An ultrasensitive sorting mechanism for EGF receptor endocytosis

Background The EGF receptor has been shown to internalize via clathrin-independent endocytosis (CIE) in a ligand concentration dependent manner. From a modeling point of view, this resembles an ultrasensitive response, which is the ability of signaling networks to suppress a response for low input values and to increase to a pre-defined level for inputs exceeding a certain threshold. Several mechanisms to generate this behaviour have been described theoretically, the underlying assumptions of which, however, have not been experimentally demonstrated for the EGF receptor internalization network. Results Here, we present a mathematical model of receptor sorting into alternative pathways that explains the EGF-concentration dependent response of CIE. The described mechanism involves a saturation effect of the dominant clathrin-dependent endocytosis pathway and implies distinct steady-states into which the system is forced for low vs high EGF stimulations. The model is minimal since no experimentally unjustified reactions or parameter assumptions are imposed. We demonstrate the robustness of the sorting effect for large parameter variations and give an analytic derivation for alternative steady-states that are reached. Further, we describe extensibility of the model to more than two pathways which might play a role in contexts other than receptor internalization. Conclusions Our main result is that a scenario where different endocytosis routes consume the same form of receptor corroborates the observation of a clear-cut, stimulus dependent sorting. This is especially important since a receptor modification discriminating between the pathways has not been found. The model is not restricted to EGF receptor internalization and might account for ultrasensitivity in other cellular contexts

As conferências educacionais: projetos para a nação e modernidade pedagógica nos anos de 1920 - Brasil

Tese (doutorado) - Universidade Federal de Santa Catarina, Centro de Ciências da Educação, Programa de Pós-Graduação em Educação, Florianópolis, 2014.Esta pesquisa constitui-se por uma abordagem na área da história da educação com centralidade em cinco conferências educacionais ocorridas no Brasil nos anos de 1920: Conferência Interestadual do Ensino Primário (Rio de Janeiro, 1921); Congresso de Ensino Primário e Normal (Paraná, 1926); Primeiro Congresso de Instrução Primária (Minas Gerais, 1927); Primeira Conferência Estadual do Ensino Primário (Santa Catarina, 1927); Primeira Conferência Nacional de Educação, promovida por intermédio da ABE (Curitiba, 1927). Para as análises realizadas e apresentação textual, foram mobilizados alguns conceitos - moderno/modernidade, repertório, intelectuais, permanência, representação, instruir e educar por meio do ensino primário - com o objetivo central de investigar aspectos e elementos que se entrecruzam e que podem ser tomados como representativos de projetos para a nação e da modernidade pedagógica requeridos, no Brasil dos anos de 1920. Apresenta-se a seguinte questão-problema: Como pensar as conferências educacionais como integrantes de um repertório que mobilizou sujeitos - intelectuais - em defesa e disputa de concepções e projetos, no intento de estabelecer sob que sentidos e significados a modernidade pedagógica deveria estar assentada no Brasil dos anos de 1920? Os intelectuais em destaque foram Orestes de Oliveira Guimarães, Antonio de Sampaio Dória, Lysimaco Ferreira da Costa, Antonio de Arruda Carneiro Leão, Francisco Luís da Silva Campos, Manoel Bergström Lourenço Filho. A demarcação do período histórico desta pesquisa - anos de 1920 - é representada pela ocorrência da primeira iniciativa, no período republicano, em nível federal, para a realização de uma conferência, em 1921, que pretendia discutir e propor para o campo educacional, em nível nacional, e pela continuidade de eventos congêneres, no alongar desta década, por iniciativa de Estados brasileiros, bem como pela Primeira Conferência Nacional de Educação, proposta, em 1927, pela Associação Brasileira de Educação - ABE. As conferências educacionais, no Brasil dos anos de 1920, podem ser interpretadas por seu caráter educacional, pedagógico e político e como integrantes de um repertório de ações no intento de estabelecer propostas (projetos) e encontrar soluções para os problemas ligados ao contexto educacional ou escolar e que isto pudesse colaborar com o progresso do Brasil. Considera-se que as conferências educacionais constituíram-se como lugares de discussão e disputas entre sujeitos e ideias pelas balizas do que deveria compor a modernidade pedagógica para a formação do cidadão republicano, onde a escola primária teria papel preponderante neste intento. Inseridas em um programa de constituição ou de fortalecimento da identidade, sentimento e consciência nacionais do período, com perspectivas para além dele - para o futuro, para o progresso -, as conferências educacionais, como estruturas políticas de oportunidades, tiveram projeção no sentido de intervir nos espaços e problemas mais amplos da sociedade que transcendiam às questões educacionais e pedagógicas e permitiram que seus propositores ou participantes alçassem outros postos ou ocupassem outros lugares e posições, tanto relacionados à esfera educacional quanto à política.<br

