Cantu syndrome–associated SUR2 (ABCC9) mutations in distinct structural domains result in KATP channel gain-of-function by differential mechanisms

The complex disorder Cantu syndrome (CS) arises from gainof-function mutations in either KCNJ8 or ABCC9, the genes encoding the Kir6.1 and SUR2 subunits of ATP-sensitive potassium (KATP) channels, respectively. Recent reports indicate that such mutations can increase channel activity by multiple molecular mechanisms. In this study, we determined the mechanism by which KATP function is altered by several substitutions in distinct structural domains of SUR2: D207E in the intracellular L0-linker and Y985S, G989E, M1060I, and R1154Q/R1154W in TMD2. We engineered substitutions at their equivalent positions in rat SUR2A (D207E, Y981S, G985E, M1056I, and R1150Q/R1150W) and investigated functional consequences using macroscopic rubidium (86Rb-) efflux assays and patchclamp electrophysiology. Our results indicate that D207E increases KATP channel activity by increasing intrinsic stability of the open state, whereas the cluster of Y981S/G985E/M1056I substitutions, as well as R1150Q/R1150W, augmented Mg-nucleotide activation. We also tested the responses of these channel variants to inhibition by the sulfonylurea drug glibenclamide, a potential pharmacotherapy for CS. None of the D207E, Y981S, G985E, or M1056I substitutions had a significant effect on glibenclamide sensitivity. However, Gln and Trp substitution at Arg-1150 significantly decreased glibenclamide potency. In summary, these results provide additional confirmation that mutations in CS-Associated SUR2 mutations result in KATP gain-of-function. They help link CS genotypes to phenotypes and shed light on the underlying molecular mechanisms, including consequences for inhibitory drug sensitivity, insights that may inform the development of therapeutic approaches to manage CS

Towards Applying River Formation Dynamics in Continuous Optimization Problems

River Formation Dynamics (RFD) is a metaheuristic that has been successfully used by different research groups to deal with a wide variety of discrete combinatorial optimization problems. However, no attempt has been done to adapt it to continuous optimization domains. In this paper we propose a first approach to obtain such objective, and we evaluate its usefulness by comparing RFD results against those obtained by other more mature metaheuristics for continuous domains. In particular, we compare with the results obtained by Particle Swarm Optimization, Artificial Bee Colony, Firefly Algorithm, and Social Spider Optimization

Charged Higgs in 3-3-1 Model Through e−e+e^-e^+ Collisions

In this work we present an analysis of production and signature of charged Higgs bosons $H_2^{\pm}$ in the version of the 3-3-1 model containing heavy leptons at the CLIC (Cern Linear Collider). The production rate is found to be significant for the direct production of $e^{-} e^{+} \rightarrow H_{2}^{+} H_{2}^{-}$. We also studied the possibility to identify it using their respective branching ratios.Comment: 16 pages, 9 Figures. arXiv admin note: substantial text overlap with arXiv:1408.5944; text overlap with arXiv:1311.0845, arXiv:1205.404

mTORC1 activity is supported by spatial association with focal adhesions

The mammalian target of rapamycin complex 1 (mTORC1) integrates mitogenic and stress signals to control growth and metabolism. Activation of mTORC1 by amino acids and growth factors involves recruitment of the complex to the lysosomal membrane and is further supported by lysosome distribution to the cell periphery. Here, we show that translocation of lysosomes toward the cell periphery brings mTORC1 into proximity with focal adhesions (FAs). We demonstrate that FAs constitute discrete plasma membrane hubs mediating growth factor signaling and amino acid input into the cell. FAs, as well as the translocation of lysosome-bound mTORC1 to their vicinity, contribute to both peripheral and intracellular mTORC1 activity. Conversely, lysosomal distribution to the cell periphery is dispensable for the activation of mTORC1 constitutively targeted to FAs. This study advances our understanding of spatial mTORC1 regulation by demonstrating that the localization of mTORC1 to FAs is both necessary and sufficient for its activation by growth-promoting stimuli

Ajuste da metodologia camponês a camponês com abordagem territorial agroecológica.

Demandas pela compreensão da abordagem territorial e formas pertinentes de viabilidade de inovação agroecológica em territórios de identidade rural motivaram a realização desta pesquisa-ação. Neste contexto o objetivo da pesquisa foi de ajuste da metodologia ?campesino a campesino? visando contribuir para dotar a agricultura camponesa de autonomia alimentar, tecnológica, de insumos e energética, visando um desenvolvimento territorial justo e solidário. A pesquisa-ação foi realizada no Território de identidade rural Sul Sergipano situado na região litorânea do estado de Sergipe, pertencente ao bioma mata atlântica do Nordeste Brasileiro. A metodologia consistiu do emprego do diagnóstico rural rápido participativo (DRP); da construção de redes de agroecologia e do ajuste da metodologia campesino a campesino. Os principais resultados se referem à identificação de eixos de desenvolvimento rural da região; ações para a consolidação das redes existentes e o arranjo de formas inovadoras de intercâmbio de experiências potencializadas pela metodologia de construção de conhecimento. As conclusões referem-se à função sine qua non de construção coletiva do conhecimento e, a necessidade de construção de uma nova abordagem para a extensão rural agroecológica nestes espaços

Construção de conhecimento agroecológico em território de identidade rural de Sergipe.

bitstream/item/131823/1/COT-154.pd

Experiências agroecológicas do Território Sul sergipano.

bitstream/item/132861/1/Doc-188.pd

Estratégias para a inovação agroecológica em territórios de identidade rural.

bitstream/item/173031/1/COT-211.pd