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D.1 Efficacy, safety, and tolerability of subcutaneous efgartigimod in chronic inflammatory demyelinating polyneuropathy: results from the ADHERE trial
- Z Siddiqi, JA Allen, I Basta, C Eggers, J Guptill, K Gwathmey, C Hewamadduma, E Hofman, Y Hussain, S Kuwabara, F Leypoldt, J Lin, M Lipowska, M Lowe, G Lauria Pinter, L Querol, N Suresh, T Chang, A Tse, P Ulrichts, PA van Doorn, B Van Hoorick, R Yamasaki, RA Lewis
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- Canadian Journal of Neurological Sciences / Volume 51 / Issue s1 / June 2024
- Published online by Cambridge University Press:
- 24 May 2024, pp. S8-S9
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Background: Efgartigimod, a human immunoglobulin G (IgG)1 antibody Fc fragment, blocks the neonatal Fc receptor, decreasing IgG recycling and reducing pathogenic IgG autoantibody levels. ADHERE assessed the efficacy and safety of efgartigimod PH20 subcutaneous (SC; co-formulated with recombinant human hyaluronidase PH20) in chronic inflammatory demyelinating polyneuropathy (CIDP). Methods: ADHERE enrolled participants with CIDP (treatment naive or on standard treatments withdrawn during run-in period) and consisted of open-label Stage A (efgartigimod PH20 SC once weekly [QW]), and randomized (1:1) Stage B (efgartigimod or placebo QW). Primary outcomes were clinical improvement (assessed with aINCAT, I-RODS, or mean grip strength; Stage A) and time to first aINCAT score deterioration (relapse; Stage B). Secondary outcomes included treatment-emergent adverse events (TEAEs) incidence. Results: 322 participants entered Stage A. 214 (66.5%) were considered responders, randomized, and treated in Stage B. Efgartigimod significantly reduced the risk of relapse (HR: 0.394; 95% CI: 0.25–0.61) versus placebo (p=0.000039). Reduced risk of relapse occurred in participants receiving corticosteroids, intravenous or SC immunoglobulin, or no treatment before study entry. Most TEAEs were mild to moderate; 3 deaths occurred, none related to efgartigimod. Conclusions: Participants treated with efgartigimod PH20 SC maintained a clinical response and remained relapse-free longer than those treated with placebo.
Validation of a mathematical model of the bovine estrous cycle for cows with different estrous cycle characteristics
- H. M. T. Boer, S. T. Butler, C. Stötzel, M. F. W. te Pas, R. F. Veerkamp, H. Woelders
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A recently developed mechanistic mathematical model of the bovine estrous cycle was parameterized to fit empirical data sets collected during one estrous cycle of 31 individual cows, with the main objective to further validate the model. The a priori criteria for validation were (1) the resulting model can simulate the measured data correctly (i.e. goodness of fit), and (2) this is achieved without needing extreme, probably non-physiological parameter values. We used a least squares optimization procedure to identify parameter configurations for the mathematical model to fit the empirical in vivo measurements of follicle and corpus luteum sizes, and the plasma concentrations of progesterone, estradiol, FSH and LH for each cow. The model was capable of accommodating normal variation in estrous cycle characteristics of individual cows. With the parameter sets estimated for the individual cows, the model behavior changed for 21 cows, with improved fit of the simulated output curves for 18 of these 21 cows. Moreover, the number of follicular waves was predicted correctly for 18 of the 25 two-wave and three-wave cows, without extreme parameter value changes. Estimation of specific parameters confirmed results of previous model simulations indicating that parameters involved in luteolytic signaling are very important for regulation of general estrous cycle characteristics, and are likely responsible for differences in estrous cycle characteristics between cows.
Central genomic regulation of the expression of oestrous behaviour in dairy cows: a review
- H. Woelders, T. van der Lende, A. Kommadath, M. F. W. te Pas, M. A. Smits, L. M. T. E. Kaal
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The expression of oestrous behaviour in Holstein Friesian dairy cows has progressively decreased over the past 50 years. Reduced oestrus expression is one of the factors contributing to the current suboptimal reproductive efficiency in dairy farming. Variation between and within cows in the expression of oestrous behaviour is associated with variation in peripheral blood oestradiol concentrations during oestrus. In addition, there is evidence for a priming role of progesterone for the full display of oestrous behaviour. A higher rate of metabolic clearance of ovarian steroids could be one of the factors leading to lower peripheral blood concentrations of oestradiol and progesterone in high-producing dairy cows. Oestradiol acts on the brain by genomic, non-genomic and growth factor-dependent mechanisms. A firm base of understanding of the ovarian steroid-driven central genomic regulation of female sexual behaviour has been obtained from studies on rodents. These studies have resulted in the definition of five modules of oestradiol-activated genes in the brain, referred to as the GAPPS modules. In a recent series of studies, gene expression in the anterior pituitary and four brain areas (amygdala, hippocampus, dorsal hypothalamus and ventral hypothalamus) in oestrous and luteal phase cows, respectively, has been measured, and the relation with oestrous behaviour of these cows was analysed. These studies identified a number of genes of which the expression was associated with the intensity of oestrous behaviour. These genes could be grouped according to the GAPPS modules, suggesting close similarity of the regulation of oestrous behaviour in cows and female sexual behaviour in rodents. A better understanding of the central genomic regulation of the expression of oestrous behaviour in dairy cows may in due time contribute to improved (genomic) selection strategies for appropriate oestrus expression in high-producing dairy cows.