PIP3-dependent macropinocytosis is incompatible with chemotaxis

In eukaryotic chemotaxis, the mechanisms connecting external signals to the motile apparatus remain unclear. The role of the lipid phosphatidylinositol 3,4,5-trisphosphate (PIP3) has been particularly controversial. PIP3 has many cellular roles, notably in growth control and macropinocytosis as well as cell motility. Here we show that PIP3 is not only unnecessary for Dictyostelium discoideum to migrate toward folate, but actively inhibits chemotaxis. We find that macropinosomes, but not pseudopods, in growing cells are dependent on PIP3. PIP3 patches in these cells show no directional bias, and overall only PIP3-free pseudopods orient up-gradient. The pseudopod driver suppressor of cAR mutations (SCAR)/WASP and verprolin homologue (WAVE) is not recruited to the center of PIP3 patches, just the edges, where it causes macropinosome formation. Wild-type cells, unlike the widely used axenic mutants, show little macropinocytosis and few large PIP3 patches, but migrate more efficiently toward folate. Tellingly, folate chemotaxis in axenic cells is rescued by knocking out phosphatidylinositide 3-kinases (PI 3-kinases). Thus PIP3 promotes macropinocytosis and interferes with pseudopod orientation during chemotaxis of growing cells

Locomotion Policy Guided Traversability Learning using Volumetric Representations of Complex Environments

Despite the progress in legged robotic locomotion, autonomous navigation in unknown environments remains an open problem. Ideally, the navigation system utilizes the full potential of the robots' locomotion capabilities while operating within safety limits under uncertainty. The robot must sense and analyze the traversability of the surrounding terrain, which depends on the hardware, locomotion control, and terrain properties. It may contain information about the risk, energy, or time consumption needed to traverse the terrain. To avoid hand-crafted traversability cost functions we propose to collect traversability information about the robot and locomotion policy by simulating the traversal over randomly generated terrains using a physics simulator. Thousand of robots are simulated in parallel controlled by the same locomotion policy used in reality to acquire 57 years of real-world locomotion experience equivalent. For deployment on the real robot, a sparse convolutional network is trained to predict the simulated traversability cost, which is tailored to the deployed locomotion policy, from an entirely geometric representation of the environment in the form of a 3D voxel-occupancy map. This representation avoids the need for commonly used elevation maps, which are error-prone in the presence of overhanging obstacles and multi-floor or low-ceiling scenarios. The effectiveness of the proposed traversability prediction network is demonstrated for path planning for the legged robot ANYmal in various indoor and natural environments.Comment: accepted for 2022 IEEE/RSJ International Conference on Intelligent Robots and Systems (IROS 2022

Systematic review of the use of granulocyte-macrophage colony-stimulating factor in patients with advanced melanoma.

Several immunomodulatory checkpoint inhibitors have been approved for the treatment of patients with advanced melanoma, including ipilimumab, nivolumab and pembrolizumab. Talimogene laherparepvec is the first oncolytic virus to gain regulatory approval in the USA; it is also approved in Europe. Talimogene laherparepvec expresses granulocyte-macrophage colony-stimulating factor (GM-CSF), and with other GM-CSF-expressing oncolytic viruses in development, understanding the clinical relevance of this cytokine in treating advanced melanoma is important. Results of trials of GM-CSF in melanoma have been mixed, and while GM-CSF has the potential to promote anti-tumor responses, some preclinical data suggest that GM-CSF may sometimes promote tumor growth. GM-CSF has not been approved as a melanoma treatment. We undertook a systematic literature review of studies of GM-CSF in patients with advanced melanoma (stage IIIB-IV). Of the 503 articles identified, 26 studies met the eligibility criteria. Most studies investigated the use of GM-CSF in combination with another treatment, such as peptide vaccines or chemotherapy, or as an adjuvant to surgery. Some clinical benefit was reported in patients who received GM-CSF as an adjuvant to surgery, or in combination with other treatments. In general, outcomes for patients receiving peptide vaccines were not improved with the addition of GM-CSF. GM-CSF may be a valuable therapeutic adjuvant; however, further studies are needed, particularly head-to-head comparisons, to confirm the optimal dosing regimen and clinical effectiveness in patients with advanced melanoma

Can the Severity of Normal Tissue Damage after Radiation Therapy Be Predicted?

Begg discusses a new study by Svensson and colleagues in which the researchers attempted to elucidate genetic factors involved in late radiation toxicity