The Role of Oxidative Stress in Cardiac Disease: From Physiological Response to Injury Factor

Reactive oxygen species (ROS) are highly reactive chemical species containing oxygen, controlled by both enzymatic and nonenzymatic antioxidant defense systems. In the heart, ROS play an important role in cell homeostasis, by modulating cell proliferation, differentiation, and excitation-contraction coupling. Oxidative stress occurs when ROS production exceeds the buffering capacity of the antioxidant defense systems, leading to cellular and molecular abnormalities, ultimately resulting in cardiac dysfunction. In this review, we will discuss the physiological sources of ROS in the heart, the mechanisms of oxidative stress-related myocardial injury, and the implications of experimental studies and clinical trials with antioxidant therapies in cardiovascular diseases

Molecular characterization of bacteria associated with the trophosome and the tube of Lamellibrachia sp., a siboglinid annelid from cold seeps in the eastern Mediterranean

Specimens of Lamellibrachia (Annelida: Siboglinidae) were recently discovered at cold seeps in the eastern Mediterranean. In this study, we have investigated the phylogeny and function of intracellular bacterial symbionts inhabiting the trophosome of specimens of Lamellibrachia sp. from the Amon mud volcano, as well as the bacterial assemblages associated with their tube. The dominant intracellular symbiont of Lamellibrachia sp. is a gammaproteobacterium closely related to other sulfide-oxidizing tubeworm symbionts. In vivo uptake experiments show that the tubeworm relies on sulfide for its metabolism, and does not utilize methane. Bacterial communities associated with the tube form biofilms and occur from the anterior to the posterior end of the tube. The diversity of 16S rRNA gene phylotypes includes representatives from the same divisions previously identified from the tube of the vent species Riftia pachyptila, and others commonly found at seeps and vents

Investigation of elimination rate, persistent subpopulation removal and relapse rates of Mycobacterium tuberculosis by combinations of first-line drugs in a modified Cornell mouse model.

Currently, the most effective tuberculosis control method resides in case-finding and 6 months chemotherapy. There is a need to improve our understanding about drug interactions, combination activities and the ability to remove persistent bacteria in the current regimens, particularly in relation to relapse. We aimed to investigate the therapeutic effects of three main components, rifampicin (RMP), isoniazid (INH), and pyrazinamide (PZA), in current drug regimens using a modified version of the Cornell mouse model. We evaluated the post-treatment levels of persistent Mycobacterium tuberculosis in the organs of mice using culture filtrate derived from M. tuberculosis strain H37Rv. When RMP was combined with INH, PZA or INH-PZA, significant additive activities were observed compared to each of the single drug treatments. However, the combination of INH and PZA showed a less significant additive effect than either of the drugs used on their own. Apparent culture negativity of mouse organs was achieved at 14 weeks of treatment with RMP-INH, RMP-PZA and RMP-INH-PZA but not with INH-PZA, when conventional tests, namely culture on solid agar and in liquid broth indicated that the organs were bacteria negative. The relapse rates for RMP-containing regimens were not significantly different to a 100% relapse rate at the numbers of mice examined in this study. In parallel, we examined the organs for the presence of culture filtrate-dependent persistent bacilli after 14 weeks of treatment. Culture filtrate treatment of the organs revealed persistent M. tuberculosis Modelling of mycobacterial elimination rates and evaluation of culture-filtrate dependent organisms showed promise as surrogate methods for efficient factorial evaluation of drug combinations in tuberculosis in mouse models and should be further evaluated against relapse. The presence of culture filtrate-dependent persistent M. tuberculosis is the likely cause of disease relapse in this modified Cornell mouse model

The Fornax Deep Survey with VST. I. The extended and diffuse stellar halo of NGC~1399 out to 192 kpc

