Impaired Function of HDAC6 Slows Down Axonal Growth and Interferes with Axon Initial Segment Development

The development of morphological neuronal polarity starts by the formation and elongation of an axon. At the same time the axon initial segment (AIS) is generated and creates a diffusion barrier which differentiate axon and somatodendritic compartment. Different structural and functional proteins that contribute to the generation of neuronal action potential are concentrated at the axon initial segment. While axonal elongation is controlled by signalling pathways that regulate cytoskeleton through microtubule associated proteins and tubulin modifications, the microtubule cytoskeleton under the AIS is mostly unknown. Thus, understanding which proteins modify tubulin, where in the neuron and at which developmental stage is crucial to understanding how morphological and functional neuronal polarity is achieved. In this study performed in mice and using a well established model of murine cultured hippocampal neurons, we report that the tubulin deacetylase HDAC6 is localized at the distal region of the axon, and its inhibition with TSA or tubacin slows down axonal growth. Suppression of HDAC6 expression with HDAC6 shRNAs or expression of a non-active mutant of HDAC6 also reduces axonal length. Furthermore, HDAC6 inhibition or suppression avoids the concentration of ankyrinG and sodium channels at the axon initial segment (AIS). Moreover, treatment of mouse cultured hippocampal neurons with detergents to eliminate the soluble pool of microtubules identified a pool of detergent resistant acetylated microtubules at the AIS, not present at the rest of the axon. Inhibition or suppression of HDAC6 increases acetylation all along the axon and disrupts the specificity of AIS cytoskeleton, modifying the axonal distal gradient localization of KIF5C to a somatodendritic and axonal localization. In conclusion, our results reveal a new role of HDAC6 tubulin deacetylase as a regulator of microtubule characteristics in the axon distal region where axonal elongation takes place, and allowing the development of acetylated microtubules microdomains where HDAC6 is not concentrated, such as the axon initial segment

Estudio comparativo de extractos crudos de plantas como alternativa en el control del cáncer bacteriano en jitomate

"Las enfermedades en los cultivos de interés agrícola siempre ha sido un problema que impacta negativamente al productor y consumidor con el desabasto de alimentos básicos; aunado a esto, factores externos complican el problema con la aparición o desarrollo de cepas fitopatógenas resistentes al control químico convencional. El jitomate es la hortaliza de mayor producción, ya que se cultiva para atender la demanda nacional y la exportación. Entre las hortalizas que México exporta, el jitomate es la más importante, por la derrama económica que representa para los agricultores y comercializadores su venta externa. Por otro lado, existen factores que limitan la producción, entre ellos resaltan los problemas fitosanitarios como el cáncer bacteriano que es ocasionado por la bacteria Clavibacter michiganensis ssp michiganensis (Cmm), una enfermedad cuarentenada y de impacto internacional por las pérdidas económicas que ocasiona en la producción de jitomate, principalmente en invernadero. Debido a la problemática expuesta, el desarrollo de este proyecto se justifica ampliamente, ya que buscaremos aprovechar algunos cultivos; Jamaica, Maracuyá y Naranja Agria; para la extracción de productos naturales empleados como complementemos o sustitutos de agentes químicos en el control de plagas de cultivos de interés agroindustrial"

Programa Municipal para la Preservación de los Recursos Hídricos Caso: Coatepec Harinas, Estado de México.

Una administración con miras al futuro, orientada a la prevención de los problemas es lo que no tuvimos antes y es por ellos que estamos en riesgo. El problema del agua requiere en nosotros cambios de valores, de paradigmas, de maneras de uso del recurso con el fin de ser flexibles y adaptarnos a los nuevos modos de uso del recurso natural tratado en este trabajo y así lograr hacer más perdurable en el tiempo este elixir que la naturaleza o hasta alguna deidad nos ha regalado

The regional network capital index in Mexico from 2012 to 2016

Abstract Based-off the regional development theory developed from knowledge and innovation, Huggins & Thompson [1] have proposed the concept of Network Capital, which aims to explain the importance of knowledge flow, knowledge absorptive capacity and investments on associations between firms and Universities or Scientific Centers or other firms in order to increase regional development. This paper used empirical data from Mexico for the period 2012–2016 to propose an alternative to the calculation of Network Capital at State level as an alternative to the Huggins and Thompson proposal. The data used cover all the 32 Mexican States about innovation activities. On this paper is shown the deep differences between Mexican States about the knowledge qualities, the absorptive capacity of knowledge and the investments on strategic associations, it that might be typical at non-innovation Nations. Although the proposal on this paper cannot be directly compared to that of Huggins and Thompson, both shows evidence that, the greater network capital, the greater the potential development based on knowledge

