The structural impact of DNA mismatches

© 2015 © The Author(s) 2015. Published by Oxford University Press on behalf of Nucleic Acids Research. The structure and dynamics of all the transversion and transition mismatches in three different DNA environments have been characterized by molecular dynamics simulations and NMR spectroscopy. We found that the presence of mismatches produced significant local structural alterations, especially in the case of purine transversions. Mismatched pairs often show promiscuous hydrogen bonding patterns, which interchange among each other in the nanosecond time scale. This therefore defines flexible base pairs, where breathing is frequent, and where distortions in helical parameters are strong, resulting in significant alterations in groove dimension. Even if the DNA structure is plastic enough to absorb the structural impact of the mismatch, local structural changes can be propagated far from the mismatch site, following the expected through-backbone and a previously unknown through-space mechanism. The structural changes related to the presence of mismatches help to understand the different susceptibility of mismatches to the action of repairing proteins.Peer Reviewe

Cardiac Bmi1(+) cells contribute to myocardial renewal in the murine adult heart

Introduction: The mammalian adult heart maintains a continuous, low cardiomyocyte turnover rate throughout life. Although many cardiac stem cell populations have been studied, the natural source for homeostatic repair has not yet been defined. The Polycomb protein BMI1 is the most representative marker of mouse adult stem cell systems. We have evaluated the relevance and role of cardiac Bmi1(+) cells in cardiac physiological homeostasis. Methods: Bmi1(CreER/+); Rosa26(YFP/+) (Bmi1-YFP) mice were used for lineage tracing strategy. After tamoxifen (TM) induction, yellow fluorescent protein (YFP) is expressed under the control of Rosa26 regulatory sequences in Bmi1(+) cells. These cells and their progeny were tracked by FACS, immunofluorescence and RT-qPCR techniques from 5 days to 1 year. Results: FACS analysis of non-cardiomyocyte compartment from TM-induced Bmi1-YFP mice showed a Bmi1 (+)-expressing cardiac progenitor cell (Bmi1-CPC: B-CPC) population, SCA-1 antigen-positive (95.9 +/- 0.4 \%) that expresses some stemness-associated genes. B-CPC were also able to differentiate in vitro to the three main cardiac lineages. Pulse-chase analysis showed that B-CPC remained quite stable for extended periods (up to 1 year), which suggests that this Bmi1(+) population contains cardiac progenitors with substantial self-maintenance potential. Specific immunostaining of Bmi1-YFP hearts serial sections 5 days post-TM induction indicated broad distribution of B-CPC, which were detected in variably sized clusters, although no YFP+ cardiomyocytes (CM) were detected at this time. Between 2 to 12 months after TM induction, YFP+ CM were clearly identified (3 +/- 0.6 \% to 6.7 +/- 1.3 \%) by immunohistochemistry of serial sections and by flow cytometry of total freshly isolated CM. B-CPC also contributed to endothelial and smooth muscle (SM) lineages in vivo. Conclusions: High Bmi1 expression identifies a non-cardiomyocyte resident cardiac population (B-CPC) that contributes to the main lineages of the heart in vitro and in vivo.We wish to thank M. Torres, J.M. Perez-Pomares and B.G. Galvez for critical discussions of the manuscript, A. M. Santos for assistance with confocal microscopy and dynamic imaging, R.M. Carmona for help with the animal colony management, F.S. Cabo for bioinformatics and statistical support, J.M Ligos for the sorting strategy, and K. McCreath and C. Mark for editorial support. This study was supported by grants to A.B. from the Ministry of Science and Innovation (SAF2012-34327; PLE2009-0147 and PSE-010000-2009-3), the Research Program of the Comunidad Autonoma de Madrid (S2010/BMD-2420), the Instituto de Salud Carlos III (RETICS-RD12/0019/0018 and RETICS-RD12/0019/0023) and the European Commission (Proposal 242038). The CNB-CSIC and CNIC are supported by the Spanish Ministry of Economy and Competitiveness.S

