28 results on '"Ramel, D."'
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2. La integración de datos geológicos, hidrogeológicos y geofísicos con el fin de identificar los recursos de aguas subterráneas en zonas de basamento granítico (Macizo de Guéra, Chad)
- Author
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Nouradine, H., primary, Schamper, C., additional, Valdes, D., additional, Moussa, I., additional, Ramel, D., additional, and Plagnes, V., additional
- Published
- 2024
- Full Text
- View/download PDF
3. Best Participatory Practices in Mangrove Conservation Management: The Case in the Mangrove Rehabilitation Program in the Fishing Villages in the Philippines
- Author
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Ramel D. Tomaquin
- Subjects
General Medicine - Abstract
The mangrove conservation program is one of the measures to address climate change at the village or community level and is the most effective and sustainable. For it entails a community participatory approach and is anchored on the participation of the private sector, and people’s organizations. Bayabas, a coastal municipality of Surigao del Sur, in the Philippines with the communities Cabugo, Magobawok, Belete, and La Paz, the sites of the study, has a robust mangrove conservation program. The study used mixed methods of survey, ethnographic, and observation/case study methods which capture the organizational culture of the sites. The findings of the study include the following: The Mangrove Conservation sites were established in response to the significant provisions of the Local Government Code of 1991 bearing on Environmental Conservation duly supported by an Ordinance of the LGU of Bayabas. The operation of the Mangrove Conservation sites was being assisted by the People’s Organization (PO) which is also a quasi-cooperative for fishers. The POs were established by a joint effort of the PFAR/BFAR and the LGU of Bayabas. Sagip Wakatan, the Mangrove Conservation Program of the LGU of Bayabas was anchored on food security, sustainable development, people’s empowerment, eco-tourism, and the response to climate change initiatives at the grassroots levels. Livelihood integration is one of the most important features of the Mangrove Conservation Program and was directly channeled into the four (4) People’s Organizations (POs). The fishers across four (4) sites are active enough in their participation in the Mangrove Conservation.
- Published
- 2023
4. Healing Practices of the Spiritual Folk Healers of Tandag: A Construct of their Social Reality and Mysticism
- Author
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Ramel D. Tomaquin
- Abstract
The paper discusses the rituals performed by the diviner or spiritual healer in curing the clients. It involves prayers, chants and elaborate ceremonies addressed to the supreme deity. It combines animistic beliefs with Folk Christian beliefs which had been handed by generations of diviners or healers. A descriptive qualitative method was used aided by the participant and non-participant observations. It can be deduced from the study that Spiritual folk healing practices had been robustly practiced by the healers or diviners with spiritual themes but it is also tented with the mysticism of animism. The diviner or healer is the main officiating person in the curing rituals which is usually assisted by the assistant curer or diviner.
- Published
- 2022
5. Best Participatory Practices in Mangrove Conservation Management: The Case in the Mangrove Rehabilitation Program in the Fishing Villages in the Philippines
- Author
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Tomaquin, Ramel D., primary
- Published
- 2023
- Full Text
- View/download PDF
6. HEALING PRACTICES OF THE SPIRITUAL FOLK HEALERS OF TANDAG: A CONSTRUCT OF THEIR SOCIAL REALITY AND MYSTICISM
- Author
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Ramel D. Tomaquin, PhD
- Subjects
Spiritual, Diviner, Curer, Shaman, Folk, Mananambal, Tambalon, Healer - Abstract
The paper discusses the rituals performed by the diviner or spiritual healer in curing the clients. It involves prayers, chants and elaborate ceremonies addressed to the supreme deity. It combines animistic beliefs with Folk Christian beliefs which had been handed by generations of diviners or healers. A descriptive qualitative method was used aided by the participant and non-participant observations. It can be deduced from the study that Spiritual folk healing practices had been robustly practiced by the healers or diviners with spiritual themes but it is also tented with the mysticism of animism. The diviner or healer is the main officiating person in the curing rituals which is usually assisted by the assistant curer or diviner.
- Published
- 2023
- Full Text
- View/download PDF
7. Contextualized and Localized Science Teaching and Learning Materials and Its Characteristics to Improve Students' Learning Performance
- Author
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Bello, Jayson B., Loewela S. Concon, Ma. Cindy Cristine Polache, Ayaton, Mechelle Jane C., Ramel D. Manlicayan, Jemerie P. Campomanes, and Saro, Jeffry M.
