33 results on '"Combe R"'
Search Results
2. Experimental characterization of a fast, pixelated CMOS sensor and design of a Recoil-Proton Telescope for neutron spectrometry
- Author
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Combe, R., primary, Arbor, N., additional, Higueret, S., additional, and Husson, D., additional
- Published
- 2019
- Full Text
- View/download PDF
3. Analysis of mammalian gene function through broad-based phenotypic screens across a consortium of mouse clinics
- Author
-
Hrabe de Angelis, M. (M), Nicholson, G. (G), Selloum, M. (Mohammed), White, J. (J) K. (K), Morgan, H. (H), Ramirez-Solis, R. (R), Sorg, T. (Tania), Wells, S. (S), Fuchs, H. (H), Fray, M. (M), Adams, D. (D) J. (J), Adams, N. (N) C. (C), Adler, T. (T), Aguilar-Pimentel, A. (A), Ali-Hadji, D. (Dalila), Amann, G. (Grégory), Andre, P. (Philippe), Atkins, S. (S), Auburtin, A. (Aurélie), Ayadi, A. (Abdelkader), Becker, J. (Julien), Becker, L. (L), Bedu, E. (Elodie), Bekeredjian, R. (R), Birling, M. (Marie-Christine), Blake, A. (A), Bottomley, J. (J), Bowl, M. (M) R. (R), Brault, V. (Véronique), Busch, D. (D) H. (H), Bussell, J. (J) N. (N), Calzada-Wack, J. (J), Cater, H. (H), Champy, M. (Marie-France), Charles, P. (Philippe), Chevalier, C. (Claire), Chiani, F. (F), Codner, G. (G) F. (F), Combe, R. (R), Cox, R. (R), Dalloneau, E. (E), Dierich, A. (A), Di Fenza, A. (A), Doe, B. (B), Duchon, A. (Arnaud), Eickelberg, O. (O), Esapa, C. (C) T. (T), Fertak, L. (L) E. (E), Feigel, T. (T), Emelyanova, I. (I), Estabel, J. (J), Favor, J. (J), Flenniken, A. (A), Gambadoro, A. (A), Garrett, L. (L), Gates, H. (H), Gerdin, A. (A) K. (K), Gkoutos, G. (G), Greenaway, S. (S), Glasl, L. (L), Goetz, P. (P), Da Cruz, I. (I) G. (G), Gotz, A. (A), Graw, J. (J), Guimond, A. (Alain), Hans, W. (W), Hicks, G. (G), Holter, S. (S) M. (M), Hofler, H. (H), Hancock, J. (J) M. (M), Hoehndorf, R. (R), Hough, T. (T), Houghton, R. (R), Hurt, A. (A), Ivandic, B. (B), Jacobs, H. (Hugues), Jacquot, S. (Sylvie), Jones, N. (N), Karp, N. (N) A. (A), Katus, H. (H) A. (A), Kitchen, S. (S), Klein-Rodewald, T. (T), Klingenspor, M. (M), Klopstock, T. (T), Lalanne, V. (Valérie), Leblanc, S. (Sophie), Lengger, C. (C), le Marchand, E. (Elise), Ludwig, T. (T), Lux, A. (Aline), McKerlie, C. (C), Maier, H. (H), Mandel, J. (Jean-Louis), Marschall, S. (S), Mark, M. (Manuel), Melvin, D. (D) G. (G), Meziane, H. (Hamid), Micklich, K. (K), Mittelhauser, C. (C), Monassier, L. (Laurent), Moulaert, D. (David), Muller, S. (Stéphanie), Naton, B. (B), Neff, F. (F), Nolan, P. (P) M. (M), Nutter, L. (L) M. (M), Ollert, M. (M), Pavlovic, G. (Guillaume), Pellegata, N. (N) S. (S), Peter, E. (E), Petit-Demouliere, B. (Benoît), Pickard, A. (A), Podrini, C. (C), Potter, P. (P), Pouilly, L. (Laurent), Puk, O. (O), Richardson, D. (D), Rousseau, S. (Stéphane), Quintanilla-Fend, L. (L), Quwailid, M. (M) M. (M), Racz, I. (I), Rathkolb, B. (B), Riet, F. (Fabrice), Rossant, J. (J), Roux, M. (Michel), Rozman, J. (J), Ryder, E. (E), Salisbury, J. (J), Santos, L. (L), Schable, K. (K) H. (H), Schiller, E. (E), Schrewe, A. (A), Schulz, H. (H), Steinkamp, R. (R), Simon, M. (M), Stewart, M. (M), Stoger, C. (C), Stoger, T. (T), Sun, M. (M), Sunter, D. (D), Teboul, L. (L), Tilly, I. (I), Tocchini-Valentini, G. (G) P. (P), Tost, M. (M), Treise, I. (I), Vasseur, L. (Laurent), Velot, E. (E), Vogt-Weisenhorn, D. (D), Wagner, C. (Christel), Walling, A. (A), Wattenhofer-Donze, M. (Marie), Weber, B. (Bruno), Wendling, O. (Olivia), Westerberg, H. (H), Willershauser, M. (M), Wolf, E. (E), Wolter, A. (A), Wood, J. (J), Wurst, W. (W), Yildirim, A. (A) O. (O), Zeh, R. (R), Zimmer, A. (A), Zimprich, A. (A), Consortium, E. (Eumodic), Holmes, C. (C), Steel, K. (K) P. (P), Herault, Y. (Yann), Gailus-Durner, V. (V), Mallon, A. (A) M. (M), and Brown, S. (S) D. (D)
- Subjects
Genetics ,Male ,Mice, Knockout ,Heterozygote ,Mutant ,Homozygote ,Aucun ,Molecular Sequence Annotation ,Biology ,Phenotype ,Mice, Inbred C57BL ,Pleiotropy ,ddc:570 ,Mutation ,Animals ,Humans ,Human genome ,Female ,Allele ,Gene ,Gene knockout ,Genetic Association Studies - Abstract
The function of the majority of genes in the mouse and human genomes remains unknown. The mouse embryonic stem cell knockout resource provides a basis for the characterization of relationships between genes and phenotypes. The EUMODIC consortium developed and validated robust methodologies for the broad-based phenotyping of knockouts through a pipeline comprising 20 disease-oriented platforms. We developed new statistical methods for pipeline design and data analysis aimed at detecting reproducible phenotypes with high power. We acquired phenotype data from 449 mutant alleles, representing 320 unique genes, of which half had no previous functional annotation. We captured data from over 27,000 mice, finding that 83% of the mutant lines are phenodeviant, with 65% demonstrating pleiotropy. Surprisingly, we found significant differences in phenotype annotation according to zygosity. New phenotypes were uncovered for many genes with previously unknown function, providing a powerful basis for hypothesis generation and further investigation in diverse systems. Comment in : Genetic differential calculus. [Nat Genet. 2015] Comment in : Scaling up phenotyping studies. [Nat Biotechnol. 2015]
