Cdc14 phosphatase:warning, no delay allowed for chromosome segregation!

Cycling events in nature start and end to restart again and again. In the cell cycle, whose purpose is to become two where there was only one, cyclin-dependent kinases (CDKs) are the beginning and, therefore, phosphatases must play a role in the ending. Since CDKs are drivers of the cell cycle and cancer cells uncontrollably divide, much attention has been put into knocking down CDK activity. However, much less is known on the consequences of interfering with the phosphatases that put an end to the cell cycle. We have addressed in recent years the consequences of transiently inactivating the only master cell cycle phosphatase in the model yeast Saccharomyces cerevisiae, Cdc14. Transient inactivation is expected to better mimic the pharmacological action of drugs. Interestingly, we have found that yeast cells tolerate badly a relatively brief inactivation of Cdc14 when cells are already committed into anaphase, the first cell cycle stage where this phosphatase plays important roles. First, we noticed that the segregation of distal regions in the chromosome arm that carries the ribosomal DNA array was irreversibly impaired, leading to an anaphase bridge (AB). Next, we found that this AB could eventually be severed by cytokinesis and led to two different types of genetically compromised daughter cells. All these previous studies were done in haploid cells. We have now recently expanded this analysis to diploid cells and used the advantage of making hybrid diploids to study chromosome rearrangements and changes in the ploidy of the surviving progeny. We have found that the consequences for the genome integrity were far more dramatic than originally envisioned

Contribution of the HIV-1 Envelope Glycoprotein to AIDS Pathogenesis and Clinical Progression

In the absence of antiviral therapy, HIV-1 infection progresses to a wide spectrum of clinical manifestations that are the result of an entangled contribution of host, immune and viral factors. The contribution of these factors is not completely established. Several investigations have described the involvement of the immune system in the viral control. In addition, distinct HLA-B alleles, HLA-B27, -B57-58, were associated with infection control. The combination of these elements and antiviral host restriction factors results in different clinical outcomes. The role of the viral proteins in HIV-1 infection has been, however, less investigated. We will review contributions dedicated to the pathogenesis of HIV-1 infection focusing on studies identifying the function of the viral envelope glycoprotein (Env) in the clinical progression because of its essential role in the initial events of the virus life-cycle. Some analysis showed that inefficient viral Envs were dominant in non-progressor individuals. These poorly-functional viral proteins resulted in lower cellular activation, viral replication and minor viral loads. This limited viral antigenic production allows a better immune response and a lower immune exhaustion. Thus, the properties of HIV-1 Env are significant in the clinical outcome of the HIV-1 infection and AIDS pathogenesis.This work was funded by the Spanish AIDS network “Red Temática Cooperativa de Investigación en SIDA” RD12/0017/0002, RD12/0017/0028, RD12/0017/0034, RD16/0025/0011, RDCIII16/0002/0005 and RD16/0025/0041 as part of the Plan Nacional R + D+I and co-funded by the Spanish “Instituto de Salud Carlos III (ISCIII)-Subdirección General de Evaluación y el Fondo Europeo de Desarrollo Regional (FEDER)”. J.B. is a researcher from “Fundació Institut de Recerca en Ciències de la Salut Germans Trias i Pujol” supported by the Health Department of the Catalonian Government/Generalitat de Catalunya and ISCIII grant Nos. PI17/01318 and PI20/00093 (to J.B.). Work in C.C. Lab was supported by grants SAF (2010-17226) and (2016-77894-R) from MINECO (Spain), FIS (PI13/02269, ISCIII) and PI20/00093. A.-V.F.’s Lab is supported by the European Regional Development Fund (ERDF), PID2021-123031OB-I00 (“Ministerio de Ciencia e Innovación”, Spain), RTI2018-093747-B-100 (“Ministerio de Ciencia, Innovación y Universidades”, Spain), ProID2020010093 (“Agencia Canaria de Investigación, Innovación y Sociedad de la Información” and the European Social Fund), UNLL10-3E-783 (ERDF and “Fundación CajaCanarias”) and “SEGAI-ULL”. S.-P.Y. is funded by “Fundación Doctor Manuel Morales” (La Palma, Spain) and “Contrato Pre-doctoral Ministerio-ULL Formación de Doctores” (2019 Program) (“Ministerio de Ciencia, Innovación y Universidades”, Spain). R.-C.R. is funded by RD16/0025/0011 and ProID2020010093 (“Agencia Canaria de Investigación, Innovación y Sociedad de la Información” and European Social Fund). J.-G.L. is funded by the “Juan de la Cierva de Incorporación” Spanish Program (IJC2019-038902-I) (“Ayudas Juan de la Cierva de incorporación; Agencia Estatal de Investigación. Ministerio de Ciencia e Innovación”).S

