Activity in area V3A predicts positions of moving objects

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[¹⁸F]fluorination of biorelevant arylboronic acid pinacol ester scaffolds synthesized by convergence techniques

Aim: The development of small molecules through convergent multicomponent reactions (MCR) has been boosted during the last decade due to the ability to synthesize, virtually without any side-products, numerous small drug-like molecules with several degrees of structural diversity.(1) The association of positron emission tomography (PET) labeling techniques in line with the “one-pot” development of biologically active compounds has the potential to become relevant not only for the evaluation and characterization of those MCR products through molecular imaging, but also to increase the library of radiotracers available. Therefore, since the [18F]fluorination of arylboronic acid pinacol ester derivatives tolerates electron-poor and electro-rich arenes and various functional groups,(2) the main goal of this research work was to achieve the 18F-radiolabeling of several different molecules synthesized through MCR. Materials and Methods: [18F]Fluorination of boronic acid pinacol esters was first extensively optimized using a benzaldehyde derivative in relation to the ideal amount of Cu(II) catalyst and precursor to be used, as well as the reaction solvent. Radiochemical conversion (RCC) yields were assessed by TLC-SG. The optimized radiolabeling conditions were subsequently applied to several structurally different MCR scaffolds comprising biologically relevant pharmacophores (e.g. β-lactam, morpholine, tetrazole, oxazole) that were synthesized to specifically contain a boronic acid pinacol ester group. Results: Radiolabeling with fluorine-18 was achieved with volumes (800 μl) and activities (≤ 2 GBq) compatible with most radiochemistry techniques and modules. In summary, an increase in the quantities of precursor or Cu(II) catalyst lead to higher conversion yields. An optimal amount of precursor (0.06 mmol) and Cu(OTf)2(py)4 (0.04 mmol) was defined for further reactions, with DMA being a preferential solvent over DMF. RCC yields from 15% to 76%, depending on the scaffold, were reproducibly achieved. Interestingly, it was noticed that the structure of the scaffolds, beyond the arylboronic acid, exerts some influence in the final RCC, with electron-withdrawing groups in the para position apparently enhancing the radiolabeling yield. Conclusion: The developed method with high RCC and reproducibility has the potential to be applied in line with MCR and also has a possibility to be incorporated in a later stage of this convergent “one-pot” synthesis strategy. Further studies are currently ongoing to apply this radiolabeling concept to fluorine-containing approved drugs whose boronic acid pinacol ester precursors can be synthesized through MCR (e.g. atorvastatin)

Prior knowledge contribution to declarative learning. A study in amnesia, aging and Alzheimer's disease