Relationship between target organ damage and blood pressure, retinal vessel calibre, oxidative stress and polymorphisms in VAV-2 and VAV-3 genes in patients with hypertension: a case-control study protocol (LOD- Hipertensión)

This is an Open Access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 3.0) license.[Introduction]: Target organ damage (TOD) is associated with increased cardiovascular risk. The study objectives were to analyse the relationship of TOD to blood pressure, size of retinal arteries and veins, oxidative stress and different polymorphisms in the VAV-2 and VAV-3 genes in participants with hypertension. [Methods and analysis]: A case-control study to analyse the relationship between clinical, biochemical and genetic parameters and presence of cardiac, vascular and renal TOD in 486 patients with hypertension. Participants with TOD will be considered as cases, and those without TOD will be enrolled as controls. This will be a collaborative study conducted by the groups of Primary Care, Cardiovascular and Metabolic and Degenerative Diseases of the Instituto de Investigación Biomédica of Salamanca (IBSAL). Assessment of cardiac, renal and vascular TOD. Measurement of peripheral and central blood pressure, size of eye fundus arteries and veins, and oxidative stress, and polymorphisms in the VAV-2 and VAV-3 genes. [Ethics and dissemination]: The study will be conducted after approval is obtained from the Ethics Committee of Hospital Clínico Universitario of Salamanca. All study participants will sign an informed consent to agree to participate in the study, and another consent to agree on the genetic study, in compliance with the Declaration of Helsinki and the WHO standards for observational studies. The results of this study will allow for an understanding of the relationship of the different TODs with blood pressure, retinal artery and vein diameters, oxidative stress and polymorphisms in VAV-2 and VAV-3 genes. [Trial registration number]: Clinical Trials. gov Identifier: NCT02022618.This project has been supported by the Castilla y León Health Service (BIO/SA05/13), Carlos III Institute of Health of the Spanish Ministry of Health (RETICS RD12/0005, RedIAPP, and RD12/0021, RedinRen), and Infosalud Foundation.Peer Reviewe

Activation of Secondary Metabolism in Citrus Plants Is Associated to Sensitivity to Combined Drought and High Temperatures

Drought and heat stresses are two of the most frequent environmental factors that take place simultaneously in the field constraining global crop productivity. Metabolism reconfiguration is often behind the adaptation of plants to adverse environmental conditions. Carrizo citrange and Cleopatra mandarin, two citrus genotypes with contrasting ability to tolerate combined heat and drought conditions, showed different metabolite patterns. Increased levels of phenylpropanoid metabolites were observed in Cleopatra in response to stress, including scopolin, a metabolite involved in defense mechanisms. Tolerant Carrizo accumulated sinapic acid and sinapoyl aldehyde, direct precursors of lignins. Finally, Cleopatra showed an accumulation of flavonols and glycosylated and polymethoxylated flavones such as tangeritin. The activation of flavonoid biosynthesis in Cleopatra could be aimed to mitigate the higher oxidative damage observed in this genotype. In general, limonoids were more severely altered in Cleopatra than in Carrizo in response to stress imposition. To conclude, all metabolite changes observed in Cleopatra suggest the activation of energy metabolism along with metabolic pathways leading to the accumulation of photoprotective and antioxidant secondary metabolites, oriented to mitigate the damaging effects of stress. Conversely, the higher ability of Carrizo to retain a high photosynthetic activity and to cope with oxidative stress allowed the maintenance of the metabolic activity and prevented the accumulation of antioxidant metabolites.This work was supported by Ministerio de Economía y Competitividad (MINECO) [AGL2013-42038-R, AGL2016-76574-R] and Universitat Jaume I [UJI-B2016-23/UJI-B2016-24]. SZ was supported by a predoctoral fellowship from Universitat Jaume I