Targeting the TWEAK–Fn14 pathway prevents dysfunction in cardiac calcium handling after acute kidney injury

Heart and kidney have a closely interrelated pathophysiology. Acute kidney injury (AKI) is associated with significantly increased rates of cardiovascular events, a relationship defined as cardiorenal syndrome type 3 (CRS3). The underlying mechanisms that trigger heart disease remain, however, unknown, particularly concerning the clinical impact of AKI on cardiac outcomes and overall mortality. Tumour necrosis factor-like weak inducer of apoptosis (TWEAK) and its receptor fibroblast growth factor-inducible 14 (Fn14) are independently involved in the pathogenesis of both heart and kidney failure, and recent studies have proposed TWEAK as a possible therapeutic target; however, its specific role in cardiac damage associated with CRS3 remains to be clarified. Firstly, we demonstrated in a retrospective longitudinal clinical study that soluble TWEAK plasma levels were a predictive biomarker of mortality in patients with AKI. Furthermore, the exogenous application of TWEAK to native ventricular cardiomyocytes induced relevant calcium (Ca2+) handling alterations. Next, we investigated the role of the TWEAK–Fn14 axis in cardiomyocyte function following renal ischaemia–reperfusion (I/R) injury in mice. We observed that TWEAK–Fn14 signalling was activated in the hearts of AKI mice. Mice also showed significantly altered intra-cardiomyocyte Ca2+ handling and arrhythmogenic Ca2+ events through an impairment in sarcoplasmic reticulum Ca2+-adenosine triphosphatase 2a pump (SERCA2a) and ryanodine receptor (RyR2) function. Administration of anti-TWEAK antibody after reperfusion significantly improved alterations in Ca2+ cycling and arrhythmogenic events and prevented SERCA2a and RyR2 modifications. In conclusion, this study establishes the relevance of the TWEAK–Fn14 pathway in cardiac dysfunction linked to CRS3, both as a predictor of mortality in patients with AKI and as a Ca2+ mishandling inducer in cardiomyocytes, and highlights the cardioprotective benefits of TWEAK targeting in CRS3This work was mainly supported by projects from the Instituto de Salud Carlos III (ISCIII) (PI20/00763, PI20/01482, CPII20/00022, FI18/00261, FI21/00212, CD19/00029, IFEQ21/00012, PI19/00588, PI22/00469) and co-funded by the European Union, Ministerio de Universidades (FPU20/03005), Ministerio de Ciencia e Innovaci on (RYR2019-026916-I), the Education and Research Council of Madrid (PEJ-2021- AI/SAL-21426), Biomedicine Network Comunidad de Madrid (P2022/BMD-7223 CIFRA_COR-CM), Spanish Network in Inflammasoma and Pyroptosis in Chronic Disease and Cancer (RED2022-134511-T), and the Spanish Society of Nephrology SEN/SENEFRO Foundatio

Transactive Response DNA-Binding Protein (TARDBP/TDP-43) Regulates Cell Permissivity to HIV-1 Infection by Acting on HDAC6