Systems biology in animal sciences
- H. Woelders, M. F. W. Te Pas, A. Bannink, R. F. Veerkamp, M. A. Smits
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Systems biology is a rapidly expanding field of research and is applied in a number of biological disciplines. In animal sciences, omics approaches are increasingly used, yielding vast amounts of data, but systems biology approaches to extract understanding from these data of biological processes and animal traits are not yet frequently used. This paper aims to explain what systems biology is and which areas of animal sciences could benefit from systems biology approaches. Systems biology aims to understand whole biological systems working as a unit, rather than investigating their individual components. Therefore, systems biology can be considered a holistic approach, as opposed to reductionism. The recently developed ‘omics’ technologies enable biological sciences to characterize the molecular components of life with ever increasing speed, yielding vast amounts of data. However, biological functions do not follow from the simple addition of the properties of system components, but rather arise from the dynamic interactions of these components. Systems biology combines statistics, bioinformatics and mathematical modeling to integrate and analyze large amounts of data in order to extract a better understanding of the biology from these huge data sets and to predict the behavior of biological systems. A ‘system’ approach and mathematical modeling in biological sciences are not new in itself, as they were used in biochemistry, physiology and genetics long before the name systems biology was coined. However, the present combination of mass biological data and of computational and modeling tools is unprecedented and truly represents a major paradigm shift in biology. Significant advances have been made using systems biology approaches, especially in the field of bacterial and eukaryotic cells and in human medicine. Similarly, progress is being made with ‘system approaches’ in animal sciences, providing exciting opportunities to predict and modulate animal traits.
Advances in research on the prenatal development of skeletal muscle in animals in relation to the quality of muscle-based food. II – Genetic factors related to animal performance and advances in methodology
- C. Rehfeldt, M. F. W. Te Pas, K. Wimmers, J. M. Brameld, P. M. Nissen, C. Berri, L. M. P. Valente, D. M. Power, B. Picard, N. C. Stickland, N. Oksbjerg
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Selective breeding is an effective tool to improve livestock. Several selection experiments have been conducted to study direct selection responses as well as correlated responses in traits of skeletal muscle growth and function. Moreover, comparisons of domestic with wild-type species and of extreme breeds provide information on the genetic background of the skeletal muscle phenotype. Structural muscular components that differed with increasing distance in lean growth or meat quality in mammals were found to be myofibre number, myofibre size, proportions of fibre types as well as the numbers and proportions of secondary and primary fibres. Furthermore, markers of satellite cell proliferation, metabolic enzyme activities, glycogen and fat contents, the expression of myosin heavy chain isoforms, of activated AMPKα and other proteins in skeletal muscle tissue and circulating IGF1 and IGF-binding proteins have been identified to be involved in selection responses observed in pigs, cattle and/or chicken. The use of molecular methods for selective breeding of fish has only recently been adopted in aquaculture and studies of the genetic basis of growth and flesh quality traits are scarce. Some of the molecular markers of muscle structure/metabolism in livestock have also been identified in fish, but so far no studies have linked them with selection response. Genome scans have been applied to identify genomic regions exhibiting quantitative trait loci that control traits of interest, for example, muscle structure and meat quality in pigs and growth rate in chicken. As another approach, polymorphisms in candidate genes reveal the relationship between genetic variation and target traits. Thus, in large-scale studies with pigs’ associations of polymorphisms in the HMGA2, CA3, EPOR, NME1 and TTN genes with traits of carcass and meat quality were detected. Other studies revealed the significance of mutations in the IGF2 and RYR1 genes for carcass lean and muscle fibre traits in pigs. Mutations in the myostatin (MSTN) gene in fish were also examined. Advances in research of the genetic and environmental control of traits related to meat quality and growth have been made by the application of holistic ‘omics’ techniques that studied the whole muscle-specific genome, transcriptome and proteome in relation to muscle and meat traits, the development of new methods for muscle fibre typing and the adaptation of biophysical measures to develop parameters of muscle fibre traits as well as the application of in vitro studies. Finally, future research priorities in the field are defined.