- Subjects
students ,localized ,science teaching ,learning materials ,t-test ,contextualized - Abstract
The K–12 curriculum in the Philippines emphasizes the innovative teaching and learning methodologies of localization and contextualization. Contextualization might help Filipino culture advance and encourage the next generation of educators to be more original and innovative. The purpose of the study was to determine and attest to the result of the contextualized and localized learning materials in teaching science to improve students’ learning performance among randomly selected learners in the academic year 2021–2022. The study has employed an experimental research design and followed a sampling technique in determining the participants to perform the study. The study's total sample population included 40 students. Furthermore, the assessment or examination consisted of 50 knowledge multiple-choice questions with four answers. A paired t-test for correlated means was used to determine the significant improvement between the two groups utilized in the study’s performance, and an independent t-test was used to check the significant difference between the two groups' posttest learning performances. Based on the findings, the calculated statistic t-test value was -39.722, and the p-value was 0.000 when a localized and contextualized teaching and learning process was used. And for the other group (without), it was shown that the calculated statistic value was -21.078 with a p-value of 0.000 (highly significant) for this t-test. It means that both tests were significantly better than each other because the p-value was lower than the alpha of 0.05. Therefore, when teaching and learning processes were localized and contextualized, learning performance increased considerably.
- Published
- 2023
- Full Text
- View/download PDF
8. THE SOCIO-CULTURAL VIEWS OF THE MAMANWAS OF TANDAG: AN ETHNOGRAPHIC STUDY OF THE PEACE-LOVING COMMUNITY
- Author
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Ramel D. Tomaquin and Retsy Tomaquin-Malong
- Subjects
Peace, Community, Discourse, Socio-Cultural, Mamanwas, Tandag - Abstract
The following sociocultural practices or worldviews are based on a series of interviews with the Mamanwas presented in an ethnographic manner. It will discuss its birth and initiation rites, engagement and wedding customs, burial practices, indigenous value system, worldviews on natural phenomena, and indigenous values system.
- Published
- 2022
- Full Text
- View/download PDF
9. A PI3KCIIALPHA/primary cilium-dependent autophagy program protects endothelial cells in response to atheroprone shear stress
- Author
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Nasr, M., primary, Fay, A., additional, Lupieri, A., additional, Malet, N., additional, Zahreddine, R., additional, Swiader, A., additional, Wahart, A., additional, Negre-Salvayre, A., additional, Hirsch, E., additional, Monteyne, D., additional, Perez-Morga, D., additional, Dupont, N., additional, Codogno, P., additional, Ramel, D., additional, Morel, E., additional, Laffargue, M., additional, and Gayral, S., additional
- Published
- 2022
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10. WS18.02 A PI3Kγ mimetic peptide triggers CFTR gating, bronchodilation and reduced inflammation in obstructive airway diseases
- Author
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Murabito, A., primary, Sala, V., additional, Pisano, A.R., additional, Bertolini, S., additional, Gianotti, A., additional, Caci, E., additional, Montresor, A., additional, Premchandar, A., additional, Pirozzi, F., additional, Ren, K., additional, Sala, A. Della, additional, Mergiotti, M., additional, Richter, W., additional, De Poel, E., additional, Matthey, M., additional, Caldrer, S., additional, Cardone, R.A., additional, Civiletti, F., additional, Costamagna, A., additional, Quinney, N.L., additional, Butnarasu, C., additional, Visentin, S., additional, Ruggiero, M.R., additional, Baroni, S., additional, Crich, S. Geninatti, additional, Ramel, D., additional, Laffargue, M., additional, Tocchetti, C.G., additional, Levi, R., additional, Conti, M., additional, Lu, X.-Y., additional, Melotti, P., additional, Sorio, C., additional, De Rose, V., additional, Facchinetti, F., additional, Fanelli, V., additional, Wenzel, D., additional, Fleischmann, B.K., additional, Mall, M.A., additional, Beekman, J., additional, Laudanna, C., additional, Gentzsch, M., additional, Lukacs, G.L., additional, Pedemonte, N., additional, Hirsch, E., additional, and Ghigo, A., additional
- Published
- 2022
- Full Text
- View/download PDF
11. Healing Practices of the Spiritual Folk Healers of Tandag: A Construct of their Social Reality and Mysticism
- Author
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Tomaquin, Ramel D., primary
- Published
- 2022
- Full Text
- View/download PDF
12. The Socio-Cultural Views of the Mamanwas of Tandag: An Ethnographic Study of the Peace-Loving Community
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Tomaquin, Ramel D., primary
- Published
- 2022