L'étude expérimentale de la mémoire humaine a connu deux moments historiques dans les soixante dernières années. 1957 marque la découverte du rôle du lobe temporal interne bilatéral dans l'apprentissage conscient, déclaratif. 1997 marque la découverte de deux systèmes de mémoire déclarative, épisodique et sémantique. Ces découvertes résultent d'études de cas en neuropsychologie. Cette thèse s'inscrit dans la tradition neuropsychologique: sa genèse doit tout à un patient souffrant d'une forme atypique d'amnésie développementale, le patient KA. Son point de départ est une étude de cas approfondie, avec deux résultats surprenants. Malgré une amnésie sévère, KA dispose de connaissances sémantiques exceptionnelles. Par ailleurs, il montre des capacités préservées d'apprentissage explicite, mais uniquement pour des stimuli concrets, pas abstraits. En conséquence, cette thèse a exploré deux pistes de recherche. Premièrement, nous avons caractérisé les processus préservés d'apprentissage déclaratif et l'anatomie cérébrale chez ce patient. Deuxièmement, nous avons étudié le rôle des connaissances préalables dans l'apprentissage: comment ce que l'on sait influence ce dont nous nous souvenons ? Une première série d'expériences montre chez ce patient une atteinte sévère et sélective de l'ensemble du système hippocampique, alors que les structures sous- hippocampiques (cortex entorhinal, périrhinal et parahippocampique) sont préservées. Malgré une amnésie épisodique sévère, nous montrons des connaissances sémantiques supranormales et des aptitudes d'apprentissage explicite rapide. Ces aptitudes sont toutefois restreintes aux stimuli associés à des connaissances préalables. Une seconde série d'expériences explore l'hypothèse selon laquelle les connaissances préalables facilitent l'apprentissage en mémoire déclarative, même dans les situations où le lobe temporal interne est fragilisé, comme dans le vieillissement, ou lésé, comme chez le patient KA ou dans la maladie d'Alzheimer. Nos résultats suggèrent l'existence de processus d'apprentissage rapide en mémoire déclarative, indépendants du système hippocampique et sensibles à la présence de représentations préexistantes. Ces processus semblent affectés par la maladie d'Alzheimer, et ce en lien avec un défaut d'activité des régions sous-hippocampiques antérieures. A l'inverse, les sujets âgés sains peuvent utiliser les connaissances préalables et pourraient ainsi compenser le déclin de la mémoire associative. Ce travail s'accorde avec les modèles postulant une dissociation fonctionnelle au sein du lobe temporal interne pour l'apprentissage déclaratif. Il soutient les propositions neurocognitives et computationnelles récentes, suggérant une voie d'apprentissage néocortical rapide mobilisable dans certaines circonstances. Il met en exergue la dynamique des apprentissages en mémoire déclarative et notamment l'intrication fondamentale entre "savoir" et "se souvenir". Ce que je sais a un impact profond sur ce dont je vais me souvenir. Cette thèse permet d'envisager de nouveaux outils cognitifs pour le diagnostic de la maladie d'Alzheimer. De plus, il semble que des lésions temporales internes auront un impact distinct sur l'apprentissage selon le statut des informations à mémoriser en mémoire à long terme, offrant un regard nouveau sur les effets stimulus-dépendants dans l'amnésie. Une considération approfondie des connaissances préalables associées au contenu de nos expériences, et leur caractérisation détaillée, est requise pour affiner les modèles de la mémoire déclarative. Ces résultats apportent de nouvelles pistes de recherche quant aux circonstances épargnant l'apprentissage, notamment associatif, lors du vieillissement. Plus généralement, ils contribuent à la compréhension des déterminants d'un apprentissage réussi, en mettant l'accent sur les recouvrements entre processus de récupération et d'acquisition. Des applications potentielles en découlent dans le domaine éducatif.The experimental study of human memory has had two historic moments in the last sixty years. 1957 marks the discovery of the role of the medial temporal lobes in conscious learning. 1997 marks the discovery of two systems of declarative memory, namely episodic and semantic memories. These major breakthroughs are owed to clinical case studies in neuropsychology. This thesis follows on from the neuropsychological tradition: its genesis owes everything to a patient suffering from an atypical form of developmental amnesia, the patient KA. The starting point of this work was a thorough neuropsychological study of this patient. Two striking findings shortly arose. First, despite lifelong amnesia, KA had acquired exceptional levels of knowledge about the world. Second, remaining explicit learning abilities were restricted to meaningful, not meaningless, memoranda. As a consequence, we have investigated two research pathways in that thesis. First, we aimed at better characterizing preserved learning abilities and brain structure of the patient KA. Second, our goal was to explore how prior knowledge affects new declarative learning or, put simply, how do we learn what we know? In a first series of behavioural and neuroimaging experiments, we have shown in this patient a severe and selective damage of the whole extended hippocampal system, but preserved subhippocampal structures (entorhinal, perirhinal and parahippocampal cortex). The patient suffers from severe episodic amnesia, but we bring striking evidence for supranormal semantic knowledge as well as normal explicit learning skills. These skills were, however, restricted to familiar stimuli, that is, stimuli carrying pre-experimental knowledge. In a second series of behavioural and neuroimaging experiments, we explored the hypothesis that prior knowledge can facilitate new learning in declarative memory, even in aging or in situations where structures of the medial temporal lobe are or injured, as in amnesia or Alzheimer's disease. Our results suggest the existence of processes allowing fast learning in declarative memory, independently of the hippocampal system, and that are sensitive to the presence of pre-existing representations in long-term memory. Such learning processes appear to be selectively affected by Alzheimer's disease at the pre-dementia stage, in relation to a lack of activation of subhippocampal regions. In contrast, healthy elderly were able to rely on these learning processes to compensate for the decline in associative memory associated with aging. This work lends support to the models postulating a functional dissociation with respect to learning in declarative memory. It indeed strengthens recent neurocognitive and computational accounts that suggest a rapid neocortical learning path under certain circumstances. It highlights the dynamics of learning in declarative memory and in particular the fundamental entanglement between "knowing" and "remembering". What I know profoundly impacts what I will remember. The present thesis points towards new cognitive tools for the diagnosis of Alzheimer's disease. It further brings evidence that medial temporal lesions differentially impact learning depending on the status of the memoranda in long-term memory, which sheds a new light on material-specific effects in amnesia. Our work speaks for a thorough consideration of whether the contents of events have prior representations within long-term memory, and to further better characterize their nature if we are to better understand learning mechanisms. It also brings additional clues for a deeper understanding of how learning and memory can be preserved in aging. More generally, it contributes to a better understanding of the factors determining successful learning, with a focus on how retrieval and acquisition processes overlap during learning. Such findings have potential applications in the educational field