- Published
- 2015
4. Old spontaneously hypertensive rats gather together typical features of human chronic left-ventricular dysfunction with preserved ejection fraction
- Author
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Marzak, H. (Halim), Ayme-Dietrich, E. (Estelle), Lawson, R. (Roland), Mokni, W. (Walid), Combe, R. (Roy), Becker, J. (Julien), El Fertak, L. (Lahcen) E. (E), Champy Methlin, M. (Marie-France), and Monassier, L. (Laurent)
- Subjects
cardiovascular system ,cardiovascular diseases ,Sciences du Vivant [q-bio]/Médecine humaine et pathologie - Abstract
OBJECTIVE: Heart failure with preserved left-ventricular ejection fraction (HF-PEF) is an entity leading to pulmonary congestion because of impaired diastolic filling. This syndrome usually strikes those who have experienced a long history of hypertension or metabolic risk factors. Pathophysiological mechanisms are not fully understood, and standard therapy is not established. Relevant preclinical models are still lacking. The aim of this work was to evaluate aging spontaneously hypertensive rats (SHRs) as a model of HF-PEF. METHODS: Serial echocardiographic and blood pressure (BP) measurements were performed in 28, 36, 43, 47 and 51-week-old SHRs and their normotensive controls (Wistar-Kyoto rats). In 52-53-week-old animals, final investigations included ECG, invasive left-ventricular (LV) and aortic catheterization, brain natriuretic peptide (BNP) plasma concentrations, ventricular reverse transcription-qPCR evaluations (beta-myosin heavy chain, atrial natriuretic peptide, BNP, sarco/endoplasmic reticulum calcium ATPase 2a and collagens 1a, 3a and 2a) and cardiac histology. RESULTS: SHRs develop a progressive alteration of the early diastole, some of the echocardiographic parameters being not sensitive to BP reduction by the calcium blocker, nicardipine. The systolic function evaluated by echocardiography and invasive catheterization was preserved. When the observation period was over, an increase in collagen synthesis and deposits were identified in subendocardial layers. This attested a probable myocardial ischemia that was confirmed by ECG changes of the ST segment. BNP increased in the blood and at the mRNA level in the myocardium. CONCLUSION: When aging, SHRs progressively develop HF-PEF showed by impaired LV relaxation and hypertrophy, BNP increase but preserved contractility and fibrosis. This model seems pertinent for further pharmacological preclinical studies in the field.
- Published
- 2014
5. Résultats théoriques et expérimentaux concernant les guides d’ondes chargés et les cavités partiellement coaxiales
- Author
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Combe, R. and Feix, M.
- Published
- 1960
- Full Text
- View/download PDF
6. Comptes rendus de livers
- Author
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Cardot, C., Combe, R., Villeneuve, R., and Poincelot, P.
- Published
- 1955
- Full Text
- View/download PDF
7. Conception of a New Recoil Proton Telescope for Real-Time Neutron Spectrometry in Proton-Therapy
- Author
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Combe Rodolphe, Arbor Nicolas, el Bitar Ziad, Higueret Stéphane, and Husson Daniel
- Subjects
Physics ,QC1-999 - Abstract
Neutrons are the main type of secondary particles emitted in proton-therapy. Because of the risk of secondary cancer and other late occurring effects, the neutron dose should be included in the out-of-field dose calculations. A neutron spectrometer has to be used to take into account the energy dependence of the neutron radiological weighting factor. Due to its high dependence on various parameters of the irradiation (beam, accelerator, patient), the neutron spectrum should be measured independently for each treatment. The current reference method for the measurement of the neutron energy, the Bonner Sphere System, consists of several homogeneous polyethylene spheres with increasing diameters equipped with a proportional counter. It provides a highresolution reconstruction of the neutron spectrum but requires a time-consuming work of signal deconvolution. New neutron spectrometers are being developed, but the main experimental limitation remains the high neutron flux in proton therapy treatment rooms. A new model of a real-time neutron spectrometer, based on a Recoil Proton Telescope technology, has been developed at the IPHC. It enables a real-time high-rate reconstruction of the neutron spectrum from the measurement of the recoil proton trajectory and energy. A new fast-readout microelectronic integrated sensor, called FastPixN, has been developed for this specific purpose.A first prototype, able to detect neutrons between 5 and 20 MeV, has already been validated for metrology with the AMANDE facility at Cadarache. The geometry of the new Recoil Proton Telescope has been optimized via extensive Geant4 Monte Carlo simulations. Uncertainty sources have been carefully studied in order to improve simultaneously efficiency and energy resolution, and solutions have been found to suppress the various expected backgrounds. We are currently upgrading the prototype for secondary neutron detection in proton therapy applications.