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13. A murine model to study neoatherosclerosis after angioplasty: Impact of diabetes on arterial lesion
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Wahart, A., primary, Auge, N., additional, Solinhac, R., additional, Cavalerie, H., additional, Sarthou, M.-K., additional, Grzesiak, L., additional, Malet, N., additional, Salvayre, A. Negre, additional, Gayral, S., additional, Ramel, D., additional, and Laffargue, M., additional
- Published
- 2021
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14. Noncatalytic function of PI3Kγ drives smooth muscle cell proliferation after arterial damage
- Author
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Lupieri, A., primary, Blaise, R., additional, Ghigo, A., additional, Smirnova, N., additional, Sarthou, M.-K., additional, Malet, N., additional, Limon, I., additional, Vincent, P., additional, Hirsch, E., additional, Gayral, S., additional, Ramel, D., additional, and Laffargue, M., additional
- Published
- 2020
- Full Text
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15. Molecular dynamics study in the Ce0.9M0.1O1.95 (M=Gd, Sm) doped and co-doped CeO2 systems: Structure and oxygen diffusion
- Author
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Vives, S., primary, Ramel, D., additional, and Meunier, C., additional
- Published
- 2019
- Full Text
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16. A PI3Kγ mimetic peptide triggers CFTR gating, bronchodilation, and reduced inflammation in obstructive airway diseases
- Author
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Alessandra Ghigo, Alessandra Murabito, Valentina Sala, Anna Rita Pisano, Serena Bertolini, Ambra Gianotti, Emanuela Caci, Alessio Montresor, Aiswarya Premchandar, Flora Pirozzi, Kai Ren, Angela Della Sala, Marco Mergiotti, Wito Richter, Eyleen de Poel, Michaela Matthey, Sara Caldrer, Rosa A. Cardone, Federica Civiletti, Andrea Costamagna, Nancy L. Quinney, Cosmin Butnarasu, Sonja Visentin, Maria Rosaria Ruggiero, Simona Baroni, Simonetta Geninatti Crich, Damien Ramel, Muriel Laffargue, Carlo G. Tocchetti, Renzo Levi, Marco Conti, Xiao-Yun Lu, Paola Melotti, Claudio Sorio, Virginia De Rose, Fabrizio Facchinetti, Vito Fanelli, Daniela Wenzel, Bernd K. Fleischmann, Marcus A. Mall, Jeffrey Beekman, Carlo Laudanna, Martina Gentzsch, Gergely L. Lukacs, Nicoletta Pedemonte, Emilio Hirsch, Ghigo, A., Murabito, A., Sala, V., Pisano, A. R., Bertolini, S., Gianotti, A., Caci, E., Montresor, A., Premchandar, A., Pirozzi, F., Ren, K., Sala, A. D., Mergiotti, M., Richter, W., de Poel, E., Matthey, M., Caldrer, S., Cardone, R. A., Civiletti, F., Costamagna, A., Quinney, N. L., Butnarasu, C., Visentin, S., Ruggiero, M. R., Baroni, S., Crich, S. G., Ramel, D., Laffargue, M., Tocchetti, C. G., Levi, R., Conti, M., Lu, X. -Y., Melotti, P., Sorio, C., De Rose, V., Facchinetti, F., Fanelli, V., Wenzel, D., Fleischmann, B. K., Mall, M. A., Beekman, J., Laudanna, C., Gentzsch, M., Lukacs, G. L., Pedemonte, N., and Hirsch, E.
- Subjects
Inflammation ,Animal ,Cystic Fibrosis Transmembrane Conductance Regulator ,bronchus ,General Medicine ,PI3K ,Article ,lung ,Mice ,Phosphatidylinositol 3-Kinases ,CFTR, PI3K, cAMP, PKA, inflammation, lung, bronchus, airways ,cAMP ,Peptide ,Animals ,Class Ib Phosphatidylinositol 3-Kinase ,Humans ,PKA ,CFTR ,Phosphatidylinositol 3-Kinase ,airways ,Peptides ,Human - Abstract
Cyclic adenosine 3′,5′-monophosphate (cAMP)–elevating agents, such as β 2 -adrenergic receptor (β 2 -AR) agonists and phosphodiesterase (PDE) inhibitors, remain a mainstay in the treatment of obstructive respiratory diseases, conditions characterized by airway constriction, inflammation, and mucus hypersecretion. However, their clinical use is limited by unwanted side effects because of unrestricted cAMP elevation in the airways and in distant organs. Here, we identified the A-kinase anchoring protein phosphoinositide 3-kinase γ (PI3Kγ) as a critical regulator of a discrete cAMP signaling microdomain activated by β 2 -ARs in airway structural and inflammatory cells. Displacement of the PI3Kγ-anchored pool of protein kinase A (PKA) by an inhaled, cell-permeable, PI3Kγ mimetic peptide (PI3Kγ MP) inhibited a pool of subcortical PDE4B and PDE4D and safely increased cAMP in the lungs, leading to airway smooth muscle relaxation and reduced neutrophil infiltration in a murine model of asthma. In human bronchial epithelial cells, PI3Kγ MP induced unexpected cAMP and PKA elevations restricted to the vicinity of the cystic fibrosis transmembrane conductance regulator (CFTR), the ion channel controlling mucus hydration that is mutated in cystic fibrosis (CF). PI3Kγ MP promoted the phosphorylation of wild-type CFTR on serine-737, triggering channel gating, and rescued the function of F508del-CFTR, the most prevalent CF mutant, by enhancing the effects of existing CFTR modulators. These results unveil PI3Kγ as the regulator of a β 2 -AR/cAMP microdomain central to smooth muscle contraction, immune cell activation, and epithelial fluid secretion in the airways, suggesting the use of a PI3Kγ MP for compartment-restricted, therapeutic cAMP elevation in chronic obstructive respiratory diseases.
