Perspectivas epistemológicas no estudo científico e a avaliação clínica das funções executivas

En este artículo se examinan perspectivas epistemológicas que han moldeado e influenciado la búsqueda científica orientada hacia comprender aquello que los neuropsicólogos denominan las "funciones ejecutivas (FE). El término funciones ejecutivas se refiere a aspectos de control de la cognición y la conducta. Las ideas expuestas en este manuscrito presuponen que la orientación epistemológica de una persona determina la manera en la que ella conceptualiza la interacción entre las funciones cerebrales y su entorno físico. Cada una de esas orientaciones conlleva suposiciones acerca del modo como operan las FE y, por ende, el modo como deben ser evaluadas. Hasta fechas recientes esto se había abordado principalmente desde el punto de vista de dos perspectivas teóricas. Una de ellas, la analítica, tiene sus raíces en el movimiento positivista. La otra, también conocida como "ciencia romántica" es sintética, y provee las bases del trabajo científico del muy celebrado neuropsicólogo ruso A.R. Luria. Una tercera perspectiva, formulada en el marco de la "cognición corpórea", ha sido propuesta en los últimos 20 años, y está más estrechamente asociada con los trabajos de Francisco Varela. Se examina aquí, por medio de una revisión reflexiva e integradora de la literatura pertinente, la manera como esas tres perspectivas epistemológicas han influido sobre la investigación y la práctica clínica de la neuropsicología.In this article, epistemological perspectives that have shaped and affected the scientific quest for understanding what neuropsychologists term "executive functions" are reviewed. Executive functions refer to the control functions of cognition and behavior. The underlying thesis of the paper is that one's epistemological orientation determines how one sees the interaction between brain functions and our status in the world. Each different orientation thus carries with it implications with regard to how executive functions operate, as well as how, therefore, one should try to assess them. Until recently, these functions were approached through two primary epistemological points of view. One is analytic, which has its roots in the positivistic movement. The other approach is synthetic, otherwise known as "romantic science", and forms the basis of the work of the prominent Russian neuropsychologist A.R. Luria. A third epistemological perspective, articulated under the umbrella of 'embodied cognition' approaches, has been advanced in the last 20 years, and is associated most closely with the work of Francisco Varela. A review of, and reflection on how these perspectives have affected research and clinical practice in neuropsychology is provided.Neste artigo examinam-se as perspectivas epistemológicas que moldaram e influenciaram a busca científica orientada à compreender aquilo que os neuropsicólogos denominam as "funções executivas (FE). O termo funções executivas se refere a aspectos de controle da cognição e a conduta. As ideias expostas neste manuscrito pressupõem que a orientação epistemológica de uma pessoa determina a maneira em que ela conceitualiza a interação entre as funções cerebrais e seu entorno físico. Cada uma dessas orientações leva a suposições sobre o modo como operam as FE e, portanto, o modo como devem ser avaliadas. Até datas recentes isto havia sido abordado principalmente desde o ponto de vista de duas perspectivas teóricas. Uma delas, a analítica, tem suas raízes no movimento positivista. A outra, também conhecida como "ciência romântica" é sintética, e fornece as bases do trabalho científico do muito celebrado neuropsicólogo russo A.R. Luria. Uma terceira perspectiva, formulada no marco da "cognição corpórea", foi proposta nos últimos 20 anos, e está mais estreitamente associada com os trabalhos de Francisco Varela. Examina-se aqui, através de uma revisão reflexiva e integradora da literatura pertinente, a maneira como essas três perspectivas epistemológicas influíram sobre a pesquisa e a prática da neuropsicologia

Detection of cannabinoid receptor type 2 in native cells and zebrafish with a highly potent, cell-permeable fluorescent probe.

Despite its essential role in the (patho)physiology of several diseases, CB2R tissue expression profiles and signaling mechanisms are not yet fully understood. We report the development of a highly potent, fluorescent CB2R agonist probe employing structure-based reverse design. It commences with a highly potent, preclinically validated ligand, which is conjugated to a silicon-rhodamine fluorophore, enabling cell permeability. The probe is the first to preserve interspecies affinity and selectivity for both mouse and human CB2R. Extensive cross-validation (FACS, TR-FRET and confocal microscopy) set the stage for CB2R detection in endogenously expressing living cells along with zebrafish larvae. Together, these findings will benefit clinical translatability of CB2R based drugs

Epistemological perspectives in the scientific study and evaluation of executive function