- Published
- 2018
- Full Text
- View/download PDF
8. Un accélérateur linéaire d'électrons de 2,3 MeV
- Author
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Frelot, Th., primary, Combe, R., additional, and Feix, M., additional
- Published
- 1956
- Full Text
- View/download PDF
9. New high-energy implosion seismic source
- Author
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Combe, R
- Published
- 1973
10. Differential physiological roles for BIN1 isoforms in skeletal muscle development, function and regeneration.
- Author
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Prokic I, Cowling BS, Kutchukian C, Kretz C, Tasfaout H, Gache V, Hergueux J, Wendling O, Ferry A, Toussaint A, Gavriilidis C, Nattarayan V, Koch C, Lainé J, Combe R, Tiret L, Jacquemond V, Pilot-Storck F, and Laporte J
- Subjects
- Animals, Animals, Newborn, Exons genetics, Feeding Behavior, Homozygote, Mice, Inbred C57BL, Muscle Fibers, Skeletal metabolism, Muscle Fibers, Skeletal ultrastructure, Muscle, Skeletal ultrastructure, Organ Specificity, Protein Isoforms metabolism, Sequence Deletion, Survival Analysis, Adaptor Proteins, Signal Transducing metabolism, Muscle Development physiology, Muscle, Skeletal physiology, Nerve Tissue Proteins metabolism, Regeneration physiology, Tumor Suppressor Proteins metabolism
- Abstract
Skeletal muscle development and regeneration are tightly regulated processes. How the intracellular organization of muscle fibers is achieved during these steps is unclear. Here, we focus on the cellular and physiological roles of amphiphysin 2 (BIN1), a membrane remodeling protein mutated in both congenital and adult centronuclear myopathies (CNM), that is ubiquitously expressed and has skeletal muscle-specific isoforms. We created and characterized constitutive muscle-specific and inducible Bin1 homozygous and heterozygous knockout mice targeting either ubiquitous or muscle-specific isoforms. Constitutive Bin1 -deficient mice died at birth from lack of feeding due to a skeletal muscle defect. T-tubules and other organelles were misplaced and altered, supporting a general early role for BIN1 in intracellular organization, in addition to membrane remodeling. Although restricted deletion of Bin1 in unchallenged adult muscles had no impact, the forced switch from the muscle-specific isoforms to the ubiquitous isoforms through deletion of the in-frame muscle-specific exon delayed muscle regeneration. Thus, ubiquitous BIN1 function is necessary for muscle development and function, whereas its muscle-specific isoforms fine tune muscle regeneration in adulthood, supporting that BIN1 CNM with congenital onset are due to developmental defects, whereas later onset may be due to regeneration defects., Competing Interests: Competing interestsB.S.C. and J. Laporte are co-founders of Dynacure, and B.S.C. is a Dynacure employee., (© 2020. Published by The Company of Biologists Ltd.)
- Published
- 2020
- Full Text
- View/download PDF
11. Atp6ap2 ablation in adult mice impairs viability through multiple organ deficiencies.
- Author
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Wendling O, Champy MF, Jaubert S, Pavlovic G, Dubos A, Lindner L, Jacobs H, Mark M, Combe R, Da Cruz IG, Luche H, Mudgett JS, Rosahl T, Sorg T, Malissen M, Reilly PT, and Hérault Y
- Subjects
- Animals, Gene Knockout Techniques, Mice, Survival Analysis, Multiple Organ Failure mortality, Multiple Organ Failure pathology, Proton-Translocating ATPases deficiency, Receptors, Cell Surface deficiency
- Abstract
ATP6AP2 codes for the (pro)renin receptor and is an essential component of vacuolar H+ ATPase. Activating (pro)renin for conversion of Angiotensinogen to Angiotensin makes ATP6AP2 attractive for drug intervention. Tissue-specific ATP6AP2 inactivation in mouse suggested a strong impact on various organs. Consistent with this, we found that embryonic ablation of Atp6ap2 resulted in both male hemizygous lethality and female haploinsufficiency. Next, we examined the phenotype of an induced inactivation in the adult animal, most akin to detect potential effect of functional interference of ATP6AP2 through drug therapy. Induced ablation of Atp6ap2, even without equal efficiency in all tissues (aorta, brain and kidney), resulted in rapid lethality marked by weight loss, changes in nutritional as well as blood parameters, leukocyte depletion, and bone marrow hypoplasia. Upon Atp6ap2 ablation, the colon demonstrated a rapid disruption of crypt morphology, aberrant proliferation, cell-death activation, as well as generation of microadenomas. Consequently, disruption of ATP6AP2 is extremely poorly tolerated in the adult, and severely affects various organ systems demonstrating that ATP6AP2 is an essential gene implicated in basic cellular mechanisms and necessary for multiple organ function. Accordingly, any potential drug targeting of this gene product must be strictly assessed for safety.
- Published
- 2017
- Full Text
- View/download PDF
12. Mfn2 is critical for brown adipose tissue thermogenic function.
- Author
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Boutant M, Kulkarni SS, Joffraud M, Ratajczak J, Valera-Alberni M, Combe R, Zorzano A, and Cantó C
- Subjects
- Animals, GTP Phosphohydrolases deficiency, Mice, Mice, Knockout, Perilipin-1 metabolism, Protein Binding, Adipose Tissue, Brown metabolism, GTP Phosphohydrolases metabolism, Mitochondria metabolism, Thermogenesis
- Abstract
Mitochondrial fusion and fission events, collectively known as mitochondrial dynamics, act as quality control mechanisms to ensure mitochondrial function and fine-tune cellular bioenergetics. Defective mitofusin 2 (Mfn2) expression and enhanced mitochondrial fission in skeletal muscle are hallmarks of insulin-resistant states. Interestingly, Mfn2 is highly expressed in brown adipose tissue (BAT), yet its role remains unexplored. Using adipose-specific Mfn2 knockout (Mfn2-adKO) mice, we demonstrate that Mfn2, but not Mfn1, deficiency in BAT leads to a profound BAT dysfunction, associated with impaired respiratory capacity and a blunted response to adrenergic stimuli. Importantly, Mfn2 directly interacts with perilipin 1, facilitating the interaction between the mitochondria and the lipid droplet in response to adrenergic stimulation. Surprisingly, Mfn2-adKO mice were protected from high-fat diet-induced insulin resistance and hepatic steatosis. Altogether, these results demonstrate that Mfn2 is a mediator of mitochondria to lipid droplet interactions, influencing lipolytic processes and whole-body energy homeostasis., (© 2017 The Authors. Published under the terms of the CC BY NC ND 4.0 license.)