- Published
- 2022
17. PI3KCIIα-Dependent Autophagy Program Protects From Endothelial Dysfunction and Atherosclerosis in Response to Low Shear Stress in Mice.
- Author
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Nasr M, Fay A, Lupieri A, Malet N, Darmon A, Zahreddine R, Swiader A, Wahart A, Viaud J, Nègre-Salvayre A, Hirsch E, Monteyne D, Perez-Morgà D, Dupont N, Codogno P, Ramel D, Morel E, Laffargue M, and Gayral S
- Subjects
- Animals, Humans, Mice, Apolipoproteins E genetics, Apolipoproteins E metabolism, Autophagy, Cells, Cultured, Human Umbilical Vein Endothelial Cells metabolism, Mammals, Mechanistic Target of Rapamycin Complex 1 metabolism, Stress, Mechanical, Atherosclerosis genetics, Atherosclerosis prevention & control, Atherosclerosis metabolism, Class I Phosphatidylinositol 3-Kinases metabolism
- Abstract
Background: The ability to respond to mechanical forces is a basic requirement for maintaining endothelial cell (ECs) homeostasis, which is continuously subjected to low shear stress (LSS) and high shear stress (HSS). In arteries, LSS and HSS have a differential impact on EC autophagy processes. However, it is still unclear whether LSS and HSS differently tune unique autophagic machinery or trigger specific autophagic responses in ECs., Methods: Using fluid flow system to generate forces on EC and multiscale imaging analyses on ApoE
-/- mice whole arteries, we studied the cellular and molecular mechanism involved in autophagic response to LSS or HSS on the endothelium., Results: We found that LSS and HSS trigger autophagy activation by mobilizing specific autophagic signaling modules. Indeed, LSS-induced autophagy in endothelium was independent of the class III PI3K (phosphoinositide 3-kinase) VPS34 (vacuolar sorting protein 34) but controlled by the α isoform of class II PI3K (phosphoinositide 3-kinase class II α [PI3KCIIα]). Accordingly, reduced PI3KCIIα expression in ApoE-/- mice (ApoE-/- PI3KCIIα+/- ) led to EC dysfunctions associated with increased plaque deposition in the LSS regions. Mechanistically, we revealed that PI3KCIIα inhibits mTORC1 (mammalian target of rapamycin complex 1) activation and that rapamycin treatment in ApoE-/- PI3KCIIα+/- mice specifically rescue autophagy in arterial LSS regions. Finally, we demonstrated that absence of PI3KCIIα led to decreased endothelial primary cilium biogenesis in response to LSS and that ablation of primary cilium mimics PI3KCIIα-decreased expression in EC dysfunction, suggesting that this organelle could be the mechanosensor linking PI3KCIIα and EC homeostasis., Conclusions: Our data reveal that mechanical forces variability within the arterial system determines EC autophagic response and supports a central role of PI3KCIIα/mTORC1 axis to prevent EC dysfunction in LSS regions., Competing Interests: Disclosures None.- Published
- 2024
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18. Leucine-Rich Alpha-2 Glycoprotein 1 Accumulates in Complicated Atherosclerosis and Promotes Calcification.
- Author
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Grzesiak L, Amaya-Garrido A, Feuillet G, Malet N, Swiader A, Sarthou MK, Wahart A, Ramel D, Gayral S, Schanstra JP, Klein J, and Laffargue M
- Subjects
- Animals, Humans, Mice, Endothelial Cells metabolism, Glycoproteins genetics, Glycoproteins metabolism, Leucine metabolism, Mice, Knockout, Myocytes, Smooth Muscle metabolism, Plaque, Atherosclerotic metabolism, Atherosclerosis genetics, Atherosclerosis metabolism, Renal Insufficiency, Chronic metabolism, Vascular Calcification etiology, Vascular Calcification metabolism
- Abstract
Atherosclerosis is the primary cause of cardiovascular disease. The development of plaque complications, such as calcification and neo-angiogenesis, strongly impacts plaque stability and is a good predictor of mortality in patients with atherosclerosis. Despite well-known risk factors of plaque complications, such as diabetes mellitus and chronic kidney disease, the mechanisms involved are not fully understood. We and others have identified that the concentration of circulating leucine-rich α-2 glycoprotein 1 (LRG1) was increased in diabetic and chronic kidney disease patients. Using apolipoprotein E knockout mice (ApoE-/-) (fed with Western diet) that developed advanced atherosclerosis and using human carotid endarterectomy, we showed that LRG1 accumulated into an atherosclerotic plaque, preferentially in calcified areas. We then investigated the possible origin of LRG1 and its functions on vascular cells and found that LRG1 expression was specifically enhanced in endothelial cells via inflammatory mediators and not in vascular smooth muscle cells (VSMC). Moreover, we identified that LRG1 was able to induce calcification and SMAD1/5-signaling pathways in VSMC. In conclusion, our results identified for the first time that LRG1 is a direct contributor to vascular calcification and suggest a role of this molecule in the development of plaque complications in patients with atherosclerosis.