Advances in research on the prenatal development of skeletal muscle in animals in relation to the quality of muscle-based food. I. Regulation of myogenesis and environmental impact
- C. Rehfeldt, M. F. W. Te Pas, K. Wimmers, J. M. Brameld, P. M. Nissen, C. Berri, L. M. P. Valente, D. M. Power, B. Picard, N. C. Stickland, N. Oksbjerg
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Skeletal muscle development in vertebrates – also termed myogenesis – is a highly integrated process. Evidence to date indicates that the processes are very similar across mammals, poultry and fish, although the timings of the various steps differ considerably. Myogenesis is regulated by the myogenic regulatory factors and consists of two to three distinct phases when different fibre populations appear. The critical times when myogenesis is prone to hormonal or environmental influences depend largely on the developmental stage. One of the main mechanisms for both genetic and environmental effects on muscle fibre development is via the direct action of the growth hormone–insulin-like growth factor (GH–IGF) axis. In mammals and poultry, postnatal growth and function of muscles relate mainly to the hypertrophy of the fibres formed during myogenesis and to their fibre-type composition in terms of metabolic and contractile properties, whereas in fish hyperplasia still plays a major role. Candidate genes that are important in skeletal muscle development, for instance, encode for IGFs and IGF-binding proteins, myosin heavy chain isoforms, troponin T, myosin light chain and others have been identified. In mammals, nutritional supply in utero affects myogenesis and the GH–IGF axis may have an indirect action through the partitioning of nutrients towards the gravid uterus. Impaired myogenesis resulting in low skeletal myofibre numbers is considered one of the main reasons for negative long-term consequences of intrauterine growth retardation. Severe undernutrition in utero due to natural variation in litter or twin-bearing species or insufficient maternal nutrient supply may impair myogenesis and adversely affect carcass quality later in terms of reduced lean and increased fat deposition in the progeny. On the other hand, increases in maternal feed intake above standard requirement seem to have no beneficial effects on the growth of the progeny with myogenesis not or only slightly affected. Initial studies on low and high maternal protein feeding are published. Although there are only a few studies, first results also reveal an influence of nutrition on skeletal muscle development in fish and poultry. Finally, environmental temperature has been identified as a critical factor for growth and development of skeletal muscle in both fish and poultry.
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- By Rose Teteki Abbey, K. C. Abraham, David Tuesday Adamo, LeRoy H. Aden, Efrain Agosto, Victor Aguilan, Gillian T. W. Ahlgren, Charanjit Kaur AjitSingh, Dorothy B E A Akoto, Giuseppe Alberigo, Daniel E. Albrecht, Ruth Albrecht, Daniel O. Aleshire, Urs Altermatt, Anand Amaladass, Michael Amaladoss, James N. Amanze, Lesley G. Anderson, Thomas C. Anderson, Victor Anderson, Hope S. Antone, María Pilar Aquino, Paula Arai, Victorio Araya Guillén, S. Wesley Ariarajah, Ellen T. Armour, Brett Gregory Armstrong, Atsuhiro Asano, Naim Stifan Ateek, Mahmoud Ayoub, John Alembillah Azumah, Mercedes L. García Bachmann, Irena Backus, J. Wayne Baker, Mieke Bal, Lewis V. Baldwin, William Barbieri, António Barbosa da Silva, David Basinger, Bolaji Olukemi Bateye, Oswald Bayer, Daniel H. Bays, Rosalie Beck, Nancy Elizabeth Bedford, Guy-Thomas Bedouelle, Chorbishop Seely Beggiani, Wolfgang Behringer, Christopher M. Bellitto, Byard Bennett, Harold V. Bennett, Teresa Berger, Miguel A. Bernad, Henley Bernard, Alan E. Bernstein, Jon L. Berquist, Johannes Beutler, Ana María Bidegain, Matthew P. Binkewicz, Jennifer Bird, Joseph Blenkinsopp, Dmytro Bondarenko, Paulo Bonfatti, Riet en Pim Bons-Storm, Jessica A. Boon, Marcus J. Borg, Mark Bosco, Peter C. Bouteneff, François Bovon, William D. Bowman, Paul S. Boyer, David Brakke, Richard E. Brantley, Marcus Braybrooke, Ian Breward, Ênio José da Costa Brito, Jewel Spears Brooker, Johannes Brosseder, Nicholas Canfield Read Brown, Robert F. Brown, Pamela K. Brubaker, Walter Brueggemann, Bishop Colin O. Buchanan, Stanley M. Burgess, Amy Nelson Burnett, J. Patout Burns, David B. Burrell, David Buttrick, James P. Byrd, Lavinia Byrne, Gerado Caetano, Marcos Caldas, Alkiviadis Calivas, William J. Callahan, Salvatore Calomino, Euan K. Cameron, William S. Campbell, Marcelo Ayres Camurça, Daniel