- Published
- 2017
- Full Text
- View/download PDF
13. Real-time detection of fast and thermal neutrons in radiotherapy with CMOS sensors.
- Author
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Arbor N, Higueret S, Elazhar H, Combe R, Meyer P, Dehaynin N, Taupin F, and Husson D
- Subjects
- Gamma Rays therapeutic use, Monte Carlo Method, Radiometry instrumentation, Radiotherapy methods, Radiotherapy Dosage, Fast Neutrons therapeutic use, Radiotherapy instrumentation
- Abstract
The peripheral dose distribution is a growing concern for the improvement of new external radiation modalities. Secondary particles, especially photo-neutrons produced by the accelerator, irradiate the patient more than tens of centimeters away from the tumor volume. However the out-of-field dose is still not estimated accurately by the treatment planning softwares. This study demonstrates the possibility of using a specially designed CMOS sensor for fast and thermal neutron monitoring in radiotherapy. The 14 microns-thick sensitive layer and the integrated electronic chain of the CMOS are particularly suitable for real-time measurements in γ/n mixed fields. An experimental field size dependency of the fast neutron production rate, supported by Monte Carlo simulations and CR-39 data, has been observed. This dependency points out the potential benefits of a real-time monitoring of fast and thermal neutron during beam intensity modulated radiation therapies.
- Published
- 2017
- Full Text
- View/download PDF
14. How Does Circadian Rhythm Impact Salt Sensitivity of Blood Pressure in Mice? A Study in Two Close C57Bl/6 Substrains.
- Author
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Combe R, Mudgett J, El Fertak L, Champy MF, Ayme-Dietrich E, Petit-Demoulière B, Sorg T, Herault Y, Madwed JB, and Monassier L
- Subjects
- Animals, Blood Pressure Determination methods, Diet, Sodium-Restricted, Heart Rate drug effects, Heart Rate physiology, Hypertension chemically induced, Male, Mice, Inbred C57BL genetics, Potassium blood, Potassium pharmacology, Potassium urine, Sodium blood, Sodium urine, Sodium Chloride, Dietary adverse effects, Sodium, Dietary adverse effects, Sodium, Dietary pharmacology, Telemetry, Blood Pressure drug effects, Blood Pressure physiology, Circadian Rhythm physiology, Hypertension physiopathology, Sodium Chloride, Dietary pharmacology
- Abstract
Background: Mouse transgenesis has provided the unique opportunity to investigate mechanisms underlying sodium kidney reabsorption as well as end organ damage. However, understanding mouse background and the experimental conditions effects on phenotypic readouts of engineered mouse lines such as blood pressure presents a challenge. Despite the ability to generate high sodium and chloride plasma levels during high-salt diet, observed changes in blood pressure are not consistent between wild-type background strains and studies., Methods: The present work was designed in an attempt to determine guidelines in the field of salt-induced hypertension by recording continuously blood pressure by telemetry in mice submitted to different sodium and potassium loaded diets and changing experimental conditions in both C57BL/6N and C57BL/6J mice strain (Normal salt vs. Low salt vs. High-salt/normal potassium vs. High salt/low potassium, standard vs. modified light cycle, Non-invasive tail cuff blood pressure vs. telemetry)., Results: In this study, we have shown that, despite a strong blood pressure (BP) basal difference between C57BL/6N and C57BL/6J mice, High salt/normal potassium diet increases BP and heart rate during the active phase only (dark period) in the same extent in both strains. On the other hand, while potassium level has no effect on salt-induced hypertension in C57BL/6N mice, high-salt/low potassium diet amplifies the effect of the high-salt challenge only in C57BL/6J mice. Indeed, in this condition, salt-induced hypertension can also be detected during light period even though this BP increase is lower compared to the one occurring during the dark period. Finally, from a methodological perspective, light cycle inversion has no effect on this circadian BP phenotype and tail-cuff method is less sensitive than telemetry to detect BP phenotypes due to salt challenges., Conclusions: Therefore, to carry investigations on salt-induced hypertension in mice, chronic telemetry and studies in the active phase are essential prerequisites.
- Published
- 2016
- Full Text
- View/download PDF
15. Contribution of serotonin to cardiac remodeling associated with hypertensive diastolic ventricular dysfunction in rats.