- Published
- 2023
- Full Text
- View/download PDF
19. Comparison of the different distribution functions in Gd-doped ceria system by molecular dynamics simulations.
- Author
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Vives S, Ramel D, and Meunier C
- Abstract
Cerium dioxide-based materials are among the most studied for applications in the energy and environmental fields and are also of interest in biology and medicine. The fluorite structure of CeO
2 is locally distorted by the concomitant presence of doping cations, such as Gd3+ and oxygen vacancies. The cation-anion bond length distribution then becomes increasingly asymmetric with the doping ratio and temperature. In these cases, the MD simulation results indicate that the commonly used maximum of the pair correlation function g ( r ) first peak can no longer be adopted to estimate the mean bond length. To determine the true cation-anion bond length, the analysis of the radial distribution function R ( r ) first peak is necessary. Furthermore, the asymmetry of this peak must be accounted for when extracting the mean value of the distribution. The gap between the g ( r ) maximum and the R ( r ) mean position derived from the fit using a skewed Gaussian function clearly increases with the doping ratio and temperature, leading to different conclusions concerning bond length evolution. The present study also suggests that care must be taken when the bond length is deduced from the pair distribution functions Gpdf ( r ) as is the case in total scattering experiments (x-ray and neutrons). Finally, relations between the cumulants of the effective distribution of distances as determined in extended x-ray absorption fine structure experiments and the cumulants describing the real distance distribution are proposed considering that both these distributions are modelled by a skewed Gaussian function., (© 2023 IOP Publishing Ltd.)- Published
- 2023
- Full Text
- View/download PDF
20. A PI3Kγ mimetic peptide triggers CFTR gating, bronchodilation, and reduced inflammation in obstructive airway diseases.
- Author
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Ghigo A, Murabito A, Sala V, Pisano AR, Bertolini S, Gianotti A, Caci E, Montresor A, Premchandar A, Pirozzi F, Ren K, Della Sala A, Mergiotti M, Richter W, de Poel E, Matthey M, Caldrer S, Cardone RA, Civiletti F, Costamagna A, Quinney NL, Butnarasu C, Visentin S, Ruggiero MR, Baroni S, Crich SG, Ramel D, Laffargue M, Tocchetti CG, Levi R, Conti M, Lu XY, Melotti P, Sorio C, De Rose V, Facchinetti F, Fanelli V, Wenzel D, Fleischmann BK, Mall MA, Beekman J, Laudanna C, Gentzsch M, Lukacs GL, Pedemonte N, and Hirsch E
- Subjects
- Animals, Class Ib Phosphatidylinositol 3-Kinase, Humans, Inflammation, Mice, Peptides metabolism, Phosphatidylinositol 3-Kinases metabolism, Cystic Fibrosis Transmembrane Conductance Regulator metabolism, Phosphatidylinositol 3-Kinase metabolism
- Abstract
Cyclic adenosine 3',5'-monophosphate (cAMP)-elevating agents, such as β
2 -adrenergic receptor (β2 -AR) agonists and phosphodiesterase (PDE) inhibitors, remain a mainstay in the treatment of obstructive respiratory diseases, conditions characterized by airway constriction, inflammation, and mucus hypersecretion. However, their clinical use is limited by unwanted side effects because of unrestricted cAMP elevation in the airways and in distant organs. Here, we identified the A-kinase anchoring protein phosphoinositide 3-kinase γ (PI3Kγ) as a critical regulator of a discrete cAMP signaling microdomain activated by β2 -ARs in airway structural and inflammatory cells. Displacement of the PI3Kγ-anchored pool of protein kinase A (PKA) by an inhaled, cell-permeable, PI3Kγ mimetic peptide (PI3Kγ MP) inhibited a pool of subcortical PDE4B and PDE4D and safely increased cAMP in the lungs, leading to airway smooth muscle relaxation and reduced neutrophil infiltration in a murine model of asthma. In human bronchial epithelial cells, PI3Kγ MP induced unexpected cAMP and PKA elevations restricted to the vicinity of the cystic fibrosis transmembrane conductance regulator (CFTR), the ion channel controlling mucus hydration that is mutated in cystic fibrosis (CF). PI3Kγ MP promoted the phosphorylation of wild-type CFTR on serine-737, triggering channel gating, and rescued the function of F508del-CFTR, the most prevalent CF mutant, by enhancing the effects of existing CFTR modulators. These results unveil PI3Kγ as the regulator of a β2 -AR/cAMP microdomain central to smooth muscle contraction, immune cell activation, and epithelial fluid secretion in the airways, suggesting the use of a PI3Kγ MP for compartment-restricted, therapeutic cAMP elevation in chronic obstructive respiratory diseases.- Published
