regimens: 4.5% and 6.5% of patient isolates were predicted to have resistance to regimens containing efavirenz or rilpivirine, respectively, independent of current NRTI backbones. Conclusions. Although TDR was highest for NRTIs, the impact of baseline drug resistance patterns on susceptibility was largest for NNRTIs. The prevalence of TDR assessed by epidemiological surveys does not clearly indicate to what degree susceptibility to different drug classes is affected. PMID:26620652

  10. Memory Reactivation Predicts Resistance to Retroactive Interference: Evidence from Multivariate Classification and Pattern Similarity Analyses

    PubMed Central

    Rugg, Michael D.

    2016-01-01

    Memory reactivation—the reinstatement of processes and representations engaged when an event is initially experienced—is believed to play an important role in strengthening and updating episodic memory. The present study examines how memory reactivation during a potentially interfering event influences memory for a previously experienced event. Participants underwent fMRI during the encoding phase of an AB/AC interference task in which some words were presented twice in association with two different encoding tasks (AB and AC trials) and other words were presented once (DE trials). The later memory test required retrieval of the encoding tasks associated with each of the study words. Retroactive interference was evident for the AB encoding task and was particularly strong when the AC encoding task was remembered rather than forgotten. We used multivariate classification and pattern similarity analysis (PSA) to measure reactivation of the AB encoding task during AC trials. The results demonstrated that reactivation of generic task information measured with multivariate classification predicted subsequent memory for the AB encoding task regardless of whether interference was strong and weak (trials for which the AC encoding task was remembered or forgotten, respectively). In contrast, reactivation of neural patterns idiosyncratic to a given AB trial measured with PSA only predicted memory when the strength of interference was low. These results suggest that reactivation of features of an initial experience shared across numerous events in the same category, but not features idiosyncratic to a particular event, are important in resisting retroactive interference caused by new learning. SIGNIFICANCE STATEMENT Reactivating a previously encoded memory is believed to provide an opportunity to strengthen the memory, but also to return the memory to a labile state, making it susceptible to interference. However, there is debate as to how memory reactivation elicited by

  11. Evaluation of genomic prediction methods for fusarium head blight resistance in wheat

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Fusarium head blight (FHB) resistance is quantitative and difficult to evaluate. Genomic selection (GS) could accelerate FHB resistance breeding. We used US cooperative FHB wheat nursery data to evaluate GS models for several FHB resistance traits including deoxynivalenol (DON) levels. For all trait...

  12. Field-evolved resistance to Bt maize by western corn rootworm: predictions from the laboratory and effects in the field.

    PubMed

    Gassmann, Aaron J

    2012-07-01

    Crops engineered to produce insecticidal toxins derived from the bacterium Bacillus thuringiensis (Bt) provide an effective management tool for many key insect pests. However, pest species have repeatedly demonstrated their ability to adapt to management practices. Results from laboratory selection experiments illustrate the capacity of pest species to evolve Bt resistance. Furthermore, resistance has been documented to Bt sprays in the field and greenhouse, and more recently, by some pests to Bt crops in the field. In 2009, fields were discovered in Iowa (USA) with populations of western corn rootworm, Diabrotica virgifera virgifera LeConte, that had evolved resistance to maize that produces the Bt toxin Cry3Bb1. Fields with resistant insects in 2009 had been planted to Cry3Bb1 maize for at least three consecutive years and as many as 6years. Computer simulation models predicted that the western corn rootworm might evolve resistance to Bt maize in as few as 3years. Laboratory and field data for interactions between western corn rootworm and Bt maize indicate that currently commercialized products are not high-dose events, which increases the risk of resistance evolution because non-recessive resistance traits may enhance survival on Bt maize. Furthermore, genetic analysis of laboratory strains of western corn rootworm has found non-recessive inheritance of resistance. Field studies conducted in two fields identified as harboring Cry3Bb1-resistant western corn rootworm found that survival of western corn rootworm did not differ between Cry3Bb1 maize and non-Bt maize and that root injury to Cry3Bb1 maize was higher than injury to other types of Bt maize or to maize roots protected with a soil insecticide. These first cases of field-evolved resistance to Bt maize by western corn rootworm provide an early warning and point to the need to apply better integrated pest management practices when using Bt maize to manage western corn rootworm.

  13. Predictive analysis of transmissible quinolone resistance indicates Stenotrophomonas maltophilia as a potential source of a novel family of Qnr determinants

    PubMed Central

    Sánchez, María B; Hernández, Alvaro; Rodríguez-Martínez, José M; Martínez-Martínez, Luis; Martínez, José L

    2008-01-01

    Background Predicting antibiotic resistance before it emerges at clinical settings constitutes a novel approach for preventing and fighting resistance of bacterial pathogens. To analyse the possibility that novel plasmid-encoded quinolone resistance determinants (Qnr) can emerge and disseminate among bacterial pathogens, we searched the presence of those elements in nearly 1000 bacterial genomes and metagenomes. Results We have found a number of novel potential qnr genes in the chromosomes of aquatic bacteria and in metagenomes from marine organisms. Functional studies of the Stenotrophomonas maltophilia Smqnr gene show that plasmid-encoded SmQnr confers quinolone resistance upon its expression in a heterologous host. Conclusion Altogether, the data presented in our work support the notion that predictive studies on antibiotic resistance are feasible, using currently available information on bacterial genomes and with the aid of bioinformatic and functional tools. Our results confirm that aquatic bacteria can be the origin of plasmid-encoded Qnr, and highlight the potential role of S. maltophilia as a source of novel Qnr determinants. PMID:18793450

  14. Predicting Antibiotic Resistance in Urinary Tract Infection Patients with Prior Urine Cultures.

    PubMed

    Dickstein, Yaakov; Geffen, Yuval; Andreassen, Steen; Leibovici, Leonard; Paul, Mical

    2016-08-01

    To improve antibiotic prescribing, we sought to establish the probability of a resistant organism in urine culture given a previous resistant culture in a setting endemic for multidrug-resistant (MDR) organisms. We performed a retrospective analysis of inpatients with paired positive urine cultures. We focused on ciprofloxacin-resistant (cipro(r)) Gram-negative bacteria, extended-spectrum-beta-lactamase (ESBL)-producing Enterobacteriaceae, carbapenem-resistant Enterobacteriaceae (CRE), and carbapenem-resistant nonfermenters (CRNF). Comparisons were made between the frequency of each resistance phenotype following a previous culture with the same phenotype and the overall frequency of that phenotype, and odds ratios (ORs) were calculated. We performed a regression to assess the effects of other variables on the likelihood of a repeat resistant culture. A total of 4,409 patients (52.5% women; median age, 70 years) with 19,546 paired positive urine cultures were analyzed. The frequencies of cipro(r) bacteria, ESBL-producing Enterobacteriaceae, CRE, and CRNF among all cultures were 47.7%, 30.6%, 1.7%, and 2.6%, respectively. ORs for repeated resistance phenotypes were 1.87, 3.19, 48.25, and 19.02 for cipro(r) bacteria, ESBL-producing Enterobacteriaceae, CRE, and CRNF, respectively (P < 0.001 for all). At 1 month, the frequencies of repeated resistance phenotypes were 77.4%, 66.4%, 57.1%, and 33.3% for cipro(r) bacteria, ESBL-producing Enterobacteriaceae, CRE, and CRNF, respectively. Increasing time between cultures and the presence of an intervening nonresistant culture significantly reduced the chances of a repeat resistant culture. Associations were statistically significant over the duration of follow-up (60 months) for CRE and for up to 6 months for all other pathogens. Knowledge of microbiology results in the six preceding months may assist with antibiotic stewardship and improve the appropriateness of empirical treatment for urinary tract infections (UTIs).

  15. Neuromedin U: a candidate biomarker and therapeutic target to predict and overcome resistance to HER-tyrosine kinase inhibitors.

    PubMed

    Rani, Sweta; Corcoran, Claire; Shiels, Liam; Germano, Serena; Breslin, Susan; Madden, Stephen; McDermott, Martina S; Browne, Brigid C; O'Donovan, Norma; Crown, John; Gogarty, Martina; Byrne, Annette T; O'Driscoll, Lorraine

    2014-07-15

    Intrinsic and acquired resistance to HER-targeting drugs occurs in a significant proportion of HER2-overexpressing breast cancers. Thus, there remains a need to identify predictive biomarkers that could improve patient selection and circumvent these types of drug resistance. Here, we report the identification of neuromedin U (NmU) as an extracellular biomarker in cells resistant to HER-targeted drugs. NmU overexpression occurred in cells with acquired or innate resistance to lapatinib, trastuzumab, neratinib, and afatinib, all of which displayed a similar trend upon short-term exposure, suggesting NmU induction may be an early response. An analysis of 3,489 cases of breast cancer showed NmU to be associated with poor patient outcome, particularly those with HER2-overexpressing tumors independent of established prognostic indicators. Ectopic overexpression of NmU in drug-sensitive cells conferred resistance to all HER-targeting drugs, whereas RNAi-mediated attenuation sensitized cells exhibiting acquired or innate drug resistance. Mechanistic investigations suggested that NmU acted through HSP27 as partner protein to stabilize HER2 protein levels. We also obtained evidence of functional NmU receptors on HER2-overexpressing cells, with the addition of exogenous NmU eliciting an elevation in HER2 and EGFR expression along with drug resistance. Finally, we found that NmU seemed to function in cell motility, invasion, and anoikis resistance. In vivo studies revealed that NmU attenuation impaired tumor growth and metastasis. Taken together, our results defined NmU as a candidate drug response biomarker for HER2-overexpressing cancers and as a candidate therapeutic target to limit metastatic progression and improve the efficacy of HER-targeted drugs. PMID:24876102

  16. Prediction of multi-drug resistance transporters using a novel sequence analysis method [version 2; referees: 2 approved

    DOE PAGES

    McDermott, Jason E.; Bruillard, Paul; Overall, Christopher C.; Gosink, Luke; Lindemann, Stephen R.

    2015-03-09

    There are many examples of groups of proteins that have similar function, but the determinants of functional specificity may be hidden by lack of sequencesimilarity, or by large groups of similar sequences with different functions. Transporters are one such protein group in that the general function, transport, can be easily inferred from the sequence, but the substrate specificity can be impossible to predict from sequence with current methods. In this paper we describe a linguistic-based approach to identify functional patterns from groups of unaligned protein sequences and its application to predict multi-drug resistance transporters (MDRs) from bacteria. We first showmore » that our method can recreate known patterns from PROSITE for several motifs from unaligned sequences. We then show that the method, MDRpred, can predict MDRs with greater accuracy and positive predictive value than a collection of currently available family-based models from the Pfam database. Finally, we apply MDRpred to a large collection of protein sequences from an environmental microbiome study to make novel predictions about drug resistance in a potential environmental reservoir.« less

  17. Prediction of multi-drug resistance transporters using a novel sequence analysis method [version 2; referees: 2 approved

    SciTech Connect

    McDermott, Jason E.; Bruillard, Paul; Overall, Christopher C.; Gosink, Luke; Lindemann, Stephen R.

    2015-03-09

    There are many examples of groups of proteins that have similar function, but the determinants of functional specificity may be hidden by lack of sequencesimilarity, or by large groups of similar sequences with different functions. Transporters are one such protein group in that the general function, transport, can be easily inferred from the sequence, but the substrate specificity can be impossible to predict from sequence with current methods. In this paper we describe a linguistic-based approach to identify functional patterns from groups of unaligned protein sequences and its application to predict multi-drug resistance transporters (MDRs) from bacteria. We first show that our method can recreate known patterns from PROSITE for several motifs from unaligned sequences. We then show that the method, MDRpred, can predict MDRs with greater accuracy and positive predictive value than a collection of currently available family-based models from the Pfam database. Finally, we apply MDRpred to a large collection of protein sequences from an environmental microbiome study to make novel predictions about drug resistance in a potential environmental reservoir.

  18. Client Resistance as Predicted by Therapist Behavior: A Study of Sequential Dependence.

    ERIC Educational Resources Information Center

    Bischoff, Mary M.; Tracey, Terence J. G.

    1995-01-01

    Examines the relation of client resistant behavior to therapist directive behavior in a sample of ten archival therapy sessions. Results indicated an overall trend, with therapist directive behavior slightly increasing the probability of subsequent client resistance. No similar effect of client behavior on subsequent therapist behavior was found.…

  19. Integrated thermal-microstructure model to predict the property gradients in resistance spot steel welds

    SciTech Connect

    Babu, S.S.; Riemer, B.W.; Santella, M.L.; Feng, Z.

    1998-11-01

    An integrated model approach was proposed for relating resistance welding parameters to weldment properties. An existing microstructure model was used to determine the microstructural and property gradients in resistance spot welds of plain carbon steel. The effect of these gradients on the weld integrity was evaluated with finite element analysis. Further modifications to this integrated thermal-microstructure model are discussed.

  20. A simple model to predict soil resistance to driving for long piles in deepwater normally consolidated clays

    SciTech Connect

    Dutt, R.N.; Doyle, E.H.; Collins, J.T.; Ganguly, P.

    1995-12-01

    As the exploration and development for offshore oil and gas reserves moves into the deepwater environment of the continental slope, a good model is necessary to evaluate drivability of large-diameter, long piles in normally consolidated clays. Procedures are available to predict soil resistance to driving in stiff to hard overconsolidated clays of the North Sea and the Arabian Gulf. Use of these procedures in normally consolidated clays grossly overpredicts soil resistance. Such gross overpredictions result in the mobilization of larger hammers or thicker pile wall than necessary for pile installation. A simple model is proposed to estimate soil resistance to driving. Case histories of recent deepwater pile installations are presented to illustrate the adequacy of the new procedure in deepwater normally consolidated clays.

  1. Penicillin-Binding Protein Transpeptidase Signatures for Tracking and Predicting β-Lactam Resistance Levels in Streptococcus pneumoniae

    PubMed Central

    Metcalf, Benjamin J.; Chochua, Sopio; Li, Zhongya; Gertz, Robert E.; Walker, Hollis; Hawkins, Paulina A.; Tran, Theresa; Whitney, Cynthia G.; McGee, Lesley; Beall, Bernard W.

    2016-01-01

    ABSTRACT β-Lactam antibiotics are the drugs of choice to treat pneumococcal infections. The spread of β-lactam-resistant pneumococci is a major concern in choosing an effective therapy for patients. Systematically tracking β-lactam resistance could benefit disease surveillance. Here we developed a classification system in which a pneumococcal isolate is assigned to a “PBP type” based on sequence signatures in the transpeptidase domains (TPDs) of the three critical penicillin-binding proteins (PBPs), PBP1a, PBP2b, and PBP2x. We identified 307 unique PBP types from 2,528 invasive pneumococcal isolates, which had known MICs to six β-lactams based on broth microdilution. We found that increased β-lactam MICs strongly correlated with PBP types containing divergent TPD sequences. The PBP type explained 94 to 99% of variation in MICs both before and after accounting for genomic backgrounds defined by multilocus sequence typing, indicating that genomic backgrounds made little independent contribution to β-lactam MICs at the population level. We further developed and evaluated predictive models of MICs based on PBP type. Compared to microdilution MICs, MICs predicted by PBP type showed essential agreement (MICs agree within 1 dilution) of >98%, category agreement (interpretive results agree) of >94%, a major discrepancy (sensitive isolate predicted as resistant) rate of <3%, and a very major discrepancy (resistant isolate predicted as sensitive) rate of <2% for all six β-lactams. Thus, the PBP transpeptidase signatures are robust indicators of MICs to different β-lactam antibiotics in clinical pneumococcal isolates and serve as an accurate alternative to phenotypic susceptibility testing. PMID:27302760

  2. Anti-Platelet Drug Resistance in the Prediction of Thromboembolic Complications after Neurointervention

    PubMed Central

    Ryu, Dal-Sung; Sim, Yoo-Sik; Kim, Chang-Hyun; Jung, Jin-Young; Joo, Jin-Yang

    2010-01-01

    Objective The aim of this study was to analyze the correlation between thromboembolic complications and antiplatelet drugs before and after neurointervention. Methods Blood samples and radiographic data of patients who received a neurointervention (coil embolization, stent placement or both) were collected prospectively. Rapid platelet function assay-aspirin (RPFA-ASA) was used to calculate aspirin resistance in aspirin reaction units (ARU). For clopidogrel resistance, a P2Y12 assay was used to analyze the percentage of platelet inhibition. ARU > 550 and platelet inhibition < 40% were defined as aspirin and clopidogrel resistance, respectively. Results Both aspirin and clopidogrel oral pills were administered in fifty-three patients before and after neurointerventional procedures. The mean resistance values of all patients were 484 ARU and < 39%. Ten (17.0%) of 53 patients showed resistance to aspirin with an average of 597 ARU, and 33 (62.3%) of 53 patients showed resistance to clopidogrel with an average of < 26%. Ten patients demonstrated resistance to both drugs, 5 of which suffered a thromboembolic complication after neurointervention (mean values : 640 ARU and platelet inhibition < 23%). Diabetic patients and patients with hypercholesterolemia displayed mean aspirin resistances of 513.7 and 501.8 ARU, and mean clopidogrel resistances of < 33.8% and < 40.7%, respectively. Conclusion Identifying individuals with poor platelet inhibition using standard regimens is of great clinical importance and may help prevent cerebral ischemic events in the future. Neurointerventional research should focus on ideal doses, timing, choices, safety, and reliable measurements of antiplatelet drug therapy, as well as confirming the clinical relevance of aggregometry in cerebrovascular patients. PMID:21113358

  3. Flow network QSAR for the prediction of physicochemical properties by mapping an electrical resistance network onto a chemical reaction poset.

    PubMed

    Ivanciuc, Ovidiu; Ivanciuc, Teodora; Klein, Douglas J

    2013-06-01

    Usual quantitative structure-activity relationship (QSAR) models are computed from unstructured input data, by using a vector of molecular descriptors for each chemical in the dataset. Another alternative is to consider the structural relationships between the chemical structures, such as molecular similarity, presence of certain substructures, or chemical transformations between compounds. We defined a class of network-QSAR models based on molecular networks induced by a sequence of substitution reactions on a chemical structure that generates a partially ordered set (or poset) oriented graph that may be used to predict various molecular properties with quantitative superstructure-activity relationships (QSSAR). The network-QSAR interpolation models defined on poset graphs, namely average poset, cluster expansion, and spline poset, were tested with success for the prediction of several physicochemical properties for diverse chemicals. We introduce the flow network QSAR, a new poset regression model in which the dataset of chemicals, represented as a reaction poset, is transformed into an oriented network of electrical resistances in which the current flow results in a potential at each node. The molecular property considered in the QSSAR model is represented as the electrical potential, and the value of this potential at a particular node is determined by the electrical resistances assigned to each edge and by a system of batteries. Each node with a known value for the molecular property is attached to a battery that sets the potential on that node to the value of the respective molecular property, and no external battery is attached to nodes from the prediction set, representing chemicals for which the values of the molecular property are not known or are intended to be predicted. The flow network QSAR algorithm determines the values of the molecular property for the prediction set of molecules by applying Ohm's law and Kirchhoff's current law to the poset

  4. Whole-Genome Sequencing Analysis Accurately Predicts Antimicrobial Resistance Phenotypes in Campylobacter spp.

    PubMed Central

    Tyson, G. H.; Chen, Y.; Li, C.; Mukherjee, S.; Young, S.; Lam, C.; Folster, J. P.; Whichard, J. M.; McDermott, P. F.

    2015-01-01

    The objectives of this study were to identify antimicrobial resistance genotypes for Campylobacter and to evaluate the correlation between resistance phenotypes and genotypes using in vitro antimicrobial susceptibility testing and whole-genome sequencing (WGS). A total of 114 Campylobacter species isolates (82 C. coli and 32 C. jejuni) obtained from 2000 to 2013 from humans, retail meats, and cecal samples from food production animals in the United States as part of the National Antimicrobial Resistance Monitoring System were selected for study. Resistance phenotypes were determined using broth microdilution of nine antimicrobials. Genomic DNA was sequenced using the Illumina MiSeq platform, and resistance genotypes were identified using assembled WGS sequences through blastx analysis. Eighteen resistance genes, including tet(O), blaOXA-61, catA, lnu(C), aph(2″)-Ib, aph(2″)-Ic, aph(2′)-If, aph(2″)-Ig, aph(2″)-Ih, aac(6′)-Ie-aph(2″)-Ia, aac(6′)-Ie-aph(2″)-If, aac(6′)-Im, aadE, sat4, ant(6′), aad9, aph(3′)-Ic, and aph(3′)-IIIa, and mutations in two housekeeping genes (gyrA and 23S rRNA) were identified. There was a high degree of correlation between phenotypic resistance to a given drug and the presence of one or more corresponding resistance genes. Phenotypic and genotypic correlation was 100% for tetracycline, ciprofloxacin/nalidixic acid, and erythromycin, and correlations ranged from 95.4% to 98.7% for gentamicin, azithromycin, clindamycin, and telithromycin. All isolates were susceptible to florfenicol, and no genes associated with florfenicol resistance were detected. There was a strong correlation (99.2%) between resistance genotypes and phenotypes, suggesting that WGS is a reliable indicator of resistance to the nine antimicrobial agents assayed in this study. WGS has the potential to be a powerful tool for antimicrobial resistance surveillance programs. PMID:26519386

  5. Predictability of Phenotype in Relation to Common β-Lactam Resistance Mechanisms in Escherichia coli and Klebsiella pneumoniae.

    PubMed

    Agyekum, Alex; Fajardo-Lubián, Alicia; Ai, Xiaoman; Ginn, Andrew N; Zong, Zhiyong; Guo, Xuejun; Turnidge, John; Partridge, Sally R; Iredell, Jonathan R

    2016-05-01

    The minimal concentration of antibiotic required to inhibit the growth of different isolates of a given species with no acquired resistance mechanisms has a normal distribution. We have previously shown that the presence or absence of transmissible antibiotic resistance genes has excellent predictive power for phenotype. In this study, we analyzed the distribution of six β-lactam antibiotic susceptibility phenotypes associated with commonly acquired resistance genes in Enterobacteriaceae in Sydney, Australia. Escherichia coli (n = 200) and Klebsiella pneumoniae (n = 178) clinical isolates, with relevant transmissible resistance genes (blaTEM, n = 33; plasmid AmpC, n = 69; extended-spectrum β-lactamase [ESBL], n = 116; and carbapenemase, n = 100), were characterized. A group of 60 isolates with no phenotypic resistance to any antibiotics tested and carrying none of the important β-lactamase genes served as comparators. The MICs for all drug-bacterium combinations had a normal distribution, varying only in the presence of additional genes relevant to the phenotype or, for ertapenem resistance in K. pneumoniae, with a loss or change in the outer membrane porin protein OmpK36. We demonstrated mutations in ompK36 or absence of OmpK36 in all isolates in which reduced susceptibility to ertapenem (MIC, >1 mg/liter) was evident. Ertapenem nonsusceptibility in K. pneumoniae was most common in the context of an OmpK36 variant with an ESBL or AmpC gene. Surveillance strategies to define appropriate antimicrobial therapies should include genotype-phenotype relationships for all major transmissible resistance genes and the characterization of mutations in relevant porins in organisms, like K. pneumoniae. PMID:26912748

  6. Comparison of Clinical Prediction Models for Resistant Bacteria in Community-onset Pneumonia

    PubMed Central

    Self, Wesley H.; Wunderink, Richard G.; Williams, Derek J.; Barrett, Tyler W.; Baughman, Adrienne H.; Grijalva, Carlos G.

    2015-01-01

    Objectives Six recently published algorithms classify pneumonia patients presenting from the community into high- and low-risk groups for resistant bacteria. Our objective was to compare performance of these algorithms for identifying patients infected with bacteria resistant to traditional community-acquired pneumonia antibiotics. Methods This was a retrospective study of consecutive adult patients diagnosed with pneumonia in an emergency department and subsequently hospitalized. Each patient was classified as high- or low-risk for resistant bacteria according to the following algorithms: original health care-associated pneumonia (HCAP) criteria, Summit criteria, Brito and Niederman strategy, Shorr model, Aliberti model, and Shindo model. The reference for comparison was detection of resistant bacteria, defined as methicillin-resistant Staphylococcus aureus or gram-negative bacteria resistant to ceftriaxone or levofloxacin. Results Six hundred fourteen patients were studied, including 36 (5.9%) with resistant bacteria. The HCAP criteria classified 304 (49.5%) patients as high-risk, with an area under the receiver operating characteristic curve (AUC) of 0.63 (95% CI = 0.54 to 0.72), sensitivity of 0.69 (95% CI = 0.52 to 0.83), and specificity of 0.52 (95% CI = 0.48 to 0.56). None of the other algorithms improved both sensitivity and specificity, or significantly improved the AUC. Compared to the HCAP criteria, the Shorr and Aliberti models classified more patients as high-risk, resulting in higher sensitivity and lower specificity. The Shindo model classified fewer patients as high-risk, with lower sensitivity and higher specificity. Conclusions All algorithms for identification of resistant bacteria included in this study had suboptimal performance to guide antibiotic selection. New strategies for selecting empirical antibiotics for community-onset pneumonia are necessary. PMID:25996620

  7. Improving predictions of the risk of resistance development against new and old antibiotics.

    PubMed

    Andersson, D I

    2015-10-01

    The methods used today by academic researchers and the pharmaceutical industry to assess the risk of emergence of resistance, for example during development of new antibiotics or when assessing an old antibiotic, are sub-optimal. Even though easy to perform, the presently used serial passage procedures, minimal prevention concentration measurements and determination of mutation rates in vitro are generally providing inadequate knowledge for risk assessment and making decisions to continue/discontinue drug development. These methods need to be complemented and replaced with more relevant methods such as determination of whether resistance genes already pre-exist in various metagenomes, and the likelihood that these genes can transfer into the relevant pathogens and be stably maintained. Furthermore, to determine the risk of emergence of mutationally conferred resistance the fitness effect of the resistance mechanism is key, as this parameter will determine the ability of the resistant mutants to be maintained and enriched in the host after they have emerged. This information combined with knowledge of bacterial population sizes and growth and killing dynamics at relevant infection sites should allow for better forecasting of the risk of resistance emerging in clinical settings.

  8. Improved model predictive control of resistive wall modes by error field estimator in EXTRAP T2R

    NASA Astrophysics Data System (ADS)

    Setiadi, A. C.; Brunsell, P. R.; Frassinetti, L.

    2016-12-01

    Many implementations of a model-based approach for toroidal plasma have shown better control performance compared to the conventional type of feedback controller. One prerequisite of model-based control is the availability of a control oriented model. This model can be obtained empirically through a systematic procedure called system identification. Such a model is used in this work to design a model predictive controller to stabilize multiple resistive wall modes in EXTRAP T2R reversed-field pinch. Model predictive control is an advanced control method that can optimize the future behaviour of a system. Furthermore, this paper will discuss an additional use of the empirical model which is to estimate the error field in EXTRAP T2R. Two potential methods are discussed that can estimate the error field. The error field estimator is then combined with the model predictive control and yields better radial magnetic field suppression.

  9. Cardiovascular Disease Biomarkers Predict Susceptibility or Resistance to Lung Injury in World Trade Center Dust Exposed Firefighters

    PubMed Central

    Weiden, Michael D.; Naveed, Bushra; Kwon, Sophia; Cho, Soo Jung; Comfort, Ashley L.; Prezant, David J.; Rom, William N.; Nolan, Anna

    2013-01-01

    Pulmonary vascular loss is an early feature of chronic obstructive pulmonary disease. Biomarkers of inflammation and of metabolic syndrome, predicts loss of lung function in World Trade Center Lung Injury (WTC-LI). We investigated if other cardiovascular disease (CVD) biomarkers also predicted WTC-LI. This nested case-cohort study used 801 never smoker, WTC exposed firefighters with normal pre-9/11 lung function presenting for subspecialty pulmonary evaluation (SPE) before March, 2008. A representative sub-cohort of 124/801 with serum drawn within six months of 9/11 defined CVD biomarker distribution. Post-9/11/01 FEV1 at subspecialty exam defined cases: susceptible WTC-LI cases with FEV1≤77% predicted (66/801) and resistant WTC-LI cases with FEV1≥107% (68/801). All models were adjusted for WTC exposure intensity, BMI at SPE, age at 9/11, and pre-9/11 FEV1. Susceptible WTC-LI cases had higher levels of Apo-AII, CRP, and MIP-4 with significant RRs of 3.85, 3.93, and 0.26 respectively with an area under the curve (AUC) of 0.858. Resistant WTC-LI cases had significantly higher sVCAM and lower MPO with RRs of 2.24, and 2.89 respectively; AUC 0.830. Biomarkers of CVD in serum six-month post-9/11 predicted either susceptibility or resistance to WTC-LI. These biomarkers may define pathways producing or protecting subjects from pulmonary vascular disease and associated loss of lung function after an irritant exposure. PMID:22903969

  10. Predictive value of molecular drug resistance testing of Mycobacterium tuberculosis isolates in Valle del Cauca, Colombia.

    PubMed

    Ferro, Beatriz E; García, Pamela K; Nieto, Luisa Maria; van Soolingen, Dick

    2013-07-01

    Previous evaluations of the molecular GenoType tests have promoted their use to detect resistance to first- and second-line antituberculosis drugs in different geographical regions. However, there are known geographic variations in the mutations associated with drug resistance in Mycobacterium tuberculosis, and especially in South America, there is a paucity of information regarding the frequencies and types of mutations associated with resistance to first- and second-line antituberculosis drugs. We therefore evaluated the performance of the GenoType kits in this region by testing 228 M. tuberculosis isolates in Colombia, including 134 resistant and 94 pansusceptible strains. Overall, the sensitivity and specificity of the GenoType MTBDRplus test ranged from 92 to 96% and 97 to 100%, respectively; the agreement index was optimal (Cohen's kappa, >0.8). The sensitivity of the GenoType MTBDRsl test ranged from 84 to 100% and the specificity from 88 to 100%. The most common mutations were katG S315T1, rpoB S531L, embB M306V, gyrA D94G, and rrs A1401G. Our results reflect the utility of the GenoType tests in Colombia; however, as some discordance still exists between the conventional and molecular approaches in resistance testing, we adhere to the recommendation that the GenoType tests serve as early guides for therapy, followed by phenotypic drug susceptibility testing for all cases.

  11. Predictive Value of Molecular Drug Resistance Testing of Mycobacterium tuberculosis Isolates in Valle del Cauca, Colombia

    PubMed Central

    García, Pamela K.; Nieto, Luisa Maria; van Soolingen, Dick

    2013-01-01

    Previous evaluations of the molecular GenoType tests have promoted their use to detect resistance to first- and second-line antituberculosis drugs in different geographical regions. However, there are known geographic variations in the mutations associated with drug resistance in Mycobacterium tuberculosis, and especially in South America, there is a paucity of information regarding the frequencies and types of mutations associated with resistance to first- and second-line antituberculosis drugs. We therefore evaluated the performance of the GenoType kits in this region by testing 228 M. tuberculosis isolates in Colombia, including 134 resistant and 94 pansusceptible strains. Overall, the sensitivity and specificity of the GenoType MTBDRplus test ranged from 92 to 96% and 97 to 100%, respectively; the agreement index was optimal (Cohen's kappa, >0.8). The sensitivity of the GenoType MTBDRsl test ranged from 84 to 100% and the specificity from 88 to 100%. The most common mutations were katG S315T1, rpoB S531L, embB M306V, gyrA D94G, and rrs A1401G. Our results reflect the utility of the GenoType tests in Colombia; however, as some discordance still exists between the conventional and molecular approaches in resistance testing, we adhere to the recommendation that the GenoType tests serve as early guides for therapy, followed by phenotypic drug susceptibility testing for all cases. PMID:23658272

  12. Numerical, micro-mechanical prediction of crack growth resistance in a fibre-reinforced/brittle matrix composite

    NASA Technical Reports Server (NTRS)

    Jenkins, Michael G.; Ghosh, Asish; Salem, Jonathan A.

    1990-01-01

    Micromechanics fracture models are incorporated into three distinct fracture process zones which contribute to the crack growth resistance of fibrous composites. The frontal process zone includes microcracking, fiber debonding, and some fiber failure. The elastic process zone is related only to the linear elastic creation of new matrix and fiber fracture surfaces. The wake process zone includes fiber bridging, fiber pullout, and fiber breakage. The R-curve predictions of the model compare well with empirical results for a unidirectional, continuous fiber C/C composite. Separating the contributions of each process zone reveals the wake region to contain the dominant crack growth resistance mechanisms. Fractography showed the effects of the micromechanisms on the macroscopic fracture behavior.

  13. Reliable prediction of insulin resistance by a school-based fitness test in middle-school children.

    PubMed

    Varness, Todd; Carrel, Aaron L; Eickhoff, Jens C; Allen, David B

    2009-01-01

    Objectives. (1) Determine the predictive value of a school-based test of cardiovascular fitness (CVF) for insulin resistance (IR); (2) compare a "school-based" prediction of IR to a "laboratory-based" prediction, using various measures of fitness and body composition. Methods. Middle school children (n = 82) performed the Progressive Aerobic Cardiovascular Endurance Run (PACER), a school-based CVF test, and underwent evaluation of maximal oxygen consumption treadmill testing (VO(2) max), body composition (percent body fat and BMI z score), and IR (derived homeostasis model assessment index [HOMA(IR)]). Results. PACER showed a strong correlation with VO(2) max/kg (r(s) = 0.83, P < .001) and with HOMA(IR) (r(s) = -0.60, P < .001). Multivariate regression analysis revealed that a school-based model (using PACER and BMI z score) predicted IR similar to a laboratory-based model (using VO(2) max/kg of lean body mass and percent body fat). Conclusions. The PACER is a valid school-based test of CVF, is predictive of IR, and has a similar relationship to IR when compared to complex laboratory-based testing. Simple school-based measures of childhood fitness (PACER) and fatness (BMI z score) could be used to identify childhood risk for IR and evaluate interventions.

  14. Biomarkers for the prediction of the resistance and susceptibility of grapevine leaves to downy mildew.

    PubMed

    Batovska, Daniela Ilieva; Todorova, Iva Todorova; Parushev, Stoyan Parushev; Nedelcheva, Daniela Valentinova; Bankova, Vassya Stefanova; Popov, Simeon Simeonov; Ivanova, Iliana Ivanova; Batovski, Stancho Atanassov

    2009-05-01

    We examined metabolic profiles of acetone and butanol extracts obtained from the leaves of 18 seedlings of the Bulgarian wine-making cultivar Storgozia. The acetone extracts contained the components from the leaf surface, while the butanol extracts were enriched with polar components from inside the leaf tissue. The leaves displayed different degrees of resistance and susceptibility to the etiological agent downy mildew, Plasmopara viticola. Based on the statistically significant correlations (P<0.05) between the GC-MS data of the identified metabolites and the estimated leaf resistances, 10 individual components were proposed as possible biomarkers for the downy mildew resistance and susceptibility in grapevine. All were found in the butanol extracts, and can be considered to form two groups: compounds with high correlations (r=+/-0.50 to +/-1.00) - 3-hydroxybutanoic acid, 2,3,4-trihydroxybutanoic acid, 2,3,4-trihydroxybutanoic acid (isomer), hexadecanoic acid, 3-hydroxyhexanoic acid and myo-inositol, and compounds with moderate correlations (r=+/-0.30 to +/-0.49) hydroxybutanedioic acid, alanine, glutamine, arabinoic acid and aldohexoses. Among them, the more polar compounds were related to sensitivity, and only hexadecanoic and the monohydroxycarboxylic acids were related to resistance in grapevine. PMID:19013664

  15. Post-Spaceflight Orthostatic Hypotension Occurs Mostly in Women and is Predicted by Low Vascular Resistance

    NASA Technical Reports Server (NTRS)

    Waters, Wendy W.; Ziegler, Michael G.; Meck, Janice V.

    2001-01-01

    About 20% of astronauts suffer post-spaceflight presyncope, but the underlying etiology remains elusive. We studied responses to standing in 36 astronauts before and after spaceflight (5- 16 days). Individuals were separated into presyncopal women, presyncopal men, and non-presyncopal men based on their ability to stand for 10 min postflight. Preflight, presyncopal women and presyncopal men had low vascular resistance, with the women having the lowest. Postflight, women experienced significantly higher rates of presyncope (P<0.01) and significantly greater losses of plasma volume than the men (P<0.05). Both presyncopal women and men had lower standing arterial pressure (P<=0.001) and vascular resistance (P<0.05), smaller increases in norepinephrine (P<=0.058) and greater increases in epinephrine (P<=0.058) than nonpresyncopal men. Both presyncopal groups had a strong dependence (P<=0.05) on plasma volume to maintain standing stroke volume. These findings suggest that postflight presyncope is ascribed to a combination of inherently low resistance responses, a strong dependence on volume status, and spaceflight-induced hypoadrenergic responses. In contrast, high vascular resistance and spaceflight-induced hyperadrenergic responses prevent presyncope.

  16. Predicting Aerobic versus Resistance Exercise Using the Theory of Planned Behavior.

    ERIC Educational Resources Information Center

    Bryan, Angela D.; Rocheleau, Courtney A.

    2002-01-01

    Tested the theory of planned behavior (TPB) in aerobic versus resistance training, investigating relationships between TPB variables, extroversion, and perceived health among college students who completed initial and follow-up measurements and provided reasons for exercise. TPB variables, extroversion, and perceived health collectively accounted…

  17. Biomarkers for the prediction of the resistance and susceptibility of grapevine leaves to downy mildew.

    PubMed

    Batovska, Daniela Ilieva; Todorova, Iva Todorova; Parushev, Stoyan Parushev; Nedelcheva, Daniela Valentinova; Bankova, Vassya Stefanova; Popov, Simeon Simeonov; Ivanova, Iliana Ivanova; Batovski, Stancho Atanassov

    2009-05-01

    We examined metabolic profiles of acetone and butanol extracts obtained from the leaves of 18 seedlings of the Bulgarian wine-making cultivar Storgozia. The acetone extracts contained the components from the leaf surface, while the butanol extracts were enriched with polar components from inside the leaf tissue. The leaves displayed different degrees of resistance and susceptibility to the etiological agent downy mildew, Plasmopara viticola. Based on the statistically significant correlations (P<0.05) between the GC-MS data of the identified metabolites and the estimated leaf resistances, 10 individual components were proposed as possible biomarkers for the downy mildew resistance and susceptibility in grapevine. All were found in the butanol extracts, and can be considered to form two groups: compounds with high correlations (r=+/-0.50 to +/-1.00) - 3-hydroxybutanoic acid, 2,3,4-trihydroxybutanoic acid, 2,3,4-trihydroxybutanoic acid (isomer), hexadecanoic acid, 3-hydroxyhexanoic acid and myo-inositol, and compounds with moderate correlations (r=+/-0.30 to +/-0.49) hydroxybutanedioic acid, alanine, glutamine, arabinoic acid and aldohexoses. Among them, the more polar compounds were related to sensitivity, and only hexadecanoic and the monohydroxycarboxylic acids were related to resistance in grapevine.

  18. New insights into the in silico prediction of HIV protease resistance to nelfinavir.

    PubMed

    Antunes, Dinler A; Rigo, Maurício M; Sinigaglia, Marialva; de Medeiros, Rúbia M; Junqueira, Dennis M; Almeida, Sabrina E M; Vieira, Gustavo F

    2014-01-01

    The Human Immunodeficiency Virus type 1 protease enzyme (HIV-1 PR) is one of the most important targets of antiretroviral therapy used in the treatment of AIDS patients. The success of protease-inhibitors (PIs), however, is often limited by the emergence of protease mutations that can confer resistance to a specific drug, or even to multiple PIs. In the present study, we used bioinformatics tools to evaluate the impact of the unusual mutations D30V and V32E over the dynamics of the PR-Nelfinavir complex, considering that codons involved in these mutations were previously related to major drug resistance to Nelfinavir. Both studied mutations presented structural features that indicate resistance to Nelfinavir, each one with a different impact over the interaction with the drug. The D30V mutation triggered a subtle change in the PR structure, which was also observed for the well-known Nelfinavir resistance mutation D30N, while the V32E exchange presented a much more dramatic impact over the PR flap dynamics. Moreover, our in silico approach was also able to describe different binding modes of the drug when bound to different proteases, identifying specific features of HIV-1 subtype B and subtype C proteases.

  19. Reprogramming of the ERRα and ERα target gene landscape triggers tamoxifen resistance in breast cancer.

    PubMed

    Thewes, Verena; Simon, Ronald; Schroeter, Petra; Schlotter, Magdalena; Anzeneder, Tobias; Büttner, Reinhard; Benes, Vladimir; Sauter, Guido; Burwinkel, Barbara; Nicholson, Robert I; Sinn, Hans-Peter; Schneeweiss, Andreas; Deuschle, Ulrich; Zapatka, Marc; Heck, Stefanie; Lichter, Peter

    2015-02-15

    Endocrine treatment regimens for breast cancer that target the estrogen receptor-α (ERα) are effective, but acquired resistance remains a limiting drawback. One mechanism of acquired resistance that has been hypothesized is functional substitution of the orphan receptor estrogen-related receptor-α (ERRα) for ERα. To examine this hypothesis, we analyzed ERRα and ERα in recurrent tamoxifen-resistant breast tumors and conducted a genome-wide target gene profiling analysis of MCF-7 breast cancer cell populations that were sensitive or resistant to tamoxifen treatment. This analysis uncovered a global redirection in the target genes controlled by ERα, ERRα, and their coactivator AIB1, defining a novel set of target genes in tamoxifen-resistant cells. Beyond differences in the ERα and ERRα target gene repertoires, both factors were engaged in similar pathobiologic processes relevant to acquired resistance. Functional analyses confirmed a requirement for ERRα in tamoxifen- and fulvestrant-resistant MCF-7 cells, with pharmacologic inhibition of ERRα sufficient to partly restore sensitivity to antiestrogens. In clinical specimens (n = 1041), increased expression of ERRα was associated with enhanced proliferation and aggressive disease parameters, including increased levels of p53 in ERα-positive cases. In addition, increased ERRα expression was linked to reduced overall survival in independent tamoxifen-treated patient cohorts. Taken together, our results suggest that ERα and ERRα cooperate to promote endocrine resistance, and they provide a rationale for the exploration of ERRα as a candidate drug target to treat endocrine-resistant breast cancer.

  20. Application of PK/PD Modeling in Veterinary Field: Dose Optimization and Drug Resistance Prediction.

    PubMed

    Ahmad, Ijaz; Huang, Lingli; Hao, Haihong; Sanders, Pascal; Yuan, Zonghui

    2016-01-01

    Among veterinary drugs, antibiotics are frequently used. The true mean of antibiotic treatment is to administer dose of drug that will have enough high possibility of attaining the preferred curative effect, with adequately low chance of concentration associated toxicity. Rising of antibacterial resistance and lack of novel antibiotic is a global crisis; therefore there is an urgent need to overcome this problem. Inappropriate antibiotic selection, group treatment, and suboptimal dosing are mostly responsible for the mentioned problem. One approach to minimizing the antibacterial resistance is to optimize the dosage regimen. PK/PD model is important realm to be used for that purpose from several years. PK/PD model describes the relationship between drug potency, microorganism exposed to drug, and the effect observed. Proper use of the most modern PK/PD modeling approaches in veterinary medicine can optimize the dosage for patient, which in turn reduce toxicity and reduce the emergence of resistance. The aim of this review is to look at the existing state and application of PK/PD in veterinary medicine based on in vitro, in vivo, healthy, and disease model. PMID:26989688

  1. Magnetic tunnel junctions with ferroelectric barriers: prediction of four resistance States from first principles.

    PubMed

    Velev, Julian P; Duan, Chun-Gang; Burton, J D; Smogunov, Alexander; Niranjan, Manish K; Tosatti, Erio; Jaswal, S S; Tsymbal, Evgeny Y

    2009-01-01

    Magnetic tunnel junctions (MTJs), composed of two ferromagnetic electrodes separated by a thin insulating barrier layer, are currently used in spintronic devices, such as magnetic sensors and magnetic random access memories. Recently, driven by demonstrations of ferroelectricity at the nanoscale, thin-film ferroelectric barriers were proposed to extend the functionality of MTJs. Due to the sensitivity of conductance to the magnetization alignment of the electrodes (tunneling magnetoresistance) and the polarization orientation in the ferroelectric barrier (tunneling electroresistance), these multiferroic tunnel junctions (MFTJs) may serve as four-state resistance devices. On the basis of first-principles calculations, we demonstrate four resistance states in SrRuO(3)/BaTiO(3)/SrRuO(3) MFTJs with asymmetric interfaces. We find that the resistance of such a MFTJ is significantly changed when the electric polarization of the barrier is reversed and/or when the magnetizations of the electrodes are switched from parallel to antiparallel. These results reveal the exciting prospects of MFTJs for application as multifunctional spintronic devices. PMID:19113889

  2. Application of PK/PD Modeling in Veterinary Field: Dose Optimization and Drug Resistance Prediction

    PubMed Central

    Ahmad, Ijaz; Huang, Lingli; Hao, Haihong; Sanders, Pascal; Yuan, Zonghui

    2016-01-01

    Among veterinary drugs, antibiotics are frequently used. The true mean of antibiotic treatment is to administer dose of drug that will have enough high possibility of attaining the preferred curative effect, with adequately low chance of concentration associated toxicity. Rising of antibacterial resistance and lack of novel antibiotic is a global crisis; therefore there is an urgent need to overcome this problem. Inappropriate antibiotic selection, group treatment, and suboptimal dosing are mostly responsible for the mentioned problem. One approach to minimizing the antibacterial resistance is to optimize the dosage regimen. PK/PD model is important realm to be used for that purpose from several years. PK/PD model describes the relationship between drug potency, microorganism exposed to drug, and the effect observed. Proper use of the most modern PK/PD modeling approaches in veterinary medicine can optimize the dosage for patient, which in turn reduce toxicity and reduce the emergence of resistance. The aim of this review is to look at the existing state and application of PK/PD in veterinary medicine based on in vitro, in vivo, healthy, and disease model. PMID:26989688

  3. Host life history and host-parasite syntopy predict behavioural resistance and tolerance of parasites.

    PubMed

    Sears, Brittany F; Snyder, Paul W; Rohr, Jason R

    2015-05-01

    There is growing interest in the role that life-history traits of hosts, such as their 'pace-of-life', play in the evolution of resistance and tolerance to parasites. Theory suggests that, relative to host species that have high syntopy (local spatial and temporal overlap) with parasites, host species with low syntopy should have lower selection pressures for more constitutive (always present) and costly defences, such as tolerance, and greater reliance on more inducible and cheaper defences, such as behaviour. Consequently, we postulated that the degree of host-parasite syntopy, which is negatively correlated with host pace-of-life (an axis reflecting the developmental rate of tadpoles and the inverse of their size at metamorphosis) in our tadpole-parasitic cercarial (trematode) system, would be a negative and positive predictor of behavioural resistance and tolerance, respectively. To test these hypotheses, we exposed seven tadpole species to a range of parasite (cercarial) doses crossed with anaesthesia treatments that controlled for anti-parasite behaviour. We quantified host behaviour, successful and unsuccessful infections, and each species' reaction norm for behavioural resistance and tolerance, defined as the slope between cercarial exposure (or attempted infections) and anti-cercarial behaviours and mass change, respectively. Hence, tolerance is capturing any cost of parasite exposure. As hypothesized, tadpole pace-of-life was a significant positive predictor of behavioural resistance and negative predictor of tolerance, a result that is consistent with a trade-off between behavioural resistance and tolerance across species that warrants further investigation. Moreover, these results were robust to considerations of phylogeny, all possible re-orderings of the three fastest or slowest paced species, and various measurements of tolerance. These results suggest that host pace-of-life and host-parasite syntopy are powerful drivers of both the strength and type

  4. Host life history and host-parasite syntopy predict behavioural resistance and tolerance of parasites.

    PubMed

    Sears, Brittany F; Snyder, Paul W; Rohr, Jason R

    2015-05-01

    There is growing interest in the role that life-history traits of hosts, such as their 'pace-of-life', play in the evolution of resistance and tolerance to parasites. Theory suggests that, relative to host species that have high syntopy (local spatial and temporal overlap) with parasites, host species with low syntopy should have lower selection pressures for more constitutive (always present) and costly defences, such as tolerance, and greater reliance on more inducible and cheaper defences, such as behaviour. Consequently, we postulated that the degree of host-parasite syntopy, which is negatively correlated with host pace-of-life (an axis reflecting the developmental rate of tadpoles and the inverse of their size at metamorphosis) in our tadpole-parasitic cercarial (trematode) system, would be a negative and positive predictor of behavioural resistance and tolerance, respectively. To test these hypotheses, we exposed seven tadpole species to a range of parasite (cercarial) doses crossed with anaesthesia treatments that controlled for anti-parasite behaviour. We quantified host behaviour, successful and unsuccessful infections, and each species' reaction norm for behavioural resistance and tolerance, defined as the slope between cercarial exposure (or attempted infections) and anti-cercarial behaviours and mass change, respectively. Hence, tolerance is capturing any cost of parasite exposure. As hypothesized, tadpole pace-of-life was a significant positive predictor of behavioural resistance and negative predictor of tolerance, a result that is consistent with a trade-off between behavioural resistance and tolerance across species that warrants further investigation. Moreover, these results were robust to considerations of phylogeny, all possible re-orderings of the three fastest or slowest paced species, and various measurements of tolerance. These results suggest that host pace-of-life and host-parasite syntopy are powerful drivers of both the strength and type

  5. Host life history and host–parasite syntopy predict behavioural resistance and tolerance of parasites

    PubMed Central

    Sears, Brittany F.; Snyder, Paul W.; Rohr, Jason R.

    2016-01-01

    Summary There is growing interest in the role that life-history traits of hosts, such as their ‘pace-of-life’, play in the evolution of resistance and tolerance to parasites.Theory suggests that, relative to host species that have high syntopy (local spatial and temporal overlap) with parasites, host species with low syntopy should have lower selection pressures for more constitutive (always present) and costly defences, such as tolerance, and greater reliance on more inducible and cheaper defences, such as behaviour. Consequently, we postulated that the degree of host–parasite syntopy, which is negatively correlated with host pace-of-life (an axis reflecting the developmental rate of tadpoles and the inverse of their size at metamorphosis) in our tadpole–parasitic cercarial (trematode) system, would be a negative and positive predictor of behavioural resistance and tolerance, respectively.To test these hypotheses, we exposed seven tadpole species to a range of parasite (cercarial) doses crossed with anaesthesia treatments that controlled for anti-parasite behaviour. We quantified host behaviour, successful and unsuccessful infections, and each species’ reaction norm for behavioural resistance and tolerance, defined as the slope between cercarial exposure (or attempted infections) and anti-cercarial behaviours and mass change, respectively. Hence, tolerance is capturing any cost of parasite exposure.As hypothesized, tadpole pace-of-life was a significant positive predictor of behavioural resistance and negative predictor of tolerance, a result that is consistent with a trade-off between behavioural resistance and tolerance across species that warrants further investigation. Moreover, these results were robust to considerations of phylogeny, all possible re-orderings of the three fastest or slowest paced species, and various measurements of tolerance.These results suggest that host pace-of-life and host–parasite syntopy are powerful drivers of both the

  6. A predicted protein interactome identifies conserved global networks and disease resistance subnetworks in maize

    PubMed Central

    Musungu, Bryan; Bhatnagar, Deepak; Brown, Robert L.; Fakhoury, Ahmad M.; Geisler, Matt

    2015-01-01

    Interactomes are genome-wide roadmaps of protein-protein interactions. They have been produced for humans, yeast, the fruit fly, and Arabidopsis thaliana and have become invaluable tools for generating and testing hypotheses. A predicted interactome for Zea mays (PiZeaM) is presented here as an aid to the research community for this valuable crop species. PiZeaM was built using a proven method of interologs (interacting orthologs) that were identified using both one-to-one and many-to-many orthology between genomes of maize and reference species. Where both maize orthologs occurred for an experimentally determined interaction in the reference species, we predicted a likely interaction in maize. A total of 49,026 unique interactions for 6004 maize proteins were predicted. These interactions are enriched for processes that are evolutionarily conserved, but include many otherwise poorly annotated proteins in maize. The predicted maize interactions were further analyzed by comparing annotation of interacting proteins, including different layers of ontology. A map of pairwise gene co-expression was also generated and compared to predicted interactions. Two global subnetworks were constructed for highly conserved interactions. These subnetworks showed clear clustering of proteins by function. Another subnetwork was created for disease response using a bait and prey strategy to capture interacting partners for proteins that respond to other organisms. Closer examination of this subnetwork revealed the connectivity between biotic and abiotic hormone stress pathways. We believe PiZeaM will provide a useful tool for the prediction of protein function and analysis of pathways for Z. mays researchers and is presented in this paper as a reference tool for the exploration of protein interactions in maize. PMID:26089837

  7. Neoadjuvant Chemotherapy Induces Expression Levels of Breast Cancer Resistance Protein That Predict Disease-Free Survival in Breast Cancer

    PubMed Central

    Kim, Baek; Fatayer, Hiba; Hanby, Andrew M.; Horgan, Kieran; Perry, Sarah L.; Valleley, Elizabeth M.A.; Verghese, Eldo T.; Williams, Bethany J.; Thorne, James L.; Hughes, Thomas A.

    2013-01-01

    Three main xenobiotic efflux pumps have been implicated in modulating breast cancer chemotherapy responses. These are P-glycoprotein (Pgp), Multidrug Resistance-associated Protein 1 (MRP1), and Breast Cancer Resistance Protein (BCRP). We investigated expression of these proteins in breast cancers before and after neoadjuvant chemotherapy (NAC) to determine whether their levels define response to NAC or subsequent survival. Formalin-fixed paraffin-embedded tissues were collected representing matched pairs of core biopsy (pre-NAC) and surgical specimen (post-NAC) from 45 patients with invasive ductal carcinomas. NAC regimes were anthracyclines +/− taxanes. Immunohistochemistry was performed for Pgp, MRP1 and BCRP and expression was quantified objectively using computer-aided scoring. Pgp and MRP1 were significantly up-regulated after exposure to NAC (Wilcoxon signed-rank p = 0.0024 and p<0.0001), while BCRP showed more variation in response to NAC, with frequent up- (59% of cases) and down-regulation (41%) contributing to a lack of significant difference overall. Pre-NAC expression of all markers, and post-NAC expression of Pgp and MRP1 did not correlate with NAC response or with disease-free survival (DFS). Post-NAC expression of BCRP did not correlate with NAC response, but correlated significantly with DFS (Log rank p = 0.007), with longer DFS in patients with low post-NAC BCRP expression. In multivariate Cox regression analyses, post-NAC BCRP expression levels proved to predict DFS independently of standard prognostic factors, with high expression associated with a hazard ratio of 4.04 (95% confidence interval 1.3–12.2; p = 0.013). We conclude that NAC-induced expression levels of BCRP predict survival after NAC for breast cancer, while Pgp and MRP1 expression have little predictive value. PMID:23658771

  8. The use of model-test data for predicting full-scale ACV resistance

    NASA Astrophysics Data System (ADS)

    Forstell, B. G.; Harry, C. W.

    The paper summarizes the analysis of test data obtained with a 1/12-scale model of the Amphibious Assault Landing Craft (AALC) JEFF(B). The analysis was conducted with the objective of improving the accuracy of drag predictions for a JEFF(B)-type air-cushion vehicle (ACV). Model test results, scaled to full-scale, are compared with full-scale drag obtained in various sea states during JEFF(B) trials. From the results of this comparison, it is found that the Froude-scale model rough-water drag data is consistently greater than full-scale derived drag, and is a function of both wave height and craft forward speed. Results are presented indicating that Froude scaling model data obtained in calm water also causes an over-prediction of calm-water drag at full-scale. An empirical correction that was developed for use on a JEFF(B)-type craft is discussed.