- Author
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Ayme-Dietrich E, Marzak H, Lawson R, Mokni W, Wendling O, Combe R, Becker J, El Fertak L, Champy MF, Matz R, Andriantsitohaina R, Doly S, Boutourlinsky K, Maroteaux L, and Monassier L
- Subjects
- Animals, Blood Pressure physiology, Echocardiography, Heart Failure metabolism, Heart Failure physiopathology, Heart Ventricles drug effects, Heart Ventricles metabolism, Heart Ventricles physiopathology, Hypertension physiopathology, Hypertrophy, Left Ventricular physiopathology, Male, Mice, Mice, Knockout, Natriuretic Peptide, Brain metabolism, Pyrimidines pharmacology, Rats, Rats, Inbred SHR, Receptor, Serotonin, 5-HT2A genetics, Receptor, Serotonin, 5-HT2A metabolism, Receptor, Serotonin, 5-HT2B genetics, Receptor, Serotonin, 5-HT2B metabolism, Ventricular Dysfunction, Left physiopathology, Blood Pressure drug effects, Hypertension metabolism, Hypertrophy, Left Ventricular metabolism, Serotonin metabolism, Serotonin Antagonists pharmacology, Ventricular Dysfunction, Left metabolism
- Abstract
Objective: Left-ventricular hypertrophy and interstitial fibrosis are the main pathophysiological factors of heart failure with preserved ejection fraction. Blockade of the serotonin 5-HT2B receptor (5-HT2BR) has been shown to reduce cardiac hypertrophy, oxidative stress, and extracellular cell matrix activation. In this study, we evaluated the effects of the 5-HT2BR blockade, on hemodynamic and cardiac remodeling, in spontaneously hypertensive rats (SHRs) that display a diastolic dysfunction with preserved ejection fraction., Method: Thirty-seven-week-old SHRs were randomized in four groups receiving either saline, the selective 5-HT2BR antagonist RS-127445 (1 mg/kg per day), a calcium channel blocker nicardipine (6 mg/kg per day), or RS-127445 + nicardipine. During the 14 weeks of treatment period, cardiac function and blood pressure were monitored by echocardiography and tail-cuff. Finally, electrocardiograms and invasive hemodynamics were obtained before blood collection. Heart was analyzed for morphology and mRNA expression. A complementary study evaluated the cardiac and vascular effects of serotonin on wild-type and mice knockout for the 5-HT2BR (Htr2B) and/or the 5-HT2AR (Htr2A)., Results: Despite the left ventricular 5-HT2BR overexpression, 5-HT2BR blockade by RS-127445 did not affect left ventricular hypertrophy and fibrosis in SHRs. This antagonist did not improve diastolic dysfunction, neither alone nor in combination with nicardipine, although it induced plasma brain natriuretic peptide decrease. Moreover, RS-127445 amplified subendocardial fibrosis and favored left ventricular dilatation. Finally, a subendocardial left ventricular fibrosis was induced by chronic serotonin in wild-type mice, which was increased in Htr2B animals, but prevented in Htr2A and Htr2A/2B mice, and could be explained by a contribution of the endothelial 5-HT2BRs to coronary vasodilatation., Conclusion: This work is the first to identify a cardioprotective function of the 5-HT2BR in an integrated model of diastolic dysfunction with preserved ejection fraction.
- Published
- 2015
- Full Text
- View/download PDF
16. Analysis of mammalian gene function through broad-based phenotypic screens across a consortium of mouse clinics.
- Author
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de Angelis MH, Nicholson G, Selloum M, White J, Morgan H, Ramirez-Solis R, Sorg T, Wells S, Fuchs H, Fray M, Adams DJ, Adams NC, Adler T, Aguilar-Pimentel A, Ali-Hadji D, Amann G, André P, Atkins S, Auburtin A, Ayadi A, Becker J, Becker L, Bedu E, Bekeredjian R, Birling MC, Blake A, Bottomley J, Bowl M, Brault V, Busch DH, Bussell JN, Calzada-Wack J, Cater H, Champy MF, Charles P, Chevalier C, Chiani F, Codner GF, Combe R, Cox R, Dalloneau E, Dierich A, Di Fenza A, Doe B, Duchon A, Eickelberg O, Esapa CT, El Fertak L, Feigel T, Emelyanova I, Estabel J, Favor J, Flenniken A, Gambadoro A, Garrett L, Gates H, Gerdin AK, Gkoutos G, Greenaway S, Glasl L, Goetz P, Da Cruz IG, Götz A, Graw J, Guimond A, Hans W, Hicks G, Hölter SM, Höfler H, Hancock JM, Hoehndorf R, Hough T, Houghton R, Hurt A, Ivandic B, Jacobs H, Jacquot S, Jones N, Karp NA, Katus HA, Kitchen S, Klein-Rodewald T, Klingenspor M, Klopstock T, Lalanne V, Leblanc S, Lengger C, le Marchand E, Ludwig T, Lux A, McKerlie C, Maier H, Mandel JL, Marschall S, Mark M, Melvin DG, Meziane H, Micklich K, Mittelhauser C, Monassier L, Moulaert D, Muller S, Naton B, Neff F, Nolan PM, Nutter LM, Ollert M, Pavlovic G, Pellegata NS, Peter E, Petit-Demoulière B, Pickard A, Podrini C, Potter P, Pouilly L, Puk O, Richardson D, Rousseau S, Quintanilla-Fend L, Quwailid MM, Racz I, Rathkolb B, Riet F, Rossant J, Roux M, Rozman J, Ryder E, Salisbury J, Santos L, Schäble KH, Schiller E, Schrewe A, Schulz H, Steinkamp R, Simon M, Stewart M, Stöger C, Stöger T, Sun M, Sunter D, Teboul L, Tilly I, Tocchini-Valentini GP, Tost M, Treise I, Vasseur L, Velot E, Vogt-Weisenhorn D, Wagner C, Walling A, Weber B, Wendling O, Westerberg H, Willershäuser M, Wolf E, Wolter A, Wood J, Wurst W, Yildirim AÖ, Zeh R, Zimmer A, Zimprich A, Holmes C, Steel KP, Herault Y, Gailus-Durner V, Mallon AM, and Brown SD
- Subjects
- Animals, Female, Heterozygote, Homozygote, Humans, Male, Mice, Inbred C57BL, Mice, Knockout, Molecular Sequence Annotation, Mutation, Phenotype, Genetic Association Studies
- Abstract
The function of the majority of genes in the mouse and human genomes remains unknown. The mouse embryonic stem cell knockout resource provides a basis for the characterization of relationships between genes and phenotypes. The EUMODIC consortium developed and validated robust methodologies for the broad-based phenotyping of knockouts through a pipeline comprising 20 disease-oriented platforms. We developed new statistical methods for pipeline design and data analysis aimed at detecting reproducible phenotypes with high power. We acquired phenotype data from 449 mutant alleles, representing 320 unique genes, of which half had no previous functional annotation. We captured data from over 27,000 mice, finding that 83% of the mutant lines are phenodeviant, with 65% demonstrating pleiotropy. Surprisingly, we found significant differences in phenotype annotation according to zygosity. New phenotypes were uncovered for many genes with previously unknown function, providing a powerful basis for hypothesis generation and further investigation in diverse systems.