Neuroimaging - Clinical Applications

Modern neuroimaging tools allow unprecedented opportunities for understanding brain neuroanatomy and function in health and disease. Each available technique carries with it a particular balance of strengths and limitations, such that converging evidence based on multiple methods provides the most powerful approach for advancing our knowledge in the fields of clinical and cognitive neuroscience. The scope of this book is not to provide a comprehensive overview of methods and their clinical applications but to provide a "snapshot" of current approaches using well established and newly emerging techniques

Smoking and Second Hand Smoking in Adolescents with Chronic Kidney Disease: A Report from the Chronic Kidney Disease in Children (CKiD) Cohort Study

The goal of this study was to determine the prevalence of smoking and second hand smoking [SHS] in adolescents with CKD and their relationship to baseline parameters at enrollment in the CKiD, observational cohort study of 600 children (aged 1-16 yrs) with Schwartz estimated GFR of 30-90 ml/min/1.73m2. 239 adolescents had self-report survey data on smoking and SHS exposure: 21 [9%] subjects had “ever” smoked a cigarette. Among them, 4 were current and 17 were former smokers. Hypertension was more prevalent in those that had “ever” smoked a cigarette (42%) compared to non-smokers (9%), p\u3c0.01. Among 218 non-smokers, 130 (59%) were male, 142 (65%) were Caucasian; 60 (28%) reported SHS exposure compared to 158 (72%) with no exposure. Non-smoker adolescents with SHS exposure were compared to those without SHS exposure. There was no racial, age, or gender differences between both groups. Baseline creatinine, diastolic hypertension, C reactive protein, lipid profile, GFR and hemoglobin were not statistically different. Significantly higher protein to creatinine ratio (0.90 vs. 0.53, p\u3c0.01) was observed in those exposed to SHS compared to those not exposed. Exposed adolescents were heavier than non-exposed adolescents (85th percentile vs. 55th percentile for BMI, p\u3c 0.01). Uncontrolled casual systolic hypertension was twice as prevalent among those exposed to SHS (16%) compared to those not exposed to SHS (7%), though the difference was not statistically significant (p= 0.07). Adjusted multivariate regression analysis [OR (95% CI)] showed that increased protein to creatinine ratio [1.34 (1.03, 1.75)] and higher BMI [1.14 (1.02, 1.29)] were independently associated with exposure to SHS among non-smoker adolescents. These results reveal that among adolescents with CKD, cigarette use is low and SHS is highly prevalent. The association of smoking with hypertension and SHS with increased proteinuria suggests a possible role of these factors in CKD progression and cardiovascular outcomes