F. Caner, Paul E. Capetz, Carlos F. Cardoza-Orlandi, Patrick W. Carey, Barbara Carvill, Hal Cauthron, Subhadra Mitra Channa, Mark D. Chapman, James H. Charlesworth, Kenneth R. Chase, Chen Zemin, Luciano Chianeque, Philip Chia Phin Yin, Francisca H. Chimhanda, Daniel Chiquete, John T. Chirban, Soobin Choi, Robert Choquette, Mita Choudhury, Gerald Christianson, John Chryssavgis, Sejong Chun, Esther Chung-Kim, Charles M. A. Clark, Elizabeth A. Clark, Sathianathan Clarke, Fred Cloud, John B. Cobb, W. Owen Cole, John A Coleman, John J. Collins, Sylvia Collins-Mayo, Paul K. Conkin, Beth A. Conklin, Sean Connolly, Demetrios J. Constantelos, Michael A. Conway, Paula M. Cooey, Austin Cooper, Michael L. Cooper-White, Pamela Cooper-White, L. William Countryman, Sérgio Coutinho, Pamela Couture, Shannon Craigo-Snell, James L. Crenshaw, David Crowner, Humberto Horacio Cucchetti, Lawrence S. Cunningham, Elizabeth Mason Currier, Emmanuel Cutrone, Mary L. Daniel, David D. Daniels, Robert Darden, Rolf Darge, Isaiah Dau, Jeffry C. Davis, Jane Dawson, Valentin Dedji, John W. de Gruchy, Paul DeHart, Wendy J. Deichmann Edwards, Miguel A. De La Torre, George E. Demacopoulos, Thomas de Mayo, Leah DeVun, Beatriz de Vasconcellos Dias, Dennis C. Dickerson, John M. Dillon, Luis Miguel Donatello, Igor Dorfmann-Lazarev, Susanna Drake, Jonathan A. Draper, N. Dreher Martin, Otto Dreydoppel, Angelyn Dries, A. J. Droge, Francis X. D'Sa, Marilyn Dunn, Nicole Wilkinson Duran, Rifaat Ebied, Mark J. Edwards, William H. Edwards, Leonard H. Ehrlich, Nancy L. Eiesland, Martin Elbel, J. Harold Ellens, Stephen Ellingson, Marvin M. Ellison, Robert Ellsberg, Jean Bethke Elshtain, Eldon Jay Epp, Peter C. Erb, Tassilo Erhardt, Maria Erling, Noel Leo Erskine, Gillian R. Evans, Virginia Fabella, Michael A. Fahey, Edward Farley, Margaret A. Farley, Wendy Farley, Robert Fastiggi, Seena Fazel, Duncan S. Ferguson, Helwar Figueroa, Paul Corby Finney, Kyriaki Karidoyanes FitzGerald, Thomas E. FitzGerald, John R. Fitzmier, Marie Therese Flanagan, Sabina Flanagan, Claude Flipo, Ronald B. Flowers, Carole Fontaine, David Ford, Mary Ford, Stephanie A. Ford, Jim Forest, William Franke, Robert M. Franklin, Ruth Franzén, Edward H. Friedman, Samuel Frouisou, Lorelei F. Fuchs, Jojo M. Fung, Inger Furseth, Richard R. Gaillardetz, Brandon Gallaher, China Galland, Mark Galli, Ismael García, Tharscisse Gatwa, Jean-Marie Gaudeul, Luis María Gavilanes del Castillo, Pavel L. Gavrilyuk, Volney P. Gay, Metropolitan Athanasios Geevargis, Kondothra M. George, Mary Gerhart, Simon Gikandi, Maurice Gilbert, Michael J. Gillgannon, Verónica Giménez Beliveau, Terryl Givens, Beth Glazier-McDonald, Philip Gleason, Menghun Goh, Brian Golding, Bishop Hilario M. Gomez, Michelle A. Gonzalez, Donald K. Gorrell, Roy Gottfried, Tamara Grdzelidze, Joel B. Green, Niels Henrik Gregersen, Cristina Grenholm, Herbert Griffiths, Eric W. Gritsch, Erich S. Gruen, Christoffer H. Grundmann, Paul H. Gundani, Jon P. Gunnemann, Petre Guran, Vidar L. Haanes, Jeremiah M. 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Yee, Viktor Yelensky, Yeo Khiok-Khng, Gustav K. K. Yeung, Angela Yiu, Amos Yong, Yong Ting Jin, You Bin, Youhanna Nessim Youssef, Eliana Yunes, Robert Michael Zaller, Valarie H. Ziegler, Barbara Brown Zikmund, Joyce Ann Zimmerman, Aurora Zlotnik, Zhuo Xinping
- Edited by Daniel Patte, Vanderbilt University, Tennessee
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- The Cambridge Dictionary of Christianity
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- 20 September 2010, pp xi-xliv
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Gene expression patterns in anterior pituitary associated with quantitative measure of oestrous behaviour in dairy cows
- A. Kommadath, H. A. Mulder, A. A. C. de Wit, H. Woelders, M. A. Smits, B. Beerda, R. F. Veerkamp, A. C. J. Frijters, M. F. W. te Pas
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Intensive selection for high milk yield in dairy cows has raised production levels substantially but at the cost of reduced fertility, which manifests in different ways including reduced expression of oestrous behaviour. The genomic regulation of oestrous behaviour in bovines remains largely unknown. Here, we aimed to identify and study those genes that were associated with oestrous behaviour among genes expressed in the bovine anterior pituitary either at the start of oestrous cycle or at the mid-cycle (around day 12 of cycle), or regardless of the phase of cycle. Oestrous behaviour was recorded in each of 28 primiparous cows from 30 days in milk onwards till the day of their sacrifice (between 77 and 139 days in milk) and