Transcription-mediated replication hindrance: a major driver of genome instability

Genome replication involves dealing with obstacles that can result from DNA damage but also from chromatin alterations, topological stress, tightly bound proteins or non-B DNA structures such as R loops. Experimental evidence reveals that an engaged transcription machinery at the DNA can either enhance such obstacles or be an obstacle itself. Thus, transcription can become a potentially hazardous process promoting localized replication fork hindrance and stress, which would ultimately cause genome instability, a hallmark of cancer cells. Understanding the causes behind transcription–replication conflicts as well as how the cell resolves them to sustain genome integrity is the aim of this review

Rpd3L and Hda1 histone deacetylases facilitate repair of broken forks by promoting sister chromatid cohesion

Genome stability involves accurate replication and DNA repair. Broken replication forks, such as those encountering a nick, lead to double strand breaks (DSBs), which are preferentially repaired by sister-chromatid recombination (SCR). To decipher the role of chromatin in eukaryotic DSB repair, here we analyze a collection of yeast chromatin-modifying mutants using a previously developed system for the molecular analysis of repair of replication-born DSBs by SCR based on a mini-HO site. We confirm the candidates through FLP-based systems based on a mutated version of the FLP flipase that causes nicks on either the leading or lagging DNA strands. We demonstrate that Rpd3L and Hda1 histone deacetylase (HDAC) complexes contribute to the repair of replication-born DSBs by facilitating cohesin loading, with no effect on other types of homology-dependent repair, thus preventing genome instability. We conclude that histone deacetylation favors general sister chromatid cohesion as a necessary step in SCR

R-loops do not accumulate in transcription-defective hpr1-101 mutants: implications for the functional role of THO/TREX

To get further insight into the effect that THO/TREX and R-loops have in transcription-associated recombination and transcription, we analyzed the ability to form R-loops of hpr1-101, a THO mutation that impairs transcription and mRNP biogenesis without triggering hyper-recombination. Human AID, a cytidine deaminase that acts on ssDNA displaced by RNA-DNA hybrids, strongly induced both hyper-recombination and hyper-mutation in hpr1-101, similar to hpr1Δ mutants. However, in contrast to hpr1Δ, AID-induced mutations in hpr1-101 occur at similar frequencies in both the transcribed and non-transcribed strands, implying that the enhanced AID action in these mutants is not caused by co-transcriptional R-loops. These results indicate for the first time that THO has a transcriptional function that is not mediated by R-loops, providing a new perspective for the understanding of the coupling of transcription with mRNP biogenesis and export

DNA-RNA hybrids: The risks of DNA breakage during transcription

Although R loops can occur at different genomic locations, the factors that determine their formation and frequency remain unclear. Emerging evidence indicates that DNA breaks stimulate DNA-RNA hybrid formation. Here, we discuss the possibility that formation of hybrids may be an inevitable risk of DNA breaks that occur within actively transcribed regions. While such hybrids must be removed to permit repair, their potential role as repair intermediates remains to be established

Tourism stock prices, systemic risk and tourism growth: a kalman filter with prior update DSGE-VAR model

Dynamic Stochastic General Equilibrium (DSGE) and Vector Autoregressive (VAR) models allow for probabilistic estimations to formulate macroeconomic policies and monitor them. One of the objectives of creating these models is to explain and understand financial fluc tuations through a consistent theoretical framework. In the tourism sector, stock price and sys temic risk are key financial variables in the international transmission of business cycles. Ad vances in Bayesian theory are providing an increasing range of tools that researchers can employ to estimate and evaluate DSGE and VAR models. One area of interest in previous literature has been to design a Bayesian robust filter, that performs well concerning an uncertainty class of possible models compatible with prior knowledge. In this study, we propose to apply the Bayes ian Kalman Filter with Prior Update (BKPU) in a tourism field to increase the robustness of DSGE and VAR models built for small samples and with irregular data. Our results indicate that BKPU improves the estimation of these models in two aspects. Firstly, the accuracy levels of the computing of the Markov Chain Monte Carlo model are increased, and secondly, the cost of the resources used is reduced due to the need for a shorter run time. Our model can play an essential role in the monetary policy process, as central bankers could use it to investigate the relative importance of different macroeconomic shocks and the effects of tourism stock prices and achieve a country´s international competitiveness and trade balance for this sectorUniversidad de Málaga. Campus de Excelencia Internacional Andalucía Tech

