Les Rémorines (REM) du groupe 1 sont des protéines spécifiques du monde végétale. Malgré leur caractère hydrophile elles sont localisées à la membrane plasmique. La phosphorylation des REM serait potentiellement impliquée dans la signalisation précoce et la défense des végétaux contre les pathogènes. Benschop et al. (2007) détecte AtREM1.3 (Arabidopsis thaliana, groupe 1b) phosphorylée en réponse au traitement par l'éliciteur générale flg22, tandis que Widjaja et al. (2008) a suggéré que la phosphorylation de AtREM1.2 est potentiellement impliquée dans la signalisation précoce à l'infection par Pseudomonas syringae. La fonction précise de la phosphorylation des protéines REM du groupe 1 reste inconnue. Des travaux antérieurs dans le laboratoire ont montré que le mouvement du virus X de la pomme de terre (PVX) est inversement corrélée à l'accumulation de StREM1.3 (Solanum tuberosum) et que StREM1.3 peut interagir physiquement avec la protéine de mouvement TRIPLE GENE BLOC Protein 1 (TGBp1) du PVX (Raffaele et al., 2009). Dans ce travail, nous avons étudié les mécanismes qui sous-tendent les interactions REM-TGBp1 et nous avons essayé de caractériser biochimiquement la kinase qui phosphoryle REM. Les conséquences physiologiques de l'interaction TGBp1 / StREM1.3 et de la phosphorylation de REM en terme de propagation des virus, d’inactivation génique post-transcriptionnelle, de régulation de l’ouverture des plasmodesmes, et d’activation de kinase ont également été étudiés. / The group 1 Remorin (REM) proteins are plant-specific oligomeric proteins that have been reported to localize to the plasma membrane despite their overall hydrophilic nature. There is evidence that the REM protein phosphorylation is potentially implicated in the early signaling and defense. Benschop et al. (2007) detected the AtREM1.3 (Arabidopsis thaliana group 1b of REM protein family) to be phosphorylated in response to treatment with the general elicitor flg22, while the Widjaja et al. (2008) suggested that the phosphorylation of AtREM1.2 is potentially implicated in early signaling upon infection with Pseudomonas syringae. The precise exact function of the group 1 REM protein phosphorylation remains unknown. Previous work in the laboratory showed that Potato virus X (PVX) movement is inversely correlated to potato StREM1.3 accumulation and that StREM1.3 can physically interacts with the movement protein TRIPLE GENE BLOCK PROTEIN 1 (TGBp1) from PVX (Raffaele et al., 2009). In this work, we studied the mechanism underlying the REM-TGBp1 interactions and we tried to characterise biochemically the kinase that phosphorylate REM. The physiological consequences of TGBp1/ StREM1.3 interaction and REM phosphorylation in terms of virus spreading, post-transcriptional gene silencing, plasmodesmata gating, kinase activation were also investigated.

Mon travail de thèse concerne l’étude des leucémies aiguës lymphoblastiques T (LAL-T). Il se décline en deux projets. Le premier, Le Saracatinib affecte les LAL-T humaines en ciblant la kinase LCK dans les cellules riches en radeaux lipidiques, nous a permis d’identifier une nouvelle voie métabolique importante pour la prolifération des cellules leucémiques. Nous avons montré que la kinase LCK est intégrée dans les radeaux lipidiques et impliquée dans la croissance des cellules leucémiques. L’inhibiteur de LCK Saracatinib affecte les cellules de LAL-T in vitro et in vivo en ciblant particulièrement les cellules les plus agressives ayant beaucoup de radeaux lipidiques à leur surface. Ces résultats permettent d’envisager une nouvelle stratégie thérapeutique pour traiter les LAL-T et ont fait l’objet d’une publication parue dans Leukemia en janvier 2018. Le second projet, Les leucémies aiguës lymphoblastiques T produisent l’interleukine 7 de manière autocrine, démontre pour la première fois que pour la plupart des LAL-T, les cellules sont capables de sécréter elles-mêmes la cytokine IL-7. Nous avons complété cette étude par une analyse des mécanismes épigénétiques impliqués dans la régulation de cette sécrétion autocrine. Nos résultats montrent qu’elle est activée par la fixation des facteurs de transcription IRF-1 (Interferon Regulatory Factor 1) et IRF-2 au