- Published
- 2015
- Full Text
- View/download PDF
17. Old spontaneously hypertensive rats gather together typical features of human chronic left-ventricular dysfunction with preserved ejection fraction.
- Author
-
Marzak H, Ayme-Dietrich E, Lawson R, Mokni W, Combe R, Becker J, Fertak LE, Champy MF, and Monassier L
- Subjects
- Animals, Blood Pressure, Body Weight, Collagen metabolism, Disease Models, Animal, Echocardiography, Fibrosis, Gene Expression Profiling, Gene Expression Regulation, Heart Failure physiopathology, Heart Rate, Heart Ventricles pathology, Humans, Male, Myocardial Contraction, Rats, Rats, Inbred SHR, Risk Factors, Ultrasonography, Doppler, Ventricular Function, Left, Aging, Diastole, Ventricular Dysfunction, Left physiopathology
- Abstract
Objective: Heart failure with preserved left-ventricular ejection fraction (HF-PEF) is an entity leading to pulmonary congestion because of impaired diastolic filling. This syndrome usually strikes those who have experienced a long history of hypertension or metabolic risk factors. Pathophysiological mechanisms are not fully understood, and standard therapy is not established. Relevant preclinical models are still lacking. The aim of this work was to evaluate aging spontaneously hypertensive rats (SHRs) as a model of HF-PEF., Methods: Serial echocardiographic and blood pressure (BP) measurements were performed in 28, 36, 43, 47 and 51-week-old SHRs and their normotensive controls (Wistar-Kyoto rats). In 52-53-week-old animals, final investigations included ECG, invasive left-ventricular (LV) and aortic catheterization, brain natriuretic peptide (BNP) plasma concentrations, ventricular reverse transcription-qPCR evaluations (β-myosin heavy chain, atrial natriuretic peptide, BNP, sarco/endoplasmic reticulum calcium ATPase 2a and collagens 1a, 3a and 2a) and cardiac histology., Results: SHRs develop a progressive alteration of the early diastole, some of the echocardiographic parameters being not sensitive to BP reduction by the calcium blocker, nicardipine. The systolic function evaluated by echocardiography and invasive catheterization was preserved. When the observation period was over, an increase in collagen synthesis and deposits were identified in subendocardial layers. This attested a probable myocardial ischemia that was confirmed by ECG changes of the ST segment. BNP increased in the blood and at the mRNA level in the myocardium., Conclusion: When aging, SHRs progressively develop HF-PEF showed by impaired LV relaxation and hypertrophy, BNP increase but preserved contractility and fibrosis. This model seems pertinent for further pharmacological preclinical studies in the field.
- Published
- 2014
- Full Text
- View/download PDF
18. A comparative phenotypic and genomic analysis of C57BL/6J and C57BL/6N mouse strains.
- Author
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Simon MM, Greenaway S, White JK, Fuchs H, Gailus-Durner V, Wells S, Sorg T, Wong K, Bedu E, Cartwright EJ, Dacquin R, Djebali S, Estabel J, Graw J, Ingham NJ, Jackson IJ, Lengeling A, Mandillo S, Marvel J, Meziane H, Preitner F, Puk O, Roux M, Adams DJ, Atkins S, Ayadi A, Becker L, Blake A, Brooker D, Cater H, Champy MF, Combe R, Danecek P, di Fenza A, Gates H, Gerdin AK, Golini E, Hancock JM, Hans W, Hölter SM, Hough T, Jurdic P, Keane TM, Morgan H, Müller W, Neff F, Nicholson G, Pasche B, Roberson LA, Rozman J, Sanderson M, Santos L, Selloum M, Shannon C, Southwell A, Tocchini-Valentini GP, Vancollie VE, Westerberg H, Wurst W, Zi M, Yalcin B, Ramirez-Solis R, Steel KP, Mallon AM, de Angelis MH, Herault Y, and Brown SD
- Subjects
- Animals, Behavior, Animal, Disease Resistance immunology, Eye pathology, Female, Femur diagnostic imaging, Hypersensitivity immunology, INDEL Mutation genetics, Killer Cells, Natural immunology, Listeriosis immunology, Listeriosis microbiology, Male, Maze Learning, Mice, Inbred C57BL, Phenotype, Polymorphism, Single Nucleotide genetics, Spleen immunology, X-Ray Microtomography, Genome genetics
- Abstract
Background: The mouse inbred line C57BL/6J is widely used in mouse genetics and its genome has been incorporated into many genetic reference populations. More recently large initiatives such as the International Knockout Mouse Consortium (IKMC) are using the C57BL/6N mouse strain to generate null alleles for all mouse genes. Hence both strains are now widely used in mouse genetics studies. Here we perform a comprehensive genomic and phenotypic analysis of the two strains to identify differences that may influence their underlying genetic mechanisms., Results: We undertake genome sequence comparisons of C57BL/6J and C57BL/6N to identify SNPs, indels and structural variants, with a focus on identifying all coding variants. We annotate 34 SNPs and 2 indels that distinguish C57BL/6J and C57BL/6N coding sequences, as well as 15 structural variants that overlap a gene. In parallel we assess the comparative phenotypes of the two inbred lines utilizing the EMPReSSslim phenotyping pipeline, a broad based assessment encompassing diverse biological systems. We perform additional secondary phenotyping assessments to explore other phenotype domains and to elaborate phenotype differences identified in the primary assessment. We uncover significant phenotypic differences between the two lines, replicated across multiple centers, in a number of physiological, biochemical and behavioral systems., Conclusions: Comparison of C57BL/6J and C57BL/6N demonstrates a range of phenotypic differences that have the potential to impact upon penetrance and expressivity of mutational effects in these strains. Moreover, the sequence variants we identify provide a set of candidate genes for the phenotypic differences observed between the two strains.
