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1. Mps1 expression is critical for chromosome orientation and segregation in yeast with high ploidy

Author

Gish M, Sartin A, LaVictoire R, Régis E. Meyer, Haworth D, and Harsha J

Subjects
Chromosome segregation, Mutant, Cancer cell, Chromosome, Ploidy, Prometaphase, Biology, Protein kinase A, Loss function, Cell biology
Abstract

In aneuploid cancer cells, the chromosome segregation apparatus is sensitive to increased chromosome number. The conserved protein kinase, Mps1, is a critical actor of this machinery, orienting the chromosomes properly on the spindle. Abnormally high levels of this kinase have been found in tumors with elevated chromosome number. However, it remains unclear, mechanistically, if and how cells with higher ploidy become dependent upon increased Mps1 levels. To answer these questions, we explored Mps1 dependence in yeast cells with increased sets of chromosomes. We discovered that having more chromosomes affects the ability of cells to orient chromosomes properly. The cells with increased numbers of chromosomes are particularly sensitive to the reduction of Mps1 activity. Inmps1loss of function mutants, cells display an extended prometaphase with a longer spindle and a delay in orienting properly the chromosomes. Altogether, our results suggest that increased numbers of chromosomes render cells more dependent on Mps1 for orienting chromosomes on the spindle. The phenomenon described here may be relevant in understanding why hyperdiploid cancer cells become excessively reliant on high Mps1 expression for successful chromosome segregation.Author summaryMost cells in solid tumors usually carry far more chromosomes than normal cells. Losing or gaining chromosomes during cell division can lead to aneuploidy (an abnormal number of chromosomes), cancer, and other diseases. Mps1 is a master regulator of cell division that is critical to keep the correct number chromosomes in each daughter cell. This master regulator has been shown to target and affect the function of various actors involved in cell division. Abnormally high levels of this master regulator are found in tumors with elevated chromosome numbers. The high levels of this regulator appear to be protecting these tumor cells. To answer if and how cells with higher ploidy become so dependent of Mps1, we generated yeast cells with increased set of chromosomes. Here, we report that cells with elevated chromosome number are particularly sensitive to the reduction of Mps1 level. In cells with higher ploidy and reduced level of Mps1, the progression during cell division is delayed. In the mutant cells, their ability to properly orient and segregate their chromosomes on the spindle is greatly reduced.

Published
2020
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2. Blood pressure-lowering effects of nifedipine/candesartan combinations in high-risk individuals: Subgroup analysis of the DISTINCT randomised trial

