Role of phosphorylation in the regulation of PRMT5

PRMT5 is a member of a group of proteins that mediate arginine methylation. It is involved in diverse cellular processes, including cell differentiation, splicing, transcription elongation and epigenetic silencing, and its expression is dysregulated in many cancers. Due to its pleiotropic functions, PRMT5 is subject to multi-level regulation. Post-translational modification (PTM) of proteins can modulate an array of cellular processes by regulating both protein interactions and protein structural changes. PRMT5 is commonly found associated with other proteins; these interactions seem to control both its catalytic activity and its substrate specificity. Recently, it became clear that PRMT5 is phosphorylated at a number of residues, which prompted us to investigate whether phosphorylation of PRMT5 regulates its subcellular localization and/or substrate choice, by facilitating phospho-dependent protein-protein interactions. To study how phosphorylation affects PRMT5 function, protein microarrays were used to identify novel phosphodependent-interacting proteins. This analysis revealed that phosphorylation mediates the interaction of PRMT5 with several SH2-domain containing proteins, 14-3-3 proteins and the FHA domain of MDC1. These novel phospho-dependent PRMT5 interactions suggest that crosstalk between kinases and arginine methyltransferases may play a pivotal role in modulating the different cellular functions of PRMT5. Additionally, we have found that the C-terminal region of PRMT5 has a recognition motif shared by PDZ domains and 14-3-3 proteins. In order to bind to this motif, 14-3-3 proteins require the C-terminus to be phosphorylated, while PDZ domain recognition is phospho-independent. From these data, a new regulatory mechanism that affects PRMT5 behavior was proposed; the action of kinases and phosphatases on PRMT5 may function as a switch to regulate interactions between 14-3-3 and PDZ domain-containing proteins. We additionally observed this paradigm with a number of proteins, suggesting that this phosphorylation dependent switch, regulating binding to 14-3-3 and PDZ domains, occurs in a wide range of protein-protein interactions. Among the recently discovered PDZ-binding partners, we have found that PRMT5 interacts with NHERF2, a membrane-associated protein that regulates the sodium ion exchanger NHE3. Through this interaction, PRMT5 is placed in close proximity to the membrane and therefore may regulate the influx of ions through selective ion channels. Overall, we hypothesize that the direct interaction of PRMT5 with selected partners mediates the appropriate localization of PRMT5, allowing it to methylate specific substrates. Physiological processes including muscle contraction, cell homeostasis and neurotransmission are controlled by the selective conduction of ions across cell membranes. Ion channels and exchangers are proteins that span cell membranes and form channels or pores, facilitating the movement of ions in and out of cells. Abnormal cellular response to the microenvironment is one of the key factors in the progression of many diseases. To study the role of the C-terminus of PRMT5 in vivo, we used CRISPR/Cas9 technology to create a mouse with the last six amino acids of PRMT5 replaced with an HA tag, as well with an altered PRMT5 C-terminus. Both mouse models lack the critical 14-3-3/PDZ binding motif. This approach revealed that the C-terminus of PRMT5 is essential for viability as no homozygous mutant embryos were recovered. Likewise, no homozygous PRMT5Δ+HA ES cell lines could be created. The results described here represent progress toward understanding PRMT5 function and regulation