- Published
- 2013
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19. Absence of TI-VAMP/Vamp7 leads to increased anxiety in mice.
- Author
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Danglot L, Zylbersztejn K, Petkovic M, Gauberti M, Meziane H, Combe R, Champy MF, Birling MC, Pavlovic G, Bizot JC, Trovero F, Della Ragione F, Proux-Gillardeaux V, Sorg T, Vivien D, D'Esposito M, and Galli T
- Subjects
- Animals, Anxiety etiology, Anxiety psychology, COS Cells, Cells, Cultured, Chlorocebus aethiops, Male, Mice, Mice, 129 Strain, Mice, Inbred C57BL, Mice, Knockout, Rabbits, Anxiety genetics, Metalloendopeptidases administration & dosage, R-SNARE Proteins deficiency, R-SNARE Proteins genetics, Tetanus Toxin administration & dosage
- Abstract
Vesicular (v)- and target (t)-SNARE proteins assemble in SNARE complex to mediate membrane fusion. Tetanus neurotoxin-insensitive vesicular-associated membrane protein (TI-VAMP/VAMP7), a vesicular SNARE expressed in several cell types including neurons, was previously shown to play a major role in exocytosis involved in neurite growth in cultured neurons. Here we generated a complete constitutive knock-out by deleting the exon 3 of Vamp7. Loss of TI-VAMP expression did not lead to any striking developmental or neurological defect. Knock-out mice displayed decreased brain weight and increased third ventricle volume. Axon growth appeared normal in cultured knock-out neurons. Behavioral characterization unraveled that TI-VAMP knock-out was associated with increased anxiety. Our results thus suggest compensatory mechanisms allowing the TI-VAMP knock-out mice to fulfill major developmental processes. The phenotypic traits unraveled here further indicate an unexpected role of TI-VAMP-mediated vesicular traffic in anxiety and suggest a role for TI-VAMP in higher brain functions.
- Published
- 2012
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20. Identification of the UBP1 locus as a critical blood pressure determinant using a combination of mouse and human genetics.
- Author
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Koutnikova H, Laakso M, Lu L, Combe R, Paananen J, Kuulasmaa T, Kuusisto J, Häring HU, Hansen T, Pedersen O, Smith U, Hanefeld M, Williams RW, and Auwerx J
- Subjects
- Adult, Aged, Animals, Cohort Studies, DNA-Binding Proteins metabolism, Female, Humans, Hypertension physiopathology, Male, Mice, Mice, Inbred Strains, Middle Aged, Pedigree, Polymorphism, Single Nucleotide, Quantitative Trait Loci, Transcription Factors metabolism, Blood Pressure, DNA-Binding Proteins genetics, Hypertension genetics, Transcription Factors genetics
- Abstract
Hypertension is a major health problem of largely unknown genetic origins. To identify new genes responsible for hypertension, genetic analysis of recombinant inbred strains of mice followed by human association studies might prove powerful and was exploited in our current study. Using a set of 27 recombinant BXD strains of mice we identified a quantitative trait locus (QTL) for blood pressure (BP) on distal chromosome 9. The association analysis of markers encompassing the syntenic region on human chromosome 3 gave in an additive genetic model the strongest association for rs17030583 C/T and rs2291897 G/A, located within the UBP1 locus, with systolic and diastolic BP (rs17030583: 1.3+/-0.4 mmHg p<0.001, 0.8+/-0.3 mmHg p = 0.006, respectively and rs2291897: 1.5+/-0.4 mmHg p<0.001, 0.8+/-0.3 mmHg p = 0.003, respectively) in three separate studies. Our study, which underscores the marked complementarities of mouse and human genetic approaches, identifies the UBP1 locus as a critical blood pressure determinant. UBP1 plays a role in cholesterol and steroid metabolism via the transcriptional activation of CYP11A, the rate-limiting enzyme in pregnenolone and aldosterone biosynthesis. We suggest that UBP1 and its functional partners are components of a network controlling blood pressure., Competing Interests: The authors have declared that no competing interests exist.
- Published
- 2009
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21. The monosodium iodoacetate model of osteoarthritis: a model of chronic nociceptive pain in rats?
- Author
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Combe R, Bramwell S, and Field MJ
- Subjects
- Analysis of Variance, Animals, Chronic Disease, Enzyme Inhibitors, Functional Laterality, Hyperalgesia physiopathology, Male, Morphine therapeutic use, Osteoarthritis drug therapy, Osteoarthritis physiopathology, Pain drug therapy, Pain Measurement methods, Rats, Rats, Sprague-Dawley, Time Factors, Weight-Bearing physiology, Disease Models, Animal, Iodoacetates, Osteoarthritis chemically induced, Pain physiopathology
- Abstract
Osteoarthritis (OA) is a widespread condition affecting the elderly population. One of the most prominent features but least studied symptoms is chronic pain associated with OA. The study objective was to determine pain endpoints in rats with monosodium iodoacetate (MIA) induced OA, and to investigate the efficacy of common nociceptive agents. Sprague-Dawley rats received an intraarticular injection of either 25 microl 80 mg/ml MIA or 25 microl 0.9% sterile saline into the right knee joint. Changes in von Frey thresholds and latencies to stroking with a cotton bud (punctate and dynamic allodynia, respectively) were measured pre- and for up to 10 weeks post-intraarticular injection. Changes in hind paw weight distribution were also determined. Both punctate allodynia and a weight bearing deficit were observed in MIA-treated rats for up to 10 weeks. Interestingly, dynamic allodynia was not detected at any time point tested. Morphine (0.3-3 mg/kg, s.c.) and tramadol (3-100 mg/kg, p.o.) dose-dependently inhibited punctate allodynia and partially reversed weight bearing deficit. In conclusion, the MIA model of OA is reproducible and mimics OA pain in humans. Analgesic drug studies indicate this model may be useful for investigating chronic nociceptive pain.