Author

Mancia, G, Cha, G, Gil-Extremera, B, Harvey, P, Lewin, AJ, Villa, G, Kjeldsen, SE, Agaiby, J, Aggarwal, N, Ainsworth, P, Akhras, R, Amaluan, V, Ballarin, A, Bardauskiene, L, Berra, FC, Blagden, M, Bodalia, B, Borghi, C, Bundy, C, Burgess, L, Buynak, R, Cafferata, A, Cahill, T, Capiau, L, Capuano, V, Casanova, R, Cecil, J, Chapman, J, Chilvers, M, Christensen, S, Cho, Y-H, Chung, W-B, Cipollone, F, Coca, A, Colombo, H, Contreras, EM, Crowley, D, Cusco-Prieto, B, Decarlini, F, Doh, J-H, Dzongowski, P, Dzyak, G, Ellery, A, Extremera, BG, Farias, E, Farrington, C, Fidelholtz, J, Fouche, L, Gabito, A, Gainza, M, Gani, M, Gaunt, R, Gelersztein, E, Giuliano, M, Glazunov, A, Glorioso, N, Goloschekin, B, Gumbley, M, Gupta, A, Guzman, L, Ha, J-W, Hart, R, Haworth, D, Henein, S, Henry, D, Her, S-H, Heyvaert, F, Hollanders, G, Hominal, M, Hong, B-K, Hong, T-J, Hwang, K-K, Jacovides, A, Jacqmein, J, Jeon, HK, Jones, N, Kanani, S, Kang, H, Karpenko, O, Kenton, D, Kimzey, N, Kovalenko, V, Kushnir, M, Lasko, B, Lee, KJ, Lee, N, Lewin, A, Litvak, M, Luksiene, D, Majul, C, Mannarino, E, Manuale, O, Marcadis, A, Miller, D, Mills, R, Misik, K, Mortelmans, J, O'Mahony, M, O'Mahony, W, Park, C, Pedrinelli, R, Petrulioniene, Z, Pettyjohn, F, Piskorz, D, Poss, G, Pudi, K, Pyun, WB, Raad, G, Raila, G, Ramirez Espinosa, MF, Ramlachan, P, Rhee, M, Rudenko, L, Ruiz, TS, Ryan, J, Schacter, G, Shin, J-H, Short, D, Sica, D, Sirenko, Y, Slapikas, R, Somani, R, Stanislavchuk, M, Stewart, R, Svishchenko, Y, Sychov, O, Teitelbaum, I, Tseluyko, V, Van Rensburg, DJ, Vaquer Perez, JV, Via, LM, Vico, M, Vizir, V, Vogel, D, Wellmann, H, Yoo, BS, DIPARTIMENTO DI SCIENZE MEDICHE E CHIRURGICHE, Facolta' di MEDICINA e CHIRURGIA, AREA MIN. 06 - Scienze mediche, Mancia, G, Cha, G, Gil-Extremera, B, Harvey, P, Lewin, A, Villa, G, Kjeldsen, S, Agaiby, J, Aggarwal, N, Ainsworth, P, Akhras, R, Amaluan, V, Ballarin, A, Bardauskiene, L, Berra, F, Blagden, M, Bodalia, B, Borghi, C, Bundy, C, Burgess, L, Buynak, R, Cafferata, A, Cahill, T, Capiau, L, Capuano, V, Casanova, R, Cecil, J, Chapman, J, Chilvers, M, Christensen, S, Cho, Y, Chung, W, Cipollone, F, Coca, A, Colombo, H, Contreras, E, Crowley, D, Cusco-Prieto, B, Decarlini, F, Doh, J, Dzongowski, P, Dzyak, G, Ellery, A, Extremera, B, Farias, E, Farrington, C, Fidelholtz, J, Fouche, L, Gabito, A, Gainza, M, Gani, M, Gaunt, R, Gelersztein, E, Giuliano, M, Glazunov, A, Glorioso, N, Goloschekin, B, Gumbley, M, Gupta, A, Guzman, L, Ha, J, Hart, R, Haworth, D, Henein, S, Henry, D, Her, S, Heyvaert, F, Hollanders, G, Hominal, M, Hong, B, Hong, T, Hwang, K, Jacovides, A, Jacqmein, J, Jeon, H, Jones, N, Kanani, S, Kang, H, Karpenko, O, Kenton, D, Kimzey, N, Kovalenko, V, Kushnir, M, Lasko, B, Lee, K, Lee, N, Litvak, M, Luksiene, D, Majul, C, Mannarino, E, Manuale, O, Marcadis, A, Miller, D, Mills, R, Misik, K, Mortelmans, J, O'Mahony, M, O'Mahony, W, Park, C, Pedrinelli, R, Petrulioniene, Z, Pettyjohn, F, Piskorz, D, Poss, G, Pudi, K, Pyun, W, Raad, G, Raila, G, Ramirez Espinosa, M, Ramlachan, P, Rhee, M, Rudenko, L, Ruiz, T, Ryan, J, Schacter, G, Shin, J, Short, D, Sica, D, Sirenko, Y, Slapikas, R, Somani, R, Stanislavchuk, M, Stewart, R, Svishchenko, Y, Sychov, O, Teitelbaum, I, Tseluyko, V, Van Rensburg, D, Vaquer Perez, J, Via, L, Vico, M, Vizir, V, Vogel, D, Wellmann, H, Yoo, B, Mancia, G., Cha, G., Gil-Extremera, B., Harvey, P., Lewin, A.J., Villa, G., Kjeldsen, S.E., Agaiby, J., Aggarwal, N., Ainsworth, P., Akhras, R., Amaluan, V., Ballarin, A., Bardauskiene, L., Berra, F.C., Blagden, M., Bodalia, B., Borghi, C., Bundy, C., Burgess, L., Buynak, R., Cafferata, A., Cahill, T., Capiau, L., Capuano, V., Casanova, R., Cecil, J., Chapman, J., Chilvers, M., Christensen, S., Cho, Y.-H., Chung, W.-B., Cipollone, F., Coca, A., Colombo, H., Contreras, E.M., Crowley, D., Cusco-Prieto, B., Decarlini, F., Doh, J.-H., Dzongowski, P., Dzyak, G., Ellery, A., Extremera, B.G., Farias, E., Farrington, C., Fidelholtz, J., Fouche, L., Gabito, A., Gainza, M., Gani, M., Gaunt, R., Gelersztein, E., Giuliano, M., Glazunov, A., Glorioso, N., Goloschekin, B., Gumbley, M., Gupta, A., Guzman, L., Ha, J.-W., Hart, R., Haworth, D., Henein, S., Henry, D., Her, S.-H., Heyvaert, F., Hollanders, G., Hominal, M., Hong, B.-K., Hong, T.-J., Hwang, K.-K., Jacovides, A., Jacqmein, J., Jeon, H.K., Jones, N., Kanani, S., Kang, H., Karpenko, O., Kenton, D., Kimzey, N., Kovalenko, V., Kushnir, M., Lasko, B., Lee, K.J., Lee, N., Lewin, A., Litvak, M., Luksiene, D., Majul, C., Mannarino, E., Manuale, O., Marcadis, A., Miller, D., Mills, R., Misik, K., Mortelmans, J., O'Mahony, M., O'Mahony, W., Park, C., Pedrinelli, R., Petrulioniene, Z., Pettyjohn, F., Piskorz, D., Poss, G., Pudi, K., Pyun, W.B., Raad, G., Raila, G., Ramirez Espinosa, M.F., Ramlachan, P., Rhee, M., Rudenko, L., Ruiz, T.S., Ryan, J., Schacter, G., Shin, J.-H., Short, D., Sica, D., Sirenko, Y., Slapikas, R., Somani, R., Stanislavchuk, M., Stewart, R., Svishchenko, Y., Sychov, O., Teitelbaum, I., Tseluyko, V., Van Rensburg, D.J., Vaquer Perez, J.V., Via, L.M., Vico, M., Vizir, V., Vogel, D., Wellmann, H., Yoo, B.S., DISTINCT Investigators, and [Mancia,G] Unit and Department of Clinical Medicine, University of Milano-Bicocca, IRCCS Istituto Auxologico Italiano, Milan, Italy. [Cha,G] KRK Medical Research Institute, Dallas, TX, USA. [Gil-Extremera,B] Hospital Universitario San Cecilio, Granada, Spain. [Harvey,P] Formerly in The Crouch Oak Family Practice, Addlestone, UK. [Lewin,AJ] National Research Institute, Los Angeles, CA, USA. [Villa,G] Fondazione Salvatore Maugeri—IRCCS, Pavia, Italy. [Kjeldsen,SE] Oslo University Hospital Ullevaal, University of Oslo, Oslo, Norway.

