Increased activity of D5R-Kv1.3 pathway in cholinergic interneurons contributes to the hypercholinergic state of parkinsonism and dyskinesias

Balanced actions of dopamine (DA) and acetylcholine (ACh) shape striatal function. Striatal cholinergic interneurons (ChIs) are the main striatal ACh source. In Parkinson´s disease (PD), DAergic nigrostriatal neurons degenerate, leading to a hypercholinergic state. L-dopa treatment can induce dyskinesias (LID). Previously, we found that ChIs are hyperexcitable in a mouse model of PD as result of a reduced Kv1.3 current, and, recently, that ChIs from LID mice are even more hyperexcitable. Our aim is to identify the mechanisms underlying this hyperexcitability, which are potential new therapeutic targets for Parkinson?s disease and dyskinesias. Since hyperexcitability occurs in the absence of DA or L-dopa treatment, we hypothesize that physiologic activation of D5R, which results in increased excitability, reduces Kv1.3 current. Because the D5R, which has constitutive (ligand-independent) activity, excites ChIs in physiological conditions, we hypothesize that an alteration of D5R signaling causes ChIs hyperexcitability in PD. With ex-vivo electrophysiological recordings, we found that D5R increases ChIs excitability by reducing a Kv1.3 current through a cAMP dependent signaling cascade. Moreover, in PD and LID mouse models, elevated levels of cAMP contribute to ChIs hyperexcitability. Finally, preliminary results suggest that this pathway is overactive due to an increased constitutive activation of D5R that entails an increased cAMP production followed by a reduction in Kv1.3 current, resulting in ChIs hyperexcitability.Fil: Tubert, Cecilia. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Fisiología y Biofísica Bernardo Houssay. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Fisiología y Biofísica Bernardo Houssay; ArgentinaFil: Paz, Rodrigo Manuel. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Fisiología y Biofísica Bernardo Houssay. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Fisiología y Biofísica Bernardo Houssay; ArgentinaFil: Stahl, Agostina Mónica. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Fisiología y Biofísica Bernardo Houssay. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Fisiología y Biofísica Bernardo Houssay; ArgentinaFil: Rela, Lorena. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Fisiología y Biofísica Bernardo Houssay. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Fisiología y Biofísica Bernardo Houssay; ArgentinaFil: Murer, Mario Gustavo. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Fisiología y Biofísica Bernardo Houssay. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Fisiología y Biofísica Bernardo Houssay; ArgentinaXXXV Reunión Anual de la Sociedad Argentina de Investigación en NeurocienciasCiudad Autónoma de Buenos AiresArgentinaSociedad Argentina de Investigación en Neurociencia

Functional resilience against climate-driven extinctions: comparing the functional diversity of European and North Americantree floras

Future global change scenarios predict a dramatic loss of biodiversity for many regions in the world, potentially reducing the resistance and resilience of ecosystem functions. Once before, during Plio-Pleistocene glaciations, harsher climatic conditions in Europe as compared to North America led to a more depauperate tree flora. Here we hypothesize that this climate driven species loss has also reduced functional diversity in Europe as compared to North America. We used variation in 26 traits for 154 North American and 66 European tree species and grid-based co-occurrences derived from distribution maps to compare functional diversity patterns of the two continents. First, we identified similar regions with respect to contemporary climate in the temperate zone of North America and Europe. Second, we compared the functional diversity of both continents and for the climatically similar subregions using the functional dispersion-index (FDis) and the functional richness index (FRic). Third, we accounted in these comparisons for grid-scale differences in species richness, and, fourth, investigated the associated trait spaces using dimensionality reduction. For gymnosperms we find similar functional diversity on both continents, whereas for angiosperms functional diversity is significantly greater in Europe than in North America. These results are consistent across different scales, for climatically similar regions and considering species richness patterns. We decomposed these differences in trait space occupation into differences in functional diversity vs. differences in functional identity. We show that climate-driven species loss on a continental scale might be decoupled from or at least not linearly related to changes in functional diversity. This might be important when analyzing the effects of climate-driven biodiversity change on ecosystem functioning

The cuticle mutant eca2 modifies plant defense responses to biotrophic and necrotrophic pathogens and herbivory insects

We isolated previously several Arabidopsis thaliana mutants with constitutive expression of the early microbe-associated molecular pattern–induced gene ATL2, named eca (expresión constitutiva de ATL2). Here, we further explored the interaction of eca mutants with pest and pathogens. Of all eca mutants, eca2 was more resistant to a fungal pathogen (Botrytis cinerea) and a bacterial pathogen (Pseudomonas syringae) as well as to a generalist herbivorous insect (Spodoptera littoralis). Permeability of the cuticle is increased in eca2; chemical characterization shows that eca2 has a significant reduction of both cuticular wax and cutin. Additionally, we determined that eca2 did not display a similar compensatory transcriptional response, compared with a previously characterized cuticular mutant, and that resistance to B. cinerea is mediated by the priming of the early and late induced defense responses, including salicylic acid– and jasmonic acid–induced genes. These results suggest that ECA2-dependent responses are involved in the nonhost defense mechanism against biotrophic and necrotrophic pathogens and against a generalist insect by modulation and priming of innate immunity and late defense responses. Making eca2 an interesting model to characterize the molecular basis for plant defenses against different biotic interactions and to study the initial events that take place in the cuticle surface of the aerial organs