- Published
- 2004
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22. Evaluation of the quality of generic polymethylmethacrylate intraocular lenses marketed in India.
- Author
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Combe R, Watkins R, and Brian G
- Subjects
- Biocompatible Materials standards, Humans, India, Prescriptions, Quality Control, Therapeutic Equivalency, Visual Acuity, Lenses, Intraocular standards, Manufactured Materials standards, Polymethyl Methacrylate
- Abstract
Purpose: To determine the quality of single-piece, allpolymethylmethacrylate (PMMA) Intraocular lenses (IOLs) from eght generic manufacturers marketing their product in India. This assessment of quality was made with respect to compliance with internationa standards for the manufacture of IOLs, specifically those parameters most likely to affect patient postoperat ve visual acuity and the long-term biocompatibility of the implanted lens., Methods: Ten IOLs from each of eight manufacturers were purchased randomly from commercial retail outlets in India. Each IOL, in a masked fashion, had its physical dimensions, optical performance and cosmetic appearance assessed, using the methods prescribed in ISO 11979-2 and 11979-3. Validation of manufacturing process controls were determined by statistical process contro techniques. Four IOLs from each manufacturer were also tested for the presence of unpolymerized PMMA using gas chromatography., Results: Only lenses from two IOL manufacturers complied with the optical and mechanical standards. All other manufacturers' lenses failed one or more of these tests. Intraocular lenses from only two producers met with surface quality and bulk homogeneity standards. All others exhibited defects such as surface contamination and scratches, poor polishing, and chipped or rough positioning holes. Lenses from two producers exhibited high levels of methylmethacrylate monomer (MMA)., Conclusions: Non-clinical grade PMMA starting material may have been used in the manufacture of IOLs by some producers. Critical manufacturing defects occurred in the IOLs from five of the eight producers tested. Only one manufacturer's IOLs met all specifications, and on statistical analysis demonstrated good manufacturing process contro with respect to the properties tested. With the widespread acceptance of IOL implantation in developing countries, such as India, it is essential that in the rush to make this the norm, the quality of implants used not be overlooked.
- Published
- 2001
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23. [Pancreatic cyto-steatonecrosis and pancreatic-pleural fistula: successful surgical management].
- Author
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Grand L, Combe R, Klisnick A, and Foulon D
- Subjects
- Adult, Humans, Male, Necrosis, Pancreas pathology, Pancreas surgery, Treatment Outcome, Fat Necrosis surgery, Pancreatic Fistula surgery, Pleura surgery
- Published
- 1999
24. [Blood disorders in a premature infant after guanethidine and hydrochlorothiazide administration during pregnancy].
- Author
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Combe R
- Subjects
- Humans, Infant, Newborn, Leukopenia etiology, Male, Purpura etiology, Thrombocytopenia etiology, Fetus drug effects, Guanethidine adverse effects, Hematologic Diseases etiology, Hydrochlorothiazide adverse effects, Infant, Premature, Diseases etiology
- Published
- 1978
25. Hypogammaglobulinemia and pyoderma.
- Author
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COMBE R
- Subjects
- Pyoderma blood, gamma-Globulins deficiency
- Published
- 1956
26. [APROPOS OF A CASE OF CAVITARY AND INFECTIVE PULMONARY TUBERCULOSIS AFTER B.C.G. VACCINATION].
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TANGUY JJ and COMBE R
- Subjects
- Adolescent, Humans, BCG Vaccine, Mycobacterium bovis, Tuberculosis, Tuberculosis, Pulmonary, Vaccination
- Published
- 1964
27. [Toxoplasmosis].
- Author
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MOURIQUAND G, BOULEZ N, FAYARD C, and COMBE R
- Subjects
- Toxoplasmosis
- Published
- 1950
28. [Periarteritis nodosa in children. Its treatment by nivaquine].
- Author
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BERNHEIM M, COMBE R, and BETHENOD M
- Subjects
- Child, Humans, Infant, Chloroquine therapy, Polyarteritis Nodosa
- Published
- 1962
29. Rhizexes are practical.
- Author
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COMBE R
- Subjects
- Humans, Tooth
- Published
- 1948
30. [One case of cyclopia with D trisomy].
- Author
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Philippe N, Requin C, Combe R, and Germain D
- Subjects
- Abnormalities, Multiple, Chromosome Aberrations, Female, Humans, Infant, Newborn, Karyotyping, Brain abnormalities, Eye Abnormalities, Nose Deformities, Acquired, Trisomy
- Published
- 1972
31. [Elliptocytosis, probably homozygote, in an infant].
- Author
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GAILLARD L, MOURIQUAND C, DELPHIN D, COMBE R, and BRUGIERE P
- Subjects
- Child, Humans, Infant, Anemia, Elliptocytosis, Hereditary, Hematologic Diseases, Homozygote
- Published
- 1960
32. [Familial glucose-6-phosphate dehydrogenase deficiency].
- Author
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Combe R
- Subjects
- Child, Humans, Male, Pedigree, Glucosephosphate Dehydrogenase Deficiency genetics
- Published
- 1972
33. [Sensitization to the gamma globulin-histamine complex].
- Author
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COMBE R and TANGUY JJ
- Subjects
- Asthma therapy, Globulins, Histamine therapy, Hypersensitivity etiology, Immune System Diseases, Nervous System Physiological Phenomena, gamma-Globulins therapy
- Published
- 1962
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