Subjects
Male, Chemicals and Drugs::Heterocyclic Compounds::Heterocyclic Compounds, 1-Ring::Pyridines::Dihydropyridines::Nifedipine [Medical Subject Headings], Phenomena and Processes::Physiological Phenomena::Body Constitution::Body Weights and Measures::Body Mass Index [Medical Subject Headings], Tetrazoles, Blood Pressure, DISTINCT study, Índice de masa corporal, 030204 cardiovascular system & hematology, Benzimidazole, Analytical, Diagnostic and Therapeutic Techniques and Equipment::Investigative Techniques::Epidemiologic Methods::Statistics as Topic::Probability::Risk::Risk Factors [Medical Subject Headings], law.invention, Organisms::Eukaryota::Animals::Chordata::Vertebrates::Mammals::Primates::Haplorhini::Catarrhini::Hominidae::Humans [Medical Subject Headings], Bencimidazoles, 0302 clinical medicine, Randomized controlled trial, law, Phenomena and Processes::Reproductive and Urinary Physiological Phenomena::Urinary Tract Physiological Phenomena::Glomerular Filtration Rate [Medical Subject Headings], Medicine, Tasa de filtración glomerular, 030212 general & internal medicine, Hipercolesterolemia, Tetrazole, Chemicals and Drugs::Heterocyclic Compounds::Heterocyclic Compounds, 2-Ring::Benzimidazoles [Medical Subject Headings], Middle Aged, Calcium Channel Blockers, Presión sanguínea, Humanos, Antihypertensive Agent, Chemicals and Drugs::Organic Chemicals::Hydrocarbons::Hydrocarbons, Cyclic::Hydrocarbons, Aromatic::Benzene Derivatives::Biphenyl Compounds [Medical Subject Headings], Hypertension, Diseases::Nutritional and Metabolic Diseases::Metabolic Diseases::Glucose Metabolism Disorders::Diabetes Mellitus::Diabetes Mellitus, Type 2 [Medical Subject Headings], Compuestos de bifenilo, Diabetes mellitus Tipo 2, Nifedipino, Original Article, Drug Therapy, Combination, Female, Calcium Channel Blocker, Factores de riesgo, medicine.drug, Human, medicine.medical_specialty, Combination therapy, Nifedipine, Subgroup analysis, Placebo, Nifedipine GITS, Diseases::Cardiovascular Diseases::Vascular Diseases::Hypertension [Medical Subject Headings], 03 medical and health sciences, candesartan, high blood pressure, Internal medicine, Hipertensión, Phenomena and Processes::Circulatory and Respiratory Physiological Phenomena::Cardiovascular Physiological Phenomena::Hemodynamics::Blood Pressure [Medical Subject Headings], Internal Medicine, Humans, Antihypertensive Agents, business.industry, Biphenyl Compounds, Diseases::Nutritional and Metabolic Diseases::Metabolic Diseases::Lipid Metabolism Disorders::Dyslipidemias::Hyperlipidemias::Hypercholesterolemia [Medical Subject Headings], Chemicals and Drugs::Heterocyclic Compounds::Heterocyclic Compounds, 1-Ring::Azoles::Tetrazoles [Medical Subject Headings], Candesartan, Endocrinology, Blood pressure, Benzimidazoles, business, Body mass index
Abstract