quantified as heat scores. An average heat score value was calculated for each cow from heat scores observed during consecutive oestrous cycles excluding the cycle on the day of sacrifice. A microarray experiment was designed to measure gene expression in the anterior pituitary of these cows, 14 of which were sacrificed at the start of oestrous cycle (day 0) and 14 around day 12 of cycle (day 12). Gene expression was modelled as a function of the orthogonally transformed average heat score values using a Bayesian hierarchical mixed model on data from day 0 cows alone (analysis 1), day 12 cows alone (analysis 2) and the combined data from day 0 and day 12 cows (analysis 3). Genes whose expression patterns showed significant linear or non-linear relationships with average heat scores were identified in all three analyses (177, 142 and 118 genes, respectively). Gene ontology terms enriched among genes identified in analysis 1 revealed processes associated with expression of oestrous behaviour whereas the terms enriched among genes identified in analysis 2 and 3 were general processes which may facilitate proper expression of oestrous behaviour at the subsequent oestrus. Studying these genes will help to improve our understanding of the genomic regulation of oestrous behaviour, ultimately leading to better management strategies and tools to improve or monitor reproductive performance in bovines.
Expression profiles of genes regulating dairy cow fertility: recent findings, ongoing activities and future possibilities*
- B. Beerda, J. Wyszynska-Koko, M. F. W. te Pas, A. A. C. de Wit, R. F. Veerkamp
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Subfertility has negative effects for dairy farm profitability, animal welfare and sustainability of animal production. Increasing herd sizes and economic pressures restrict the amount of time that farmers can spend on counteractive management. Genetic improvement will become increasingly important to restore reproductive performance. Complementary to traditional breeding value estimation procedures, genomic selection based on genome-wide information will become more widely applied. Functional genomics, including transcriptomics (gene expression profiling), produces the information to understand the consequences of selection as it helps to unravel physiological mechanisms underlying female fertility traits. Insight into the latter is needed to develop new effective management strategies to combat subfertility. Here, the importance of functional genomics for dairy cow reproduction so far and in the near future is evaluated. Recent gene profiling studies in the field of dairy cow fertility are reviewed and new data are presented on genes that are expressed in the brains of dairy cows and that are involved in dairy cow oestrus (behaviour). Fast-developing new research areas in the field of functional genomics, such as epigenetics, RNA interference, variable copy numbers and nutrigenomics, are discussed including their promising future value for dairy cow fertility.
The IGF2-intron3-G3072A substitution explains a major imprinted QTL effect on backfat thickness in a Meishan×European white pig intercross
- BART J. JUNGERIUS, ANNE-SOPHIE VAN LAERE, MARINUS F. W. TE PAS, BERNARD A. VAN OOST, LEIF ANDERSSON, MARTIEN A. M. GROENEN
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- Journal:
- Genetical Research / Volume 84 / Issue 2 / October 2004
- Published online by Cambridge University Press:
- 26 November 2004, pp. 95-101
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A paternally expressed QTL for muscle growth and backfat thickness (BFT) has previously been identified near the IGF2 locus on the distal tip of pig chromosome 2 (SSC2p) in three experimental F2 populations. Recently, a mutation in a regulatory element of the IGF2 gene was identified as the quantitative trait nucleotide (QTN) underlying the major QTL effect on muscle growth and BFT in crosses between Large White and Wild Boar or Pietrain. This study demonstrates that the IGF2 mutation also controls the paternally expressed QTL for backfat thickness in a cross between Meishan and European Whites. In addition, a comparison of QTL of backfat thickness measured by Hennessy grading probe (HGP) and by ultrasound measurement (USM) was made. In the USM analyses, the IFG2 mutation explains the entire QTL effect on SSC2p, whereas in the HGP analysis the presence of a second minor QTL can not be excluded. Finally, this study shows that this particular IGF2 mutation does not cause the paternally expressed QTL for teat number mapping to the same region of SSC2p as the BFT QTL.