  9. Resistance Training Predicts Six-Year Body Composition Change in Postmenopausal Women

    PubMed Central

    Bea, Jennifer W.; Cussler, Ellen C; Going, Scott B.; Blew, Robert M.; Metcalfe, Lauve L.; Lohman, Timothy G

    2010-01-01

    Purpose The aim of this study was to examine the association of exercise frequency (ExFreq) and volume (total weight lifted by military press (MP) and squats (SQ)) with change in body composition among postmenopausal women participating in a progressive resistance training study. Methods Previously sedentary women (n=122, age 56.3±4.3 years) were followed for 6yrs. At 6yrs, there were women who had been randomly assigned to resistance training at baseline (n=65) controls that were permitted to cross-over to the exercise program at 1yr (n=32), and 25 true controls. Exercisers and crossovers directed to perform 8 core exercises for two sets of eight repetitions at 70–80% of one repetition maximum, three times weekly, plus progressive weight bearing, stretching, and balance. Body weight and fat were measured at baseline and annually using anthropometry and dual-energy x-ray absorptiometry. Results Average change in body weight and total body fat were 0.83±5.39 kg and 0.64±4.95 kg at six years, respectively. In multiple linear regression, ExFreq, MP, and SQ were significantly, inversely associated with change in body weight (standardized beta coefficient (SBC)=−0.22 to −0.28, p<0.01), fat (SBC=−0.25 to −0.33, p<0.01) and trunk fat (SBC=−0.20 to −0.31, p<0.03) after adjusting for age, years on hormone therapy, change in lean soft tissue, baseline body composition, and baseline habitual exercise. The lowest tertile of SQ (equivalent to 2.5% attendance) demonstrated significant gain in weight, fat, and trunk fat over 6 years (p<0.004), whereas the highest tertile SQ (equivalent to 64% attendance) was able to maintain their weight, total and regional fat. Conclusion We conclude that resistance training is a viable long-term method to prevent weight gain and deleterious changes in body composition in postmenopausal women. PMID:20019638

  10. Cytotoxic Virulence Predicts Mortality in Nosocomial Pneumonia Due to Methicillin-Resistant Staphylococcus aureus.

    PubMed

    Rose, Hannah R; Holzman, Robert S; Altman, Deena R; Smyth, Davida S; Wasserman, Gregory A; Kafer, Jared M; Wible, Michelle; Mendes, Rodrigo E; Torres, Victor J; Shopsin, Bo

    2015-06-15

    The current study identified bacterial factors that may improve management of methicillin-resistant Staphylococcus aureus (MRSA) nosocomial pneumonia. Isolates were obtained from 386 patients enrolled in a randomized, controlled study of antibiotic efficacy. Isolates were screened for production of virulence factors and for vancomycin susceptibility. After adjustment for host factors such as severity of illness and treatment modality, cytotoxic activity was strongly and inversely associated with mortality; however, it had no effect on clinical cure. Isolates having low cytotoxicity, which were derived largely from healthcare-associated clones, exhibited a greater prevalence of vancomycin heteroresistance, and they were recovered more often from patients who were older and frailer. Additionally, a clone with low cytotoxic activity was associated with death and poor clinical improvement. Clone specificity and attenuated virulence appear to be associated with outcome. To our knowledge, these are the first correlations between MRSA virulence and mortality in nosocomial pneumonia.

  11. Cytotoxic Virulence Predicts Mortality in Nosocomial Pneumonia Due to Methicillin-Resistant Staphylococcus aureus

    PubMed Central

    Rose, Hannah R.; Holzman, Robert S.; Altman, Deena R.; Smyth, Davida S.; Wasserman, Gregory A.; Kafer, Jared M.; Wible, Michelle; Mendes, Rodrigo E.; Torres, Victor J.; Shopsin, Bo

    2015-01-01

    The current study identified bacterial factors that may improve management of methicillin-resistant Staphylococcus aureus (MRSA) nosocomial pneumonia. Isolates were obtained from 386 patients enrolled in a randomized, controlled study of antibiotic efficacy. Isolates were screened for production of virulence factors and for vancomycin susceptibility. After adjustment for host factors such as severity of illness and treatment modality, cytotoxic activity was strongly and inversely associated with mortality; however, it had no effect on clinical cure. Isolates having low cytotoxicity, which were derived largely from healthcare-associated clones, exhibited a greater prevalence of vancomycin heteroresistance, and they were recovered more often from patients who were older and frailer. Additionally, a clone with low cytotoxic activity was associated with death and poor clinical improvement. Clone specificity and attenuated virulence appear to be associated with outcome. To our knowledge, these are the first correlations between MRSA virulence and mortality in nosocomial pneumonia. PMID:25298028

  12. ERK phosphorylation is predictive of resistance to IGF-1R inhibition in small cell lung cancer.

    PubMed

    Zinn, Rebekah L; Gardner, Eric E; Marchionni, Luigi; Murphy, Sara C; Dobromilskaya, Irina; Hann, Christine L; Rudin, Charles M

    2013-06-01

    New therapies are critically needed to improve the outcome for patients with small cell lung cancer (SCLC). Insulin-like growth factor 1 receptor (IGF-1R) inhibition is a potential treatment strategy for SCLC: the IGF-1R pathway is commonly upregulated in SCLC and has been associated with inhibition of apoptosis and stimulation of proliferation through downstream signaling pathways, including phosphatidylinositol-3-kinase-Akt and mitogen-activated protein kinase. To evaluate potential determinants of response to IGF-1R inhibition, we assessed the relative sensitivity of 19 SCLC cell lines to OSI-906, a small molecule inhibitor of IGF-1R, and the closely related insulin receptor. Approximately one third of these cell lines were sensitive to OSI-906, with an IC50 < 1 μmol/L. Cell line expression of IGF-1R, IR, IGF-1, IGF-2, IGFBP3, and IGFBP6 did not correlate with sensitivity to OSI-906. Interestingly, OSI-906 sensitive lines expressed significantly lower levels of baseline phospho-ERK relative to resistant lines (P = 0.006). OSI-906 treatment resulted in dose-dependent inhibition of phospho-IGF-1R and phospho-Akt in both sensitive and resistant cell lines, but induced apoptosis and cell-cycle arrest only in sensitive lines. We tested the in vivo efficacy of OSI-906 using an NCI-H187 xenograft model and two SCLC patient xenografts in mice. OSI-906 treatment resulted in 50% tumor growth inhibition in NCI-H187 and 30% inhibition in the primary patient xenograft models compared with mock-treated animals. Taken together our data support IGF-1R inhibition as a viable treatment strategy for a defined subset of SCLC and suggest that low pretreatment levels of phospho-ERK may be indicative of sensitivity to this therapeutic approach. PMID:23515613

  13. Mutation of the rice XA21 predicted nuclear localization sequence does not affect resistance to Xanthomonas oryzae pv. oryzae

    PubMed Central

    Ho, Yuen Ting

    2016-01-01

    Background The rice receptor kinase XA21 confers robust resistance to the bacterial pathogen Xanthomonas oryzaepv. oryzae(Xoo). We previously reported that XA21 is cleaved in transgenic plants overexpressing XA21 with a GFP tag (Ubi-XA21-GFP) and that the released C-terminal domain is localized to the nucleus. XA21 carries a predicted nuclear localization sequence (NLS) that directs the C-terminal domain to the nucleus in transient assays, whereas alanine substitutions in the NLS disrupt the nuclear localization. Methods To determine if the predicted NLS is required for XA21-mediated immunity in planta, we generated transgenic plants overexpressing an XA21 variant carrying the NLS with the same alanine substitutions (Ubi-XA21nls-GFP). Results Ubi-XA21nls-GFP plants displayed slightly longer lesion lengths, higher Xoobacterial populations after inoculation and lower levels of reactive oxygen species production compared with the Ubi-XA21-GFP control plants. However, the Ubi-XA21nls-GFP plants express lower levels of protein than that observed in Ubi-XA21-GFP. Discussion These results demonstrate that the predicted NLS is not required for XA21-mediated immunity. PMID:27761320

  14. Downregulation of amplified in breast cancer 1 contributes to the anti-tumor effects of sorafenib on human hepatocellular carcinoma

    PubMed Central

    Dan, Yuzhen; Tong, Zhangwei; Chen, Wenbo; Qin, Liping; Liu, Kun; Li, Wengang; Mo, Pingli; Yu, Chundong

    2016-01-01

    Multi-kinase inhibitor sorafenib represents a major breakthrough in the therapy of advanced hepatocellular carcinoma (HCC). Amplified in breast cancer 1 (AIB1) is frequently overexpressed in human HCC tissues and promotes HCC progression. In this study, we investigated the effects of sorafenib on AIB1 expression and the role of AIB1 in anti-tumor effects of sorafenib. We found that sorafenib downregulated AIB1 protein expression by inhibiting AIB1 mRNA translation through simultaneously blocking eIF4E and mTOR/p70S6K/RP-S6 signaling. Knockdown of AIB1 significantly promoted sorafenib-induced cell death, whereas overexpression of AIB1 substantially diminished sorafenib-induced cell death. Downregulation of AIB1 contributed to sorafenib-induced cell death at least in part through upregulating the levels of reactive oxygen species in HCC cells. In addition, resistance to sorafenib-induced downregulation of AIB1 protein contributes to the acquired resistance of HCC cells to sorafenib-induced cell death. Collectively, our study implicates that AIB1 is a molecular target of sorafenib and downregulation of AIB1 contributes to the anti-tumor effects of sorafenib. PMID:27105488

  15. Maximal strength on different resistance training rowing exercises predicts start phase performance in elite kayakers.

    PubMed

    Ualí, Ismael; Herrero, Azael J; Garatachea, Nuria; Marín, Pedro J; Alvear-Ordenes, Ildefonso; García-López, David

    2012-04-01

    This study aimed to examine the relationship existing between maximum strength values in 2 common resistance training row exercises (bilateral bench pull [BBP] and one-arm cable row [OACR]) and short sprint performance in elite kayakers. Ten junior kayakers (5 women and 5 men) were tested on different days for 1 repetition maximum (1RM) and maximal voluntary isometric contraction in both exercises. Moreover, a 12-m sprint kayak was performed in a dew pond to record split times (2, 5, and 10 m), peak velocity, distance completed considering the first 8 strokes, and mean acceleration induced by right blade and left blade strokes. No differences (p > 0.05) were observed when right and left arms were compared in sprint testing or strength testing variables. Maximal strength values in BBP and OACR were significantly correlated with short sprint performance variables, showing the bilateral exercise with slightly stronger correlation coefficients than the unilateral seated row. Moreover, the relationship between strength testing and sprint testing variables is stronger when maximal force is measured through a dynamic approach (1RM) in comparison with an isometric approach. In conclusion, maximal strength in BBP and OACR is a good predictor of the start phase performance in elite sprint kayakers, mainly the 1RM value in BBP.

  16. Alterations in neuronal morphology in infralimbic cortex predict resistance to fear extinction following acute stress

    PubMed Central

    Moench, Kelly M.; Maroun, Mouna; Kavushansky, Alexandra; Wellman, Cara

    2015-01-01

    Dysfunction in corticolimbic circuits that mediate the extinction of learned fear responses is thought to underlie the perseveration of fear in stress-related psychopathologies, including post-traumatic stress disorder. Chronic stress produces dendritic hypertrophy in basolateral amygdala (BLA) and dendritic hypotrophy in medial prefrontal cortex, whereas acute stress leads to hypotrophy in both BLA and prelimbic cortex. Additionally, both chronic and acute stress impair extinction retrieval. Here, we examined the effects of a single elevated platform stress on extinction learning and dendritic morphology in infralimbic cortex, a region considered to be critical for extinction. Acute stress produced resistance to extinction, as well as dendritic retraction in infralimbic cortex. Spine density on apical and basilar terminal branches was unaffected by stress. However, animals that underwent conditioning and extinction had decreased spine density on apical terminal branches. Thus, whereas dendritic morphology in infralimbic cortex appears to be particularly sensitive to stress, changes in spines may more sensitively reflect learning. Further, in stressed rats that underwent conditioning and extinction, the level of extinction learning was correlated with spine densities, in that rats with poorer extinction retrieval had more immature spines and fewer thin spines than rats with better extinction retrieval, suggesting that stress may have impaired learning-related spine plasticity. These results may have implications for understanding the role of medial prefrontal cortex in learning deficits associated with stress-related pathologies. PMID:26844245

  17. Prediction of the quality of resistance welds by computer based color image analysis

    SciTech Connect

    Pechersky, M.J.; Zeoli, K.A.; Kestin, P.A.

    1992-11-01

    This report discusses experiments which have been completed to correlate the quality of electric resistance pinch welds with an automated computer analysis of the weld surface. The pinch welds were performed on small diameter stainless steel tubes after they were annealed in air at several different temperatures to form an oxide layer on the weld surfaces. The images of the tube bore were collected with a borescope, stored in a computer and analyzed. The analysis consisted of computing a parameter which gave a representation of the color integrated over the inspected region. This color parameter was then used to rank the tubes in order of their relative oxidation level. Once this was performed the tubes were welded and low magnification metallography was performed on the welds. It was found that the color analysis gave a perfect correlation with the oxidation levels and that the weld quality was inversely proportional to the amount of oxidation. It was also shown that the color analysis was robust in the sense that the sorting was independent of the borescope illumination level over a large range for both oxidized and unoxidized stems. Thus the color parameter chosen was an excellent predictor of the weld quality.

  18. Prediction of the quality of resistance welds by computer based color image analysis

    SciTech Connect

    Pechersky, M.J.; Zeoli, K.A.; Kestin, P.A.

    1992-01-01

    This report discusses experiments which have been completed to correlate the quality of electric resistance pinch welds with an automated computer analysis of the weld surface. The pinch welds were performed on small diameter stainless steel tubes after they were annealed in air at several different temperatures to form an oxide layer on the weld surfaces. The images of the tube bore were collected with a borescope, stored in a computer and analyzed. The analysis consisted of computing a parameter which gave a representation of the color integrated over the inspected region. This color parameter was then used to rank the tubes in order of their relative oxidation level. Once this was performed the tubes were welded and low magnification metallography was performed on the welds. It was found that the color analysis gave a perfect correlation with the oxidation levels and that the weld quality was inversely proportional to the amount of oxidation. It was also shown that the color analysis was robust in the sense that the sorting was independent of the borescope illumination level over a large range for both oxidized and unoxidized stems. Thus the color parameter chosen was an excellent predictor of the weld quality.

  19. Genome-enabled prediction for tick resistance in Hereford and Braford beef cattle via reaction norm models.

    PubMed

    Mota, R R; Lopes, P S; Tempelman, R J; Silva, F F; Aguilar, I; Gomes, C C G; Cardoso, F F

    2016-05-01

    Very few studies have been conducted to infer genotype × environment interaction (G×E) based in genomic prediction models using SNP markers. Therefore, our main objective was to compare a conventional genomic-based single-step model (HBLUP) with its reaction norm model extension (genomic 1-step linear reaction norm model [HLRNM]) to provide EBV for tick resistance as well as to compare predictive performance of these models with counterpart models that ignore SNP marker information, that is, a linear animal model (ABLUP) and its reaction norm extension (1-step linear reaction norm model [ALRNM]). Phenotypes included 10,673 tick counts on 4,363 Hereford and Braford animals, of which 3,591 were genotyped. Using the deviance information criterion for model choice, ABLUP and HBLUP seemed to be poorer fitting in comparison with their respective genomic model extensions. The HLRNM estimated lower average and reaction norm genetic variability compared with the ALRNM, whereas ABLUP and HBLUP seemed to be poorer fitting in comparison with their respective genomic reaction norm model extensions. Heritability and repeatability estimates varied along the environmental gradient (EG) and the genetic correlations were remarkably low between high and low EG, indicating the presence of G×E for tick resistance in these populations. Based on 5-fold -means partitioning, mean cross-validation estimates with their respective SE of predictive accuracy were 0.66 (SE 0.02), 0.67 (SE 0.02), 0.67 (SE 0.02), and 0.66 (SE 0.02) for ABLUP, HBLUP, HLRNM, and ALRNM, respectively. For 5-fold random partitioning, HLRNM (0.71 ± 0.01) was statistically different from ABLUP (0.67 ± 0.01). However, no statistical significance was reported when considering HBLUP (0.70 ± 0.01) and ALRNM (0.70 ± 0.01). Our results suggest that SNP marker information does not lead to higher prediction accuracies in reaction norm models. Furthermore, these accuracies decreased as the tick infestation level increased

  20. Pharmacokinetic-Pharmacodynamic Model for Gentamicin and Its Adaptive Resistance with Predictions of Dosing Schedules in Newborn Infants

    PubMed Central

    Nielsen, Elisabet I.; Cars, Otto; Friberg, Lena E.

    2012-01-01

    Gentamicin is commonly used in the management of neonatal infections. Development of adaptive resistance is typical for aminoglycosides and reduces the antibacterial effect. There is, however, a lack of understanding of how this phenomenon influences the effect of different dosing schedules. The aim was to develop a pharmacokinetic-pharmacodynamic (PKPD) model that describes the time course of the bactericidal activity of gentamicin and its adaptive resistance and to investigate different dosing schedules in preterm and term newborn infants based on the developed model. In vitro time-kill curve experiments were conducted on a strain of Escherichia coli (MIC of 2 mg/liter). The gentamicin exposure was either constant (0.125 to 16 mg/liter) or dynamic (simulated concentration-time profiles in a kinetic system with peak concentrations of 2.0, 3.9, 7.8, and 16 mg/liter given as single doses or as repeated doses every 6, 12, or 24 h). Semimechanistic PKPD models were fitted to the bacterial counts in the NONMEM (nonlinear mixed effects modeling) program. A model with compartments for growing and resting bacteria, with a function allowing the maximal bacterial killing of gentamicin to reduce with exposure, characterized both the fast bactericidal effect and the adaptive resistance. Despite a lower peak concentration, preterm neonates were predicted to have a higher bacterial killing effect than term neonates for the same per-kg dose because of gentamicin's longer half-life. The model supported an extended dosing interval of gentamicin in preterm neonates, and for all neonates, dosing intervals of 36 to 48 h were as effective as a 24-h dosing interval for the same total dose. PMID:22037853

  1. Computational classification models for predicting the interaction of drugs with P-glycoprotein and breast cancer resistance protein.

    PubMed

    Erić, S; Kalinić, M; Ilić, K; Zloh, M

    2014-01-01

    P-glycoprotein (P-gp/ABCB1) and breast cancer resistance protein (BCRP/ABCG2) are two members of the adenosine triphosphate (ATP) binding cassette (ABC) family of transporters which function as membrane efflux transporters and display considerable substrate promiscuity. Both are known to significantly influence the absorption, distribution and elimination of drugs, mediate drug-drug interactions and contribute to multiple drug resistance (MDR) of cancer cells. Correspondingly, timely characterization of the interaction of novel leads and drug candidates with these two transporters is of great importance. In this study, several computational classification models for prediction of transport and inhibition of P-gp and BCRP, respectively, were developed based on newly compiled and critically evaluated experimental data. Artificial neural network (ANN) and support vector machine (SVM) ensemble based models were explored, as well as knowledge-based approaches to descriptor selection. The average overall classification accuracy of best performing models was 82% for P-gp transport, 88% for BCRP transport, 89% for P-gp inhibition and 87% for BCRP inhibition, determined across an array of different test sets. An analysis of substrate overlap between P-gp and BCRP was also performed. The accuracy, simplicity and interpretability of the proposed models suggest that they could be of significant utility in the drug discovery and development settings.

  2. The TG/HDL-C ratio does not predict insulin resistance in overweight women of African descent: a study of South African, African American and West African women.

    PubMed

    Knight, Michael G; Goedecke, Julia H; Ricks, Madia; Evans, Juliet; Levitt, Naomi S; Tulloch-Reid, Marshall K; Sumner, Anne E

    2011-01-01

    Women of African descent have a high prevalence of diseases caused by insulin resistance. To positively impact cardiometabolic health in Black women, effective screening tests for insulin resistance must be identified. Recently, the TG/HDL-C ratio has been recommended as a tool to predict insulin resistance in overweight people. While the ratio predicts insulin resistance in White women, it is ineffective in African American women. As there are no data for African women, we tested the ability of the TG/HDL-C ratio to predict insulin resistance in Black women from South Africa, West Africa and the United States. For comparison, the ratio was also tested in White women from South Africa. Participants were 801 women (157 Black South African, 382 African American, 119 West African, 143 White South African, age 36 +/- 9y [mean +/- SD]). Standardized scores were created from log-transformed homeostasis model assessment-insulin resistance values from each population. Participants in the upper third of their population distribution were classified as insulin-resistant. To predict insulin resistance by the TC/HDL-C ratio, area under the receiver operating characteristic (AUC-ROC) curve was used and criteria were: 0.50 for no discrimination and > or = 0.70 for acceptable. Seventy-one percent of the Black women were overweight vs 51% of White women (P<.01). In overweight White women, AUC-ROC curve for prediction of insulin resistance by TG/HDL-C was 0.76 +/- 0.06, but below the 0.70 threshold in each group of overweight Black women (Black South African: 0.64 +/- 0.06, African American: 0.66 +/- 0.03, and West African: 0.63 +/- 0.07). Therefore, TG/HDL-C does not predict insulin resistance in overweight African American women and this investigation extends that finding to overweight Black South African and West African women. Resources to identify effective markers of insulin resistance are needed to improve cardiometabolic health in women of African descent.

  3. Performance of HIV-1 Drug Resistance Testing at Low-Level Viremia and Its Ability to Predict Future Virologic Outcomes and Viral Evolution in Treatment-Naive Individuals

    PubMed Central

    Gonzalez-Serna, A.; Min, J. E.; Woods, C.; Chan, D.; Lima, V. D.; Montaner, J. S. G.; Harrigan, P. R.; Swenson, L. C.

    2014-01-01

    Background. Low-level viremia (LLV; human immunodeficiency virus [HIV-1] RNA 50–999 copies/mL) occurs frequently in patients receiving antiretroviral therapy (ART), but there are few or no data available demonstrating that HIV-1 drug resistance testing at a plasma viral load (pVL) <1000 copies/mL provides potentially clinically useful information. Here, we assess the ability to perform resistance testing by genotyping at LLV and whether it is predictive of future virologic outcomes in patients beginning ART. Methods. Resistance testing by genotyping at LLV was attempted on 4915 plasma samples from 2492 patients. A subset of previously ART-naive patients was analyzed who achieved undetectable pVL and subsequently rebounded with LLV (n = 212). A genotypic sensitivity score (GSS) was calculated based on therapy and resistance testing results by genotyping, and stratified according to number of active drugs. Results. Eighty-eight percent of LLV resistance assays produced useable sequences, with higher success at higher pVL. Overall, 16 of 212 (8%) patients had pretherapy resistance. Thirty-eight of 196 (19%) patients without pretherapy resistance evolved resistance to 1 or more drug classes, primarily the nucleoside reverse transcriptase (14%) and/or nonnucleoside reverse transcriptase (9%) inhibitors. Patients with resistance at LLV (GSS <3) had a 2.1-fold higher risk of virologic failure (95% confidence interval, 1.2- to 3.7-fold) than those without resistance (P = .007). Progressively lower GSS scores at LLV were associated with a higher increase in pVL over time (P < .001). Acquisition of additional resistance mutations to a new class of antiretroviral drugs during LLV was not found in a subset of patients. Conclusions. Routine HIV-1 genotyping of LLV samples can be performed with a reasonably high success rate, and the results appear predictive of future virologic outcomes. PMID:24429436

  4. Predicting Antimicrobial Resistance Prevalence and Incidence from Indicators of Antimicrobial Use: What Is the Most Accurate Indicator for Surveillance in Intensive Care Units?

    PubMed Central

    Fortin, Élise; Platt, Robert W.; Fontela, Patricia S.; Buckeridge, David L.; Quach, Caroline

    2015-01-01

    Objective The optimal way to measure antimicrobial use in hospital populations, as a complement to surveillance of resistance is still unclear. Using respiratory isolates and antimicrobial prescriptions of nine intensive care units (ICUs), this study aimed to identify the indicator of antimicrobial use that predicted prevalence and incidence rates of resistance with the best accuracy. Methods Retrospective cohort study including all patients admitted to three neonatal (NICU), two pediatric (PICU) and four adult ICUs between April 2006 and March 2010. Ten different resistance / antimicrobial use combinations were studied. After adjustment for ICU type, indicators of antimicrobial use were successively tested in regression models, to predict resistance prevalence and incidence rates, per 4-week time period, per ICU. Binomial regression and Poisson regression were used to model prevalence and incidence rates, respectively. Multiplicative and additive models were tested, as well as no time lag and a one 4-week-period time lag. For each model, the mean absolute error (MAE) in prediction of resistance was computed. The most accurate indicator was compared to other indicators using t-tests. Results Results for all indicators were equivalent, except for 1/20 scenarios studied. In this scenario, where prevalence of carbapenem-resistant Pseudomonas sp. was predicted with carbapenem use, recommended daily doses per 100 admissions were less accurate than courses per 100 patient-days (p = 0.0006). Conclusions A single best indicator to predict antimicrobial resistance might not exist. Feasibility considerations such as ease of computation or potential external comparisons could be decisive in the choice of an indicator for surveillance of healthcare antimicrobial use. PMID:26710322

  5. Artificial Intelligence and Amikacin Exposures Predictive of Outcomes in Multidrug-Resistant Tuberculosis Patients.

    PubMed

    Modongo, Chawangwa; Pasipanodya, Jotam G; Magazi, Beki T; Srivastava, Shashikant; Zetola, Nicola M; Williams, Scott M; Sirugo, Giorgio; Gumbo, Tawanda

    2016-10-01

    Aminoglycosides such as amikacin continue to be part of the backbone of treatment of multidrug-resistant tuberculosis (MDR-TB). We measured amikacin concentrations in 28 MDR-TB patients in Botswana receiving amikacin therapy together with oral levofloxacin, ethionamide, cycloserine, and pyrazinamide and calculated areas under the concentration-time curves from 0 to 24 h (AUC0-24). The patients were followed monthly for sputum culture conversion based on liquid cultures. The median duration of amikacin therapy was 184 (range, 28 to 866) days, at a median dose of 17.30 (range 11.11 to 19.23) mg/kg. Only 11 (39%) patients had sputum culture conversion during treatment; the rest failed. We utilized classification and regression tree analyses (CART) to examine all potential predictors of failure, including clinical and demographic features, comorbidities, and amikacin peak concentrations (Cmax), AUC0-24, and trough concentrations. The primary node for failure had two competing variables, Cmax of <67 mg/liter and AUC0-24 of <568.30 mg · h/L; weight of >41 kg was a secondary node with a score of 35% relative to the primary node. The area under the receiver operating characteristic curve for the CART model was an R(2) = 0.90 on posttest. In patients weighing >41 kg, sputum conversion was 3/3 (100%) in those with an amikacin Cmax of ≥67 mg/liter versus 3/15 (20%) in those with a Cmax of <67 mg/liter (relative risk [RR] = 5.00; 95% confidence interval [CI], 1.82 to 13.76). In all patients who had both amikacin Cmax and AUC0-24 below the threshold, 7/7 (100%) failed, compared to 7/15 (47%) of those who had these parameters above threshold (RR = 2.14; 95% CI, 1.25 to 43.68). These amikacin dose-schedule patterns and exposures are virtually the same as those identified in the hollow-fiber system model. PMID:27458224

  6. Artificial Intelligence and Amikacin Exposures Predictive of Outcomes in Multidrug-Resistant Tuberculosis Patients.

    PubMed

    Modongo, Chawangwa; Pasipanodya, Jotam G; Magazi, Beki T; Srivastava, Shashikant; Zetola, Nicola M; Williams, Scott M; Sirugo, Giorgio; Gumbo, Tawanda

    2016-10-01

    Aminoglycosides such as amikacin continue to be part of the backbone of treatment of multidrug-resistant tuberculosis (MDR-TB). We measured amikacin concentrations in 28 MDR-TB patients in Botswana receiving amikacin therapy together with oral levofloxacin, ethionamide, cycloserine, and pyrazinamide and calculated areas under the concentration-time curves from 0 to 24 h (AUC0-24). The patients were followed monthly for sputum culture conversion based on liquid cultures. The median duration of amikacin therapy was 184 (range, 28 to 866) days, at a median dose of 17.30 (range 11.11 to 19.23) mg/kg. Only 11 (39%) patients had sputum culture conversion during treatment; the rest failed. We utilized classification and regression tree analyses (CART) to examine all potential predictors of failure, including clinical and demographic features, comorbidities, and amikacin peak concentrations (Cmax), AUC0-24, and trough concentrations. The primary node for failure had two competing variables, Cmax of <67 mg/liter and AUC0-24 of <568.30 mg · h/L; weight of >41 kg was a secondary node with a score of 35% relative to the primary node. The area under the receiver operating characteristic curve for the CART model was an R(2) = 0.90 on posttest. In patients weighing >41 kg, sputum conversion was 3/3 (100%) in those with an amikacin Cmax of ≥67 mg/liter versus 3/15 (20%) in those with a Cmax of <67 mg/liter (relative risk [RR] = 5.00; 95% confidence interval [CI], 1.82 to 13.76). In all patients who had both amikacin Cmax and AUC0-24 below the threshold, 7/7 (100%) failed, compared to 7/15 (47%) of those who had these parameters above threshold (RR = 2.14; 95% CI, 1.25 to 43.68). These amikacin dose-schedule patterns and exposures are virtually the same as those identified in the hollow-fiber system model.

  7. Artificial Intelligence and Amikacin Exposures Predictive of Outcomes in Multidrug-Resistant Tuberculosis Patients

    PubMed Central

    Modongo, Chawangwa; Pasipanodya, Jotam G.; Magazi, Beki T.; Srivastava, Shashikant; Zetola, Nicola M.; Williams, Scott M.; Sirugo, Giorgio

    2016-01-01

    Aminoglycosides such as amikacin continue to be part of the backbone of treatment of multidrug-resistant tuberculosis (MDR-TB). We measured amikacin concentrations in 28 MDR-TB patients in Botswana receiving amikacin therapy together with oral levofloxacin, ethionamide, cycloserine, and pyrazinamide and calculated areas under the concentration-time curves from 0 to 24 h (AUC0–24). The patients were followed monthly for sputum culture conversion based on liquid cultures. The median duration of amikacin therapy was 184 (range, 28 to 866) days, at a median dose of 17.30 (range 11.11 to 19.23) mg/kg. Only 11 (39%) patients had sputum culture conversion during treatment; the rest failed. We utilized classification and regression tree analyses (CART) to examine all potential predictors of failure, including clinical and demographic features, comorbidities, and amikacin peak concentrations (Cmax), AUC0–24, and trough concentrations. The primary node for failure had two competing variables, Cmax of <67 mg/liter and AUC0–24 of <568.30 mg · h/L; weight of >41 kg was a secondary node with a score of 35% relative to the primary node. The area under the receiver operating characteristic curve for the CART model was an R2 = 0.90 on posttest. In patients weighing >41 kg, sputum conversion was 3/3 (100%) in those with an amikacin Cmax of ≥67 mg/liter versus 3/15 (20%) in those with a Cmax of <67 mg/liter (relative risk [RR] = 5.00; 95% confidence interval [CI], 1.82 to 13.76). In all patients who had both amikacin Cmax and AUC0–24 below the threshold, 7/7 (100%) failed, compared to 7/15 (47%) of those who had these parameters above threshold (RR = 2.14; 95% CI, 1.25 to 43.68). These amikacin dose-schedule patterns and exposures are virtually the same as those identified in the hollow-fiber system model. PMID:27458224

  8. Semi-analytical prediction of hydraulic resistance and heat transfer for pipe and channel flows of water at supercritical pressure

    SciTech Connect

    Laurien, E.

    2012-07-01

    Within the Generation IV International Forum the Supercritical Water Reactor is investigated. For its core design and safety analysis the efficient prediction of flow and heat transfer parameters such as the wall-shear stress and the heat-transfer coefficient for pipe and channel flows is needed. For circular pipe flows a numerical model based on the one-dimensional conservation equations of mass, momentum end energy in the radial direction is presented, referred to as a 'semi-analytical' method. An accurate, high-order numerical method is employed to evaluate previously derived analytical solutions of the governing equations. Flow turbulence is modeled using the algebraic approach of Prandtl/van-Karman, including a model for the buffer layer. The influence of wall roughness is taken into account by a new modified numerical damping function of the turbulence model. The thermo-hydraulic properties of water are implemented according to the international standard of 1997. This method has the potential to be used within a sub-channel analysis code and as wall-functions for CFD codes to predict the wall shear stress and the wall temperature. The present study presents a validation of the method with comparison of model results with experiments and multi-dimensional computational (CFD) studies in a wide range of flow parameters. The focus is laid on forced convection flows related to reactor design and near-design conditions. It is found, that the method can accurately predict the wall temperature even under deterioration conditions as they occur in the selected experiments (Yamagata el al. 1972 at 24.5 MPa, Ornatski et al. 1971 at 25.5 and Swenson et al. 1963 at 22.75 MPa). Comparison of the friction coefficient under high heat flux conditions including significant viscosity and density reductions near the wall with various correlations for the hydraulic resistance will be presented; the best agreement is achieve with the correlation of Pioro et al. 2004. It is

  9. Mathematical Modeling of Bacterial Kinetics to Predict the Impact of Antibiotic Colonic Exposure and Treatment Duration on the Amount of Resistant Enterobacteria Excreted

    PubMed Central

    Nguyen, Thu Thuy; Guedj, Jeremie; Chachaty, Elisabeth; de Gunzburg, Jean; Andremont, Antoine; Mentré, France

    2014-01-01

    Fecal excretion of antibiotics and resistant bacteria in the environment are major public health threats associated with extensive farming and modern medical care. Innovative strategies that can reduce the intestinal antibiotic concentrations during treatments are in development. However, the effect of lower exposure on the amount of resistant enterobacteria excreted has not been quantified, making it difficult to anticipate the impact of these strategies. Here, we introduce a bacterial kinetic model to capture the complex relationships between drug exposure, loss of susceptible enterobacteria and growth of resistant strains in the feces of piglets receiving placebo, 1.5 or 15 mg/kg/day ciprofloxacin, a fluoroquinolone, for 5 days. The model could well describe the kinetics of drug susceptible and resistant enterobacteria observed during treatment, and up to 22 days after treatment cessation. Next, the model was used to predict the expected amount of resistant enterobacteria excreted over an average piglet's lifetime (150 days) when varying drug exposure and treatment duration. For the clinically relevant dose of 15 mg/kg/day for 5 days, the total amount of resistant enterobacteria excreted was predicted to be reduced by 75% and 98% when reducing treatment duration to 3 and 1 day treatment, respectively. Alternatively, for a fixed 5-days treatment, the level of resistance excreted could be reduced by 18%, 33%, 57.5% and 97% if 3, 5, 10 and 30 times lower levels of colonic drug concentrations were achieved, respectively. This characterization on in vivo data of the dynamics of resistance to antibiotics in the colonic flora could provide new insights into the mechanism of dissemination of resistance and can be used to design strategies aiming to reduce it. PMID:25210849

  10. Development of a prediction rule for methicillin-resistant Staphylococcus aureus and vancomycin-resistant enterococcus carriage in a Veterans Affairs Medical Center population.

    PubMed

    Riedel, Stefan; Von Stein, Diana; Richardson, Kelly; Page, Joann; Miller, Sara; Winokur, Patricia; Diekema, Daniel

    2008-10-01

    A history of hospital admission in the prior year was the most sensitive predictor of methicillin-resistant Staphylococcus aureus or vancomycin-resistant Enterococcus colonization at admission to a Veterans Affairs Medical Center (VAMC) but missed more than one-third of carriers and required screening more than one-half of admitted patients. PMID:18702599

  11. Modeling the carbon cost of plant nitrogen acquisition: Mycorrhizal trade-offs and multipath resistance uptake improve predictions of retranslocation

    NASA Astrophysics Data System (ADS)

    Brzostek, Edward R.; Fisher, Joshua B.; Phillips, Richard P.

    2014-08-01

    Accurate projections of the future land carbon (C) sink by terrestrial biosphere models depend on how nutrient constraints on net primary production are represented. While nutrient limitation is nearly universal, current models do not have a C cost for plant nutrient acquisition. Also missing are symbiotic mycorrhizal fungi, which can consume up to 20% of net primary production and supply up to 50% of a plant's nitrogen (N) uptake. Here we integrate simultaneous uptake and mycorrhizae into a cutting-edge plant N model—Fixation and Uptake of Nitrogen (FUN)—that can be coupled into terrestrial biosphere models. The C cost of N acquisition varies as a function of mycorrhizal type, with plants that support arbuscular mycorrhizae benefiting when N is relatively abundant and plants that support ectomycorrhizae benefiting when N is strongly limiting. Across six temperate forested sites (representing arbuscular mycorrhizal- and ectomycorrhizal-dominated stands and 176 site years), including multipath resistance improved the partitioning of N uptake between aboveground and belowground sources. Integrating mycorrhizae led to further improvements in predictions of N uptake from soil (R2 = 0.69 increased to R2 = 0.96) and from senescing leaves (R2 = 0.29 increased to R2 = 0.73) relative to the original model. On average, 5% and 9% of net primary production in arbuscular mycorrhizal- and ectomycorrhizal-dominated forests, respectively, was needed to support mycorrhizal-mediated acquisition of N. To the extent that resource constraints to net primary production are governed by similar trade-offs across all terrestrial ecosystems, integrating these improvements to FUN into terrestrial biosphere models should enhance predictions of the future land C sink.

  12. Evaluation of genome-enabled selection for bacterial cold water disease resistance using progeny performance data in Rainbow Trout: Insights on genotyping methods and genomic prediction models

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Bacterial cold water disease (BCWD) causes significant economic losses in salmonid aquaculture, and traditional family-based breeding programs aimed at improving BCWD resistance have been limited to exploiting only between-family variation. We used genomic selection (GS) models to predict genomic br...

  13. Hairpin RNA-mediated silencing of Plum pox virus P1 and HC-Pro genes for efficient and predictable resistance to the virus.

    PubMed

    Di Nicola-Negri, Elisa; Brunetti, Angela; Tavazza, Mario; Ilardi, Vincenza

    2005-12-01

    We report the application of the hairpin-mediated RNA silencing technology for obtaining resistance to Plum pox virus (PPV) infection in Nicotiana benthamiana plants. Four sequences, covering the P1 and silencing suppressor HC-Pro genes of an Italian PPV M isolate, were introduced into N. benthamiana plants as two inverted repeats separated by an intron sequence under the transcriptional control of the Cauliflower Mosaic Virus 35S promoter. In a leaf disk infection assay, 38 out of 40 T0 transgenic plants were resistant to PPV infection. Eight lines, 2 for each construct, randomly selected among the 38 resistant plants were further analysed. Two hundred forty eight out of 253 T1 transgenic plants were resistant to local and systemic PPV infection. All transgenic single locus lines were completely resistant. These data indicate that the RNA silencing of PPV P1/HCPro sequences results in an efficient and predictable PPV resistance, which may be utilized in obtaining stone fruit plants resistant to the devastating Sharka disease.

  14. Time series analysis as a tool to predict the impact of antimicrobial restriction in antibiotic stewardship programs using the example of multidrug-resistant Pseudomonas aeruginosa.

    PubMed

    Willmann, Matthias; Marschal, Matthias; Hölzl, Florian; Schröppel, Klaus; Autenrieth, Ingo B; Peter, Silke

    2013-04-01

    The association between antimicrobial consumption and resistance in nonfermentative Gram-negative bacteria is well-known. Antimicrobial restriction, implemented in clinical routines by antibiotic stewardship programs (ASPs), is considered a means to reduce resistance rates. Whether and how antimicrobial restriction can accomplish this goal is still unknown though. This leads to an element of uncertainty when designing strategies for ASPs. From January 2002 until December 2011, an observational study was performed at the University Hospital Tübingen, Tübingen, Germany, to investigate the association between antimicrobial use and resistance rates in Pseudomonas aeruginosa. Transfer function models were used to determine such associations and to simulate antimicrobial restriction strategies. Various positive associations between antimicrobial consumption and resistance were observed in our setting. Surprisingly, impact estimations of different antimicrobial restriction strategies revealed relatively low intervention expenses to effectively attenuate the observed increase in resistance. For example, a simulated intervention of an annual 4% reduction in the use of meropenem over 3 years from 2009 until 2011 yielded a 62.5% attenuation (95% confidence interval, 15% to 110%) in the rising trend of multidrug-resistant Pseudomonas aeruginosa (three- and four-class-resistant P. aeruginosa [34MRGN-PA]). Time series analysis models derived from past data may be a tool to predict the outcome of antimicrobial restriction strategies, and could be used to design ASPs.

  15. Neck circumference as a new anthropometric indicator for prediction of insulin resistance and components of metabolic syndrome in adolescents: Brazilian Metabolic Syndrome Study

    PubMed Central

    da Silva, Cleliani de Cassia; Zambon, Mariana Porto; Vasques, Ana Carolina J.; Rodrigues, Ana Maria de B.; Camilo, Daniella Fernandes; Antonio, Maria Ângela R. de G. M.; Cassani, Roberta Soares L.; Geloneze, Bruno

    2014-01-01

    OBJECTIVE: To evaluate the correlation between neck circumference and insulin resistance and components of metabolic syndrome in adolescents with different adiposity levels and pubertal stages, as well as to determine the usefulness of neck circumference to predict insulin resistance in adolescents. METHODS: Cross-sectional study with 388 adolescents of both genders from ten to 19 years old. The adolescents underwent anthropometric and body composition assessment, including neck and waist circumferences, and biochemical evaluation. The pubertal stage was obtained by self-assessment, and the blood pressure, by auscultation. Insulin resistance was evaluated by the Homeostasis Model Assessment-Insulin Resistance. The correlation between two variables was evaluated by partial correlation coefficient adjusted for the percentage of body fat and pubertal stage. The performance of neck circumference to identify insulin resistance was tested by Receiver Operating Characteristic Curve. RESULTS: After the adjustment for percentage body fat and pubertal stage, neck circumference correlated with waist circumference, blood pressure, triglycerides and markers of insulin resistance in both genders. CONCLUSIONS: The results showed that the neck circumference is a useful tool for the detection of insulin resistance and changes in the indicators of metabolic syndrome in adolescents. The easiness of application and low cost of this measure may allow its use in Public Health services. PMID:25119754

  16. Predictive models of insulin resistance derived from simple morphometric and biochemical indices related to obesity and the metabolic syndrome in baboons

    PubMed Central

    Chavez, Alberto O; Gastaldelli, Amalia; Guardado-Mendoza, Rodolfo; Lopez-Alvarenga, Juan C; Leland, M Michelle; Tejero, M Elizabeth; Sorice, GianPio; Casiraghi, Francesca; Davalli, Alberto; Bastarrachea, Raúl A; Comuzzie, Anthony G; DeFronzo, Ralph A; Folli, Franco

    2009-01-01

    Background Non-human primates are valuable models for the study of insulin resistance and human obesity. In baboons, insulin sensitivity levels can be evaluated directly with the euglycemic clamp and is highly predicted by adiposity, metabolic markers of obesity and impaired glucose metabolism (i.e. percent body fat by DXA and HbA1c). However, a simple method to screen and identify obese insulin resistant baboons for inclusion in interventional studies is not available. Methods We studied a population of twenty baboons with the euglycemic clamp technique to characterize a population of obese nondiabetic, insulin resistant baboons, and used a multivariate linear regression analysis (adjusted for gender) to test different predictive models of insulin sensitivity (insulin-stimulated glucose uptake = Rd) using abdominal circumference and fasting plasma insulin. Alternatively, we tested in a separate baboon population (n = 159), a simpler model based on body weight and fasting plasma glucose to predict the whole-body insulin sensitivity (Rd/SSPI) derived from the clamp. Results In the first model, abdominal circumference explained 59% of total insulin mediated glucose uptake (Rd). A second model, which included fasting plasma insulin (log transformed) and abdominal circumference, explained 64% of Rd. Finally, the model using body weight and fasting plasma glucose explained 51% of Rd/SSPI. Interestingly, we found that percent body fat was directly correlated with the adipocyte insulin resistance index (r = 0.755, p < 0.0001). Conclusion In baboons, simple morphometric measurements of adiposity/obesity, (i.e. abdominal circumference), plus baseline markers of glucose/lipid metabolism, (i.e. fasting plasma glucose and insulin) provide a feasible method to screen and identify overweight/obese insulin resistant baboons for inclusion in interventional studies aimed to study human obesity, insulin resistance and type 2 diabetes mellitus. PMID:19389241

  17. Whole blood defensin mRNA expression is a predictive biomarker of docetaxel response in castration-resistant prostate cancer.

    PubMed

    Kohli, Manish; Young, Charles Yf; Tindall, Donald J; Nandy, Debashis; McKenzie, Kyle M; Bevan, Graham H; Donkena, Krishna Vanaja

    2015-01-01

    This study tested the potential of circulating RNA-based signals as predictive biomarkers for docetaxel response in patients with metastatic castration-resistant prostate cancer (CRPC). RNA was analyzed in blood from six CRPC patients by whole-transcriptome sequencing (total RNA-sequencing) before and after docetaxel treatment using the Illumina's HiSeq platform. Targeted RNA capture and sequencing was performed in an independent cohort of ten patients with CRPC matching the discovery cohort to confirm differential expression of the genes. Response to docetaxel was defined on the basis of prostate-specific antigen levels and imaging criteria. Two-way analysis of variance was used to compare differential gene expression in patients classified as responders versus nonresponders before and after docetaxel treatment. Thirty-four genes with two-fold differentially expressed transcripts in responders versus nonresponders were selected from total RNA-sequencing for further validation. Targeted RNA capture and sequencing showed that 13/34 genes were differentially expressed in responders. Alpha defensin genes DEFA1, DEFA1B, and DEFA3 exhibited significantly higher expression in responder patients compared with nonresponder patients before administration of chemotherapy (fold change >2.5). In addition, post-docetaxel treatment significantly increased transcript levels of these defensin genes in responders (fold change >2.8). Our results reveal that patients with higher defensin RNA transcripts in blood respond well to docetaxel therapy. We suggest that monitoring DEFA1, DEFA1B, and DEFA3 RNA transcripts in blood prior to treatment will be helpful to determine which patients are better candidates to receive docetaxel chemotherapy.

  18. [PK/PD Modeling as a Tool for Predicting Bacterial Resistance to Antibiotics: Alternative Analyses of Experimental Data].

    PubMed

    Golikova, M V; Strukova, E N; Portnoy, Y A; Firsov, A A

    2015-01-01

    Postexposure number of mutants (NM) is a conventional endpoint in bacterial resistance studies using in vitro dynamic models that simulate antibiotic pharmacokinetics. To compare NM with a recently introduced integral parameter AUBC(M), the area under the time course of resistance mutants, the enrichment of resistant Staphylococcus aureus was studied in vitro by simulation of mono(daptomycin, doxycycline) and combined treatments (daptomycin + rifampicin, rifampicin + linezolid). Differences in the time courses of resistant S. aureus could be reflected by AUBC(M) but not N(M). Moreover, unlike AUBC(M), N(M) did not reflect the pronounced differences in the time courses of S. aureus mutants resistant to 2x, 4x, 8x and 16xMIC of doxycycline and rifampicin. The findings suggested that AUBC(M) was a more appropriate endpoint of the amplification of resistant mutants than N(M).

  19. Measurement and prediction of the resistivity of ash/sorbent mixtures produced by sulfur oxide control processes. Final report, Sep 86-Jun 88

    SciTech Connect

    Young, R.P.

    1991-12-01

    The report describes the development of (1) a modified procedure for obtaining consistent and reproducible laboratory resistivity values for mixtures of coal fly ash and partially spent sorbent, and (2) an approach for predicting resistivity based on the chemical composition of the sample and the resistivities of the key compounds in the sample that are derived from the sorbent. Furnace and cold-side sorbent injection technologies for reducing the emission of sulfur oxides from electric generating plants firing medium- to high-sulfur coal are under development for retrofit applications. The particulate resulting from injecting this sorbent will be a mixture of coal fly ash and partially spent sorbent. The presence of this sorbent causes the resistivity of the mixture to be significantly higher than that of the fly ash alone. Since higher resistivity dusts are more difficult to collect in an electrostatic precipitator (ESP), accurate knowledge of the resistivity of the mixture is needed to determine if the ESP will operate within an acceptable efficiency range.

  20. MET Gene Amplification and MET Receptor Activation Are Not Sufficient to Predict Efficacy of Combined MET and EGFR Inhibitors in EGFR TKI-Resistant NSCLC Cells.

    PubMed

    Presutti, Dario; Santini, Simonetta; Cardinali, Beatrice; Papoff, Giuliana; Lalli, Cristiana; Samperna, Simone; Fustaino, Valentina; Giannini, Giuseppe; Ruberti, Giovina

    2015-01-01

    are not sufficient to predict a positive response of NSCLC cells to a cocktail of MET and EGFR inhibitors and highlights the importance of identifying more reliable biomarkers to predict the efficacy of treatments in NSCLC patients resistant to EGFR TKI. PMID:26580964

  1. MET Gene Amplification and MET Receptor Activation Are Not Sufficient to Predict Efficacy of Combined MET and EGFR Inhibitors in EGFR TKI-Resistant NSCLC Cells

    PubMed Central

    Presutti, Dario; Santini, Simonetta; Cardinali, Beatrice; Papoff, Giuliana; Lalli, Cristiana; Samperna, Simone; Fustaino, Valentina; Giannini, Giuseppe; Ruberti, Giovina

    2015-01-01

    are not sufficient to predict a positive response of NSCLC cells to a cocktail of MET and EGFR inhibitors and highlights the importance of identifying more reliable biomarkers to predict the efficacy of treatments in NSCLC patients resistant to EGFR TKI. PMID:26580964

  2. Predictive urinary biomarkers for steroid-resistant and steroid-sensitive focal segmental glomerulosclerosis using high resolution mass spectrometry and multivariate statistical analysis

    PubMed Central

    2014-01-01

    Background Focal segmental glomerulosclerosis (FSGS) is a glomerular scarring disease diagnosed mostly by kidney biopsy. Since there is currently no diagnostic test that can accurately predict steroid responsiveness in FSGS, prediction of the responsiveness of patients to steroid therapy with noninvasive means has become a critical issue. In the present study urinary proteomics was used as a noninvasive tool to discover potential predictive biomarkers. Methods Urinary proteome of 10 patients (n = 6 steroid-sensitive, n = 4 steroid-resistant) with biopsy proven FSGS was analyzed using nano-LC-MS/MS and supervised multivariate statistical analysis was performed. Results Twenty one proteins were identified as discriminating species among which apolipoprotein A-1 and Matrix-remodeling protein 8 had the most drastic fold changes being over- and underrepresented, respectively, in steroid sensitive compared to steroid resistant urine samples. Gene ontology enrichment analysis revealed acute inflammatory response as the dominant biological process. Conclusion The obtained results suggest a panel of predictive biomarkers for FSGS. Proteins involved in the inflammatory response are shown to be implicated in the responsiveness. As a tool for biomarker discovery, urinary proteomics is especially fruitful in the area of prediction of responsiveness to drugs. Further validation of these biomarkers is however needed. PMID:25182141

  3. Fouling resistance prediction using artificial neural network nonlinear auto-regressive with exogenous input model based on operating conditions and fluid properties correlations

    NASA Astrophysics Data System (ADS)

    Biyanto, Totok R.

    2016-06-01

    Fouling in a heat exchanger in Crude Preheat Train (CPT) refinery is an unsolved problem that reduces the plant efficiency, increases fuel consumption and CO2 emission. The fouling resistance behavior is very complex. It is difficult to develop a model using first principle equation to predict the fouling resistance due to different operating conditions and different crude blends. In this paper, Artificial Neural Networks (ANN) MultiLayer Perceptron (MLP) with input structure using Nonlinear Auto-Regressive with eXogenous (NARX) is utilized to build the fouling resistance model in shell and tube heat exchanger (STHX). The input data of the model are flow rates and temperatures of the streams of the heat exchanger, physical properties of product and crude blend data. This model serves as a predicting tool to optimize operating conditions and preventive maintenance of STHX. The results show that the model can capture the complexity of fouling characteristics in heat exchanger due to thermodynamic conditions and variations in crude oil properties (blends). It was found that the Root Mean Square Error (RMSE) are suitable to capture the nonlinearity and complexity of the STHX fouling resistance during phases of training and validation.

  4. Potential role of exosome-associated microRNA panels and in vivo environment to predict drug resistance for patients with multiple myeloma.

    PubMed

    Zhang, Li; Pan, Ling; Xiang, Bing; Zhu, Huanling; Wu, Yu; Chen, Meng; Guan, Pujun; Zou, Xingli; Valencia, C Alexander; Dong, Biao; Li, Jianjun; Xie, Liping; Ma, Hongbing; Wang, Fangfang; Dong, Tian; Shuai, Xiao; Niu, Ting; Liu, Ting

    2016-05-24

    Multiple myeloma (MM) is the second most common hematologic neoplasms and an appropriate in vivo environment for myeloma cells has potential implications for initiation, progression, and metastasis of MM. Exosomes, entities carrying microRNAs (miRNAs) to target locations, participate in the cross-talk between myeloma cells and nonmalignant components of the in vivo environment. This study disclosed the emerging roles of circulating exosome-associated miRNAs in drug resistance (DR) of MM. To this end, the medical records of consecutively hospitalized MM patients, who received novel agents-based therapies, were analyzed. Then, an optimized procedure was established for exosome isolation and exosomal RNA analysis. The exosome-associated miRNA expression patterns for predicting bortezomib (Bz) resistance of MM were further examined using a microarray. In total, 204 patients were enrolled with DR rates of 36.5%, 73.1% and 81.8% in the bortezomib (Bz), thalidomide and lenalidomide containing groups. The serum total light chain ratio ≥ 100, CRP ≥ 20 mg/L, and the second-line usage increased risks of acquired Bz-resistance. Among 68 cases having genetic tests, a high risk factor for predicting de novo DR was 1q21 amplification, which also correlated with lower levels of cholesterol and LDL-C. Moreover, nano-sized exosomes were isolated with significantly increasing internal RNAs and down-regulation of exosomal miR-16-5p, miR-15a-5p and miR-20a-5p, miR-17-5p was revealed in the patients resistant to Bz. The routine workup of MM hardly suggested a value for DR prediction. The circulating exosomes carrying miRNAs provided a window that permits a better understanding of the in vivo intercellular crosstalk in MM patients. PMID:27129167

  5. Evaluation of Genome-Enabled Selection for Bacterial Cold Water Disease Resistance Using Progeny Performance Data in Rainbow Trout: Insights on Genotyping Methods and Genomic Prediction Models

    PubMed Central

    Vallejo, Roger L.; Leeds, Timothy D.; Fragomeni, Breno O.; Gao, Guangtu; Hernandez, Alvaro G.; Misztal, Ignacy; Welch, Timothy J.; Wiens, Gregory D.; Palti, Yniv

    2016-01-01

    Bacterial cold water disease (BCWD) causes significant economic losses in salmonid aquaculture, and traditional family-based breeding programs aimed at improving BCWD resistance have been limited to exploiting only between-family variation. We used genomic selection (GS) models to predict genomic breeding values (GEBVs) for BCWD resistance in 10 families from the first generation of the NCCCWA BCWD resistance breeding line, compared the predictive ability (PA) of GEBVs to pedigree-based estimated breeding values (EBVs), and compared the impact of two SNP genotyping methods on the accuracy of GEBV predictions. The BCWD phenotypes survival days (DAYS) and survival status (STATUS) had been recorded in training fish (n = 583) subjected to experimental BCWD challenge. Training fish, and their full sibs without phenotypic data that were used as parents of the subsequent generation, were genotyped using two methods: restriction-site associated DNA (RAD) sequencing and the Rainbow Trout Axiom® 57 K SNP array (Chip). Animal-specific GEBVs were estimated using four GS models: BayesB, BayesC, single-step GBLUP (ssGBLUP), and weighted ssGBLUP (wssGBLUP). Family-specific EBVs were estimated using pedigree and phenotype data in the training fish only. The PA of EBVs and GEBVs was assessed by correlating mean progeny phenotype (MPP) with mid-parent EBV (family-specific) or GEBV (animal-specific). The best GEBV predictions were similar to EBV with PA values of 0.49 and 0.46 vs. 0.50 and 0.41 for DAYS and STATUS, respectively. Among the GEBV prediction methods, ssGBLUP consistently had the highest PA. The RAD genotyping platform had GEBVs with similar PA to those of GEBVs from the Chip platform. The PA of ssGBLUP and wssGBLUP methods was higher with the Chip, but for BayesB and BayesC methods it was higher with the RAD platform. The overall GEBV accuracy in this study was low to moderate, likely due to the small training sample used. This study explored the potential of GS for

  6. Evaluation of Genome-Enabled Selection for Bacterial Cold Water Disease Resistance Using Progeny Performance Data in Rainbow Trout: Insights on Genotyping Methods and Genomic Prediction Models.

    PubMed

    Vallejo, Roger L; Leeds, Timothy D; Fragomeni, Breno O; Gao, Guangtu; Hernandez, Alvaro G; Misztal, Ignacy; Welch, Timothy J; Wiens, Gregory D; Palti, Yniv

    2016-01-01

    Bacterial cold water disease (BCWD) causes significant economic losses in salmonid aquaculture, and traditional family-based breeding programs aimed at improving BCWD resistance have been limited to exploiting only between-family variation. We used genomic selection (GS) models to predict genomic breeding values (GEBVs) for BCWD resistance in 10 families from the first generation of the NCCCWA BCWD resistance breeding line, compared the predictive ability (PA) of GEBVs to pedigree-based estimated breeding values (EBVs), and compared the impact of two SNP genotyping methods on the accuracy of GEBV predictions. The BCWD phenotypes survival days (DAYS) and survival status (STATUS) had been recorded in training fish (n = 583) subjected to experimental BCWD challenge. Training fish, and their full sibs without phenotypic data that were used as parents of the subsequent generation, were genotyped using two methods: restriction-site associated DNA (RAD) sequencing and the Rainbow Trout Axiom® 57 K SNP array (Chip). Animal-specific GEBVs were estimated using four GS models: BayesB, BayesC, single-step GBLUP (ssGBLUP), and weighted ssGBLUP (wssGBLUP). Family-specific EBVs were estimated using pedigree and phenotype data in the training fish only. The PA of EBVs and GEBVs was assessed by correlating mean progeny phenotype (MPP) with mid-parent EBV (family-specific) or GEBV (animal-specific). The best GEBV predictions were similar to EBV with PA values of 0.49 and 0.46 vs. 0.50 and 0.41 for DAYS and STATUS, respectively. Among the GEBV prediction methods, ssGBLUP consistently had the highest PA. The RAD genotyping platform had GEBVs with similar PA to those of GEBVs from the Chip platform. The PA of ssGBLUP and wssGBLUP methods was higher with the Chip, but for BayesB and BayesC methods it was higher with the RAD platform. The overall GEBV accuracy in this study was low to moderate, likely due to the small training sample used. This study explored the potential of GS for

  7. Evaluation of Genome-Enabled Selection for Bacterial Cold Water Disease Resistance Using Progeny Performance Data in Rainbow Trout: Insights on Genotyping Methods and Genomic Prediction Models.