none 140 si The DISTINCT study (reDefining Intervention with Studies Testing Innovative Nifedipine GITS - Candesartan Therapy) investigated the efficacy and safety of nifedipine GITS/candesartan cilexetil combinations vs respective monotherapies and placebo in patients with hypertension. This descriptive sub-analysis examined blood pressure (BP)-lowering effects in high-risk participants, including those with renal impairment (estimated glomerular filtration rate

Published
2017

3. Large-Eddy Simulation of in-Cylinder Flows Simulation à grande échelle des écoulements internes dans les moteurs

Author

Haworth D. C.

Subjects
lcsh:TP1-1185, lcsh:Chemical technology, lcsh:HD9502-9502.5, lcsh:Energy industries. Energy policy. Fuel trade
Abstract

Advances in physical models, numerical methods, and computational power together have brought large-eddy simulation (LES) to the point where it warrants serious consideration for computing in-cylinder turbulent flows. This article includes: a discussion of LES and how it differs from Reynolds-averaged Navier Stokes (RANS) modeling; motivation for transitioning to LES for in-cylinder flow in IC engines; and quantitative results for two motored engine configurations. Dynamicsubgrid-scale stress models are emphasized, and results from two different numerical approaches are discussed. Compared to RANS, LES requires a low level of empirical input, provides more complete information on in-cylinder flow structure, and makes previously inaccessible phenomena (e. g. , cycle-to-cycle variability) amenable to analysis. Les progrès des modèles physiques, des méthodes numériques et de la puissance de calcul permettent qu'on puisse prendre en considération les simulations à grande échelle (LES) pour le calcul des écoulements turbulents dans les moteurs. La synthèse présentée comprend : une discussion sur la LES montrant ses différences avec la modélisation aux moyennes de Reynolds (RANS) ; les motivations pour passer à la LES pour les écoulements internes aux moteurs ; des résultats quantitatifs pour deux configurations de moteur entraîné. Des modèles de sous-maille dynamiquedes tenseurs sont développés, par ailleurs, nous discutons des résultats donnés par deux approches numériques différentes. En comparaison avec la méthodologie RANS, la LES requiert peu d'apports empiriques, donne plus de détails sur la structure de l'écoulement dans le cylindre et permet l'analyse de phénomènes jusqu'alors inaccessibles, comme les variations cycliques.

Published
2006

4. Nifedipine plus candesartan combination increases blood pressure control regardless of race and improves the side effect profile: DISTINCT randomized trial results