Exploiting lattice structures in shape grammar implementations

The ability to work with ambiguity and compute new designs based on both defined and emergent shapes are unique advantages of shape grammars. Realizing these benefits in design practice requires the implementation of general purpose shape grammar interpreters that support: (a) the detection of arbitrary subshapes in arbitrary shapes and (b) the application of shape rules that use these subshapes to create new shapes. The complexity of currently available interpreters results from their combination of shape computation (for subshape detection and the application of rules) with computational geometry (for the geometric operations need to generate new shapes). This paper proposes a shape grammar implementation method for three-dimensional circular arcs represented as rational quadratic Bézier curves based on lattice theory that reduces this complexity by separating steps in a shape computation process from the geometrical operations associated with specific grammars and shapes. The method is demonstrated through application to two well-known shape grammars: Stiny's triangles grammar and Jowers and Earl's trefoil grammar. A prototype computer implementation of an interpreter kernel has been built and its application to both grammars is presented. The use of Bézier curves in three dimensions opens the possibility to extend shape grammar implementations to cover the wider range of applications that are needed before practical implementations for use in real life product design and development processes become feasible

PROGRAMAS DE ESTIMULOS A LA INNOVACION EMPRESARIAL EN MEXICO, PRINCIPALES CIFRAS Y RESULTADOS

México se encuentra en el lugar 56 de 126 países en el Global Innovation Index 2018, un índice elaborado en conjunto por la Universidad de Cornell y Organización Mundial de Propiedad Intelectual, el indicador identifica como muy débil el aspecto de inversión y financiamiento a la innovación en México, pilar donde se sitúa en el lugar 102 de 126 países. El gasto en actividades de Innovación y Desarrollo en México proviene en su mayoría del gobierno federal, el cual lleva a cabo programas para incentivar la inversión del sector privado, que tan solo contribuye con un 22 por ciento, mientras que el resto proviene tanto de los gobiernos estatales a través de universidades y diversas fuentes de índole internacional. Este documento plantea hacer uso de un análisis descriptivo para obtener un balance del estado actual de las principales cifras y resultados que permitan identificar los sectores de actividad económica, los estados y las empresas más beneficiadas por los dos principales programas de estímulos a la innovación empresarial en México en el periodo de 2009 a 2018, con el fin de destacar elementos importantes en la operación de éstos en el contexto de las empresas mexicanas. Estos programas son el Programa de Estímulos a la Innovación (PEI) y el Estímulo Fiscal a la investigación y Desarrollo de la Tecnología (EFIDT). El tema de ésta investigación resulta de interés en el momento actual, ya que ha sido motivo de controversia de los actuales cambios en el marco de la política de la nueva administración federal, en el caso concreto el Programa de Estímulos a la innovación que recientemente ha sido cancelado. Los resultados del análisis descriptivo del programa también nos alertan de la necesidad de seguir profundizando en un diseño de políticas públicas en materia de CTI en mejorar la correcta distribución de los recursos de los programas de apoyo a las actividades de innovación de las empresas con una perspectiva local, regional y sectorial que considere las áreas de oportunidad respectivas. El reto, radica en este sentido en las brechas entre los estados, los sectores y las empresas más desarrolladas y el resto parece que se está ampliando y no reduciendo. El balance de las cifras a casi 20 años de operación de los programas de estímulos directos e indirectos a la innovación en las empresas desde 2001 a 2018, nos muestran una alta concentración tanto en el número de proyectos aprobados como en el monto de los recursos otorgados a un grupo de regiones, sectores industriales y grandes empresas beneficiarias de los programas

Current Regulatory Requirements for Biosimilars in Six Member Countries of BRICS-TM: Challenges and Opportunities