Mejora de sistemas de autenticación de personas basados en dinámica de ratón

En este Trabajo Fin de Grado se estudia e implementa un sistema de autenticación de personas basado en dinámica de ratón. Los sistemas de autenticación de personas a partir de rasgos biométricos de comportamiento tienen cada vez mayor demanda. En este sentido, la dinámica de ratón se ha convertido en los últimos años en una interesante línea de investigación. Motivada por el impacto de la biometría web y de comportamiento, ésta biometría presenta gran potencial en multitud de escenarios dado su bajo coste y fácil implantación. Igual que la dinámica de tecleo, la dinámica de ratón se plantea como una alternativa a los sistemas tradicionales de autenticación y una garantía de la tan importante seguridad cibernética. Además, frente a otras tecnologías, permite llevar a cabo una monitorización continua de los usuarios, es decir, permite autenticación continua durante el uso de un servicio en contrapunto a la autenticación puntual única realizada al acceder al servicio. Todos estos factores han convertido a la dinámica de ratón en una herramienta muy atractiva para la industria digital. Los trabajos realizados en este campo reseñan su utilidad y refuerzan su validez con sus resultados. Así, el objetivo del presente trabajo es evaluar el rendimiento de los sistemas planteados en la literatura y estudiar posibles mejoras de los mismos. Por tanto, el primer punto de este trabajo pasa por realizar una revisión del estado del arte. De todos los trabajos propuestos, se emplea un artículo de referencia. En éste se plantea una evaluación del rendimiento de diferentes implementaciones del problema. En base a ello, se diseña el sistema de mejor resultado y se analiza su rendimiento de acuerdo a las diferentes variables que componen el problema (usuarios, tareas, características). De forma paralela, se estudian nuevas aproximaciones del problema, ya empleadas en rasgos como la firma, basadas en modelos neuromotores asociados a la producción de las señales dinámicas involucradas en la dinámica de ratón. Tras el diseño de los diversos sistemas, se llevan a cabo una serie de experimentos a fin de efectuar diferentes evaluaciones. Finalmente, se presentan las conclusiones y se proponen futuras líneas de trabajo.This Bachelor Thesis presents the study and implementation of an authentication system based on mouse dynamics. User authentication systems using behavioural biometrics are in increasing demand. In this regard, mouse dynamics has recently become an interesting research line. Driven by the impact of web and behavioural biometrics, mouse dynamics biometric shows great potential for many areas given its low cost and easy implementation. As with keystroke, mouse dynamics is proposed as an alternative to traditional authentication system and a guarantee of cybersecurity. In addition, compared to other technologies, it can be used in passive authentication, continuously validating user’s identity while using a service in contrast to one-off authentication performed when accessing a service. All this factors have made mouse dynamics an attractive tool for the digital industry. Previous research done in the area note its usefulness and reinforce its validity with their results. Thus, the aim of this study is to evaluate the performance of systems proposed in the literature and to study potential improvements. Therefore, the first block of this document is a review of the state of art. Of all research proposals, it is used one reference paper in particular. This paper presents a performance evaluation of different system implementations. On this basis, it is design the best system and its performance is analysed according to different parameters that define the problem (users, tasks, features). Alternatively, we study new approaches, already used in behavioural biometrics such as signature, based on neuromotor models associated to the production of dynamic signals involved in mouse activities. After the design stage, we conduct some experiments in order to perform different evaluations. Finally, we present the conclusions and, based on them, some future research lines

AID Induces Double-Strand Breaks at Immunoglobulin Switch Regions and c-MYC Causing Chromosomal Translocations in Yeast THO Mutants