The transactive response DNA-binding protein (TARDBP/TDP-43) influences the processing of diverse transcripts, including that of histone deacetylase 6 (HDAC6). Here, we assessed TDP-43 activity in terms of regulating CD4+ T-cell permissivity to HIV-1 infection. We observed that overexpression of wt-TDP-43 increased both mRNA and protein levels of HDAC6, resulting in impaired HIV-1 infection independently of the viral envelope glycoprotein complex (Env) tropism. Consistently, using an HIV-1 Env-mediated cell-to-cell fusion model, the overexpression of TDP-43 levels negatively affected viral Env fusion capacity. Silencing of endogenous TDP-43 significantly decreased HDAC6 levels and increased the fusogenic and infection activities of the HIV-1 Env. Using pseudovirus bearing primary viral Envs from HIV-1 individuals, overexpression of wt-TDP-43 strongly reduced the infection activity of Envs from viremic non-progressors (VNP) and rapid progressors (RP) patients down to the levels of the inefficient HIV-1 Envs observed in long-term non-progressor elite controllers (LTNP-EC). On the contrary, silencing endogenous TDP-43 significantly favored the infectivity of primary Envs from VNP and RP individuals, and notably increased the infection of those from LTNP-EC. Taken together, our results indicate that TDP-43 shapes cell permissivity to HIV-1 infection, affecting viral Env fusion and infection capacities by altering the HDAC6 levels and associated tubulin-deacetylase anti-HIV-1 activity.This work is supported by the Spanish AIDS network “Red Temática Cooperativa de Investigación en SIDA” RD12/0017/0002, RD12/0017/0028, RD12/0017/0034, RD16/0025/0011, RDCIII16/0002/0005 and RD16/0025/0041 as part of the Plan Nacional R + D+I and co-funded by the Spanish “Instituto de Salud Carlos III (ISCIII)-Subdirección General de Evaluación y el Fondo Europeo de Desarrollo Regional (FEDER)”. J.B. is a researcher from “Fundació Institut de Recerca en Ciències de la Salut Germans Trias i Pujol” supported by the Health Department of the Catalonian Government/Generalitat de Catalunya and ISCIII grant numbers PI17/01318 and PI20/00093 (to J.B.). Work in CC Lab was supported by grants SAF (2010-17226) and (2016-77894-R) from MINECO (Spain), FIS (PI 13/02269, ISCIII) and PI20/00093. Work in CF Lab was supported by the Cabildo Insular de Tenerife (grants CGIEU0000219140 and “Apuestas científicas del ITER para colaborar en la lucha contra la COVID-19”); the agreement with the Instituto Tecnológico y de Energías Renovables (ITER) to strengthen scientific and technological education, training research, development and innovation in Genomics, Personalized Medicine and Biotechnology (grant number OA17/008). A.V.-F.’s Lab is supported by the European Regional Development Fund (ERDF), RTI2018-093747-B-100 (“Ministerio de Ciencia e Innovación”, Spain), “Ministerio de Ciencia, Innovación y Universidades” (Spain), ProID2020010093 (“Agencia Canaria de Investigación, Innovación y Sociedad de la Información” and European Social Fund), UNLL10-3E-783 (ERDF and “Fundación CajaCanarias”) and “SEGAI-ULL”. S.P-Y is funded by “Fundación Doctor Manuel Morales” (La Palma, Spain) and “Contrato Predoctoral Ministerio-ULL Formación de Doctores” (2019 Program) (“Ministerio de Ciencia, Innovación y Universidades”, Spain). R.C.-R. is funded by RD16/0025/0011 and ProID2020010093 (“Agencia Canaria de Investigación, Innovación y Sociedad de la Información” and European Social Fund). J.G.-L. is funded by the “Juan de la Cierva de Incorporación” Spanish Program (IJC2019-038902-I) (“Ayudas Juan de la Cierva de incorporación; Agencia Estatal de Investigación. Ministerio de Ciencia e Innovación”).S

Ingeniería Geológica en Terrenos Volcánicos. Métodos, Técnicas y Experiencias en las Islas Canarias

