Functional Link Between Mitochondria and Rnr3, the Minor Catalytic Subunit of Yeast Ribonucleotide Reductase

International audienceRibonucleotide reductase (RNR) is an essential holoenzyme required for de novo synthesis of dNTPs. The Saccharomyces cerevisiae genome encodes for two catalytic subunits, Rnr1 and Rnr3. While Rnr1 is required for DNA replication and DNA damage repair, the function(s) of Rnr3 is unknown. Here, we show that carbon source, an essential nutrient, impacts Rnr1 and Rnr3 abundance: Non-fermentable carbon sources or limiting concentrations of glucose down regulate Rnr1 and induce Rnr3 expression. Oppositely, abundant glucose induces Rnr1 expression and down regulates Rnr3. The carbon source dependent regulation of Rnr3 is mediated by Mec1, the budding yeast ATM/ATR checkpoint response kinase. Unexpectedly, this regulation is independent of all currently known components of the Mec1 DNA damage response network, including Rad53, Dun1, and Tel1, implicating a novel Mec1 signalling axis. rnr3Δ leads to growth defects under respiratory conditions and rescues temperature sensitivity conferred by the absence of Tom6, a component of the mitochondrial TOM (translocase of outer membrane) complex responsible for mitochondrial protein import. Together, these results unveil involvement of Rnr3 in mitochondrial functions and Mec1 in mediating the carbon source dependent regulation of Rnr3

Estrategias orientadoras ante la inequidad psicosocial

El presente artículo corresponde a una primera etapa del proyecto de investigación denominado: Investigación evaluativa sobre estrategias de orientación vocacional integral para contribuir a revertir la inequidad psicosocial, que se está llevando a cabo en la actualidad. Se hará una síntesis de las primeras estrategias metodológicas, que incluyen la modalidad de investigación-acción. En esta primera etapa, se analizan los primeros resultados de: a) Los talleres de Información Orientada, y b) La escala de afrontamiento para adolescentes. Cada una de estas intervenciones, que apuntan a diferentes objetivos, van brindando insumos para un primer nivel de análisis. Dicha intervención permite conocer qué recursos les brinda la institución escuela a estos jóvenes para la elección de un proyecto educativo, laboral, personal y social. Se comprueba la importancia de: tener un espacio de información y reflexión compartida; analizar las distorsiones en la información; y profundizar los interrogantes que produce todo cambio. Asimismo, comprobar cómo pueden afrontar dichos jóvenes, pertenecientes a escuelas medias denominadas «vulnerables», diversas situaciones de la vida diaria. En este trabajo, se realiza un análisis comparativo con otra institución educativa de prestigio en la región, cuya población se encuentra en una mejor situación socioeconómica

Transcription of ribosomal genes can cause nondisjunction

Mitotic disjunction of the repetitive ribosomal DNA (rDNA) involves specialized segregation mechanisms dependent on the conserved phosphatase Cdc14. The reason behind this requirement is unknown. We show that rDNA segregation requires Cdc14 partly because of its physical length but most importantly because a fraction of ribosomal RNA (rRNA) genes are transcribed at very high rates. We show that cells cannot segregate rDNA without Cdc14 unless they undergo genetic rearrangements that reduce rDNA copy number. We then demonstrate that cells with normal length rDNA arrays can segregate rDNA in the absence of Cdc14 as long as rRNA genes are not transcribed. In addition, our study uncovers an unexpected role for the replication barrier protein Fob1 in rDNA segregation that is independent of Cdc14. These findings demonstrate that highly transcribed loci can cause chromosome nondisjunction

Essential and checkpoint functions of budding yeast ATM and ATR during meiotic prophase are facilitated by differential phosphorylation of a meiotic adaptor protein, Hop1