    PubMed

    Vallejo, Roger L; Leeds, Timothy D; Fragomeni, Breno O; Gao, Guangtu; Hernandez, Alvaro G; Misztal, Ignacy; Welch, Timothy J; Wiens, Gregory D; Palti, Yniv

    2016-01-01

    Bacterial cold water disease (BCWD) causes significant economic losses in salmonid aquaculture, and traditional family-based breeding programs aimed at improving BCWD resistance have been limited to exploiting only between-family variation. We used genomic selection (GS) models to predict genomic breeding values (GEBVs) for BCWD resistance in 10 families from the first generation of the NCCCWA BCWD resistance breeding line, compared the predictive ability (PA) of GEBVs to pedigree-based estimated breeding values (EBVs), and compared the impact of two SNP genotyping methods on the accuracy of GEBV predictions. The BCWD phenotypes survival days (DAYS) and survival status (STATUS) had been recorded in training fish (n = 583) subjected to experimental BCWD challenge. Training fish, and their full sibs without phenotypic data that were used as parents of the subsequent generation, were genotyped using two methods: restriction-site associated DNA (RAD) sequencing and the Rainbow Trout Axiom® 57 K SNP array (Chip). Animal-specific GEBVs were estimated using four GS models: BayesB, BayesC, single-step GBLUP (ssGBLUP), and weighted ssGBLUP (wssGBLUP). Family-specific EBVs were estimated using pedigree and phenotype data in the training fish only. The PA of EBVs and GEBVs was assessed by correlating mean progeny phenotype (MPP) with mid-parent EBV (family-specific) or GEBV (animal-specific). The best GEBV predictions were similar to EBV with PA values of 0.49 and 0.46 vs. 0.50 and 0.41 for DAYS and STATUS, respectively. Among the GEBV prediction methods, ssGBLUP consistently had the highest PA. The RAD genotyping platform had GEBVs with similar PA to those of GEBVs from the Chip platform. The PA of ssGBLUP and wssGBLUP methods was higher with the Chip, but for BayesB and BayesC methods it was higher with the RAD platform. The overall GEBV accuracy in this study was low to moderate, likely due to the small training sample used. This study explored the potential of GS for

  8. Predicting resistance to health education messages for cannabis use: the role of rebelliousness, autic mastery, health value and ethnicity.

    PubMed

    Boddington, Ellen L; McDermott, Mark R

    2013-02-01

    The prevalent use of cannabis by adolescents and young adults, combined with the common misconception that smoking cannabis is relatively harmless, warrants the exploration of factors influencing resistance to health education messages about cannabis use. This investigation did so within a Reversal Theory framework. One hundred and thirteen undergraduate students responded to an informative leaflet detailing the health effects of smoking cannabis. The most significant independent predictor of message resistance was frequency of cannabis use, followed by proactive rebelliousness, autic mastery, health value and ethnicity. These findings have implications for the development, design and targeting of cannabis health education programmes. PMID:22459759

  9. Insulin Resistance Predicts Retreatment Failure in an Efficacy Study of Peginterferon-α-2a and Ribavirin in HIV/HCV Co-infected Patients

    PubMed Central

    Vachon, Marie-Louise C.; Factor, Stephanie H.; Branch, Andrea D.; Fiel, Maria-Isabel; Rodriguez-Torres, Maribel; Bräu, Norbert; Sterling, Richard K.; Slim, Jihad; Talal, Andrew H.; Dieterich, Douglas T.; Sulkowski, Mark S.

    2010-01-01

    Background and Aims Few studies evaluated the efficacy of HCV re-treatment and the predictors of response in HIV/HCV co-infected patients. The role of insulin resistance as a predictor of response in this population is unknown. To evaluate safety and efficacy of pegylated interferon-α-2a and ribavirin in re-treatment of HIV/HCV co-infected patients, predictors of sustained virological response including insulin resistance, and the relationship between insulin resistance and liver histology. Methods This prospective, multi-centered study included HIV/HCV co-infected patients with prior interferon-based treatment failure. Patients received pegylated interferon-α-2a and ribavirin for 48 weeks. Serum HCV RNA was measured 24 weeks post treatment to assess sustained virological response. Insulin resistance was defined as HOMA-IR >2. Correlations between baseline insulin resistance and steatosis and/or cirrhosis were determined. Results Sustained virological response was achieved by 14/96 (15%) patients. Of those with HOMA-IR <2, 35% (6/17) achieved sustained virological response vs 14% (15/36) of those with HOMA-IR between 2–4 and 7% (3/41) of those with HOMA-IR >4 (p=0.01). In multivariable analysis, insulin resistance and log10 HCV RNA were negatively associated with sustained virological response [AOR 0.17; 95%CI 0.05–0.64, p=0.009, and AOR 0.36; 95%CI 0.14–0.93, p=0.04, respectively). Steatosis and cirrhosis correlated with insulin resistance (p=0.02 and 0.03, respectively) but neither independently predicted sustained virological response. Discontinuations due to severe adverse events occurred in 8% and 2 patients died of unrelated cause. Conclusions In HIV/HCV co-infected patients undergoing re-treatment, sustained virological response rate is low; those without insulin resistance are significantly more likely to achieve sustained virological response. PMID:20974502

  10. Concomitant inactivation of the p53- and pRB- functional pathways predicts resistance to DNA damaging drugs in breast cancer in vivo.

    PubMed

    Knappskog, Stian; Berge, Elisabet O; Chrisanthar, Ranjan; Geisler, Stephanie; Staalesen, Vidar; Leirvaag, Beryl; Yndestad, Synnøve; de Faveri, Elise; Karlsen, Bård O; Wedge, David C; Akslen, Lars A; Lilleng, Peer K; Løkkevik, Erik; Lundgren, Steinar; Østenstad, Bjørn; Risberg, Terje; Mjaaland, Ingvild; Aas, Turid; Lønning, Per E

    2015-10-01

    Chemoresistance is the main obstacle to cancer cure. Contrasting studies focusing on single gene mutations, we hypothesize chemoresistance to be due to inactivation of key pathways affecting cellular mechanisms such as apoptosis, senescence, or DNA repair. In support of this hypothesis, we have previously shown inactivation of either TP53 or its key activators CHK2 and ATM to predict resistance to DNA damaging drugs in breast cancer better than TP53 mutations alone. Further, we hypothesized that redundant pathway(s) may compensate for loss of p53-pathway signaling and that these are inactivated as well in resistant tumour cells. Here, we assessed genetic alterations of the retinoblastoma gene (RB1) and its key regulators: Cyclin D and E as well as their inhibitors p16 and p27. In an exploratory cohort of 69 patients selected from two prospective studies treated with either doxorubicin monotherapy or 5-FU and mitomycin for locally advanced breast cancers, we found defects in the pRB-pathway to be associated with therapy resistance (p-values ranging from 0.001 to 0.094, depending on the cut-off value applied to p27 expression levels). Although statistically weaker, we observed confirmatory associations in a validation cohort from another prospective study (n = 107 patients treated with neoadjuvant epirubicin monotherapy; p-values ranging from 7.0 × 10(-4) to 0.001 in the combined data sets). Importantly, inactivation of the p53-and the pRB-pathways in concert predicted resistance to therapy more strongly than each of the two pathways assessed individually (exploratory cohort: p-values ranging from 3.9 × 10(-6) to 7.5 × 10(-3) depending on cut-off values applied to ATM and p27 mRNA expression levels). Again, similar findings were confirmed in the validation cohort, with p-values ranging from 6.0 × 10(-7) to 6.5 × 10(-5) in the combined data sets. Our findings strongly indicate that concomitant inactivation of the p53- and pRB- pathways predict

  11. Performance and Verification of a Real-Time PCR Assay Targeting the gyrA Gene for Prediction of Ciprofloxacin Resistance in Neisseria gonorrhoeae

    PubMed Central

    Hemarajata, P.; Yang, S.; Soge, O. O.; Klausner, J. D.

    2016-01-01

    In the United States, 19.2% of Neisseria gonorrhoeae isolates are resistant to ciprofloxacin. We evaluated a real-time PCR assay to predict ciprofloxacin susceptibility using residual DNA from the Roche Cobas 4800 CT/NG assay. The results of the assay were 100% concordant with agar dilution susceptibility test results for 100 clinical isolates. Among 76 clinical urine and swab specimens positive for N. gonorrhoeae by the Cobas assay, 71% could be genotyped. The test took 1.5 h to perform, allowing the physician to receive results in time to make informed clinical decisions. PMID:26739156

  12. Performance and Verification of a Real-Time PCR Assay Targeting the gyrA Gene for Prediction of Ciprofloxacin Resistance in Neisseria gonorrhoeae.

    PubMed

    Hemarajata, P; Yang, S; Soge, O O; Humphries, R M; Klausner, J D

    2016-03-01

    In the United States, 19.2% of Neisseria gonorrhoeae isolates are resistant to ciprofloxacin. We evaluated a real-time PCR assay to predict ciprofloxacin susceptibility using residual DNA from the Roche Cobas 4800 CT/NG assay. The results of the assay were 100% concordant with agar dilution susceptibility test results for 100 clinical isolates. Among 76 clinical urine and swab specimens positive for N. gonorrhoeae by the Cobas assay, 71% could be genotyped. The test took 1.5 h to perform, allowing the physician to receive results in time to make informed clinical decisions. PMID:26739156

  13. Accumulation of ALDH1-positive cells after neoadjuvant chemotherapy predicts treatment resistance and prognosticates poor outcome in ovarian cancer

    PubMed Central

    Debald, Manuel; Rostamzadeh, Babak; Thiesler, Thore; Schröder, Lars; Barchet, Winfried; Abramian, Alina; Kaiser, Christina; Kristiansen, Glen; Kuhn, Walther; Kübler, Kirsten

    2015-01-01

    Although ovarian cancer is a highly chemosensitive disease, it is only infrequently cured. One of the major reasons lies in the presence of drug-resistant cancer stem-like cells, sufficient to fuel recurrence. We phenotyped cancer stem-like cells by flow cytometry and immunohistochemistry in 55 matched samples before and after taxane/platinum-based neoadjuvant chemotherapy. All used markers of stemness (ALDH1, CD24, CD117, CD133) isolated low frequencies of malignant cells. ALDH1 was the most valuable marker for tracking stemness in vivo. The enrichment of ALDH1 expression after treatment was associated with a poor response to chemotherapy, with platinum resistance and independently prognosticated unfavorable outcome. Our results suggest that increased ALDH1 expression after treatment identifies patients with aggressive tumor phenotypes. PMID:25999351

  14. Accumulation of ALDH1-positive cells after neoadjuvant chemotherapy predicts treatment resistance and prognosticates poor outcome in ovarian cancer.

    PubMed

    Ayub, Tiyasha H; Keyver-Paik, Mignon-Denise; Debald, Manuel; Rostamzadeh, Babak; Thiesler, Thore; Schröder, Lars; Barchet, Winfried; Abramian, Alina; Kaiser, Christina; Kristiansen, Glen; Kuhn, Walther; Kübler, Kirsten

    2015-06-30

    Although ovarian cancer is a highly chemosensitive disease, it is only infrequently cured. One of the major reasons lies in the presence of drug-resistant cancer stem-like cells, sufficient to fuel recurrence. We phenotyped cancer stem-like cells by flow cytometry and immunohistochemistry in 55 matched samples before and after taxane/platinum-based neoadjuvant chemotherapy. All used markers of stemness (ALDH1, CD24, CD117, CD133) isolated low frequencies of malignant cells. ALDH1 was the most valuable marker for tracking stemness in vivo. The enrichment of ALDH1 expression after treatment was associated with a poor response to chemotherapy, with platinum resistance and independently prognosticated unfavorable outcome. Our results suggest that increased ALDH1 expression after treatment identifies patients with aggressive tumor phenotypes. PMID:25999351

  15. Modeled velopharyngeal orifice area prediction during simulated stop consonant production in the presence of increased nasal airway resistance.

    PubMed

    Smith, B E; Maddox, C M; Kostinski, A B

    1985-07-01

    This project examined modeled velopharyngeal orifice area estimation under conditions simulating voiceless stop consonant production in the presence of nasal airway obstruction. The results indicated that accurate estimates of velopharyngeal orifice area can be obtained using Warren's hydrokinetic equation during aerodynamic events like those known to exist during speech in the presence of increased nasal airway resistance. These findings provide support for clinical and research use of Warren's pressure-flow approach to investigate velopharyngeal function during speech production.

  16. Modeled velopharyngeal orifice area prediction during simulated stop consonant production in the presence of increased nasal airway resistance.

    PubMed

    Smith, B E; Maddox, C M; Kostinski, A B

    1985-07-01

    This project examined modeled velopharyngeal orifice area estimation under conditions simulating voiceless stop consonant production in the presence of nasal airway obstruction. The results indicated that accurate estimates of velopharyngeal orifice area can be obtained using Warren's hydrokinetic equation during aerodynamic events like those known to exist during speech in the presence of increased nasal airway resistance. These findings provide support for clinical and research use of Warren's pressure-flow approach to investigate velopharyngeal function during speech production. PMID:3860307

  17. Mechanics based model for predicting structure-induced rolling resistance (SRR) of the tire-pavement system

    NASA Astrophysics Data System (ADS)

    Shakiba, Maryam; Ozer, Hasan; Ziyadi, Mojtaba; Al-Qadi, Imad L.

    2016-05-01

    The structure-induced rolling resistance of pavements, and its impact on vehicle fuel consumption, is investigated in this study. The structural response of pavement causes additional rolling resistance and fuel consumption of vehicles through deformation of pavement and various dissipation mechanisms associated with inelastic material properties and damping. Accurate and computationally efficient models are required to capture these mechanisms and obtain realistic estimates of changes in vehicle fuel consumption. Two mechanistic-based approaches are currently used to calculate vehicle fuel consumption as related to structural rolling resistance: dissipation-induced and deflection-induced methods. The deflection-induced approach is adopted in this study, and realistic representation of pavement-vehicle interactions (PVIs) is incorporated. In addition to considering viscoelastic behavior of asphalt concrete layers, the realistic representation of PVIs in this study includes non-uniform three-dimensional tire contact stresses and dynamic analysis in pavement simulations. The effects of analysis type, tire contact stresses, pavement viscoelastic properties, pavement damping coefficients, vehicle speed, and pavement temperature are then investigated.

  18. Strong n-type molecule as low bias negative differential resistance device predicted by first-principles study

    NASA Astrophysics Data System (ADS)

    Min, Y.; Zhong, C. G.; Dong, Z. C.; Zhao, Z. Y.; Zhou, P. X.; Yao, K. L.

    2016-10-01

    A first-principles study of the transport properties of two thiolated pentacenes sandwiching ethyl is performed. The thiolated pentacene molecule shows strong n-type characteristics when contact Ag lead because of low work function about metal Ag. A strong negative differential resistance (NDR) effect with large peak-to-valley ratio of 758% is present under low bias. Our investigations indicate that strong n- or p-type molecules can be used as low bias molecular NDR devices and that the molecular NDR effect based on molecular-level leaving not on molecular-level crossing has no hysteresis.

  19. Investigation of NS3 Protease Resistance-Associated Variants and Phenotypes for the Prediction of Treatment Response to HCV Triple Therapy

    PubMed Central

    Susser, Simone; Vermehren, Johannes; Peiffer, Kai-Henrik; Filmann, Natalie; Bon, Dimitra; Kuntzen, Thomas; Mauss, Stefan; Grammatikos, Georgios; Perner, Dany; Berkowski, Caterina; Herrmann, Eva; Zeuzem, Stefan; Bartenschlager, Ralf; Sarrazin, Christoph

    2016-01-01

    Triple therapy of chronic hepatitis C virus (HCV) infection with boceprevir (BOC) or telaprevir (TVR) leads to virologic failure in many patients which is often associated with the selection of resistance-associated variants (RAVs). These resistance profiles are of importance for the selection of potential rescue treatment options. In this study, we sequenced baseline NS3 RAVs population-based and investigated the sensitivity of NS3 phenotypes in an HCV replicon assay together with clinical factors for a prediction of treatment response in a cohort of 165 German and Swiss patients treated with a BOC or TVR-based triple therapy. Overall, the prevalence of baseline RAVs was low, although the frequency of RAVs was higher in patients with virologic failure compared to those who achieved a sustained virologic response (SVR) (7% versus 1%, P = 0.06). The occurrence of RAVs was associated with a resistant NS3 quasispecies phenotype (P<0.001), but the sensitivity of phenotypes was not associated with treatment outcome (P = 0.2). The majority of single viral and host predictors of SVR was only weakly associated with treatment response. In multivariate analyses, low AST levels, female sex and an IFNL4 CC genotype were independently associated with SVR. However, a combined analysis of negative predictors revealed a significantly lower overall number of negative predictors in patients with SVR in comparison to individuals with virologic failure (P<0.0001) and the presence of 2 or less negative predictors was indicative for SVR. These results demonstrate that most single baseline viral and host parameters have a weak influence on the response to triple therapy, whereas the overall number of negative predictors has a high predictive value for SVR. PMID:27281344

  20. Systematic Mutagenesis of Genes Encoding Predicted Autotransported Proteins of Burkholderia pseudomallei Identifies Factors Mediating Virulence in Mice, Net Intracellular Replication and a Novel Protein Conferring Serum Resistance

    PubMed Central

    Adler, Natalie R. Lazar; Stevens, Mark P.; Dean, Rachel E.; Saint, Richard J.; Pankhania, Depesh; Prior, Joann L.; Atkins, Timothy P.; Kessler, Bianca; Nithichanon, Arnone; Lertmemongkolchai, Ganjana; Galyov, Edouard E.

    2015-01-01

    Burkholderia pseudomallei is the causative agent of the severe tropical disease melioidosis, which commonly presents as sepsis. The B. pseudomallei K96243 genome encodes eleven predicted autotransporters, a diverse family of secreted and outer membrane proteins often associated with virulence. In a systematic study of these autotransporters, we constructed insertion mutants in each gene predicted to encode an autotransporter and assessed them for three pathogenesis-associated phenotypes: virulence in the BALB/c intra-peritoneal mouse melioidosis model, net intracellular replication in J774.2 murine macrophage-like cells and survival in 45% (v/v) normal human serum. From the complete repertoire of eleven autotransporter mutants, we identified eight mutants which exhibited an increase in median lethal dose of 1 to 2-log10 compared to the isogenic parent strain (bcaA, boaA, boaB, bpaA, bpaC, bpaE, bpaF and bimA). Four mutants, all demonstrating attenuation for virulence, exhibited reduced net intracellular replication in J774.2 macrophage-like cells (bimA, boaB, bpaC and bpaE). A single mutant (bpaC) was identified that exhibited significantly reduced serum survival compared to wild-type. The bpaC mutant, which demonstrated attenuation for virulence and net intracellular replication, was sensitive to complement-mediated killing via the classical and/or lectin pathway. Serum resistance was rescued by in trans complementation. Subsequently, we expressed recombinant proteins of the passenger domain of four predicted autotransporters representing each of the phenotypic groups identified: those attenuated for virulence (BcaA), those attenuated for virulence and net intracellular replication (BpaE), the BpaC mutant with defects in virulence, net intracellular replication and serum resistance and those displaying wild-type phenotypes (BatA). Only BcaA and BpaE elicited a strong IFN-γ response in a restimulation assay using whole blood from seropositive donors and were

  1. Systematic mutagenesis of genes encoding predicted autotransported proteins of Burkholderia pseudomallei identifies factors mediating virulence in mice, net intracellular replication and a novel protein conferring serum resistance.

    PubMed

    Lazar Adler, Natalie R; Stevens, Mark P; Dean, Rachel E; Saint, Richard J; Pankhania, Depesh; Prior, Joann L; Atkins, Timothy P; Kessler, Bianca; Nithichanon, Arnone; Lertmemongkolchai, Ganjana; Galyov, Edouard E

    2015-01-01

    Burkholderia pseudomallei is the causative agent of the severe tropical disease melioidosis, which commonly presents as sepsis. The B. pseudomallei K96243 genome encodes eleven predicted autotransporters, a diverse family of secreted and outer membrane proteins often associated with virulence. In a systematic study of these autotransporters, we constructed insertion mutants in each gene predicted to encode an autotransporter and assessed them for three pathogenesis-associated phenotypes: virulence in the BALB/c intra-peritoneal mouse melioidosis model, net intracellular replication in J774.2 murine macrophage-like cells and survival in 45% (v/v) normal human serum. From the complete repertoire of eleven autotransporter mutants, we identified eight mutants which exhibited an increase in median lethal dose of 1 to 2-log10 compared to the isogenic parent strain (bcaA, boaA, boaB, bpaA, bpaC, bpaE, bpaF and bimA). Four mutants, all demonstrating attenuation for virulence, exhibited reduced net intracellular replication in J774.2 macrophage-like cells (bimA, boaB, bpaC and bpaE). A single mutant (bpaC) was identified that exhibited significantly reduced serum survival compared to wild-type. The bpaC mutant, which demonstrated attenuation for virulence and net intracellular replication, was sensitive to complement-mediated killing via the classical and/or lectin pathway. Serum resistance was rescued by in trans complementation. Subsequently, we expressed recombinant proteins of the passenger domain of four predicted autotransporters representing each of the phenotypic groups identified: those attenuated for virulence (BcaA), those attenuated for virulence and net intracellular replication (BpaE), the BpaC mutant with defects in virulence, net intracellular replication and serum resistance and those displaying wild-type phenotypes (BatA). Only BcaA and BpaE elicited a strong IFN-γ response in a restimulation assay using whole blood from seropositive donors and were

  2. Graphing Predictions

    ERIC Educational Resources Information Center

    Connery, Keely Flynn

    2007-01-01

    Graphing predictions is especially important in classes where relationships between variables need to be explored and derived. In this article, the author describes how his students sketch the graphs of their predictions before they begin their investigations on two laboratory activities: Distance Versus Time Cart Race Lab and Resistance; and…

  3. Fall frost resistance in willows used for biomass production. II. Predictive relationships with sugar concentration and dry matter content.

    PubMed

    Ogren, Erling

    1999-09-01

    The accumulation of sugars and dry matter in stems in fall was examined in relation to frost hardening in eight willow clones (six clones of Salix viminalis L. and one clone each of S. viminalis x S. schwerenii E. Wolf and S. dasyclados Wimm.). Evidence is presented that three sources of variation in fall frost resistance among the eight clones could be assessed from an analysis of stem composition. First, the pre-hardening value of frost resistance could be assessed from the total sugar concentration. Second, the start of induction of apical growth cessation and hence frost hardening could be distinguished by a stepwise increase in sucrose-to-glucose ratio. Third, the progress of frost hardening during its first phase could be followed from a proportional rise in total sugar concentration and, even more accurately, from a proportional rise in dry-to-fresh weight ratio. In contrast, the second phase of frost hardening was largely uncoupled from sugar and dry matter accumulation. Raffinose and sucrose accumulation seemed to be under differential environmental controls. Sucrose accumulation started with the initiation of growth cessation controlled by photoperiod, whereas raffinose accumulation started with falling temperatures later on. Starch reserves that built up in stems in early fall were partially mobilized later on to support sugar accumulation. In contrast to stems, leaves did not exhibit a preferential accumulation of sucrose in fall. PMID:12651315

  4. Regulation of hypothalamic neuropeptides gene expression in diet induced obesity resistant rats: possible targets for obesity prediction?

    PubMed

    Cifani, Carlo; Micioni Di Bonaventura, Maria V; Pucci, Mariangela; Giusepponi, Maria E; Romano, Adele; Di Francesco, Andrea; Maccarrone, Mauro; D'Addario, Claudio

    2015-01-01

    Several factors play a role in obesity (i.e., behavior, environment, and genetics) and epigenetic regulation of gene expression has emerged as a potential contributor in the susceptibility and development of obesity. To investigate the individual sensitivity to weight gain/resistance, we here studied gene transcription regulation of several hypothalamic neuropeptides involved in the control of energy balance in rats developing obesity (diet-induced obesity, DIO) or not (diet resistant, DR), when fed with a high fat diet. Rats have been followed up to 21 weeks of high fat diet exposure. After 5 weeks high fat diet exposure, the obese phenotype was developed and we observed a selective down-regulation of the orexigenic neuropeptide Y (NPY) and peroxisome proliferator-activated receptor gamma (PPAR-γ) genes. No changes were observed in the expression of the agouti-related protein (AgRP), as well as for all the anorexigenic genes under study. After long-term high fat diet exposure (21 weeks), NPY and PPAR-γ, as well as most of the genes under study, resulted not be different between DIO and DR, whereas a lower expression of the anorexigenic pro-opio-melanocortin (POMC) gene was observed in DIO rats when compared to DR rats. Moreover we observed that changes in NPY and POMC mRNA were inversely correlated with gene promoters DNA methylation. Our findings suggest that selective alterations in hypothalamic peptide genes regulation could contribute to the development of overweight in rats and that environmental factor, as in this animal model, might be partially responsible of these changes via epigenetic mechanism.

  5. Regulation of hypothalamic neuropeptides gene expression in diet induced obesity resistant rats: possible targets for obesity prediction?

    PubMed Central

    Cifani, Carlo; Micioni Di Bonaventura, Maria V.; Pucci, Mariangela; Giusepponi, Maria E.; Romano, Adele; Di Francesco, Andrea; Maccarrone, Mauro; D'Addario, Claudio

    2015-01-01

    Several factors play a role in obesity (i.e., behavior, environment, and genetics) and epigenetic regulation of gene expression has emerged as a potential contributor in the susceptibility and development of obesity. To investigate the individual sensitivity to weight gain/resistance, we here studied gene transcription regulation of several hypothalamic neuropeptides involved in the control of energy balance in rats developing obesity (diet-induced obesity, DIO) or not (diet resistant, DR), when fed with a high fat diet. Rats have been followed up to 21 weeks of high fat diet exposure. After 5 weeks high fat diet exposure, the obese phenotype was developed and we observed a selective down-regulation of the orexigenic neuropeptide Y (NPY) and peroxisome proliferator-activated receptor gamma (PPAR-γ) genes. No changes were observed in the expression of the agouti-related protein (AgRP), as well as for all the anorexigenic genes under study. After long-term high fat diet exposure (21 weeks), NPY and PPAR-γ, as well as most of the genes under study, resulted not be different between DIO and DR, whereas a lower expression of the anorexigenic pro-opio-melanocortin (POMC) gene was observed in DIO rats when compared to DR rats. Moreover we observed that changes in NPY and POMC mRNA were inversely correlated with gene promoters DNA methylation. Our findings suggest that selective alterations in hypothalamic peptide genes regulation could contribute to the development of overweight in rats and that environmental factor, as in this animal model, might be partially responsible of these changes via epigenetic mechanism. PMID:26106286

  6. Predictability of childhood adiposity and insulin for developing insulin resistance syndrome (syndrome X) in young adulthood: the Bogalusa Heart Study.

    PubMed

    Srinivasan, Sathanur R; Myers, Leann; Berenson, Gerald S

    2002-01-01

    The occurrence of insulin resistance syndrome (syndrome X) is common in the general population. However, information is scant on the childhood predictors of syndrome X. This study examined the relative contribution of childhood adiposity and insulin to the adulthood risk of developing syndrome X in a biracial (black-white) community-based longitudinal cohort (n = 745; baseline age, 8-17 years; mean +/- SD follow-up period, 11.6 +/- 3.4 years). The four criterion risk variables considered were the highest quartile (specific for age, race, sex, and study year) of 1) BMI, 2) fasting insulin, 3) systolic or mean arterial blood pressure, and 4) total cholesterol to HDL cholesterol ratio or triglycerides to HDL cholesterol ratio. Clustering was defined as the combination of all four risk variables. In addition to the criterion risk variables, clustered adults had adverse levels of total cholesterol, triglycerides, LDL cholesterol, HDL cholesterol, diastolic blood pressure, and glucose compared with those who did not cluster (P < 0.001). Childhood variables, except glucose, showed adverse trends with increasing number of criterion risk variables present in adulthood (P for trend, 0.01-0.0001). The proportion of individuals who developed clustering as adults increased across childhood BMI (P for trend <0.0001) and insulin (P for trend <0.01) quartiles. The relationship to childhood BMI remained significant even after adjusting for childhood insulin. In contrast, corresponding association with childhood insulin disappeared after adjusting for childhood BMI. In a logistic regression model, childhood BMI and insulin were significant predictors of adulthood clustering, with BMI being the strongest and showing a curvilinear relationship. Using an insulin resistance index instead of insulin did not change the above findings. These results indicate that childhood obesity is a powerful predictor of development of syndrome X and underscore the importance of weight control early in

  7. Prediction of Fracture Initiation in Hot Compression of Burn-Resistant Ti-35V-15Cr-0.3Si-0.1C Alloy

    NASA Astrophysics Data System (ADS)

    Zhang, Saifei; Zeng, Weidong; Zhou, Dadi; Lai, Yunjin

    2015-11-01

    An important concern in hot working of metals is whether the desired deformation can be accomplished without fracture of the material. This paper builds a fracture prediction model to predict fracture initiation in hot compression of a burn-resistant beta-stabilized titanium alloy Ti-35V-15Cr-0.3Si-0.1C using a combined approach of upsetting experiments, theoretical failure criteria and finite element (FE) simulation techniques. A series of isothermal compression experiments on cylindrical specimens were conducted in temperature range of 900-1150 °C, strain rate of 0.01-10 s-1 first to obtain fracture samples and primary reduction data. Based on that, a comparison of eight commonly used theoretical failure criteria was made and Oh criterion was selected and coded into a subroutine. FE simulation of upsetting experiments on cylindrical specimens was then performed to determine the fracture threshold values of Oh criterion. By building a correlation between threshold values and the deforming parameters (temperature and strain rate, or Zener-Hollomon parameter), a new fracture prediction model based on Oh criterion was established. The new model shows an exponential decay relationship between threshold values and Zener-Hollomon parameter (Z), and the relative error of the model is less than 15%. This model was then applied successfully in the cogging of Ti-35V-15Cr-0.3Si-0.1C billet.

  8. Predictions of the emergence of vaccine-resistant hepatitis B in The Gambia using a mathematical model.

    PubMed Central

    Wilson, J. N.; Nokes, D. J.; Carman, W. F.

    2000-01-01

    Vaccine escape variants of hepatitis B virus (HBV) have been identified world-wide. A mathematical model of HBV transmission is used to investigate the potential pattern of emergence of such variants. Attention is focused on The Gambia as a country with high quality epidemiological data, universal infant immunization and in which escape mutants after childhood infections have been observed. We predict that a variant cannot become dominant for at least 20 years from the start of vaccination, even when using a vaccine which affords no cross protection. The dominant factor responsible for this long time scale is the low rate of infectious contacts between infected and susceptible individuals (we estimate the basic reproduction number of hepatitis B in The Gambia to be 1.7). A variant strain that achieves high prevalence will also take many years to control, and it is questionable whether emergence will be identifiable by sero-surveillance until of high prevalence. The sensitivity of the model predictions to epidemiological and demographic factors is explored. PMID:10813156

  9. Loss of B-cell translocation gene 2 expression in estrogen receptor-positive breast cancer predicts tamoxifen resistance

    PubMed Central

    Takahashi, Maiko; Hayashida, Tetsu; Okazaki, Hiroshi; Miyao, Kazuhiro; Jinno, Hiromitsu; Kitagawa, Yuko

    2014-01-01

    B-cell translocation gene 2 (BTG2), a gene suppressed in a subset of aggressive breast cancer, is repressed by estrogen. BTG2 inhibits the expression of HER ligands and promotes AKT activation, which plays an essential role in the tamoxifen resistance of estrogen receptor (ER)-positive breast cancer. To determine if BTG2 expression modifies tamoxifen efficacy, a cohort of 60 patients treated with adjuvant tamoxifen monotherapy was analyzed. We found that increased BTG2 expression showed better clinical survival and was the only independent prognostic factor for disease-free survival (hazard ratio, 0.691; 95% confidence interval, 0.495–0.963; P = 0.029). Tamoxifen suppressed the human epidermal growth factor receptor 2 (HER2)-Akt signaling in BTG2 expressing ER-positive breast cancer cells with a correlated increase in sensitivity, whereas BTG2 knockdown abrogated this sensitivity. Consistent with this observation, tamoxifen significantly suppressed the growth ratio, tumor weight and Ki-67 expression in BTG2 expressing breast cancer xenografts in mice. These studies demonstrate that BTG2 is a significant factor in tamoxifen response, acting through modification of AKT activation in ER-positive/HER2-negative breast cancer. PMID:24698107

  10. Testing and prediction of erosion-corrosion for corrosion resistant alloys used in the oil and gas production industry

    NASA Astrophysics Data System (ADS)

    Rincon, Hernan E.

    The corrosion behavior of CRAs has been thoroughly investigated and documented in the public literature by many researchers; however, little work has been done to investigate erosion-corrosion of such alloys. When sand particles are entrained in the flow, the degradation mechanism is different from that observed for sand-free corrosive environment. There is a need in the oil and gas industry to define safe service limits for utilization of such materials. The effects of flow conditions, sand rate, pH and temperature on the erosion-corrosion of CRAs were widely studied. An extensive experimental work was conducted using scratch tests and flow loop tests using several experimental techniques. At high erosivity conditions, a synergistic effect between erosion and corrosion was observed. Under the high sand rate conditions tested, erosivity is severe enough to damage the passive layer protecting the CRA thereby enhancing the corrosion rate. In most cases there is likely a competition between the rates of protective film removal due to mechanical erosion and protective film healing. Synergism occurs for each of the three alloys examined (13Cr and Super13Cr and 22Cr); however, the degree of synergism is quite different for the three alloys and may not be significant for 22Cr for field conditions where erosivities are typically much lower that those occurring in the small bore loop used in this research. Predictions of the corrosion component of erosion-corrosion based on scratch test data compared reasonably well to test results from flow loops for the three CRAs at high erosivity conditions. Second order behavior appears to be an appropriate and useful model for representing the repassivation process of CRAs. A framework for a procedure to predict penetration rates for erosion-corrosion conditions was developed based on the second order model behavior observed for the re-healing process of the passive film of CRAs and on computational fluid dynamics (CFD) simulations

  11. [PI3K-AKT-mTOR pathway: Description, therapeutic development, resistance, predictive/prognostic biomarkers and therapeutic applications for cancer].

    PubMed

    Brotelle, Thibault; Bay, Jacques-Olivier

    2016-01-01

    Among many cancer cells signaling pathways, PI3K-AKT-mTOR plays a major role in growth, proliferation and cellular survival. This is a complex pathway activated either by an extracellular way (receptors with tyrosine kinase activity) or by an intracellular way with transformed or overexpressed proteins involved in the signal transduction. To date, there are many applications of mTOR inhibitors in oncology with an expanding development rapidly. However, resistances appear to mTOR inhibitors which lead to 2nd generation mTOR inhibitors development. A better knowledge of predictive and prognostic biomarkers will allow to specify the group of patients who may benefit from these treatments and help to the choice. PMID:26582734

  12. Methicillin-resistant Staphylococcus aureus (MRSA) nasal real-time PCR: a predictive tool for contamination of the hospital environment.

    PubMed

    Livorsi, Daniel J; Livorsi, David J; Arif, Sana; Garry, Patricia; Kundu, Madan G; Satola, Sarah W; Davis, Thomas H; Batteiger, Byron; Kressel, Amy B

    2015-01-01

    OBJECTIVE We sought to determine whether the bacterial burden in the nares, as determined by the cycle threshold (CT) value from real-time MRSA PCR, is predictive of environmental contamination with MRSA. METHODS Patients identified as MRSA nasal carriers per hospital protocol were enrolled within 72 hours of room admission. Patients were excluded if (1) nasal mupirocin or chlorhexidine body wash was used within the past month or (2) an active MRSA infection was suspected. Four environmental sites, 6 body sites and a wound, if present, were cultured with premoistened swabs. All nasal swabs were submitted for both a quantitative culture and real-time PCR (Roche Lightcycler, Indianapolis, IN). RESULTS At study enrollment, 82 patients had a positive MRSA-PCR. A negative correlation of moderate strength was observed between the CT value and the number of MRSA colonies in the nares (r=-0.61; P<0.01). Current antibiotic use was associated with lower levels of MRSA nasal colonization (CT value, 30.2 vs 27.7; P<0.01). Patients with concomitant environmental contamination had a higher median log MRSA nares count (3.9 vs 2.5, P=0.01) and lower CT values (28.0 vs 30.2; P<0.01). However, a ROC curve was unable to identify a threshold MRSA nares count that reliably excluded environmental contamination. CONCLUSIONS Patients with a higher burden of MRSA in their nares, based on the CT value, were more likely to contaminate their environment with MRSA. However, contamination of the environment cannot be predicted solely by the degree of MRSA nasal colonization.

  13. Immobility time during the forced swimming test predicts sensitivity to amitriptyline, whereas traveled distance in the circular corridor indicates resistance to treatment in female Wistar rats.

    PubMed

    Flores-Serrano, Ana G; Zaldívar-Rae, Jaime; Salgado, Humberto; Pineda, Juan C

    2015-03-25

    Among the main issues in the pharmacological treatment of depression are the wide variation in response to antidepressants among individual patients and the lack of indexes that allow prediction of which drug will be effective in a particular case. We evaluated whether differential sensitivity to amitriptyline is related to dichotomous categorization of individuals on the basis of their behavioral responses to two common paradigms used to evaluate the potential of tricyclic drugs as antidepressants. Hence, we categorized a cohort of 38 female rats on the basis of their immobility time in the conditioning phase of the forced swimming test [FST; high immobility (HI) vs. low immobility (LI) rats] and their locomotor behavior in the circular corridor test [high locomotor response (HR) vs. low locomotor response (LR) rats]. We subjected the rodents to the FST while under the influence of vehicle (n=20) or amitriptyline (15 mg/kg; n=18). We found no statistical evidence of dependence between categorizations of rats on the basis of their behavior in the FST and circular corridor test. Rats categorized as HI/LI and HR/LR significantly differed in their sensitivity/resistance to amitriptyline, as evidenced by changes (or lack thereof) in their immobility time, climbing time, and swimming time during the FST. These results confirm that different behavioral styles among rats are linked to differential sensitivity/resistance to antidepressants. However, we specifically found that categorizing rats as HI/LI better reflected sensitivity to amitriptyline, whereas categorizing them as HR/LR better revealed resistance to the drug. These differential responses should be considered in experimental approaches. PMID:25646581

  14. Predictive model for the reduction of heat resistance of Listeria monocytogenes in ground beef by the combined effect of sodium chloride and apple polyphenols.

    PubMed

    Juneja, Vijay K; Altuntaş, Evrim Güneş; Ayhan, Kamuran; Hwang, Cheng-An; Sheen, Shiowshuh; Friedman, Mendel

    2013-06-01

    We investigated the combined effect of three internal temperatures (57.5, 60, and 62.5°C) and different concentrations (0 to 3.0 wt/wt.%) of sodium chloride (NaCl) and apple polyphenols (APP), individually and in combination, on the heat-resistance of a five-strain cocktail of Listeria monocytogenes in ground beef. A complete factorial design (3×4×4) was used to assess the effects and interactions of heating temperature, NaCl, and APP. All 48 combinations were tested twice, to yield 96 survival curves. Mathematical models were then used to quantitate the combined effect of these parameters on heat resistance of the pathogen. The theoretical analysis shows that compared with heat alone, the addition of NaCl enhanced and that of APP reduced the heat resistance of L. monocytogenes measured as D-values. By contrast, the protective effect of NaCl against thermal inactivation of the pathogen was reduced when both additives were present in combination, as evidenced by reduction of up to ~68% in D-values at 57.5°C; 65% at 60°C; and 25% at 62.5°C. The observed high antimicrobial activity of the combination of APP and low salt levels (e.g., 2.5% APP and 0.5% salt) suggests that commercial and home processors of meat could reduce the salt concentration by adding APP to the ground meat. The influence of the combined effect allows a reduction of the temperature of heat treatments as well as the salt content of the meat. Meat processors can use the predictive model to design processing times and temperatures that can protect against adverse effects of contaminated meat products. Additional benefits include reduced energy use in cooking, and the addition of antioxidative apple polyphenols may provide beneficial health affects to consumers. PMID:23587714

  15. Predictive model for the reduction of heat resistance of Listeria monocytogenes in ground beef by the combined effect of sodium chloride and apple polyphenols.

    PubMed

    Juneja, Vijay K; Altuntaş, Evrim Güneş; Ayhan, Kamuran; Hwang, Cheng-An; Sheen, Shiowshuh; Friedman, Mendel

    2013-06-01

    We investigated the combined effect of three internal temperatures (57.5, 60, and 62.5°C) and different concentrations (0 to 3.0 wt/wt.%) of sodium chloride (NaCl) and apple polyphenols (APP), individually and in combination, on the heat-resistance of a five-strain cocktail of Listeria monocytogenes in ground beef. A complete factorial design (3×4×4) was used to assess the effects and interactions of heating temperature, NaCl, and APP. All 48 combinations were tested twice, to yield 96 survival curves. Mathematical models were then used to quantitate the combined effect of these parameters on heat resistance of the pathogen. The theoretical analysis shows that compared with heat alone, the addition of NaCl enhanced and that of APP reduced the heat resistance of L. monocytogenes measured as D-values. By contrast, the protective effect of NaCl against thermal inactivation of the pathogen was reduced when both additives were present in combination, as evidenced by reduction of up to ~68% in D-values at 57.5°C; 65% at 60°C; and 25% at 62.5°C. The observed high antimicrobial activity of the combination of APP and low salt levels (e.g., 2.5% APP and 0.5% salt) suggests that commercial and home processors of meat could reduce the salt concentration by adding APP to the ground meat. The influence of the combined effect allows a reduction of the temperature of heat treatments as well as the salt content of the meat. Meat processors can use the predictive model to design processing times and temperatures that can protect against adverse effects of contaminated meat products. Additional benefits include reduced energy use in cooking, and the addition of antioxidative apple polyphenols may provide beneficial health affects to consumers.

  16. Immobility time during the forced swimming test predicts sensitivity to amitriptyline, whereas traveled distance in the circular corridor indicates resistance to treatment in female Wistar rats.

    PubMed

    Flores-Serrano, Ana G; Zaldívar-Rae, Jaime; Salgado, Humberto; Pineda, Juan C

    2015-03-25

    Among the main issues in the pharmacological treatment of depression are the wide variation in response to antidepressants among individual patients and the lack of indexes that allow prediction of which drug will be effective in a particular case. We evaluated whether differential sensitivity to amitriptyline is related to dichotomous categorization of individuals on the basis of their behavioral responses to two common paradigms used to evaluate the potential of tricyclic drugs as antidepressants. Hence, we categorized a cohort of 38 female rats on the basis of their immobility time in the conditioning phase of the forced swimming test [FST; high immobility (HI) vs. low immobility (LI) rats] and their locomotor behavior in the circular corridor test [high locomotor response (HR) vs. low locomotor response (LR) rats]. We subjected the rodents to the FST while under the influence of vehicle (n=20) or amitriptyline (15 mg/kg; n=18). We found no statistical evidence of dependence between categorizations of rats on the basis of their behavior in the FST and circular corridor test. Rats categorized as HI/LI and HR/LR significantly differed in their sensitivity/resistance to amitriptyline, as evidenced by changes (or lack thereof) in their immobility time, climbing time, and swimming time during the FST. These results confirm that different behavioral styles among rats are linked to differential sensitivity/resistance to antidepressants. However, we specifically found that categorizing rats as HI/LI better reflected sensitivity to amitriptyline, whereas categorizing them as HR/LR better revealed resistance to the drug. These differential responses should be considered in experimental approaches.

  17. Risk factors for methicillin-resistant Staphylococcus aureus colonisation or infection in intensive care units and their reliability for predicting MRSA on ICU admission.

    PubMed

    Callejo-Torre, Fernando; Eiros Bouza, Jose Maria; Olaechea Astigarraga, Pedro; Coma Del Corral, Maria Jesus; Palomar Martínez, Mercedes; Alvarez-Lerma, Francisco; López-Pueyo, Maria Jesús

    2016-09-01

    Predicting methicillin-resistant Staphylococcus aureus (MRSA) in intensive care units (ICUs) avoids inappropriate antimicrobial empirical treatment and enhances infection control. We describe risk factors for colonisation/infection related to MRSA (MRSA-C/I) in critically ill patients once in the ICU and on ICU admission, and search for an easy-to-use predictive model for MRSA colonisation/infection on ICU admission. This multicentre cohort study included 69,894 patients admitted consecutively (stay>24h) in April-June in the five-year period 2006-2010 from 147 Spanish ICUs participating in the National Surveillance Study of Nosocomial Infections in ICUs (ENVIN-HELICS). Data from all patients included were used to identify risk factors for MRSA-C/I during ICU stays, from admission to discharge, using uni- and multivariable analysis (Poisson regression) to check that the sample to be used to develop the predictive models was representative of standard critical care population. To identify risk factors for MRSA-C/I on ICU admission and to develop prediction models, multivariable logistic regression analysis were then performed only on those admitted in 2010 (n=16950, 2/3 for analysis and 1/3 for subsequent validation). We found that, in the period 2006-2010, 1046 patients were MRSA-C/I. Independent risk factors for MRSA-C/I in ICU were: age>65, trauma or medical patient, high APACHE-II score, admitted from a long-term care facility, urinary catheter, previous antibiotic treatment and skin-soft tissue or post-surgical superficial skin infections. Colonisation with several different MDRs significantly increased the risk of MRSA-C/I. Risk factors on ICU admission were: male gender, trauma critical patient, urgent surgery, admitted from other ICUs, hospital ward or long-term facility, immunosuppression and skin-soft tissue infection. Although the best model to identify carriers of MRSA had a good discrimination (AUC-ROC, 0.77; 95% CI, 0.72-0.82), sensitivity was 67% and

  18. Early Prediction of Therapy Response to Abiraterone Acetate Using PSA Subforms in Patients with Castration Resistant Prostate Cancer

    PubMed Central

    Schlack, Katrin; Krabbe, Laura-Maria; Fobker, Manfred; Schrader, Andres Jan; Semjonow, Axel; Boegemann, Martin

    2016-01-01

    The purpose of this study was to evaluate the prognostic ability of early changes of total prostate specific antigen (tPSA), free PSA (fPSA), [−2]proPSA and the Prostate Health Index (PHI) following initiation of Abiraterone-therapy in men with castration resistant prostate cancer (mCRPC). In 25 patients, PSA-subforms were analyzed before and at 8–12 weeks under therapy as prognosticators of progression-free-survival (PFS) and overall survival (OS). Comparing patients with a PFS < vs. ≥12 months by using Mann–Whitney–Wilcoxon Tests, the relative-median-change of tPSA (−0.1% vs. −86.8%; p = 0.02), fPSA (12.1% vs. −55.3%; p = 0.03) and [−2]proPSA (8.1% vs. −59.3%; p = 0.05) differed significantly. For men with ≤ vs. >15 months of OS there was a non-significant trend for a difference in the relative-median-change of fPSA (17.0% vs. −46.3%; p = 0.06). In Kaplan–Meier analyses, declining fPSA and [−2]proPSA were associated with a longer median PFS (13 months, 95% confidence interval (CI): 9.6–16.4 vs. 10 months, 95% CI: 3.5–16.5; p = 0.11), respectively. Correspondingly, decreasing fPSA and [−2]proPSA values indicated an OS of 32 months (95% CI: not reached (NR)) compared to 21 months in men with rising values (95% CI: 7.7–34.3; p = 0.14), respectively. We concluded that the addition of fPSA- and [−2]proPSA-changes to tPSA-information might be further studied as potential markers of early Abiraterone response in mCRPC patients. PMID:27618028

  19. Early Prediction of Therapy Response to Abiraterone Acetate Using PSA Subforms in Patients with Castration Resistant Prostate Cancer.

    PubMed

    Schlack, Katrin; Krabbe, Laura-Maria; Fobker, Manfred; Schrader, Andres Jan; Semjonow, Axel; Boegemann, Martin

    2016-01-01

    The purpose of this study was to evaluate the prognostic ability of early changes of total prostate specific antigen (tPSA), free PSA (fPSA), [-2]proPSA and the Prostate Health Index (PHI) following initiation of Abiraterone-therapy in men with castration resistant prostate cancer (mCRPC). In 25 patients, PSA-subforms were analyzed before and at 8-12 weeks under therapy as prognosticators of progression-free-survival (PFS) and overall survival (OS). Comparing patients with a PFS < vs. ≥12 months by using Mann-Whitney-Wilcoxon Tests, the relative-median-change of tPSA (-0.1% vs. -86.8%; p = 0.02), fPSA (12.1% vs. -55.3%; p = 0.03) and [-2]proPSA (8.1% vs. -59.3%; p = 0.05) differed significantly. For men with ≤ vs. >15 months of OS there was a non-significant trend for a difference in the relative-median-change of fPSA (17.0% vs. -46.3%; p = 0.06). In Kaplan-Meier analyses, declining fPSA and [-2]proPSA were associated with a longer median PFS (13 months, 95% confidence interval (CI): 9.6-16.4 vs. 10 months, 95% CI: 3.5-16.5; p = 0.11), respectively. Correspondingly, decreasing fPSA and [-2]proPSA values indicated an OS of 32 months (95% CI: not reached (NR)) compared to 21 months in men with rising values (95% CI: 7.7-34.3; p = 0.14), respectively. We concluded that the addition of fPSA- and [-2]proPSA-changes to tPSA-information might be further studied as potential markers of early Abiraterone response in mCRPC patients. PMID:27618028

  20. Prediction of the Evolution of Ceftazidime Resistance in Extended-Spectrum β-Lactamase CTX-M-9

    PubMed Central

    Delmas, J.; Robin, F.; Carvalho, F.; Mongaret, C.; Bonnet, R.

    2006-01-01

    A random mutagenesis technique was used to predict the evolutionary potential of β-lactamase CTX-M-9 toward the acquisition of improved catalytic activity against ceftazidime. Thirty CTX-M mutants were obtained during three rounds of mutagenesis. These mutants conferred 1- to 128-fold-higher MICs of ceftazidime than the parental enzyme CTX-M-9. The CTX-M mutants contained one to six amino acid substitutions. Mutants harbored the substitutions Asp240Gly and Pro167Ser, which were previously observed in clinical CTX-M enzymes. Additional substitutions, notably Arg164His, Asp179Gly, and Arg276Ser, were observed near the active site. The kinetic constants of the three most active mutants revealed two distinct ways of improving catalytic efficiency against ceftazidime. One enzyme had a 17-fold-higher kcat value than CTX-M-9 against ceftazidime. The other two had 75- to 300-fold-lower Km values than CTX-M-9 against ceftazidime. The current emergence of CTX-M β-lactamases with improved activity against ceftazidime may therefore be the beginning of an evolutionary process which might subsequently generate a great diversity of CTX-M-type ceftazidimases. PMID:16436733

  1. Predictive Factors of Lapatinib and Capecitabine Activity in Patients with HER2-Positive, Trastuzumab-Resistant Metastatic Breast Cancer: Results from the Italian Retrospective Multicenter HERLAPAC Study

    PubMed Central

    Gori, Stefania; Inno, Alessandro; Rossi, Valentina; Turazza, Monica; Fiorio, Elena; Fabi, Alessandra; Bisagni, Giancarlo; Foglietta, Jennifer; Santini, Daniele; Pavese, Ida; Pellegrino, Arianna; Zambelli, Alberto; Vici, Patrizia; Leonardi, Vita; Barni, Sandro; Saracchini, Silvana; Bogina, Giuseppe; Marchetti, Fabiana; Duranti, Simona; Lunardi, Gianluigi; Montemurro, Filippo

    2016-01-01

    Background There are no validated predictive markers for lapatinib and capecitabine in patients with trastuzumab-resistant HER2 positive metastatic breast cancer. Methods Data of 148 consecutive patients treated with lapatinib and capecitabine from March 2007 to December 2013 were collected from 13 Italian institutions. Estimates of progression-free survival (PFS) and overall survival (OS) were obtained with the Kaplan-Meier method and compared with logrank test. The association of clinicopathological variables and the outcome was studied by binary logistic regression analysis and Cox proportional hazard analysis. Results At a median follow-up of 41 months, median PFS and OS were 7 and 21 months, respectively. Patents with a PFS longer than 7 months had a significantly longer OS, compared with patients with a PFS equal to or shorter than 7 months (36 vs 15 months; p<0.001). Multivariate analysis revealed the benefit of lapatinib-based therapy in terms of PFS and OS was significantly associated with time-to-progression (TTP) on prior first-line trastuzumab-based therapy. In particular, each additional month on first-line trastuzumab based therapy was associated with a reduction in hazard of progression and death after the initiation of lapatinib-based therapy of 2% and 4%, respectively. Conclusions A longer TTP to first line trastuzumab seems to predict a prolonged PFS and OS with subsequent lapatinib and capecitabine. PMID:27224517

  2. Association genetics of oleoresin flow in loblolly pine: discovering genes and predicting phenotype for improved resistance to bark beetles and bioenergy potential.

    PubMed

    Westbrook, Jared W; Resende, Marcio F R; Munoz, Patricio; Walker, Alejandro R; Wegrzyn, Jill L; Nelson, C Dana; Neale, David B; Kirst, Matias; Huber, Dudley A; Gezan, Salvador A; Peter, Gary F; Davis, John M

    2013-07-01

    Rapidly enhancing oleoresin production in conifer stems through genomic selection and genetic engineering may increase resistance to bark beetles and terpenoid yield for liquid biofuels. We integrated association genetic and genomic prediction analyses of oleoresin flow (g 24 h(-1)) using 4854 single nucleotide polymorphisms (SNPs) in expressed genes within a pedigreed population of loblolly pine (Pinus taeda) that was clonally replicated at three sites in the southeastern United States. Additive genetic variation in oleoresin flow (h(2) ≈ 0.12-0.30) was strongly correlated between years in which precipitation varied (r(a) ≈ 0.95), while the genetic correlation between sites declined from 0.8 to 0.37 with increasing differences in soil and climate among sites. A total of 231 SNPs were significantly associated with oleoresin flow, of which 81% were specific to individual sites. SNPs in sequences similar to ethylene signaling proteins, ABC transporters, and diterpenoid hydroxylases were associated with oleoresin flow across sites. Despite this complex genetic architecture, we developed a genomic prediction model to accelerate breeding for enhanced oleoresin flow that is robust to environmental variation. Results imply that breeding could increase oleoresin flow 1.5- to 2.4-fold in one generation.

  3. The VACS Index Accurately Predicts Mortality and Treatment Response among Multi-Drug Resistant HIV Infected Patients Participating in the Options in Management with Antiretrovirals (OPTIMA) Study

    PubMed Central

    Brown, Sheldon T.; Tate, Janet P.; Kyriakides, Tassos C.; Kirkwood, Katherine A.; Holodniy, Mark; Goulet, Joseph L.; Angus, Brian J.; Cameron, D. William; Justice, Amy C.

    2014-01-01

    Objectives The VACS Index is highly predictive of all-cause mortality among HIV infected individuals within the first few years of combination antiretroviral therapy (cART). However, its accuracy among highly treatment experienced individuals and its responsiveness to treatment interventions have yet to be evaluated. We compared the accuracy and responsiveness of the VACS Index with a Restricted Index of age and traditional HIV biomarkers among patients enrolled in the OPTIMA study. Methods Using data from 324/339 (96%) patients in OPTIMA, we evaluated associations between indices and mortality using Kaplan-Meier estimates, proportional hazards models, Harrel’s C-statistic and net reclassification improvement (NRI). We also determined the association between study interventions and risk scores over time, and change in score and mortality. Results Both the Restricted Index (c = 0.70) and VACS Index (c = 0.74) predicted mortality from baseline, but discrimination was improved with the VACS Index (NRI = 23%). Change in score from baseline to 48 weeks was more strongly associated with survival for the VACS Index than the Restricted Index with respective hazard ratios of 0.26 (95% CI 0.14–0.49) and 0.39(95% CI 0.22–0.70) among the 25% most improved scores, and 2.08 (95% CI 1.27–3.38) and 1.51 (95%CI 0.90–2.53) for the 25% least improved scores. Conclusions The VACS Index predicts all-cause mortality more accurately among multi-drug resistant, treatment experienced individuals and is more responsive to changes in risk associated with treatment intervention than an index restricted to age and HIV biomarkers. The VACS Index holds promise as an intermediate outcome for intervention research. PMID:24667813

  4. Toward Predicting Drug-Induced Liver Injury: Parallel Computational Approaches to Identify Multidrug Resistance Protein 4 and Bile Salt Export Pump Inhibitors

    PubMed Central

    Welch, Matthew A.; Köck, Kathleen; Urban, Thomas J.; Brouwer, Kim L. R.

