The Construct of Sensory Suggestibility: A Factor Analysis

The construct of “suggestibility” has garnered great interest in the field of psychology over the years. It has been invoked as an explanatory construct in social, clinical, and forensic psychology. Yet, the nature of the construct and of its factor structure is unclear. In an earlier study we operationalized suggestibility by measuring conformity, interrogative suggestibility, placebo effects, persuasibility and hypnotizability. There was no discernible factor structure. In the present study, we narrowed our focus to sensory suggestibility alone expecting to find some cohesion among responsiveness to these types of suggestive situations by examining this phenomenon across eight sensory measures (tactile, auditory, visual and olfactory). Additionally, we investigated the relationship between hypnotizability and the sensory suggestibility measures used. We applied factor analytic methodologies using Analysis of Movement Structures (AMOS) and found no support for a unitary or multi-factorial solution. None of the sensory measures used in this study correlated with hypnotizability. Results and implications of these findings are discussed

Biometric and physiological factors in human ocular perfusion

By addressing the vascular features that characterise myopia, this thesis aims to provide an understanding of the early structural changes associated with human myopia and the progression to co-morbidity with age. This thesis addresses three main areas of study: 1. Ocular perfusion features and autoregulatory mechanisms in human myopia; 2. Choroidal thickness at the macular area of myopic eyes; 3. Effect of chronic smoking on the ocular haemodynamics and autoregulation. This thesis demonstrated a reduced resting ocular pulse amplitude and retrobulbar blood flow in human myopia, associated with an apparent oversensitivity to the vasodilatory effects of hypercapnia, which may be due to anatomical differences in the volume of the vessel beds. In young smokers, normal resting state vascular characteristics were present; however there also appeared to be increased reactivity to hypercapnia, possibly due to relative chronic hypoxia. The systemic circulation in myopes and smokers over-reacted similarly to hypercapnia suggesting that physiologic differences are not confined to the eye. Age also showed a negative effect on autoregulatory capacity in otherwise normal eyes. Collectively, these findings suggest that myopes and smokers require greater autoregulatory capacity to maintain appropriate oxygenation of retinal tissue, and since the capacity for such regulation reduces with age, these groups are at greater risk of insufficient autoregulation and relative hypoxia with age

Identification of N-terminal protein acetylation and arginine methylation of the voltage-gated sodium channel in end-stage heart failure human heart

The α subunit of the cardiac voltage-gated sodium channel, Naᵥ1.5, provides the rapid sodium inward current that initiates cardiomyocyte action potentials. Here, we analyzed for the first time the post-translational modifications of Naᵥ1.5 purified from end-stage heart failure human cardiac tissue. We identified R526 methylation as the major post-translational modification of any Naᵥ1.5 arginine or lysine residue. Unexpectedly, we found that the N terminus of Naᵥ1.5 was: 1) devoid of the initiation methionine, and 2) acetylated at the resulting initial alanine residue. This is the first evidence for N-terminal acetylation in any member of the voltage-gated ion channel superfamily. Our results open the door to explore Naᵥ1.5 N-terminal acetylation and arginine methylation levels as drivers or markers of end-stage heart failure

Provenance and clinical benefit of medicines introduced to the French market, 2008 to 2018

IMPORTANCE Both the commercial sector and academia play a vital role in medicine development. Ongoing debates exist on their contribution and the value of medicinal products entering the market. OBJECTIVE To identify the provenance and clinical benefit of medicines that entered the French market between 2008 and 2018. DESIGN AND SETTING In this cross-sectional study, the provenance of each medicine in the French market was established via a review of multiple sources documenting at least 2 matching findings per product. The clinical benefit was assigned using the matched scale developed from the Prescrire and Haute Autorité de Santé (HAS) gradings. The χ2 test was used to analyze the proportions and frequencies of medicines graded by Prescrire and HAS by origin, therapeutic category, and clinical benefit. MAIN OUTCOMES AND MEASURES The origins and therapeutic categories of medicines. Clinical benefit based on Prescrire and HAS grading. Concordance of Prescrire and HAS grading. RESULTS Of the 632 medicines that entered the French market between 2008 and 2018, 464 originated (73%) in the commercial sector, and 168 originated (27%) in the academic setting or in collaboration with commercial enterprises. Prescrire graded psychotropic agents (13/14 [93%]), whereas HAS graded respiratory agents (24/25 [96%]) as the highest percentage of medicines that provided no added benefit. Prescrire graded 360 medicines (77.6%) that originated in the industry and 108 medicines (64.3%) that originated in the academic setting (P = .001) to have no added clinical benefit. HAS assigned such grading to 331 ([71.3%] industry) vs 104 ([61.9%] academia) (P = .02). Based on the Prescrire grading, academia invented more medicines delivering some added benefit 57 (33.9%) vs 98 (21.1%) invented by industry (P = .001). HAS grading on some added benefit 51 ([30.4%] academia) vs 121 ([26.1%] industry) did not reach statistical significance (P = .29). However, HAS grading on substantial added clinical benefit reached statistical significance in favor of academia (13 [7.7%] vs 12 [2.6%] in the industry; P = .003), whereas Prescrire grading did not (1.8% academia vs 1.3% industry; P = .64). CONCLUSIONS AND RELEVANCE More than 70% of medicines that entered the French market during the 10-year period originated in the commercial sector. Although most medicines were not graded as providing clinical benefit, medicines originating in the academic setting were more likely to be graded as conferring clinical benefit than those originating in the commercial setting