A hallmark of the conserved ATM/ATR signalling is its ability to mediate a wide range of functions utilizing only a limited number of adaptors and effector kinases. During meiosis, Tel1 and Mec1, the budding yeast ATM and ATR, respectively, rely on a meiotic adaptor protein Hop1, a 53BP1/Rad9 functional analog, and its associated kinase Mek1, a CHK2/Rad53-paralog, to mediate multiple functions: control of the formation and repair of programmed meiotic DNA double strand breaks, enforcement of inter-homolog bias, regulation of meiotic progression, and implementation of checkpoint responses. Here, we present evidence that the multi-functionality of the Tel1/Mec1-to-Hop1/Mek1 signalling depends on stepwise activation of Mek1 that is mediated by Tel1/Mec1 phosphorylation of two specific residues within Hop1: phosphorylation at the threonine 318 (T318) ensures the transient basal level Mek1 activation required for viable spore formation during unperturbed meiosis. Phosphorylation at the serine 298 (S298) promotes stable Hop1-Mek1 interaction on chromosomes following the initial phospho-T318 mediated Mek1 recruitment. In the absence of Dmc1, the phospho-S298 also promotes Mek1 hyper-activation necessary for implementing meiotic checkpoint arrest. Taking these observations together, we propose that the Hop1 phospho-T318 and phospho-S298 constitute key components of the Tel1/Mec1- based meiotic recombination surveillance (MRS) network and facilitate effective coupling of meiotic recombination and progression during both unperturbed and challenged meiosis

Budding yeast ATM/ATR control meiotic double-strand break (DSB) levels by down-regulating Rec114, an essential component of the DSB-machinery

An essential feature of meiosis is Spo11 catalysis of programmed DNA double strand breaks (DSBs). Evidence suggests that the number of DSBs generated per meiosis is genetically determined and that this ability to maintain a pre-determined DSB level, or "DSB homeostasis", might be a property of the meiotic program. Here, we present direct evidence that Rec114, an evolutionarily conserved essential component of the meiotic DSB-machinery, interacts with DSB hotspot DNA, and that Tel1 and Mec1, the budding yeast ATM and ATR, respectively, down-regulate Rec114 upon meiotic DSB formation through phosphorylation. Mimicking constitutive phosphorylation reduces the interaction between Rec114 and DSB hotspot DNA, resulting in a reduction and/or delay in DSB formation. Conversely, a non-phosphorylatable rec114 allele confers a genome-wide increase in both DSB levels and in the interaction between Rec114 and the DSB hotspot DNA. These observations strongly suggest that Tel1 and/or Mec1 phosphorylation of Rec114 following Spo11 catalysis down-regulates DSB formation by limiting the interaction between Rec114 and DSB hotspots. We also present evidence that Ndt80, a meiosis specific transcription factor, contributes to Rec114 degradation, consistent with its requirement for complete cessation of DSB formation. Loss of Rec114 foci from chromatin is associated with homolog synapsis but independent of Ndt80 or Tel1/Mec1 phosphorylation. Taken together, we present evidence for three independent ways of regulating Rec114 activity, which likely contribute to meiotic DSBs-homeostasis in maintaining genetically determined levels of breaks

Atrasentan and renal events in patients with type 2 diabetes and chronic kidney disease (SONAR): a double-blind, randomised, placebo-controlled trial

Background: Short-term treatment for people with type 2 diabetes using a low dose of the selective endothelin A receptor antagonist atrasentan reduces albuminuria without causing significant sodium retention. We report the long-term effects of treatment with atrasentan on major renal outcomes. Methods: We did this double-blind, randomised, placebo-controlled trial at 689 sites in 41 countries. We enrolled adults aged 18–85 years with type 2 diabetes, estimated glomerular filtration rate (eGFR)25–75 mL/min per 1·73 m 2 of body surface area, and a urine albumin-to-creatinine ratio (UACR)of 300–5000 mg/g who had received maximum labelled or tolerated renin–angiotensin system inhibition for at least 4 weeks. Participants were given atrasentan 0·75 mg orally daily during an enrichment period before random group assignment. Those with a UACR decrease of at least 30% with no substantial fluid retention during the enrichment period (responders)were included in the double-blind treatment period. Responders were randomly assigned to receive either atrasentan 0·75 mg orally daily or placebo. All patients and investigators were masked to treatment assignment. The primary endpoint was a composite of doubling of serum creatinine (sustained for ≥30 days)or end-stage kidney disease (eGFR <15 mL/min per 1·73 m 2 sustained for ≥90 days, chronic dialysis for ≥90 days, kidney transplantation, or death from kidney failure)in the intention-to-treat population of all responders. Safety was assessed in all patients who received at least one dose of their assigned study treatment. The study is registered with ClinicalTrials.gov, number NCT01858532. Findings: Between May 17, 2013, and July 13, 2017, 11 087 patients were screened; 5117 entered the enrichment period, and 4711 completed the enrichment period. Of these, 2648 patients were responders and were randomly assigned to the atrasentan group (n=1325)or placebo group (n=1323). Median follow-up was 2·2 years (IQR 1·4–2·9). 79 (6·0%)of 1325 patients in the atrasentan group and 105 (7·9%)of 1323 in the placebo group had a primary composite renal endpoint event (hazard ratio [HR]0·65 [95% CI 0·49–0·88]; p=0·0047). Fluid retention and anaemia adverse events, which have been previously attributed to endothelin receptor antagonists, were more frequent in the atrasentan group than in the placebo group. Hospital admission for heart failure occurred in 47 (3·5%)of 1325 patients in the atrasentan group and 34 (2·6%)of 1323 patients in the placebo group (HR 1·33 [95% CI 0·85–2·07]; p=0·208). 58 (4·4%)patients in the atrasentan group and 52 (3·9%)in the placebo group died (HR 1·09 [95% CI 0·75–1·59]; p=0·65). Interpretation: Atrasentan reduced the risk of renal events in patients with diabetes and chronic kidney disease who were selected to optimise efficacy and safety. These data support a potential role for selective endothelin receptor antagonists in protecting renal function in patients with type 2 diabetes at high risk of developing end-stage kidney disease. Funding: AbbVie