© 2021 Rahalkar, Sheppard, Santos, Dasgupta, Perez-Tapia, Lopez-Morales and Salek. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). https://creativecommons.org/licenses/by/4.0/Background: The aim of the study was to identify, interpret, and compare the current perspectives of regulatory agencies in six member countries of BRICS-TM (Brazil, Russia, India, China, South Africa, Turkey, and Mexico) on the different criteria used for biosimilar development and marketing authorisation process. Methods: A semi-quantitative questionnaire was developed covering the organisation of agency, biosimilar development criteria and marketing authorisation process and sent to seven regulatory agencies covering the BRICS-TM countries. All data was kept anonymous and confidential. Data processing and analysis was carried out; descriptive statistics were used for quantitative data and content analysis was employed to generate themes for qualitative data. Results: Out of the seven regulatory agencies included in the study, six representatives provided the responses. The perspectives of these six regulatory agencies varied on a number of aspects relating to the review criteria for biosimilar development and licencing process. The most prevalent model for data assessment is the “full review” of a marketing authorisation application. There is lack of a standard approach across the agencies on sourcing of the reference biological product, in vivo toxicity studies and confirmatory clinical studies. Most agencies restrict interaction with biosimilar developers and any scientific advice is non-binding. The marketing authorisation approval depends on scientific assessment of the dossier, sample analysis and GMP certification. The agencies do not issue any public assessment report specifying the summary basis of biosimilar approval. Conclusion: Regulatory agencies across the six emerging economies are steadily improving the regulatory mechanism in the area of biosimilars. However, there remains scope for increasing the effectiveness and efficiency of the processes by encouraging open and transparent interaction with developers, adopting a flexible approach toward accepting advanced analytical data in lieu of clinical studies and enhancing regulatory reliance amongst agencies. This will help to simplify the new biosimilar development programmes and make them more cost-effective.Peer reviewe

A polytopic strategy for improved non-asymptotic robust control via implicit Lyapunov functions

International audienceThis paper is concerned with finite-and fixed-time robust stabilization of uncertain multi-input nonlinear systems via the implicit Lyapunov function method. Instead of splitting the system into a linear nominal model and an additive perturbation which gathers nonlinearities, parametric uncertainties , and exogenous disturbances, the methodology hereby proposed preserves some nonlinear terms in the nominal system via an exact polytopic representation which leads to design conditions in the form of linear matrix inequalities. As a result, feasible solutions are found where former approaches fail; these solutions have more accurate settling-time estimates with reduced control effort. The corresponding control law includes well-known high-order sliding modes as a particular case. Numerical simulations are provided to illustrate the advantages of the proposal

Discovery of a gatekeeper residue in the C terminal tail of the extracellular signal-regulated protein kinase 5 (ERK5)

The extracellular signal-regulated protein kinase 5 (ERK5) is a non-redundant mitogen-activated protein kinase (MAPK) that exhibits a unique C terminal extension which comprises distinct structural and functional properties. Here, we sought to elucidate the significance of phosphoacceptor sites in the C terminal transactivation domain of ERK5. We have found that Thr732 acted as a functional gatekeeper residue controlling C terminal-mediated nuclear translocation and transcriptional enhancement. Consistently, using a non-bias quantitative mass spectrometry approach, we demonstrated that phosphorylation at Thr732 conferred selectivity for binding interactions of ERK5 with proteins related to chromatin and RNA biology, whereas a number of metabolic regulators were associated with full-length wild type ERK5. Additionally, our proteomic analysis revealed that phosphorylation of the Ser730-Glu-Thr732-Pro motif could occur independently of dual phosphorylation at Thr218-Glu-Tyr220 in the activation loop. Together these results firmly establish the significance of C terminal phosphorylation in regulating ERK5 function, independently of MEK5. This novel mechanism may be of particular relevance in cancer cells where ERK5 has be found to be hyperphosphoryated on its C terminal tail

ZO Proteins Redundantly Regulate the Transcription Factor DbpA/ZONAB

The localization and activities of DbpA/ZONAB and YAP transcription factors are in part regulated by the density-dependent assembly of epithelial junctions. DbpA activity and cell proliferation are inhibited by exogenous overexpression of the tight junction (TJ) protein ZO-1, leading to a model whereby ZO-1 acts by sequestering DbpA at the TJ. However, mammary epithelial cells and mouse tissues knock-out for ZO-1 do not show increased proliferation, as predicted by this model. To address this discrepancy, we examined the localization and activity of DbpA and YAP in Madin-Darby canine kidney cells depleted either of ZO-1, or one of the related proteins ZO-2 and ZO-3 (ZO proteins), or all three together. Depletion of only one ZO protein had no effect on DbpA localization and activity, whereas depletion of ZO-1 and ZO-2, which is associated with reduced ZO-3 expression, resulted in increased DbpA localization in the cytoplasm. Only depletion of ZO-2 reduced the nuclear import of YAP. Mammary epithelial (Eph4) cells KO for ZO-1 showed junctional DbpA, demonstrating that ZO-1 is not required to sequester DbpA at junctions. However, further depletion of ZO-2 in Eph4 ZO-1KO cells, which do not express ZO-3, caused decreased junctional localization and expression of DbpA, which were rescued by the proteasome inhibitor MG132. In vitro binding assays showed that full-length ZO-1 does not interact with DbpA. These results show that ZO-2 is implicated in regulating the nuclear shuttling of YAP, whereas ZO proteins redundantly control the junctional retention and stability of DbpA, without affecting its shuttling to the nucleus