- 2022
- Full Text
- View/download PDF
21. A non-catalytic function of PI3Kγ drives smooth muscle cell proliferation after arterial damage.
- Author
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Lupieri A, Blaise R, Ghigo A, Smirnova N, Sarthou MK, Malet N, Limon I, Vincent P, Hirsch E, Gayral S, Ramel D, and Laffargue M
- Subjects
- Animals, Arteries, Cell Proliferation, Mice, Myocytes, Smooth Muscle, Phosphatidylinositol 3-Kinase, Phosphatidylinositol 3-Kinases genetics
- Abstract
Arterial remodeling in hypertension and intimal hyperplasia involves inflammation and disrupted flow, both of which contribute to smooth muscle cell dedifferentiation and proliferation. In this context, our previous results identified phosphoinositide 3-kinase γ (PI3Kγ) as an essential factor in inflammatory processes of the arterial wall. Here, we identify for the first time a kinase-independent role of nonhematopoietic PI3Kγ in the vascular wall during intimal hyperplasia using PI3Kγ-deleted mice and mice expressing a kinase-dead version of the enzyme. Moreover, we found that the absence of PI3Kγ in vascular smooth muscle cells (VSMCs) leads to modulation of cell proliferation, associated with an increase in intracellular cAMP levels. Real-time analysis of cAMP dynamics revealed that PI3Kγ modulates the degradation of cAMP in primary VSMCs independently of its kinase activity through regulation of the enzyme phosphodiesterase 4. Importantly, the use of an N-terminal competing peptide of PI3Kγ blocked primary VSMC proliferation. These data provide evidence for a kinase-independent role of PI3Kγ in arterial remodeling and reveal novel strategies targeting the docking function of PI3Kγ for the treatment of cardiovascular diseases., Competing Interests: Competing interestsThe authors declare no competing or financial interests., (© 2020. Published by The Company of Biologists Ltd.)
- Published
- 2020
- Full Text
- View/download PDF
22. Protein phosphatase 1 activity controls a balance between collective and single cell modes of migration.
- Author
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Chen Y, Kotian N, Aranjuez G, Chen L, Messer CL, Burtscher A, Sawant K, Ramel D, Wang X, and McDonald JA
- Subjects
- Animals, Drosophila Proteins metabolism, Drosophila melanogaster enzymology, Drosophila melanogaster genetics, Female, Genes genetics, Genes physiology, Male, Protein Phosphatase 1 genetics, Protein Phosphatase 1 metabolism, Cell Movement physiology, Drosophila Proteins physiology, Protein Phosphatase 1 physiology
- Abstract
Collective cell migration is central to many developmental and pathological processes. However, the mechanisms that keep cell collectives together and coordinate movement of multiple cells are poorly understood. Using the Drosophila border cell migration model, we find that Protein phosphatase 1 (Pp1) activity controls collective cell cohesion and migration. Inhibition of Pp1 causes border cells to round up, dissociate, and move as single cells with altered motility. We present evidence that Pp1 promotes proper levels of cadherin-catenin complex proteins at cell-cell junctions within the cluster to keep border cells together. Pp1 further restricts actomyosin contractility to the cluster periphery rather than at individual internal border cell contacts. We show that the myosin phosphatase Pp1 complex, which inhibits non-muscle myosin-II (Myo-II) activity, coordinates border cell shape and cluster cohesion. Given the high conservation of Pp1 complexes, this study identifies Pp1 as a major regulator of collective versus single cell migration., Competing Interests: YC, NK, GA, LC, CM, AB, KS, DR, XW, JM No competing interests declared, (© 2020, Chen et al.)
- Published
- 2020
- Full Text
- View/download PDF
23. Small GTPases orchestrate cell-cell communication during collective cell movement.
- Author
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Combedazou A, Gayral S, Colombié N, Fougerat A, Laffargue M, and Ramel D
- Subjects
- Animals, Endocytosis, Humans, cdc42 GTP-Binding Protein metabolism, Cell Communication, Cell Movement, Monomeric GTP-Binding Proteins metabolism
- Abstract
Collective cell migration is a critical mechanism involved in cell movement during various physiological and pathological processes such as angiogenesis and metastasis formation. During collective movement, cells remain functionally connected and can coordinate individual cell behaviors to ensure efficient migration. A cell-cell communication process ensures this complex coordination. Although the mechanisms regulating cell-cell communication remain unclear, recent findings indicate that it is based on acto-myosin cytoskeleton tension transmission from cell to cell through adherens junctions. As for single cell migration, small GTPases of the Rho and Rab families have been shown to be critical regulators of collective motion. Here, we discuss our current understanding on how these small GTPases are themselves regulated and how they control cell-cell communication during collective migration. Moreover, we also shed light on the key role of cell-cell communication and RhoGTPases in the physiological context of endothelial cell migration during angiogenesis.