    2015-01-01

    Drug-induced liver injury (DILI) is an important cause of drug toxicity. Inhibition of multidrug resistance protein 4 (MRP4), in addition to bile salt export pump (BSEP), might be a risk factor for the development of cholestatic DILI. Recently, we demonstrated that inhibition of MRP4, in addition to BSEP, may be a risk factor for the development of cholestatic DILI. Here, we aimed to develop computational models to delineate molecular features underlying MRP4 and BSEP inhibition. Models were developed using 257 BSEP and 86 MRP4 inhibitors and noninhibitors in the training set. Models were externally validated and used to predict the affinity of compounds toward BSEP and MRP4 in the DrugBank database. Compounds with a score above the median fingerprint threshold were considered to have significant inhibitory effects on MRP4 and BSEP. Common feature pharmacophore models were developed for MRP4 and BSEP with LigandScout software using a training set of nine well characterized MRP4 inhibitors and nine potent BSEP inhibitors. Bayesian models for BSEP and MRP4 inhibition/noninhibition were developed with cross-validated receiver operator curve values greater than 0.8 for the test sets, indicating robust models with acceptable false positive and false negative prediction rates. Both MRP4 and BSEP inhibitor pharmacophore models were characterized by hydrophobic and hydrogen-bond acceptor features, albeit in distinct spatial arrangements. Similar molecular features between MRP4 and BSEP inhibitors may partially explain why various drugs have affinity for both transporters. The Bayesian (BSEP, MRP4) and pharmacophore (MRP4, BSEP) models demonstrated significant classification accuracy and predictability. PMID:25735837

  5. Expression of DNA Translesion Synthesis Polymerase η in Head and Neck Squamous Cell Cancer Predicts Resistance to Gemcitabine and Cisplatin-Based Chemotherapy

    PubMed Central

    Zhou, Wendi; Chen, Yih-wen; Liu, Xiyong; Chu, Peiguo; Loria, Sofia; Wang, Yafan; Yen, Yun; Chou, Kai-Ming

    2013-01-01

    Purpose The development of resistance against anticancer drugs has been a persistent clinical problem for the treatment of locally advanced malignancies in the head and neck mucosal derived squamous cell carcinoma (HNSCC). Recent evidence indicates that the DNA translesion synthesis (TLS) polymerase η (Pol η; hRad30a gene) reduces the effectiveness of gemcitabine/cisplatin. The goal of this study is to examine the relationship between the expression level of Pol η and the observed resistance against these chemotherapeutic agents in HNSCC, which is currently unknown. Methods Sixty-four mucosal derived squamous cell carcinomas of head and neck (HNSCC) from 1989 and 2007 at the City of Hope National Medical Center (Duarte, CA) were retrospectively analyzed. Pretreatment samples were immunostained with anti-Pol η antibody and the correlation between the expression level of Pol η and clinical outcomes were evaluated. Forty-nine cases treated with platinum (n=40) or gemcitabine (n=9) based chemotherapy were further examined for Pol η expression level for comparison with patient response to chemotherapy. Results The expression of Pol η was elevated in 67% of the head and neck tumor samples. Pol η expression level was significantly higher in grade 1 to grade 2 tumors (well to moderately differentiated). The overall benefit rate (complete response+ partial response) in patients treated with platinum and gemcitabine based chemotherapy was 79.5%, where low Pol η level was significantly associated with high complete response rate (p=0.03), although not associated with overall survival. Furthermore, no significant correlation was observed between Pol η expression level with gender, age, tobacco/alcohol history, tumor stage and metastatic status. Conclusions Our data suggest that Pol η expression may be a useful prediction marker for the effectiveness of platinum or gemcitabine based therapy for HNSCC. PMID:24376779

  6. Characterization and structure prediction of partial length protein sequences of pcoA, pcoR and chrB genes from heavy metal resistant bacteria from the Klip River, South Africa.

    PubMed

    Chihomvu, Patience; Stegmann, Peter; Pillay, Michael

    2015-01-01

    The Klip River has suffered from severe anthropogenic effects from industrial activities such as mining. Long-term exposure to heavy metal pollution has led to the development of heavy metal resistant strains of Pseudomonas sp. KR23, Lysinibacillus sp. KR25, and E. coli KR29. The objectives of this study were to characterize the genetics of copper and chromate resistance of the isolates. Copper and chromate resistance determinants were cloned and sequenced. Open reading frames (ORFs) related to the genes CopA and CopR were identified in E. coli KR29, PcoA in Lysinibacillus sp. KR25 and none related to chromate resistance were detected. The 3D-models predicted by I-TASSER disclose that the PcoA proteins consist of β-sheets, which form a part of the cupredoxin domain of the CopA copper resistance family of genes. The model for PcoR_29 revealed the presence of a helix turn helix; this forms part of a DNA binding protein, which is part of a heavy metal transcriptional regulator. The bacterial strains were cured using ethidium bromide. The genes encoding for heavy metal resistance and antibiotic resistance were found to be located on the chromosome for both Pseudomonas sp. (KR23) and E. coli (KR29). For Lysinibacillus (KR25) the heavy metal resistance determinants are suspected to be located on a mobile genetic element, which was not detected using gel electrophoresis. PMID:25837632

  7. Characterization and Structure Prediction of Partial Length Protein Sequences of pcoA, pcoR and chrB Genes from Heavy Metal Resistant Bacteria from the Klip River, South Africa

    PubMed Central

    Chihomvu, Patience; Stegmann, Peter; Pillay, Michael

    2015-01-01

    The Klip River has suffered from severe anthropogenic effects from industrial activities such as mining. Long-term exposure to heavy metal pollution has led to the development of heavy metal resistant strains of Pseudomonas sp. KR23, Lysinibacillus sp. KR25, and E. coli KR29. The objectives of this study were to characterize the genetics of copper and chromate resistance of the isolates. Copper and chromate resistance determinants were cloned and sequenced. Open reading frames (ORFs) related to the genes CopA and CopR were identified in E. coli KR29, PcoA in Lysinibacillus sp. KR25 and none related to chromate resistance were detected. The 3D-models predicted by I-TASSER disclose that the PcoA proteins consist of β-sheets, which form a part of the cupredoxin domain of the CopA copper resistance family of genes. The model for PcoR_29 revealed the presence of a helix turn helix; this forms part of a DNA binding protein, which is part of a heavy metal transcriptional regulator. The bacterial strains were cured using ethidium bromide. The genes encoding for heavy metal resistance and antibiotic resistance were found to be located on the chromosome for both Pseudomonas sp. (KR23) and E. coli (KR29). For Lysinibacillus (KR25) the heavy metal resistance determinants are suspected to be located on a mobile genetic element, which was not detected using gel electrophoresis. PMID:25837632

  8. Progression-free and overall survival in metastatic castration-resistant prostate cancer treated with abiraterone acetate can be predicted with serial C11-acetate PET/CT

    PubMed Central

    Farnebo, Jacob; Wadelius, Agnes; Sandström, Per; Nilsson, Sten; Jacobsson, Hans; Blomqvist, Lennart; Ullén, Anders

    2016-01-01

    Abstract In this retrospective study, we evaluated the benefit of repeated carbon 11 (C11)-acetate positron emission tomography/computed tomography (PET/CT) to assess response in patients with metastatic castration-resistant prostate cancer (mCRPC) treated with abiraterone acetate (AA). A total of 30 patients with mCRPC were monitored with C11-acetate PET/CT and PSA levels during their treatment with AA. Retrospective evaluation of their response was made after 102 days (median; range 70–155) of treatment. Statistical analyses were employed to detect predictors of progression-free survival (PFS) and overall survival (OS), and potential correlation between serum levels of PSA, standardized uptake values (SUVpeak), and bone lesion index measured from PET were investigated. At follow-up 10 patients exhibited partial response (PR), 10 progressive disease (PD), and 10 stable disease (SD), as assessed by PET/CT. In survival analysis, both PR and PD were significantly associated with PFS and OS. CT response was also associated with OS, but only 19/30 patients demonstrated a lesion meeting target lesion criteria according to RECIST 1.1. No PET/CT baseline characteristic was significantly associated with PFS or OS. A PSA response (reduction in the level by >50%) could also predict PFS and OS. In the subgroup lacking a PSA response, those with PD had significantly shorter OS than those with PR or SD. PFS and OS in patients with mCRPC treated with AA can be predicted from repeated C11-acetate PET/CT. This may be of particular clinical value in patients who do not exhibit a PSA response to treatment. PMID:27495034

  9. Progression-free and overall survival in metastatic castration-resistant prostate cancer treated with abiraterone acetate can be predicted with serial C11-acetate PET/CT.

    PubMed

    Farnebo, Jacob; Wadelius, Agnes; Sandström, Per; Nilsson, Sten; Jacobsson, Hans; Blomqvist, Lennart; Ullén, Anders

    2016-08-01

    In this retrospective study, we evaluated the benefit of repeated carbon 11 (C11)-acetate positron emission tomography/computed tomography (PET/CT) to assess response in patients with metastatic castration-resistant prostate cancer (mCRPC) treated with abiraterone acetate (AA).A total of 30 patients with mCRPC were monitored with C11-acetate PET/CT and PSA levels during their treatment with AA. Retrospective evaluation of their response was made after 102 days (median; range 70-155) of treatment. Statistical analyses were employed to detect predictors of progression-free survival (PFS) and overall survival (OS), and potential correlation between serum levels of PSA, standardized uptake values (SUVpeak), and bone lesion index measured from PET were investigated.At follow-up 10 patients exhibited partial response (PR), 10 progressive disease (PD), and 10 stable disease (SD), as assessed by PET/CT. In survival analysis, both PR and PD were significantly associated with PFS and OS. CT response was also associated with OS, but only 19/30 patients demonstrated a lesion meeting target lesion criteria according to RECIST 1.1. No PET/CT baseline characteristic was significantly associated with PFS or OS. A PSA response (reduction in the level by >50%) could also predict PFS and OS. In the subgroup lacking a PSA response, those with PD had significantly shorter OS than those with PR or SD.PFS and OS in patients with mCRPC treated with AA can be predicted from repeated C11-acetate PET/CT. This may be of particular clinical value in patients who do not exhibit a PSA response to treatment. PMID:27495034

  10. Detection of AR-V7 mRNA in whole blood may not predict the effectiveness of novel endocrine drugs for castration-resistant prostate cancer

    PubMed Central

    Takeuchi, Takumi; Okuno, Yumiko; Hattori-Kato, Mami; Zaitsu, Masayoshi; Mikami, Koji

    2016-01-01

    A splice variant of androgen receptor (AR), AR-V7, lacks in androgen-binding portion and leads to aggressive cancer characteristics. Reverse transcription-polymerase chain reactions (PCRs) and subsequent nested PCRs for the amplification of AR-V7 and prostate-specific antigen (PSA) transcripts were done for whole blood of patients with prostate cancer and male controls. With primary reverse transcription PCRs, AR-V7 and PSA were detected in 4.5% and 4.7% of prostate cancer, respectively. With nested PCRs, AR-V7 messenger RNA (mRNA) was positive in 43.8% of castration-sensitive prostate cancer and 48.1% of castration-resistant prostate cancer (CRPC), while PSA mRNA was positive in 6.3% of castration-sensitive prostate cancer and 18.5% of CRPC. Whole-blood samples of controls showed AR-V7 mRNA expression by nested PCR. Based on multivariate analysis, expression of AR-V7 mRNA in whole blood was not significantly correlated with clinical parameters and PSA mRNA in blood, while univariate analysis showed a correlation between AR-V7 mRNA and metastasis at initial diagnosis. Detection of AR-V7 mRNA did not predict the reduction of serum PSA in patients with CRPC following abiraterone and enzalutamide administration. In conclusion, AR-V7 mRNA expression in normal hematopoietic cells may have annihilated the manifestation of aggressiveness of prostate cancer and the prediction of the effectiveness of abiraterone and enzalutamide by the assessment of AR-V7 mRNA in blood. PMID:26870716

  11. Detection of AR-V7 mRNA in whole blood may not predict the effectiveness of novel endocrine drugs for castration-resistant prostate cancer.

    PubMed

    Takeuchi, Takumi; Okuno, Yumiko; Hattori-Kato, Mami; Zaitsu, Masayoshi; Mikami, Koji

    2016-01-01

    A splice variant of androgen receptor (AR), AR-V7, lacks in androgen-binding portion and leads to aggressive cancer characteristics. Reverse transcription-polymerase chain reactions (PCRs) and subsequent nested PCRs for the amplification of AR-V7 and prostate-specific antigen (PSA) transcripts were done for whole blood of patients with prostate cancer and male controls. With primary reverse transcription PCRs, AR-V7 and PSA were detected in 4.5% and 4.7% of prostate cancer, respectively. With nested PCRs, AR-V7 messenger RNA (mRNA) was positive in 43.8% of castration-sensitive prostate cancer and 48.1% of castration-resistant prostate cancer (CRPC), while PSA mRNA was positive in 6.3% of castration-sensitive prostate cancer and 18.5% of CRPC. Whole-blood samples of controls showed AR-V7 mRNA expression by nested PCR. Based on multivariate analysis, expression of AR-V7 mRNA in whole blood was not significantly correlated with clinical parameters and PSA mRNA in blood, while univariate analysis showed a correlation between AR-V7 mRNA and metastasis at initial diagnosis. Detection of AR-V7 mRNA did not predict the reduction of serum PSA in patients with CRPC following abiraterone and enzalutamide administration. In conclusion, AR-V7 mRNA expression in normal hematopoietic cells may have annihilated the manifestation of aggressiveness of prostate cancer and the prediction of the effectiveness of abiraterone and enzalutamide by the assessment of AR-V7 mRNA in blood.

  12. Computational Ranking of Yerba Mate Small Molecules Based on Their Predicted Contribution to Antibacterial Activity against Methicillin-Resistant Staphylococcus aureus

    SciTech Connect

    Rempe, Caroline S.; Burris, Kellie P.; Woo, Hannah L.; Goodrich, Benjamin; Gosnell, Denise Koessler; Tschaplinski, Timothy J.; Stewart, C. Neal

    2015-05-08

    We report that the aqueous extract of yerba mate, a South American tea beverage made from Ilex paraguariensis leaves, has demonstrated bactericidal and inhibitory activity against bacterial pathogens, including methicillin-resistant Staphylococcus aureus (MRSA). The gas chromatography-mass spectrometry (GC-MS) analysis of two unique fractions of yerba mate aqueous extract revealed 8 identifiable small molecules in those fractions with antimicrobial activity. For a more comprehensive analysis, a data analysis pipeline was assembled to prioritize compounds for antimicrobial testing against both MRSA and methicillin-sensitive S. aureus using forty-two unique fractions of the tea extract that were generated in duplicate, assayed for activity, and analyzed with GC-MS. As validation of our automated analysis, we checked our predicted active compounds for activity in literature references and used authentic standards to test for antimicrobial activity. 3,4-dihydroxybenzaldehyde showed the most antibacterial activity against MRSA at low concentrations in our bioassays. In addition, quinic acid and quercetin were identified using random forests analysis and 5-hydroxy pipecolic acid was identified using linear discriminant analysis. We also generated a ranked list of unidentified compounds that may contribute to the antimicrobial activity of yerba mate against MRSA. Here we utilized GC-MS data to implement an automated analysis that resulted in a ranked list of compounds that likely contribute to the antimicrobial activity of aqueous yerba mate extract against MRSA.

  13. Computational Ranking of Yerba Mate Small Molecules Based on Their Predicted Contribution to Antibacterial Activity against Methicillin-Resistant Staphylococcus aureus

    DOE PAGES

    Rempe, Caroline S.; Burris, Kellie P.; Woo, Hannah L.; Goodrich, Benjamin; Gosnell, Denise Koessler; Tschaplinski, Timothy J.; Stewart, C. Neal

    2015-05-08

    We report that the aqueous extract of yerba mate, a South American tea beverage made from Ilex paraguariensis leaves, has demonstrated bactericidal and inhibitory activity against bacterial pathogens, including methicillin-resistant Staphylococcus aureus (MRSA). The gas chromatography-mass spectrometry (GC-MS) analysis of two unique fractions of yerba mate aqueous extract revealed 8 identifiable small molecules in those fractions with antimicrobial activity. For a more comprehensive analysis, a data analysis pipeline was assembled to prioritize compounds for antimicrobial testing against both MRSA and methicillin-sensitive S. aureus using forty-two unique fractions of the tea extract that were generated in duplicate, assayed for activity, andmore » analyzed with GC-MS. As validation of our automated analysis, we checked our predicted active compounds for activity in literature references and used authentic standards to test for antimicrobial activity. 3,4-dihydroxybenzaldehyde showed the most antibacterial activity against MRSA at low concentrations in our bioassays. In addition, quinic acid and quercetin were identified using random forests analysis and 5-hydroxy pipecolic acid was identified using linear discriminant analysis. We also generated a ranked list of unidentified compounds that may contribute to the antimicrobial activity of yerba mate against MRSA. Here we utilized GC-MS data to implement an automated analysis that resulted in a ranked list of compounds that likely contribute to the antimicrobial activity of aqueous yerba mate extract against MRSA.« less

  14. Battery Life Predictive Model

    2009-12-31

    The Software consists of a model used to predict battery capacity fade and resistance growth for arbitrary cycling and temperature profiles. It allows the user to extrapolate from experimental data to predict actual life cycle.

  15. Integrated Stable Isotope Labeling by Amino Acids in Cell Culture (SILAC) and Isobaric Tags for Relative and Absolute Quantitation (iTRAQ) Quantitative Proteomic Analysis Identifies Galectin-1 as a Potential Biomarker for Predicting Sorafenib Resistance in Liver Cancer.

    PubMed

    Yeh, Chao-Chi; Hsu, Chih-Hung; Shao, Yu-Yun; Ho, Wen-Ching; Tsai, Mong-Hsun; Feng, Wen-Chi; Chow, Lu-Ping

    2015-06-01

    Sorafenib has become the standard therapy for patients with advanced hepatocellular carcinoma (HCC). Unfortunately, most patients eventually develop acquired resistance. Therefore, it is important to identify potential biomarkers that could predict the efficacy of sorafenib. To identify target proteins associated with the development of sorafenib resistance, we applied stable isotope labelling with amino acids in cell culture (SILAC)-based quantitative proteomic approach to analyze differences in protein expression levels between parental HuH-7 and sorafenib-acquired resistance HuH-7 (HuH-7(R)) cells in vitro, combined with an isobaric tags for relative and absolute quantitation (iTRAQ) quantitative analysis of HuH-7 and HuH-7(R) tumors in vivo. In total, 2,450 quantified proteins were identified in common in SILAC and iTRAQ experiments, with 81 showing increased expression (>2.0-fold) with sorafenib resistance and 75 showing decreased expression (<0.5-fold). In silico analyses of these differentially expressed proteins predicted that 10 proteins were related to cancer with involvements in cell adhesion, migration, and invasion. Knockdown of one of these candidate proteins, galectin-1, decreased cell proliferation and metastasis in HuH-7(R) cells and restored sensitivity to sorafenib. We verified galectin-1 as a predictive marker of sorafenib resistance and a downstream target of the AKT/mTOR/HIF-1α signaling pathway. In addition, increased galectin-1 expression in HCC patients' serum was associated with poor tumor control and low response rate. We also found that a high serum galectin-1 level was an independent factor associated with poor progression-free survival and overall survival. In conclusion, these results suggest that galectin-1 is a possible biomarker for predicting the response of HCC patients to treatment with sorafenib. As such, it may assist in the stratification of HCC and help direct personalized therapy.

  16. Integrated Stable Isotope Labeling by Amino Acids in Cell Culture (SILAC) and Isobaric Tags for Relative and Absolute Quantitation (iTRAQ) Quantitative Proteomic Analysis Identifies Galectin-1 as a Potential Biomarker for Predicting Sorafenib Resistance in Liver Cancer*

    PubMed Central

    Yeh, Chao-Chi; Hsu, Chih-Hung; Shao, Yu-Yun; Ho, Wen-Ching; Tsai, Mong-Hsun; Feng, Wen-Chi; Chow, Lu-Ping

    2015-01-01

    Sorafenib has become the standard therapy for patients with advanced hepatocellular carcinoma (HCC). Unfortunately, most patients eventually develop acquired resistance. Therefore, it is important to identify potential biomarkers that could predict the efficacy of sorafenib. To identify target proteins associated with the development of sorafenib resistance, we applied stable isotope labelling with amino acids in cell culture (SILAC)-based quantitative proteomic approach to analyze differences in protein expression levels between parental HuH-7 and sorafenib-acquired resistance HuH-7 (HuH-7R) cells in vitro, combined with an isobaric tags for relative and absolute quantitation (iTRAQ) quantitative analysis of HuH-7 and HuH-7R tumors in vivo. In total, 2,450 quantified proteins were identified in common in SILAC and iTRAQ experiments, with 81 showing increased expression (>2.0-fold) with sorafenib resistance and 75 showing decreased expression (<0.5-fold). In silico analyses of these differentially expressed proteins predicted that 10 proteins were related to cancer with involvements in cell adhesion, migration, and invasion. Knockdown of one of these candidate proteins, galectin-1, decreased cell proliferation and metastasis in HuH-7R cells and restored sensitivity to sorafenib. We verified galectin-1 as a predictive marker of sorafenib resistance and a downstream target of the AKT/mTOR/HIF-1α signaling pathway. In addition, increased galectin-1 expression in HCC patients' serum was associated with poor tumor control and low response rate. We also found that a high serum galectin-1 level was an independent factor associated with poor progression-free survival and overall survival. In conclusion, these results suggest that galectin-1 is a possible biomarker for predicting the response of HCC patients to treatment with sorafenib. As such, it may assist in the stratification of HCC and help direct personalized therapy. PMID:25850433

  17. Shifting focus from the population to the individual as a way forward in understanding, predicting and managing the complexities of evolution of resistance to pesticides.

    PubMed

    Renton, Michael

    2013-02-01

    The evolution of resistance to pesticides is often conceptualised and modelled at a population level, but population-based approaches ignore important aspects of variability between individuals within populations that may be essential drivers of resistance. Here it is argued that individual-based modelling has the potential to generate new insights and perspectives, thus deepening our understanding of the complexities of the evolutionary dynamics of resistance to pesticides.

  18. Combination of circulating tumor cell enumeration and tumor marker detection in predicting prognosis and treatment effect in metastatic castration-resistant prostate cancer

    PubMed Central

    Chang, Kun; Kong, Yun-Yi; Dai, Bo; Ye, Ding-Wei; Qu, Yuan-Yuan; Wang, Yue; Jia, Zhong-Wei; Li, Gao-Xiang

    2015-01-01

    Although circulating tumor cell (CTC) enumeration in peripheral blood has already been validated as a reliable biomarker in predicting prognosis in metastatic castration-resistant prostate cancer (mCRPC), patients with favorable CTC counts (CTC < 5/7.5 ml) still experience various survival times. Assays that can reduce patients' risks are urgently needed. In this study, we set up a real-time quantitative polymerase chain reaction (RT-qPCR) method to detect epithelial-mesenchymal transition (EMT) and stem cell gene expression status in peripheral blood to validate whether they could complement CTC enumeration. From January 2013 to June 2014 we collected peripheral blood from 70 mCRPC patients and enumerated CTC in these blood samples using CellSearch system. At the same time, stem cell-related genes (ABCG2, PROM1 and PSCA) and EMT-related genes (TWIST1 and vimentin) were detected in these peripheral blood samples using an RT-qPCR assay. Patient overall survival (OS) and treatment methods were recorded in the follow-up. For patients who received first-line chemotherapy, docetaxel plus prednisone, PSA progression-free survival (PSA-PFS) and PSA response rate were recorded. At the time of analysis, 35 patients had died of prostate cancer with a median follow-up of 16.0 months. Unfavorable CTC enumerations (CTC ≥5/7.5 ml) were predictive of shorter OS (p = 0.01). Also, positive stem cell gene expression indicated poor prognosis in mCRPC patients (p = 0.01). However, EMT gene expression status failed to show any prognostic value in OS (p = 0.78). A multivariate analysis indicated that serum albumin (p = 0.04), ECOG performance status (p < 0.01), CTC enumeration (p = 0.02) and stem cell gene expression status (p = 0.01) were independent prognostic factors for OS. For the 40 patients categorized into the favorable CTC enumeration group, positive stem cell gene expression also suggested poor prognosis (p < 0.01). A combined prognostic model consisting of stem cell gene

  19. Combination of circulating tumor cell enumeration and tumor marker detection in predicting prognosis and treatment effect in metastatic castration-resistant prostate cancer.

    PubMed

    Chang, Kun; Kong, Yun-Yi; Dai, Bo; Ye, Ding-Wei; Qu, Yuan-Yuan; Wang, Yue; Jia, Zhong-Wei; Li, Gao-Xiang

    2015-12-01

    Although circulating tumor cell (CTC) enumeration in peripheral blood has already been validated as a reliable biomarker in predicting prognosis in metastatic castration-resistant prostate cancer (mCRPC), patients with favorable CTC counts (CTC < 5/7.5 ml) still experience various survival times. Assays that can reduce patients' risks are urgently needed. In this study, we set up a real-time quantitative polymerase chain reaction (RT-qPCR) method to detect epithelial-mesenchymal transition (EMT) and stem cell gene expression status in peripheral blood to validate whether they could complement CTC enumeration. From January 2013 to June 2014 we collected peripheral blood from 70 mCRPC patients and enumerated CTC in these blood samples using CellSearch system. At the same time, stem cell-related genes (ABCG2, PROM1 and PSCA) and EMT-related genes (TWIST1 and vimentin) were detected in these peripheral blood samples using an RT-qPCR assay. Patient overall survival (OS) and treatment methods were recorded in the follow-up. For patients who received first-line chemotherapy, docetaxel plus prednisone, PSA progression-free survival (PSA-PFS) and PSA response rate were recorded. At the time of analysis, 35 patients had died of prostate cancer with a median follow-up of 16.0 months. Unfavorable CTC enumerations (CTC ≥5/7.5 ml) were predictive of shorter OS (p = 0.01). Also, positive stem cell gene expression indicated poor prognosis in mCRPC patients (p = 0.01). However, EMT gene expression status failed to show any prognostic value in OS (p = 0.78). A multivariate analysis indicated that serum albumin (p = 0.04), ECOG performance status (p < 0.01), CTC enumeration (p = 0.02) and stem cell gene expression status (p = 0.01) were independent prognostic factors for OS. For the 40 patients categorized into the favorable CTC enumeration group, positive stem cell gene expression also suggested poor prognosis (p < 0.01). A combined prognostic model consisting of stem cell gene

  20. Using Agent-Based Modelling to Predict the Role of Wild Refugia in the Evolution of Resistance of Sea Lice to Chemotherapeutants

    PubMed Central

    McEwan, Gregor F.; Groner, Maya L.; Fast, Mark D.; Revie, Crawford W.

    2015-01-01

    A major challenge for Atlantic salmon farming in the northern hemisphere is infestation by the sea louse parasite Lepeophtheirus salmonis. The most frequent method of controlling these sea louse infestations is through the use of chemical treatments. However, most major salmon farming areas have observed resistance to common chemotherapeutants. In terrestrial environments, many strategies employed to manage the evolution of resistance involve the use of refugia, where a portion of the population is left untreated to maintain susceptibility. While refugia have not been deliberately used in Atlantic salmon farming, wild salmon populations that migrate close to salmon farms may act as natural refugia. In this paper we describe an agent-based model that explores the influence of different sizes of wild salmon populations on resistance evolution in sea lice on a salmon farm. Using the model, we demonstrate that wild salmon populations can act as refugia that limit the evolution of resistance in the sea louse populations. Additionally, we demonstrate that an increase in the size of the population of wild salmon results in an increased effect in slowing the evolution of resistance. We explore the effect of a population fitness cost associated with resistance, finding that in some cases it substantially reduces the speed of evolution to chemical treatments. PMID:26485023

  1. Using Agent-Based Modelling to Predict the Role of Wild Refugia in the Evolution of Resistance of Sea Lice to Chemotherapeutants.

    PubMed

    McEwan, Gregor F; Groner, Maya L; Fast, Mark D; Gettinby, George; Revie, Crawford W

    2015-01-01

    A major challenge for Atlantic salmon farming in the northern hemisphere is infestation by the sea louse parasite Lepeophtheirus salmonis. The most frequent method of controlling these sea louse infestations is through the use of chemical treatments. However, most major salmon farming areas have observed resistance to common chemotherapeutants. In terrestrial environments, many strategies employed to manage the evolution of resistance involve the use of refugia, where a portion of the population is left untreated to maintain susceptibility. While refugia have not been deliberately used in Atlantic salmon farming, wild salmon populations that migrate close to salmon farms may act as natural refugia. In this paper we describe an agent-based model that explores the influence of different sizes of wild salmon populations on resistance evolution in sea lice on a salmon farm. Using the model, we demonstrate that wild salmon populations can act as refugia that limit the evolution of resistance in the sea louse populations. Additionally, we demonstrate that an increase in the size of the population of wild salmon results in an increased effect in slowing the evolution of resistance. We explore the effect of a population fitness cost associated with resistance, finding that in some cases it substantially reduces the speed of evolution to chemical treatments. PMID:26485023

  2. Using Agent-Based Modelling to Predict the Role of Wild Refugia in the Evolution of Resistance of Sea Lice to Chemotherapeutants.

    PubMed

    McEwan, Gregor F; Groner, Maya L; Fast, Mark D; Gettinby, George; Revie, Crawford W

    2015-01-01

    A major challenge for Atlantic salmon farming in the northern hemisphere is infestation by the sea louse parasite Lepeophtheirus salmonis. The most frequent method of controlling these sea louse infestations is through the use of chemical treatments. However, most major salmon farming areas have observed resistance to common chemotherapeutants. In terrestrial environments, many strategies employed to manage the evolution of resistance involve the use of refugia, where a portion of the population is left untreated to maintain susceptibility. While refugia have not been deliberately used in Atlantic salmon farming, wild salmon populations that migrate close to salmon farms may act as natural refugia. In this paper we describe an agent-based model that explores the influence of different sizes of wild salmon populations on resistance evolution in sea lice on a salmon farm. Using the model, we demonstrate that wild salmon populations can act as refugia that limit the evolution of resistance in the sea louse populations. Additionally, we demonstrate that an increase in the size of the population of wild salmon results in an increased effect in slowing the evolution of resistance. We explore the effect of a population fitness cost associated with resistance, finding that in some cases it substantially reduces the speed of evolution to chemical treatments.

  3. Antibiotic resistance in bacteria isolated from freshwater aquacultures and prediction of the persistence and toxicity of antimicrobials in the aquatic environment.

    PubMed

    Lim, Seung J; Jang, Eunhee; Lee, Sang-Hun; Yoo, Byeong-Hak; Kim, Sun-Kyoung; Kim, Tak-Hyun

    2013-01-01

    The occurrence of antibiotic-resistant bacteria isolated from freshwater aquaculture effluents was investigated. The bacterial strains were collected from four different freshwater aquaculture effluents (catfish, trout, eel, and loach). Based on sequence of 16S rRNA, a total of 20 bacterial strains was isolated and one half of the isolated bacteria were Aeromonas sp. The antimicrobial sensitivity test was performed using the disc diffusion method. Individual antibiotic-resistant bacteria to antimicrobials were 41.7% and multiple antibiotic resistant bacteria were 58.3%. The disinfection of antibiotic-resistant bacteria by electron beam (E-beam) irradiation was carried out using an electron accelerator. Antibiotic-resistant bacteria were effectively disinfected by E-beam irradiation. The isolated bacteria were completely disinfected at a dose of less than 2 kGy. The persistence and toxicity of each antimicrobial in the aquatic environment was estimated due to the human health and ecosystems. In order to estimate the persistence and toxicity of antimicrobials in the aquatic environment, two quantitative structure activity relationship (QSAR) models were used. The persistence and toxicity of each antimicrobial were influenced on its hydrophobicity. In addition, QSAR models showed that isoelectric point and hydrogen bonding acceptor are key parameters to estimate the persistence and toxicity of antimicrobials in the aquatic environment.

  4. The development of an in vitro test method for predicting the abrasion resistance of textile and metal components of endovascular stent grafts.

    PubMed

    Yao, Tong; Choules, Brian D; Rust, Jon P; King, Martin W

    2014-04-01

    Implantable endovascular stent grafts have become a frequent option for the treatment of abdominal and thoracic aneurysms. Given that such devices are permanent implants, the question of long-term biostability needs to be addressed. This article describes the development of an in vitro stent graft abrasion test method between the graft fabric and metal stent of an endovascular device. Three endpoints were established to determine the abrasion resistance between the fabric and stent surfaces after a predetermined number of abrasion cycles. During initial testing, two types of graft fabric materials, multifilament woven polyester fabric and monofilament woven polyester fabric, and two types of stent materials, laser cut nitinol stents and regular nitinol stent wire, were evaluated under dry and wet conditions. The results have shown that this test method is viable for testing the relative abrasion resistance of the components of endovascular stent grafts. The abrasion resistance of both fabrics was lower in a wet environment compared to being tested dry. Additionally, the multifilament polyester fabric had better abrasion resistance than the monofilament polyester fabric. The laser cut nitinol stent was more aggressive in creating holes and breaking yarns, while the regular nitinol stent wire caused a greater loss in fabric strength.

  5. The development of an in vitro test method for predicting the abrasion resistance of textile and metal components of endovascular stent grafts.

    PubMed

    Yao, Tong; Choules, Brian D; Rust, Jon P; King, Martin W

    2014-04-01

    Implantable endovascular stent grafts have become a frequent option for the treatment of abdominal and thoracic aneurysms. Given that such devices are permanent implants, the question of long-term biostability needs to be addressed. This article describes the development of an in vitro stent graft abrasion test method between the graft fabric and metal stent of an endovascular device. Three endpoints were established to determine the abrasion resistance between the fabric and stent surfaces after a predetermined number of abrasion cycles. During initial testing, two types of graft fabric materials, multifilament woven polyester fabric and monofilament woven polyester fabric, and two types of stent materials, laser cut nitinol stents and regular nitinol stent wire, were evaluated under dry and wet conditions. The results have shown that this test method is viable for testing the relative abrasion resistance of the components of endovascular stent grafts. The abrasion resistance of both fabrics was lower in a wet environment compared to being tested dry. Additionally, the multifilament polyester fabric had better abrasion resistance than the monofilament polyester fabric. The laser cut nitinol stent was more aggressive in creating holes and breaking yarns, while the regular nitinol stent wire caused a greater loss in fabric strength. PMID:24115449

  6. Predictive model for the reduction of heat resistance of Listeria monocytogenes in ground beef by the combined effect of sodium chloride and apple polyphenols

    Technology Transfer Automated Retrieval System (TEKTRAN)

    We investigated the combined effect of three internal temperatures (57.5, 60, and 62.5C) and different concentrations (0 to 3.0 wt/wt %) of sodium chloride (NaCl) and apple polyphenols (APP), individually and in combination, on the heat-resistance of a five-strain cocktail of Listeria monocytogenes ...

  7. Genome-wide association and prediction analysis in African cassava (Manihot esculenta) reveals the genetic architecture of resistance to cassava mosaic disease and prospects for rapid genetic improvement

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Cassava (Manihot esculenta) is a crucial, under-researched crop feeding millions worldwide, especially in Africa. Cassava mosaic disease (CMD) has plagued production in Africa for over a century. Bi-parental mapping studies suggest primarily a single major gene mediates resistance. To be certain and...

  8. Resistance-resistant antibiotics.

    PubMed

    Oldfield, Eric; Feng, Xinxin

    2014-12-01

    New antibiotics are needed because drug resistance is increasing while the introduction of new antibiotics is decreasing. We discuss here six possible approaches to develop 'resistance-resistant' antibiotics. First, multitarget inhibitors in which a single compound inhibits more than one target may be easier to develop than conventional combination therapies with two new drugs. Second, inhibiting multiple targets in the same metabolic pathway is expected to be an effective strategy owing to synergy. Third, discovering multiple-target inhibitors should be possible by using sequential virtual screening. Fourth, repurposing existing drugs can lead to combinations of multitarget therapeutics. Fifth, targets need not be proteins. Sixth, inhibiting virulence factor formation and boosting innate immunity may also lead to decreased susceptibility to resistance. Although it is not possible to eliminate resistance, the approaches reviewed here offer several possibilities for reducing the effects of mutations and, in some cases, suggest that sensitivity to existing antibiotics may be restored in otherwise drug-resistant organisms.

  9. Resistance, Reactance, and Consultation.

    ERIC Educational Resources Information Center

    Hughes, Jan N.; Falk, Robert S.

    1981-01-01

    Presents a review of techniques for dealing with consultee resistance. Suggests the social psychological theory of reactance is a useful conceptual framework for considering resistance in consultation. Discusses examples of its application, variables that predict the likely effectiveness of a reactance utilization intervention, and ethical issues.…

  10. Computational Prediction of Cryogenic Micro-nano Solid Nitrogen Particle Production Using Laval Nozzle for Physical Photo Resist Removal-cleaning Technology

    NASA Astrophysics Data System (ADS)

    Ishimoto, Jun; Abe, Haruto; Ochiai, Naoya

    The fundamental characteristics of the cryogenic single-component micro-nano solid nitrogen (SN2) particle production using super adiabatic Laval nozzle and its application to the physical photo resist removal-cleaning technology are investigated by a new type of integrated measurement coupled computational technique. As a result of present computation, it is found that high-speed ultra-fine SN2 particles are continuously generated due to the freezing of liquid nitrogen (LN2) droplets induced by rapid adiabatic expansion of transonic subcooled two-phase nitrogen flow passing through the Laval nozzle. Furthermore, the effect of SN2 particle diameter, injection velocity, and attack angle to the wafer substrate on resist removal-cleaning performance is investigated in detail by integrated measurement coupled computational technique.

  11. Utility of a single nasal polymerase chain reaction assay in predicting absence of skin and environmental contamination in hospitalized patients with past methicillin-resistant Staphylococcus aureus.

    PubMed

    Guerrero, Dubert M; Wagner, Matthew; Carson, Grace; Hanish, Christine; Thompson, Jody; Orr, Megan; Roth, Felix; Carson, Paul J

    2016-06-01

    We evaluated hospitalized patients with a history of methicillin-resistant Staphylococcus aureus (MRSA) for persistent colonization and need for contact precautions. Up to 3 daily cultures of nares, skin, and any present wounds were compared with a single nasal polymerase chain reaction (PCR) assay. Most patients (76.2%) were no longer colonized with MRSA. A single PCR assay was sufficient to exclude persistent colonization and environmental contamination and remove the contact precautions.

  12. Extensively drug-resistant bacteria are an independent predictive factor of mortality in 130 patients with spontaneous bacterial peritonitis or spontaneous bacteremia

    PubMed Central

    Alexopoulou, Alexandra; Vasilieva, Larisa; Agiasotelli, Danai; Siranidi, Kyriaki; Pouriki, Sophia; Tsiriga, Athanasia; Toutouza, Marina; Dourakis, Spyridon P

    2016-01-01

    AIM: To evaluate the epidemiology and outcomes of culture-positive spontaneous bacterial peritonitis (SBP) and spontaneous bacteremia (SB) in decompensated cirrhosis. METHODS: We prospectively collected clinical, laboratory characteristics, type of administered antibiotic, susceptibility and resistance of bacteria to antibiotics in one hundred thirty cases (68.5% males) with positive ascitic fluid and/or blood cultures during the period from January 1, 2012 to May 30, 2014. All patients with SBP had polymorphonuclear cell count in ascitic fluid > 250/mm3. In patients with SB a thorough study did not reveal any other cause of bacteremia. The patients were followed-up for a 30-d period following diagnosis of the infection. The final outcome of the patients was recorded in the end of follow-up and comparison among 3 groups of patients according to the pattern of drug resistance was performed. RESULTS: Gram-positive-cocci (GPC) were found in half of the cases. The most prevalent organisms in a descending order were Escherichia coli (33), Enterococcus spp (30), Streptococcus spp (25), Klebsiella pneumonia (16), S. aureus (8), Pseudomanas aeruginosa (5), other Gram-negative-bacteria (GNB) (11) and anaerobes (2). Overall, 20.8% of isolates were multidrug-resistant (MDR) and 10% extensively drug-resistant (XDR). Health-care-associated (HCA) and/or nosocomial infections were present in 100% of MDR/XDR and in 65.5% of non-DR cases. Meropenem was the empirically prescribed antibiotic in HCA/nosocomial infections showing a drug-resistance rate of 30.7% while third generation cephalosporins of 43.8%. Meropenem was ineffective on both XDR bacteria and Enterococcus faecium (E. faecium). All but one XDR were susceptible to colistin while all GPC (including E. faecium) and the 86% of GNB to tigecycline. Overall 30-d mortality was 37.7% (69.2% for XDR and 34.2% for the rest of the patients) (log rank, P = 0.015). In multivariate analysis, factors adversely affecting outcome included

  13. Fluoroquinolone and Macrolide Exposure Predict Clostridium difficile Infection with the Highly Fluoroquinolone- and Macrolide-Resistant Epidemic C. difficile Strain BI/NAP1/027.

    PubMed

    Wieczorkiewicz, Jeffrey T; Lopansri, Bert K; Cheknis, Adam; Osmolski, James R; Hecht, David W; Gerding, Dale N; Johnson, Stuart

    2015-11-02

    Antibiotics have been shown to influence the risk of infection with specific Clostridium difficile strains as well as the risk of C. difficile infection (CDI). We performed a retrospective case-control study of patients infected with the epidemic BI/NAP1/027 strain in a U.S. hospital following recognition of increased CDI severity and culture of stools positive by C. difficile toxin immunoassay. Between 2005 and 2007, 72% (103/143) of patients with first-episode CDIs were infected with the BI strain by restriction endonuclease analysis (REA) typing. Most patients received multiple antibiotics within 6 weeks of CDI onset (median of 3 antibiotic classes). By multivariate analysis, fluoroquinolone and macrolide exposure was more frequent among BI cases than among non-BI-infected controls (odds ratio [OR] for fluoroquinolones, 3.2; 95% confidence interval [CI], 1.3 to 7.5; (P < 0.001; OR for macrolides, 5.2; 95% CI, 1.1 to 24.0; P = 0.04)). In contrast, clindamycin use was less frequent among the BI cases than among the controls (OR, 0.1; 95% CI, 0.03 to 0.4; P = 0.001). High-level resistance to moxifloxacin and azithromycin was more frequent among BI strains (moxifloxacin, 49/102 [48%] BI versus 0/40 non-BI, P = 0.0001; azithromycin, 100/102 [98%] BI versus 22/40 [55%] non-BI, P = 0.0001). High-level resistance to clindamycin was more frequent among non-BI strains (22/40 [55%] non-BI versus 7/102 [7%] BI, P = 0.0001). Fluoroquinolone use, macrolide use, and C. difficile resistance to these antibiotic classes were associated with infection by the epidemic BI strain of C. difficile in a U.S. hospital during a time when CDI rates were increasing nationally due to the highly fluoroquinolone-resistant BI/NAP1/027 strain.

  14. Fluoroquinolone and Macrolide Exposure Predict Clostridium difficile Infection with the Highly Fluoroquinolone- and Macrolide-Resistant Epidemic C. difficile Strain BI/NAP1/027

    PubMed Central

    Wieczorkiewicz, Jeffrey T.; Lopansri, Bert K.; Cheknis, Adam; Osmolski, James R.; Hecht, David W.; Gerding, Dale N.

    2015-01-01

    Antibiotics have been shown to influence the risk of infection with specific Clostridium difficile strains as well as the risk of C. difficile infection (CDI). We performed a retrospective case-control study of patients infected with the epidemic BI/NAP1/027 strain in a U.S. hospital following recognition of increased CDI severity and culture of stools positive by C. difficile toxin immunoassay. Between 2005 and 2007, 72% (103/143) of patients with first-episode CDIs were infected with the BI strain by restriction endonuclease analysis (REA) typing. Most patients received multiple antibiotics within 6 weeks of CDI onset (median of 3 antibiotic classes). By multivariate analysis, fluoroquinolone and macrolide exposure was more frequent among BI cases than among non-BI-infected controls (odds ratio [OR] for fluoroquinolones, 3.2; 95% confidence interval [CI], 1.3 to 7.5; (P < 0.001; OR for macrolides, 5.2; 95% CI, 1.1 to 24.0; P = 0.04)). In contrast, clindamycin use was less frequent among the BI cases than among the controls (OR, 0.1; 95% CI, 0.03 to 0.4; P = 0.001). High-level resistance to moxifloxacin and azithromycin was more frequent among BI strains (moxifloxacin, 49/102 [48%] BI versus 0/40 non-BI, P = 0.0001; azithromycin, 100/102 [98%] BI versus 22/40 [55%] non-BI, P = 0.0001). High-level resistance to clindamycin was more frequent among non-BI strains (22/40 [55%] non-BI versus 7/102 [7%] BI, P = 0.0001). Fluoroquinolone use, macrolide use, and C. difficile resistance to these antibiotic classes were associated with infection by the epidemic BI strain of C. difficile in a U.S. hospital during a time when CDI rates were increasing nationally due to the highly fluoroquinolone-resistant BI/NAP1/027 strain. PMID:26525793

  15. Preliminary application of a novel algorithm to monitor changes in pre-flight total peripheral resistance for prediction of post-flight orthostatic intolerance in astronauts

    NASA Astrophysics Data System (ADS)

    Arai, Tatsuya; Lee, Kichang; Stenger, Michael B.; Platts, Steven H.; Meck, Janice V.; Cohen, Richard J.

    2011-04-01

    Orthostatic intolerance (OI) is a significant challenge for astronauts after long-duration spaceflight. Depending on flight duration, 20-80% of astronauts suffer from post-flight OI, which is associated with reduced vascular resistance. This paper introduces a novel algorithm for continuously monitoring changes in total peripheral resistance (TPR) by processing the peripheral arterial blood pressure (ABP). To validate, we applied our novel mathematical algorithm to the pre-flight ABP data previously recorded from twelve astronauts ten days before launch. The TPR changes were calculated by our algorithm and compared with the TPR value estimated using cardiac output/heart rate before and after phenylephrine administration. The astronauts in the post-flight presyncopal group had lower pre-flight TPR changes (1.66 times) than those in the non-presyncopal group (2.15 times). The trend in TPR changes calculated with our algorithm agreed with the TPR trend calculated using measured cardiac output in the previous study. Further data collection and algorithm refinement are needed for pre-flight detection of OI and monitoring of continuous TPR by analysis of peripheral arterial blood pressure.

  16. Evaluation of Oxacillin and Cefoxitin Disk and MIC Breakpoints for Prediction of Methicillin Resistance in Human and Veterinary Isolates of Staphylococcus intermedius Group.

    PubMed

    Wu, M T; Burnham, C-A D; Westblade, L F; Dien Bard, J; Lawhon, S D; Wallace, M A; Stanley, T; Burd, E; Hindler, J; Humphries, R M

    2016-03-01

    Staphylococcus pseudintermedius is a coagulase-positive species that colonizes the nares and anal mucosa of healthy dogs and cats. Human infections with S. pseudintermedius range in severity from bite wounds and rhinosinusitis to endocarditis; historically, these infections were thought to be uncommon, but new laboratory methods suggest that their true incidence is underreported. Oxacillin and cefoxitin disk and MIC tests were evaluated for the detection of mecA- or mecC-mediated methicillin resistance in 115 human and animal isolates of the Staphylococcus intermedius group (SIG), including 111 Staphylococcus pseudintermediusand 4 Staphylococcus delphini isolates, 37 of which were mecA positive. The disk and MIC breakpoints evaluated included the Clinical and Laboratory Standards Institute (CLSI) M100-S25 Staphylococcus aureus/Staphylococcus lugdunensis oxacillin MIC breakpoints and cefoxitin disk and MIC breakpoints, the CLSI M100-S25 coagulase-negative Staphylococcus (CoNS) oxacillin MIC breakpoint and cefoxitin disk breakpoint, the CLSI VET01-S2 S. pseudintermedius oxacillin MIC and disk breakpoints, and the European Committee on Antimicrobial Susceptibility Testing (EUCAST) S. pseudintermedius cefoxitin disk breakpoint. The oxacillin results interpreted by the VET01-S2 (disk and MIC) and M100-S25 CoNS (MIC) breakpoints agreed with the results of mecA/mecC PCR for all isolates, with the exception of one false-resistant result (1.3% of mecA/mecC PCR-negative isolates). In contrast, cefoxitin tests performed poorly, ranging from 3 to 89% false susceptibility (very major errors) and 0 to 48% false resistance (major errors). BD Phoenix, bioMérieux Vitek 2, and Beckman Coulter MicroScan commercial automated susceptibility test panel oxacillin MIC results were also evaluated and demonstrated >95% categorical agreement with mecA/mecC PCR results if interpreted by using the M100-S25 CoNS breakpoint. The Alere penicillin-binding protein 2a test accurately detected all

  17. Evaluation of Oxacillin and Cefoxitin Disk and MIC Breakpoints for Prediction of Methicillin Resistance in Human and Veterinary Isolates of Staphylococcus intermedius Group

    PubMed Central

    Wu, M. T.; Westblade, L. F.; Dien Bard, J.; Wallace, M. A.; Stanley, T.; Burd, E.; Hindler, J.

    2015-01-01

    Staphylococcus pseudintermedius is a coagulase-positive species that colonizes the nares and anal mucosa of healthy dogs and cats. Human infections with S. pseudintermedius range in severity from bite wounds and rhinosinusitis to endocarditis; historically, these infections were thought to be uncommon, but new laboratory methods suggest that their true incidence is underreported. Oxacillin and cefoxitin disk and MIC tests were evaluated for the detection of mecA- or mecC-mediated methicillin resistance in 115 human and animal isolates of the Staphylococcus intermedius group (SIG), including 111 Staphylococcus pseudintermediusand 4 Staphylococcus delphini isolates, 37 of which were mecA positive. The disk and MIC breakpoints evaluated included the Clinical and Laboratory Standards Institute (CLSI) M100-S25 Staphylococcus aureus/Staphylococcus lugdunensis oxacillin MIC breakpoints and cefoxitin disk and MIC breakpoints, the CLSI M100-S25 coagulase-negative Staphylococcus (CoNS) oxacillin MIC breakpoint and cefoxitin disk breakpoint, the CLSI VET01-S2 S. pseudintermedius oxacillin MIC and disk breakpoints, and the European Committee on Antimicrobial Susceptibility Testing (EUCAST) S. pseudintermedius cefoxitin disk breakpoint. The oxacillin results interpreted by the VET01-S2 (disk and MIC) and M100-S25 CoNS (MIC) breakpoints agreed with the results of mecA/mecC PCR for all isolates, with the exception of one false-resistant result (1.3% of mecA/mecC PCR-negative isolates). In contrast, cefoxitin tests performed poorly, ranging from 3 to 89% false susceptibility (very major errors) and 0 to 48% false resistance (major errors). BD Phoenix, bioMérieux Vitek 2, and Beckman Coulter MicroScan commercial automated susceptibility test panel oxacillin MIC results were also evaluated and demonstrated >95% categorical agreement with mecA/mecC PCR results if interpreted by using the M100-S25 CoNS breakpoint. The Alere penicillin-binding protein 2a test accurately detected all

  18. Consumption of added sugars from liquid but not solid sources predicts impaired glucose homeostasis and insulin resistance among youth at risk of obesity.

    PubMed

    Wang, Jiawei; Light, Kelly; Henderson, Mélanie; O'Loughlin, Jennifer; Mathieu, Marie-Eve; Paradis, Gilles; Gray-Donald, Katherine

    2014-01-01

    Little is known about longitudinal associations between added sugar consumption (solid and liquid sources) and glucose-insulin homeostasis among youth. Caucasian children (8-10 y) with at least one obese biological parent were recruited in the QUébec Adipose and Lifestyle InvesTigation in Youth (QUALITY) cohort (n = 630) and followed-up 2 y later (n = 564). Added sugars were assessed by 3 24-h dietary recalls at baseline. Two-year changes were examined in multivariate linear regression models, adjusting for baseline level, age, sex, Tanner stage, energy intake, fat mass (dual-energy X-ray absorptiometry), and physical activity (7 d accelerometer). Added sugar intake in either liquid or solid sources was not related to changes in adiposity measures (fat mass, body mass index, or waist circumference). However, a higher consumption (10 g/d) of added sugars from liquid sources was associated with 0.04 mmol/L higher fasting glucose, 2.3 pmol/L higher fasting insulin, 0.1 unit higher homeostasis model assessment of insulin resistance (HOMA-IR), and 0.4 unit lower Matsuda-insulin sensitivity index (Matsuda-ISI) in all participants (P < 0.01). No associations were observed with consumption of added sugars from solid sources. Overweight/obese children at baseline had greater increases in adiposity indicators, fasting insulin, and HOMA-IR and decreases in Matsuda-ISI during those 2 y than normal-weight children. Consumption of added sugars from liquid or solid sources was not associated with changes in adiposity, but liquid added sugars were a risk factor for the development of impaired glucose homeostasis and insulin resistance over 2 y among youth at risk of obesity. PMID:24198307

  19. Consumption of added sugars from liquid but not solid sources predicts impaired glucose homeostasis and insulin resistance among youth at risk of obesity.

    PubMed

    Wang, Jiawei; Light, Kelly; Henderson, Mélanie; O'Loughlin, Jennifer; Mathieu, Marie-Eve; Paradis, Gilles; Gray-Donald, Katherine

    2014-01-01

    Little is known about longitudinal associations between added sugar consumption (solid and liquid sources) and glucose-insulin homeostasis among youth. Caucasian children (8-10 y) with at least one obese biological parent were recruited in the QUébec Adipose and Lifestyle InvesTigation in Youth (QUALITY) cohort (n = 630) and followed-up 2 y later (n = 564). Added sugars were assessed by 3 24-h dietary recalls at baseline. Two-year changes were examined in multivariate linear regression models, adjusting for baseline level, age, sex, Tanner stage, energy intake, fat mass (dual-energy X-ray absorptiometry), and physical activity (7 d accelerometer). Added sugar intake in either liquid or solid sources was not related to changes in adiposity measures (fat mass, body mass index, or waist circumference). However, a higher consumption (10 g/d) of added sugars from liquid sources was associated with 0.04 mmol/L higher fasting glucose, 2.3 pmol/L higher fasting insulin, 0.1 unit higher homeostasis model assessment of insulin resistance (HOMA-IR), and 0.4 unit lower Matsuda-insulin sensitivity index (Matsuda-ISI) in all participants (P < 0.01). No associations were observed with consumption of added sugars from solid sources. Overweight/obese children at baseline had greater increases in adiposity indicators, fasting insulin, and HOMA-IR and decreases in Matsuda-ISI during those 2 y than normal-weight children. Consumption of added sugars from liquid or solid sources was not associated with changes in adiposity, but liquid added sugars were a risk factor for the development of impaired glucose homeostasis and insulin resistance over 2 y among youth at risk of obesity.

  20. Transcriptional Signatures Related to Glucose and Lipid Metabolism Predict Treatment Response to the Tumor Necrosis Factor Antagonist Infliximab in Patients with Treatment-Resistant Depression

    PubMed Central

    Mehta, Divya; Raison, Charles L.; Woolwine, Bobbi J.; Haroon, Ebrahim; Binder, Elisabeth B.; Miller, Andrew H.; Felger, Jennifer C.