La presente obra es un compendio de conceptos, metodologías y técnicas útiles para acometer proyectos y obras en terrenos volcánicos desde el punto de vista de la ingeniería geológica y la geotecnia. El libro se presenta en tres partes diferenciadas. La primera es conceptual y metodológica, con capítulos que tratan sobre la clasificación de las rocas volcánicas con fines geotécnicos, la caracterización geomecánica, los problemas geotécnicos y constructivos asociados a los distintos materiales, y una guía metodológica para la redacción de informes geotécnicos para la edificación. La segunda parte aborda las aplicaciones a obras de ingeniería, incluyendo deslizamientos, obras subterráneas,infraestructuras marítimas y obras públicas. La tercera parte recoge capítulos dedicados a describir distintos casos prácticos de obras y proyectos en los que la problemática geotécnica en terrenos volcánicos ha tenido un papel relevante. Los capítulos han sido elaborados por técnicos y científicos de reconocido prestigio en el campo de la ingeniería geológica en terrenos volcánicos, que han plasmado en ellos sus conocimientos y experiencias en la materia.Los editores y autores de parte de los capítulos del libro, los Doctores Luis E. Hernández Gutiérrez (Geólogo) y Juan Carlos Santamarta Cerezal (Ingeniero de Montes, Civil y Minas), son los responsables del grupo de investigación INGENIA (Ingeniería Geológica, Innovación y Aguas). Su actividad investigadora comprende más de 200 publicaciones en el área de la ingeniería geológica, la geotecnia, medio ambiente y el aprovechamiento del agua en islas y terrenos volcánicos. En relación a la docencia han impartido y dirigido más de 90 seminarios y cursos de especialización a nivel nacional e internacional, incluyendo la organización de 4 congresos internacionales. Fueron premiados por la Universidad de La Laguna en los años 2012, 2013 y 2014 por su calidad docente e innovación universitaria, y son pioneros en los laboratorios virtuales para la enseñanza de la ingeniería. Participan activamente como profesores colaboradores e investigadores en varias universidades e instituciones españolas e internacionales. Todas sus publicaciones están disponibles en internet, con libre acceso. Ingeniería geológica en terrenos volcánicos, es una obra de gran interés para, consultores, técnicos de administraciones públicas, proyectistas y demás profesionales implicados en obras y proyectos de infraestructuras en terrenos volcánicos; también es útil para académicos y estudiantes de ingeniería o ciencias geológicas que quieran investigar o iniciarse en las singularidades que presentan los materiales volcánicos en la edificación o en la ingeniería civil y minera

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

Nondisjunction of a Single Chromosome Leads to Breakage and Activation of DNA Damage Checkpoint in G2

The resolution of chromosomes during anaphase is a key step in mitosis. Failure to disjoin chromatids compromises the fidelity of chromosome inheritance and generates aneuploidy and chromosome rearrangements, conditions linked to cancer development. Inactivation of topoisomerase II, condensin, or separase leads to gross chromosome nondisjunction. However, the fate of cells when one or a few chromosomes fail to separate has not been determined. Here, we describe a genetic system to induce mitotic progression in the presence of nondisjunction in yeast chromosome XII right arm (cXIIr), which allows the characterisation of the cellular fate of the progeny. Surprisingly, we find that the execution of karyokinesis and cytokinesis is timely and produces severing of cXIIr on or near the repetitive ribosomal gene array. Consequently, one end of the broken chromatid finishes up in each of the new daughter cells, generating a novel type of one-ended double-strand break. Importantly, both daughter cells enter a new cycle and the damage is not detected until the next G2, when cells arrest in a Rad9-dependent manner. Cytologically, we observed the accumulation of damage foci containing RPA/Rad52 proteins but failed to detect Mre11, indicating that cells attempt to repair both chromosome arms through a MRX-independent recombinational pathway. Finally, we analysed several surviving colonies arising after just one cell cycle with cXIIr nondisjunction. We found that aberrant forms of the chromosome were recovered, especially when RAD52 was deleted. Our results demonstrate that, in yeast cells, the Rad9-DNA damage checkpoint plays an important role responding to compromised genome integrity caused by mitotic nondisjunction

Innovación en las enseñanzas universitarias: experiencias presentadas en las III Jornadas de Innovación Educativa de la ULL