[Abrigded] We have started a new deep, multi-imaging survey of the Fornax cluster, dubbed Fornax Deep Survey (FDS), at the VLT Survey Telescope. In this paper we present the deep photometry inside two square degrees around the bright galaxy NGC1399 in the core of the cluster. We found a very extended and diffuse envelope surrounding the luminous galaxy NGC1399: we map the surface brightness out to 33 arcmin (~ 192 kpc) from the galaxy center and down to about 31 mag/arcsec^2 in the g band. The deep photometry allows us to detect a faint stellar bridge in the intracluster region between NGC1399 and NGC1387. By analyzing the integrated colors of this feature, we argue that it could be due to the ongoing interaction between the two galaxies, where the outer envelope of NGC1387 on its east side is stripped away. By fitting the light profile, we found that it exists a physical break radius in the total light distribution at R=10 arcmin (~58 kpc) that sets the transition region between the bright central galaxy and the outer exponential stellar halo. We discuss the main implications of this work on the build-up of the stellar halo at the center of the Fornax cluster. By comparing with the numerical simulations of the stellar halo formation for the most massive BCGs, we find that the observed stellar halo mass fraction is consistent with a halo formed through the multiple accretion of progenitors with a stellar mass in the range 10^8 - 10^11 M_sun. This might suggest that the halo of NGC1399 has also gone through a major merging event. The absence of a significant number of luminous stellar streams and tidal tails out to 192 kpc suggests that the epoch of this strong interaction goes back to an early formation epoch. Therefore, differently from the Virgo cluster, the extended stellar halo around NGC1399 is characterised by a more diffuse and well-mixed component, including the ICL.Comment: Accepted for publication in ApJ; 25 pages and 14 figures. An higher resolution file is available at the following link https://www.dropbox.com/s/fvltppduysdn6pb/NGC1399_fin_2c.pdf?dl=

Optically variable active galactic nuclei in the 3 yr VST survey of the COSMOS field

The analysis of the variability of active galactic nuclei (AGNs) at different wavelengths and the study of possible correlations among different spectral windows are nowadays a major field of inquiry. Optical variability has been largely used to identify AGNs in multivisit surveys. The strength of a selection based on optical variability lies in the chance to analyze data from surveys of large sky areas by ground-based telescopes. However the effectiveness of optical variability selection, with respect to other multiwavelength techniques, has been poorly studied down to the depth expected from next generation surveys. Here we present the results of our r-band analysis of a sample of 299 optically variable AGN candidates in the VST survey of the COSMOS field, counting 54 visits spread over three observing seasons spanning > 3 yr. This dataset is > 3 times larger in size than the one presented in our previous analysis (De Cicco et al. 2015), and the observing baseline is ~8 times longer. We push towards deeper magnitudes (r(AB) ~23.5 mag) compared to past studies; we make wide use of ancillary multiwavelength catalogs in order to confirm the nature of our AGN candidates, and constrain the accuracy of the method based on spectroscopic and photometric diagnostics. We also perform tests aimed at assessing the relevance of dense sampling in view of future wide-field surveys. We demonstrate that the method allows the selection of high-purity (> 86%) samples. We take advantage of the longer observing baseline to achieve great improvement in the completeness of our sample with respect to X-ray and spectroscopically confirmed samples of AGNs (59%, vs. ~15% in our previous work), as well as in the completeness of unobscured and obscured AGNs. The effectiveness of the method confirms the importance to develop future, more refined techniques for the automated analysis of larger datasets.Comment: 21 pages, 10 figures; accepted for publication in A&

The Fornax Deep Survey with VST. II. Fornax A: a two-phase assembly caught on act