Cristina senadora 2.0 : un análisis sociosemiótico de la campaña 2017 de Cristina Fernández de Kirchner en Facebook

Esta investigación tiene como objetivo general indagar en la construcción del discurso político de Fernández de Kirchner en las redes sociales y cuenta con 4 objetivos específicos. El primero corresponde a indagar la estrategia enunciativa de campaña de Fernández de Kirchner en Facebook desde la aparición de Unidad\nCiudadana en junio de 2017 hasta las elecciones generales en octubre del mismo año. Además, se busca dar cuenta de las operaciones de interrelación mediática en la cuenta de Facebook de Cristina Fernández de Kirchner. Por otro lado, analizar los momentos más significativos a nivel de la circulación hipermediática en la campaña de 2017. Y por último, investigar la emergencia de contenidos relacionados a lo público y lo privado.\n La metodología que se utiliza en este proyecto corresponde al análisis del discurso, la sociosemiótica y la metodología de análisis de la circulación hipermediática (Carlón, 2004, 2008, 2015; Carlón y Scolari, 2009; Fernández, 1994, 2008, 2018; Steimberg, 1993; Verón, 1987, 1998 &#91;1995&#93;, 2001, 2013) a través de una investigación comparativa de la campaña en Facebook de actual vicepresidenta para las dos Elecciones Legislativas de 2017; las elecciones PASO y las Generales del 22 de octubre de 2017.\n Las unidades de análisis del presente trabajo están conformadas por las publicaciones de la cuenta de Facebook de Fernández de Kirchner durante el período que se extiende desde junio a octubre de 2017. Se analiza específicamente los posteos realizados durante los 21 días previos a cada elección. El rasgo distintivo del período seleccionado refiere a que esta es la primera\ncampaña a senadora nacional de Fernández de Kirchner cuyos discursos estuvieron mediados por las redes sociales, motivo por el cual se buscará detectar\ncontinuidades y rupturas en su estrategia enunciativa en torno a dos posteos en particular, seleccionados dada su apelación a lo privado e íntimo de la figura política, configurándose como una variante poco frecuente durante su campaña en Facebook.\n Como resultado, se halla que, durante el período previo a las elecciones PASO, la candidata despliega diversos mecanismos que tendieron a construir una apelación al paradestinatario con la intención marcada de un corrimiento de su figura como líder de un movimiento, para pasar a ser una “periodista” que se acerca a la población con la finalidad de conocer de primera mano sus necesidades y demandas. Dados los resultados desfavorables que los comicios le significaron al espacio de Unidad Ciudadana, la estrategia comunicativa en redes sufrió una transformación, por lo que se intenta apelar a acciones más tradicionales que tienen a la figura política en el centro de la escena, con apelaciones al prodestinatario o sujeto que comparte sus creencias.Fil: Cha, María Rita. Universidad de Buenos Aires. Facultad de Ciencias Sociales. Buenos Aires, ArgentinaFil: Spengler, Natalia Soledad. Universidad de Buenos Aires. Facultad de Ciencias Sociales. Buenos Aires, Argentin