Reversal of terminal differentiation and control of DNA replication

DNA replication in mammalian cells occurs in discrete nuclear foci. Here we show that terminally differentiated myotubes can be induced to reenter S phase and show the same pattern of replication foci as cycling cells. We used this cellular system to analyze the interaction of cell cycle proteins with these foci in vivo. Cyclin A and cdk2, but not cyclin B1 and cdc2, were specifically localized at nuclear replication foci, just like the replication protein proliferating cell nuclear antigen. A potential target of cyclin A and cdk2 is the 34 kd subunit of replication protein A (RPA34). In contrast with the 70 kd subunit, which localizes to the foci, RPA34 was not detected at these replication sites, which may reflect a transient interaction. The specific localization of cyclin A and cdk2 at nuclear replication foci provides a direct link between cell cycle regulation and DNA replication

Gaia kinematics reveal a complex lopsided and twisted Galactic disc warp

There are few warp kinematic models of the Galaxy able to characterise structure and kinematics. These models are necessary to study the lopsidedness of the warp and the twisting of the line-of-nodes of the stellar warp, already seen in gas and dust. We use the \Gaia~Data Release 2 astrometric data up to $G=20$mag to characterise the structure of the Galactic warp, the vertical motions and the dependency on the age. We use two populations up to galactocentric distances of $16$kpc, a young (OB-type) and an old (Red Giant Branch, RGB). We use the nGC3 PCM and LonKin methods based on the Gaia observables, together with 2D projections of the positions and proper motions in the Galactic plane. We confirm the age dependency of the Galactic warp, both in positions and kinematics, being the height of the Galactic warp of about $0.2$kpc for the OB sample and of $1.$kpc for the RGB at a galactocentric distance of $14$kpc. Both methods find that the onset radius is $12\sim 13$kpc for the OB sample and $10\sim 11$kpc for the RGB. From the RGB sample, we find from galactocentric distances larger than $10$kpc the line-of-nodes twists away from the Sun-anticentre line towards galactic azimuths $\sim 180-200^{\circ}$ increasing with radius, though possibly influenced by extinction. The RGB sample reveals a slightly lopsided stellar warp with $\sim 250$pc between the up and down sides. The line of maximum of proper motions in latitude is systematically offset from the line-of-nodes estimated from the spatial data, which our models predict as a kinematic signature of lopsidedness. We also show a prominent wave-like pattern of a bending mode different in the OB and RGB, and substructures that might not be related to the Galactic warp nor to a bending mode. GDR2 triggers the need for complex kinematic models, flexible enough to combine both wave-like patterns and an S-shaped lopsided warp.[abridged]Comment: 14 pages (+7 pages of appendix), matches the accepted version in A&A after referee comments (June 5th 2019

Large Eddy simulations of isolated and installed jet noise using the high-order discontinuous Galerkin method

A recently developed computational framework for jet noise is used to compute the noise generated by an isolated and installed jet. The framework consists of two parts. In the first part, the spectral/hp element framework Nektar++ is used to compute the near-field flow. Nektar++ solves the unfiltered Navier-Stokes equations on unstructured grids using the high-order discontinuous Galerkin method. The discrete equations are integrated in time using an implicit scheme based on the matrix-free Newton-GMRES method. In the second part, the Antares library is used to compute the far-field noise. Antares solves the Ffowcs Williams - Hawkings equation for a permeable integration surface in the time domain using a source-time dominant algorithm. The simulations are validated against experimental data obtained in the Doak Laboratory Flight Jet Rig, located at the University of Southampton. For the isolated jet, good agreement is achieved, both in terms of the flow statistics and the far-field noise. The discrepancies observed for the isolated jet are believed to be caused by an under-resolved boundary layer in the simulations. For the installed jet, the flow statistics are also well predicted. In the far-field, very good agreement is achieved for downstream observers. For upstream observers, some discrepancies are observed for very high and very low frequencies

Regioselective alkylation reaction of purines under microwave irradiation

The alkylation of purines which is generally carried out after anion formation by treatment with a base and alkyl halide is complicated and in the best cases, mixtures of N-alkylated compounds are obtained. Purine derivatives can be acquired from alkylation at N-7 and N-9. In this work, the reaction conditions have been optimized to obtain the alkylation products of N-9 regioselectively. Different bases have been tried and tetrabutylammonium hydroxide has led to the best results. The reaction depends on the type of base and solvent used and improves considerably when the aid of microwave irradiation is used, which also considerably reduces the reaction time by reducing the formation of secondary products

Deuteration around the ultracompact HII region Mon R2

The massive star-forming region Mon R2 hosts the closest ultra-compact HII region that can be spatially resolved with current single-dish telescopes. We used the IRAM-30m telescope to carry out an unbiased spectral survey toward two important positions (namely IF and MP2), in order to studying the chemistry of deuterated molecules toward Mon R2. We found a rich chemistry of deuterated species at both positions, with detections of C2D, DCN, DNC, DCO+, D2CO, HDCO, NH2D, and N2D+ and their corresponding hydrogenated species and isotopologs. Our high spectral resolution observations allowed us to resolve three velocity components: the component at 10 km/s is detected at both positions and seems associated with the layer most exposed to the UV radiation from IRS 1; the component at 12 km/s is found toward the IF position and seems related to the molecular gas; finally, a component at 8.5 km/s is only detected toward the MP2 position, most likely related to a low-UV irradiated PDR. We derived the column density of all the species, and determined the deuterium fractions (Dfrac). The values of Dfrac are around 0.01 for all the observed species, except for HCO+ and N2H+ which have values 10 times lower. The values found in Mon R2 are well explained with pseudo-time-dependent gas-phase model in which deuteration occurs mainly via ion-molecule reactions with H2D+, CH2D+ and C2HD+. Finally, the [H13CN]/[HN13C] ratio is very high (~11) for the 10 km/s component, which also agree with our model predictions for an age of ~0.01-0.1 Myr. The deuterium chemistry is a good tool for studying star-forming regions. The low-mass star-forming regions seem well characterized with Dfrac(N2H+) or Dfrac(HCO+), but it is required a complete chemical modeling to date massive star-forming regions, because the higher gas temperature together with the rapid evolution of massive protostars.Comment: 14 pages of manuscript, 17 pages of apendix, 7 figures in the main text, accepted for publication in A&