How does Trypanosoma equiperdum fit into the Trypanozoon group? A cluster analysis by RAPD and Multiplex-endonuclease genotyping approach
- F. CLAES, E. C. AGBO, M. RADWANSKA, M. F. W. TE PAS, T. BALTZ, D. T. DE WAAL, B. M. GODDEERIS, E. CLAASSEN, P. BÜSCHER
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- Journal:
- Parasitology / Volume 126 / Issue 5 / May 2003
- Published online by Cambridge University Press:
- 07 May 2003, pp. 425-431
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The pathogenic trypanosomes Trypanosoma equiperdum, T. evansi as well as T. brucei are morphologically identical. In horses, these parasites are considered to cause respectively dourine, surra and nagana. Previous molecular attempts to differentiate these species were not successful for T. evansi and T. equiperdum; only T. b. brucei could be differentiated to a certain extent. In this study we analysed 10 T. equiperdum, 8 T. evansi and 4 T. b. brucei using Random Amplified Polymorphic DNA (RAPD) and multiplex-endonuclease fingerprinting, a modified AFLP technique. The results obtained confirm the homogeneity of the T. evansi group tested. The T. b. brucei clustered out in a heterogenous group. For T. equiperdum the situation is more complex: 8 out of 10 T. equiperdum clustered together with the T. evansi group, while 2 T. equiperdum strains were more related to T. b. brucei. Hence, 2 hypotheses can be formulated: (1) only 2 T. equiperdum strains are genuine T. equiperdum causing dourine; all other T. equiperdum strains actually are T. evansi causing surra or (2) T. equiperdum does not exist at all. In that case, the different clinical outcome of horse infections with T. evansi or T. b. brucei is primarily related to the host immune response.
Molecular variation of Trypanosoma brucei subspecies as revealed by AFLP fingerprinting
- E. E. C. AGBO, P. A. O. MAJIWA, H. J. H. M. CLAASSEN, M. F. W. TE PAS
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- Journal:
- Parasitology / Volume 124 / Issue 4 / April 2002
- Published online by Cambridge University Press:
- 01 August 2002, pp. 349-358
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Genetic analysis of Trypanosoma spp. depends on the detection of variation between strains. We have used the amplified fragment length polymorphism (AFLP) technique to develop a convenient and reliable method for genetic characterization of Trypanosome (sub)species. AFLP accesses multiple independent sites within the genome and would allow a better definition of the relatedness of different Trypanosome (sub)species. Nine isolates (3 from each T. brucei subspecies) were tested with 40 AFLP primer combinations to identify the most appropriate pairs of restriction endonucleases and selective primers. Primers based on the recognition sequences of EcoRI and BglII were chosen and used to analyse 31 T. brucei isolates. Similarity levels calculated with the Pearson correlation coefficient ranged from 15 to 98%, and clusters were determined using the unweighted pair-group method using arithmetic averages (UPGMA). At the intraspecific level, AFLP fingerprints were grouped by numerical analysis in 2 main clusters, allowing a clear separation of T. b. gambiense (cluster I) from T. b. brucei and T. b. rhodesiense isolates (cluster II). Interspecies evaluation of this customized approach produced heterogeneous AFLP patterns, with unique genetic markers, except for T. evansi and T. equiperdum, which showed identical patterns and clustered together.
A transmission/disequilibrium test approach to screen for quantitative trait loci in two selected lines of Large White pigs
- MARCO C. A. M. BINK, MARINUS F. W. TE PAS, FRANK L. HARDERS, LUC L. G. JANSS
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- Journal:
- Genetical Research / Volume 75 / Issue 1 / February 2000
- Published online by Cambridge University Press:
- 01 February 2000, pp. 115-121
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Pedigree and marker data from a multiple-generation pig selection experiment have been analysed to screen for loci affecting quantitative traits (QTL). Pigs from a base population were selected either for low backfat thickness at fixed live weight (L-line) or high live weight at fixed age (F-line). Selection was based on single-trait own performance and DNA was available on selected individuals only. Genotypes for three marker loci with known positions on chromosome 4 were available. The transmission/disequilibrium test (TDT) was originally described in human genetics to test for linkage between a genetic marker and a disease-susceptibility locus, in the presence of association. Here, we adapt the TDT to test for linkage between a marker and QTL favoured by selection, and for linkage disequilibrium between them in the base population. The a priori unknown distribution of the test statistic under the null hypothesis, no linkage, was obtained via Monte Carlo simulation. Significant TDT statistics were found for markers AFABP and SW818 in the F-line, indicating the presence of a closely linked QTL affecting growth performance. In the L-line, none of the markers studied showed significance. This study emphasizes the potential of the TDT as a quick and simple approach to screen for QTL in situations where marker genotypes are available on selected individuals. The results suggest that previously identified QTL in crosses of genetically diverse breeds may also segregate in commercial selection lines.