Author

Kjeldsen, Sverre E, Sica, Domenic, Haller, Hermann, Cha, Gloria, Gil Extremera, Blas, Harvey, Peter, Heyvaert, Frank, Lewin, Andrew J., Villa, Giuseppe, Mancia, Giuseppe, the DISTINCT investigators: Agaiby, J, Aggarwal, N, Ainsworth, P, Akhras, R, Amaluan, V, Ballarin, A, Bardauskiene, L, Berra, Fc, Blagden, M, Bodalia, B, Borghi, C, Bundy, C, Burgess, L, Buynak, R, Cafferata, A, Cahill, T, Capiau, L, Capuano, V, Casanova, R, Cecil, J, Cha, G, Chapman, J, Chilvers, M, Christensen, S, Cho, Yh, Chung, Wb, Cipollone, F, Coca, A, Colombo, H, Contreras, Em, Crowley, D, Cusco Prieto, B, Decarlini, F, Doh, Jh, Dzongowski, P, Dzyak, G, Ellery, A, Extremera, Bg, Farias, E, Farrington, C, Fidelholtz, J, Fouche, L, Gabito, A, Gainza, M, Gani, M, Gaunt, R, Gelersztein, E, Giuliano, M, Glazunov, A, Glorioso, N, Goloschekin, B, Gumbley, M, Gupta, A, Guzman, L, Ha, Jw, Hart, R, Harvey, P, Haworth, D, Henein, S, Henry, D, Her, Sh, Heyvaert, F, Hollanders, G, Hominal, M, Hong, Bk, Hong, Tj, Hwang, Kk, Jacovides, A, Jacqmein, J, Jeon, Hk, Jones, N, Kanani, S, Kang, H, Karpenko, O, Kenton, D, Kimzey, N, Kjeldsen, Se, Kovalenko, V, Kushnir, M, Lasko, B, Lee, Kj, Lee, N, Lewin, A, Litvak, M, Luksiene, D, Majul, C, Mannarino, E, Manuale, O, Marcadis, A, Miller, D, Mills, R, Misik, K, Mortelmans, J, O'Mahony, M, O'Mahony, W, Park, C, Pedrinelli, Roberto, Petrulioniene, Z, Pettyjohn, F, Piskorz, D, Poss, G, Pudi, K, Pyun, Wb, Raad, G, Raila, G, Ramirez Espinosa MF, Ramlachan, P, Rhee, M, Rudenko, L, Ruiz, Ts, Ryan, J, Schacter, G, Shin, Jh, Short, D, Sica, D, Sirenko, Y, Slapikas, R, Somani, R, Stanislavchuk, M, Stewart, R, Svishchenko, Y, Sychov, O, Teitelbaum, I, Tseluyko, V, Van Rensburg DJ, Vaquer Perez JV, Via, Lm, Vico, M, Villa, G, Vizir, V, Vogel, D, Wellmann, H, Yoo, B. S., Kjeldsen, Sverre E, Sica, Domenic, Haller, Hermann, Cha, Gloria, Gil-Extremera, Bla, Harvey, Peter, Heyvaert, Frank, Lewin, Andrew J, Villa, Giuseppe, Mancia, Giuseppe, Borghi, Claudio, Kjeldsen, S, Sica, D, Haller, H, Cha, G, Gil-Extremera, B, Harvey, P, Heyvaert, F, Lewin, A, Villa, G, and Mancia, G

Subjects
Male, Physiology, Ethnic Group, Administration, Oral, Tetrazoles, Blood Pressure, DISTINCT study, Pharmacology, Benzimidazole, law.invention, combination therapy, Randomized controlled trial, candesartan cilexetil, combination therapy, DISTINCT study, essential hypertension, nifedipine GITS, vasodilatory side effects, law, Ethnicity, Tetrazole, Middle Aged, candesartan cilexetil, Biphenyl compound, Antihypertensive Agent, Treatment Outcome, Tolerability, Aged, Antihypertensive Agents, Benzimidazoles, Biphenyl Compounds, Double-Blind Method, Drug Therapy, Combination, Drug-Related Side Effects and Adverse Reactions, Ethnic Groups, Female, Humans, Hypertension, Nifedipine, Cardiology and Cardiovascular Medicine, Internal Medicine, Administration, Combination, Cardiology, Vasodilatory side effect, ORIGINAL PAPERS: Therapeutic aspects, medicine.drug, Human, Oral, medicine.medical_specialty, Side effect, Combination therapy, Drug Therapy, Internal medicine, medicine, vasodilatory side effects, business.industry, essential hypertension, nifedipine GITS, Candesartan, Blood pressure, Biphenyl Compound, business, Drug-Related Side Effects and Adverse Reaction
Abstract

Objectives: DISTINCT (reDefining Intervention with Studies Testing Innovative Nifedipine GITS – Candesartan Therapy) aimed to determine the dose–response and tolerability of nifedipine GITS and/or candesartan cilexetil therapy in participants with hypertension. Methods: In this 8-week, multinational, multicentre, randomized, double-blind, placebo-controlled study, adults with mean seated DBP of at least 95 to less than 110 mmHg received combination or monotherapy with nifedipine GITS (N) 20, 30 or 60 mg and candesartan cilexetil (C) 4, 8, 16 or 32 mg, or placebo. The primary endpoint, change in DBP from baseline to Week 8, was analysed using the response surface model (RSM); this analysis was repeated for mean seated SBP. Results: Overall, 1381 participants (mean baseline SBP/DBP: 156.5/99.6 mmHg) were randomized. Both N and C contributed independently to SBP/DBP reductions [P

Published
2014

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