EVIDENCIAÇÃO DE INFORMAÇÕES AMBIENTAIS: PROPOSTA DE UM INDICADOR A PARTIR DA PERCEPÇÃO DE ESPECIALISTAS

This paper is aimed at listing environmental attributes, according to the degree of importance of disclosure, to compose a truly Brazilian indicator that assesses the quality of environmental information disclosure. “Environmental accounting/sustainability” experts and environmental disclosure attributes were selected, based on Brazilian and international studies. Through Delphi rounds, the experts outlined the list of the most relevant attributes to compose the indicator. The Environmental Disclosure Indicator – EDI consists of ten attributes than combine practicality and representativeness of the quality of environmental information disclosure. The results revealed a high degree of importance and, therefore, a greater weight of qualitative attributes, such as “Environmental Impacts of Products and Processes” and “Information about Residues”. The study contributes by revealing “what” should be disclosed prioritarily, that is, which are the essential environmental attributes. It contributes to verify whether the amount of environmental information companies have disclosed have necessarily meant disclosure quality. As it provides an instrument to quantify the quality of environmental disclosure, the study permits further research about the association between this disclosure and other company aspects, such as performance and corporate governance.O artigo tem por objetivo elencar atributos ambientais, conforme o grau de importância de disclosure, para composição de um indicador genuinamente brasileiro que avalie qualidade de evidenciação de informações ambientais. Selecionaram-se especialistas da área “contabilidade ambiental/sustentabilidade” e atributos de evidenciação ambiental subsidiados por estudos nacionais e internacionais. Por meio de rodadas Delphi, os especialistas delinearam o rol de atributos mais relevantes para a composição do indicador. O Indicador de Disclosure Ambiental – IDA é composto por dez atributos que combinam praticidade e representatividade da qualidade de evidenciação de informações ambientais. Os resultados revelaram alto grau de importância e, portanto, maior peso para atributos qualitativos, como “Impactos Ambientais de Produtos e Processos” e “Informações sobre Resíduos”. A contribuição do estudo consiste em revelar “o que” se deve evidenciar prioritariamente, ou seja, quais são os atributos ambientais essenciais. Contribui para que verifique se a quantidade de informações ambientais evidenciadas pelas companhias tem significado necessariamente qualidade de disclosure. Por fornecer um instrumento para quantificação da qualidade do disclosure ambiental, o estudo possibilita pesquisas posteriores sobre a associação entre esta evidenciação e demais aspectos das companhias, como desempenho e governança corporativ

Tipologías de consumidores de alcohol dentro de la práctica del botellón en tres ciudades españolas.

En este trabajo se entrevistó a 6.009 jóvenes que practican botellón (14-25 años) en tres ciudades de la Comunidad Valenciana, realizando un muestreo estratifi cado de centros de Secundaria, Bachiller,CF y Universidad. Se efectuó un análisis de conglomerados en dos fases con cada muestra con dos objetivos: identifi car tipologías de consumidores de alcohol en el botellón y realizar una validación cruzada de la solución obtenida. Las variables consideradas en los análisis fueron: sexo, grupo de edad (universitarios: U; estudiantes Secundaria: ES), realización o no de episodios intensivos de consumo, años practicando botellón y gramos de alcohol ingeridos. Los resultados muestran evidencia de validez de la estructura obtenida para los jóvenes que realizan episodios intensivos de consumo de alcohol, ya que aparece una estructura de cuatro grupos en las tres muestras (varones U, varones ES, mujeres U,mujeres ES), siendo siempre los varones quienes más consumen. Además, los ES consumen iguales cantidades de hol que los U, aunque llevan menos años consumiendo. Por su parte, entre los jóvenes que no realizan episodios intensivos de consumo de alcohol se observa cierta variabilidad en la estructura, siendo manifi esta la tendencia de las mujeres a igualar su consumo con el de los varones. Different typologies of alcohol consumers in the practice of «botellon» in three Spanish cities. In this work, 6,009 youngsters (14-25 years old) who practice the «botellon» were interviewed in three cities of the Valencian Community. After a stratifi ed sampling among college and noncollege students, a two-step cluster analysis was carried out for each sample with two aims: to identify different types of alcohol consumers in the practice of the «botellon» and to carry out a crossed validation of the results obtained. The variables included in the analysis were the following: gender, age group (university students: U; adolescent students: ES), performance of intensive episodes of consumption (yes/no), number of years practicing the «botellon» and grams of alcohol ingested. The results show the validity of the structure obtained for youngsters, revealing intensive episodes of alcohol consumption, as a fourgroup structure appeared in all three samples (male U, male ES, female U, female ES), in which men were always at the top of alcohol ingestion. Furthermore, ES consumed the same amount of alcohol as U, even though they had been consuming for less time. However, the youngsters who did not report intensive episodes of alcohol consumption showed some structure variability, with a tendency among women to match men"s levels of alcohol consumptio

Momento Económico (38)

Temas de hoy. 2/ De la ganaderización de la agricultura a la desganaderización actual. Retos y perspectivas Rosario Pérez Espejo. 3/ El mejoramiento en el transporte colectivo. una necesidad insoslayable Bernardo Navarro Benitez. 8/ La reconversión industrial también afecta al sector educativo Leticia Campos, 10/ México y el marco internacional de la inflación Mario J. Zepeda M. 12/ El petróleo y el conflicto del Medio Oriente Arturo Bonilla. 13

Etude du croisement entre les races ovines Fleischschaf et Aragonaise pour les caractères de croissance et d'abattage