Optimization of Ti and Co Self-Aligned Silicide RTP for 0.10 μm CMOS
- J. A. Kittl, Q. Z. Hong, H. Yang, N. Yu, M. Rodder, P. P. Apte, W. T. Shiau, C. P. Chao, T. Breedijk, M. F. Pas
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- Journal:
- MRS Online Proceedings Library Archive / Volume 514 / 1998
- Published online by Cambridge University Press:
- 10 February 2011, 255
- Print publication:
- 1998
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As CMOS technologies are scaled to 0.10 μm and beyond, self-aligned silicide (salicide) processes find difficult challenges. As junction depths and linewidths are scaled, achieving both low sheet resistance and low contact resistance maintaining low diode leakage becomes increasingly difficult. In this paper we present studies of Ti and Co salicide processes implemented into a 0.10 μm CMOS technology. We show that both for Ti and Co, the optimization of RTP parameters plays a crucial roll in achieving a successful implementation. For Co salicide, optimization of RTP conditions results in elimination of shallow junction leakage (its main scaling problem). Two-step RTP and one-step RTP Ti salicide processes are compared, showing the advantages of one-step RTP. The RTP process windows for low resistance narrow gates (the main scaling issue for Ti salicide) are analyzed. Processes with pre-amorphization, with Mo doping and with a combination of both are compared. An optimal process using Mo and preamorphization implants and one-step RTP is shown to result in excellent device characteristics and low resistance to 0.06 μm gates.
Optimization of Ti and Co Self-Aligned Silicide RTP for 0.10 μm Cmos
- J. A. Kittl, Q. Z. Hong, H. Yang, N. Yu, M. Rodder, P. P. Apte, W. T. Shiau, C. P. Chao, T. Breedijk, M. F. Pas
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- Journal:
- MRS Online Proceedings Library Archive / Volume 525 / 1998
- Published online by Cambridge University Press:
- 10 February 2011, 331
- Print publication:
- 1998
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As CMOS technologies are scaled to 0.10 μm and beyond, self-aligned silicide (salicide) processes find difficult challenges. As junction depths and linewidths are scaled, achieving both low sheet resistance and low contact resistance maintaining low diode leakage becomes increasingly difficult. In this paper we present studies of Ti and Co salicide processes implemented into a 0.10 μm CMOS technology. We show that both for Ti and Co, the optimization of RTP parameters plays a crucial roll in achieving a successful implementation. For Co salicide, optimization of RTP conditions results in elimination of shallow junction leakage (its main scaling problem). Two-step RTP and one-step RTP Ti salicide processes are compared, showing the advantages of one-step RTP. The RTP process windows for low resistance narrow gates (the main scaling issue for Ti salicide) are analyzed. Processes with pre-amorphization, with Mo doping and with a combination of both are compared. An optimal process using Mo and preamorphization implants and one-step RTP is shown to result in excellent device characteristics and low resistance to 0.06 μm gates.
Hydrogen Incorporation During Deposition of a-Si:H From an Intense Source of SiH3
- M. C. M. Van De Sanden, R. J. Severens, W. M. M. Kessels, F. Van De Pas, L. Van Ijzendoorn, D. C. Schram
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- Journal:
- MRS Online Proceedings Library Archive / Volume 467 / 1997
- Published online by Cambridge University Press:
- 15 February 2011, 621
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- 1997
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The incorporation of hydrogen during the fast deposition of a-Si:H from an expanding thermal arc is investigated by means of isotope labeling of the precursor gases silane and hydrogen. It is found that hydrogen in a-Si.H originates dominantly from the silyl radical. A small fraction of the hydrogen in a-Si:H is due to exchange reaction of atomic hydrogen in the plasma with hydrogen chemisorbed on the surface during growth.
Rapid Thermal Processing: When Will it Replace Batch Processing?