    2013-01-01

    The tumor necrosis factor (TNF) antagonist infliximab was recently found to reduce depressive symptoms in patients with increased baseline inflammation as reflected by a plasma C-reactive protein concentration >5mg/L. To further explore predictors and targets of response to infliximab, differential gene expression was examined in peripheral blood mononuclear cells from infliximab responders (n=13) versus non-responders (n=14) compared to placebo at baseline and 6hr, 24hr, and 2 weeks after the first infliximab infusion. Treatment response was defined as 50% reduction in depressive symptoms at any point during the 12-week trial. One-hundred-forty-eight gene transcripts were significantly associated (1.2 fold, adjusted p≤0.01) with response to infliximab and were distinct from placebo responders. Transcripts predictive of infliximab response were associated with gluconeogenesis and cholesterol transport, and were enriched in a network regulated by hepatocyte nuclear factor (HNF)4-alpha, a transcription factor involved in gluconeogenesis and cholesterol and lipid homeostasis. Of the 148 transcripts differentially expressed at baseline, 48% were significantly regulated over time in infliximab responders, including genes related to gluconeogenesis and the HNF4-alpha network, indicating that these predictive genes were responsive to infliximab. Responders also demonstrated inhibition of genes related to apoptosis through TNF signaling at 6hr and 24hr after infusion. Transcripts down-regulated in responders 2 weeks after infliximab were related to innate immune signaling and nuclear factor-kappa B. Thus, baseline transcriptional signatures reflective of alterations in glucose and lipid metabolism predicted antidepressant response to infliximab, and infliximab response involved regulation of metabolic genes and inhibition of genes related to innate immune activation. PMID:23624296

  1. Resistance-Resistant Antibiotics

    PubMed Central

    Oldfield, Eric; Feng, Xinxin

    2014-01-01

    New antibiotics are needed because as drug resistance is increasing, the introduction of new antibiotics is decreasing. Here, we discuss six possible approaches to develop ‘resistance-resistant’ antibiotics. First, multi-target inhibitors in which a single compound inhibits more than one target may be easier to develop than conventional combination therapies with two new drugs. Second, inhibiting multiple targets in the same metabolic pathway is expected to be an effective strategy due to synergy. Third, discovering multiple-target inhibitors should be possible by using sequential virtual screening. Fourth, re-purposing existing drugs can lead to combinations of multi-target therapeutics. Fifth, targets need not be proteins. Sixth, inhibiting virulence factor formation and boosting innate immunity may also lead to decreased susceptibility to resistance. Although it is not possible to eliminate resistance, the approaches reviewed here offer several possibilities for reducing the effects of mutations and in some cases suggest that sensitivity to existing antibiotics may be restored, in otherwise drug resistant organisms. PMID:25458541

  2. Differential PAX5 levels promote malignant B cell infiltration, progression and drug resistance and predict a poor prognosis in MCL patients independent of CCND1

    PubMed Central

    Teo, Albert E.; Chen, Zheng; Miranda, Roberto N.; McDonnell, Timothy; Medeiros, L. Jeffrey; McCarty, Nami

    2015-01-01

    Reduced PAX5 levels play important roles in the pathogenesis of human B-cell acute lymphoblastic leukemia. However, the role of PAX5 in human lymphoma remains unclear. We generated PAX5-silenced cells using mantle cell lymphoma (MCL) as a model system. These PAX5− MCL cells exhibited unexpected phenotypes, including increased proliferation in vitro, enhanced tumor infiltration in vivo, robust adhesion to bone marrow stromal cells, and increased retention of quiescent stem-like cells. These phenotypes were attributed to alterations in the expression of genes including p53 and Rb and to PI3 kinase/mTOR and pSTAT3 pathway hyperactivation. Upon PAX5 silencing, the MCL cells displayed upregulated IL-6 expression and increased responses to paracrine IL-6. Moreover, decreased PAX5 levels in CD19+ MCL cells correlated with their increased infiltration and progression; thus, PAX5 levels can be used as a prognostic marker independent of cyclin D1 in advanced MCL patients. Importantly, high-throughput screening of 3800 chemical compounds revealed that PAX5−MCL cells are highly drug-resistant compared to PAX5 wild-type MCL cells. Collectively, the results of our study support a paradigm shift regarding the functions of PAX5 in human B cell cancer and encourage future efforts to design effective therapies against MCL. PMID:26073757

  3. The Methicillin-resistant Staphylococcus aureus (MRSA) Nasal Real-time PCR: A Predictive Tool for Contamination of the Hospital Environment

    PubMed Central

    Livorsi, DJ; Arif, S; Garry, P; Kundu, MG; Satola, SW; Davis, TH; Batteiger, B; Kressel, AB

    2016-01-01

    Introduction We sought to determine whether the bacterial burden in the nares, as determined by the cycle threshold (CT) value from real-time MRSA PCR, is predictive of environmental contamination with MRSA. Methods Patients identified as MRSA nasal carriers per hospital protocol were enrolled within 72 hours of room admission. Patients were excluded if 1) nasal mupirocin or chlorhexidine body-wash was used within the past month or 2) an active MRSA infection was suspected. Four environmental sites, 6 body sites and a wound, if present, were cultured with pre-moistened swabs. All nasal swabs were submitted for both a quantitative culture and real-time PCR (Roche Lightcycler, Indianapolis, IN). Results 82 patients had a positive MRSA-PCR at study enrollment. There was a negative correlation of moderate strength between the CT value and the number of MRSA colonies in the nares (r= −0.61, p<0.01). Current antibiotic use was associated with lower levels of MRSA nasal colonization (CT value: 30.2 vs. 27.7, p<0.01). Patients who had concomitant environmental contamination had higher median log MRSA nares count (3.9 vs. 2.5, p=0.01) and lower CT values (28.0 vs. 30.2, p<0.01). However, a ROC curve was unable to identify a threshold MRSA nares count that reliably excluded environmental contamination. Conclusions Patients with a higher burden of MRSA in their nares, based on the CT value, were more likely to contaminate their environment with MRSA. However, contamination of the environment cannot be predicted solely by the degree of MRSA nasal colonization. PMID:25627759

  4. Antibiotic Resistance

    MedlinePlus

    ... lives. But there is a growing problem of antibiotic resistance. It happens when bacteria change and become able ... resistant to several common antibiotics. To help prevent antibiotic resistance Don't use antibiotics for viruses like colds ...

  5. Drug Resistance

    MedlinePlus

    HIV Treatment Drug Resistance (Last updated 3/1/2016; last reviewed 3/1/2016) Key Points As HIV multiplies in the ... the risk of drug resistance. What is HIV drug resistance? Once a person becomes infected with HIV, ...

  6. A prognostic index model for predicting overall survival in patients with metastatic castration-resistant prostate cancer treated with abiraterone acetate after docetaxel

    PubMed Central

    Chi, K. N.; Kheoh, T.; Ryan, C. J.; Molina, A.; Bellmunt, J.; Vogelzang, N. J.; Rathkopf, D. E.; Fizazi, K.; Kantoff, P. W.; Li, J.; Azad, A. A.; Eigl, B. J.; Heng, D. Y. C.; Joshua, A. M.; de Bono, J. S.; Scher, H. I.

    2016-01-01

    Background Few prognostic models for overall survival (OS) are available for patients with metastatic castration-resistant prostate cancer (mCRPC) treated with recently approved agents. We developed a prognostic index model using readily available clinical and laboratory factors from a phase III trial of abiraterone acetate (hereafter abiraterone) in combination with prednisone in post-docetaxel mCRPC. Patients and methods Baseline data were available from 762 patients treated with abiraterone–prednisone. Factors were assessed for association with OS through a univariate Cox model and used in a multivariate Cox model with a stepwise procedure to identify those of significance. Data were validated using an independent, external, population-based cohort. Results Six risk factors individually associated with poor prognosis were included in the final model: lactate dehydrogenase > upper limit of normal (ULN) [hazard ratio (HR) = 2.31], Eastern Cooperative Oncology Group performance status of 2 (HR = 2.19), presence of liver metastases (HR = 2.00), albumin ≤4 g/dl (HR = 1.54), alkaline phosphatase > ULN (HR = 1.38) and time from start of initial androgen-deprivation therapy to start of treatment ≤36 months (HR = 1.30). Patients were categorized into good (n = 369, 46%), intermediate (n = 321, 40%) and poor (n = 107, 13%) prognosis groups based on the number of risk factors and relative HRs. The C-index was 0.70 ± 0.014. The model was validated by the external dataset (n = 286). Conclusion This analysis identified six factors used to model survival in mCRPC and categorized patients into three distinct risk groups. Prognostic stratification with this model could assist clinical practice decisions for follow-up and monitoring, and may aid in clinical trial design. Trial registration numbers NCT00638690. PMID:26685010

  7. Pathways to Tamoxifen Resistance

    PubMed Central

    Riggins, Rebecca B.; Schrecengost, Randy S.; Guerrero, Michael S.; Bouton, Amy H.

    2007-01-01

    Therapies that target the synthesis of estrogen or the function of estrogen receptor(s) have been developed to treat breast cancer. While these approaches have proven to be beneficial to a large number of patients, both de novo and acquired resistance to these drugs is a significant problem. Recent advances in our understanding of the molecular mechanisms that contribute to resistance have provided a means to begin to predict patient responses to these drugs and develop rational approaches for combining therapeutic agents to circumvent or desensitize the resistant phenotype. Here, we review common mechanisms of antiestrogen resistance and discuss the implications for prediction of response and design of effective combinatorial treatments. PMID:17475399

  8. Nadir Testosterone Within First Year of Androgen-Deprivation Therapy (ADT) Predicts for Time to Castration-Resistant Progression: A Secondary Analysis of the PR-7 Trial of Intermittent Versus Continuous ADT

    PubMed Central

    Klotz, Laurence; O'Callaghan, Chris; Ding, Keyue; Toren, Paul; Dearnaley, David; Higano, Celestia S.; Horwitz, Eric; Malone, Shawn; Goldenberg, Larry; Gospodarowicz, Mary; Crook, Juanita M.

    2015-01-01

    Purpose Three small retrospective studies have suggested that patients undergoing continuous androgen deprivation (CAD) have superior survival and time to progression if lower castrate levels of testosterone (< 0.7 nmol/L) are achieved. Evidence from prospective large studies has been lacking. Patients and Methods The PR-7 study randomly assigned patients experiencing biochemical failure after radiation therapy or surgery plus radiation therapy to CAD or intermittent androgen deprivation. The relationship between testosterone levels in the first year and cause-specific survival (CSS) and time to androgen-independent progression in men in the CAD arm was evaluated using Cox regression. Results There was a significant difference in CSS (P = .015) and time to hormone resistance (P = .02) among those who had first-year minimum nadir testosterone ≤ 0.7, > 0.7 to ≤ 1.7, and ≥ 1.7 nmol/L. Patients with first-year nadir testosterone consistently > 0.7 nmol/L had significantly higher risks of dying as a result of disease (0.7 to 1.7 nmol/L: hazard ratio [HR], 2.08; 95% CI, 1.28 to 3.38; > 1.7 nmol/L: HR, 2.93; 95% CI, 0.70 to 12.30) and developing hormone resistance (0.7 to 1.7 nmol/L: HR, 1.62; 95% CI, 1.20 to 2.18; ≥ 1.7 nmol/L: HR, 1.90; 95% CI, 0.77 to 4.70). Maximum testosterone ≥ 1.7 nmol/L predicted for a higher risk of dying as a result of disease (P = .02). Conclusion Low nadir serum testosterone (ie, < 0.7 mmol/L) within the first year of androgen-deprivation therapy correlates with improved CSS and duration of response to androgen deprivation in men being treated for biochemical failure undergoing CAD. PMID:25732157

  9. Initial Molecular Response at 3 Months May Predict Both Response and Event-Free Survival at 24 Months in Imatinib-Resistant or -Intolerant Patients With Philadelphia Chromosome–Positive Chronic Myeloid Leukemia in Chronic Phase Treated With Nilotinib

    PubMed Central

    Branford, Susan; Kim, Dong-Wook; Soverini, Simona; Haque, Ariful; Shou, Yaping; Woodman, Richard C.; Kantarjian, Hagop M.; Martinelli, Giovanni; Radich, Jerald P.; Saglio, Giuseppe; Hochhaus, Andreas; Hughes, Timothy P.; Müller, Martin C.

    2012-01-01

    Purpose The association between initial molecular response and longer-term outcomes with nilotinib was examined. Patients and Methods Patients with imatinib-resistant or -intolerant chronic myeloid leukemia in chronic phase from the phase II nilotinib registration study with available postbaseline BCR-ABL1 transcript assessments were included (N = 237). Results BCR-ABL1 transcript levels (International Scale [IS]) at 3 months correlated with complete cytogenetic response (CCyR) by 24 months. Patients with BCR-ABL1 (IS) of > 1% to ≤ 10% at 3 months with nilotinib had higher cumulative incidence of CCyR by 24 months than patients with BCR-ABL1 (IS) of > 10% (53% v 16%). BCR-ABL1 (IS) at 3 months predicted major molecular response (MMR) by 24 months. Cumulative incidence of MMR by 24 months for patients with BCR-ABL1 (IS) of > 0.1% to ≤ 1%, > 1% to ≤ 10%, and > 10% was 65%, 27%, and 9%, respectively. These differences were observed for patients with or without baseline BCR–ABL1 mutations and for those with imatinib resistance or intolerance. Estimated event-free survival (EFS) rates at 24 months decreased with higher transcript levels at 3 months; patients with BCR-ABL1 (IS) of ≤ 1% had an estimated 24-month EFS rate of 82%, compared with 70% for patients with BCR-ABL1 (IS) of > 1% to ≤ 10% and 48% for patients with BCR-ABL1 (IS) of > 10%. Conclusion Patients with BCR-ABL1 (IS) of > 10% at 3 months had a lower cumulative incidence of CCyR and MMR and lower rates of EFS versus patients with BCR-ABL1 (IS) of ≤ 10%. Prospective studies may determine whether close monitoring or alternative therapies are warranted for patients with minimal initial molecular response. PMID:23109697

  10. The Prehistory of Antibiotic Resistance.

    PubMed

    Perry, Julie; Waglechner, Nicholas; Wright, Gerard

    2016-01-01

    Antibiotic resistance is a global problem that is reaching crisis levels. The global collection of resistance genes in clinical and environmental samples is the antibiotic "resistome," and is subject to the selective pressure of human activity. The origin of many modern resistance genes in pathogens is likely environmental bacteria, including antibiotic producing organisms that have existed for millennia. Recent work has uncovered resistance in ancient permafrost, isolated caves, and in human specimens preserved for hundreds of years. Together with bioinformatic analyses on modern-day sequences, these studies predict an ancient origin of resistance that long precedes the use of antibiotics in the clinic. Understanding the history of antibiotic resistance is important in predicting its future evolution. PMID:27252395

  11. Antibiotic Resistance

    MedlinePlus

    ... For Consumers Consumer Information by Audience For Women Antibiotic Resistance Share Tweet Linkedin Pin it More sharing options ... these products really help. To Learn More about Antibiotic Resistance Get Smart About Antibiotics (Video) Fact Sheets and ...

  12. RESISTIVITY METHODS

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Resistivity methods were among the first geophysical techniques developed. The basic concept originated with Conrad Schlumberger, who conducted the initial resistivity field tests in Normandy, France during 1912. The resistivity method, employed in its earliest and most conventional form, uses an ex...

  13. Antimicrobial (Drug) Resistance

    MedlinePlus

    ... Antimicrobial (Drug) Resistance Antibiotic-Resistant Mycobacterium tuberculosis (TB) Methicillin-Resistant Staphylococcus aureus (MRSA) Vancomycin-Resistant Enterococci (VRE) Multidrug-Resistant Neisseria ...

  14. Antibiotic resistance of Streptococcus agalactiae from cows with mastitis.

    PubMed

    Gao, Jian; Yu, Fu-Qing; Luo, Li-Ping; He, Jian-Zhong; Hou, Rong-Guang; Zhang, Han-Qi; Li, Shu-Mei; Su, Jing-Liang; Han, Bo

    2012-12-01

    The aim of this study was to characterise the phenotypic and genotypic antibiotic resistance patterns of Streptococcus agalactiae isolated from cows with mastitis in China. Antibiotic resistance was based on minimum inhibitory concentrations and detection of resistance genes by PCR. S. agalactiae isolates most frequently exhibited phenotypic resistance to tetracycline, while the resistance genes most frequently detected were ermB, tetL and tetM. Resistance genes were detected in some susceptible isolates, whereas no resistance genes could be detected in some resistant isolates, indicating that the resistance genotype does not accurately predict phenotypic resistance. PMID:22627045

  15. Transgenic resistance.

    PubMed

    Cillo, Fabrizio; Palukaitis, Peter

    2014-01-01

    Transgenic resistance to plant viruses is an important technology for control of plant virus infection, which has been demonstrated for many model systems, as well as for the most important plant viruses, in terms of the costs of crop losses to disease, and also for many other plant viruses infecting various fruits and vegetables. Different approaches have been used over the last 28 years to confer resistance, to ascertain whether particular genes or RNAs are more efficient at generating resistance, and to take advantage of advances in the biology of RNA interference to generate more efficient and environmentally safer, novel "resistance genes." The approaches used have been based on expression of various viral proteins (mostly capsid protein but also replicase proteins, movement proteins, and to a much lesser extent, other viral proteins), RNAs [sense RNAs (translatable or not), antisense RNAs, satellite RNAs, defective-interfering RNAs, hairpin RNAs, and artificial microRNAs], nonviral genes (nucleases, antiviral inhibitors, and plantibodies), and host-derived resistance genes (dominant resistance genes and recessive resistance genes), and various factors involved in host defense responses. This review examines the above range of approaches used, the viruses that were tested, and the host species that have been examined for resistance, in many cases describing differences in results that were obtained for various systems developed in the last 20 years. We hope this compilation of experiences will aid those who are seeking to use this technology to provide resistance in yet other crops, where nature has not provided such.

  16. Resistance mechanisms

    PubMed Central

    Cag, Yasemin; Caskurlu, Hulya; Fan, Yanyan; Cao, Bin

    2016-01-01

    By definition, the terms sepsis and septic shock refer to a potentially fatal infectious state in which the early administration of an effective antibiotic is the most significant determinant of the outcome. Because of the global spread of resistant bacteria, the efficacy of antibiotics has been severely compromised. S. pneumonia, Escherichia coli (E. coli), Klebsiella, Acinetobacter, and Pseudomonas are the predominant pathogens of sepsis and septic shock. It is common for E. coli, Klebsiella, Acinetobacter and Pseudomonas to be resistant to multiple drugs. Multiple drug resistance is caused by the interplay of multiple resistance mechanisms those emerge via the acquisition of extraneous resistance determinants or spontaneous mutations. Extended-spectrum beta-lactamases (ESBLs), carbapenemases, aminoglycoside-modifying enzymes (AMEs) and quinolone resistance determinants are typically external and disseminate on mobile genetic elements, while porin-efflux mechanisms are activated by spontaneous modifications of inherited structures. Porin and efflux mechanisms are frequent companions of multiple drug resistance in Acinetobacter and P. aeruginosa, but only occasionally detected among E. coli and Klebsiella. Antibiotic resistance became a global health threat. This review examines the major resistance mechanisms of the leading microorganisms of sepsis. PMID:27713884

  17. Transgenic resistance.

    PubMed

    Cillo, Fabrizio; Palukaitis, Peter

    2014-01-01

    Transgenic resistance to plant viruses is an important technology for control of plant virus infection, which has been demonstrated for many model systems, as well as for the most important plant viruses, in terms of the costs of crop losses to disease, and also for many other plant viruses infecting various fruits and vegetables. Different approaches have been used over the last 28 years to confer resistance, to ascertain whether particular genes or RNAs are more efficient at generating resistance, and to take advantage of advances in the biology of RNA interference to generate more efficient and environmentally safer, novel "resistance genes." The approaches used have been based on expression of various viral proteins (mostly capsid protein but also replicase proteins, movement proteins, and to a much lesser extent, other viral proteins), RNAs [sense RNAs (translatable or not), antisense RNAs, satellite RNAs, defective-interfering RNAs, hairpin RNAs, and artificial microRNAs], nonviral genes (nucleases, antiviral inhibitors, and plantibodies), and host-derived resistance genes (dominant resistance genes and recessive resistance genes), and various factors involved in host defense responses. This review examines the above range of approaches used, the viruses that were tested, and the host species that have been examined for resistance, in many cases describing differences in results that were obtained for various systems developed in the last 20 years. We hope this compilation of experiences will aid those who are seeking to use this technology to provide resistance in yet other crops, where nature has not provided such. PMID:25410101

  18. Climate prediction and predictability

    NASA Astrophysics Data System (ADS)

    Allen, Myles

    2010-05-01

    Climate prediction is generally accepted to be one of the grand challenges of the Geophysical Sciences. What is less widely acknowledged is that fundamental issues have yet to be resolved concerning the nature of the challenge, even after decades of research in this area. How do we verify or falsify a probabilistic forecast of a singular event such as anthropogenic warming over the 21st century? How do we determine the information content of a climate forecast? What does it mean for a modelling system to be "good enough" to forecast a particular variable? How will we know when models and forecasting systems are "good enough" to provide detailed forecasts of weather at specific locations or, for example, the risks associated with global geo-engineering schemes. This talk will provide an overview of these questions in the light of recent developments in multi-decade climate forecasting, drawing on concepts from information theory, machine learning and statistics. I will draw extensively but not exclusively from the experience of the climateprediction.net project, running multiple versions of climate models on personal computers.

  19. Resistant Hypertension.

    PubMed

    Doroszko, Adrian; Janus, Agnieszka; Szahidewicz-Krupska, Ewa; Mazur, Grzegorz; Derkacz, Arkadiusz

    2016-01-01

    Resistant hypertension is a severe medical condition which is estimated to appear in 9-18% of hypertensive patients. Due to higher cardiovascular risk, this disorder requires special diagnosis and treatment. The heterogeneous etiology, risk factors and comorbidities of resistant hypertension stand in need of sophisticated evaluation to confirm the diagnosis and select the best therapeutic options, which should consider lifestyle modifications as well as pharmacological and interventional treatment. After having excluded pseudohypertension, inappropriate blood pressure measurement and control as well as the white coat effect, suspicion of resistant hypertension requires an analysis of drugs which the hypertensive patient is treated with. According to one definition - ineffective treatment with 3 or more antihypertensive drugs including diuretics makes it possible to diagnose resistant hypertension. A multidrug therapy including angiotensin - converting enzyme inhibitors, angiotensin II receptor blockers, beta blockers, diuretics, long-acting calcium channel blockers and mineralocorticoid receptor antagonists has been demonstrated to be effective in resistant hypertension treatment. Nevertheless, optional, innovative therapies, e.g. a renal denervation or baroreflex activation, may create a novel pathway of blood pressure lowering procedures. The right diagnosis of this disease needs to eliminate the secondary causes of resistant hypertension e.g. obstructive sleep apnea, atherosclerosis and renal or hormonal disorders. This paper briefly summarizes the identification of the causes of resistant hypertension and therapeutic strategies, which may contribute to the proper diagnosis and an improvement of the long term management of resistant hypertension.

  20. Managing Resistance.

    ERIC Educational Resources Information Center

    Maag, John W.

    2000-01-01

    This article presents some considerations and ideas for managing students' resistance. They are organized around four topics: the impact of context on behavior, the importance of being comprehensive and nonrestrictive in behavior, the adaptive function of resistant behavior, and the benefit of joining children in their frame of reference.…

  1. Resisting HRD's Resistance to Diversity

    ERIC Educational Resources Information Center

    Bierema, Laura L.

    2010-01-01

    Purpose: The purpose of this paper is to empirically illustrate how human resource development (HRD) resists and omits issues of diversity in academic programs, textbooks, and research; analyze the research on HRD and diversity over a ten-year period; discuss HRD's resistance to diversity; and offer some recommendations for a more authentic…

  2. Earthquake prediction

    NASA Technical Reports Server (NTRS)

    Turcotte, Donald L.

    1991-01-01

    The state of the art in earthquake prediction is discussed. Short-term prediction based on seismic precursors, changes in the ratio of compressional velocity to shear velocity, tilt and strain precursors, electromagnetic precursors, hydrologic phenomena, chemical monitors, and animal behavior is examined. Seismic hazard assessment is addressed, and the applications of dynamical systems to earthquake prediction are discussed.

  3. Resistivity analysis

    DOEpatents

    Bruce, Michael R.; Bruce, Victoria J.; Ring, Rosalinda M.; Cole, Edward Jr. I.; Hawkins, Charles F.; Tangyungong, Paiboon

    2006-06-13

    According to an example embodiment of the present invention a semiconductor die having a resistive electrical connection is analyzed. Heat is directed to the die as the die is undergoing a state-changing operation to cause a failure due to suspect circuitry. The die is monitored, and a circuit path that electrically changes in response to the heat is detected and used to detect that a particular portion therein of the circuit is resistive. In this manner, the detection and localization of a semiconductor die defect that includes a resistive portion of a circuit path is enhanced.

  4. Antimicrobial Resistance

    MedlinePlus

    ... and health professionals can play their part; rewarding innovation and development of new treatment options and other ... and industry can help tackle resistance by: fostering innovation and research and development of new vaccines, diagnostics, ...

  5. Antimicrobial Resistance

    MedlinePlus

    ... antibiotic are known as methicillin-resistant S. aureus or MRSA. Antibiotics and other antimicrobial drugs first became widely ... factors for infection are known as community-associated MRSA (CA-MRSA). Recently, several cases overseas and in ...

  6. Lantibiotic Resistance

    PubMed Central

    Draper, Lorraine A.; Ross, R. Paul

    2015-01-01

    SUMMARY The dramatic rise in the incidence of antibiotic resistance demands that new therapeutic options will have to be developed. One potentially interesting class of antimicrobials are the modified bacteriocins termed lantibiotics, which are bacterially produced, posttranslationally modified, lanthionine/methyllanthionine-containing peptides. It is interesting that low levels of resistance have been reported for lantibiotics compared with commercial antibiotics. Given that there are very few examples of naturally occurring lantibiotic resistance, attempts have been made to deliberately induce resistance phenotypes in order to investigate this phenomenon. Mechanisms that hinder the action of lantibiotics are often innate systems that react to the presence of any cationic peptides/proteins or ones which result from cell well damage, rather than being lantibiotic specific. Such resistance mechanisms often arise due to altered gene regulation following detection of antimicrobials/cell wall damage by sensory proteins at the membrane. This facilitates alterations to the cell wall or changes in the composition of the membrane. Other general forms of resistance include the formation of spores or biofilms, which are a common mechanistic response to many classes of antimicrobials. In rare cases, bacteria have been shown to possess specific antilantibiotic mechanisms. These are often species specific and include the nisin lytic protein nisinase and the phenomenon of immune mimicry. PMID:25787977

  7. Lantibiotic resistance.

    PubMed

    Draper, Lorraine A; Cotter, Paul D; Hill, Colin; Ross, R Paul

    2015-06-01

    The dramatic rise in the incidence of antibiotic resistance demands that new therapeutic options will have to be developed. One potentially interesting class of antimicrobials are the modified bacteriocins termed lantibiotics, which are bacterially produced, posttranslationally modified, lanthionine/methyllanthionine-containing peptides. It is interesting that low levels of resistance have been reported for lantibiotics compared with commercial antibiotics. Given that there are very few examples of naturally occurring lantibiotic resistance, attempts have been made to deliberately induce resistance phenotypes in order to investigate this phenomenon. Mechanisms that hinder the action of lantibiotics are often innate systems that react to the presence of any cationic peptides/proteins or ones which result from cell well damage, rather than being lantibiotic specific. Such resistance mechanisms often arise due to altered gene regulation following detection of antimicrobials/cell wall damage by sensory proteins at the membrane. This facilitates alterations to the cell wall or changes in the composition of the membrane. Other general forms of resistance include the formation of spores or biofilms, which are a common mechanistic response to many classes of antimicrobials. In rare cases, bacteria have been shown to possess specific antilantibiotic mechanisms. These are often species specific and include the nisin lytic protein nisinase and the phenomenon of immune mimicry. PMID:25787977

  8. Prediction of drug-resistance using genotypic and docking analysis among anti-retroviral therapy naïve and first-line treatment failures in Salem, Tamil Nadu, India.

    PubMed

    Dharmalingam, Thirunavukkarasu; Udhaya, V; Umaarasu, T; Elangovan, V; Rajesh, S V; Shanmugam, Gnanendra

    2015-01-01

    The emergence of drug resistance among HIV-positive patients undergoing Anti- Retroviral Therapy (ART) with poor adherence to the HAART is a major concern in India. As the HIV accumulates the key mutations, the drug resistance occurs, that pose challenges to the ART regimens currently being used. Thus, the present study was carried out among the ART- naïve patients attending ART Centre at Salem district, Tamil Nadu, India. The mutations that concern the drug resistance were discriminated by determining the viral load before and after 6 months. The drug resistance was analyzed by HIV genotyping from the patients possessing a viral load of >1000 copies/mL after 6 months of ART. The mutations pertaining to drug resistance were analyzed by the online Stanford HIV Database. The 3D structures of the RT were modeled and the drugs used in the first-line regimens were docked to explore the effect of mutations on the binding pattern of the drugs. Among the 250 patients, the viral load data were obtained for 213 patients. The study found 23 patients with both virological and immunological failures and HIV drug mutations were also revealed by genotyping. The mutations of I135R/T/V/X, L178 I/M, M184V/I, D67N, K70R, and K103N were the most common among these 23 patients. The present study revealed that the NACO recommended first-line ART regimen is efficient in most of the patients attending ART center. The emergence of drug resistance of HIV variant is common even under the best circumstance of ART. This study reveals that there is a necessity for the implementation of improved and economically systematic attempt that allows the clinicians to make a rational choice of therapy regimen to overcome the first-line therapy failures among the ART- naive.

  9. Novel resistance functions uncovered using functional metagenomic investigations of resistance reservoirs

    PubMed Central

    Pehrsson, Erica C.; Forsberg, Kevin J.; Gibson, Molly K.; Ahmadi, Sara; Dantas, Gautam

    2013-01-01

    Rates of infection with antibiotic-resistant bacteria have increased precipitously over the past several decades, with far-reaching healthcare and societal costs. Recent evidence has established a link between antibiotic resistance genes in human pathogens and those found in non-pathogenic, commensal, and environmental organisms, prompting deeper investigation of natural and human-associated reservoirs of antibiotic resistance. Functional metagenomic selections, in which shotgun-cloned DNA fragments are selected for their ability to confer survival to an indicator host, have been increasingly applied to the characterization of many antibiotic resistance reservoirs. These experiments have demonstrated that antibiotic resistance genes are highly diverse and widely distributed, many times bearing little to no similarity to known sequences. Through unbiased selections for survival to antibiotic exposure, functional metagenomics can improve annotations by reducing the discovery of false-positive resistance and by allowing for the identification of previously unrecognizable resistance genes. In this review, we summarize the novel resistance functions uncovered using functional metagenomic investigations of natural and human-impacted resistance reservoirs. Examples of novel antibiotic resistance genes include those highly divergent from known sequences, those for which sequence is entirely unable to predict resistance function, bifunctional resistance genes, and those with unconventional, atypical resistance mechanisms. Overcoming antibiotic resistance in the clinic will require a better understanding of existing resistance reservoirs and the dissemination networks that govern horizontal gene exchange, informing best practices to limit the spread of resistance-conferring genes to human pathogens. PMID:23760651

  10. [Resistant fungi].

    PubMed

    Vehreschild, M J G T; Cornely, O A

    2015-11-01

    Particularly in the area of hematology/oncology and intensive care medicine, infections due to resistant fungi are to be expected. Emergence of resistance in fungi is a less dynamic process than in bacteria; it can, however, have an equally important impact on treatment strategies. In the following article, the most important resistance patterns of yeasts and molds (Candida albicans , Aspergillus fumigatus, the order Mucorales and the genus Fusarium) will be presented and discussed. Their diagnosis mostly being based on blood cultures, resistance testing for yeasts is usually readily available. Culture-based therapeutic adjustments in mold infections are, however, only rarely possible, as most antifungal therapies for these infections are initiated on an empirical basis after identification of typical infiltrates on a CT scan. Response to therapy is then evaluated on the basis of clinical signs and symptoms in combination with follow-up CT scans. In case of therapeutic failure or appearance of suspicious infiltrates under antifungal prophylaxis, an open or CT-guided biopsy is recommended to allow efficient adaptation of antifungal treatment. In individual cases, particularly in patients diagnosed with mucormycosis, resection of the focus of infection may be necessary to achieve a satisfactory treatment response.

  11. The evolution of fungicide resistance.

    PubMed

    Lucas, John A; Hawkins, Nichola J; Fraaije, Bart A

    2015-01-01

    Fungicides are widely used in developed agricultural systems to control disease and safeguard crop yield and quality. Over time, however, resistance to many of the most effective fungicides has emerged and spread in pathogen populations, compromising disease control. This review describes the development of resistance using case histories based on four important diseases of temperate cereal crops: eyespot (Oculimacula yallundae and Oculimacula acuformis), Septoria tritici blotch (Zymoseptoria tritici), powdery mildew (Blumeria graminis), and Fusarium ear blight (a complex of Fusarium and Microdochium spp). The sequential emergence of variant genotypes of these pathogens with reduced sensitivity to the most active single-site fungicides, methyl benzimidazole carbamates, demethylation inhibitors, quinone outside inhibitors, and succinate dehydrogenase inhibitors illustrates an ongoing evolutionary process in response to the introduction and use of different chemical classes. Analysis of the molecular mechanisms and genetic basis of resistance has provided more rapid and precise methods for detecting and monitoring the incidence of resistance in field populations, but when or where resistance will occur remains difficult to predict. The extent to which the predictability of resistance evolution can be improved by laboratory mutagenesis studies and fitness measurements, comparison between pathogens, and reconstruction of evolutionary pathways is discussed. Risk models based on fungal life cycles, fungicide properties, and exposure to the fungicide are now being refined to take account of additional traits associated with the rate of pathogen evolution. Experimental data on the selection of specific mutations or resistant genotypes in pathogen populations in response to fungicide treatments can be used in models evaluating the most effective strategies for reducing or preventing resistance. Resistance management based on robust scientific evidence is vital to prolong

  12. Fine mapping of QTL and genomic prediction using allele-specific expression SNPs demonstrates that the complex trait of genetic resistance to Marek’s disease is predominantly determined by transcriptional regulation

    Technology Transfer Automated Retrieval System (TEKTRAN)

    The hypothesis that polymorphisms associated with transcriptional regulation are critical for viral disease resistance was tested by selecting birds using SNPs exhibiting allele-specific expression (ASE) in response to viral challenge. Analysis indicates ASE markers account for 83% of the disease re...

  13. Static penetration resistance of soils

    NASA Technical Reports Server (NTRS)

    Durgunoglu, H. T.; Mitchell, J. K.

    1973-01-01

    Model test results were used to define the failure mechanism associated with the static penetration resistance of cohesionless and low-cohesion soils. Knowledge of this mechanism has permitted the development of a new analytical method for calculating the ultimate penetration resistance which explicitly accounts for penetrometer base apex angle and roughness, soil friction angle, and the ratio of penetration depth to base width. Curves relating the bearing capacity factors to the soil friction angle are presented for failure in general shear. Strength parameters and penetrometer interaction properties of a fine sand were determined and used as the basis for prediction of the penetration resistance encountered by wedge, cone, and flat-ended penetrometers of different surface roughness using the proposed analytical method. Because of the close agreement between predicted values and values measured in laboratory tests, it appears possible to deduce in-situ soil strength parameters and their variation with depth from the results of static penetration tests.

  14. Anthelmintic resistance.

    PubMed

    Waller, P J

    1997-11-01

    Since the first reports of resistance to the broad spectrum anthelmintics were made some three decades ago, this phenomenon has changed from being considered merely as a parasitological curiosity to a state of industry crisis in certain livestock sectors. This extreme situation exists with the small ruminant industry of the tropical/sub-tropical region of southern Latin America where resistance to the entire broad spectrum anthelmintic arsenal now occurs. In contrast, the cattle industry does not appear to be threatened--or so it seems. Although field reports of resistance have been made to the range of broad spectrum anthelmintics in nematode parasites of cattle, it appears that the evolution of resistance in cattle parasites is not as dramatic as for sheep worms. However, one cannot remain confident that this state of affairs will remain static. Concern is shared amongst parasitologists that we have not looked closely enough. In regions of the world where internal parasites are considered a problem in cattle and drenching occurs frequently, no widespread surveys have been carried out. It appears that because of the very high costs and risks associated with taking a new active drug down the development track to marketing, that the pharmaceutical industry has, in general, turned away from this activity. By implication, the international small ruminant industry is too small for these companies to make the necessary investment. This begs two questions: What is the fate of the sheep (and goat) industries in those parts of the world where resistance is rampant and immediate ameliorative parasite control options are required? What will be the response if significant resistance is found in cattle parasites? There is a body of opinion which suggests that if resistance becomes an issue in the control of cattle parasites then the pharmaceutical industry will find it commercially attractive to re-enter the anthelmintic discovery and development business. This is based on the

  15. [Resistant hypertension].

    PubMed

    Feldstein, Carlos A

    2008-04-01

    Resistant hypertension, defined as a persistent blood pressure over 140/90 mmHg despite the use of three antihypertensive drugs including a diuretic, is unusual. The diagnosis requires ruling out initially pseudoresistance and a lack of compliance with treatment. Ambulatory blood pressure recording allow the recognition of white coat hypertension. When there is a clinical or laboratory suspicion, secondary causes of hypertension should be discarded. Excessive salt intake, the presence of concomitant diseases such as diabetes mellitus, chronic renal disease, obesity, and psychiatric conditions such as panic attacks, anxiety and depression, should also be sought. The presence of target organ damage requires a more aggressive treatment of hypertension. Recent clinical studies indicate that the administration of aldosterone antagonists as a fourth therapeutic line provides significant additional blood pressure reduction, when added to previous antihypertensive regimens in subjects with resistant hypertension. The possible blood pressure lowering effects of prolonged electrical activation of carotid baroreceptors is under investigation. PMID:18769797

  16. [Resistant hypertension].

    PubMed

    Feldstein, Carlos A

    2008-04-01

    Resistant hypertension, defined as a persistent blood pressure over 140/90 mmHg despite the use of three antihypertensive drugs including a diuretic, is unusual. The diagnosis requires ruling out initially pseudoresistance and a lack of compliance with treatment. Ambulatory blood pressure recording allow the recognition of white coat hypertension. When there is a clinical or laboratory suspicion, secondary causes of hypertension should be discarded. Excessive salt intake, the presence of concomitant diseases such as diabetes mellitus, chronic renal disease, obesity, and psychiatric conditions such as panic attacks, anxiety and depression, should also be sought. The presence of target organ damage requires a more aggressive treatment of hypertension. Recent clinical studies indicate that the administration of aldosterone antagonists as a fourth therapeutic line provides significant additional blood pressure reduction, when added to previous antihypertensive regimens in subjects with resistant hypertension. The possible blood pressure lowering effects of prolonged electrical activation of carotid baroreceptors is under investigation.

  17. PREDICTIVE MODELS

    SciTech Connect

    Ray, R.M. )

    1986-12-01

    PREDICTIVE MODELS is a collection of five models - CFPM, CO2PM, ICPM, PFPM, and SFPM - used in the 1982-1984 National Petroleum Council study of enhanced oil recovery (EOR) potential. Each pertains to a specific EOR process designed to squeeze additional oil from aging or spent oil fields. The processes are: 1) chemical flooding, where soap-like surfactants are injected into the reservoir to wash out the oil; 2) carbon dioxide miscible flooding, where carbon dioxide mixes with the lighter hydrocarbons making the oil easier to displace; 3) in-situ combustion, which uses the heat from burning some of the underground oil to thin the product; 4) polymer flooding, where thick, cohesive material is pumped into a reservoir to push the oil through the underground rock; and 5) steamflood, where pressurized steam is injected underground to thin the oil. CFPM, the Chemical Flood Predictive Model, models micellar (surfactant)-polymer floods in reservoirs, which have been previously waterflooded to residual oil saturation. Thus, only true tertiary floods are considered. An option allows a rough estimate of oil recovery by caustic or caustic-polymer processes. CO2PM, the Carbon Dioxide miscible flooding Predictive Model, is applicable to both secondary (mobile oil) and tertiary (residual oil) floods, and to either continuous CO2 injection or water-alternating gas processes. ICPM, the In-situ Combustion Predictive Model, computes the recovery and profitability of an in-situ combustion project from generalized performance predictive algorithms. PFPM, the Polymer Flood Predictive Model, is switch-selectable for either polymer or waterflooding, and an option allows the calculation of the incremental oil recovery and economics of polymer relative to waterflooding. SFPM, the Steamflood Predictive Model, is applicable to the steam drive process, but not to cyclic steam injection (steam soak) processes.

  18. Pre-resistance-welding resistance check

    DOEpatents

    Destefan, Dennis E.; Stompro, David A.

    1991-01-01

    A preweld resistance check for resistance welding machines uses an open circuited measurement to determine the welding machine resistance, a closed circuit measurement to determine the parallel resistance of a workpiece set and the machine, and a calculation to determine the resistance of the workpiece set. Any variation in workpiece set or machine resistance is an indication that the weld may be different from a control weld.

  19. Predicting asthma outcomes.

    PubMed

    Sears, Malcolm R

    2015-10-01

    This review addresses predictors of remission or persistence of wheezing and asthma from early childhood through adulthood. Early childhood wheezing is common, but predicting who will remit or have persistent childhood asthma remains difficult. By adding parental history of asthma and selected infant biomarkers to the history of recurrent wheezing, the Asthma Predictive Index and its subsequent modifications provide better predictions of persistence than simply the observation of recurrent wheeze. Sensitization, especially to multiple allergens, increases the likelihood of development of classic childhood asthma. Remission is more likely in male subjects and those with milder disease (less frequent and less severe symptoms), less atopic sensitization, a lesser degree of airway hyperresponsiveness, and no concomitant allergic disease. Conversely, persistence is linked strongly to allergic sensitization, greater frequency and severity of symptoms, abnormal lung function, and a greater degree of airway hyperresponsiveness. A genetic risk score might predict persistence more accurately than family history. Remission of established adult asthma is substantially less common than remission during childhood and adolescence. Loss of lung function can begin early in life and tracks through childhood and adolescence. Despite therapy which controls symptoms and exacerbations, the outcomes of asthma appear largely resistant to pharmacologic therapy.

  20. Reliability Prediction

    NASA Technical Reports Server (NTRS)

    1993-01-01

    RELAV, a NASA-developed computer program, enables Systems Control Technology, Inc. (SCT) to predict performance of aircraft subsystems. RELAV provides a system level evaluation of a technology. Systems, the mechanism of a landing gear for example, are first described as a set of components performing a specific function. RELAV analyzes the total system and the individual subsystem probabilities to predict success probability, and reliability. This information is then translated into operational support and maintenance requirements. SCT provides research and development services in support of government contracts.

  1. Successful Predictions

    NASA Astrophysics Data System (ADS)

    Pierrehumbert, R.

    2012-12-01

    In an observational science, it is not possible to test hypotheses through controlled laboratory experiments. One can test parts of the system in the lab (as is done routinely with infrared spectroscopy of greenhouse gases), but the collective behavior cannot be tested experimentally because a star or planet cannot be brought into the lab; it must, instead, itself be the lab. In the case of anthropogenic global warming, this is all too literally true, and the experiment would be quite exciting if it weren't for the unsettling fact that we and all our descendents for the forseeable future will have to continue making our home in the lab. There are nonetheless many routes though which the validity of a theory of the collective behavior can be determined. A convincing explanation must not be a"just-so" story, but must make additional predictions that can be verified against observations that were not originally used in formulating the theory. The field of Earth and planetary climate has racked up an impressive number of such predictions. I will also admit as "predictions" statements about things that happened in the past, provided that observations or proxies pinning down the past climate state were not available at the time the prediction was made. The basic prediction that burning of fossil fuels would lead to an increase of atmospheric CO2, and that this would in turn alter the Earth's energy balance so as to cause tropospheric warming, is one of the great successes of climate science. It began in the lineage of Fourier, Tyndall and Arrhenius, and was largely complete with the the radiative-convective modeling work of Manabe in the 1960's -- all well before the expected warming had progressed far enough to be observable. Similarly, long before the increase in atmospheric CO2 could be detected, Bolin formulated a carbon cycle model and used it to predict atmospheric CO2 out to the year 2000; the actual values come in at the high end of his predicted range, for

  2. Awake Measures of Nasal Resistance and Upper Airway Resistance on CPAP during Sleep

    PubMed Central

    Masdeu, Maria J.; Seelall, Vijay; Patel, Amit V.; Ayappa, Indu; Rapoport, David M.

    2011-01-01

    Study Objectives: Since on CPAP, the nose is the primary determinant of upper airway resistance, we assess utility of noninvasive measures of nasal resistance during wakefulness as a predictor of directly assessed upper airway resistance on CPAP during sleep in patients with obstructive sleep apnea/hypopnea syndrome. Methods: Patients with complaints of snoring and excessive daytime sleepiness were recruited. 14 subjects underwent daytime evaluations including clinical assessment, subjective questionnaires to assess nasal symptoms and evaluation of nasal resistance with acoustic rhinometry (AR) and active anterior rhinomanometry (RM) in the sitting and supine positions. Patients underwent nocturnal polysomnography on optimal CPAP with measurements of supraglottic pressure to evaluate upper airway resistance. Comparisons were made between nasal resistance using AR and RM during wakefulness, and between AR and RM awake and upper airway resistance during sleep. Results: Our study shows that measures of awake nasal resistance using AR and RM had little or no correlation to each other in the sitting position, whereas there was significant but weak correlation in the supine position. Upper airway resistance measured while on CPAP during sleep did not show significant relationships to any of the awake measures of nasal resistance (AR or RM). Conclusion: Awake measurements of nasal resistance do not seem to be predictive of upper airway resistance during sleep on CPAP. Citation: Masdeu MJ; Seelall V; Patel AV; Ayappa I; Rapoport DM. Awake Measures of Nasal Resistance and Upper Airway Resistance on CPAP during Sleep. J Clin Sleep Med 2011;7(1):31-40. PMID:21344056

  3. Systematic Review of the Performance of Rapid Rifampicin Resistance Testing for Drug-Resistant Tuberculosis

    PubMed Central

    Arentz, Matthew; Sorensen, Bess; Horne, David J.; Walson, Judd L.

    2013-01-01

    Introduction Rapid tests for rifampicin resistance may be useful for identifying isolates at high risk of drug resistance, including multidrug-resistant TB (MDR-TB). However, choice of diagnostic test and prevalence of rifampicin resistance may both impact a diagnostic strategy for identifying drug resistant-TB. We performed a systematic review to evaluate the performance of WHO-endorsed rapid tests for rifampicin resistance detection. Methods We searched MEDLINE, Embase and the Cochrane Library through January 1, 2012. For each rapid test, we determined pooled sensitivity and specificity estimates using a hierarchical random effects model. Predictive values of the tests were determined at different prevalence rates of rifampicin resistance and MDR-TB. Results We identified 60 publications involving six different tests (INNO-LiPA Rif. TB assay, Genotype MTBDR assay, Genotype MTBDRplus assay, Colorimetric Redox Indicator (CRI) assay, Nitrate Reductase Assay (NRA) and MODS tests): for all tests, negative predictive values were high when rifampicin resistance prevalence was ≤ 30%. However, positive predictive values were considerably reduced for the INNO-LiPA Rif. TB assay, the MTBDRplus assay and MODS when rifampicin resistance prevalence was < 5%. Limitations In many studies, it was unclear whether patient selection or index test performance could have introduced bias. In addition, we were unable to evaluate critical concentration thresholds for the colorimetric tests. Discussion Rapid tests for rifampicin resistance alone cannot accurately predict rifampicin resistance or MDR-TB in areas with a low prevalence of rifampicin resistance. However, in areas with a high prevalence of rifampicin resistance and MDR-TB, these tests may be a valuable component of an MDR-TB management strategy. PMID:24098523

  4. ENSO predictability

    NASA Astrophysics Data System (ADS)

    Larson, Sarah Michelle

    The overarching goal of this work is to explore seasonal El Nino -- Southern Oscillation (ENSO) predictability. More specifically, this work investigates how intrinsic variability affects ENSO predictability using a state-of-the-art climate model. Topics related to the effects of systematic model errors and external forcing are not included in this study. Intrinsic variability encompasses a hierarchy of temporal and spatial scales, from high frequency small-scale noise-driven processes including coupled instabilities to low frequency large-scale deterministic climate modes. The former exemplifies what can be considered intrinsic "noise" in the climate system that hinders predictability by promoting rapid error growth whereas the latter often provides the slow thermal ocean inertia that supplies the coupled ENSO system with predictability. These two ends of the spectrum essentially provide the lower and upper bounds of ENSO predictability that can be attributed to internal variability. The effects of noise-driven coupled instabilities on sea surface temperature (SST) predictability in the ENSO region is quantified by utilizing a novel coupled model methodology paired with an ensemble approach. The experimental design allows for rapid growth of intrinsic perturbations that are not prescribed. Several cases exhibit sufficiently rapid growth to produce ENSO-like final states that do not require a previous ENSO event, large-scale wind trigger, or subsurface heat content precursor. Results challenge conventional ENSO theory that considers the subsurface precursor as a necessary condition for ENSO. Noise-driven SST error growth exhibits strong seasonality and dependence on the initialization month. A dynamical analysis reveals that much of the error growth behavior is linked to the seasonal strength of the Bjerknes feedback in the model, indicating that the noise-induced perturbations grow via an ENSO-like mechanism. The daily error fields reveal that persistent

  5. Prediction techniques

    NASA Astrophysics Data System (ADS)

    1981-12-01

    Prediction methods and related propagation results for the evaluation of Earth-space communication paths operating above 10 GHz are presented. Gaseous attenuation, rain, cloud, fog, sand, and dust attenuation, path diversity, signal fluctuations and low angle fading, depolarization effects, bandwidth coherence, and sky noise are considered.

  6. Progress and problems in erosion prediction

    NASA Technical Reports Server (NTRS)

    Heymann, F. J.

    1974-01-01

    Methods for predicting erosion resulting from repeated localized impulsive loadings, such a impacts from droplets or in cavitation flow from microjets and bubbles, are examined. The parameters which determine the adequacy of a component to resist the loads put upon it are identified. The development of erosion rate models is discussed. The expected accuracy of the prediction and the sources of error are analyzed.

  7. Will tuberculosis become resistant to all antibiotics?

    PubMed Central

    Dye, C; Espinal, M A

    2001-01-01

    The discovery of high prevalences of antibiotic resistance in some pathogens, in some parts of the world, has provoked fears of a widespread loss of drug efficacy. Here, we use a mathematical model to investigate the evolution of resistance to four major anti-tuberculosis drugs (isoniazid, rifampicin, ethambutol and streptomycin) in 47 sites around the world. The model provides a new method of estimating the relative risk of treatment failure for patients carrying drug-resistant strains and the proportion of patients who develop resistance after failing treatment. Using estimates of these two quantities together with other published data, we reconstructed the epidemic spread of isoniazid resistance over the past 50 years. The predicted median prevalence of resistance among new cases today was 7.0% (range 0.9-64.3%), close to the 6.3% (range 0-28.1%) observed. Predicted and observed prevalences of resistance to isoniazid plus rifampicin (multidrug-resistant or MDR-TB) after 30 years of combined drug use were also similar, 0.9% (0.1-5.9%) and 1.0% (range 0-14.1%), respectively. With current data, and under prevailing treatment practices, it appears that MDR-TB will remain a localized problem, rather than becoming a global obstacle to tuberculosis control. To substantiate this result, further measurements are needed of the relative fitness of drug-resistant strains. PMID:12123297

  8. Role of copper transporters in platinum resistance

    PubMed Central

    Kilari, Deepak; Guancial, Elizabeth; Kim, Eric S

    2016-01-01

    Platinum (Pt)-based antitumor agents are effective in the treatment of many solid malignancies. However, their efficacy is limited by toxicity and drug resistance. Reduced intracellular Pt accumulation has been consistently shown to correlate with resistance in tumors. Proteins involved in copper homeostasis have been identified as Pt transporters. In particular, copper transporter receptor 1 (CTR1), the major copper influx transporter, has been shown to play a significant role in Pt resistance. Clinical studies demonstrated that expression of CTR1 correlated with intratumoral Pt concentration and outcomes following Pt-based therapy. Other CTRs such as CTR2, ATP7A and ATP7B, may also play a role in Pt resistance. Recent clinical studies attempting to modulate CTR1 to overcome Pt resistance may provide novel strategies. This review discusses the role of CTR1 as a potential predictive biomarker of Pt sensitivity and a therapeutic target for overcoming Pt resistance. PMID:26862494

  9. Mechanisms of Antimicrobial Resistance in ESKAPE Pathogens

    PubMed Central

    Santajit, Sirijan; Indrawattana, Nitaya

    2016-01-01

    The ESKAPE pathogens (Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa, and Enterobacter species) are the leading cause of nosocomial infections throughout the world. Most of them are multidrug resistant isolates, which is one of the greatest challenges in clinical practice. Multidrug resistance is amongst the top three threats to global public health and is usually caused by excessive drug usage or prescription, inappropriate use of antimicrobials, and substandard pharmaceuticals. Understanding the resistance mechanisms of these bacteria is crucial for the development of novel antimicrobial agents or other alternative tools to combat these public health challenges. Greater mechanistic understanding would also aid in the prediction of underlying or even unknown mechanisms of resistance, which could be applied to other emerging multidrug resistant pathogens. In this review, we summarize the known antimicrobial resistance mechanisms of ESKAPE pathogens. PMID:27274985

  10. GIPSy: Genomic island prediction software.

    PubMed

    Soares, Siomar C; Geyik, Hakan; Ramos, Rommel T J; de Sá, Pablo H C G; Barbosa, Eudes G V; Baumbach, Jan; Figueiredo, Henrique C P; Miyoshi, Anderson; Tauch, Andreas; Silva, Artur; Azevedo, Vasco

    2016-08-20

    Bacteria are highly diverse organisms that are able to adapt to a broad range of environments and hosts due to their high genomic plasticity. Horizontal gene transfer plays a pivotal role in this genome plasticity and in evolution by leaps through the incorporation of large blocks of genome sequences, ordinarily known as genomic islands (GEIs). GEIs may harbor genes encoding virulence, metabolism, antibiotic resistance and symbiosis-related functions, namely pathogenicity islands (PAIs), metabolic islands (MIs), resistance islands (RIs) and symbiotic islands (SIs). Although many software for the prediction of GEIs exist, they only focus on PAI prediction and present other limitations, such as complicated installation and inconvenient user interfaces. Here, we present GIPSy, the genomic island prediction software, a standalone and user-friendly software for the prediction of GEIs, built on our previously developed pathogenicity island prediction software (PIPS). We also present four application cases in which we crosslink data from literature to PAIs, MIs, RIs and SIs predicted by GIPSy. Briefly, GIPSy correctly predicted the following previously described GEIs: 13 PAIs larger than 30kb in Escherichia coli CFT073; 1 MI for Burkholderia pseudomallei K96243, which seems to be a miscellaneous island; 1 RI of Acinetobacter baumannii AYE, named AbaR1; and, 1 SI of Mesorhizobium loti MAFF303099 presenting a mosaic structure. GIPSy is the first life-style-specific genomic island prediction software to perform analyses of PAIs, MIs, RIs and SIs, opening a door for a better understanding of bacterial genome plasticity and the adaptation to new traits. PMID:26376473

  11. GIPSy: Genomic island prediction software.

    PubMed

    Soares, Siomar C; Geyik, Hakan; Ramos, Rommel T J; de Sá, Pablo H C G; Barbosa, Eudes G V; Baumbach, Jan; Figueiredo, Henrique C P; Miyoshi, Anderson; Tauch, Andreas; Silva, Artur; Azevedo, Vasco

    2016-08-20

    Bacteria are highly diverse organisms that are able to adapt to a broad range of environments and hosts due to their high genomic plasticity. Horizontal gene transfer plays a pivotal role in this genome plasticity and in evolution by leaps through the incorporation of large blocks of genome sequences, ordinarily known as genomic islands (GEIs). GEIs may harbor genes encoding virulence, metabolism, antibiotic resistance and symbiosis-related functions, namely pathogenicity islands (PAIs), metabolic islands (MIs), resistance islands (RIs) and symbiotic islands (SIs). Although many software for the prediction of GEIs exist, they only focus on PAI prediction and present other limitations, such as complicated installation and inconvenient user interfaces. Here, we present GIPSy, the genomic island prediction software, a standalone and user-friendly software for the prediction of GEIs, built on our previously developed pathogenicity island prediction software (PIPS). We also present four application cases in which we crosslink data from literature to PAIs, MIs, RIs and SIs predicted by GIPSy. Briefly, GIPSy correctly predicted the following previously described GEIs: 13 PAIs larger than 30kb in Escherichia coli CFT073; 1 MI for Burkholderia pseudomallei K96243, which seems to be a miscellaneous island; 1 RI of Acinetobacter baumannii AYE, named AbaR1; and, 1 SI of Mesorhizobium loti MAFF303099 presenting a mosaic structure. GIPSy is the first life-style-specific genomic island prediction software to perform analyses of PAIs, MIs, RIs and SIs, opening a door for a better understanding of bacterial genome plasticity and the adaptation to new traits.

  12. Predicting Epileptic Seizures in Advance

    PubMed Central

    Moghim, Negin; Corne, David W.

