The Proteasomal Deubiquitinating Enzyme PSMD14 Regulates Macroautophagy by Controlling Golgi-to-ER Retrograde Transport

Ubiquitination regulates several biological processes, however the role of specific members of the ubiquitinome on intracellular membrane trafficking is not yet fully understood. Here, we search for ubiquitin-related genes implicated in protein membrane trafficking performing a High-Content siRNA Screening including 1187 genes of the human “ubiquitinome” using amyloid precursor protein (APP) as a reporter. We identified the deubiquitinating enzyme PSMD14, a subunit of the 19S regulatory particle of the proteasome, specific for K63-Ub chains in cells, as a novel regulator of Golgi-to-endoplasmic reticulum (ER) retrograde transport. Silencing or pharmacological inhibition of PSMD14 with Capzimin (CZM) caused a robust increase in APP levels at the Golgi apparatus and the swelling of this organelle. We showed that this phenotype is the result of rapid inhibition of Golgi-to-ER retrograde transport, a pathway implicated in the early steps of the autophagosomal formation. Indeed, we observed that inhibition of PSMD14 with CZM acts as a potent blocker of macroautophagy by a mechanism related to the retention of Atg9A and Rab1A at the Golgi apparatus. As pharmacological inhibition of the proteolytic core of the 20S proteasome did not recapitulate these effects, we concluded that PSMD14, and the K63-Ub chains, act as a crucial regulatory factor for macroautophagy by controlling Golgi-to-ER retrograde transport

Synthesis of silica chitosan oligosaccharides nanoparticles

Objective: To obtain chitosan oligosaccharides (COS) and evaluate COS uses for the obtention of nanosystem based on silica as vehicle and compare the COS-silica nanosystem with the chitosan (Chi) precursor system as Chitosan-silica nanosystems. Design/methodology/approach: A combination of hydrolysis chemical and mechanical (microwave assisted) were used to obtain COS with the oxidative action of hydrogen peroxide. Sol-Gel adapted method was used to synthetize silica nanoparticles (SiNPs) from sodium metasilicate and the electrostatic interactions between SiNPs and Chi/COS were used to functionalize the SiNPs surface with Chi/COS.   Results: Nanosystem composed from COS and SiNPs were obtained successful as A COS-SiNPs and C COS-SiNPs with particle size of 139.35 nm and 251.8 nm and zeta potential of 30.40 mV and 34.67 mV respectively with antimicrobial activity against Escherichia coli and Staphylococcus aureus. Limitations on study/implications: Stabilize the systems compound of chitosan-silica nanoparticles due to the molecular weight of chitosan which loss the stabilized the SiNPs suspension and due the incompatibility of both systems pH. Findings/conclusions: COS and COS-SiNPs stable systems were obtained with an improvement of the antimicrobial activity of the system in contrast of Chi-SiNPs systems

Autophagosomes cooperate in the degradation of intracellular C-terminal fragments of the amyloid precursor protein <i>via </i>the MVB/lysosomal pathway

© FASEB. Brain regions affected by Alzheimer disease (AD) displaywell-recognized early neuropathologic features in the endolysosomal and autophagy systems of neurons, including enlargement of endosomal compartments, progressive accumulation of autophagic vacuoles, and lysosomal dysfunction.Although the primary causes of these disturbances are still under investigation, a growing body of evidence suggests that the amyloid precursor protein (APP) intracellular C-terminal fragment b (C99), generated by cleavage of APP by b-site APP cleaving enzyme 1 (BACE-1), is the primary cause of the endosome enlargement inADand the earliest initiator of synaptic plasticity and long-termmemory impairment. The aimof the present study was to evaluate the possible relationship between the endolysosomal degradation pathway and autophagy on the proteolytic processing and turnover of C99. We found that pharmacologic treatments that either inhibit autophagosomeformationorblock the fusionof autophagosomes to

El papel de la enseñanza de la historia en el desarrollo comunicativo del profesional de la salud / The Role of History teaching in the communicative development of the Health Professional