niveau du promoteur du gène IL 7, lorsque celui-ci est peu méthylé. Grâce à l’inactivation du gène IL-7 dans un de nos modèles de LAL-T, nous avons pu démontrer que la sécrétion autocrine favorise le développement de la leucémie chez la souris xénogreffée en impactant la prise de greffe et le nombre de cellules initiatrices de leucémie. Ainsi, la régulation épigénétique de la sécrétion autocrine d’IL-7 pourrait être impliquée dans les premières étapes de la leucémogenèse des LAL-T. / My PhD work concerns T-cells acute lymphoblastic leukemia (T-ALL) and includes two projects. The first one, Saracatinib impairs maintenance of human T-ALL by targeting the LCK tyrosine kinase in cells displaying high level of lipid rafts, allow us to identify a new signaling pathway important for the proliferation of T-ALL cells. We showed that LCK is localized into lipid rafts and is involved in the growth of T-ALL cells. The LCK inhibitor Saracatinib affects T-ALL cells in vitro and in vivo by targeting the most aggressive cells displaying high level of lipid rafts. These results highlight a new therapeutic strategy to treat T-ALL and were published in Leukemia in January 2018. The second project, T cell acute lymphoblastic leukemia produces autocrine interleukin 7, demonstrated for the first time that T-ALL cells are able to produce IL-7 cytokine. We performed an analysis of epigenetic mechanisms involved in the regulation of this autocrine secretion. Our results showed that when the IL-7 gene promoter is low methylated, Interferon Regulatory Factor 1 (IRF-1) and (IRF-2) transcription factors bind IRF-E sequence and upregulate IL-7 gene transcription. Thanks to IL 7 gene inactivation in one of our T ALL models, we demonstrated that autocrine secretion promotes leukemia development on xenografted mice through increasing engraftment cells capacity and leukemia initiating cells number. Thus, epigenetic regulation of IL-7 autocrine secretion may be involved in the leukemogenesis of T-ALL.

Les astrocytes participent activement au fonctionnement cérébral. Ils réalisent des échanges métaboliques et trophiques avec les neurones et exercent un contrôle sur l'entrée des substrats énergétiques dans le parenchyme cérébral. Ils sont aussi res ponsables -par le biais de leurs transporteurs GLAST et GLT-1- de la recapture et du recyclage du glutamate, le principal neurotransmetteur excitateur qui a aussi un potentiel neurotoxique. Les astrocytes répondent à des situations pathologiques variées en devenant réactifs. Ils apparaissent hypertrophiques et surexpriment certaines protéines comme les filaments intermédiaires. Bien que cette modification du phénotype astrocytaire soit connue depuis longtemps, ses conséquences fonctionnelles sont toujours débattues. S'agit-il d'un mécanisme de protection et d'adaptation à des conditions pathologiques ou, au contraire, d'un processus délétère participant à la dégénérescence neuronale ? Nous avons développé un modèle in vivo d'activation astrocytaire en utilisant un lentivirus (lenti-CNTF) pour induire une surexpression dans le striatum de rat du Ciliary Neurotrophic Factor (CNTF), un activateur endogène des astrocytes. Grâce à ce modèle d'activation stable et reproductible des astrocytes, nous avons pu mettre en évidence des modifications profondes du métabolisme énergétique cérébral avec une augmentation de l'utilisation des corps cétoniques au dépend du glucose. Par ailleurs, l'activation astrocytaire par le CNTF induit de nombreux changements dans la machinerie de recapture du glutamate. Les transporteurs astrocytaires sont hyperglycosylés et sont enrichis dans les microdomaines membranaires rafts. En conditions excitotoxiques, la gestion du glutamate, l'apport énergétique et la survie neuronale sont significativement améliorés dans le groupe lenti-CNTF. Ces résultats soulignent le rôle bénéfique des astrocytes activés qui présentent un phénotype et un fonctionnement favorables à la survie des neurones. Cette étude permet à la fois de mieux cerner le rôle et l'intérêt de la réponse astrocytaire dans les processus pathologiques et également de caractériser les effets du CNTF , qui est un candidat thérapeutique pour différentes maladies neurodégénératives.