In this article, epistemological perspectives that have shaped and affected the scientific quest for understanding what neuropsychologists term "executive functions" are reviewed. Executive functions refer to the control functions of cognition and behavior. The underlying thesis of the paper is that one's epistemological orientation determines how one sees the interaction between brain functions and our status in the world. Each different orientation thus carries with it implications with regard to how executive functions operate, as well as how, therefore, one should try to assess them. Until recently, these functions were approached through two primary epistemological points of view. One is analytic, which has its roots in the positivistic movement. The other approach is synthetic, otherwise known as "romantic science", and forms the basis of the work of the prominent Russian neuropsychologist A.R. Luria. A third epistemological perspective, articulated under the umbrella of 'embodied cognition' approaches, has been advanced in the last 20 years, and is associated most closely with the work of Francisco Varela. A review of, and reflection on how these perspectives have affected research and clinical practice in neuropsychology is provided.Neste artigo examinam-se as perspectivas epistemológicas que moldaram e influenciaram a busca científica orientada à compreender aquilo que os neuropsicólogos denominam as "funções executivas (FE). O termo funções executivas se refere a aspectos de controle da cognição e a conduta. As ideias expostas neste manuscrito pressupõem que a orientação epistemológica de uma pessoa determina a maneira em que ela conceitualiza a interação entre as funções cerebrais e seu entorno físico. Cada uma dessas orientações leva a suposições sobre o modo como operam as FE e, portanto, o modo como devem ser avaliadas. Até datas recentes isto havia sido abordado principalmente desde o ponto de vista de duas perspectivas teóricas. Uma delas, a analítica, tem suas raízes no movimento positivista. A outra, também conhecida como "ciência romântica" é sintética, e fornece as bases do trabalho científico do muito celebrado neuropsicólogo russo A.R. Luria. Uma terceira perspectiva, formulada no marco da "cognição corpórea", foi proposta nos últimos 20 anos, e está mais estreitamente associada com os trabalhos de Francisco Varela. Examina-se aqui, através de uma revisão reflexiva e integradora da literatura pertinente, a maneira como essas três perspectivas epistemológicas influíram sobre a pesquisa e a prática da neuropsicologia.En este artículo se examinan perspectivas epistemológicas que han moldeado e influenciado la búsqueda científica orientada hacia comprender aquello que los neuropsicólogos denominan las "funciones ejecutivas (FE). El término funciones ejecutivas se refiere a aspectos de control de la cognición y la conducta. Las ideas expuestas en este manuscrito presuponen que la orientación epistemológica de una persona determina la manera en la que ella conceptualiza la interacción entre las funciones cerebrales y su entorno físico. Cada una de esas orientaciones conlleva suposiciones acerca del modo como operan las FE y, por ende, el modo como deben ser evaluadas. Hasta fechas recientes esto se había abordado principalmente desde el punto de vista de dos perspectivas teóricas. Una de ellas, la analítica, tiene sus raíces en el movimiento positivista. La otra, también conocida como "ciencia romántica" es sintética, y provee las bases del trabajo científico del muy celebrado neuropsicólogo ruso A.R. Luria. Una tercera perspectiva, formulada en el marco de la "cognición corpórea", ha sido propuesta en los últimos 20 años, y está más estrechamente asociada con los trabajos de Francisco Varela. Se examina aquí, por medio de una revisión reflexiva e integradora de la literatura pertinente, la manera como esas tres perspectivas epistemológicas han influido sobre la investigación y la práctica clínica de la neuropsicología

Epigenetic analysis leads to identification of HNF1B as a subtype-specific susceptibility gene for ovarian cancer

Contains fulltext : 118378.pdf (publisher's version ) (Open Access)HNF1B is overexpressed in clear cell epithelial ovarian cancer, and we observed epigenetic silencing in serous epithelial ovarian cancer, leading us to hypothesize that variation in this gene differentially associates with epithelial ovarian cancer risk according to histological subtype. Here we comprehensively map variation in HNF1B with respect to epithelial ovarian cancer risk and analyse DNA methylation and expression profiles across histological subtypes. Different single-nucleotide polymorphisms associate with invasive serous (rs7405776 odds ratio (OR)=1.13, P=3.1 x 10(-10)) and clear cell (rs11651755 OR=0.77, P=1.6 x 10(-8)) epithelial ovarian cancer. Risk alleles for the serous subtype associate with higher HNF1B-promoter methylation in these tumours. Unmethylated, expressed HNF1B, primarily present in clear cell tumours, coincides with a CpG island methylator phenotype affecting numerous other promoters throughout the genome. Different variants in HNF1B associate with risk of serous and clear cell epithelial ovarian cancer; DNA methylation and expression patterns are also notably distinct between these subtypes. These findings underscore distinct mechanisms driving different epithelial ovarian cancer histological subtypes

Drug Derived Fluorescent Probes for the Specific Visualization of Cannabinoid Type 2 Receptor - A Toolbox Approach

Cannabinoid type 2 receptor (CB2R) is a fundamental part of the endocannabinoid signaling system (eCB system), and is known to play an important role in tissue injury, inflammation, cancer and pain. In stark contrast to its significance, the underlying signaling mechanisms and tissue expression profiles are poorly understood. Due to its low expression in healthy tissue and lack of reliable chemical tools, CB2R visualization in live cells remains uncharted. Here we report the development of a drug derived toolbox of highly potent, CB2R-selective fluorescent probes based on reverse design. Extensive validation in several applications such as CB2R detection in flow cytometry and time-resolved imaging, and the development of a novel fluorescent-based TR-FRET assay to generate kinetic and equilibrium binding data demonstrate the high versatility of our toolbox. These probes are the first to preserve affinity and efficacy in both human and mouse CB2R, a crucial aspect for preclinical translatability, and to enable imaging of CB2R internalization in living cells using confocal microscopy

Highly Specific, Fluorescent Cannabinoid Type 2 Receptor Probes Enable Applications in Microscopy, Flow Cytometry and FRET-based Binding Assays

Pharmacological modulation of cannabinoid type 2 receptor (CB2R) holds promise for the treatment of numerous conditions including inflammatory diseases, autoimmune disorders, pain, and cancer. Despite its significance, researchers lack reliable tools to address questions concerning the complex mechanism of CB2R signaling and its downstream consequences, especially in cell-type and tissue-dependent contexts. Herein, we report highly specific CB2R fluorescent probes and their use in a variety of applications: flow cytometry with overexpressing as well as endogenously expressing cells, real-time confocal microscopy of living cells, and a novel FRET-based, CB2R binding assay amenable to high throughput screening.<br /