    2014-01-01

    Epilepsy is the second most common neurological disorder, affecting 0.6–0.8% of the world's population. In this neurological disorder, abnormal activity of the brain causes seizures, the nature of which tend to be sudden. Antiepileptic Drugs (AEDs) are used as long-term therapeutic solutions that control the condition. Of those treated with AEDs, 35% become resistant to medication. The unpredictable nature of seizures poses risks for the individual with epilepsy. It is clearly desirable to find more effective ways of preventing seizures for such patients. The automatic detection of oncoming seizures, before their actual onset, can facilitate timely intervention and hence minimize these risks. In addition, advance prediction of seizures can enrich our understanding of the epileptic brain. In this study, drawing on the body of work behind automatic seizure detection and prediction from digitised Invasive Electroencephalography (EEG) data, a prediction algorithm, ASPPR (Advance Seizure Prediction via Pre-ictal Relabeling), is described. ASPPR facilitates the learning of predictive models targeted at recognizing patterns in EEG activity that are in a specific time window in advance of a seizure. It then exploits advanced machine learning coupled with the design and selection of appropriate features from EEG signals. Results, from evaluating ASPPR independently on 21 different patients, suggest that seizures for many patients can be predicted up to 20 minutes in advance of their onset. Compared to benchmark performance represented by a mean S1-Score (harmonic mean of Sensitivity and Specificity) of 90.6% for predicting seizure onset between 0 and 5 minutes in advance, ASPPR achieves mean S1-Scores of: 96.30% for prediction between 1 and 6 minutes in advance, 96.13% for prediction between 8 and 13 minutes in advance, 94.5% for prediction between 14 and 19 minutes in advance, and 94.2% for prediction between 20 and 25 minutes in advance. PMID:24911316

  13. Mechanisms of drug resistance: quinolone resistance

    PubMed Central

    Hooper, David C.; Jacoby, George A.

    2015-01-01

    Quinolone antimicrobials are synthetic and widely used in clinical medicine. Resistance emerged with clinical use and became common in some bacterial pathogens. Mechanisms of resistance include two categories of mutation and acquisition of resistance-conferring genes. Resistance mutations in one or both of the two drug target enzymes, DNA gyrase and DNA topoisomerase IV, are commonly in a localized domain of the GyrA and ParE subunits of the respective enzymes and reduce drug binding to the enzyme-DNA complex. Other resistance mutations occur in regulatory genes that control the expression of native efflux pumps localized in the bacterial membrane(s). These pumps have broad substrate profiles that include quinolones as well as other antimicrobials, disinfectants, and dyes. Mutations of both types can accumulate with selection pressure and produce highly resistant strains. Resistance genes acquired on plasmids can confer low-level resistance that promotes the selection of mutational high-level resistance. Plasmid-encoded resistance is due to Qnr proteins that protect the target enzymes from quinolone action, one mutant aminoglycoside-modifying enzyme that also modifies certain quinolones, and mobile efflux pumps. Plasmids with these mechanisms often encode additional antimicrobial resistances and can transfer multidrug resistance that includes quinolones. Thus, the bacterial quinolone resistance armamentarium is large. PMID:26190223

  14. How can we predict ureteral obstruction after gynecological surgery? The changes in Doppler resistive index and plasma creatinine and magnesium concentrations after surgical, unilateral ureteral obstruction in a rabbit model.

    PubMed

    Terek, M C; Tamsel, S; Aygul, S; Akman, L; Irer, S V; Itil, I M; Alper, G

    2006-01-01

    The aim of this study is to evaluate the changes in Doppler resistive index (RI) and plasma creatinine and magnesium concentrations after unilateral ureteral obstruction in a rabbit model. Fourteen adult female rabbits were used in this study. In seven rabbits, the left ureter was ligated with silk suture, and the control group was sham operated. Before surgery and on the second and seventh days after surgery, blood samples were obtained to measure plasma creatinine and magnesium concentrations. Doppler RIs of both kidneys were also measured before surgery and on the second and seventh days after the surgical procedure. With regard to magnesium levels, there was a significant within-subjects sessions difference [F(2, 20) = 15.21, P= 0.001] indicating a decrease through sessions. Magnesium concentrations decreased significantly at the postoperative second and seventh days compared to preoperative baseline levels (P= 0.003 and P= 0.001, respectively). Multifactorial analysis of variance was applied for each session separately with laterality, and groups as factors. The Doppler RI and the creatinine level did not show any significant differences or interactions for all sessions (P > 0.05). The decreasing plasma magnesium concentration after surgery may indicate ureteral injury; however, Doppler studies and creatinine levels may not be useful as well. PMID:16445661

  15. How can we predict ureteral obstruction after gynecological surgery? The changes in Doppler resistive index and plasma creatinine and magnesium concentrations after surgical, unilateral ureteral obstruction in a rabbit model.

    PubMed

    Terek, M C; Tamsel, S; Aygul, S; Akman, L; Irer, S V; Itil, I M; Alper, G

    2006-01-01

    The aim of this study is to evaluate the changes in Doppler resistive index (RI) and plasma creatinine and magnesium concentrations after unilateral ureteral obstruction in a rabbit model. Fourteen adult female rabbits were used in this study. In seven rabbits, the left ureter was ligated with silk suture, and the control group was sham operated. Before surgery and on the second and seventh days after surgery, blood samples were obtained to measure plasma creatinine and magnesium concentrations. Doppler RIs of both kidneys were also measured before surgery and on the second and seventh days after the surgical procedure. With regard to magnesium levels, there was a significant within-subjects sessions difference [F(2, 20) = 15.21, P= 0.001] indicating a decrease through sessions. Magnesium concentrations decreased significantly at the postoperative second and seventh days compared to preoperative baseline levels (P= 0.003 and P= 0.001, respectively). Multifactorial analysis of variance was applied for each session separately with laterality, and groups as factors. The Doppler RI and the creatinine level did not show any significant differences or interactions for all sessions (P > 0.05). The decreasing plasma magnesium concentration after surgery may indicate ureteral injury; however, Doppler studies and creatinine levels may not be useful as well.

  16. HIV Genotypic Resistance Testing

    MedlinePlus

    ... be limited. Home Visit Global Sites Search Help? HIV Antiretroviral Drug Resistance Testing, Genotypic Share this page: Was this page helpful? Also known as: Anti-retroviral Drug Resistance Testing; ARV Resistance Testing Formal name: ...

  17. Animation of Antimicrobial Resistance

    MedlinePlus

    ... 08 Animation of Antimicrobial Resistance (text version) Arabic Translation - Animation of Antimicrobial Resistance (WMV - 19.2MB) Chinese Translation - Animation of Antimicrobial Resistance (WMV - 19.2MB) French ...

  18. Resisting Resistors: Resistance in Critical Pedagogy Classrooms.

    ERIC Educational Resources Information Center

    Filax, Gloria

    1997-01-01

    Contends that resistance is not adequately problematized in the critical pedagogy literature. Asserts that clarification is necessary to point out the multiple resistances in classrooms and their implications rather than situating resistance only with students and only in relation to social inequality or critical pedagogy. (16 citations) (VWC)

  19. Serum level of hepatocyte growth factor is a novel marker of predicting the outcome and resistance to the treatment with trastuzumab in HER2-positive patients with metastatic gastric cancer

    PubMed Central

    Takahashi, Naoki; Furuta, Koh; Taniguchi, Hirokazu; Sasaki, Yusuke; Shoji, Hirokazu; Honma, Yoshitaka; Iwasa, Satoru; Okita, Natsuko; Takashima, Atsuo; Kato, Ken; Hamaguchi, Tetsuya; Shimada, Yasuhiro; Yamada, Yasuhide

    2016-01-01

    HER2-overexpression in tumor tissue is observed in 6 to 23% of advanced gastric cancer (GC) cases, and trastuzumab is an active molecular drug for these patients. There are no data available on whether serum levels of ligands are associated with the response and resistance to trastuzumab in HER2-positive patients with metastatic GC. HER2 screening of 502 patients with advanced gastric cancer was performed in our institution. Among these patients, 84 patients (16.8%) were diagnosed as HER2-positive, and those who were treated with trastuzumab and met the inclusion criteria were enrolled in the present study. Serum levels of ligands that affect the HER2 signal pathway were measured by an enzyme-linked immunosorbent assay. Forty-six HER2-positive patients were enrolled in this study, and 26 patients (56.5%) achieved a partial response to treatment with trastuzumab. Among several ligands, the serum level of hepatocyte growth factor (HGF) was significantly lower in responders compared with that in non-responders (p = 0.014). Multivariate analyses showed that a high level of serum HGF was a poor prognostic factor for overall survival (OS) compared with low levels of HGF (adjusted HR: 3.857, 95% CI: 1.309–11.361, p = 0.014). Among 25 patients without initial disease progression on the treatment with trastuzumab, the mean value of serum HGF at disease progression was significantly higher than that at pre-treatment (p = 0.041). As novel findings, our study indicated that serum level of HGF was associated with tumor shrinkage and time to progression of trastuzumab in HER2-positive patients with metastatic GC. PMID:26716644

  20. Fracture Toughness Prediction for MWCNT Reinforced Ceramics

    SciTech Connect

    Henager, Charles H.; Nguyen, Ba Nghiep

    2013-09-01

    This report describes the development of a micromechanics model to predict fracture toughness of multiwall carbon nanotube (MWCNT) reinforced ceramic composites to guide future experimental work for this project. The modeling work described in this report includes (i) prediction of elastic properties, (ii) development of a mechanistic damage model accounting for matrix cracking to predict the composite nonlinear stress/strain response to tensile loading to failure, and (iii) application of this damage model in a modified boundary layer (MBL) analysis using ABAQUS to predict fracture toughness and crack resistance behavior (R-curves) for ceramic materials containing MWCNTs at various volume fractions.

  1. Resistance to disruption in a classroom setting.

    PubMed

    Parry-Cruwys, Diana E; Neal, Carrie M; Ahearn, William H; Wheeler, Emily E; Premchander, Raseeka; Loeb, Melissa B; Dube, William V

    2011-01-01

    Substantial experimental evidence indicates that behavior reinforced on a denser schedule is more resistant to disruption than is behavior reinforced on a thinner schedule. The present experiment studied resistance to disruption in a natural educational environment. Responding during familiar activities was reinforced on a multiple variable-interval (VI) 7-s VI 30-s schedule for 6 participants with developmental disabilities. Resistance to disruption was measured by presenting a distracting item. Response rates in the disruption components were compared to within-session response rates in prior baseline components. Results were consistent with the predictions of behavioral momentum theory for 5 of 6 participants.

  2. Resistance to disruption in a classroom setting.

    PubMed

    Parry-Cruwys, Diana E; Neal, Carrie M; Ahearn, William H; Wheeler, Emily E; Premchander, Raseeka; Loeb, Melissa B; Dube, William V

    2011-01-01

    Substantial experimental evidence indicates that behavior reinforced on a denser schedule is more resistant to disruption than is behavior reinforced on a thinner schedule. The present experiment studied resistance to disruption in a natural educational environment. Responding during familiar activities was reinforced on a multiple variable-interval (VI) 7-s VI 30-s schedule for 6 participants with developmental disabilities. Resistance to disruption was measured by presenting a distracting item. Response rates in the disruption components were compared to within-session response rates in prior baseline components. Results were consistent with the predictions of behavioral momentum theory for 5 of 6 participants. PMID:21709794

  3. Facts about Antibiotic Resistance

    MedlinePlus

    ... Trends and Cost Español: Datos breves Facts about Antibiotic Resistance Antibiotic resistance has been called one of the world’s most ... antibiotic use is a key strategy to control antibiotic resistance. Antibiotic resistance in children is of particular concern ...

  4. Quantification of thermal and contact resistances of scanning thermal probes

    SciTech Connect

    Kim, Kyeongtae E-mail: meyhofer@umich.edu Jeong, Wonho; Lee, Woochul; Sadat, Seid; Thompson, Dakotah; Meyhofer, Edgar E-mail: meyhofer@umich.edu; Reddy, Pramod E-mail: meyhofer@umich.edu

    2014-11-17

    Scanning thermal probes are widely used for imaging temperature fields with nanoscale resolution, for studying near-field radiative heat transport and for locally heating samples. In all these applications, it is critical to know the thermal resistance to heat flow within the probe and the thermal contact resistance between the probe and the sample. Here, we present an approach for quantifying the aforementioned thermal resistances using picowatt resolution heat flow calorimeters. The measured contact resistance is found to be in good agreement with classical predictions for thermal contact resistance. The techniques developed here are critical for quantitatively probing heat flows at the nanoscale.

  5. Pyrazinamide resistance in Mycobacterium tuberculosis fails to bite?

    PubMed

    den Hertog, Alice L; Sengstake, Sarah; Anthony, Richard M

    2015-08-01

    In contrast to most other antimycobacterial drugs where--particularly in multidrug-resistant (MDR) strains--a limited number of resistance mutations dominate, pyrazinamide (PZA) resistance associated mutations remain highly diverse with limited clustering. This apparent lack of evolutionary selection for successful PZA resistance mechanisms deserves attention. A clear understanding of the epidemiology of PZA resistance acquisition and spread would be expected to result in important insights into how PZA might be better exploited in treatment regimens to minimize the amplification of Mycobacterium tuberculosis (MTB) drug resistance. We propose that PZA resistance typically induces a fitness cost that impairs MTB transmission. This would explain the lack of extensive clustering for PZA-resistant mutants. Our hypothesis also leads to a series of testable predictions which we outline that could confirm or refute our ideas.

  6. Erosion resistance of irrigated soils in the republic of Azerbaijan

    NASA Astrophysics Data System (ADS)

    Babaev, M. P.; Gurbanov, E. A.

    2010-12-01

    It was found that the average size of water-stable aggregates in irrigated soils varies in the range 0.23-2.0 mm, and the eroding flow velocity is 0.03-0.12 m/s. A five-point scale was used for assessing erosion resistance, predicting irrigation erosion, and developing erosion control measures on irrigated soils. According to this system, gray-brown soils and light sierozems were classified as the least erosion-resistant, sierozemic and meadow-sierozemic soils as low erosion-resistant, gray-cinnamonic soils as moderately erosion-resistant, mountain gray-cinnamonic soils as highly erosion-resistant, and steppe mountain cinnamonic soils as very highly erosion-resistant ones. The determination of the erosion resistance of soils is of great importance for assessing the erosion-resistance potential of irrigated areas and developing erosion control measures.

  7. Resistivity of pristine and intercalated graphite fiber epoxy composites

    NASA Technical Reports Server (NTRS)

    Gaier, James R.; Hambourger, Paul D.; Slabe, Melissa E.

    1989-01-01

    Laminar composites were fabricated from pristine and bromine intercalated Amoco P-55, P-75, and P-100 graphite fibers and Hysol-Grafil EAG101-1 film epoxy. The thickness and r.f. eddy current resistivity of several samples were measured at grid points and averaged point by point to obtain final values. Although the values obtained this way have high precision (less than 3 percent deviation), the resistivity values appear to be 20 to 90 percent higher than resistivities measured on high aspect ratio samples using multi-point techniques, and by those predicted by theory. The temperature dependence of the resistivity indicates that the fibers are neither damaged nor deintercalated by the composite fabrication process. The resistivity of the composites is a function of sample thickness (i.e., resin content). Composite resistivity is dominated by fiber resistivity, so lowering the resistivity of the fibers, either through increased graphitization or intercalation, results in a lower composite resistivity. A modification of the simple rule of mixtures model appears to predict the conductivity of high aspect ratio samples measured along a fiber direction, but a directional dependence appears which is not predicted by the theory. The resistivity of these materials is clearly more complex than that of homogeneous materials.

  8. Rodent models of treatment-resistant depression

    PubMed Central

    Caldarone, Barbara J.; Zachariou, Venetia; King, Sarah L

    2015-01-01

    Major depression is a prevalent and debilitating disorder and a substantial proportion of patients fail to reach remission following standard antidepressant pharmacological treatment. Limited efficacy with currently available antidepressant drugs highlights the need to develop more effective medications for treatment resistant patients and emphasizes the importance of developing better preclinical models that focus on treatment resistant populations. This review discusses methods to adapt and refine rodent behavioral models that are predictive of antidepressant efficacy to identify populations that show reduced responsiveness or are resistant to traditional antidepressants. Methods include separating antidepressant responders from non-responders, administering treatments that render animals resistant to traditional pharmacological treatments, and identifying genetic models that show antidepressant resistance. This review also examines pharmacological and non-pharmacological treatments regimes that have been effective in refractory patients and how some of these approaches have been used to validate animal models of treatment-resistant depression. The goals in developing rodent models of treatment-resistant depression are to understand the neurobiological mechanisms involved in antidepressant resistance and to develop valid models to test novel therapies that would be effective in patients that do not respond to traditional monoaminergic antidepressants. PMID:25460020

  9. Coinfection and the evolution of drug resistance.

    PubMed

    Hansen, J; Day, T

    2014-12-01

    Recent experimental work in the rodent malaria model has shown that when two or more strains share a host, there is competitive release of drug-resistant strains upon treatment. In other words, the propagule output of a particular strain is repressed when competing with other strains and increases upon the removal of this competition. This within-host effect is predicted to have an important impact on the evolution and growth of resistant strains. However, how this effect translates to epidemiological parameters at the between-host level, the level at which disease and resistance spread, has yet to be determined. Here we present a general, between-host epidemiological model that explicitly takes into account the effect of coinfection and competitive release. Although our model does show that when there is coinfection competitive release may contribute to the emergence of resistance, it also highlights an additional between-host effect. It is the combination of these two effects, the between-host effect and the within-host effect, that determines the overall influence of coinfection on the emergence of resistance. Therefore, even when competitive release of drug-resistant strains occurs, within an infected individual, it is not necessarily true that coinfection will result in the increased emergence of resistance. These results have important implications for the control of the emergence and spread of drug resistance. PMID:25417787

  10. Validated predictive modelling of the environmental resistome.

    PubMed

    Amos, Gregory C A; Gozzard, Emma; Carter, Charlotte E; Mead, Andrew; Bowes, Mike J; Hawkey, Peter M; Zhang, Lihong; Singer, Andrew C; Gaze, William H; Wellington, Elizabeth M H

    2015-06-01

    Multi-drug-resistant bacteria pose a significant threat to public health. The role of the environment in the overall rise in antibiotic-resistant infections and risk to humans is largely unknown. This study aimed to evaluate drivers of antibiotic-resistance levels across the River Thames catchment, model key biotic, spatial and chemical variables and produce predictive models for future risk assessment. Sediment samples from 13 sites across the River Thames basin were taken at four time points across 2011 and 2012. Samples were analysed for class 1 integron prevalence and enumeration of third-generation cephalosporin-resistant bacteria. Class 1 integron prevalence was validated as a molecular marker of antibiotic resistance; levels of resistance showed significant geospatial and temporal variation. The main explanatory variables of resistance levels at each sample site were the number, proximity, size and type of surrounding wastewater-treatment plants. Model 1 revealed treatment plants accounted for 49.5% of the variance in resistance levels. Other contributing factors were extent of different surrounding land cover types (for example, Neutral Grassland), temporal patterns and prior rainfall; when modelling all variables the resulting model (Model 2) could explain 82.9% of variations in resistance levels in the whole catchment. Chemical analyses correlated with key indicators of treatment plant effluent and a model (Model 3) was generated based on water quality parameters (contaminant and macro- and micro-nutrient levels). Model 2 was beta tested on independent sites and explained over 78% of the variation in integron prevalence showing a significant predictive ability. We believe all models in this study are highly useful tools for informing and prioritising mitigation strategies to reduce the environmental resistome. PMID:25679532

  11. Validated predictive modelling of the environmental resistome.

    PubMed

    Amos, Gregory C A; Gozzard, Emma; Carter, Charlotte E; Mead, Andrew; Bowes, Mike J; Hawkey, Peter M; Zhang, Lihong; Singer, Andrew C; Gaze, William H; Wellington, Elizabeth M H

    2015-06-01

    Multi-drug-resistant bacteria pose a significant threat to public health. The role of the environment in the overall rise in antibiotic-resistant infections and risk to humans is largely unknown. This study aimed to evaluate drivers of antibiotic-resistance levels across the River Thames catchment, model key biotic, spatial and chemical variables and produce predictive models for future risk assessment. Sediment samples from 13 sites across the River Thames basin were taken at four time points across 2011 and 2012. Samples were analysed for class 1 integron prevalence and enumeration of third-generation cephalosporin-resistant bacteria. Class 1 integron prevalence was validated as a molecular marker of antibiotic resistance; levels of resistance showed significant geospatial and temporal variation. The main explanatory variables of resistance levels at each sample site were the number, proximity, size and type of surrounding wastewater-treatment plants. Model 1 revealed treatment plants accounted for 49.5% of the variance in resistance levels. Other contributing factors were extent of different surrounding land cover types (for example, Neutral Grassland), temporal patterns and prior rainfall; when modelling all variables the resulting model (Model 2) could explain 82.9% of variations in resistance levels in the whole catchment. Chemical analyses correlated with key indicators of treatment plant effluent and a model (Model 3) was generated based on water quality parameters (contaminant and macro- and micro-nutrient levels). Model 2 was beta tested on independent sites and explained over 78% of the variation in integron prevalence showing a significant predictive ability. We believe all models in this study are highly useful tools for informing and prioritising mitigation strategies to reduce the environmental resistome.

  12. Emergence and spread of antibiotic resistance: setting a parameter space

    PubMed Central

    Baquero, Fernando

    2014-01-01

    The emergence and spread of antibiotic resistance among human pathogens is a relevant problem for human health and one of the few evolution processes amenable to experimental studies. In the present review, we discuss some basic aspects of antibiotic resistance, including mechanisms of resistance, origin of resistance genes, and bottlenecks that modulate the acquisition and spread of antibiotic resistance among human pathogens. In addition, we analyse several parameters that modulate the evolution landscape of antibiotic resistance. Learning why some resistance mechanisms emerge but do not evolve after a first burst, whereas others can spread over the entire world very rapidly, mimicking a chain reaction, is important for predicting the evolution, and relevance for human health, of a given mechanism of resistance. Because of this, we propose that the emergence and spread of antibiotic resistance can only be understood in a multi-parameter space. Measuring the effect on antibiotic resistance of parameters such as contact rates, transfer rates, integration rates, replication rates, diversification rates, and selection rates, for different genes and organisms, growing under different conditions in distinct ecosystems, will allow for a better prediction of antibiotic resistance and possibilities of focused interventions. PMID:24678768

  13. Pneumococcal resistance to antibiotics.

    PubMed Central

    Klugman, K P

    1990-01-01

    The geographic distribution of pneumococci resistant to one or more of the antibiotics penicillin, erythromycin, trimethoprim-sulfamethoxazole, and tetracycline appears to be expanding, and there exist foci of resistance to chloramphenicol and rifampin. Multiply resistant pneumococci are being encountered more commonly and are more often community acquired. Factors associated with infection caused by resistant pneumococci include young age, duration of hospitalization, infection with a pneumococcus of serogroup 6, 19, or 23 or serotype 14, and exposure to antibiotics to which the strain is resistant. At present, the most useful drugs for the management of resistant pneumococcal infections are cefotaxime, ceftriaxone, vancomycin, and rifampin. If the strains are susceptible, chloramphenicol may be useful as an alternative, less expensive agent. Appropriate interventions for the control of resistant pneumococcal outbreaks include investigation of the prevalence of resistant strains, isolation of patients, possible treatment of carriers, and reduction of usage of antibiotics to which the strain is resistant. The molecular mechanisms of penicillin resistance are related to the structure and function of penicillin-binding proteins, and the mechanisms of resistance to other agents involved in multiple resistance are being elucidated. Recognition is increasing of the standard screening procedure for penicillin resistance, using a 1-microgram oxacillin disk. PMID:2187594

  14. Superinfection and the evolution of resistance to antimalarial drugs.

    PubMed

    Klein, Eili Y; Smith, David L; Laxminarayan, Ramanan; Levin, Simon

    2012-09-22

    A major issue in the control of malaria is the evolution of drug resistance. Ecological theory has demonstrated that pathogen superinfection and the resulting within-host competition influences the evolution of specific traits. Individuals infected with Plasmodium falciparum are consistently infected by multiple parasites; however, while this probably alters the dynamics of resistance evolution, there are few robust mathematical models examining this issue. We developed a general theory for modelling the evolution of resistance with host superinfection and examine: (i) the effect of transmission intensity on the rate of resistance evolution; (ii) the importance of different biological costs of resistance; and (iii) the best measure of the frequency of resistance. We find that within-host competition retards the ability and slows the rate at which drug-resistant parasites invade, particularly as the transmission rate increases. We also find that biological costs of resistance that reduce transmission are less important than reductions in the duration of drug-resistant infections. Lastly, we find that random sampling of the population for resistant parasites is likely to significantly underestimate the frequency of resistance. Considering superinfection in mathematical models of antimalarial drug resistance may thus be important for generating accurate predictions of interventions to contain resistance.

  15. Superinfection and the evolution of resistance to antimalarial drugs

    PubMed Central

    Klein, Eili Y.; Smith, David L.; Laxminarayan, Ramanan; Levin, Simon

    2012-01-01

    A major issue in the control of malaria is the evolution of drug resistance. Ecological theory has demonstrated that pathogen superinfection and the resulting within-host competition influences the evolution of specific traits. Individuals infected with Plasmodium falciparum are consistently infected by multiple parasites; however, while this probably alters the dynamics of resistance evolution, there are few robust mathematical models examining this issue. We developed a general theory for modelling the evolution of resistance with host superinfection and examine: (i) the effect of transmission intensity on the rate of resistance evolution; (ii) the importance of different biological costs of resistance; and (iii) the best measure of the frequency of resistance. We find that within-host competition retards the ability and slows the rate at which drug-resistant parasites invade, particularly as the transmission rate increases. We also find that biological costs of resistance that reduce transmission are less important than reductions in the duration of drug-resistant infections. Lastly, we find that random sampling of the population for resistant parasites is likely to significantly underestimate the frequency of resistance. Considering superinfection in mathematical models of antimalarial drug resistance may thus be important for generating accurate predictions of interventions to contain resistance. PMID:22787024

  16. An Empirical Test of a Model of Resistance to Persuasion.

    ERIC Educational Resources Information Center

    And Others; Burgoon, Michael

    1978-01-01

    Tests a model of resistance to persuasion based upon variables not considered by earlier congruity and inoculation models. Supports the prediction that the kind of critical response set induced and the target of the criticism are mediators of resistance to persuasion. (JMF)

  17. Further development of a predictive pitting model for gears: Improvements in the life prediction analysis

    NASA Astrophysics Data System (ADS)

    Blake, J. W.; Draper, C. F.

    1994-04-01

    A predictive pitting model for gear design applications was recently developed by Blake and Cheng. Life estimates were based on predicting the growth of surface-breaking cracks leading to pit formation. While trends predicted by the model reflected observed behavior, estimated lives were lower than expected. The crack growth model has been improved by modifying the original shear-driven, two-dimensional propagation model to reflect three-dimensional cracks driven by both shear and lubricant pressure effects. Resistance to crack growth due to friction between the crack faces has also been considered. These changes have led to a net increase in predicted lives, which better reflects observed pitting behavior.

  18. Flame-resistant textiles

    NASA Technical Reports Server (NTRS)

    Fogg, L. C.; Stringham, R. S.; Toy, M. S.

    1980-01-01

    Flame resistance treatment for acid resistant polyamide fibers involving photoaddition of fluorocarbons to surface has been scaled up to treat 10 yards of commercial width (41 in.) fabric. Process may be applicable to other low cost polyamides, polyesters, and textiles.

  19. Antibiotics and Resistance: Glossary

    MedlinePlus

    ... induced by natural or human activity on the ecology and living organisms. Ecology The study of the relationships and interactions between ... antibiotics The Cost of Resistance Science of Resistance Ecology Antibiotics in Agriculture Antibacterial Agents Glossary References Web ...

  20. Power to Resist

    ERIC Educational Resources Information Center

    Crossland, Janice

    1975-01-01

    Transferrable drug resistance has been observed in bacteria for over ten years. Concern now is that livestock that have been fed with grain supplemented with antibiotics for growth stimulation will infect humans with potentially dangerous resistant bacteria. (MA)

  1. Reversibility of antibiotic resistance

    PubMed Central

    2014-01-01

    Although theoretically attractive, the reversibility of resistance has proven difficult in practice, even though antibiotic resistance mechanisms induce a fitness cost to the bacterium. Associated resistance to other antibiotics and compensatory mutations seem to ameliorate the effect of antibiotic interventions in the community. In this paper the current understanding of the concepts of reversibility of antibiotic resistance and the interventions performed in hospitals and in the community are reviewed. PMID:24836051

  2. Grafting for disease resistance

    Technology Transfer Automated Retrieval System (TEKTRAN)

    The primary purpose of grafting vegetables worldwide has been to provide resistance to soil-borne diseases. The potential loss of methyl bromide as a soil fumigant combined with pathogen resistance to commonly used pesticides will make resistance to soil-borne pathogens even more important in the fu...

  3. Resisting Mind Control.

    ERIC Educational Resources Information Center

    Anderson, Susan M.; Zimbardo, Philip G.

    1980-01-01

    Provides conceptual analyses of mind control techniques along with practical advice on how to resist these techniques. The authors stress that effective mind control stems more from everyday social relations than from exotic technological gimmicks. Suggestions are given for resisting persuasion, resisting systems, and challenging the system.…

  4. Reform, Resistance, . . . Retreat? The Predictable Politics of Accountability in Virginia

    ERIC Educational Resources Information Center

    Hess, Frederick M.

    2002-01-01

    In the 1990s, Virginia launched one of the nation's most ambitious standards-based reform efforts. Encouraged by a budding national accountability movement and motivated by conservative distrust of the public school establishment, state officials sought to clarify what students needed to know and to hold students and educators accountable for…

  5. Insect resistance management in GM crops: past, present and future.

    PubMed

    Bates, Sarah L; Zhao, Jian-Zhou; Roush, Richard T; Shelton, Anthony M

    2005-01-01

    Transgenic plants expressing insecticidal proteins from the bacterium Bacillus thuringiensis (Bt) were first commercialized in 1996 amid concern from some scientists, regulators and environmentalists that the widespread use of Bt crops would inevitably lead to resistance and the loss of a 'public good,' specifically, the susceptibility of insect pests to Bt proteins. Eight years later, Bt corn and cotton have been grown on a cumulative area >80 million ha worldwide. Despite dire predictions to the contrary, resistance to a Bt crop has yet to be documented, suggesting that resistance management strategies have been effective thus far. However, current strategies to delay resistance remain far from ideal. Eight years without resistance provides a timely opportunity for researchers, regulators and industry to reassess the risk of resistance and the most effective strategies to preserve Bt and other novel insect-resistant crops in development.

  6. Radiation coloration resistant glass

    DOEpatents

    Tomozawa, M.; Watson, E.B.; Acocella, J.

    1986-11-04

    A radiation coloration resistant glass is disclosed which is used in a radiation environment sufficient to cause coloration in most forms of glass. The coloration resistant glass includes higher proportions by weight of water and has been found to be extremely resistant to color change when exposed to such radiation levels. The coloration resistant glass is free of cerium oxide and has more than about 0.5% by weight water content. Even when exposed to gamma radiation of more than 10[sup 7] rad, the coloration resistant glass does not lose transparency. 3 figs.

  7. Radiation coloration resistant glass

    DOEpatents

    Tomozawa, Minoru; Watson, E. Bruce; Acocella, John

    1986-01-01

    A radiation coloration resistant glass is disclosed which is used in a radiation environment sufficient to cause coloration in most forms of glass. The coloration resistant glass includes higher proportions by weight of water and has been found to be extremely resistant to color change when exposed to such radiation levels. The coloration resistant glass is free of cerium oxide and has more than about 0.5% by weight water content. Even when exposed to gamma radiation of more than 10.sup.7 rad, the coloration resistant glass does not lose transparency.

  8. Making detailed predictions makes (some) predictions worse

    NASA Astrophysics Data System (ADS)

    Kelly, Theresa F.

    In this paper, we investigate whether making detailed predictions about an event makes other predictions worse. Across 19 experiments, 10,895 participants, and 415,960 predictions about 724 professional sports games, we find that people who made detailed predictions about sporting events (e.g., how many hits each baseball team would get) made worse predictions about more general outcomes (e.g., which team would win). We rule out that this effect is caused by inattention or fatigue, thinking too hard, or a differential reliance on holistic information about the teams. Instead, we find that thinking about game-relevant details before predicting winning teams causes people to give less weight to predictive information, presumably because predicting details makes information that is relatively useless for predicting the winning team more readily accessible in memory and therefore incorporated into forecasts. Furthermore, we show that this differential use of information can be used to predict what kinds of games will and will not be susceptible to the negative effect of making detailed predictions.

  9. [Rodenticide resistance and consequences].

    PubMed

    Esther, A; Endepols, S; Freise, J; Klemann, N; Runge, M; Pelz, H-J

    2014-05-01

    Resistance to anticoagulant rodenticides, such as warfarin was first described in 1958. Polymorphisms in the vitamin K epoxide reductase complex subunit 1 (VKORC1) gene and respective substitutions of amino acids in the VKOR enzyme are the major cause for rodenticide resistance. Resistant Norway rats in Germany are characterized by the Tyr139Cys genotype, which is spread throughout the northwest of the country. Resistant house mice with the VKOR variants Tyr139Cys, Leu128Ser and Arg12Trp/Ala26Ser/Ala48Thr/Arg61Leu (spretus type) are distributed over a number of locations in Germany. Resistance can reduce management attempts with consequences for stored product protection, hygiene and animal health. Anticoagulants of the first generation (warfarin, chlorophacinone, coumatetralyl) as well as bromadiolone and difenacoum are not an option for the control of resistant Norway rats. The same applies for house mice whereby the tolerance to compounds can be different between local incidences. Due to the higher toxicity and tendency to persist, the most potent anticoagulant rodenticides brodifacoum, flocoumafen and difethialone should be applied but only where resistance is known. In other cases less toxic anticoagulants should be preferred for rodent management in order to mitigate environmental risks. Resistance effects of further VKOR polymorphisms and their combinations, the spread of resistant rats and conditions supporting and reducing resistance should be investigated in order to improve resistance management strategies. PMID:24781908

  10. Nurses resisting information technology.

    PubMed

    Timmons, Stephen

    2003-12-01

    Resistance in the workplace, by nurses, has not been extensively studied from a sociological perspective. In this paper, nurses' resistance to the implementation and use of computer systems is described and analysed, on the basis of semistructured interviews with 31 nurses in three UK NHS hospitals. While the resistance was not "successful", in that it did not prevent the implementation of the systems, it nonetheless persisted. Resistance took a wide variety of forms, including attempts to minimise or "put off" use of the systems, and extensive criticism of the systems, though outright refusal to use them was very rare. Resistance was as much about the ideas and ways of working that the systems embodied as it was about the actual technology being used. The patterns of resistance can best be summed up by the phrase "resistive compliance". PMID:14622372

  11. Genetics of metabolic resistance.

    PubMed

    Richter, Otto; Langemann, Dirk; Beffa, Roland

    2016-09-01

    Herbicide resistance has become a major issue for many weeds. Metabolic resistance refers to the biochemical processes within organisms that degrade herbicides to less toxic compounds, resulting in a shift of the dose response curve. This type of resistance involves polygenic inheritance. A model is presented linking the biochemical pathway of amino acid synthesis and the detoxifying pathway of an inhibitor of the key enzyme ALS. From this model, resistance factors for each biotype are derived, which are then applied to a polygenic population genetic model for an annual weed plant. Polygenic inheritance is described by a new approach based on tensor products of heredity matrices. Important results from the model are that low dose regimes favour fast emergence of resistant biotypes and that the emergence of resistant biotypes occurs as abrupt outbreaks. The model is used to evaluate strategies for the management of metabolic resistance. PMID:27424952

  12. Resistance of a water spark.

    SciTech Connect

    Warne, Larry Kevin; Jorgenson, Roy Eberhardt; Lehr, Jane Marie

    2005-11-01

    The later time phase of electrical breakdown in water is investigated for the purpose of improving understanding of the discharge characteristics. One dimensional simulations in addition to a zero dimensional lumped model are used to study the spark discharge. The goal is to provide better electrical models for water switches used in the pulse compression section of pulsed power systems. It is found that temperatures in the discharge channel under representative drive conditions, and assuming small initial radii from earlier phases of development, reach levels that are as much as an order of magnitude larger than those used to model discharges in atmospheric gases. This increased temperature coupled with a more rapidly rising conductivity with temperature than in air result in a decreased resistance characteristic compared to preceding models. A simple modification is proposed for the existing model to enable the approximate calculation of channel temperature and incorporate the resulting conductivity increase into the electrical circuit for the discharge channel. Comparisons are made between the theoretical predictions and recent experiments at Sandia. Although present and past experiments indicated that preceding late time channel models overestimated channel resistance, the calculations in this report seem to underestimate the resistance relative to recent experiments. Some possible reasons for this discrepancy are discussed.

  13. EPA RESISTANCE MONITORING RESEARCH (NCR)

    EPA Science Inventory

    The 2006 resistance management research program was organized around three components: development of resistance monitoring program for Bt corn using remote sensing, standardization of resistance assays, and testing of resistance management models. Each area of research has shown...

  14. Herbicide resistance modelling: past, present and future.

    PubMed

    Renton, Michael; Busi, Roberto; Neve, Paul; Thornby, David; Vila-Aiub, Martin

    2014-09-01

    Computer simulation modelling is an essential aid in building an integrated understanding of how different factors interact to affect the evolutionary and population dynamics of herbicide resistance, and thus in helping to predict and manage how agricultural systems will be affected. In this review, we first discuss why computer simulation modelling is such an important tool and framework for dealing with herbicide resistance. We then explain what questions related to herbicide resistance have been addressed to date using simulation modelling, and discuss the modelling approaches that have been used, focusing first on the earlier, more general approaches, and then on some newer, more innovative approaches. We then consider how these approaches could be further developed in the future, by drawing on modelling techniques that are already employed in other areas, such as individual-based and spatially explicit modelling approaches, as well as the possibility of better representing genetics, competition and economics, and finally the questions and issues of importance to herbicide resistance research and management that could be addressed using these new approaches are discussed. We conclude that it is necessary to proceed with caution when increasing the complexity of models by adding new details, but, with appropriate care, more detailed models will make it possible to integrate more current knowledge in order better to understand, predict and ultimately manage the evolution of herbicide resistance.

  15. Herbicide resistance modelling: past, present and future.

    PubMed

    Renton, Michael; Busi, Roberto; Neve, Paul; Thornby, David; Vila-Aiub, Martin

    2014-09-01

    Computer simulation modelling is an essential aid in building an integrated understanding of how different factors interact to affect the evolutionary and population dynamics of herbicide resistance, and thus in helping to predict and manage how agricultural systems will be affected. In this review, we first discuss why computer simulation modelling is such an important tool and framework for dealing with herbicide resistance. We then explain what questions related to herbicide resistance have been addressed to date using simulation modelling, and discuss the modelling approaches that have been used, focusing first on the earlier, more general approaches, and then on some newer, more innovative approaches. We then consider how these approaches could be further developed in the future, by drawing on modelling techniques that are already employed in other areas, such as individual-based and spatially explicit modelling approaches, as well as the possibility of better representing genetics, competition and economics, and finally the questions and issues of importance to herbicide resistance research and management that could be addressed using these new approaches are discussed. We conclude that it is necessary to proceed with caution when increasing the complexity of models by adding new details, but, with appropriate care, more detailed models will make it possible to integrate more current knowledge in order better to understand, predict and ultimately manage the evolution of herbicide resistance. PMID:24585689

  16. Antimicrobial resistance in livestock.

    PubMed

    Catry, B; Laevens, H; Devriese, L A; Opsomer, G; De Kruif, A

    2003-04-01

    Antimicrobial resistance may become a major problem in veterinary medicine as a consequence of the intensive use and misuse of antimicrobial drugs. Related problems are now arising in human medicine, such as the appearance of multi-resistant food-borne pathogens. Product characteristics, dose, treatment interval and duration of treatment influence the selection pressure for antimicrobial drug resistance. There are theoretical, experimental and clinical indications that the emergence of de novo resistance in a pathogenic population can be prevented by minimizing the time that suboptimal drug levels are present in the infected tissue compartment. Until recently, attention has been focused on target pathogens. However, it should be kept in mind that when antimicrobial drugs are used in an individual, resistance selection mainly affects the normal body flora. In the long term, this is at least equally important as resistance selection in the target pathogens, as the horizontal transfer of resistance genes converts almost all pathogenic bacteria into potential recipients for antimicrobial resistance. Other factors contributing to the epidemiology of antimicrobial resistance are the localization and size of the microbial population, and the age, immunity and contact intensity of the host. In livestock, dynamic herd-related resistance patterns have been observed in different animal species.

  17. [Resistance to antituberculous drugs].

    PubMed

    Veziris, N; Cambau, E; Sougakoff, W; Robert, J; Jarlier, V

    2005-08-01

    Mycobacteria responsible for tuberculosis (M. tuberculosis, M. bovis, M. africanum) are susceptible to a very small number of antibiotics. As soon as these drugs were used in humans all gave rise to the selection of resistant mycobacteria. Study of the mechanisms of acquired resistance, with the help of the genetics of mycobacteria, led to a more accurate understanding of the mode of action of antituberculous drugs. The antibiotics isoniazid, pyrazinamide, ethionamide and ethambutol are mycobacteria-specific because they inhibit the synthesis of mycolic acids, which are specific constituants of the bacterial wall. Mutations responsible for resistance to these drugs affect genes coding for activator enzymes (katg for isoniazid, pncA for pyrazinamide) or genes coding for their target (inhA for isoniazid/ethionamide, embB for ethambutol). With rifamycins, aminosides and quinolones, mechanisms of action and resistance are the same for mycobacteria as for non-mycobacterial organisms. No plasmid or resistance transposon has been described in M. tuberculosis. Currently a test for the quick detection of resistance to rifampicin is widely available but in the future DNA chips may allow the simultaneous detection of multiple resistances. Monitoring of antituberculous drugs shows that in France the prevalence of multiresistance ( resistance to both isoniazid and rifampicin) is 0.5%, primary resistance (before treatment) is 9%, and secondary resistance (after treatment) is 16%.

  18. Genetic resistance to flaviviruses.

    PubMed

    Brinton, Margo A; Perelygin, Andrey A

    2003-01-01

    Resistance to flavivirus-induced disease in mice was first discovered in the 1920s and was subsequently shown to be controlled by the resistant allele of a single dominant autosomal gene. While the majority of current laboratory mouse stains have a homozygous-susceptible phenotype, the resistant allele has been found to segregate in wild mouse populations in many different parts of the world. Resistance is flavivirus specific and extends to both mosquito- and tick-borne flaviviruses. Resistant animals are infected productively by flaviviruses but produce lower virus titers, especially in their brains, as compared to susceptible mice. Decreased virus production is observed in resistant animals even during a lethal infection and the times of disease onset and death are also delayed as compared to susceptible mice. An intact immune response is required to clear flaviviruses from resistant mice. The resistant phenotype is expressed constitutively and does not require interferon induction. The Flv gene was discovered using a positional cloning approach and identified as Oas1b. Susceptible mice produce a truncated Oas1b protein. A C820T transition in the fourth exon of the gene introduced a premature stop codon and was found in all susceptible mouse strains tested. Possible mechanisms by which the product of the resistant allele could confer the resistant phenotype are discussed. PMID:14689691

  19. Delayed commitment to evolutionary fate in antibiotic resistance fitness landscapes

    PubMed Central

    Baym, Michael; Kim, Seungsoo; Veres, Adrian; Bershtein, Shimon; Kishony, Roy

    2015-01-01

    Predicting evolutionary paths to antibiotic resistance is key for understanding and controlling drug resistance. When considering a single final resistant genotype, epistatic contingencies among mutations restricts evolution to a small number of adaptive paths. Less attention has been given to multi-peak landscapes, and while specific peaks can be favored, it is unknown whether and how early a commitment to final fate is made. Here we characterized a multi-peaked adaptive landscape for trimethoprim resistance by constructing all combinatorial alleles of seven resistance-conferring mutations in dihydrofolate reductase. We observe that epistatic interactions increase rather than decrease the accessibility of each peak; while they restrict the number of direct paths, they generate more indirect paths, where mutations are adaptively gained and later adaptively lost or changed. This enhanced accessibility allows evolution to proceed through many adaptive steps while delaying commitment to genotypic fate, hindering our ability to predict or control evolutionary outcomes. PMID:26060115

  20. Isolated cell behavior drives the evolution of antibiotic resistance.

    PubMed

    Artemova, Tatiana; Gerardin, Ylaine; Dudley, Carmel; Vega, Nicole M; Gore, Jeff

    2015-07-29

    Bacterial antibiotic resistance is typically quantified by the minimum inhibitory concentration (MIC), which is defined as the minimal concentration of antibiotic that inhibits bacterial growth starting from a standard cell density. However, when antibiotic resistance is mediated by degradation, the collective inactivation of antibiotic by the bacterial population can cause the measured MIC to depend strongly on the initial cell density. In cases where this inoculum effect is strong, the relationship between MIC and bacterial fitness in the antibiotic is not well defined. Here, we demonstrate that the resistance of a single, isolated cell-which we call the single-cell MIC (scMIC)-provides a superior metric for quantifying antibiotic resistance. Unlike the MIC, we find that the scMIC predicts the direction of selection and also specifies the antibiotic concentration at which selection begins to favor new mutants. Understanding the cooperative nature of bacterial growth in antibiotics is therefore essential in predicting the evolution of antibiotic resistance.

  1. Partially mixed household epidemiological model with clustered resistant individuals.

    PubMed

    Hiebeler, David E; Criner, Amanda Keck

    2007-02-01

    We study the dynamics of the spread of an infectious disease within a population partitioned into households, and stratified into resistant and nonresistant individuals. Variability in the level of resistance between households increases the initial rate of spread of the infection, as well as the infection level at the endemic equilibrium. This phenomenon is seen even when all individuals in the population are equally likely to be resistant, and can also be predicted by including spatial clustering of resistant individuals within an improved mean-field approximation.

  2. Partially mixed household epidemiological model with clustered resistant individuals

    NASA Astrophysics Data System (ADS)

    Hiebeler, David E.; Criner, Amanda Keck

    2007-02-01

    We study the dynamics of the spread of an infectious disease within a population partitioned into households, and stratified into resistant and nonresistant individuals. Variability in the level of resistance between households increases the initial rate of spread of the infection, as well as the infection level at the endemic equilibrium. This phenomenon is seen even when all individuals in the population are equally likely to be resistant, and can also be predicted by including spatial clustering of resistant individuals within an improved mean-field approximation.

  3. Fluoroquinolone Resistance among Clonal Complex 1 Group B Streptococcus Strains.

    PubMed

    Neemuchwala, Alefiya; Teatero, Sarah; Patel, Samir N; Fittipaldi, Nahuel

    2016-01-01

    Fluoroquinolone resistance in group B Streptococcus is increasingly being reported worldwide. Here, we correlated fluoroquinolone resistance with mutations in gyrA, gyrB, parC, and parE genes, identified by mining whole-genome sequencing (WGS) data of 190 clonal complex 1 group B Streptococcus strains recovered from patients with invasive diseases in North America. We report a high prevalence of fluoroquinolone resistance (12%) among GBS strains in our collection. Our approach is the first step towards accurate prediction of fluoroquinolone resistance from WGS data in this opportunistic pathogen. PMID:27559344

  4. Fluoroquinolone Resistance among Clonal Complex 1 Group B Streptococcus Strains

    PubMed Central

    Teatero, Sarah; Patel, Samir N.

    2016-01-01

    Fluoroquinolone resistance in group B Streptococcus is increasingly being reported worldwide. Here, we correlated fluoroquinolone resistance with mutations in gyrA, gyrB, parC, and parE genes, identified by mining whole-genome sequencing (WGS) data of 190 clonal complex 1 group B Streptococcus strains recovered from patients with invasive diseases in North America. We report a high prevalence of fluoroquinolone resistance (12%) among GBS strains in our collection. Our approach is the first step towards accurate prediction of fluoroquinolone resistance from WGS data in this opportunistic pathogen. PMID:27559344

  5. Drug Resistance in Leishmaniasis

    PubMed Central

    Chakravarty, Jaya; Sundar, Shyam

    2010-01-01

    The treatment options of leishmaniasis are limited and far from satisfactory. For more than 60 years, treatment of leishmaniasis has centered around pentavalent antimonials (Sbv). Widespread misuse has led to the emergence of Sbv resistance in the hyperendemic areas of North Bihar. Other antileishmanials could also face the same fate, especially in the anthroponotic cycle. The HIV/ visceral leishmaniasis (VL) coinfected patients are another potential source for the emergence of drug resistance. At present no molecular markers of resistance are available and the only reliable method for monitoring resistance of isolates is the technically demanding in vitro amastigote-macrophage model. As the armametrium of drugs for leishmaniasis is limited, it is important that effective monitoring of drug use and response should be done to prevent the spread of resistance. Regimens of simultaneous or sequential combinations should be seriously considered to limit the emergence of resistance. PMID:20606973

  6. Vancomycin-Resistant Enterococci

    PubMed Central

    Cetinkaya, Yesim; Falk, Pamela; Mayhall, C. Glen

    2000-01-01

    After they were first identified in the mid-1980s, vancomycin-resistant enterococci (VRE) spread rapidly and became a major problem in many institutions both in Europe and the United States. Since VRE have intrinsic resistance to most of the commonly used antibiotics and the ability to acquire resistance to most of the current available antibiotics, either by mutation or by receipt of foreign genetic material, they have a selective advantage over other microorganisms in the intestinal flora and pose a major therapeutic challenge. The possibility of transfer of vancomycin resistance genes to other gram-positive organisms raises significant concerns about the emergence of vancomycin-resistant Staphylococcus aureus. We review VRE, including their history, mechanisms of resistance, epidemiology, control measures, and treatment. PMID:11023964

  7. Antibiotic Resistance of Diverse Bacteria from Aquaculture in Borneo

    PubMed Central

    Kathleen, M. M.; Felecia, C.; Reagan, E. L.; Kasing, A.; Lesley, M.; Toh, S. C.

    2016-01-01

    The administration of antimicrobials in aquaculture provides a selective pressure creating a reservoir of multiple resistant bacteria in the cultured fish and shrimps as well as the aquaculture environment. The objective of this study was to determine the extent of antibiotic resistance in aquaculture products and aquaculture's surrounding environment in Sarawak, Malaysian Borneo. Ninety-four identified bacterial isolates constituted of 17 genera were isolated from sediment, water, and cultured organisms (fish and shrimp) in selected aquaculture farms. These isolates were tested for their antibiotic resistance against 22 antibiotics from several groups using the disk diffusion method. The results show that the highest resistance was observed towards streptomycin (85%, n = 20), while the lowest resistance was towards gentamicin (1.1%, n = 90). The multiple antibiotic resistant (MAR) index of the isolates tested ranged between 0 and 0.63. It was suggested that isolates with MAR index > 0.2 were recovered from sources with high risk of antibiotic resistant contamination. This study revealed low level of antibiotic resistance in the aquaculture bacterial isolates except for streptomycin and ampicillin (>50% resistance, n = 94) which have been used in the aquaculture industry for several decades. Antibiotic resistant patterns should be continuously monitored to predict the emergence and widespread of MAR. Effective action is needed to keep the new resistance from further developing and spreading. PMID:27746817

  8. Multidrug Resistant Acinetobacter

    PubMed Central

    Manchanda, Vikas; Sanchaita, Sinha; Singh, NP

    2010-01-01

    Emergence and spread of Acinetobacter species, resistant to most of the available antimicrobial agents, is an area of great concern. It is now being frequently associated with healthcare associated infections. Literature was searched at PUBMED, Google Scholar, and Cochrane Library, using the terms ‘Acinetobacter Resistance, multidrug resistant (MDR), Antimicrobial Therapy, Outbreak, Colistin, Tigecycline, AmpC enzymes, and carbapenemases in various combinations. The terms such as MDR, Extensively Drug Resistant (XDR), and Pan Drug Resistant (PDR) have been used in published literature with varied definitions, leading to confusion in the correlation of data from various studies. In this review various mechanisms of resistance in the Acinetobacter species have been discussed. The review also probes upon the current therapeutic options, including combination therapies available to treat infections due to resistant Acinetobacter species in adults as well as children. There is an urgent need to enforce infection control measures and antimicrobial stewardship programs to prevent the further spread of these resistant Acinetobacter species and to delay the emergence of increased resistance in the bacteria. PMID:20927292

  9. Meeting the resistance problem

    PubMed Central

    Brown, A. W. A.

    1963-01-01

    Because resistance to new insecticides may develop rapidly and cross resistance is often encountered, even between insecticides of different classes, there is a continual demand for the development of new compounds toxic to insects. There is at present a choice between chlorinated hydrocarbons, organophosphorus compounds, carbamates, pyrethrins, synthetic pyrethroids and thiocyanates. This paper discusses thoroughly the present status of a large number of insecticides, the cross-resistances between them, and the most effective methods of application. It also examines some of the biochemical mechanisms responsible for resistance and the attempts that have been made to use substances capable of inhibiting these mechanisms as synergists of insecticides.

  10. Effective resist profile control

    NASA Astrophysics Data System (ADS)

    Liu, Chen-Yu; Wang, Chien-Wei; Huang, Chun-Ching; Chang, Ching-Yu; Ku, Yao-Ching

    2014-03-01

    To meet Moore's law, resist resolution improvement has become more and more important. However, it is difficult to improve resist resolution and keep vertical sidewall profile. For example, a high contrast hole resist may cause trench scum, due to very T-top profile. This paper reports several concepts for resist profile tuning without losing performance for lithographic factor , including mask error enhancement factor (MEEF), depth of focus (DOF), and critical dimension uniformity (CDU). To quantitative analysis the resist profile improvement, we define a new factor, Scum fail ratio (F/R%) for new techniques evaluation. The new techniques, including floatable additive, floatable PAG, and new monomer, are discussed. From X-SEM and CD-SEM data, former three concepts could improve resist sidewall profile quantitatively evaluated by Scum fail F/R% and keep lithographic factors. In addition, another key factor, resist residue defect, is also discussed. The high contrast resist with higher receding contact angle (RCA) easily generates more residue defect after development. With the new monomer composition, RCA of Resist E is decreased from 54 to 48 degree after development. Therefore, the residue defect is improved one order.

  11. Resist profile simulation with fast lithography model

    NASA Astrophysics Data System (ADS)

    He, Yan-Ying; Chou, Chih-Shiang; Tang, Yu-Po; Huang, Wen-Chun; Liu, Ru-Gun; Gau, Tsai-Sheng

    2014-03-01

    A traditional approach to construct a fast lithographic model is to match wafer top-down SEM images, contours and/or gauge CDs with a TCC model plus some simple resist representation. This modeling method has been proven and is extensively used for OPC modeling. As the technology moves forward, this traditional approach has become insufficient in regard to lithography weak point detection, etching bias prediction, etc. The drawback of this approach is from metrology and simulation. First, top-down SEM is only good for acquiring planar CD information. Some 3D metrology such as cross-section SEM or AFM is necessary to obtain the true resist profile. Second, the TCC modeling approach is only suitable for planar image simulation. In order to model the resist profile, full 3D image simulation is needed. Even though there are many rigorous simulators capable of catching the resist profile very well, none of them is feasible for full-chip application due to the tremendous consumption of computational resource. The authors have proposed a quasi-3D image simulation method in the previous study [1], which is suitable for full-chip simulation with the consideration of sidewall angles, to improve the model accuracy of planar models. In this paper, the quasi-3D image simulation is extended to directly model the resist profile with AFM and/or cross-section SEM data. Resist weak points detected by the model generated with this 3D approach are verified on the wafer.

  12. Predicting evolutionary dynamics

    NASA Astrophysics Data System (ADS)

    Balazsi, Gabor

    We developed an ordinary differential equation-based model to predict the evolutionary dynamics of yeast cells carrying a synthetic gene circuit. The predicted aspects included the speed at which the ancestral genotype disappears from the population; as well as the types of mutant alleles that establish in each environmental condition. We validated these predictions by experimental evolution. The agreement between our predictions and experimental findings suggests that cellular and population fitness landscapes can be useful to predict short-term evolution.