In this study we tested whether the prevalence or synaptic distribution of NMDA receptor subunits would be altered in the brain of the MeCP2-null mouse model of Rett syndrome. Detergent resistant membranes (DRMs) and post-synaptic densities (PSDs) were isolated from the synaptic membranes treated with TritonX-100, and resolved by sucrose density gradient centrifugation. Immunoblot analysis of the resulting density gradient fractions revealed that the relative distribution of the different NMDA receptor subunits between the DRM fractions, soluble fractions, and insoluble postsynaptic density fractions was preserved in the MeCP2-null brain. However, analysis of the overall NMDA receptor subunit prevalence within these fractions revealed a significant decrease in the expression of the NR1 and NR2A subunits, but not the NR2B subunit, in the MeCP2-null brain. The preservation of distribution of NMDAR subunits to the synaptic membranes, together with the decrease in NR1 and NR2A prevalence, suggest an imbalance in equilibrium between the mature and the immature synapses in a mouse model of Rett syndrome.

In this study we tested whether the prevalence or synaptic distribution of NMDA receptor subunits would be altered in the brain of the MeCP2-null mouse model of Rett syndrome. Detergent resistant membranes (DRMs) and post-synaptic densities (PSDs) were isolated from the synaptic membranes treated with TritonX-100, and resolved by sucrose density gradient centrifugation. Immunoblot analysis of the resulting density gradient fractions revealed that the relative distribution of the different NMDA receptor subunits between the DRM fractions, soluble fractions, and insoluble postsynaptic density fractions was preserved in the MeCP2-null brain. However, analysis of the overall NMDA receptor subunit prevalence within these fractions revealed a significant decrease in the expression of the NR1 and NR2A subunits, but not the NR2B subunit, in the MeCP2-null brain. The preservation of distribution of NMDAR subunits to the synaptic membranes, together with the decrease in NR1 and NR2A prevalence, suggest an imbalance in equilibrium between the mature and the immature synapses in a mouse model of Rett syndrome.

Dietary n-3 polyunsaturated fatty acids (PUFA) have been shown to potently attenuate T cell-mediated inflammation, in part, by suppressing T cell activation and proliferation. Apoptosis is an important mechanism for preventing chronic inflammation by maintaining T cell homeostasis through the contraction of populations of activated T cells. We hypothesized that dietary n-3 PUFA would promote T cell apoptosis, thus, providing an additional mechanism to explain the anti-inflammatory effects. We specifically examined activation-induced cell death (AICD) since it is the form of apoptosis associated with peripheral T cell deletion involved in immunological tolerance and T cell homeostasis. Female C57BL/6 mice were fed diets containing either n-6 PUFA (control) or n-3 PUFA for 14 d. Splenic T cells were stimulated with CD3/CD28, CD3/PMA, or PMA/Ionomycin for 48 h followed by reactivation with the same stimuli for 5 h. Apoptosis was measured using Annexin V/propidium iodide and flow cytometry. Cytokine analyses revealed that n-3 PUFA enhanced AICD only in T cells expressing a Th1-like cytokine profile (high IFN, low IL-4) compared to mice fed the n-6 PUFA control diet. Dietary n-3 PUFA significantly altered the fatty acid composition of phosphatidylcholine and phosphatidylethanolamine in T cell membranes. To examine the apparently selective effect of dietary n-3 PUFA on AICD in Th1 cells, CD4+ T cells were polarized in vitro to a Th1 phenotype by culture with IL-4, IL-2, and IL-12 for 2 d, followed by culture with IL-2 and IL-12 for 3 d in the presence of diet-matched homologous mouse serum (MS) to prevent loss of cell membrane fatty acids. Following polarization and reactivation, we observed that n-3 PUFA enhanced Th1 polarization and AICD only in cells cultured in the presence of MS, but not in fetal bovine serum. The n-3 PUFA enhancement of Th1 polarization and AICD was associated with the maintenance of diet-induced changes in EPA (20:5n-3) and DHA (22:6n-3) in plasma T cell membrane lipid rafts. Overall, these results suggest that dietary n-3 PUFA enhance both the polarization and deletion of pro-inflammatory Th1 cells, possibly as a result of alterations in lipid raft fatty acid composition.