En este libro se recoge un conjunto de experiencias de innovación educativa desarrolladas en la ULL en el curso 2011-12. Se abordan distintos ámbitos y ramas del conocimiento, y ocupan temáticas variadas que han sido desarrolladas con rigor, y con un claro potencial para su extrapolación a efectos de la mejora educativa en el ámbito universitario. Esta publicación constituye una primera edición de una serie que irá recogiendo las experiencias de innovación educativa de la ULL. Este es un paso relevante para su impulso en nuestra institución, como lo es el de su vinculación con la investigación educativa, para potenciar su publicación en las revistas científicas en este ámbito cada vez más pujante y relevante para las universidades. Sobre todo representan el deseo y el compromiso del profesorado de la ULL para la mejora del proceso educativo mediante la investigación, la evaluación y la reflexión compartida de nuestras prácticas y planteamientos docentes

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 2014 July. This paper describes the second data release from this phase, and the 14th from SDSS overall (making this Data Release Fourteen or DR14). This release makes the data taken by SDSS-IV in its first two years of operation (2014–2016 July) public. 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; 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 the 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 web site (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

Estudio de la segregación cromosómica en "Saccharomyces cerevisiae" bajo la presencia de uniones persistentes entre las moléculas de ADN de las cromátidas hermanas

The fidelity of chromosome inheritance is of utmost importance to all living organisms. During every cell division precisely one copy of the parental genome must be segregated into each of the two daughter cells in order to allow the stable existence of progeny. This is achieved initially by the complete and faithful duplication of the chromosomes during DNA replication. Following replication each chromosome is comprised of two identical sister chromatids. Next, sister chromatids are fully resolved from each other, ensuring that no physical connection exists between them. Finally, the sisters are segregated to opposite ends of the dividing cell, guaranteeing that when cell division is completed, both daughter cells have a full complement of genetic information. After replication sister chromatids are held together by three defined kind of linkages: 1) proteinaceous linkages, mediated by the cohesin complex: a ring shaped structure that embraces both sister chromatids. 2) Topological linkages, mostly intertwines between double helixes. 3) DNA-DNA linkages formed by regions of the chromosome that have not been fully replicated, or by intermediates of the homologous recombination (HR) DNA repair process, i.e. recombination intermediates. Complete replication of the chromosomes, cleavage of cohesin and removal of catenations are essential to segregate chromosomes correctly. If the cell leaves these linkages unresolved, they lead to the formation of DNA filaments connecting the nuclei of both daughter cells, known as chromosome bridges. If the chromosome bridges are not resolved they can be severed during cytokinesis leading to double strand breaks of the DNA molecule and genome instability. Formation of chromosome bridges is a key characteristic of tumorous cells and it is considered as one the first events in the transformation from a somatic to a cancerous cell, since it favours gross chromosomal rearrangements, amplification of oncogenes and elimination of tumour suppressor genes. However, it is unknown if recombination intermediates can lead to the formation of chromosome bridges. Recombination intermediates appear as a consequence of the DNA repair process that uses homologous recombination pathway. In this pathway the undamaged sister chromatid provides a template which facilitates the restoration of the original sequence of a broken DNA molecule. In this thesis the budding yeast Saccharomyces cerevisiae has been used as a model organism to study the sources of chromosome bridges. A haploid cdc15-2 mutant has been used as a reference strain. This mutant can be blocked in telophase with the genome correctly segregated between the two daughter cells. Using this strain it has been study whether persistent recombination intermediates, more specifically those that depend on structure specific endonucleases (SSEs) for their resolution, can lead to chromosome bridges. To this purpose, the steady-state levels of these joint molecules (JMs) were modified by deleting different combinations of the yeast SSEs genes together with exogenously forcing the cells to bypass replication stress by utilising HR. It was found that both Mus81-Mms4 and Yen1, but not Slx4-related SSEs, are essential and compensate each other in preventing and resolving a specific type of chromosome bridge, which mostly comprises noncanonical (discontinuous) forms of the Holliday Junction (HJ) molecule. In addition, it was found that the SSE Yen1 is targeted to the nucleus by the mitotic master phosphatase Cdc14, acting as a `last resort¿ endonuclease to deal with any remaining HJs that might compromise chromosome segregation. This result highlights the essential role of early-activated Cdc14; through the FEAR network, Cdc14 effects the removal of all kinds of non-proteinaceous linkage that preclude faithful sister chromatid segregation in anaphase