- Published
- 2020
- Full Text
- View/download PDF
24. Smooth muscle cells-derived CXCL10 prevents endothelial healing through PI3Kγ-dependent T cells response.
- Author
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Lupieri A, Smirnova NF, Solinhac R, Malet N, Benamar M, Saoudi A, Santos-Zas I, Zeboudj L, Ait-Oufella H, Hirsch E, Ohayon P, Lhermusier T, Carrié D, Arnal JF, Ramel D, Gayral S, and Laffargue M
- Subjects
- Animals, CD4-Positive T-Lymphocytes immunology, Carotid Artery Injuries genetics, Carotid Artery Injuries immunology, Carotid Artery Injuries pathology, Cell Proliferation, Cells, Cultured, Class Ib Phosphatidylinositol 3-Kinase deficiency, Class Ib Phosphatidylinositol 3-Kinase genetics, Disease Models, Animal, Endothelial Cells pathology, Human Umbilical Vein Endothelial Cells metabolism, Humans, Interferon-gamma metabolism, Mice, Inbred C57BL, Mice, Knockout, Muscle, Smooth, Vascular immunology, Muscle, Smooth, Vascular pathology, Myocytes, Smooth Muscle immunology, Myocytes, Smooth Muscle pathology, Paracrine Communication, Re-Epithelialization, Signal Transduction, CD4-Positive T-Lymphocytes enzymology, Carotid Artery Injuries enzymology, Chemokine CXCL10 metabolism, Class Ib Phosphatidylinositol 3-Kinase metabolism, Endothelial Cells metabolism, Muscle, Smooth, Vascular metabolism, Myocytes, Smooth Muscle metabolism, Wound Healing
- Abstract
Aims: Defects in efficient endothelial healing have been associated with complication of atherosclerosis such as post-angioplasty neoatherosclerosis and plaque erosion leading to thrombus formation. However, current preventive strategies do not consider re-endothelialization in their design. Here, we investigate mechanisms linking immune processes and defect in re-endothelialization. We especially evaluate if targeting phosphoinositide 3-kinase γ immune processes could restore endothelial healing and identify immune mediators responsible for these defects., Methods and Results: Using in vivo model of endovascular injury, we showed that both ubiquitous genetic inactivation of PI3Kγ and hematopoietic cell-specific PI3Kγ deletion improved re-endothelialization and that CD4+ T-cell population drives this effect. Accordingly, absence of PI3Kγ activity correlates with a decrease in local IFNγ secretion and its downstream interferon-inducible chemokine CXCL10. CXCL10 neutralization promoted re-endothelialization in vivo as the same level than those observed in absence of PI3Kγ suggesting a role of CXCL10 in re-endothelialization defect. Using a new established ex vivo model of carotid re-endothelialization, we showed that blocking CXCL10 restore the IFNγ-induced inhibition of endothelial healing and identify smooth muscle cells as the source of CXCL10 secretion in response to Th1 cytokine., Conclusion: Altogether, these findings expose an unforeseen cellular cross-talk within the arterial wall whereby a PI3Kγ-dependent T-cell response leads to CXCL10 production by smooth muscle cells which in turn inhibits endothelial healing. Therefore, both PI3Kγ and the IFNγ/CXCL10 axis provide novel strategies to promote endothelial healing., (Published on behalf of the European Society of Cardiology. All rights reserved. © The Author(s) 2019. For permissions, please email: journals.permissions@oup.com.)
- Published
- 2020
- Full Text
- View/download PDF
25. PI3KC2α-dependent and VPS34-independent generation of PI3P controls primary cilium-mediated autophagy in response to shear stress.