Compartmentalization of cell membranes, in particular of the apical membrane of columnar epithelia, is the topic of this thesis. The first part characterizes the apical membrane and its specialized organization and morphology, whereas the second part focuses on the formation of this unique plasma membrane domain during epithelial polarization. The apical membrane of columnar epithelia is enriched in glycosphingolipids, a class of lipids that are known to interact with cholesterol to form liquid ordered domains, also termed "rafts", in cell membranes. Imaging the apical surface of untreated and raft lipid depleted MDCK cells with atomic force microscopy revealed that raft lipids are involved in the formation and/or maintenance of microvilli, actin based protrusions of the apical plasma membrane, indicating a regulatory link between membrane domains and the cytoskeleton. Furthermore, antibody patching and photobleaching experiments performed during the work of this thesis suggest that the organization into raft and non-raft domains is very different in the apical membrane of MDCK cells compared to the plasma membrane of a fibroblast. In fact, the data support the hypothesis that the apical membrane could be a percolating raft membrane in which rafts constitute the major phase and non-raft domains exist as isolated entities. The second part of this thesis analyses the segregation of apical and basolateral membrane domains during epithelial polarization. This segregation can either be achieved by generating scaffolded domains prior to junction formation or by polarized secretory and endocytic membrane traffic after the establishment of cell junctions. While most apical and basolateral marker proteins in MDCK cells follow the latter mechanism, this thesis reports that the apical marker gp135 is confined to the dorsal face already in single attached cells. The unknown antigen was purified and identified as podocalyxin. Analysis of a series of domain mutants revealed that the C-terminal PDZ-binding motif of podocalyxin is mainly responsible for its special localization, which it shares with the PDZ protein NHERF-2. Knocking down podocalyxin by RNA interference resulted in retardation of cell growth and epithelial polarization. Taken together, the data suggest that podocalyxin and NHERF-2 could be part of an early apical polarity scaffolding system based on PDZ-binding and PDZ-containing proteins.

Este trabalho foi feito com dados de campo da Bacia de Benguela, na costa sul de Angola. Nesta área aflora uma plataforma carbonática de idade albiana, análoga às formações produtoras de petróleo de mesma idade na Bacia de Campos. Duas unidades principais compõem a seção albiana na área: uma unidade inferior caracterizada por carbonatos de águas rasas com intercalações de conglomerados e arenitos na base, totalizando 300 m de espessura total, e uma unidade superior formada por sedimentos carbonáticos de águas mais profundas com espessura de 100 m. Esta seção se apresenta em dois domínios estruturais. O norte é caracterizado por uma plataforma de cerca de 5 km de largura, 35 km de comprimento na direção NE e que se encontra próxima ao embasamento. No domínio sul, essa plataforma se apresenta em fragmentos de menos de 10 km de comprimento por até 5 km de largura, alguns deles afastados do embasamento. Dado que há evaporitos sob essa plataforma, fez-se este trabalho com o objetivo de se avaliar a influência da tectônica salífera na estruturação das rochas albianas. A utilização de imagens de satélite de domínio público permitiu a extrapolação dos dados pontuais e a construção de perfis topográficos que possibilitaram a montagem das seções geológicas. Os dados de campo indicam que a estruturação na parte norte, onde há menos sal, é influenciada pelas estruturas locais do embasamento. Já na parte sul, onde a espessura de sal é maior, a deformação é descolada das estruturas do embasamento. Foi feita uma seção geológica em cada domínio e a restauração dessas duas seções mostrou que a unidade albiana na parte sul sofreu uma distensão de 1,25 (125%) e a de norte se distendeu em 1,05 (105%). Essa diferença foi causada por uma maior espessura original de sal na parte sul, que fez com que a cobertura albiana se distendesse mais em consequência da fluência do sal mergulho abaixo, em resposta ao basculamento da bacia em direção a offshore. A intensidade da deformação na parte sul foi tal que os blocos falhados perderam os contatos entre si, formando rafts. Este efeito foi reproduzido em modelos físicos, indicando que a variação na espessura original de sal tem grande influência na estruturação das rochas que o cobrem. As variações de espessura de sal são controladas por zonas de transferência do embasamento e estas mesmas estruturas controlam os limites dos blocos que sofrem soerguimento diferencial no Cenozoico. / The present work was done with field data from Benguela Basin, which is located in the southern coast of Angola. At this site, an albian carbonatic platform, analogous to the hydrocarbon productive formations of the same age in Campos Basin, outcrops near the coast line , in the surroundings of the city of Benguela. Two major units are recognized among this section: The lower one is characterized by shallow water carbonates with sandstones and conglomerates