International audienc

Mitigating the effects of omission errors on area and area change estimates

Information on Earth's land surface and change over time has never been easier to obtain, but making informed decisions to manage land well necessitates that this information is accurate and precise. In recent years, due largely to the inevitability of classification errors in remote sensing-based maps and the marked effects of these errors on subsequent area estimates, sample-based area estimates of land cover and land change have increased in importance and use. Area estimation of land cover and change by sampling is often made more efficient by a priori knowledge of the study area to be analyzed (e.g., stratification). Satellite data, obtained free of cost for virtually all of Earth's land surface, provide an excellent source for constructing landscape stratifications in the form of maps. Errors of omission, defined as sample units observed as land change but mapped as a stable class, may introduce considerable uncertainty in parameter estimates obtained from the sample data (e.g., area estimates of land change). The effects of omission errors are exacerbated in situations where the area of intact forest is large relative to the area of forest change, a common situation in countries that seek results-based payments for reductions in deforestation and associated carbon emissions. The presence of omission errors in such situations can preclude the acquisition of statistically valid evidence of a reduction in deforestation, and thus prevent payments. International donors and countries concerned with mitigating the effects of climate change are looking for guidance on how to reduce the effects of omission errors on area estimates of land change. This article presents the underlying reasons for the effects of omission errors on area estimates, case studies highlighting real-world examples of these effects, and proposes potential solutions. Practicable approaches to efficiently splitting large stable strata are presented that may reduce the effects of omission errors and immediately improve the quality of estimates. However, more research is needed before further recommendations can be provided on how to contain, mitigate and potentially eliminate the effects of omissions errors. © 2019 Elsevier Inc.This research was funded by support from the NASA Carbon Monitoring System ( NNX16AP26G ) and USGS/SilvaCarbon to Boston University (PI Pontus Olofsson). M.J. Sanz was supported by the Spanish Government through María de Maeztu excellence accreditation MDM-2017-0714

Ground calcium carbonate as a low cost and biosafety excipient for solubility and dissolution improvement of praziquantel

Calcium carbonate is an abundant mineral with several advantages to be a successful carrier to improve oral bioavailability of poorly water-soluble drugs, such as praziquantel. Praziquantel is an antiparasitic drug classified in group II of the Biopharmaceutical Classification System hence characterized by high-permeability and low-solubility. Therefore, the dissolution rate is the limiting factor for the gastrointestinal absorption that contributes to the low bioavailability. Consequently, the therapeutic dose of the praziquantel must be high and big tablets and capsules are required, which are difficult to swallow, especially for pediatric and elderly patients. Mixtures of praziquantel and calcium carbonate using solid-solid physical mixtures and solid dispersions were prepared and characterized using several techniques (X-ray diffraction differential scanning calorimetry, thermogravimetric analysis, scanning electron microscopy, laser diffraction, Fourier transform infrared and Raman spectroscopies). Solubility of these formulations evidenced that the solubility of praziquantel-calcium carbonate interaction product increased in physiological media. In vitro dissolution tests showed that the interaction product increased the dissolution rate of the drug in acidic medium. Theoretical models were studied to understand this experimental behavior. Cytotoxicity and cell cycle studies were performed, showing that praziquantel-calcium carbonate physical mixture and interaction product were biocompatible with the HTC116 cells, because it did not produce a decrease in cell viability or alterations in the cell cycle

Late Holocene climate variability in the southwestern Mediterranean region: an integrated marine and terrestrial geochemical approach

A combination of marine (Alboran Sea cores, ODP 976 and TTR 300 G) and terrestrial (Zoñar Lake, Andalucia, Spain) geochemical proxies provides a high-resolution reconstruction of climate variability and human influence in the southwestern Mediterranean region for the last 4000 years at inter-centennial resolution. Proxies respond to changes in precipitation rather than temperature alone. Our combined terrestrial and marine archive documents a succession of dry and wet periods coherent with the North Atlantic climate signal. A dry period occurred prior to 2.7 cal ka BP – synchronously to the global aridity crisis of the third-millennium BC – and during the Medieval Climate Anomaly (1.4–0.7 cal ka BP). Wetter conditions prevailed from 2.7 to 1.4 cal ka BP. Hydrological signatures during the Little Ice Age are highly variable but consistent with more humidity than the Medieval Climate Anomaly. Additionally, Pb anomalies in sediments at the end of the Bronze Age suggest anthropogenic pollution earlier than the Roman Empire development in the Iberian Peninsula. The Late Holocene climate evolution of the in the study area confirms the see-saw pattern between the eastern and western Mediterranean regions and the higher influence of the North Atlantic dynamics in the western Mediterranean