A machine learning-based tool for open cluster membership determination in Gaia DR3

Membership studies characterising open clusters with Gaia data, most using DR2, are so far limited at magnitude G = 18 due to astrometric uncertainties at the faint end. Our goal is to extend current open cluster membership lists with faint members and to characterise the low-mass end, which members are important for many applications, in particular for ground-based spectroscopic surveys. We use a deep neural network architecture to learn the distribution of highly reliable open cluster member stars around known clusters. After that, we use the trained network to estimate new open cluster members based on their similarities in a high-dimensional space, five-dimensional astrometry plus the three photometric bands. Due to the improved astrometric precisions of Gaia DR3 with respect to DR2, we are able to homogeneously detect new faint member stars (G > 18) for the known open cluster population. Our methodology can provide extended membership lists for open clusters down to the limiting magnitude of Gaia, which will enable further studies to characterise the open cluster population, e.g. estimation of their masses, or their dynamics. These extended membership lists are also ideal target lists for forthcoming ground-based spectroscopic surveys.Comment: 10 pages, 6 figures. Submitted to Astronomy & Astrophysic

A high-throughput screening identifies microRNA inhibitors that influence neuronal maintenance and/or response to oxidative stress

Oxidative stress; Small RNA sequencing; NeurodegenerationEstrés oxidativo; Secuenciación de ARN pequeño; NeurodegeneraciónEstrès oxidatiu; Seqüenciació d'ARN petit; NeurodegeneracióSmall non-coding RNAs (sncRNAs), including microRNAs (miRNAs) are important post-transcriptional gene expression regulators relevant in physiological and pathological processes. Here, we combined a high-throughput functional screening (HTFS) platform with a library of antisense oligonucleotides (ASOs) to systematically identify sncRNAs that affect neuronal cell survival in basal conditions and in response to oxidative stress (OS), a major hallmark in neurodegenerative diseases. We considered hits commonly detected by two statistical methods in three biological replicates. Forty-seven ASOs targeting miRNAs (miRNA-ASOs) consistently decreased cell viability under basal conditions. A total of 60 miRNA-ASOs worsened cell viability impairment mediated by OS, with 36.6% commonly affecting cell viability under basal conditions. In addition, 40 miRNA-ASOs significantly protected neuronal cells from OS. In agreement with cell viability impairment, damaging miRNA-ASOs specifically induced increased free radical biogenesis. miRNAs targeted by the detrimental ASOs are enriched in the fraction of miRNAs downregulated by OS, suggesting that the miRNA expression pattern after OS contributes to neuronal damage. The present HTFS highlighted potentially druggable sncRNAs. However, future studies are needed to define the pathways by which the identified ASOs regulate cell survival and OS response and to explore the potential of translating the current findings into clinical applications.This work was supported by the Spanish Ministry of Economy and Competitiveness and FEDER funds (SAF2014-60551-R and SAF2017-88452-R). We acknowledge the support of the Spanish Ministry of Economy, Industry and Competitiveness (MEIC) to the EMBL partnership and the Centro de Excelencia Severo Ochoa 2013-2017 (SEV-2012-0208). We acknowledge the support of the Spanish Ministry of Science Innovation and Universities, Maria Maeztu Unit of Excellence Programme. We thank the staff of the Genomics Unit for the preparation of sRNA libraries and sequencing and the staff of the Biomolecular Screening and Protein Technologies Unit for their help in the setting up the high-throughput screening

A new method for unveiling Open Clusters in Gaia: new nearby Open Clusters confirmed by DR2

Context. The publication of the Gaia Data Release 2 (Gaia DR2) opens a new era in astronomy. It includes precise astrometric data (positions, proper motions, and parallaxes) for more than 1.3 billion sources, mostly stars. To analyse such a vast amount of new data, the use of data-mining techniques and machine-learning algorithms is mandatory. Aims. A great example of the application of such techniques and algorithms is the search for open clusters (OCs), groups of stars that were born and move together, located in the disc. Our aim is to develop a method to automatically explore the data space, requiring minimal manual intervention. Methods. We explore the performance of a density-based clustering algorithm, DBSCAN, to find clusters in the data together with a supervised learning method such as an artificial neural network (ANN) to automatically distinguish between real OCs and statistical clusters. Results. The development and implementation of this method in a five-dimensional space (l, b, ϖ, μα*, μδ) with the Tycho-Gaia Astrometric Solution (TGAS) data, and a posterior validation using Gaia DR2 data, lead to the proposal of a set of new nearby OCs. Conclusions. We have developed a method to find OCs in astrometric data, designed to be applied to the full Gaia DR2 archive

P365Protection against doxorubicine-induced cardiomyopathy by bergamot polyphenols through myocyte survival and cardiac stem cell activation

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