An interactive machine learning system for image advertisements

Advertising is omnipresent in all countries around the world and has a strong influence on consumer behavior. Given that advertisements aim to be memorable, attract attention and convey the intended information in a limited space, it seems striking that previous research in economics and management has mostly neglected the content and style of actual advertisements and their evolution over time. With this in mind, we collected more than one million print advertisements from the English-language weekly news magazine “The Economist” from 1843 to 2014. However, there is a lack of interactive intelligent systems capable of processing such a vast amount of image data and allowing users to automatically and manually add metadata, explore images, find and test assertions, and use machine learning techniques they did not have access to before. Inspired by the research field of interactive machine learning, we propose such a system that enables domain experts like marketing scholars to process and analyze this huge collection of image advertisements

Perceived contributions of multifunctional landscapes to human well-being : Evidence from 13 European sites

Multifunctional landscapes provide critical benefits and are essential for human well-being. The relationship between multifunctional landscapes and well-being has mostly been studied using ecosystem services as a linkage. However, there is a challenge of concretizing what human well-being exactly is and how it can be measured, particularly in relation to ecosystem services, landscape values and related discussions. In this paper, we measure self-reported well-being through applying an inductive free-listing approach to the exploration of the relationships between landscape multifunctionality and human well-being across 13 rural and peri-urban sites in Europe. We developed a face-to-face online survey (n = 2,301 respondents) integrating subjective perceptions of well-being (free-listing method) with mapping perceived ecosystem service benefits (Public Participation GIS, PPGIS approach). Applying content analysis and diverse statistical methods, we explore the links between well-being (i.e. perceived well-being items such as tranquillity, social relations and health) and social-ecological properties (i.e. respondents' sociocultural characteristics and perception of ecosystem service benefits). We identify 40 different well-being items highlighting prominently landscape values. The items form five distinct clusters: access to services; tranquillity and social capital; health and nature; cultural landscapes; and place attachment. Each cluster is related to specific study sites and explained by certain social-ecological properties. Results of our inductive approach further specify pre-defined conceptualizations on well-being and their connections to the natural environment. Results suggest that the well-being contributions of multifunctional landscapes are connected to therapeutic well-being effects, which are largely neglected in the ecosystem services literature. Our results further point to the context-specific character of linkages between landscapes and human well-being. The clusters highlight that landscape-supported well-being is related to multiple interlinked items that can inform collective visions of well-being in the future. For landscape planning and management, we highlight the need for place-specific analysis and consideration of perceptions of local people to identify the contributions to their well-being. Future research would benefit from considering the experiential qualities of value and well-being as they relate to direct experiences with the landscape and wider psychological needs, specifically over time. A free Plain Language Summary can be found within the Supporting Information of this article.Peer reviewe

Biocultural approaches to sustainability : A systematic review of the scientific literature

Current sustainability challenges demand approaches that acknowledge a plurality of human-nature interactions and worldviews, for which biocultural approaches are considered appropriate and timely. This systematic review analyses the application of biocultural approaches to sustainability in scientific journal articles published between 1990 and 2018 through a mixed methods approach combining qualitative content analysis and quantitative multivariate methods. The study identifies seven distinct biocultural lenses, that is, different ways of understanding and applying biocultural approaches, which to different degrees consider the key aspects of sustainability science-inter- and transdisciplinarity, social justice and normativity. The review suggests that biocultural approaches in sustainability science need to move from describing how nature and culture are co-produced to co-producing knowledge for sustainability solutions, and in so doing, better account for questions of power, gender and transformations, which has been largely neglected thus far. A free Plain Language Summary can be found within the Supporting Information of this article. A free Plain Language Summary can be found within the Supporting Information of this article.Peer reviewe

Niçin?

M. Turhan'ın Son Saat'te tefrika edilen Niçin? adlı romanıTefrika yarım kalmıştır. Arşivdeki eksikler nedeniyle tefrikanın tamamlanıp tamamlanmadığı bilinmemektedir

Modulation of RNA splicing enhances response to BCL2 inhibition in leukemia.

Therapy resistance is a major challenge in the treatment of cancer. Here, we performed CRISPR-Cas9 screens across a broad range of therapies used in acute myeloid leukemia to identify genomic determinants of drug response. Our screens uncover a selective dependency on RNA splicing factors whose loss preferentially enhances response to the BCL2 inhibitor venetoclax. Loss of the splicing factor RBM10 augments response to venetoclax in leukemia yet is completely dispensable for normal hematopoiesis. Combined RBM10 and BCL2 inhibition leads to mis-splicing and inactivation of the inhibitor of apoptosis XIAP and downregulation of BCL2A1, an anti-apoptotic protein implicated in venetoclax resistance. Inhibition of splicing kinase families CLKs (CDC-like kinases) and DYRKs (dual-specificity tyrosine-regulated kinases) leads to aberrant splicing of key splicing and apoptotic factors that synergize with venetoclax, and overcomes resistance to BCL2 inhibition. Our findings underscore the importance of splicing in modulating response to therapies and provide a strategy to improve venetoclax-based treatments