Transcription of the switch (S) regions of immunoglobulin genes in B cells generates stable R-loops that are targeted by Activation Induced Cytidine Deaminase (AID), triggering class switch recombination (CSR), as well as translocations with c-MYC responsible for Burkitt's lymphomas. In Saccharomyces cerevisiae, stable R-loops are formed co-transcriptionally in mutants of THO, a conserved nuclear complex involved in mRNP biogenesis. Such R-loops trigger genome instability and facilitate deamination by human AID. To understand the mechanisms that generate genome instability mediated by mRNP biogenesis impairment and by AID, we devised a yeast chromosomal system based on different segments of mammalian S regions and c-MYC for the analysis of chromosomal rearrangements in both wild-type and THO mutants. We demonstrate that AID acts in yeast at heterologous S and c-MYC transcribed sequences leading to double-strand breaks (DSBs) which in turn cause chromosomal translocations via Non-Homologous End Joining (NHEJ). AID–induced translocations were strongly enhanced in yeast THO null mutants, consistent with the idea that AID–mediated DSBs depend on R-loop formation. Our study not only provides new clues to understand the role of mRNP biogenesis in preventing genome rearrangements and the mechanism of AID-mediated genome instability, but also shows that, once uracil residues are produced by AID–mediated deamination, these are processed into DSBs and chromosomal rearrangements by the general and conserved DNA repair functions present from yeast to human cells

Design of highly stabilized nanocomposite inks based on biodegradable polymer-matrix and gold nanoparticles for Inkjet Printing

Nowadays there is a worldwide growing interest in the Inkjet Printing technology owing to its potentially high levels of geometrical complexity, personalization and resolution. There is also social concern about usage, disposal and accumulation of plastic materials. In this work, it is shown that sugar-based biodegradable polyurethane polymers exhibit outstanding properties as polymer-matrix for gold nanoparticles composites. These materials could reach exceptional stabilization levels, and demonstrated potential as novel robust inks for Inkjet based Printing. Furthermore, a physical comparison among different polymers is discussed based on stability and printability experiments to search for the best ink candidate. The University of Seville logo was printed by employing those inks, and the presence of gold was confirmed by ToF-SIMS. This approach has the potential to open new routes and applications for fabrication of enhanced biomedical nanometallic-sensors using stabilized AuNP.Spanish Ministerio de Economía y Competitividad MINECO, (Grants Nos. CTQ2016- 78703-P and MAT2016-78703-P)Junta de Andalucía (Consolidation Grant for Research Group FQM135 and 2017/FQM-386, P-2018/809)University of Seville (V y VI Plan Propio PP2016-5937

Estudio del cambio en el hábitat y su influencia en las declinaciones de anfibios en el Parque Nacional Cajas y el Bosque Protector Mazán mediante un sistema de información geográfica

En los altos Andes del Sur del Ecuador, las declinaciones de anfibios son muy conocidas y una prioridad de investigación, sin embargo la influencia de la pérdida, degradación y fragmentación de los ecosistemas en éstas, no ha tenido suficiente consideración. El objetivo de ésta investigación es explorar si existe correlación entre las declinaciones de anfibios en el Parque Nacional Cajas y el Bosque Protector Mazán y los cambios en el hábitat ocurridos en las cinco últimas décadas (1961-2009), mediante la integración en un Sistema de Información Geográfica de áreas de distribución probable de las especies y coberturas de cambio de la vegetación derivadas de fotografía aérea histórica y reciente. Con el próposito de evidenciar una posible relación espacial entre los cambios en el paisaje y la ocurrencia de las especies (ausencia-presencia), se estimaron tres variables la proximidad del cambio a las áreas de distribución probable de las especies (derivadas de registros e información de preferencia de hábitat), la naturaleza del cambio y la pendiente entre las áreas de distribución probable y los cambios en el paisaje. Se observó que en los 80´s la quema fué el cambio más severo que afectó a las especies y en el 2000 lo fueron las plantaciones de especies no nativas de pino y eucalipto. Se concluye que existe una relación positiva entre el grado de afectación en el paisaje y las desapariciones y declinaciones poblacionales de anfibios en el Bosque Protector Mazán. Así también se comprueba la efectividad del uso de bases de registros de distribución de anfibios en la predicción de cambios complejos en el uso del suelo