  13. Advances and Challenges in Genomic Selection for Disease Resistance.

    PubMed

    Poland, Jesse; Rutkoski, Jessica

    2016-08-01

    Breeding for disease resistance is a central focus of plant breeding programs, as any successful variety must have the complete package of high yield, disease resistance, agronomic performance, and end-use quality. With the need to accelerate the development of improved varieties, genomics-assisted breeding is becoming an important tool in breeding programs. With marker-assisted selection, there has been success in breeding for disease resistance; however, much of this work and research has focused on identifying, mapping, and selecting for major resistance genes that tend to be highly effective but vulnerable to breakdown with rapid changes in pathogen races. In contrast, breeding for minor-gene quantitative resistance tends to produce more durable varieties but is a more challenging breeding objective. As the genetic architecture of resistance shifts from single major R genes to a diffused architecture of many minor genes, the best approach for molecular breeding will shift from marker-assisted selection to genomic selection. Genomics-assisted breeding for quantitative resistance will therefore necessitate whole-genome prediction models and selection methodology as implemented for classical complex traits such as yield. Here, we examine multiple case studies testing whole-genome prediction models and genomic selection for disease resistance. In general, whole-genome models for disease resistance can produce prediction accuracy suitable for application in breeding. These models also largely outperform multiple linear regression as would be applied in marker-assisted selection. With the implementation of genomic selection for yield and other agronomic traits, whole-genome marker profiles will be available for the entire set of breeding lines, enabling genomic selection for disease at no additional direct cost. In this context, the scope of implementing genomics selection for disease resistance, and specifically for quantitative resistance and quarantined pathogens

  14. Advances and Challenges in Genomic Selection for Disease Resistance.

    PubMed

    Poland, Jesse; Rutkoski, Jessica

    2016-08-01

    Breeding for disease resistance is a central focus of plant breeding programs, as any successful variety must have the complete package of high yield, disease resistance, agronomic performance, and end-use quality. With the need to accelerate the development of improved varieties, genomics-assisted breeding is becoming an important tool in breeding programs. With marker-assisted selection, there has been success in breeding for disease resistance; however, much of this work and research has focused on identifying, mapping, and selecting for major resistance genes that tend to be highly effective but vulnerable to breakdown with rapid changes in pathogen races. In contrast, breeding for minor-gene quantitative resistance tends to produce more durable varieties but is a more challenging breeding objective. As the genetic architecture of resistance shifts from single major R genes to a diffused architecture of many minor genes, the best approach for molecular breeding will shift from marker-assisted selection to genomic selection. Genomics-assisted breeding for quantitative resistance will therefore necessitate whole-genome prediction models and selection methodology as implemented for classical complex traits such as yield. Here, we examine multiple case studies testing whole-genome prediction models and genomic selection for disease resistance. In general, whole-genome models for disease resistance can produce prediction accuracy suitable for application in breeding. These models also largely outperform multiple linear regression as would be applied in marker-assisted selection. With the implementation of genomic selection for yield and other agronomic traits, whole-genome marker profiles will be available for the entire set of breeding lines, enabling genomic selection for disease at no additional direct cost. In this context, the scope of implementing genomics selection for disease resistance, and specifically for quantitative resistance and quarantined pathogens

  15. Selection and characterization of cyanophage resistance in marine Synechococcus strains.

    PubMed

    Stoddard, Lauren I; Martiny, Jennifer B H; Marston, Marcia F

    2007-09-01

    Marine viruses are an important component of the microbial food web, influencing microbial diversity and contributing to bacterial mortality rates. Resistance to cooccurring cyanophages has been reported for natural communities of Synechococcus spp.; however, little is known about the nature of this resistance. This study examined the patterns of infectivity among cyanophage isolates and unicellular marine cyanobacteria (Synechococcus spp.). We selected for phage-resistant Synechococcus mutants, examined the mechanisms of phage resistance, and determined the extent of cross-resistance to other phages. Four strains of Synechococcus spp. (WH7803, WH8018, WH8012, and WH8101) and 32 previously isolated cyanomyophages were used to select for phage resistance. Phage-resistant Synechococcus mutants were recovered from 50 of the 101 susceptible phage-host pairs, and 23 of these strains were further characterized. Adsorption kinetic assays indicate that resistance is likely due to changes in host receptor sites that limit viral attachment. Our results also suggest that receptor mutations conferring this resistance are diverse. Nevertheless, selection for resistance to one phage frequently resulted in cross-resistance to other phages. On average, phage-resistant Synechococcus strains became resistant to eight other cyanophages; however, there was no significant correlation between the genetic similarity of the phages (based on g20 sequences) and cross-resistance. Likewise, host Synechococcus DNA-dependent RNA polymerase (rpoC1) genotypes could not be used to predict sensitivities to phages. The potential for the rapid evolution of multiple phage resistance may influence the population dynamics and diversity of both Synechococcus and cyanophages in marine waters.

  16. Insulin resistance: regression and clustering.

    PubMed

    Yoon, Sangho; Assimes, Themistocles L; Quertermous, Thomas; Hsiao, Chin-Fu; Chuang, Lee-Ming; Hwu, Chii-Min; Rajaratnam, Bala; Olshen, Richard A

    2014-01-01

    In this paper we try to define insulin resistance (IR) precisely for a group of Chinese women. Our definition deliberately does not depend upon body mass index (BMI) or age, although in other studies, with particular random effects models quite different from models used here, BMI accounts for a large part of the variability in IR. We accomplish our goal through application of Gauss mixture vector quantization (GMVQ), a technique for clustering that was developed for application to lossy data compression. Defining data come from measurements that play major roles in medical practice. A precise statement of what the data are is in Section 1. Their family structures are described in detail. They concern levels of lipids and the results of an oral glucose tolerance test (OGTT). We apply GMVQ to residuals obtained from regressions of outcomes of an OGTT and lipids on functions of age and BMI that are inferred from the data. A bootstrap procedure developed for our family data supplemented by insights from other approaches leads us to believe that two clusters are appropriate for defining IR precisely. One cluster consists of women who are IR, and the other of women who seem not to be. Genes and other features are used to predict cluster membership. We argue that prediction with "main effects" is not satisfactory, but prediction that includes interactions may be. PMID:24887437

  17. Macrocyclic lactone resistance in Dirofilaria immitis: Failure of heartworm preventives and investigation of genetic markers for resistance.

    PubMed

    Bourguinat, Catherine; Lee, Alice C Y; Lizundia, Regina; Blagburn, Byron L; Liotta, Janice L; Kraus, Marc S; Keller, Kathy; Epe, Christian; Letourneau, Louis; Kleinman, Claudia L; Paterson, Tara; Gomez, Elena Carreton; Montoya-Alonso, José Alberto; Smith, Hubert; Bhan, Aron; Peregrine, Andrew S; Carmichael, James; Drake, Jason; Schenker, Rudolf; Kaminsky, Ronald; Bowman, Dwight D; Geary, Timothy G; Prichard, Roger K

    2015-06-15

    Macrocyclic lactone (ML) endectocides are used as chemoprophylaxis for heartworm infection (Dirofilaria immitis) in dogs and cats. Claims of loss of efficacy (LOE) of ML heartworm preventives have become common in some locations in the USA. We directly tested whether resistance to MLs exists in LOE isolates of D. immitis and identified genetic markers that are correlated with, and therefore can predict ML resistance. ML controlled studies showed that LOE strains of D. immitis established infections in dogs despite chemoprophylaxis with oral ivermectin or injectable moxidectin. A whole genome approach was used to search for loci associated with the resistance phenotype. Many loci showed highly significant differences between pools of susceptible and LOE D. immitis. Based on 186 potential marker loci, Sequenom(®) SNP frequency analyses were conducted on 663 individual parasites (adult worms and microfilariae) which were phenotypically characterized as susceptible (SUS), confirmed ML treatment survivors/resistant (RES), or suspected resistant/loss of efficacy (LOE) parasites. There was a subset of SNP loci which appears to be promising markers for predicting ML resistance, including SNPs in some genes that have been associated with ML resistance in other parasites. These data provide unequivocal proof of ML resistance in D. immitis and identify genetic markers that could be used to monitor for ML resistance in heartworms.

  18. Impact of HIV type 1 drug resistance mutations and phenotypic resistance profile on virologic response to salvage therapy.

    PubMed

    Ross, L; Liao, Q; Gao, H; Pham, S; Tolson, J; Hertogs, K; Larder, B; Saag, M S

    2001-10-10

    This study examines the association between presence of drug resistance mutations and phenotypic resistance at baseline to virologic response to salvage therapy in a community setting. The study population consisted of 58 antiretroviral drug-experienced patients with HIV-1 infection who had recently switched therapy because of virologic failure. Drug resistance mutations in the reverse transcriptase- and protease-coding regions and phenotypic susceptibility to 13 antiretroviral drugs were assessed at baseline. Plasma HIV-1 RNA levels were assessed at baseline and at subsequent clinic visits. Results showed that three variables were significant in predicting virologic response: HIV-1 levels at baseline, number of protease mutations, and phenotypic sensitivity score for the regimen at baseline. For four drugs there was a significant association between the presence of specific drug resistance mutations and >10-fold phenotypic resistance to that drug. With phenotypic resistance defined as >4-fold resistance, the association between specific drug resistance mutations and phenotypic resistance was significant for seven drugs. Overall, these data show that phenotypic susceptibility and absence of drug resistance mutations, particularly protease mutations, are significant predictors of virologic response. For several drugs, specific combinations of drug resistance mutations are associated with decreased phenotypic susceptibility and might provide useful clinical guidelines in selecting therapeutic options.

  19. Determination of series resistance of indium phosphide solar cells

    NASA Technical Reports Server (NTRS)

    Jain, Raj K.; Weinberg, Irving

    1991-01-01

    The series resistance of a solar cell is an important parameter, which must be minimized to achieve high cell efficiencies. The cell series resistance is affected by the starting material, its design, and processing. The theoretical approach proposed by Jia, et. al., is used to calculate the series resistance of indium phosphide solar cells. It is observed that the theoretical approach does not predict the series resistance correctly in all cases. The analysis was modified to include the use of effective junction ideality factor. The calculated results were compared with the available experimental results on indium phosphide solar cells processed by different techniques. It is found that the use of process dependent junction ideality factor leads to better estimation of series resistance. An accurate comprehensive series resistance model is warranted to give proper feedback for modifying the cell processing from the design state.

  20. beta-Lactamases in laboratory and clinical resistance.

    PubMed Central

    Livermore, D M

    1995-01-01

    beta-Lactamases are the commonest single cause of bacterial resistance to beta-lactam antibiotics. Numerous chromosomal and plasmid-mediated types are known and may be classified by their sequences or phenotypic properties. The ability of a beta-lactamase to cause resistance varies with its activity, quantity, and cellular location and, for gram-negative organisms, the permeability of the producer strain. beta-Lactamases sometimes cause obvious resistance to substrate drugs in routine tests; often, however, these enzymes reduce susceptibility without causing resistance at current, pharmacologically chosen breakpoints. This review considers the ability of the prevalent beta-lactamases to cause resistance to widely used beta-lactams, whether resistance is accurately reflected in routine tests, and the extent to which the antibiogram for an organism can be used to predict the type of beta-lactamase that it produces. PMID:8665470

  1. Mechanisms of Drug Resistance: Daptomycin Resistance

    PubMed Central

    Tran, Truc T.; Munita, Jose M.; Arias, Cesar A.

    2016-01-01

    Daptomycin (DAP) is a cyclic lipopeptide with in vitro activity against a variety of Gram-positive pathogens, including multidrug-resistant organisms. Since its introduction in clinical practice in 2003, DAP has become an important key front-line antibiotic for severe or deep-seated infections caused by Gram-positive organisms. Unfortunately, DAP-resistance (R) has been extensively documented in clinically important organisms such as Staphylococcus aureus, Enterococcus spp, and Streptococcus spp. Studies on the mechanisms of DAP-R in Bacillus subtilis and other Gram-positive bacteria indicate that the genetic pathways of DAP resistance are diverse and complex. However, a common phenomenon emerging from these mechanistic studies is that DAP-R is associated with important adaptive changes in cell wall and cell membrane homeostasis with critical changes in cell physiology. Findings related to these adaptive changes have offered novel insights into the genetics and molecular mechanisms of bacterial cell envelope stress response and the manner in which Gram-positive bacteria cope with the antimicrobial peptide attack and protect vital structures of the cell envelope such as the cell membrane. In this review, we will examine the most recent findings related to the molecular mechanisms of resistance to DAP in relevant Gram-positive pathogens and discuss the clinical implications for therapy against these important bacteria. PMID:26495887

  2. Mold-Resistant Construction.

    ERIC Educational Resources Information Center

    Huckabee, Christopher

    2003-01-01

    Asserts that one of the surest ways to prevent indoor air quality and mold issues is to use preventive construction materials, discussing typical resistance to dealing with mold problems (usually budget-related) and describing mold-resistant construction, which uses concrete masonry, brick, and stone and is intended to withstand inevitable…

  3. Mechanisms of Antibiotic Resistance

    PubMed Central

    Munita, Jose M.; Arias, Cesar A.

    2015-01-01

    Emergence of resistance among the most important bacterial pathogens is recognized as a major public health threat affecting humans worldwide. Multidrug-resistant organisms have emerged not only in the hospital environment but are now often identified in community settings, suggesting that reservoirs of antibiotic-resistant bacteria are present outside the hospital. The bacterial response to the antibiotic “attack” is the prime example of bacterial adaptation and the pinnacle of evolution. “Survival of the fittest” is a consequence of an immense genetic plasticity of bacterial pathogens that trigger specific responses that result in mutational adaptations, acquisition of genetic material or alteration of gene expression producing resistance to virtually all antibiotics currently available in clinical practice. Therefore, understanding the biochemical and genetic basis of resistance is of paramount importance to design strategies to curtail the emergence and spread of resistance and devise innovative therapeutic approaches against multidrug-resistant organisms. In this chapter, we will describe in detail the major mechanisms of antibiotic resistance encountered in clinical practice providing specific examples in relevant bacterial pathogens. PMID:27227291

  4. Mechanisms of Antibiotic Resistance.

    PubMed

    Munita, Jose M; Arias, Cesar A

    2016-04-01

    Emergence of resistance among the most important bacterial pathogens is recognized as a major public health threat affecting humans worldwide. Multidrug-resistant organisms have not only emerged in the hospital environment but are now often identified in community settings, suggesting that reservoirs of antibiotic-resistant bacteria are present outside the hospital. The bacterial response to the antibiotic "attack" is the prime example of bacterial adaptation and the pinnacle of evolution. "Survival of the fittest" is a consequence of an immense genetic plasticity of bacterial pathogens that trigger specific responses that result in mutational adaptations, acquisition of genetic material, or alteration of gene expression producing resistance to virtually all antibiotics currently available in clinical practice. Therefore, understanding the biochemical and genetic basis of resistance is of paramount importance to design strategies to curtail the emergence and spread of resistance and to devise innovative therapeutic approaches against multidrug-resistant organisms. In this chapter, we will describe in detail the major mechanisms of antibiotic resistance encountered in clinical practice, providing specific examples in relevant bacterial pathogens. PMID:27227291

  5. Breaking the Spell: Combating Multidrug Resistant 'Superbugs'.

    PubMed

    Khan, Shahper N; Khan, Asad U

    2016-01-01

    Multidrug-resistant (MDR) bacteria have become a severe threat to community wellbeing. Conventional antibiotics are getting progressively more ineffective as a consequence of resistance, making it imperative to realize improved antimicrobial options. In this review we emphasized the microorganisms primarily reported of being resistance, referred as ESKAPE pathogens (Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumanii, Pseudomonas aeruginosa, and Enterobacteriaceae) accentuating their capacity to "escape" from routine antimicrobial regimes. The upcoming antimicrobial agents showing great potential and can serve as alternative therapeutic options are discussed. We also provided succinct overview of two evolving technologies; specifically network pharmacology and functional genomics profiling. Furthermore, In vivo imaging techniques can provide novel targets and a real time tool for potential lead molecule assessment. The employment of such approaches at prelude of a drug development process, will enables more informed decisions on candidate drug selection and will maximize or predict therapeutic potential before clinical testing.

  6. Governing principles can guide fungicide-resistance management tactics.

    PubMed

    van den Bosch, Frank; Oliver, Richard; van den Berg, Femke; Paveley, Neil

    2014-01-01

    Fungicide-resistance management would be more effective if principles governing the selection of resistant strains could be determined and validated. Such principles could then be used to predict whether a proposed change to a fungicide application program would decrease selection for resistant strains. In this review, we assess a governing principle that appears to have good predictive power. The principle states that reducing the product of the selection coefficient (defined as the difference between the per capita rate of increase of the sensitive and resistant strains) and the exposure time of the pathogen to the fungicide reduces the selection for resistance. We show that observations as well as modeling studies agree with the predicted effect (i.e., that a specific change to a fungicide program increased or decreased selection or was broadly neutral in its effect on selection) in 84% of the cases and that only 5% of the experimental results contradict predictions. We argue that the selection coefficient and exposure time principle can guide the development of resistance management tactics.

  7. Resistance of 4H-SiC Schottky barriers at high forward-current densities

    SciTech Connect

    Ivanov, P. A. Samsonova, T. P.; Il’inskaya, N. D.; Serebrennikova, O. Yu.; Kon’kov, O. I.; Potapov, A. S.

    2015-07-15

    The resistance of Schottky barriers based on 4H-SiC is experimentally determined at high forward-current densities. The measured resistance is found to be significantly higher than the resistance predicted by classical mechanisms of electron transport in Schottky contacts. An assumption concerning the crucial contribution of the tunnel-transparent intermediate oxide layer between the metal and semiconductor to the barrier resistance is proposed and partially justified.

  8. Targeting Antibiotic Resistance

    PubMed Central

    Chellat, Mathieu F.; Raguž, Luka

    2016-01-01

    Abstract Finding strategies against the development of antibiotic resistance is a major global challenge for the life sciences community and for public health. The past decades have seen a dramatic worldwide increase in human‐pathogenic bacteria that are resistant to one or multiple antibiotics. More and more infections caused by resistant microorganisms fail to respond to conventional treatment, and in some cases, even last‐resort antibiotics have lost their power. In addition, industry pipelines for the development of novel antibiotics have run dry over the past decades. A recent world health day by the World Health Organization titled “Combat drug resistance: no action today means no cure tomorrow” triggered an increase in research activity, and several promising strategies have been developed to restore treatment options against infections by resistant bacterial pathogens. PMID:27000559

  9. Predictive modeling of complications.

    PubMed

    Osorio, Joseph A; Scheer, Justin K; Ames, Christopher P

    2016-09-01

    Predictive analytic algorithms are designed to identify patterns in the data that allow for accurate predictions without the need for a hypothesis. Therefore, predictive modeling can provide detailed and patient-specific information that can be readily applied when discussing the risks of surgery with a patient. There are few studies using predictive modeling techniques in the adult spine surgery literature. These types of studies represent the beginning of the use of predictive analytics in spine surgery outcomes. We will discuss the advancements in the field of spine surgery with respect to predictive analytics, the controversies surrounding the technique, and the future directions.

  10. Subsurface investigation in Sarimukti landfill using DC resistivity

    NASA Astrophysics Data System (ADS)

    Kirana, Kartika Hajar; Susanto, Kusnahadi; Susilawati, Anggie

    2015-09-01

    Layering process in landfill will produce leachate that produced by the entry of a mixture of rain water or ground water into the piles solid waste. In Sarimukti landfill, leachate from landfill channeled through a pipe to the leachate pond that planted beneath the soil surface. If the pipe is leaking, the leachate will contaminate the surrounding soil and may also to contaminate groundwater. Therefore, it is necessary to investigate subsurface conditions. One type of subsurface investigation can be determined by measuring the resistivity by using DC resistivity method. Resistivity measured in Sarimukti landfill with semigriding design including 8 lines perpendicular to each other. The result show there is resistivity contrast of materials, such as the solid waste, soil, water content that is predicted as leachate, and methane gas. The range of resistivity values are from 1 Ωm to 500 Ωm with variations of depth in according to line lenght. The resistivity values respectively: leachate is 1 to 10 Ωm; Wet soil is 10 to 100 Ωm; wet waste is 100 to 400 Ωm; gas is > 400 Ωm. Then, leachate was found at depth of 25 meters and wet soil is predicted as aquifer layer with 70 meters depth. The resistivity of aquifer layer is 1 to 20 Ωm and covered by silt clay as clay cap. Thus, it can predicted that leachate not seep into the aquifer layer.

  11. Predictive and therapeutic markers in ovarian cancer

    DOEpatents

    Gray, Joe W.; Guan, Yinghui; Kuo, Wen-Lin; Fridlyand, Jane; Mills, Gordon B.

    2013-03-26

    Cancer markers may be developed to detect diseases characterized by increased expression of apoptosis-suppressing genes, such as aggressive cancers. Genes in the human chromosomal regions, 8q24, 11q13, 20q11-q13, were found to be amplified indicating in vivo drug resistance in diseases such as ovarian cancer. Diagnosis and assessment of amplification levels certain genes shown to be amplified, including PVT1, can be useful in prediction of poor outcome of patient's response and drug resistance in ovarian cancer patients with low survival rates. Certain genes were found to be high priority therapeutic targets by the identification of recurrent aberrations involving genome sequence, copy number and/or gene expression are associated with reduced survival duration in certain diseases and cancers, specifically ovarian cancer. Therapeutics to inhibit amplification and inhibitors of one of these genes, PVT1, target drug resistance in ovarian cancer patients with low survival rates is described.

  12. Echinocandin Resistance in Candida.

    PubMed

    Perlin, David S

    2015-12-01

    Invasive fungal infections are an important infection concern for patients with underlying immunosuppression. Antifungal therapy is a critical component of patient care, but therapeutic choices are limited due to few drug classes. Antifungal resistance, especially among Candida species, aggravates the problem. The echinocandin drugs (micafungin, anidulafungin, and caspofungin) are the preferred choice to treat a range of candidiasis. They target the fungal-specific enzyme glucan synthase, which is responsible for the biosynthesis of a major cell wall polymer. Therapeutic failure involves acquisition of resistance, although it is a rare event among most Candida species. However, in some settings, higher-level resistance has been reported among Candida glabrata, which is also frequently resistant to azole drugs, resulting in difficult-to-treat multidrug-resistant strains. The mechanism of echinocandin resistance involves amino acid changes in "hot spot" regions of FKS-encoded subunits of glucan synthase, which decreases the sensitivity of enzyme to drug, resulting in higher minimum inhibitory concentration values. The cellular processes promoting the formation of resistant FKS strains involve complex stress response pathways that yield a variety of adaptive compensatory genetic responses. Standardized broth microdilution techniques can be used to distinguish FKS mutant strains from wild type, but testing C. glabrata with caspofungin should be approached cautiously. Finally, clinical factors that promote echinocandin resistance include prophylaxis, host reservoirs including biofilms in the gastrointestinal tract, and intra-abdominal infections. An understanding of clinical and molecular factors that promote echinocandin resistance is critical to develop better diagnostic tools and therapeutic strategies to overcome resistance.

  13. Intracellular resistance and conduction in bullfrog atrium.

    PubMed

    Scubon-Mulieri, B; Sichel, F J

    1975-01-01

    The present study was undertaken to study the mechanism of transmission across the junctions between cells of cardiac muscle. Two cases, one with high resistance junction and the second with low resistance junctions, were modeled mathematically and each model was analyzed to predict the ratio of the transverse to longitudinal threshold field strengths. This ratio was measured experimentally for atrial trabeculae from Rana catesbiana and agreed well with the value predicted by the model in which the resistance of the membranes at the junctions is low. It can be inferred, therefore, that the resistance at the junctions between cells of bullfrog atrial muscle is low enough to permit the flow of sufficient current from the pre- to postjunctional cell to cause excitation of the latter. One parameter required in the analysis was the space constant, lambda. This was measured with the trabecula in a volume conductor using a large planar external electrode to produce a change in the transmembrane potential and a microelectrode to measure the spatial decrement of the electrotonic potential. The measurements of electrotonic decrement in 16 trabeculae are pooled to provide an estimate of the value of the space constant in frog atrial trabeculae: lambda= 0.863 +/- 0.041 mm, s.d., n=96. PMID:1083538

  14. Microbial resistance to disinfectants: mechanisms and significance

    SciTech Connect

    Hoff, J.C.; Akin, E.W.

    1986-11-01

    Drinking water disinfection provides the final barrier to transmission of a wide variety of potentially waterborne infectious agents including pathogenic bacteria, viruses, and protozoa. These agents differ greatly in their innate resistance to inactivation by disinfectants, ranging from extremely sensitive bacteria to highly resistant protozoan cysts. The close similarity between microorganism inactivation rates and the kinetics of chemical reactions has long been recognized. Ideally, under carefully controlled conditions, microorganism inactivation rates simulate first-order chemical reaction rates, making it possible to predict the effectiveness of disinfection under specific conditions. In practice, changes in relative resistance and deviations from first-order kinetics are caused by a number of factors, including microbial growth conditions, aggregation, and association with particulate materials. The net effect of all these factors is a reduction in the effectiveness and predictability of disinfection processes. To ensure effective pathogen control, disinfectant concentrations and contact times greater than experimentally determined values may be required. Of the factors causing enhanced disinfection resistance, protection by association with particulate matter is the most significant. Therefore, removal of particulate matter is an important step in increasing the effectiveness of disinfection processes.

  15. Does high serum uric acid level cause aspirin resistance?

    PubMed

    Yildiz, Bekir S; Ozkan, Emel; Esin, Fatma; Alihanoglu, Yusuf I; Ozkan, Hayrettin; Bilgin, Murat; Kilic, Ismail D; Ergin, Ahmet; Kaftan, Havane A; Evrengul, Harun

    2016-06-01

    In patients with coronary artery disease (CAD), though aspirin inhibits platelet activation and reduces atherothrombotic complications, it does not always sufficiently inhibit platelet function, thereby causing a clinical situation known as aspirin resistance. As hyperuricemia activates platelet turnover, aspirin resistance may be specifically induced by increased serum uric acid (SUA) levels. In this study, we thus investigated the association between SUA level and aspirin resistance in patients with CAD. We analyzed 245 consecutive patients with stable angina pectoris (SAP) who in coronary angiography showed more than 50% occlusion in a major coronary artery. According to aspirin resistance, two groups were formed: the aspirin resistance group (Group 1) and the aspirin-sensitive group (Group 2). Compared with those of Group 2, patients with aspirin resistance exhibited significantly higher white blood cell counts, neutrophil counts, neutrophil-to-lymphocyte ratios, SUA levels, high-sensitivity C-reactive protein levels, and fasting blood glucose levels. After multivariate analysis, a high level of SUA emerged as an independent predictor of aspirin resistance. The receiver-operating characteristic analysis provided a cutoff value of 6.45 mg/dl for SUA to predict aspirin resistance with 79% sensitivity and 65% specificity. Hyperuricemia may cause aspirin resistance in patients with CAD and high SUA levels may indicate aspirin-resistant patients. Such levels should thus recommend avoiding heart attack and stroke by adjusting aspirin dosage. PMID:26656902

  16. Linezolid Resistance in Staphylococci

    PubMed Central

    Stefani, Stefania; Bongiorno, Dafne; Mongelli, Gino; Campanile, Floriana

    2010-01-01

    Linezolid, the first oxazolidinone to be used clinically, is effective in the treatment of infections caused by various Gram-positive pathogens, including multidrug resistant enterococci and methicillin-resistant Staphylococus aureus. It has been used successfully for the treatment of patients with endocarditis and bacteraemia, osteomyelitis, joint infections and tuberculosis and it is often used for treatment of complicated infections when other therapies have failed. Linezolid resistance in Gram-positive cocci has been encountered clinically as well as in vitro, but it is still a rare phenomenon. The resistance to this antibiotic has been, until now, entirely associated with distinct nucleotide substitutions in domain V of the 23S rRNA genes. The number of mutated rRNA genes depends on the dose and duration of linezolid exposure and has been shown to influence the level of linezolid resistance. Mutations in associated ribosomal proteins also affect linezolid activity. A new phenicol and clindamycin resistance phenotype has recently been found to be caused by an RNA methyltransferase designated Cfr. This gene confers resistance to lincosamides, oxazolidinones, streptogramin A, phenicols and pleuromutilins, decrease the susceptibility of S. aureus to tylosin, to josamycin and spiramycin and thus differs from erm rRNA methylase genes. Research into new oxazolidinones with improved characteristics is ongoing. Data reported in patent applications demonstrated that some oxazolidinone derivatives, also with improved characteristics with respect to linezolid, are presently under study: at least three of them are in an advanced phase of development.

  17. AC resistance measuring instrument

    DOEpatents

    Hof, P.J.

    1983-10-04

    An auto-ranging AC resistance measuring instrument for remote measurement of the resistance of an electrical device or circuit connected to the instrument includes a signal generator which generates an AC excitation signal for application to a load, including the device and the transmission line, a monitoring circuit which provides a digitally encoded signal representing the voltage across the load, and a microprocessor which operates under program control to provide an auto-ranging function by which range resistance is connected in circuit with the load to limit the load voltage to an acceptable range for the instrument, and an auto-compensating function by which compensating capacitance is connected in shunt with the range resistance to compensate for the effects of line capacitance. After the auto-ranging and auto-compensation functions are complete, the microprocessor calculates the resistance of the load from the selected range resistance, the excitation signal, and the load voltage signal, and displays of the measured resistance on a digital display of the instrument. 8 figs.

  18. AC Resistance measuring instrument

    DOEpatents

    Hof, Peter J.

    1983-01-01

    An auto-ranging AC resistance measuring instrument for remote measurement of the resistance of an electrical device or circuit connected to the instrument includes a signal generator which generates an AC excitation signal for application to a load, including the device and the transmission line, a monitoring circuit which provides a digitally encoded signal representing the voltage across the load, and a microprocessor which operates under program control to provide an auto-ranging function by which range resistance is connected in circuit with the load to limit the load voltage to an acceptable range for the instrument, and an auto-compensating function by which compensating capacitance is connected in shunt with the range resistance to compensate for the effects of line capacitance. After the auto-ranging and auto-compensation functions are complete, the microprocessor calculates the resistance of the load from the selected range resistance, the excitation signal, and the load voltage signal, and displays of the measured resistance on a digital display of the instrument.

  19. Insulin and Insulin Resistance

    PubMed Central

    2005-01-01

    As obesity and diabetes reach epidemic proportions in the developed world, the role of insulin resistance and its consequences are gaining prominence. Understanding the role of insulin in wide-ranging physiological processes and the influences on its synthesis and secretion, alongside its actions from the molecular to the whole body level, has significant implications for much chronic disease seen in Westernised populations today. This review provides an overview of insulin, its history, structure, synthesis, secretion, actions and interactions followed by a discussion of insulin resistance and its associated clinical manifestations. Specific areas of focus include the actions of insulin and manifestations of insulin resistance in specific organs and tissues, physiological, environmental and pharmacological influences on insulin action and insulin resistance as well as clinical syndromes associated with insulin resistance. Clinical and functional measures of insulin resistance are also covered. Despite our incomplete understanding of the complex biological mechanisms of insulin action and insulin resistance, we need to consider the dramatic social changes of the past century with respect to physical activity, diet, work, socialisation and sleep patterns. Rapid globalisation, urbanisation and industrialisation have spawned epidemics of obesity, diabetes and their attendant co-morbidities, as physical inactivity and dietary imbalance unmask latent predisposing genetic traits. PMID:16278749

  20. Prediction in Multiple Regression.

    ERIC Educational Resources Information Center

    Osborne, Jason W.

    2000-01-01

    Presents the concept of prediction via multiple regression (MR) and discusses the assumptions underlying multiple regression analyses. Also discusses shrinkage, cross-validation, and double cross-validation of prediction equations and describes how to calculate confidence intervals around individual predictions. (SLD)

  1. Nonlinear Combustion Instability Prediction

    NASA Technical Reports Server (NTRS)

    Flandro, Gary

    2010-01-01

    The liquid rocket engine stability prediction software (LCI) predicts combustion stability of systems using LOX-LH2 propellants. Both longitudinal and transverse mode stability characteristics are calculated. This software has the unique feature of being able to predict system limit amplitude.

  2. Prediction in Multilevel Models

    ERIC Educational Resources Information Center

    Afshartous, David; de Leeuw, Jan

    2005-01-01

    Multilevel modeling is an increasingly popular technique for analyzing hierarchical data. This article addresses the problem of predicting a future observable y[subscript *j] in the jth group of a hierarchical data set. Three prediction rules are considered and several analytical results on the relative performance of these prediction rules are…

  3. Antibiotic Resistance Questions and Answers

    MedlinePlus

    ... on the Farm Get Smart About Antibiotics Week Antibiotic Resistance Questions and Answers Language: English Español (Spanish) Recommend ... Many ear infections Top of Page Questions about Antibiotic Resistance Examples of How Antibiotic Resistance Spreads Click for ...

  4. Resistive Exercise Device

    NASA Technical Reports Server (NTRS)

    Smith, Damon C. (Inventor)

    2005-01-01

    An exercise device 10 is particularly well suited for use in low gravity environments, and includes a frame 12 with plurality of resistance elements 30,82 supported in parallel on the frame. A load transfer member 20 is moveable relative to the frame for transferring the applied force to the free end of each captured resistance element. Load selection template 14 is removably secured both to the load transfer member, and a plurality of capture mechanisms engage the free end of corresponding resistance elements. The force applying mechanism 53 may be a handle, harness or other user interface for applying a force to move the load transfer member.

  5. A caveat concerning center of resistance

    PubMed Central

    Nägerl, Hans; Kubein-Meesenburg, Dietmar

    2013-01-01

    The center of resistance is a concept in theoretical orthodontics used to describe tooth movement under loads. It is commonly used to qualitatively predict tooth movement without recourse to complex equations or simulations. We start with a survey of the historical origin of the technical term. After this, the periodontal ligament is idealized as a linear elastic suspension. The mathematical formalism of vector and tensor calculus will clarify our reasoning. We show that a point such as the center of resistance basically only exists in two dimensions or in very special symmetric spatial configurations. In three dimensions, a simple counterexample of a suspension without a center of resistance is given. A second more tooth-like example illustrates the magnitude of the effects in question in dentistry. In conclusion, the center of resistance should be replaced by a newer and wider mathematical concept, the “center of elasticity,” together with a limiting parameter, the “radius of resistance.” PMID:24019849

  6. Antimalarial drug resistance: a review of the biology and strategies to delay emergence and spread

    PubMed Central

    Klein, E.Y.

    2013-01-01

    The emergence of resistance to former first-line antimalarial drugs has been an unmitigated disaster. In recent years, artemisinin class drugs have become standard and they are considered an essential tool for helping to eradicate the disease. However, their ability to reduce morbidity and mortality and to slow transmission requires the maintenance of effectiveness. Recently, an artemisinin delayed-clearance phenotype was described. This is believed to be the precursor to resistance and threatens local elimination and global eradication plans. Understanding how resistance emerges and spreads is important for developing strategies to contain its spread. Resistance is the result of two processes: (i) drug selection of resistant parasites; and (ii) the spread of resistance. In this review, we examine the factors that lead to both drug selection and the spread of resistance. We then examine strategies for controlling the spread of resistance, pointing out the complexities and deficiencies in predicting how resistance will spread. PMID:23394809

  7. Predicting Predictable about Natural Catastrophic Extremes

    NASA Astrophysics Data System (ADS)

    Kossobokov, Vladimir

    2015-04-01

    By definition, an extreme event is rare one in a series of kindred phenomena. Usually (e.g. in Geophysics), it implies investigating a small sample of case-histories with a help of delicate statistical methods and data of different quality, collected in various conditions. Many extreme events are clustered (far from independent) and follow fractal or some other "strange" distribution (far from uniform). Evidently, such an "unusual" situation complicates search and definition of reliable precursory behaviors to be used for forecast/prediction purposes. Making forecast/prediction claims reliable and quantitatively probabilistic in the frames of the most popular objectivists' viewpoint on probability requires a long series of "yes/no" forecast/prediction outcomes, which cannot be obtained without an extended rigorous test of the candidate method. The set of errors ("success/failure" scores and space-time measure of alarms) and other information obtained in such a control test supplies us with data necessary to judge the candidate's potential as a forecast/prediction tool and, eventually, to find its improvements. This is to be done first in comparison against random guessing, which results confidence (measured in terms of statistical significance). Note that an application of the forecast/prediction tools could be very different in cases of different natural hazards, costs and benefits that determine risks, and, therefore, requires determination of different optimal strategies minimizing reliable estimates of realistic levels of accepted losses. In their turn case specific costs and benefits may suggest a modification of the forecast/prediction tools for a more adequate "optimal" application. Fortunately, the situation is not hopeless due to the state-of-the-art understanding of the complexity and non-linear dynamics of the Earth as a Physical System and pattern recognition approaches applied to available geophysical evidences, specifically, when intending to predict

  8. Uncertainty in QSAR predictions.

    PubMed

    Sahlin, Ullrika

    2013-03-01

    It is relevant to consider uncertainty in individual predictions when quantitative structure-activity (or property) relationships (QSARs) are used to support decisions of high societal concern. Successful communication of uncertainty in the integration of QSARs in chemical safety assessment under the EU Registration, Evaluation, Authorisation and Restriction of Chemicals (REACH) system can be facilitated by a common understanding of how to define, characterise, assess and evaluate uncertainty in QSAR predictions. A QSAR prediction is, compared to experimental estimates, subject to added uncertainty that comes from the use of a model instead of empirically-based estimates. A framework is provided to aid the distinction between different types of uncertainty in a QSAR prediction: quantitative, i.e. for regressions related to the error in a prediction and characterised by a predictive distribution; and qualitative, by expressing our confidence in the model for predicting a particular compound based on a quantitative measure of predictive reliability. It is possible to assess a quantitative (i.e. probabilistic) predictive distribution, given the supervised learning algorithm, the underlying QSAR data, a probability model for uncertainty and a statistical principle for inference. The integration of QSARs into risk assessment may be facilitated by the inclusion of the assessment of predictive error and predictive reliability into the "unambiguous algorithm", as outlined in the second OECD principle.

  9. Skid Resistance Research

    NASA Technical Reports Server (NTRS)

    1977-01-01

    Skidding causes many traffic accidents. Streets and highways with skid-resisting surfaces reduce the incidence of such accidents. In fact, resurfacing roads to improve skid resistance is now required by federal law. Skid resistance is measured by road testing with specially equipped skid trailers. A project underway at NASA-Langley may considerably reduce the cost of skid trailers, thus making them more widely available to highway departments. For testing the skid resistance of aircraft runways, Langley engineers developed a relatively inexpensive test vehicle and a "pulsed braking" technique that is now being applied experimentally to road testing. The vehicle is a standard automobile modified to incorporate instrumentation, special test tires and valves, and a trailing fifth wheel for monitoring distance and velocity. The instrumentation includes a low-cost meter, a set of accelerometers that sense motion changes, and a chart recorder.

  10. Resistance to Therapy.

    PubMed

    Rivera, Gabriel; Wakelee, Heather A

    2016-01-01

    Identification of driver mutations in adenocarcinoma of the lung has revolutionized the treatment of this disease. It is now standard of care to look for activating mutations in epidermal growth factor receptor (EGFR), and translocations in anaplastic lymphoma kinase (ALK) or ROS1 in all newly diagnosed adenocarcinoma of the lung, and in many patients with squamous cell carcinoma as well. Recognition of multiple other lung cancer driver mutations has also expanded treatment options. Targeted treatments of these mutations lead to rapid and prolonged responses, but resistance inevitably develops. Until recently, traditional chemotherapy was the only alternative at that time, but better understanding of resistance mechanisms has lead to additional therapeutic options. These mechanisms of resistance and treatments are the focus of this chapter. Understanding of mechanisms of chemotherapy resistance is touched upon, along with a brief discussion of immune checkpoint inhibitors. PMID:27535395

  11. Steroid resistant asthma.

    PubMed

    Luhadia, S K

    2014-03-01

    Inspite of very safe and effective treatment, Bronchial asthmatics do not respond well in 5-10% of cases which are labelled as Refractory Asthma. Besides compliance, presence of psychogenic and trigger factors and comorbid illness, steroid insensitiveness or resistance may play a significant role in the poorly controlled/responding asthmatics. Type I Steroid resistance is due to lack of binding affinity of steroids to glucocorticoid receptors and may respond to higher doses of steroids while type II steroid resistance is because of reduced number of cells with glucocorticoid receptors, which is very rare and do not respond to even higher doses of systemic steroids and these cases require alternative/novel therapies. Future treatment of steroid resistant and severe refractory asthma is likely to be targeted towards cytokines and Bronchial Thermoplasty.

  12. Earthquake resistant design

    SciTech Connect

    Dowrick, D.J.

    1988-01-01

    The author discusses recent advances in earthquake-resistant design. This book covers the entire design process, from aspects of loading to details of construction. Early chapters offer a broad theoretical background; later chapters provide rigorous coverage of practical aspects.

  13. All about Insulin Resistance

    MedlinePlus

    ... news is that cutting calories, being active, and losing weight can reverse insulin resistance and lower your ... you’ll lose weight. Studies have shown that losing even 7% of your weight, may help. For ...

  14. Systemic Acquired Resistance

    PubMed Central

    2006-01-01

    Upon infection with necrotizing pathogens many plants develop an enhanced resistance to further pathogen attack also in the uninoculated organs. This type of enhanced resistance is referred to as systemic acquired resistance (SAR). In the SAR state, plants are primed (sensitized) to more quickly and more effectively activate defense responses the second time they encounter pathogen attack. Since SAR depends on the ability to access past experience, acquired disease resistance is a paradigm for the existence of a form of “plant memory”. Although the phenomenon has been known since the beginning of the 20th century, major progress in the understanding of SAR was made over the past sixteen years. This review covers the current knowledge of molecular, biochemical and physiological mechanisms that are associated with SAR. PMID:19521483

  15. Motivation of fitness center participants toward resistance training.

    PubMed

    Kathrins, Bess P; Turbow, David J

    2010-09-01

    There is a need to better understand the behavior and sense of motivation of fitness center participants. The purpose of this study was to assess whether or not demographic characteristics and health self-determinism (intrinsic or extrinsic motivation) of fitness center participants were predictive of their levels of resistance training. A cross-sectional design was used; participants were recruited via the Internet to complete an online survey. There were 185 participants (age = 39.1 +/- 11.3 years) in the study. The majority of respondents reported having carried out levels of resistance training that met national health organization recommendations. Regression analysis of the data revealed that health self-determinism predicted quantity of resistance training reported (p = 0.014), whereas demographics did not. Being intrinsically motivated to health self-determinism predicted meeting national resistance training recommendations compared to participants extrinsically motivated (p = 0.007). For those who work with fitness center participants, our findings are useful by identifying participants as a predominantly intrinsically motivated group of people that performs adequate quantities of resistance training; the methodology employed in this study can be used to identify participants in need of increased levels of resistance training and heightened sense of motivation to do so. PMID:20802286

  16. Characteristics of predictable MJOs

    NASA Astrophysics Data System (ADS)

    Kim, H. M.; Kim, D.; Vitart, F.; Toma, V. E.; Kug, J. S.; Webster, P. J.

    2015-12-01

    The Madden-Julian Oscillation (MJO) has been considered as a major potential source of global climate predictability on subseasonal time scales. Current operational forecasting systems are able to predict the MJO up to 3-4 weeks with the mean of ensembles, while the skill is still below the theoretical estimates of the predictability (6-7 weeks). It is well accepted that MJO prediction skill in operational systems is distinctly better when the MJO is well organized with having strong amplitude at the beginning of the forecast compared to when it starts with weak or nonexistent MJOs. However, while initially strong MJOs have better skill than weak/non MJOs, the 'initial amplitude-skill' relationship is not linear. It is not every initially strong MJO that has high skill, and not every weak/non MJO that has low skill. What physical mechanism drives some MJOs to be more predictable than others? Using dynamical MJO reforecasts, this study will show that the skill of highly predictable MJOs depends on the background environment that influence on MJO evolution. The favorable conditions for highly predictable MJOs (starting with moderate amplitude) support for stronger ocean-atmosphere coupling, and for sufficient heat and low-tropospheric moisture supply for better MJO propagation, particularly for the MJO crossing over the Maritime Continent. Understanding the characteristics of predictable MJOs may provide insights into the overall predictability of MJO, thus advance the prediction of 3-4 weeks towards its theoretical limit.

  17. Transcriptome Profiling of Antimicrobial Resistance in Pseudomonas aeruginosa.

    PubMed

    Khaledi, Ariane; Schniederjans, Monika; Pohl, Sarah; Rainer, Roman; Bodenhofer, Ulrich; Xia, Boyang; Klawonn, Frank; Bruchmann, Sebastian; Preusse, Matthias; Eckweiler, Denitsa; Dötsch, Andreas; Häussler, Susanne

    2016-08-01

    Emerging resistance to antimicrobials and the lack of new antibiotic drug candidates underscore the need for optimization of current diagnostics and therapies to diminish the evolution and spread of multidrug resistance. As the antibiotic resistance status of a bacterial pathogen is defined by its genome, resistance profiling by applying next-generation sequencing (NGS) technologies may in the future accomplish pathogen identification, prompt initiation of targeted individualized treatment, and the implementation of optimized infection control measures. In this study, qualitative RNA sequencing was used to identify key genetic determinants of antibiotic resistance in 135 clinical Pseudomonas aeruginosa isolates from diverse geographic and infection site origins. By applying transcriptome-wide association studies, adaptive variations associated with resistance to the antibiotic classes fluoroquinolones, aminoglycosides, and β-lactams were identified. Besides potential novel biomarkers with a direct correlation to resistance, global patterns of phenotype-associated gene expression and sequence variations were identified by predictive machine learning approaches. Our research serves to establish genotype-based molecular diagnostic tools for the identification of the current resistance profiles of bacterial pathogens and paves the way for faster diagnostics for more efficient, targeted treatment strategies to also mitigate the future potential for resistance evolution. PMID:27216077

  18. Transcriptome Profiling of Antimicrobial Resistance in Pseudomonas aeruginosa.

    PubMed

    Khaledi, Ariane; Schniederjans, Monika; Pohl, Sarah; Rainer, Roman; Bodenhofer, Ulrich; Xia, Boyang; Klawonn, Frank; Bruchmann, Sebastian; Preusse, Matthias; Eckweiler, Denitsa; Dötsch, Andreas; Häussler, Susanne

    2016-08-01

    Emerging resistance to antimicrobials and the lack of new antibiotic drug candidates underscore the need for optimization of current diagnostics and therapies to diminish the evolution and spread of multidrug resistance. As the antibiotic resistance status of a bacterial pathogen is defined by its genome, resistance profiling by applying next-generation sequencing (NGS) technologies may in the future accomplish pathogen identification, prompt initiation of targeted individualized treatment, and the implementation of optimized infection control measures. In this study, qualitative RNA sequencing was used to identify key genetic determinants of antibiotic resistance in 135 clinical Pseudomonas aeruginosa isolates from diverse geographic and infection site origins. By applying transcriptome-wide association studies, adaptive variations associated with resistance to the antibiotic classes fluoroquinolones, aminoglycosides, and β-lactams were identified. Besides potential novel biomarkers with a direct correlation to resistance, global patterns of phenotype-associated gene expression and sequence variations were identified by predictive machine learning approaches. Our research serves to establish genotype-based molecular diagnostic tools for the identification of the current resistance profiles of bacterial pathogens and paves the way for faster diagnostics for more efficient, targeted treatment strategies to also mitigate the future potential for resistance evolution.

  19. Predictive optimization of piston and ring stability

    SciTech Connect

    Knowland, C.G.; Russell, C.J.

    1996-09-01

    A fundamental aspect of the engine development process involves the determination of acceptable piston and ring profiles. There exists a fine balance between the requirements of the piston skirt or ring profile to resist scuffing together with the overall product objectives of reduced oil consumption, blow-by and engine noise. Taking into account these varying and often conflicting considerations, in addition to the time and cost implications of repetitive development testing, drives them towards the necessity for some form of predictive optimization scheme. Benefits from the application of such a predictive tool include: development of piston skirt profiles for adequate running clearance under operating conditions; optimization of piston stability as a function of such parameters as piston pin offset; enhanced bore reaction forces for improved NVH predictions; reduced levels of blow-by and improved oil control.

  20. Predicting ship fuel consumption: Update. Technical report

    SciTech Connect

    Schrady, D.A.; Smyth, G.K.; Vassian, R.B.

    1996-07-01

    This report is concerned with the prediction of ship propulsion fuel consumption as a function of ship speed for U.S. Navy combatant and auxiliary ships. Prediction is based on fitting an analytic function to published ship class speed-fuel use data using nonlinear regression. The form of the analytic function fitted is motivated by the literature on ship powering and resistance. The report discusses data sources and data issues, and the impact of ship propulsion plant configuration on fuel use. The regression coefficients of the exponential function fitted, tabular numerical comparison of predicted and actual fuel use data, the standard error of the estimate, and plots of actual and fitted data are given for 22 classes of Navy ships.

  1. Genetics and genomics of disease resistance in salmonid species

    PubMed Central

    Yáñez, José M.; Houston, Ross D.; Newman, Scott

    2014-01-01

    Infectious and parasitic diseases generate large economic losses in salmon farming. A feasible and sustainable alternative to prevent disease outbreaks may be represented by genetic improvement for disease resistance. To include disease resistance into the breeding goal, prior knowledge of the levels of genetic variation for these traits is required. Furthermore, the information from the genetic architecture and molecular factors involved in resistance against diseases may be used to accelerate the genetic progress for these traits. In this regard, marker assisted selection and genomic selection are approaches which incorporate molecular information to increase the accuracy when predicting the genetic merit of selection candidates. In this article we review and discuss key aspects related to disease resistance in salmonid species, from both a genetic and genomic perspective, with emphasis in the applicability of disease resistance traits into breeding programs in salmonids. PMID:25505486

  2. Resistive MHD studies of reversed shear current profiles

    SciTech Connect

    Hughes, M.H.; Phillips, M.W.

    1996-12-31

    Experiments at TFTR, DIII-D and elsewhere, in which current density distributions possessing an off-axis maximum are generated and sustained on a resistive diffusion timescale, continue to be of interest. Here, attention is concentrated on the possible role of resistive instabilities in such plasmas. Using experimental profile information from TFTR as initial data the parameters of interest are varied systematically to study the excitation of resistive instabilities over a range of p from zero to the limits determined by ideal MHD. Computationally, there is a wealth of resistive modes predicted to occur. Thus, it is found that when the minimum value of the safety factor, q{sub min}, exceeds 2 the configuration is either stable or, in some circumstances, the resistive interchange mode can be excited. When q{sub min} {le} 2 localized tearing or double tearing modes are excited at low pressures becoming more global in character as the pressure nears the ideal NHD limit.

  3. Genetics and genomics of disease resistance in salmonid species.

    PubMed

    Yáñez, José M; Houston, Ross D; Newman, Scott

    2014-01-01

    Infectious and parasitic diseases generate large economic losses in salmon farming. A feasible and sustainable alternative to prevent disease outbreaks may be represented by genetic improvement for disease resistance. To include disease resistance into the breeding goal, prior knowledge of the levels of genetic variation for these traits is required. Furthermore, the information from the genetic architecture and molecular factors involved in resistance against diseases may be used to accelerate the genetic progress for these traits. In this regard, marker assisted selection and genomic selection are approaches which incorporate molecular information to increase the accuracy when predicting the genetic merit of selection candidates. In this article we review and discuss key aspects related to disease resistance in salmonid species, from both a genetic and genomic perspective, with emphasis in the applicability of disease resistance traits into breeding programs in salmonids.

  4. Transition to zero resistance in an irradiated 2DEG

    NASA Astrophysics Data System (ADS)

    Alicea, J.; Balents, L.; Fisher, M. P. A.; Paramekanti, A.; Radzihovsky, L.

    2004-03-01

    Recent experiments have demonstrated that high mobility 2D electron systems driven with microwaves exhibit an oscillatory longitudinal resistance that vanishes for certain magnetic field strengths [1]. While theoretical calculations [2] predict a negative longitudinal resistivity, Andreev et al. (PRL 91, 056803 (2003)) showed that this renders the system unstable towards an inhomogeneous zero resistance state. We explore analytically and numerically the properties of the transition to this inhomogeneous state. [1] M. A. Zudov et al., PRL 90, 046807 (2003); R. G. Mani et al., Nature 420, 646 (2002) [2] Ryzhii, Sov. Phys. Solid State 11, 2078 (1970); Durst et al., PRL 91, 086803 (2003)

  5. Investigation of Impact Resistance of Protective Barriers Made from Cermets

    NASA Astrophysics Data System (ADS)

    Ischenko, A. N.; Tabachenko, A. N.; Afanasieva, S. A.; Belov, N. N.; Burkin, V. V.; Martsunova, L. S.; Rogaev, K. S.; Yugov, N. T.

    2016-01-01

    Ceramic-metal materials (cermets) based on titanium diboride and boron carbide are designed and produced by the method of self-propagating high-temperature synthesis, with the pressure applied to the combustion products. The data, obtained by an experimental-theoretical investigation of impact resistance of protective barriers containing the above-mentioned materials in collisions with a spherical steel projectile, are presented. A better impact resistance of TiB2 + B4C cermets compared to that of Al2O3- ceramics is demonstrated. A possibility of prediction calculations of impact resistance of the specimens containing cermets in the range of collision rates under study is shown.

  6. Predictive systems ecology.

    PubMed

    Evans, Matthew R; Bithell, Mike; Cornell, Stephen J; Dall, Sasha R X; Díaz, Sandra; Emmott, Stephen; Ernande, Bruno; Grimm, Volker; Hodgson, David J; Lewis, Simon L; Mace, Georgina M; Morecroft, Michael; Moustakas, Aristides; Murphy, Eugene; Newbold, Tim; Norris, K J; Petchey, Owen; Smith, Matthew; Travis, Justin M J; Benton, Tim G

    2013-11-22

    Human societies, and their well-being, depend to a significant extent on the state of the ecosystems that surround them. These ecosystems are changing rapidly usually in response to anthropogenic changes in the environment. To determine the likely impact of environmental change on ecosystems and the best ways to manage them, it would be desirable to be able to predict their future states. We present a proposal to develop the paradigm of predictive systems ecology, explicitly to understand and predict the properties and behaviour of ecological systems. We discuss the necessary and desirable features of predictive systems ecology models. There are places where predictive systems ecology is already being practised and we summarize a range of terrestrial and marine examples. Significant challenges remain but we suggest that ecology would benefit both as a scientific discipline and increase its impact in society if it were to embrace the need to become more predictive.

  7. Resistant starches and health.

    PubMed

    Kendall, Cyril W C; Emam, Azadeh; Augustin, Livia S A; Jenkins, David J A

    2004-01-01

    It was initially hypothesized that resistant starches, i.e., starch that enters the colon, would have protective effects on chronic colonic diseases, including reduction of colon cancer risk and in the treatment of ulcerative colitis. Recent studies have confirmed the ability of resistant starch to increase fecal bulk, increase the molar ratio of butyrate in relation to other short-chain fatty acids, and dilute fecal bile acids. However the ability of resistant starch to reduce luminal concentrations of compounds that are damaging to the colonic mucosa, including fecal ammonia, phenols, and N-nitroso compounds, still requires clear demonstration. As such, the effectiveness of resistant starch in preventing or treating colonic diseases remains to be assessed. Nevertheless, there is a fraction of what has been termed resistant (RS1) starch, which enters the colon and acts as slowly digested or lente carbohydrate in the small intestine. Foods in this class are low glycemic index and have been shown to reduce the risk of chronic disease. They have been associated with systemic physiological effects such as reduced postprandial insulin levels and higher HDL cholesterol levels. Consumption of low glycemic index foods has been shown to be related to reductions in risk of coronary heart disease and Type 2 diabetes. Type 2 diabetes has in turn been related to a higher risk of colon cancer. If carbohydrates have a protective role in colon cancer prevention this may lie partly in the systemic effects of low glycemic index foods. The colonic advantages of different carbohydrates, varying in their glycemic index and resistant starch content, therefore, remain to be determined. However, as recent positive research findings continue to mount, there is reason for optimism over the possible health advantages of those resistant starches, which are slowly digested in the small intestine. PMID:15287678

  8. The Structure of Fitness Landscapes in Antibiotic-Resistant Bacteria

    NASA Astrophysics Data System (ADS)

    Deris, Barrett; Kim, Minsu; Zhang, Zhongge; Okano, Hiroyuki; Hermsen, Rutger; Gore, Jeff; Hwa, Terence

    2014-03-01

    To predict the emergence of antibiotic resistance, quantitative relations must be established between the fitness of drug-resistant organisms and the molecular mechanisms conferring resistance. We have investigated E. coli strains expressing resistance to translation-inhibiting antibiotics. We show that resistance expression and drug inhibition are linked in a positive feedback loop arising from an innate, global effect of drug-inhibited growth on gene expression. This feedback leads generically to plateau-shaped fitness landscapes and concomitantly, for strains expressing at least moderate degrees of drug resistance, gives rise to an abrupt drop in growth rates of cultures at threshold drug concentrations. A simple quantitative model of bacterial growth based on this innate feedback accurately predicts experimental observations without ad hoc parameter fitting. We describe how drug-inhibited growth rate and the threshold drug concentration (the minimum inhibitory concentration, or MIC) depend on the few biochemical parameters that characterize the molecular details of growth inhibition and drug resistance (e.g., the drug-target dissociation constant). And finally, we discuss how these parameters can shape fitness landscapes to determine evolutionary dynamics and evolvability.

  9. Theoretical relationship between elastic wave velocity and electrical resistivity

    NASA Astrophysics Data System (ADS)

    Lee, Jong-Sub; Yoon, Hyung-Koo

    2015-05-01

    Elastic wave velocity and electrical resistivity have been commonly applied to estimate stratum structures and obtain subsurface soil design parameters. Both elastic wave velocity and electrical resistivity are related to the void ratio; the objective of this study is therefore to suggest a theoretical relationship between the two physical parameters. Gassmann theory and Archie's equation are applied to propose a new theoretical equation, which relates the compressional wave velocity to shear wave velocity and electrical resistivity. The piezo disk element (PDE) and bender element (BE) are used to measure the compressional and shear wave velocities, respectively. In addition, the electrical resistivity is obtained by using the electrical resistivity probe (ERP). The elastic wave velocity and electrical resistivity are recorded in several types of soils including sand, silty sand, silty clay, silt, and clay-sand mixture. The appropriate input parameters are determined based on the error norm in order to increase the reliability of the proposed relationship. The predicted compressional wave velocities from the shear wave velocity and electrical resistivity are similar to the measured compressional velocities. This study demonstrates that the new theoretical relationship may be effectively used to predict the unknown geophysical property from the measured values.