El presente trabajo introduce el tema en cuestión a partir del análisis de diferentes postulados teóricos sobre la comunicación y la importancia de la enseñanza de la Historia con estos propósitos, en el contexto de la formación médica, que sirvió de base para el análisis documental y la elaboración de dos instrumentos que se aplicaron corroborando la necesidad de crear vías para el desarrollo de la comunicación, y la efectividad de la experiencia aplicada desde el Programa de Historia de Cuba III en 4to año de la carrera de Medicina respectivamente. Para el desarrollo de estos propósitos se fundamentaron  teóricamente las potencialidades de la enseñanza de la asignatura y se ofreció un modelo recurrente que constituyó el estilo metodológico con que se impartieron las 16 actividades docentes  del programa para dar cumplimiento al objetivo propuesto, demostrando que el diseño de las estrategias de enseñanza aprendizaje debe estar encaminado a construir eslabones para el desarrollo de la comunicación, donde la enseñanza de la Historia constituya un fuerte puntal en este propósito, además de contribuir a solucionar los problemas de comunicación que afloren en el período de formación médica e incorpore habilidades, métodos y conocimientos al desarrollo del método clínico, cuyos resultados se evidenciaron en el análisis cualitativo y cuantitativo del instrumento aplicado .Palabras Clave: HISTORIA, ESTUDIANTES DE MEDICINA, COMUNICACIÓN, CUBA. ABSTRACT The present work is based on the teaching of History  from the analysis of different  theoretical postulates on communication  and the importance of  History teaching in the medical context,  which was used as a base  for the documented analysis and the creation of two instruments which were applied,  demonstrating the necessity of means  for the development of communication  and the effectiveness of the applied training  from the Cuban History III in the 4 academic year of Medical major. With these purposes the possibilities of the subject teaching were based theoretically  and it was offered a recurrent model which  constituted  the methodological style used for teaching 16 teaching activities of the program  fulfilling the proposed objective  which demonstrated  that the design of the teaching- learning strategies must be directed to create links  for the development of  communication  where the History teaching is a strong  support  and it also contributes to solve  the communication problems  which emerge in the medical formation period  and gives training , methods and knowledges of the clinical method development whose results  were evidenced in the qualitative and quantitative analysis of the applied instrument. Key words: HISTORY, MEDICAL STUDENTS, COMMUNICATION, CUBA

El papel de la enseñanza de la historia en el desarrollo comunicativo del profesional de la salud / The Role of History teaching in the communicative development of the Health Professional

El presente trabajo introduce el tema en cuestión a partir del análisis de diferentes postulados teóricos sobre la comunicación y la importancia de la enseñanza de la Historia con estos propósitos, en el contexto de la formación médica, que sirvió de base para el análisis documental y la elaboración de dos instrumentos que se aplicaron corroborando la necesidad de crear vías para el desarrollo de la comunicación, y la efectividad de la experiencia aplicada desde el Programa de Historia de Cuba III en 4to año de la carrera de Medicina respectivamente. Para el desarrollo de estos propósitos se fundamentaron  teóricamente las potencialidades de la enseñanza de la asignatura y se ofreció un modelo recurrente que constituyó el estilo metodológico con que se impartieron las 16 actividades docentes  del programa para dar cumplimiento al objetivo propuesto, demostrando que el diseño de las estrategias de enseñanza aprendizaje debe estar encaminado a construir eslabones para el desarrollo de la comunicación, donde la enseñanza de la Historia constituya un fuerte puntal en este propósito, además de contribuir a solucionar los problemas de comunicación que afloren en el período de formación médica e incorpore habilidades, métodos y conocimientos al desarrollo del método clínico, cuyos resultados se evidenciaron en el análisis cualitativo y cuantitativo del instrumento aplicado .Palabras Clave: HISTORIA, ESTUDIANTES DE MEDICINA, COMUNICACIÓN, CUBA. ABSTRACT The present work is based on the teaching of History  from the analysis of different  theoretical postulates on communication  and the importance of  History teaching in the medical context,  which was used as a base  for the documented analysis and the creation of two instruments which were applied,  demonstrating the necessity of means  for the development of communication  and the effectiveness of the applied training  from the Cuban History III in the 4 academic year of Medical major. With these purposes the possibilities of the subject teaching were based theoretically  and it was offered a recurrent model which  constituted  the methodological style used for teaching 16 teaching activities of the program  fulfilling the proposed objective  which demonstrated  that the design of the teaching- learning strategies must be directed to create links  for the development of  communication  where the History teaching is a strong  support  and it also contributes to solve  the communication problems  which emerge in the medical formation period  and gives training , methods and knowledges of the clinical method development whose results  were evidenced in the qualitative and quantitative analysis of the applied instrument. Key words: HISTORY, MEDICAL STUDENTS, COMMUNICATION, CUBA

Negative Modulation of Macroautophagy by Stabilized HERPUD1 is Counteracted by an Increased ER-Lysosomal Network With Impact in Drug-Induced Stress Cell Survival

Macroautophagy and the ubiquitin proteasome system work as an interconnected network in the maintenance of cellular homeostasis. Indeed, efficient activation of macroautophagy upon nutritional deprivation is sustained by degradation of preexisting proteins by the proteasome. However, the specific substrates that are degraded by the proteasome in order to activate macroautophagy are currently unknown. By quantitative proteomic analysis we identified several proteins downregulated in response to starvation independently of ATG5 expression. Among them, the most significant was HERPUD1, an ER membrane protein with low expression and known to be degraded by the proteasome under normal conditions. Contrary, under ER stress, levels of HERPUD1 increased rapidly due to a blockage in its proteasomal degradation. Thus, we explored whether HERPUD1 stability could work as a negative regulator of autophagy. In this work, we expressed a version of HERPUD1 with its ubiquitin-like domain (UBL) deleted, which is known to be crucial for its proteasome degradation. In comparison to HERPUD1-WT, we found the UBL-deleted version caused a negative role on basal and induced macroautophagy. Unexpectedly, we found stabilized HERPUD1 promotes ER remodeling independent of unfolded protein response activation observing an increase in stacked-tubular structures resembling previously described tubular ER rearrangements. Importantly, a phosphomimetic S59D mutation within the UBL mimics the phenotype observed with the UBL-deleted version including an increase in HERPUD1 stability and ER remodeling together with a negative role on autophagy. Moreover, we found UBL-deleted version and HERPUD1-S59D trigger an increase in cellular size, whereas HERPUD1-S59D also causes an increased in nuclear size. Interestingly, ER remodeling by the deletion of the UBL and the phosphomimetic S59D version led to an increase in the number and function of lysosomes. In addition, the UBL-deleted version and phosphomimetic S59D version established a tight ER-lysosomal network with the presence of extended patches of ER-lysosomal membrane-contact sites condition that reveals an increase of cell survival under stress conditions. Altogether, we propose stabilized HERPUD1 downregulates macroautophagy favoring instead a closed interplay between the ER and lysosomes with consequences in drug-cell stress survival