- M. F. Pas, S. D. Pas
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- Journal:
- MRS Online Proceedings Library Archive / Volume 470 / 1997
- Published online by Cambridge University Press:
- 10 February 2011, 147
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- 1997
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Rapid Thermal Processing (RTP) is currently well established at the < 0.5 μm nodes for implant anneal and suicide formation/anneal in logic applications. Rapid Thermal Chemical Vapor Deposition (RTCVD) is being evaluated to deposit thin nitride for the DRAM storage node dielectric. A combination RTP/RTCVD has been evaluated in the form of a cluster tool to evaluate 60 Å gate oxides. These applications of RTP are considered to be process enabling because of either improved temperature ramp control or ambient control which are not available in batch processing. However, even with these specialized applications, rapid thermal processing comprises less than 20% of the front end thermal processes in a typical 0.35 μm fab. Process and equipment issues with rapid thermal processing remain which must be overcome if it is to replace batch processing at the 0.25 μm node. Process issues which are especially critical for RTCVD processing require improved temperature measurement, high growth/deposition rate, and an efficient method of cleaning the process chamber. Equipment issues are reliability and throughput which directly affect the tool cost of ownership. In this paper, each of these issues will be addressed and compared to batch processing using a generic logic process flow.
Understanding the Impact of Batch vs. Single Wafer in Thermal Processing Using Cost of Ownership Analysis
- S. Hossain-Pas, M. F. Pas
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- Journal:
- MRS Online Proceedings Library Archive / Volume 470 / 1997
- Published online by Cambridge University Press:
- 10 February 2011, 201
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- 1997
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Batch thermal processing satisfies device requirements for 0.5μm and larger technology nodes for silicon semiconductor manufacturing and continues to satisfy these requirements as feature sizes decrease beyond 0.5μm to 0.35μm. At the transition from 0.35μm to 0.25μm, source/drain (S/D) anneal, TiSi form, and TiSi anneal require rapid thermal processing (RTP) because of improvements in thermal budget, lateral dopant diffusion, and in silicidation, with RTP. RTP and rapid thermal chemical vapor deposition (RTCVD) become enabling technology for devices at 0.25μm and smaller technology nodes.
A cost of ownership (CoO) analysis provides a comparison between the financial impact of alternatives and helps in determining the lowest cost answer for that process, assuming all other process parameters can be met equally by all alternatives. This report analyzes primary cost drivers, their importance within each analysis, and potential for improvements which may cause a significant change in CoO values at 200mm.
Modeling of Device Characteristics as Function of Ti Salicide Rapid Thermal Processing Parameters for Deep-Sub-Micron CMOS Technologies
- J. A. Kittl, D. A. Prinslow, G. Misium, M. F. Pas
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- Journal:
- MRS Online Proceedings Library Archive / Volume 429 / 1996
- Published online by Cambridge University Press:
- 10 February 2011, 175
- Print publication:
- 1996
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Rapid thermal processing is widely applied in self-aligned Ti silicide processes for deep-submicron devices. We investigated and modeled the effects of rapid thermal processing variables (silicide formation temperature and time, and anneal temperature and time) and Ti thickness on deep-sub-micron device characteristics. The effect of Ti thickness, formation temperature and time on diode leakage and bridging due to silicide lateral growth, and its correlation to silicide thickness was analyzed; as well as the effects of these and the anneal variables on n+ gate sheet resistance, silicide to source/drain contact resistance and transistor source-drain series resistance. An expression for n+ gate sheet resistance is given, as function of anneal temperature and time, silicide thickness, linewidth and TiSi2 C49 grain size after formation, based on a nucleation density model in agreement with measurements of TiSi2 C49 to C54 transformation kinetics. The tradeoffs and process window limits are discussed, as well as trends observed when scaling down lateral and vertical dimensions. We show that for advanced technologies, the scaling of silicide thickness and linewidth narrows the process window between full C49 to C54 transformation and agglomeration temperatures. Due to the high activation energy of the C49 to C54 transformation, a process window for low sheet resistance exists only for high temperature-short time processes.
Kinetics of the C49 TO C54 Phase Transformation in TiSi2 thin Films on Deep-Sub-Micron Lines
- J. A. Kittl, D. A. Prinslow, P. P Apte, M. F. Pas
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- Journal:
- MRS Online Proceedings Library Archive / Volume 402 / 1995
- Published online by Cambridge University Press:
- 15 February 2011, 269
- Print publication:
- 1995
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The kinetics of the TiSi2 C49 to C54 phase transformation in thin films on patterned deepsub- micron lines, were studied to obtain the full time, temperature and linewidth dependence of the fraction transformed during rapid thermal annealing. A Johnson-Mehl-Avrami kinetic analysis was performed, obtaining Avrami exponents of 0.8±0.2 for all sub-micron lines and 1. 9±0.2 for a 40 μm side square structure, indicating heterogeneous nucleation followed by one dimensional growth for the narrow lines, and two dimensional growth for the square structure. The activation energy, of 3.9 eV, was independent of linewidth in the sub-micron range. Transformation times increased dramatically for decreasing linewidth, as the linewidth approached the grain size of the starting C49 phase. A kinetic model based on the density of nucleation sites as a function of linewidth and C49 grain size is proposed and shown to fit the data, for samples with two different C49 grain sizes.