  10. Predicting Unsteady Aeroelastic Behavior

    NASA Technical Reports Server (NTRS)

    Strganac, Thomas W.; Mook, Dean T.

    1990-01-01

    New method for predicting subsonic flutter, static deflections, and aeroelastic divergence developed. Unsteady aerodynamic loads determined by unsteady-vortex-lattice method. Accounts for aspect ratio and angle of attack. Equations for motion of wing and flow field solved iteratively and simultaneously. Used to predict transient responses to initial disturbances, and to predict steady-state static and oscillatory responses. Potential application for research in such unsteady structural/flow interactions as those in windmills, turbines, and compressors.

  11. Predictability of Conversation Partners

    NASA Astrophysics Data System (ADS)

    Takaguchi, Taro; Nakamura, Mitsuhiro; Sato, Nobuo; Yano, Kazuo; Masuda, Naoki

    2011-08-01

    Recent developments in sensing technologies have enabled us to examine the nature of human social behavior in greater detail. By applying an information-theoretic method to the spatiotemporal data of cell-phone locations, [C. Song , ScienceSCIEAS0036-8075 327, 1018 (2010)] found that human mobility patterns are remarkably predictable. Inspired by their work, we address a similar predictability question in a different kind of human social activity: conversation events. The predictability in the sequence of one’s conversation partners is defined as the degree to which one’s next conversation partner can be predicted given the current partner. We quantify this predictability by using the mutual information. We examine the predictability of conversation events for each individual using the longitudinal data of face-to-face interactions collected from two company offices in Japan. Each subject wears a name tag equipped with an infrared sensor node, and conversation events are marked when signals are exchanged between sensor nodes in close proximity. We find that the conversation events are predictable to a certain extent; knowing the current partner decreases the uncertainty about the next partner by 28.4% on average. Much of the predictability is explained by long-tailed distributions of interevent intervals. However, a predictability also exists in the data, apart from the contribution of their long-tailed nature. In addition, an individual’s predictability is correlated with the position of the individual in the static social network derived from the data. Individuals confined in a community—in the sense of an abundance of surrounding triangles—tend to have low predictability, and those bridging different communities tend to have high predictability.

  12. Solar Cycle Predictions

    NASA Technical Reports Server (NTRS)

    Pesnell, William Dean

    2012-01-01

    Solar cycle predictions are needed to plan long-term space missions; just like weather predictions are needed to plan the launch. Fleets of satellites circle the Earth collecting many types of science data, protecting astronauts, and relaying information. All of these satellites are sensitive at some level to solar cycle effects. Predictions of drag on LEO spacecraft are one of the most important. Launching a satellite with less propellant can mean a higher orbit, but unanticipated solar activity and increased drag can make that a Pyrrhic victory as you consume the reduced propellant load more rapidly. Energetic events at the Sun can produce crippling radiation storms that endanger all assets in space. Solar cycle predictions also anticipate the shortwave emissions that cause degradation of solar panels. Testing solar dynamo theories by quantitative predictions of what will happen in 5-20 years is the next arena for solar cycle predictions. A summary and analysis of 75 predictions of the amplitude of the upcoming Solar Cycle 24 is presented. The current state of solar cycle predictions and some anticipations how those predictions could be made more accurate in the future will be discussed.

  13. Predicting cancer outcome

    SciTech Connect

    Gardner, S N; Fernandes, M

    2005-03-24

    We read with interest the paper by Michiels et al on the prediction of cancer with microarrays and the commentary by Ioannidis listing the potential as well as the limitations of this approach (February 5, p 488 and 454). Cancer is a disease characterized by complex, heterogeneous mechanisms and studies to define factors that can direct new drug discovery and use should be encouraged. However, this is easier said than done. Casti teaches that a better understanding does not necessarily extrapolate to better prediction, and that useful prediction is possible without complete understanding (1). To attempt both, explanation and prediction, in a single nonmathematical construct, is a tall order (Figure 1).

  14. Is Incident Drug-Resistance of Childhood-Onset Epilepsy Reversible? A Long-Term Follow-Up Study

    ERIC Educational Resources Information Center

    Sillanpaa, Matti; Schmidt, Dieter

    2012-01-01

    Given the grave morbidity and mortality of drug-resistant epilepsy, it is of great clinical interest to determine how often prior proven drug-resistant epilepsy is reversible without surgery and whether remission can be predicted by clinical features in children with incident drug-resistant epilepsy. We determined the likelihood of 1-, 2- and…

  15. Antibiotic resistance in wild birds

    PubMed Central

    Bonnedahl, Jonas

    2014-01-01

    Wild birds have been postulated as sentinels, reservoirs, and potential spreaders of antibiotic resistance. Antibiotic-resistant bacteria have been isolated from a multitude of wild bird species. Several studies strongly indicate transmission of resistant bacteria from human rest products to wild birds. There is evidence suggesting that wild birds can spread resistant bacteria through migration and that resistant bacteria can be transmitted from birds to humans and vice versa. Through further studies of the spatial and temporal distribution of resistant bacteria in wild birds, we can better assess their role and thereby help to mitigate the increasing global problem of antibiotic resistance. PMID:24697355

  16. Antibiotic resistance in wild birds.

    PubMed

    Bonnedahl, Jonas; Järhult, Josef D

    2014-05-01

    Wild birds have been postulated as sentinels, reservoirs, and potential spreaders of antibiotic resistance. Antibiotic-resistant bacteria have been isolated from a multitude of wild bird species. Several studies strongly indicate transmission of resistant bacteria from human rest products to wild birds. There is evidence suggesting that wild birds can spread resistant bacteria through migration and that resistant bacteria can be transmitted from birds to humans and vice versa. Through further studies of the spatial and temporal distribution of resistant bacteria in wild birds, we can better assess their role and thereby help to mitigate the increasing global problem of antibiotic resistance. PMID:24697355

  17. Genetic markers for western corn rootworm resistance to Bt toxin.

    PubMed

    Flagel, Lex E; Swarup, Shilpa; Chen, Mao; Bauer, Christopher; Wanjugi, Humphrey; Carroll, Matthew; Hill, Patrick; Tuscan, Meghan; Bansal, Raman; Flannagan, Ronald; Clark, Thomas L; Michel, Andrew P; Head, Graham P; Goldman, Barry S

    2015-03-01

    Western corn rootworm (WCR) is a major maize (Zea mays L.) pest leading to annual economic losses of more than 1 billion dollars in the United States. Transgenic maize expressing insecticidal toxins derived from the bacterium Bacillus thuringiensis (Bt) are widely used for the management of WCR. However, cultivation of Bt-expressing maize places intense selection pressure on pest populations to evolve resistance. Instances of resistance to Bt toxins have been reported in WCR. Developing genetic markers for resistance will help in characterizing the extent of existing issues, predicting where future field failures may occur, improving insect resistance management strategies, and in designing and sustainably implementing forthcoming WCR control products. Here, we discover and validate genetic markers in WCR that are associated with resistance to the Cry3Bb1 Bt toxin. A field-derived WCR population known to be resistant to the Cry3Bb1 Bt toxin was used to generate a genetic map and to identify a genomic region associated with Cry3Bb1 resistance. Our results indicate that resistance is inherited in a nearly recessive manner and associated with a single autosomal linkage group. Markers tightly linked with resistance were validated using WCR populations collected from Cry3Bb1 maize fields showing significant WCR damage from across the US Corn Belt. Two markers were found to be correlated with both diet (R2 = 0.14) and plant (R2 = 0.23) bioassays for resistance. These results will assist in assessing resistance risk for different WCR populations, and can be used to improve insect resistance management strategies.

  18. Genetic determinants of heat resistance in Escherichia coli

    PubMed Central

    Mercer, Ryan G.; Zheng, Jinshui; Garcia-Hernandez, Rigoberto; Ruan, Lifang; Gänzle, Michael G.; McMullen, Lynn M.

    2015-01-01

    Escherichia coli AW1.7 is a heat resistant food isolate and the occurrence of pathogenic strains with comparable heat resistance may pose a risk to food safety. To identify the genetic determinants of heat resistance, 29 strains of E. coli that differed in their of heat resistance were analyzed by comparative genomics. Strains were classified as highly heat resistant strains, exhibiting a D60-value of more than 6 min; moderately heat resistant strains, exhibiting a D60-value of more than 1 min; or as heat sensitive. A ~14 kb genomic island containing 16 predicted open reading frames encoding putative heat shock proteins and proteases was identified only in highly heat resistant strains. The genomic island was termed the locus of heat resistance (LHR). This putative operon is flanked by mobile elements and possesses >99% sequence identity to genomic islands contributing to heat resistance in Cronobacter sakazakii and Klebsiella pneumoniae. An additional 41 LHR sequences with >87% sequence identity were identified in 11 different species of β- and γ-proteobacteria. Cloning of the full length LHR conferred high heat resistance to the heat sensitive E. coli AW1.7ΔpHR1 and DH5α. The presence of the LHR correlates perfectly to heat resistance in several species of Enterobacteriaceae and occurs at a frequency of 2% of all E. coli genomes, including pathogenic strains. This study suggests the LHR has been laterally exchanged among the β- and γ-proteobacteria and is a reliable indicator of high heat resistance in E. coli. PMID:26441869

  19. Genetic markers for western corn rootworm resistance to Bt toxin.

    PubMed

    Flagel, Lex E; Swarup, Shilpa; Chen, Mao; Bauer, Christopher; Wanjugi, Humphrey; Carroll, Matthew; Hill, Patrick; Tuscan, Meghan; Bansal, Raman; Flannagan, Ronald; Clark, Thomas L; Michel, Andrew P; Head, Graham P; Goldman, Barry S

    2015-03-01

    Western corn rootworm (WCR) is a major maize (Zea mays L.) pest leading to annual economic losses of more than 1 billion dollars in the United States. Transgenic maize expressing insecticidal toxins derived from the bacterium Bacillus thuringiensis (Bt) are widely used for the management of WCR. However, cultivation of Bt-expressing maize places intense selection pressure on pest populations to evolve resistance. Instances of resistance to Bt toxins have been reported in WCR. Developing genetic markers for resistance will help in characterizing the extent of existing issues, predicting where future field failures may occur, improving insect resistance management strategies, and in designing and sustainably implementing forthcoming WCR control products. Here, we discover and validate genetic markers in WCR that are associated with resistance to the Cry3Bb1 Bt toxin. A field-derived WCR population known to be resistant to the Cry3Bb1 Bt toxin was used to generate a genetic map and to identify a genomic region associated with Cry3Bb1 resistance. Our results indicate that resistance is inherited in a nearly recessive manner and associated with a single autosomal linkage group. Markers tightly linked with resistance were validated using WCR populations collected from Cry3Bb1 maize fields showing significant WCR damage from across the US Corn Belt. Two markers were found to be correlated with both diet (R2 = 0.14) and plant (R2 = 0.23) bioassays for resistance. These results will assist in assessing resistance risk for different WCR populations, and can be used to improve insect resistance management strategies. PMID:25566794

  20. Genetic Markers for Western Corn Rootworm Resistance to Bt Toxin

    PubMed Central

    Flagel, Lex E.; Swarup, Shilpa; Chen, Mao; Bauer, Christopher; Wanjugi, Humphrey; Carroll, Matthew; Hill, Patrick; Tuscan, Meghan; Bansal, Raman; Flannagan, Ronald; Clark, Thomas L.; Michel, Andrew P.; Head, Graham P.; Goldman, Barry S.

    2015-01-01

    Western corn rootworm (WCR) is a major maize (Zea mays L.) pest leading to annual economic losses of more than 1 billion dollars in the United States. Transgenic maize expressing insecticidal toxins derived from the bacterium Bacillus thuringiensis (Bt) are widely used for the management of WCR. However, cultivation of Bt-expressing maize places intense selection pressure on pest populations to evolve resistance. Instances of resistance to Bt toxins have been reported in WCR. Developing genetic markers for resistance will help in characterizing the extent of existing issues, predicting where future field failures may occur, improving insect resistance management strategies, and in designing and sustainably implementing forthcoming WCR control products. Here, we discover and validate genetic markers in WCR that are associated with resistance to the Cry3Bb1 Bt toxin. A field-derived WCR population known to be resistant to the Cry3Bb1 Bt toxin was used to generate a genetic map and to identify a genomic region associated with Cry3Bb1 resistance. Our results indicate that resistance is inherited in a nearly recessive manner and associated with a single autosomal linkage group. Markers tightly linked with resistance were validated using WCR populations collected from Cry3Bb1 maize fields showing significant WCR damage from across the US Corn Belt. Two markers were found to be correlated with both diet (R2 = 0.14) and plant (R2 = 0.23) bioassays for resistance. These results will assist in assessing resistance risk for different WCR populations, and can be used to improve insect resistance management strategies. PMID:25566794

  1. Spore Resistance Properties.

    PubMed

    Setlow, Peter

    2014-10-01

    Spores of various Bacillus and Clostridium species are among the most resistant life forms known. Since the spores of some species are causative agents of much food spoilage, food poisoning, and human disease, and the spores of Bacillus anthracis are a major bioweapon, there is much interest in the mechanisms of spore resistance and how these spores can be killed. This article will discuss the factors involved in spore resistance to agents such as wet and dry heat, desiccation, UV and γ-radiation, enzymes that hydrolyze bacterial cell walls, and a variety of toxic chemicals, including genotoxic agents, oxidizing agents, aldehydes, acid, and alkali. These resistance factors include the outer layers of the spore, such as the thick proteinaceous coat that detoxifies reactive chemicals; the relatively impermeable inner spore membrane that restricts access of toxic chemicals to the spore core containing the spore's DNA and most enzymes; the low water content and high level of dipicolinic acid in the spore core that protect core macromolecules from the effects of heat and desiccation; the saturation of spore DNA with a novel group of proteins that protect the DNA against heat, genotoxic chemicals, and radiation; and the repair of radiation damage to DNA when spores germinate and return to life. Despite their extreme resistance, spores can be killed, including by damage to DNA, crucial spore proteins, the spore's inner membrane, and one or more components of the spore germination apparatus.

  2. MSMA resistance studies.

    PubMed

    Camper, N D; Keese, R J; Coker, P S

    2004-05-01

    Monosodium methanearsonate (MSMA)-resistant and -susceptible common cocklebur (Xanthium strumarium L.) and cotton (Gossypium hirsutum L.) were treated with MSMA. Plant parameters analyzed were: glutathione synthetase activity, selected amino acid (arginine, glutamic acid, alanine, citrulline, glutamine, and glutathione) content and arsenic content (MSMA, total arsenic, and arsonate). No reduction of arsenic from the parent pentavalent form present in MSMA to the trivalent form was detected. Arginine, glutamic acid, and glutamine content increased in tissue three days after MSMA treatment. Glutathione content decreased during the first three days after treatment; however, five days after treatment the resistant biotype of cocklebur and cotton had elevated glutathione levels (8-20 times greater, respectively). Glutathione Synthetase activity was higher in cotton than in either of the cocklebur biotypes; MSMA did not affect its activity in cotton or either cocklebur biotype. Resistant biotypes have a slightly higher activity than the susceptible biotype. Tolerance of cotton to MSMA may be related to glutathione synthetase activity and possibly to the presence of phytochelatins. Also, increased glutathione levels in the resistant biotype may implicate phytochelatin involvement in the resistance mechanism.

  3. The genomic basis of adaptation to the fitness cost of rifampicin resistance in Pseudomonas aeruginosa.

    PubMed

    Qi, Qin; Toll-Riera, Macarena; Heilbron, Karl; Preston, Gail M; MacLean, R Craig

    2016-01-13

    Antibiotic resistance carries a fitness cost that must be overcome in order for resistance to persist over the long term. Compensatory mutations that recover the functional defects associated with resistance mutations have been argued to play a key role in overcoming the cost of resistance, but compensatory mutations are expected to be rare relative to generally beneficial mutations that increase fitness, irrespective of antibiotic resistance. Given this asymmetry, population genetics theory predicts that populations should adapt by compensatory mutations when the cost of resistance is large, whereas generally beneficial mutations should drive adaptation when the cost of resistance is small. We tested this prediction by determining the genomic mechanisms underpinning adaptation to antibiotic-free conditions in populations of the pathogenic bacterium Pseudomonas aeruginosa that carry costly antibiotic resistance mutations. Whole-genome sequencing revealed that populations founded by high-cost rifampicin-resistant mutants adapted via compensatory mutations in three genes of the RNA polymerase core enzyme, whereas populations founded by low-cost mutants adapted by generally beneficial mutations, predominantly in the quorum-sensing transcriptional regulator gene lasR. Even though the importance of compensatory evolution in maintaining resistance has been widely recognized, our study shows that the roles of general adaptation in maintaining resistance should not be underestimated and highlights the need to understand how selection at other sites in the genome influences the dynamics of resistance alleles in clinical settings.

  4. The genomic basis of adaptation to the fitness cost of rifampicin resistance in Pseudomonas aeruginosa

    PubMed Central

    Toll-Riera, Macarena; Heilbron, Karl

    2016-01-01

    Antibiotic resistance carries a fitness cost that must be overcome in order for resistance to persist over the long term. Compensatory mutations that recover the functional defects associated with resistance mutations have been argued to play a key role in overcoming the cost of resistance, but compensatory mutations are expected to be rare relative to generally beneficial mutations that increase fitness, irrespective of antibiotic resistance. Given this asymmetry, population genetics theory predicts that populations should adapt by compensatory mutations when the cost of resistance is large, whereas generally beneficial mutations should drive adaptation when the cost of resistance is small. We tested this prediction by determining the genomic mechanisms underpinning adaptation to antibiotic-free conditions in populations of the pathogenic bacterium Pseudomonas aeruginosa that carry costly antibiotic resistance mutations. Whole-genome sequencing revealed that populations founded by high-cost rifampicin-resistant mutants adapted via compensatory mutations in three genes of the RNA polymerase core enzyme, whereas populations founded by low-cost mutants adapted by generally beneficial mutations, predominantly in the quorum-sensing transcriptional regulator gene lasR. Even though the importance of compensatory evolution in maintaining resistance has been widely recognized, our study shows that the roles of general adaptation in maintaining resistance should not be underestimated and highlights the need to understand how selection at other sites in the genome influences the dynamics of resistance alleles in clinical settings. PMID:26763710

  5. HIV antiviral drug resistance: patient comprehension.

    PubMed

    Racey, C Sarai; Zhang, Wendy; Brandson, Eirikka K; Fernandes, Kimberly A; Tzemis, Despina; Harrigan, P Richard; Montaner, Julio S G; Barrios, Rolando; Toy, Junine; Hogg, Robert S

    2010-07-01

    A patient's understanding and use of healthcare information can affect their decisions regarding treatment. Better patient understanding about HIV resistance may improve adherence to therapy, decrease population viral load and extend the use of first-line HIV therapies. We examined knowledge of developing HIV resistance and explored treatment outcomes in a cohort of HIV+ persons on highly active antiretroviral therapy (HAART). The longitudinal investigations into supportive and ancillary health services (LISA) cohort is a prospective study of HIV+ persons on HAART. A comprehensive interviewer-administrated survey collected socio-demographic variables. Drug resistance knowledge was determined using a three-part definition. Clinical markers were collected through linkage with the Drug Treatment Program (DTP) at the British Columbia Centre for Excellence in HIV/AIDS. Categorical variables were compared using Fisher's Exact Test and continuous variables using the Wilcoxon rank-sum test. Proportional odds logistic regression was performed for the adjusted multivariable analysis. Of 457 LISA participants, less than 4% completely defined HIV resistance and 20% reported that they had not discussed resistance with their physician. Overall, 61% of the cohort is >or=95% adherent based on prescription refills. Owing to small numbers pooling was preformed for analyses. The model showed that being younger (OR=0.97, 95% CI: 0.95-0.99), having greater than high school education (OR=1.64, 95% CI: 1.07-2.51), discussing medication with physicians (OR=3.67, 95% CI: 1.76-7.64), having high provider trust (OR=1.02, 95% CI: 1.01-1.03), and receiving one-to-one counseling by a pharmacist (OR=2.14, 95% CI: 1.41-3.24) are predictive of a complete or partial definition of HIV resistance. The probability of completely defining HIV resistance increased from 15.8 to 63.9% if respondents had discussed HIV medication with both a physician and a pharmacist. Although the understanding of HIV

  6. Mixtures as a fungicide resistance management tactic.

    PubMed

    van den Bosch, Frank; Paveley, Neil; van den Berg, Femke; Hobbelen, Peter; Oliver, Richard

    2014-12-01

    We have reviewed the experimental and modeling evidence on the use of mixtures of fungicides of differing modes of action as a resistance management tactic. The evidence supports the following conclusions. 1. Adding a mixing partner to a fungicide that is at-risk of resistance (without lowering the dose of the at-risk fungicide) reduces the rate of selection for fungicide resistance. This holds for the use of mixing partner fungicides that have either multi-site or single-site modes of action. The resulting predicted increase in the effective life of the at-risk fungicide can be large enough to be of practical relevance. The more effective the mixing partner (due to inherent activity and/or dose), the larger the reduction in selection and the larger the increase in effective life of the at-risk fungicide. 2. Adding a mixing partner while lowering the dose of the at-risk fungicide reduces the selection for fungicide resistance, without compromising effective disease control. The very few studies existing suggest that the reduction in selection is more sensitive to lowering the dose of the at-risk fungicide than to increasing the dose of the mixing partner. 3. Although there are very few studies, the existing evidence suggests that mixing two at-risk fungicides is also a useful resistance management tactic. The aspects that have received too little attention to draw generic conclusions about the effectiveness of fungicide mixtures as resistance management strategies are as follows: (i) the relative effect of the dose of the two mixing partners on selection for fungicide resistance, (ii) the effect of mixing on the effective life of a fungicide (the time from introduction of the fungicide mode of action to the time point where the fungicide can no longer maintain effective disease control), (iii) polygenically determined resistance, (iv) mixtures of two at-risk fungicides, (v) the emergence phase of resistance evolution and the effects of mixtures during this phase

  7. Resistance-associated signatures in breast cancer.

    PubMed

    Györffy, Balázs

    2007-01-01

    A major obstacle in the treatment of breast cancer is the lack of adequate methods for predicting patient response to a particular chemotherapy regime. To date, single tumour markers have provided limited success. DNA array technologies identifying thousands of genes simultaneously can help to solve this problem. We investigated cancer cell lines sensitive and resistant to the topoisomerase inhibitors doxorubicin and mitoxantrone. These drugs are used in several different breast cancer treatment protocols. We have identified the top genes best associated with resistance against each cytostatic agent. We applied our gene expression signatures to a set of pre-characterised patients receiving doxorubicin monotherapy. The patients classified as sensitive to chemotherapy exhibited longer survival than the resistant ones. In summary, in our study we have successfully transferred experimental results to a clinical problem, and managed to perform a predictive test for a selected monotherapy protocol. However, many different studies have been performed using microarrays, each producing a different gene list for the same classification problem. It is likely that future diagnostic tools will include the results of several different laboratories, focus on genes validated on different technological platforms and use large cohorts of patients.

  8. Pediatric fecal microbiota harbor diverse and novel antibiotic resistance genes.

    PubMed

    Moore, Aimée M; Patel, Sanket; Forsberg, Kevin J; Wang, Bin; Bentley, Gayle; Razia, Yasmin; Qin, Xuan; Tarr, Phillip I; Dantas, Gautam

    2013-01-01

    Emerging antibiotic resistance threatens human health. Gut microbes are an epidemiologically important reservoir of resistance genes (resistome), yet prior studies indicate that the true diversity of gut-associated resistomes has been underestimated. To deeply characterize the pediatric gut-associated resistome, we created metagenomic recombinant libraries in an Escherichia coli host using fecal DNA from 22 healthy infants and children (most without recent antibiotic exposure), and performed functional selections for resistance to 18 antibiotics from eight drug classes. Resistance-conferring DNA fragments were sequenced (Illumina HiSeq 2000), and reads assembled and annotated with the PARFuMS computational pipeline. Resistance to 14 of the 18 antibiotics was found in stools of infants and children. Recovered genes included chloramphenicol acetyltransferases, drug-resistant dihydrofolate reductases, rRNA methyltransferases, transcriptional regulators, multidrug efflux pumps, and every major class of beta-lactamase, aminoglycoside-modifying enzyme, and tetracycline resistance protein. Many resistance-conferring sequences were mobilizable; some had low identity to any known organism, emphasizing cryptic organisms as potentially important resistance reservoirs. We functionally confirmed three novel resistance genes, including a 16S rRNA methylase conferring aminoglycoside resistance, and two tetracycline-resistance proteins nearly identical to a bifidobacterial MFS transporter (B. longum s. longum JDM301). We provide the first report to our knowledge of resistance to folate-synthesis inhibitors conferred by a predicted Nudix hydrolase (part of the folate synthesis pathway). This functional metagenomic survey of gut-associated resistomes, the largest of its kind to date, demonstrates that fecal resistomes of healthy children are far more diverse than previously suspected, that clinically relevant resistance genes are present even without recent selective antibiotic

  9. Insecticide Resistance in Fleas

    PubMed Central

    Rust, Michael K.

    2016-01-01

    Fleas are the major ectoparasite of cats, dogs, and rodents worldwide and potential vectors of animal diseases. In the past two decades the majority of new control treatments have been either topically applied or orally administered to the host. Most reports concerning the development of insecticide resistance deal with the cat flea, Ctenocephalides felis felis. Historically, insecticide resistance has developed to many of the insecticides used to control fleas in the environment including carbamates, organophosphates, and pyrethroids. Product failures have been reported with some of the new topical treatments, but actual resistance has not yet been demonstrated. Failures have often been attributed to operational factors such as failure to adequately treat the pet and follow label directions. With the addition of so many new chemistries additional monitoring of flea populations is needed. PMID:26999217

  10. Insecticide Resistance in Fleas.

    PubMed

    Rust, Michael K

    2016-03-17

    Fleas are the major ectoparasite of cats, dogs, and rodents worldwide and potential vectors of animal diseases. In the past two decades the majority of new control treatments have been either topically applied or orally administered to the host. Most reports concerning the development of insecticide resistance deal with the cat flea, Ctenocephalides felis felis. Historically, insecticide resistance has developed to many of the insecticides used to control fleas in the environment including carbamates, organophosphates, and pyrethroids. Product failures have been reported with some of the new topical treatments, but actual resistance has not yet been demonstrated. Failures have often been attributed to operational factors such as failure to adequately treat the pet and follow label directions. With the addition of so many new chemistries additional monitoring of flea populations is needed.

  11. Insecticide Resistance in Fleas.

    PubMed

    Rust, Michael K

    2016-01-01

    Fleas are the major ectoparasite of cats, dogs, and rodents worldwide and potential vectors of animal diseases. In the past two decades the majority of new control treatments have been either topically applied or orally administered to the host. Most reports concerning the development of insecticide resistance deal with the cat flea, Ctenocephalides felis felis. Historically, insecticide resistance has developed to many of the insecticides used to control fleas in the environment including carbamates, organophosphates, and pyrethroids. Product failures have been reported with some of the new topical treatments, but actual resistance has not yet been demonstrated. Failures have often been attributed to operational factors such as failure to adequately treat the pet and follow label directions. With the addition of so many new chemistries additional monitoring of flea populations is needed. PMID:26999217

  12. Fast resistive bolometry

    SciTech Connect

    Spielman, R.B.; Deeney, C.; Fehl, D.L.; Hanson, D.L.; Keltner, N.R.; McGurn, J.S.; McKenney, J.L.

    1998-06-01

    Resistive bolometry is an accurate, robust, spectrally broadband technique for measuring absolute x-ray fluence and flux. Bolometry is an independent technique for x-ray measurements that is based on a different set of physical properties than other diagnostics such as x-ray diodes, photoconducting detectors, and P-I-N diodes. Bolometers use the temperature-driven change in element resistivity to determine the total deposited energy. The calibration of such a device is based on fundamental material properties and its physical dimensions. The authors describe the use of nickel and gold bolometers to measure x rays generated by high power Z pinches on Sandia`s Saturn and Z accelerators. The Sandia bolometer design described herein has a pulse response of {approximately}1 ns. They describe in detail the fabrication, fielding, and data analysis issues leading to highly accurate x-ray measurements. The fundamental accuracy of resistive bolometry will be discussed.

  13. The wind resistance of asphalt roofing shingles

    NASA Astrophysics Data System (ADS)

    Dixon, Craig Robert

    Asphalt shingle roofing is the leading cause of hurricane wind-related insured losses in residential buildings. Damage statistics generated from recent hurricanes indicate shingle roofs sustain damage in wind velocities below design-level with damage frequency increasing with shingle roof age. The objective of this dissertation is the identification of primary mechanisms triggering the failure of shingle roof systems in wind. The research goal is to reduce future shingle roof wind damage and improve our ability to predict asphalt shingle wind resistance. Five studies comprising this dissertation addressed the adhesive consistency and strength of aged asphalt shingles, system-level wind resistance, and the load model underpinning the ASTM D7158 wind test standard. The most significant and unexpected finding was partially unsealed shingles on field, hip, and ridge locations on Florida and Texas homes. Location on the shingle's sealant strip where unsealed and failure mode were consistent at each location. Total quantity of partially unsealed shingles in the field of the roof significantly increased with age, aligning with damage statistics. Full-scale wind tunnel tests demonstrate partially unsealed shingles are more vulnerable than fully sealed due to increased distributed force on sealant strip and concentrated force at the adhered and non-adhered interface. Uplift resistance was measured in artificially and naturally aged shingles. For artificially aged shingles, one of three products evaluated had statistically significant decreases in mean uplift resistance as exposure time increased. However, resistance was above design-level at all exposure test intervals. Naturally aged shingles also had resistance above design-level. Combined results demonstrate that reduced uplift capacity can occur, but high initial bond strength promotes long-term uplift resistance. Wind loads exerted on the shingles sealant strip load path were directly measured on fully sealed and

  14. Improved nonlinear prediction method

    NASA Astrophysics Data System (ADS)

    Adenan, Nur Hamiza; Md Noorani, Mohd Salmi

    2014-06-01

    The analysis and prediction of time series data have been addressed by researchers. Many techniques have been developed to be applied in various areas, such as weather forecasting, financial markets and hydrological phenomena involving data that are contaminated by noise. Therefore, various techniques to improve the method have been introduced to analyze and predict time series data. In respect of the importance of analysis and the accuracy of the prediction result, a study was undertaken to test the effectiveness of the improved nonlinear prediction method for data that contain noise. The improved nonlinear prediction method involves the formation of composite serial data based on the successive differences of the time series. Then, the phase space reconstruction was performed on the composite data (one-dimensional) to reconstruct a number of space dimensions. Finally the local linear approximation method was employed to make a prediction based on the phase space. This improved method was tested with data series Logistics that contain 0%, 5%, 10%, 20% and 30% of noise. The results show that by using the improved method, the predictions were found to be in close agreement with the observed ones. The correlation coefficient was close to one when the improved method was applied on data with up to 10% noise. Thus, an improvement to analyze data with noise without involving any noise reduction method was introduced to predict the time series data.

  15. Stable predictive control horizons

    NASA Astrophysics Data System (ADS)

    Estrada, Raúl; Favela, Antonio; Raimondi, Angelo; Nevado, Antonio; Requena, Ricardo; Beltrán-Carbajal, Francisco

    2012-04-01

    The stability theory of predictive and adaptive predictive control for processes of linear and stable nature is based on the hypothesis of a physically realisable driving desired trajectory (DDT). The formal theoretical verification of this hypothesis is trivial for processes with a stable inverse, but it is not for processes with an unstable inverse. The extended strategy of predictive control was developed with the purpose of overcoming methodologically this stability problem and it has delivered excellent performance and stability in its industrial applications given a suitable choice of the prediction horizon. From a theoretical point of view, the existence of a prediction horizon capable of ensuring stability for processes with an unstable inverse was proven in the literature. However, no analytical solution has been found for the determination of the prediction horizon values which guarantee stability, in spite of the theoretical and practical interest of this matter. This article presents a new method able to determine the set of prediction horizon values which ensure stability under the extended predictive control strategy formulation and a particular performance criterion for the design of the DDT generically used in many industrial applications. The practical application of this method is illustrated by means of simulation examples.

  16. Declining prevalence of HIV-1 drug resistance in antiretroviral treatment-exposed individuals in Western Europe.

    PubMed

    De Luca, Andrea; Dunn, David; Zazzi, Maurizio; Camacho, Ricardo; Torti, Carlo; Fanti, Iuri; Kaiser, Rolf; Sönnerborg, Anders; Codoñer, Francisco M; Van Laethem, Kristel; Vandamme, Anne-Mieke; Bansi, Loveleen; Ghisetti, Valeria; van de Vijver, David A M C; Asboe, David; Prosperi, Mattia C F; Di Giambenedetto, Simona

    2013-04-15

    HIV-1 drug resistance represents a major obstacle to infection and disease control. This retrospective study analyzes trends and determinants of resistance in antiretroviral treatment (ART)-exposed individuals across 7 countries in Europe. Of 20 323 cases, 80% carried at least one resistance mutation: these declined from 81% in 1997 to 71% in 2008. Predicted extensive 3-class resistance was rare (3.2% considering the cumulative genotype) and peaked at 4.5% in 2005, decreasing thereafter. The proportion of cases exhausting available drug options dropped from 32% in 2000 to 1% in 2008. Reduced risk of resistance over calendar years was confirmed by multivariable analysis.

  17. Estimates of the Diffusion Resistance of Some Large Sunflower Leaves in the Field 1

    PubMed Central

    Hunt, L. A.; Impens, Ivan I.; Lemon, E. R.

    1968-01-01

    Studies were made of resistance to gaseous exchange between large sunflower leaves and the bulk air in a crop canopy. Two components of the diffusive pathway for mass and sensible heat were evaluated; A) the resistance from the interior of the leaf to the leaf surface, and B) the resistance from the surface of the leaf through the leaf boundary air layer to the bulk air. It was found that: A) leaf resistance not only displays diurnal trends but shorter fluctuations, and B) boundary air layer resistance was significantly smaller than predicted from classical boundary layer formulae. PMID:16656801

  18. Vapor resistant arteries

    NASA Technical Reports Server (NTRS)

    Shaubach, Robert M. (Inventor); Dussinger, Peter M. (Inventor); Buchko, Matthew T. (Inventor)

    1989-01-01

    A vapor block resistant liquid artery structure for heat pipes. A solid tube artery with openings is encased in the sintered material of a heat pipe wick. The openings are limited to that side of the artery which is most remote from the heat source. The liquid in the artery can thus exit the artery through the openings and wet the sintered sheath, but vapor generated at the heat source is unlikely to move around the solid wall of the artery and reverse its direction in order to penetrate the artery through the openings. An alternate embodiment uses finer pore size wick material to resist vapor entry.

  19. Tackling antibiotic resistance.

    PubMed

    Bush, Karen; Courvalin, Patrice; Dantas, Gautam; Davies, Julian; Eisenstein, Barry; Huovinen, Pentti; Jacoby, George A; Kishony, Roy; Kreiswirth, Barry N; Kutter, Elizabeth; Lerner, Stephen A; Levy, Stuart; Lewis, Kim; Lomovskaya, Olga; Miller, Jeffrey H; Mobashery, Shahriar; Piddock, Laura J V; Projan, Steven; Thomas, Christopher M; Tomasz, Alexander; Tulkens, Paul M; Walsh, Timothy R; Watson, James D; Witkowski, Jan; Witte, Wolfgang; Wright, Gerry; Yeh, Pamela; Zgurskaya, Helen I

    2011-11-02

    The development and spread of antibiotic resistance in bacteria is a universal threat to both humans and animals that is generally not preventable but can nevertheless be controlled, and it must be tackled in the most effective ways possible. To explore how the problem of antibiotic resistance might best be addressed, a group of 30 scientists from academia and industry gathered at the Banbury Conference Centre in Cold Spring Harbor, New York, USA, from 16 to 18 May 2011. From these discussions there emerged a priority list of steps that need to be taken to resolve this global crisis.

  20. Tackling antibiotic resistance

    PubMed Central

    Bush, Karen; Courvalin, Patrice; Dantas, Gautam; Davies, Julian; Eisenstein, Barry; Huovinen, Pentti; Jacoby, George A.; Kishony, Roy; Kreiswirth, Barry N.; Kutter, Elizabeth; Lerner, Stephen A.; Levy, Stuart; Lewis, Kim; Lomovskaya, Olga; Miller, Jeffrey H.; Mobashery, Shahriar; Piddock, Laura J. V.; Projan, Steven; Thomas, Christopher M.; Tomasz, Alexander; Tulkens, Paul M.; Walsh, Timothy R.; Watson, James D.; Witkowski, Jan; Witte, Wolfgang; Wright, Gerry; Yeh, Pamela; Zgurskaya, Helen I.

    2014-01-01

    The development and spread of antibiotic resistance in bacteria is a universal threat to both humans and animals that is generally not preventable, but can nevertheless be controlled and must be tackled in the most effective ways possible. To explore how the problem of antibiotic resistance might best be addressed, a group of thirty scientists from academia and industry gathered at the Banbury Conference Centre in Cold Spring Harbor, New York, May 16-18, 2011. From these discussions emerged a priority list of steps that need to be taken to resolve this global crisis. PMID:22048738

  1. Flame Resistant Foam

    NASA Technical Reports Server (NTRS)

    1984-01-01

    Solimide manufactured by Imi-Tech Corporation, is a lightweight fire resistant material produced under a manufacturing process that allows it to be uniformly foamed. Can be produced in a variety of densities and structural configurations and remains resilient under exposure to temperatures ranging from minus 300 to plus 500 degrees Fahrenheit. Is resistant to open flame and generates virtually no smoke or toxic by-products. Used in aircraft for its superior damping characteristics, lighter weight and fire barrier properties, it's also applicable to ships and surface transportation systems such as transit cars, trains, buses and automobiles.

  2. Resisting religious coercive control.

    PubMed

    Sharp, Shane

    2014-12-01

    Religious coercive control refers to the use of religious beliefs and doctrine as means to coercively control intimate partners. Scholars have shown that some abusive partners use the Christian doctrine of submission as a means of religious coercive control. I explore how victims who experience the doctrine of submission qua religious coercive control actively resist it. I argue that victims' successful resistance of the doctrine is contingent on their religious capital-that is, the knowledge and mastery that people have of a particular religious culture-and interpretive confidence-that is, people's subjective confidence in their interpretations of religious culture-related to the doctrine.

  3. Evaluating prediction uncertainty

    SciTech Connect

    McKay, M.D.

    1995-03-01

    The probability distribution of a model prediction is presented as a proper basis for evaluating the uncertainty in a model prediction that arises from uncertainty in input values. Determination of important model inputs and subsets of inputs is made through comparison of the prediction distribution with conditional prediction probability distributions. Replicated Latin hypercube sampling and variance ratios are used in estimation of the distributions and in construction of importance indicators. The assumption of a linear relation between model output and inputs is not necessary for the indicators to be effective. A sequential methodology which includes an independent validation step is applied in two analysis applications to select subsets of input variables which are the dominant causes of uncertainty in the model predictions. Comparison with results from methods which assume linearity shows how those methods may fail. Finally, suggestions for treating structural uncertainty for submodels are presented.

  4. Toxicodynamic mechanisms and monitoring of acaricide resistance in the two-spotted spider mite.

    PubMed

    Kwon, Deok Ho; Clark, J Marshall; Lee, Si Hyeock

    2015-06-01

    The two-spotted spider (Tetranychus urticae) is one of the most serious pests world-wide and has developed resistance to many types of acaricides. Various mutations on acaricide target site genes have been determined to be responsible for toxicodynamic resistance, and the genotyping and frequency prediction of these mutations can be employed as an alternative resistance monitoring strategy. A quantitative sequencing (QS) protocol was reported as a population-based genotyping technique, and applied for the determination of resistance allele frequencies in T. urticae field populations. In addition, a modified glass vial bioassay method (residual contact vial bioassay, RCV) was implemented as a rapid on-site resistance monitoring tool. The QS protocol, together with the RCV, would greatly facilitate monitoring of T. urticae resistance. Recent completion of T. urticae genome analysis should facilitate the identification of additional resistance genetic markers that can be employed for molecular resistance monitoring. PMID:26047116

  5. Toxicodynamic mechanisms and monitoring of acaricide resistance in the two-spotted spider mite.

    PubMed

    Kwon, Deok Ho; Clark, J Marshall; Lee, Si Hyeock

    2015-06-01

    The two-spotted spider (Tetranychus urticae) is one of the most serious pests world-wide and has developed resistance to many types of acaricides. Various mutations on acaricide target site genes have been determined to be responsible for toxicodynamic resistance, and the genotyping and frequency prediction of these mutations can be employed as an alternative resistance monitoring strategy. A quantitative sequencing (QS) protocol was reported as a population-based genotyping technique, and applied for the determination of resistance allele frequencies in T. urticae field populations. In addition, a modified glass vial bioassay method (residual contact vial bioassay, RCV) was implemented as a rapid on-site resistance monitoring tool. The QS protocol, together with the RCV, would greatly facilitate monitoring of T. urticae resistance. Recent completion of T. urticae genome analysis should facilitate the identification of additional resistance genetic markers that can be employed for molecular resistance monitoring.

  6. Reinforcement context and resistance to change.

    PubMed

    Grace, Randolph C.; McLean, Anthony P.; Nevin, John A.

    2003-08-29

    Eight pigeons responded in a multiple variable-interval (VI) schedule in which a constant component always delivered 40rft/h, and an alternated component was either rich (200rft/h) or lean (6.67rft/h) in different conditions. Four tests of resistance to change were conducted in each condition: prefeeding, full extinction, constant-component-only extinction, and response-independent food. Resistance to both prefeeding and full extinction in the constant component varied inversely with the reinforcement rate in the alternated component, but resistance to response-independent food did not. The extinction and response-independent food results were consistent with [J. Exp. Psychol.: Anim. Behav. Proc. 25 (1999) 256] behavioral momentum model. Maintaining reinforcement in the alternated component increased resistance to extinction in the constant component, as predicted by the behavioral momentum model but not accounts of multiple-schedule performance based on [J. Exp. Anal. Behav. 13 (1970) 243] equation. Overall, the momentum model gave a good account of the results with the exception of the prefeeding data. Possible ways to reconcile the prefeeding results with behavioral momentum theory are considered.

  7. Resistive force theory for sand swimming

    NASA Astrophysics Data System (ADS)

    Ding, Yang; Maladen, Ryan; Li, Chen; Goldman, Daniel

    2009-11-01

    We discuss a resistive force theoryfootnotetextMaladen et. al, Science, 325, 314, 2009 that predicts the ratio of forward speed to wave speed (wave efficiency, η) of the sandfish lizard as it swims in granular media of varying volume fraction φ using a sinusoidal traveling wave body motion. In experiment η 0.5 independent of φ and is intermediate between η 0.2 for low Re Newtonian fluid undulatory swimmers like nematodes and η 0.9 for undulatory locomotion on a deformable surface. To predict η in granular media, we developed a resistive force model which balances thrust and drag force over the animal profile. We approximate the drag forces by measuring the force on a cylinder (a ``segment'' of the sandfish) oriented at different angles relative to the displacement direction. The model correctly predicts that η is independent of φ because the ratio of thrust to drag is independent of φ. The thrust component of the drag force is relatively larger in granular media than in low Re fluids, which explains why η in frictional granular media is greater than in viscous fluids.

  8. [Resistance risk, cross-resistance and biochemical resistance mechanism of Laodelphax striatellus to buprofezin].

    PubMed

    Mao, Xu-lian; Liu, Jin; Li, Xu-ke; Chi, Jia-jia; Liu, Yong-jie

    2016-01-01

    In order to investigate the resistance development law and biochemical resistance mechanism of Laodelphax striatellus to buprofezin, spraying rice seedlings was used to continuously screen resistant strains of L. striatellus and dipping rice seedlings was applied to determine the toxicity and cross-resistance of L. striatellus to insecticides. After 32-generation screening with buprofezin, L. striatellus developed 168.49 folds resistance and its reality heritability (h2) was 0.11. If the killing rate was 80%-90%, L. striatellus was expected to develop 10-fold resistance to buprofezin only after 5 to 6 generations breeding. Because the actual reality heritability of field populations was usually lower than that of the resistant strains, the production of field populations increasing with 10-fold resistance would need much longer time. The results of cross-resistance showed that resistant strain had high level cross-resistance with thiamethoxam and imidacloprid, low level cross-resistance with acetamiprid, and no cross-resistance with pymetrozine and chlorpyrifos. The activity of detoxification enzymes of different strains and the syergism of synergist were measured. The results showed that cytochrome P450 monooxygenase played a major role in the resistance of L. striatellus to buprofezin, the esterase played a minor role and the GSH-S-transferase had no effect. Therefore, L. striatellus would have high risk to develop resistance to buprofezin when used in the field and might be delayed by using pymetrozine and chlorpyrifos. PMID:27228617

  9. Cisplatin resistance associated with PARP hyperactivation.

    PubMed

    Michels, Judith; Vitale, Ilio; Galluzzi, Lorenzo; Adam, Julien; Olaussen, Ken André; Kepp, Oliver; Senovilla, Laura; Talhaoui, Ibtissam; Guegan, Justine; Enot, David Pierre; Talbot, Monique; Robin, Angélique; Girard, Philippe; Oréar, Cédric; Lissa, Delphine; Sukkurwala, Abdul Qader; Garcia, Pauline; Behnam-Motlagh, Parviz; Kohno, Kimitoshi; Wu, Gen Sheng; Brenner, Catherine; Dessen, Philippe; Saparbaev, Murat; Soria, Jean-Charles; Castedo, Maria; Kroemer, Guido

    2013-04-01

    Non-small cell lung carcinoma patients are frequently treated with cisplatin (CDDP), most often yielding temporary clinical responses. Here, we show that PARP1 is highly expressed and constitutively hyperactivated in a majority of human CDDP-resistant cancer cells of distinct histologic origin. Cells manifesting elevated intracellular levels of poly(ADP-ribosyl)ated proteins (PAR(high)) responded to pharmacologic PARP inhibitors as well as to PARP1-targeting siRNAs by initiating a DNA damage response that translated into cell death following the activation of the intrinsic pathway of apoptosis. Moreover, PARP1-overexpressing tumor cells and xenografts displayed elevated levels of PAR, which predicted the response to PARP inhibitors in vitro and in vivo more accurately than PARP1 expression itself. Thus, a majority of CDDP-resistant cancer cells appear to develop a dependency to PARP1, becoming susceptible to PARP inhibitor-induced apoptosis.

  10. Hospital costs of nosocomial multi-drug resistant Pseudomonas aeruginosa acquisition

    PubMed Central

    2012-01-01

    Background We aimed to assess the hospital economic costs of nosocomial multi-drug resistant Pseudomonas aeruginosa acquisition. Methods A retrospective study of all hospital admissions between January 1, 2005, and December 31, 2006 was carried out in a 420-bed, urban, tertiary-care teaching hospital in Barcelona (Spain). All patients with a first positive clinical culture for P. aeruginosa more than 48 h after admission were included. Patient and hospitalization characteristics were collected from hospital and microbiology laboratory computerized records. According to antibiotic susceptibility, isolates were classified as non-resistant, resistant and multi-drug resistant. Cost estimation was based on a full-costing cost accounting system and on the criteria of clinical Activity-Based Costing methods. Multivariate analyses were performed using generalized linear models of log-transformed costs. Results Cost estimations were available for 402 nosocomial incident P. aeruginosa positive cultures. Their distribution by antibiotic susceptibility pattern was 37.1% non-resistant, 29.6% resistant and 33.3% multi-drug resistant. The total mean economic cost per admission of patients with multi-drug resistant P. aeruginosa strains was higher than that for non-resistant strains (15,265 vs. 4,933 Euros). In multivariate analysis, resistant and multi-drug resistant strains were independently predictive of an increased hospital total cost in compared with non-resistant strains (the incremental increase in total hospital cost was more than 1.37-fold and 1.77-fold that for non-resistant strains, respectively). Conclusions P. aeruginosa multi-drug resistance independently predicted higher hospital costs with a more than 70% increase per admission compared with non-resistant strains. Prevention of the nosocomial emergence and spread of antimicrobial resistant microorganisms is essential to limit the strong economic impact. PMID:22621745

  11. Resistance Management Research Status

    EPA Science Inventory

    Long-term sustainability of genetically modified corn expressing Bt relies on the validity of assumptions underlying IRM models used by the EPA and the ability of EPA to monitor, detect and react to insect resistance when it develops. The EPA is developing a multi-tiered approac...

  12. Electrical Resistivity Imaging

    EPA Science Inventory

    Electrical resistivity imaging (ERI) is a geophysical method originally developed within the mining industry where it has been used for decades to explore for and characterize subsurface mineral deposits. It is one of the oldest geophysical methods with the first documented usag...

  13. Antimicrobial (Drug) Resistance Prevention

    MedlinePlus

    ... Action Plan for Combating Antibiotic-Resistant Bacteria (PDF) ​​​​​​ Javascript Error Your browser JavaScript is turned off causing certain features of the ... incorrectly. Please visit your browser settings and turn JavaScript on. Read more information on enabling JavaScript. Skip ...

  14. Overcoming Resistance to Change

    ERIC Educational Resources Information Center

    Hull, Ted H.; Balka, Don S.; Miles, Ruth Harbin

    2010-01-01

    Resistance to change is a major obstacle in developing and implementing effective instructional programs, yet it is rarely considered, discussed, or addressed. The school leaders who are responsible for improvement frequently feel that their efforts are being blocked or thwarted. For the most part, they are correct, but they may not realize that…

  15. Reform and Resistance.

    ERIC Educational Resources Information Center

    Hefferlin, JB Lon

    This article is the 7th in a series of AAHE research reports. It summarizes research that has been done on academic reform and the resistance to it and speculates what this research implies for future practice. Academic or curricular change is first of all organizational change and colleges and universities are organized and run in such a way as…

  16. Penetration resistant barrier

    DOEpatents

    Hoover, William R.; Mead, Keith E.; Street, Henry K.

    1977-01-01

    The disclosure relates to a barrier for resisting penetration by such as hand tools and oxy-acetylene cutting torches. The barrier comprises a layer of firebrick, which is preferably epoxy impregnated sandwiched between inner and outer layers of steel. Between the firebrick and steel are layers of resilient rubber-like filler.

  17. Wrinkle resistant cellulosic textiles

    SciTech Connect

    Kitchens, J.D.; Patton, R.T.; Nadar, R.S.

    1991-08-27

    This patent describes a process for treating a cellulosic textile material so as to impart wrinkle resistance and smooth drying properties. It comprises treating the cellulosic textile material with an aqueous solution comprising trans-1,2,3,4-cyclobutane tetracarboxylic acid, and a curing catalyst, and heating the treated material so as to produce esterification and crosslinking of the material with the acid.

  18. Intestinal colonization resistance

    PubMed Central

    Lawley, Trevor D; Walker, Alan W

    2013-01-01

    Dense, complex microbial communities, collectively termed the microbiota, occupy a diverse array of niches along the length of the mammalian intestinal tract. During health and in the absence of antibiotic exposure the microbiota can effectively inhibit colonization and overgrowth by invading microbes such as pathogens. This phenomenon is called ‘colonization resistance’ and is associated with a stable and diverse microbiota in tandem with a controlled lack of inflammation, and involves specific interactions between the mucosal immune system and the microbiota. Here we overview the microbial ecology of the healthy mammalian intestinal tract and highlight the microbe–microbe and microbe–host interactions that promote colonization resistance. Emerging themes highlight immunological (T helper type 17/regulatory T-cell balance), microbiota (diverse and abundant) and metabolic (short-chain fatty acid) signatures of intestinal health and colonization resistance. Intestinal pathogens use specific virulence factors or exploit antibiotic use to subvert colonization resistance for their own benefit by triggering inflammation to disrupt the harmony of the intestinal ecosystem. A holistic view that incorporates immunological and microbiological facets of the intestinal ecosystem should facilitate the development of immunomodulatory and microbe-modulatory therapies that promote intestinal homeostasis and colonization resistance. PMID:23240815

  19. Hearing the Resistance.

    ERIC Educational Resources Information Center

    Malinconico, S. Michael

    1983-01-01

    Proposes the "congruence model" as a theoretical framework for assessing the effects on organizational behavior of changes based on modern electronic technology. The nature and causes of resistance, encroachment on professional judgement, and unwillingness to deviate from standard practice when using online systems are discussed. Sixteen…

  20. Antimicrobial resistance in Canada

    PubMed Central

    Conly, John

    2002-01-01

    Antibiotic resistance has increased rapidly during the last decade, creating a serious threat to the treatment of infectious diseases. Canada is no exception to this worldwide phenomenon. Data from the Canadian Nosocomial Infection Surveillance Program have revealed that the incidence of methicillin-resistant Staphylococcus aureus, as a proportion of S. aureus isolates, increased from 1% in 1995 to 8% by the end of 2000, and vancomycin-resistant enterococcus has been documented in all 10 provinces since the first reported outbreak in 1995. The prevalence of nonsusceptible Streptococcus pneumoniae in Canada in 2000 was found to be 12%. Human antimicrobial prescriptions, adjusted for differences in the population, declined 11% based on the total number of prescriptions dispensed between 1995 and 2000. There was also a 21% decrease in β-lactam prescriptions during this same period. These data suggest that systematic efforts to reduce unnecessary prescribing of antimicrobials to outpatients in Canada, beginning after a national consensus conference in 1997, may be having an impact. There is, however, still a need for continued concerted efforts on a national, provincial and regional level to quell the rising tide of antibiotic resistance. PMID:12406948

  1. Antibiotic-Resistant Bacteria.

    ERIC Educational Resources Information Center

    Longenecker, Nevin E.; Oppenheimer, Dan

    1982-01-01

    A study conducted by high school advanced bacteriology students appears to confirm the hypothesis that the incremental administration of antibiotics on several species of bacteria (Escherichia coli, Staphylococcus epidermis, Bacillus sublitus, Bacillus megaterium) will allow for the development of antibiotic-resistant strains. (PEB)

  2. Teaching, Learning, and Resistance

    ERIC Educational Resources Information Center

    Van de Kleut, Geraldine; White, Connie

    2010-01-01

    This article is a discussion of the importance of using student resistance to inform and change teacher practice. The authors relate two narratives of practice, one of which takes place in a constructivist second-grade classroom in Ontario, and a second that takes place in a preservice classroom in California. In the first, a student uses the…

  3. Resistive Effects in EXTRAP

    NASA Astrophysics Data System (ADS)

    Tendler, M.

    1987-02-01

    Theoretical studies of the resistive equilibrium and stability of an EXTRAP Z-pinch are reported. Extending the previous analysis we reassess properties of the resistive equilibrium in EXTRAP with the emphasis on the time dependence of the latter. We also qualitatively consider the role of resistive instabilities in EXTRAP, showing that the typical timescale of the filamentation of the discharge (i.e., the non-linear development of the tearing instability) is comparable, at present, to the discharge duration. On the other hand, we emphasize that this phenomenon may still be consistent with the experimental observation of the Bennet's equilibrium. The processes of the current start-up and ramp-up are also analysed for EXTRAP and it is shown that the peculiarities of these processes may lead to the compression oscillations around an evolving rather stable equilibrium. Finally, some consequences of the average minimum-B concept for EXTRAP are discussed and it is shown that this issue virtually reduces to the appearance of the negative curvature of the magnetic field at the periphery. The maximum attainable value of β at the periphery of the pinch is obtained, as required by the ballooning stability criterion. The influence of the finite resistivity on the ballooning mode is also estimated.

  4. Prediction of bull fertility.

    PubMed

    Utt, Matthew D

    2016-06-01

    Prediction of male fertility is an often sought-after endeavor for many species of domestic animals. This review will primarily focus on providing some examples of dependent and independent variables to stimulate thought about the approach and methodology of identifying the most appropriate of those variables to predict bull (bovine) fertility. Although the list of variables will continue to grow with advancements in science, the principles behind making predictions will likely not change significantly. The basic principle of prediction requires identifying a dependent variable that is an estimate of fertility and an independent variable or variables that may be useful in predicting the fertility estimate. Fertility estimates vary in which parts of the process leading to conception that they infer about and the amount of variation that influences the estimate and the uncertainty thereof. The list of potential independent variables can be divided into competence of sperm based on their performance in bioassays or direct measurement of sperm attributes. A good prediction will use a sample population of bulls that is representative of the population to which an inference will be made. Both dependent and independent variables should have a dynamic range in their values. Careful selection of independent variables includes reasonable measurement repeatability and minimal correlation among variables. Proper estimation and having an appreciation of the degree of uncertainty of dependent and independent variables are crucial for using predictions to make decisions regarding bull fertility. PMID:26791329