interlayered at its basal levels, and a total thickness of 300 m. The upper section is composed of deep waters carbonate rocks in a 100 m thick package. This section occurs in two structural domains. The northern domain forms a 5 km wide and 35 km long platform elongated in the NE direction and close to the basement to the east. The southern part is represented by less than 10 km long and up to 5 km wide fragments, some of them displaced from the basement. Considering that evaporates underlie this platform, the main objective of this work is to investigate the influence of salt tectonics on the deformation of the albian rocks. The use of satellite images of public domain allowed the extrapolation of punctual information as well as the construction of the elevation profiles, utilized for the elaboration of the geologic sections. The field data indicate that the structuration at the northern domain, where there is less salt, is influenced by the basement structures. On the other hand, at the southern region, where the evaporitic section is thicker, the deformation is detached from the basement. One geologic section was constructed for each domain and their restorations indicated that the southern part of the platform was affected by an extension of 1,25 (125%) and that the extension at the northern part was 1,05 (105%). This variation is due to a thicker salt layer under the southern part, which conducted the albian package to extend more intensively in consequence of the downdip salt flow, when the basin was tilted toward the ocean. At this region extension was so intense that the faulted blocks lost contact with each other, forming the so called rafts. This effect was simulated in sand box models which indicated that the salt thickness plays a major role in the deformation of the overburden rocks. The variations on the original salt thickness was controlled by transfer faults in the basement and these are the same structures that controlled the boundaries of the basement blocks that responded differently to the Cenozoic uplift events

La spectroscopie de fluorescence de molécule individuelle a révolutionné le domaine des sciences biophysiques, en permettant la visualisation des interactions moléculaires dynamiques et des caractéristiques nanoscopiques avec une haute résolution spatio-temporelle. Le contrôle des réactions enzymatiques et l'étude de la dynamique de diffusion de molécules individuelles permet de comprendre l'influence et le contrôle de ces entités nanoscopiques sur plusieurs processus biophysiques. La nanophotonique basée sur la plasmonique offre des nouvelles opportunités de suivi d'évènements à molécule unique, puisque il est possible de confiner des champs électromagnétiques dans les hotspots à nano-échelle, à dimensions spatiales comparables à une molécule unique. Dans ce projet de thèse, nous explorons plusieurs plateformes de nanoantennas photoniques avec des hotspots, et nous avons démontré les applications dans l'amélioration de la spectroscopie de fluorescence de molécule individuelle. En utilisant la fluorescence burst analysis, l'analyse de fluctuations temporelle de fluorescence,TCSPC, nous quantifions les facteurs d'amélioration de fluorescence, les volumes de détection de nanoantennas; ainsi, nous discutons l'accélération de fluorescence photo dynamique. En alternative aux structures plasmoniques, des antennes diélectriques basées sur les dimères en silicone ont aussi démontré d'améliorer la détection de fluorescence à molécule unique, pour des concentrations micro molaires physiologiquement pertinentes. En outre, nous explorons des systèmes planaires antennas in box pour l'investigation de la dynamique de diffusion de la PE et de la SM dans les membranes des cellules vivantes. / Single-molecule fluorescence spectroscopy has revolutionized the field of biophysical sciences by enabling visualization of dynamic molecular interactions and nanoscopic features with high spatiotemporal resolution. Monitoring enzymatic reactions and studying diffusion dynamics of individual molecules help us understand how these nanoscopic entities influence and control various biochemical processes. Nanophotonic antennas can efficiently localize electromagnetic radiation into nanoscale spatial dimensions comparable to single bio-molecules. These confined illumination hotspots there by offer the opportunity to follow single-molecule events at physiological expression levels. In this thesis, we explore various photonic nanoantenna platforms and demonstrate their application in enhanced single-molecule fluorescence detection. Using fluorescence burst analysis, fluorescence correlation spectroscopy (FCS), time-correlated TCSPC measurements, and near field simulations, we quantify nanoantenna detection volumes, fluorescence enhancement factors and discuss the fluorescence photodynamic accelerations mediated by optical antennas. Further, using resonant planar antenna-in-box devices we investigate the diffusion dynamics of phosphoethanolamine and sphingomyelin on the plasma membrane of living cells and discuss the results in the context of lipid rafts. Together with cholesterol depletion experiments, we provide evidence of cholesterol-induced nanodomain partitioning within less than 10~nm diameters and characteristic times being ~100 microseconds.