Active Base Hybrid Organosilica Materials based on Pyrrolidine Builder Units for Fine Chemicals Production

[EN] The catalytic activity of "pyrrolidine type" fragments included or anchored in the mesoporous silica supports or polymeric frameworks have been fully reported for enantioselective transformation. Nevertheless, low attention was focused on their catalytic abilities to perform base-catalyzed reaction. Accordingly, hybrid materials including pyrrolidine fragments in the mesoporous silica supports were prepared following different synthesis methods, such as micellar and fluoride sol-gel routes in absence of structural directing agents. Their great catalytic performance was explored for various base-catalyzed reactions to the formation of C-C bond through Knoevenagel, Claisen-Schmidt and Henry condensations under microwave irradiation. The benefits of microwave irradiation combined with suitable catalytic properties of pyrrolidine hybrid materials with strong base sites and high accessibility to active centers, allowed carrying out successfully base-catalyzed condensation reactions for the production of fine chemicals. Moreover, the hybrid catalyst exhibited high selectivity and good stability over different catalytic cycles contributing to environmental sustainability.The authors are grateful for financial support from the Spanish Government, MAT2017-82288-C2-1-P and PID2020112590GB C21/AEI/10.13039/501100011033, and MULTY2HYCAT European project (EUHorizon 2020 funded project under grant agreement no. 720783).Llopis-Perez, S.; Velty, A.; Díaz Morales, UM. (2021). Active Base Hybrid Organosilica Materials based on Pyrrolidine Builder Units for Fine Chemicals Production. ChemCatChem. 13(23):5012-5024. https://doi.org/10.1002/cctc.202101031S50125024132

Influence of the Framework Topology on the Reactivity of Chiral Pyrrolidine Units Inserted in Different Porous Organosilicas