- Author
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Boukhalfa A, Nascimbeni AC, Ramel D, Dupont N, Hirsch E, Gayral S, Laffargue M, Codogno P, and Morel E
- Subjects
- Animals, Cell Line, Cell Size, Class III Phosphatidylinositol 3-Kinases genetics, Class III Phosphatidylinositol 3-Kinases metabolism, Gene Expression Regulation, Enzymologic, Gene Knockdown Techniques, Humans, Kidney Tubules, Proximal cytology, Kidney Tubules, Proximal metabolism, Mice, Inbred C57BL, Mice, Mutant Strains, Phosphatidylinositol 3-Kinases genetics, Stress, Mechanical, Autophagy physiology, Cilia physiology, Phosphatidylinositol 3-Kinases metabolism, Phosphatidylinositol Phosphates metabolism
- Abstract
Cells subjected to stress situations mobilize specific membranes and proteins to initiate autophagy. Phosphatidylinositol-3-phosphate (PI3P), a crucial lipid in membrane dynamics, is known to be essential in this context. In addition to nutriments deprivation, autophagy is also triggered by fluid-flow induced shear stress in epithelial cells, and this specific autophagic response depends on primary cilium (PC) signaling and leads to cell size regulation. Here we report that PI3KC2α, required for ciliogenesis and PC functions, promotes the synthesis of a local pool of PI3P upon shear stress. We show that PI3KC2α depletion in cells subjected to shear stress abolishes ciliogenesis as well as the autophagy and related cell size regulation. We finally show that PI3KC2α and VPS34, the two main enzymes responsible for PI3P synthesis, have different roles during autophagy, depending on the type of cellular stress: while VPS34 is clearly required for starvation-induced autophagy, PI3KC2α participates only in shear stress-dependent autophagy.
- Published
- 2020
- Full Text
- View/download PDF
26. Immune and Smooth Muscle Cells Interactions in Atherosclerosis: How to Target a Breaking Bad Dialogue?
- Author
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Ramel D, Gayral S, Sarthou MK, Augé N, Nègre-Salvayre A, and Laffargue M
- Abstract
Inflammation is a well-known pathophysiological factor of atherosclerosis but its therapeutic targeting has long been ignored. However, recent advances in the understanding of the immune mechanisms implicated in atherosclerosis have unveiled several therapeutic targets currently undergoing clinical trials. These studies have also shed light on a dialogue between the immune compartment and vascular smooth muscle cells (VSMCs) that plays a critical role in atherosclerotic disease initiation, progression, and stabilization. Our review focuses on the link between cellular and soluble immune effectors and VSMC behavior at different phases of the pathology. Furthermore, we discuss the potential targeting of these interactions to efficiently prevent cardiovascular diseases., (Copyright © 2019 Ramel, Gayral, Sarthou, Augé, Nègre-Salvayre and Laffargue.)
- Published
- 2019
- Full Text
- View/download PDF
27. Non-autonomous role of Cdc42 in cell-cell communication during collective migration.
- Author
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Colombié N, Choesmel-Cadamuro V, Series J, Emery G, Wang X, and Ramel D
- Subjects
- Animals, Cell Surface Extensions metabolism, Endocytosis, Models, Biological, Cell Communication, Cell Movement, Drosophila Proteins metabolism, Drosophila melanogaster cytology, Drosophila melanogaster metabolism, GTP-Binding Proteins metabolism
- Abstract
Collective cell migration is involved in numerous processes both physiological, such as embryonic development, and pathological such as metastasis. Compared to single cell migration, collective motion requires cell behaviour coordination through an as-yet poorly understood but critical cell-cell communication mechanism. Using Drosophila border cell migration, we show here that the small Rho GTPase Cdc42 regulates cell-cell communication. Indeed, we demonstrate that Cdc42 controls protrusion formation in a cell non-autonomous manner. Moreover, we found that the endocytic small GTPase Rab11, controls Cdc42 localisation to the periphery of migrating border cell clusters. Accordingly, over-expression of Cdc42 in border cells rescues the loss of Rab11 function. In addition, we showed that Cdc42 acts upstream of Moesin, a cytoskeletal regulator known to function downstream of rab11. Thus, our study positions Cdc42 as a new key player in cell-cell communication, acting downstream of Rab11., (Copyright © 2017 Elsevier Inc. All rights reserved.)
- Published
- 2017
- Full Text
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28. Myosin II governs collective cell migration behaviour downstream of guidance receptor signalling.
- Author
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Combedazou A, Choesmel-Cadamuro V, Gay G, Liu J, Dupré L, Ramel D, and Wang X
- Subjects
- Animals, ErbB Receptors metabolism, Rotation, Time-Lapse Imaging, Cell Movement, Drosophila Proteins metabolism, Drosophila melanogaster cytology, Drosophila melanogaster metabolism, Myosin Type II metabolism, Receptor Protein-Tyrosine Kinases metabolism, Signal Transduction
- Abstract
Border cell migration during Drosophila oogenesis is a potent model to study collective cell migration, a process involved in development and metastasis. Border cell clusters adopt two main types of behaviour during migration: linear and rotational. However, the molecular mechanism controlling the switch from one to the other is unknown. Here, we demonstrate that non-muscle Myosin II (NMII, also known as Spaghetti squash) activity controls the linear-to-rotational switch. Furthermore, we show that the regulation of NMII takes place downstream of guidance receptor signalling and is critical to ensure efficient collective migration. This study thus provides new insight into the molecular mechanism coordinating the different cell behaviours in a migrating cluster., (© 2017. Published by The Company of Biologists Ltd.)
- Published
- 2017
- Full Text
- View/download PDF
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