Este trabalho foi feito com dados de campo da Bacia de Benguela, na costa sul de Angola. Nesta área aflora uma plataforma carbonática de idade albiana, análoga às formações produtoras de petróleo de mesma idade na Bacia de Campos. Duas unidades principais compõem a seção albiana na área: uma unidade inferior caracterizada por carbonatos de águas rasas com intercalações de conglomerados e arenitos na base, totalizando 300 m de espessura total, e uma unidade superior formada por sedimentos carbonáticos de águas mais profundas com espessura de 100 m. Esta seção se apresenta em dois domínios estruturais. O norte é caracterizado por uma plataforma de cerca de 5 km de largura, 35 km de comprimento na direção NE e que se encontra próxima ao embasamento. No domínio sul, essa plataforma se apresenta em fragmentos de menos de 10 km de comprimento por até 5 km de largura, alguns deles afastados do embasamento. Dado que há evaporitos sob essa plataforma, fez-se este trabalho com o objetivo de se avaliar a influência da tectônica salífera na estruturação das rochas albianas. A utilização de imagens de satélite de domínio público permitiu a extrapolação dos dados pontuais e a construção de perfis topográficos que possibilitaram a montagem das seções geológicas. Os dados de campo indicam que a estruturação na parte norte, onde há menos sal, é influenciada pelas estruturas locais do embasamento. Já na parte sul, onde a espessura de sal é maior, a deformação é descolada das estruturas do embasamento. Foi feita uma seção geológica em cada domínio e a restauração dessas duas seções mostrou que a unidade albiana na parte sul sofreu uma distensão de 1,25 (125%) e a de norte se distendeu em 1,05 (105%). Essa diferença foi causada por uma maior espessura original de sal na parte sul, que fez com que a cobertura albiana se distendesse mais em consequência da fluência do sal mergulho abaixo, em resposta ao basculamento da bacia em direção a offshore. A intensidade da deformação na parte sul foi tal que os blocos falhados perderam os contatos entre si, formando rafts. Este efeito foi reproduzido em modelos físicos, indicando que a variação na espessura original de sal tem grande influência na estruturação das rochas que o cobrem. As variações de espessura de sal são controladas por zonas de transferência do embasamento e estas mesmas estruturas controlam os limites dos blocos que sofrem soerguimento diferencial no Cenozoico. / The present work was done with field data from Benguela Basin, which is located in the southern coast of Angola. At this site, an albian carbonatic platform, analogous to the hydrocarbon productive formations of the same age in Campos Basin, outcrops near the coast line , in the surroundings of the city of Benguela. Two major units are recognized among this section: The lower one is characterized by shallow water carbonates with sandstones and conglomerates interlayered at its basal levels, and a total thickness of 300 m. The upper section is composed of deep waters carbonate rocks in a 100 m thick package. This section occurs in two structural domains. The northern domain forms a 5 km wide and 35 km long platform elongated in the NE direction and close to the basement to the east. The southern part is represented by less than 10 km long and up to 5 km wide fragments, some of them displaced from the basement. Considering that evaporates underlie this platform, the main objective of this work is to investigate the influence of salt tectonics on the deformation of the albian rocks. The use of satellite images of public domain allowed the extrapolation of punctual information as well as the construction of the elevation profiles, utilized for the elaboration of the geologic sections. The field data indicate that the structuration at the northern domain, where there is less salt, is influenced by the basement structures. On the other hand, at the southern region, where the evaporitic section is thicker, the deformation is detached from the basement. One geologic section was constructed for each domain and their restorations indicated that the southern part of the platform was affected by an extension of 1,25 (125%) and that the extension at the northern part was 1,05 (105%). This variation is due to a thicker salt layer under the southern part, which conducted the albian package to extend more intensively in consequence of the downdip salt flow, when the basin was tilted toward the ocean. At this region extension was so intense that the faulted blocks lost contact with each other, forming the so called rafts. This effect was simulated in sand box models which indicated that the salt thickness plays a major role in the deformation of the overburden rocks. The variations on the original salt thickness was controlled by transfer faults in the basement and these are the same structures that controlled the boundaries of the basement blocks that responded differently to the Cenozoic uplift events