[EN] Three families of organosiliceous materials with different structuration level, order, and textural properties (non-ordered, M41S, and SBA-15 type materials) were prepared incorporating in their structural framework chiral pyrrolidine units with variable content. Likewise, non-ordered mesoporous hybrid solids were obtained through a sol-gel process in a fluoride medium, while M41S and SBA-15 type materials were obtained through micellar routes in the presence of long-chain neutral surfactants or block copolymers. Thanks to appropriate characterization studies and catalytic tests for the Michael addition between butyraldehyde and beta-nitrostyrene, we showed how the void shapes and sizes present in the structure of hybrid materials control the diffusion of reactants and products, as well as confine transition states and reactive intermediates. The best catalytic results, considering activity and enantioselectivity, were achieved in the presence of a non-ordered material, NOH-Pyr-5%, which exhibited the highest Brunauer-Emmett-Teller (BET) area, with a 96% yield and a 82% ee for the Michael adduct.This research was funded by the Spanish Government(MAT2017-82288-C2-1-P), Severo Ochoa Excellence Program (SEV-2016-0683), and MULTY2HYCAT (EU-Horizon 2020 funded project under grant agreement no. 720783). S. Ll. is thankful for the predoctoral fellowship from MINECO for financial support (BES-2015-072627).Llopis-Perez, S.; Velty, A.; Díaz Morales, UM. (2019). Influence of the Framework Topology on the Reactivity of Chiral Pyrrolidine Units Inserted in Different Porous Organosilicas. Catalysts. 9(8):1-21. https://doi.org/10.3390/catal9080654S12198Kuschel, A., Drescher, M., Kuschel, T., & Polarz, S. (2010). Bifunctional Mesoporous Organosilica Materials and Their Application in Catalysis: Cooperative Effects or Not? 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Bridged Polysilsesquioxanes. Highly Porous Hybrid Organic-Inorganic Materials. Chemical Reviews, 95(5), 1431-1442. doi:10.1021/cr00037a013Inagaki, S., Guan, S., Fukushima, Y., Ohsuna, T., & Terasaki, O. (1999). Novel Mesoporous Materials with a Uniform Distribution of Organic Groups and Inorganic Oxide in Their Frameworks. Journal of the American Chemical Society, 121(41), 9611-9614. doi:10.1021/ja9916658Villaverde, G., Arnanz, A., Iglesias, M., Monge, A., Sánchez, F., & Snejko, N. (2011). Development of homogeneous and heterogenized rhodium(i) and palladium(ii) complexes with ligands based on a chiral proton sponge building block and their application as catalysts. Dalton Transactions, 40(37), 9589. doi:10.1039/c1dt10597cMelde, B. J., Holland, B. T., Blanford, C. F., & Stein, A. (1999). Mesoporous Sieves with Unified Hybrid Inorganic/Organic Frameworks. Chemistry of Materials, 11(11), 3302-3308. doi:10.1021/cm9903935García-García, P., Moreno, J. M., Díaz, U., Bruix, M., & Corma, A. (2016). Organic–inorganic supramolecular solid catalyst boosts organic reactions in water. Nature Communications, 7(1). doi:10.1038/ncomms10835Moreno, J. M., Velty, A., Díaz, U., & Corma, A. (2019). Synthesis of 2D and 3D MOFs with tuneable Lewis acidity from preformed 1D hybrid sub-domains. Chemical Science, 10(7), 2053-2066. doi:10.1039/c8sc04372hSzőllősi, G., Gombkötő, D., Mogyorós, A. Z., & Fülöp, F. (2018). Surface-Improved Asymmetric Michael Addition Catalyzed by Amino Acids Adsorbed on Laponite. Advanced Synthesis & Catalysis, 360(10), 1992-2004. doi:10.1002/adsc.201701627Feng, J., Li, X., & Cheng, J.-P. (2017). Enantioselective Organocatalyzed Vinylogous Michael Reactions of 3-Alkylidene Oxindoles with Enals. The Journal of Organic Chemistry, 82(3), 1412-1419. doi:10.1021/acs.joc.6b02582Bernardi, L., Fochi, M., Carbone, R., Martinelli, A., Fox, M. E., Cobley, C. J., … Carlone, A. (2015). Organocatalytic Asymmetric Conjugate Additions to Cyclopent-1-enecarbaldehyde: A Critical Assessment of Organocatalytic Approaches towards the Telaprevir Bicyclic Core. Chemistry - A European Journal, 21(52), 19208-19222. doi:10.1002/chem.201503352Afewerki, S., Ma, G., Ibrahem, I., Liu, L., Sun, J., & Córdova, A. (2015). Highly Enantioselective Control of Dynamic Cascade Transformations by Dual Catalysis: Asymmetric Synthesis of Polysubstituted Spirocyclic Oxindoles. ACS Catalysis, 5(2), 1266-1272. doi:10.1021/cs501975uMonge-Marcet, A., Pleixats, R., Cattoën, X., Man, M. W. C., Alonso, D. A., & Nájera, C. (2011). Prolinamide bridged silsesquioxane as an efficient, eco-compatible and recyclable chiral organocatalyst. New Journal of Chemistry, 35(12), 2766. doi:10.1039/c1nj20516aSagamanova, I., Rodríguez-Escrich, C., Molnár, I. G., Sayalero, S., Gilmour, R., & Pericàs, M. A. (2015). 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Dendrimères phosphorés catanioniques inhibiteurs du VIH : propriétés physico-chimiques et activité antivirale