The Overall Coefficient of the Two-loop Superstring Amplitude Using Pure Spinors

Using the results recently obtained for computing integrals over (non-minimal) pure spinor superspace, we compute the coefficient of the massless two-loop four-point amplitude from first principles. Contrasting with the mathematical difficulties in the RNS formalism where unknown normalizations of chiral determinant formulae force the two-loop coefficient to be determined only indirectly through factorization, the computation in the pure spinor formalism can be smoothly carried out.Comment: 29 pages, harvmac TeX. v2: add reference

An Alternative Yukawa Unified SUSY Scenario

Supersymmetric SO(10) Grand Unified Theories with Yukawa unification represent an appealing possibility for physics beyond the Standard Model. However Yukawa unification is made difficult by large threshold corrections to the bottom mass. Generally one is led to consider models where the sfermion masses are large in order to suppress these corrections. Here we present another possibility, in which the top and bottom GUT scale Yukawa couplings are equal to a component of the charged lepton Yukawa matrix at the GUT scale in a basis where this matrix is not diagonal. Physically, this weak eigenstate Yukawa unification scenario corresponds to the case where the charged leptons that are in the 16 of SO(10) containing the top and bottom quarks mix with their counterparts in another SO(10) multiplet. Diagonalizing the resulting Yukawa matrix introduces mixings in the neutrino sector. Specifically we find that for a large region of parameter space with relatively light sparticles, and which has not been ruled out by current LHC or other data, the mixing induced in the neutrino sector is such that $sin^2 2\Theta_{23} \approx 1$, in agreement with data. The phenomenological implications are analyzed in some detail.Comment: 32 pages, 22 Figure

Inflation with racetrack superpotential and matter field

Several models of inflation with the racetrack superpotential for the volume modulus coupled to a matter field are investigated. In particular, it is shown that two classes of racetrack inflation models, saddle point and inflection point ones, can be constructed in a fully supersymmetric framework with the matter field F-term as a source of supersymmetry breaking and uplifting. Two models of F-term supersymmetry breaking are considered: the Polonyi model and the quantum corrected O'Raifeartaigh model. In the former case, both classes of racetrack inflation models differ significantly from the corresponding models with non-supersymmetric uplifting. The main difference is a quite strong dominance of the inflaton by the matter field. In addition, fine-tuning of the parameters is relaxed as compared to the original racetrack models. In the case of the racetrack inflation models coupled to the O'Raifeartaigh model, the matter field is approximately decoupled from the inflationary dynamics. In all of the above models the gravitino mass is larger than the Hubble scale during inflation. The possibility of having the gravitino much lighter than the Hubble scale is also investigated. It is very hard to construct models with light gravitino in which the volume modulus dominates inflation. On the other hand, models in which the inflationary dynamics is dominated by the matter field are relatively simple and seem to be more natural.Comment: 40 pages, 13 figures, references added, typos corrected, version to be publishe

X-linked Inhibitor of Apoptosis Protein negatively regulates neuronal differentiation through interaction with cRAF and Trk

Altres ajuts: CIBERNED CB06/05/0042 i CB06/05/1104, RENEVAS RD06/0026/1009 i Juan de la CiervaX-linked Inhibitor of apoptosis protein (XIAP) has been classically identified as a cell death regulator. Here, we demonstrate a novel function of XIAP as a regulator of neurite outgrowth in neuronal cells. In PC12 cells, XIAP overexpression prevents NGF-induced neuronal differentiation, whereas NGF treatment induces a reduction of endogenous XIAP levels concomitant with the induction of neuronal differentiation. Accordingly, downregulation of endogenous XIAP protein levels strongly increases neurite outgrowth in PC12 cells as well as axonal and dendritic length in primary cortical neurons. The effects of XIAP are mediated by the mitogen-activated protein kinase (MEK)/extracellular signal-regulated kinases (ERKs) pathway since blocking this pathway completely prevents the neuritogenesis mediated by XIAP downregulation. In addition, we found that XIAP binds to cRaf and Trk receptors. Our results demonstrate that XIAP plays a new role as a negative regulator of neurotrophin-induced neurite outgrowth and neuronal differentiation in developing neurons