Heteromeric clusters of ubiquitinated ER-shaping proteins drive ER-phagy

Membrane-shaping proteins characterized by reticulon homology domains play an important part in the dynamic remodelling of the endoplasmic reticulum (ER). An example of such a protein is FAM134B, which can bind LC3 proteins and mediate the degradation of ER sheets through selective autophagy (ER-phagy)1. Mutations in FAM134B result in a neurodegenerative disorder in humans that mainly affects sensory and autonomic neurons2. Here we report that ARL6IP1, another ER-shaping protein that contains a reticulon homology domain and is associated with sensory loss3, interacts with FAM134B and participates in the formation of heteromeric multi-protein clusters required for ER-phagy. Moreover, ubiquitination of ARL6IP1 promotes this process. Accordingly, disruption of Arl6ip1 in mice causes an expansion of ER sheets in sensory neurons that degenerate over time. Primary cells obtained from Arl6ip1-deficient mice or from patients display incomplete budding of ER membranes and severe impairment of ER-phagy flux. Therefore, we propose that the clustering of ubiquitinated ER-shaping proteins facilitates the dynamic remodelling of the ER during ER-phagy and is important for neuronal maintenance.</p

The Fourteenth Data Release of the Sloan Digital Sky Survey: First Spectroscopic Data from the extended Baryon Oscillation Spectroscopic Survey and from the second phase of the Apache Point Observatory Galactic Evolution Experiment

The fourth generation of the Sloan Digital Sky Survey (SDSS-IV) has been in operation since July 2014. This paper describes the second data release from this phase, and the fourteenth from SDSS overall (making this, Data Release Fourteen or DR14). This release makes public data taken by SDSS-IV in its first two years of operation (July 2014-2016). Like all previous SDSS releases, DR14 is cumulative, including the most recent reductions and calibrations of all data taken by SDSS since the first phase began operations in 2000. New in DR14 is the first public release of data from the extended Baryon Oscillation Spectroscopic Survey (eBOSS); the first data from the second phase of the Apache Point Observatory (APO) Galactic Evolution Experiment (APOGEE-2), including stellar parameter estimates from an innovative data driven machine learning algorithm known as "The Cannon"; and almost twice as many data cubes from the Mapping Nearby Galaxies at APO (MaNGA) survey as were in the previous release (N = 2812 in total). This paper describes the location and format of the publicly available data from SDSS-IV surveys. We provide references to the important technical papers describing how these data have been taken (both targeting and observation details) and processed for scientific use. The SDSS website (www.sdss.org) has been updated for this release, and provides links to data downloads, as well as tutorials and examples of data use. SDSS-IV is planning to continue to collect astronomical data until 2020, and will be followed by SDSS-V.Comment: SDSS-IV collaboration alphabetical author data release paper. DR14 happened on 31st July 2017. 19 pages, 5 figures. Accepted by ApJS on 28th Nov 2017 (this is the "post-print" and "post-proofs" version; minor corrections only from v1, and most of errors found in proofs corrected

Latin America: Reduced S&T Investment Puts Sustainable Development at Risk

Latin America is home to more than 600 million people and has considerable natural and human resources. However, investment in science and technology (S&T) lags far behind that in developed countries. This gap represents a barrier to the development of economies based on knowledge and hampers the region's ability to tackle environmental and social problems. This lack of investment is evident in the extreme case of Venezuela, where much of the science workforce has fled economic chaos, but also in every Latin American country, including science powers such as Brazil and Argentina, where federal budgets in science, technology and education have been drastically reduced in recent years. Investments in S&T foster cooperation, commerce and good will and enhance resilience in the face of environmental and social turmoil. Therefore, scientists must start to actively engage governments and encourage long-term spending in S&T to support the development of Latin American societies.Universidad de Costa Rica/[]/UCR/Costa RicaSistema Nacional de Investigación/[]/SNI/SENACYT/PanamáUCR::Vicerrectoría de Investigación::Unidades de Investigación::Ciencias Agroalimentarias::Estación Experimental Agrícola Fabio Baudrit Moreno (EEAFBM)UCR::Vicerrectoría de Investigación::Unidades de Investigación::Ciencias Agroalimentarias::Jardín Botánico Lankester (JBL