Le galactosylcéramide ou GalCer, dérivé glycolipidique, est l'un des récepteurs cellulaires du VIH. Il agit grâce à son affinité élevée pour la boucle V3 de la gp120 du VIH. Une des stratégies thérapeutiques employées consiste en la synthèse de leurres visant à mimer ce récepteur afin de bloquer la reconnaissance entre le virus et les cellules GalCer(+) et CD4(+). De plus, la plupart des processus de reconnaissance cellulaire sont multivalents. L'inhibition de ces processus est donc plus efficace quand un inhibiteur multivalent est utilisé. C'est dans ce contexte que l'utilisation de dendrimères phosphorés catanioniques analogues du GalCer mimant les surfaces cellulaires a été envisagée. Ces composés sont obtenus par une simple réaction acido-basique dans l’eau entre un dendrimère à terminaisons acide et un aminosucre à longue chaine appelé aminolactitol. Les dendrimères catanioniques résultants sont des assemblages supramoléculaires dont la stabilité est assurée par des interactions hydrophobes entre les branches du dendrimère et les chaînes de l'aminosucre. Les travaux précédents réalisés dans nos laboratoires ont ainsi montré que ces analogues multivalents du GalCer sont des très bons inhibiteurs du VIH-1 mais qu'ils possèdent une toxicité cellulaire non-négligeable. Dans le but de diminuer cette cytotoxicité et d'étudier l'influence de la périphérie du dendrimère sur l'activité anti-VIH par l'introduction de diverses modifications chimiques près de la paire d’ions, nous avons conçu une série de dendrimères de première génération à terminaison acide phosphonique et leurs analogues catanioniques du GalCer. L'hypothèse centrale de cette stratégie était la possibilité d'augmenter la stabilité de la paire d'ions grâce à des modifications chimiques, notamment par l'augmentation des effets hydrophobes apportés par une chaîne alkyle supplémentaire. Cette série d'analogues catanioniques du GalCer montre une très bonne activité mais des index thérapeutiques bas à cause des valeurs relativement élevées de la toxicité, malgré les modifications structurales réalisées. C'est pourquoi nous avons d'abord vérifié que cette cytotoxicité n'était pas liée aux propriétés d'aggrégation de ces analogues catanioniques dendritiques. Cette validation a conforté notre hypothèse initiale qui explique la cytotoxicité par un manque de stabilité de la paire d'ion in vitro, et la libération partielle d'aminolactitol dans le milieu biologique, dont les propriétés détergentes pourraient expliquer la cytotoxicité. Pour valider cette hypothèse, des études par fluorimètrie ont été réalisées avec des composés modèles, à l'aide de nouveaux analogues catanioniques fluorescents conçus pour cette étude. Les constantes de dissociation obtenues par spectrofluorométrie sont faibles (de l'ordre de 10-5 M) pour tous les dendrimères. Cela signifie que la paire d'ions est partiellement dissociée dans le milieu de culture cellulaire. Il n'est donc pas exclu que des interactions entre les aminolactitols du catanioniques et des récepteurs cellulaires renforcent la dissociation. En effet, ces constantes de dissociation sont 10000 fois plus grandes que celles correspondantes à des autres partenaires biologiques du GalCer, par exemple, la constante de dissociation du complexe GalCer-gp120 est de l'ordre de la nanomole. Bien qu'il s'agisse d'un modèle, la paire d'ions n'est pas sans doute capable de maintenir l'association catanionique. Ces travaux nous ont permis de corréler des propriétés biologiques de dendrimères catanioniques à leur comportement physico-chimique et pourraient aider à concevoir d'autres candidats analogues multivalents du galcer plus performants.The galactosylceramide or GalCer, a glycolipid derived, is a cellular receptor of the HIV. It acts through its high affinity for the V3 loop of gp120 of HIV. One therapeutic strategie employed involves the synthesis of chimeras designed to mimic the receptor and then, to block the recognition between the virus and the cells GalCer (+) and CD4 (+). In addition, the most cell recognition processes are multivalent. The inhibition of these processes is more effective when a multivalent inhibitor is used. It is within this context that the use of phosphorus dendrimers catanionic GalCer analogues mimicking cell surfaces was considered. These compounds are obtained by a simple acid-base reaction in water between an acid-terminated dendrimer and a long chain aminosugar called aminolactitol. These catanionics dendrimers are supramolecular assemblies whose stability is ensured by hydrophobic interactions between the dendrimer branches and the chains of amino sugar. Previous work conducted in our laboratories have shown that these multivalent analogs of GalCer are very good inhibitors of HIV-1 but they have a non-negligible cell toxicity. In order to reduce the cytotoxicity and to study the influence of the periphery of the dendrimer on the anti-HIV activity by introducing various chemical modifications near the ion pair, we designed a series of first generation phosphonic acid-terminated dendrimers and their catanionic analogs of GalCer. The central hypothesis of this strategy was the possibility of increasing the stability of the ion pair through chemical changes, including increased hydrophobic effects by an additional alkyl chain. This series of catanionic analogs of GalCer shows a very good activity but a low therapeutic index due to relatively high values of toxicity, despite the structural changes made. For this reason, first of all, we have verified that this cytotoxicity was not related to aggregation properties of these catanionic dendritic analogues. This validation has confirmed our initial hypothesis that explains the cytotoxicity by a lack of in vitro stability of the ion pair, and the partial release of aminolactitol in the biological environment. This detergency effect could explain this cytotoxicity. To validate this hypothesis, fluorimetry experiments were performed using model compounds. For that, new catanionic fluorescent analogues have been designed. The dissociation constants obtained by spectrofluorometry are low (about 10-5 M) for all dendrimers. This means that the ion pair is partially dissociated in the cell culture medium. It can be possible that interactions between the aminolactitols of catanionic assemblies and cellular receptors enhance the dissociation. Indeed, these dissociation constants are 10000 times larger than those corresponding to other biological partners of GalCer. For instance, the dissociation constant of the gp120-GalCer complex is the order of nanomoles. Although this is a model, the ion pair is probably not able to maintain the association catanionic. This work allowed us to correlate the biological properties of catanionic dendrimers and their physico-chemical properties and may help to design other multivalent analogs of GalCer which can be more efficient