As part of the Fornax Deep Survey with the ESO VLT Survey Telescope, we present new $g$ and $r$ bands mosaics of the SW group of the Fornax cluster. It covers an area of $3 \times 2$ square degrees around the central galaxy NGC1316. The deep photometry, the high spatial resolution of OmegaCam and the large covered area allow us to study the galaxy structure, to trace stellar halo formation and look at the galaxy environment. We map the surface brightness profile out to 33arcmin ($\sim 200$kpc $\sim15R_e$) from the galaxy centre, down to $\mu_g \sim 31$ mag arcsec$^{-2}$ and $\mu_r \sim 29$ mag arcsec$^{-2}$. This allow us to estimate the scales of the main components dominating the light distribution, which are the central spheroid, inside 5.5 arcmin ($\sim33$ kpc), and the outer stellar envelope. Data analysis suggests that we are catching in act the second phase of the mass assembly in this galaxy, since the accretion of smaller satellites is going on in both components. The outer envelope of NGC1316 still hosts the remnants of the accreted satellite galaxies that are forming the stellar halo. We discuss the possible formation scenarios for NGC1316, by comparing the observed properties (morphology, colors, gas content, kinematics and dynamics) with predictions from cosmological simulations of galaxy formation. We find that {\it i)} the central spheroid could result from at least one merging event, it could be a pre-existing early-type disk galaxy with a lower mass companion, and {\it ii)} the stellar envelope comes from the gradual accretion of small satellites.Comment: Accepeted for publication in Ap

SUDARE-VOICE variability-selection of Active Galaxies in the Chandra Deep Field South and the SERVS/SWIRE region

One of the most peculiar characteristics of Active Galactic Nuclei (AGN) is their variability over all wavelengths. This property has been used in the past to select AGN samples and is foreseen to be one of the detection techniques applied in future multi-epoch surveys, complementing photometric and spectroscopic methods. In this paper, we aim to construct and characterise an AGN sample using a multi-epoch dataset in the r band from the SUDARE-VOICE survey. Our work makes use of the VST monitoring program of an area surrounding the Chandra Deep Field South to select variable sources. We use data spanning a six month period over an area of 2 square degrees, to identify AGN based on their photometric variability. The selected sample includes 175 AGN candidates with magnitude r < 23 mag. We distinguish different classes of variable sources through their lightcurves, as well as X-ray, spectroscopic, SED, optical and IR information overlapping with our survey. We find that 12% of the sample (21/175) is represented by SN. Of the remaining sources, 4% (6/154) are stars, while 66% (102/154) are likely AGNs based on the available diagnostics. We estimate an upper limit to the contamination of the variability selected AGN sample of about 34%, but we point out that restricting the analysis to the sources with available multi-wavelength ancillary information, the purity of our sample is close to 80% (102 AGN out of 128 non-SN sources with multi-wavelength diagnostics). Our work thus confirms the efficiency of the variability selection method in agreement with our previous work on the COSMOS field; in addition we show that the variability approach is roughly consistent with the infrared selection.Comment: Published in A & A, 15 pages, 6 figure

Isolation and Characterization of Monomeric Human RAD51: A Novel Tool for Investigating Homologous Recombination in Cancer

RAD51 is a key player in the homologous recombination pathway. Upon DNA damage, RAD51 is transported into the nucleus by BRCA2, where it can repair DNA double-strand breaks. Due to the structural complexity and dynamics, researchers have not yet clarified the mechanistic details of every step of RAD51 recruitment and DNA repair. RAD51 possesses an intrinsic tendency to form oligomeric structures, which make it challenging to conduct biochemical and biophysical investigations. Here, for the first time, we report on the isolation and characterization of a human monomeric RAD51 recombinant form, obtained through a double mutation, which preserves the protein’s integrity and functionality. We investigated different buffers to identify the most suitable condition needed to definitively stabilize the monomer. The monomer of human RAD51 provides the community with a unique biological tool for investigating RAD51-mediated homologous recombination, and paves the way for more reliable structural, mechanistic, and drug discovery studies

Identification of RAD51-BRCA2 Inhibitors Using N-Acylhydrazone-Based Dynamic Combinatorial Chemistry

RAD51 is an ATP-dependent recombinase, recruited by BRCA2 to mediate DNA double-strand breaks repair through homologous recombination and represents an attractive cancer drug target. Herein, we applied for the first-time protein-templated dynamic combinatorial chemistry on RAD51 as a hit identification strategy. Upon design of N-acylhydrazone-based dynamic combinatorial libraries, RAD51 showed a clear templating effect, amplifying 19 N-acylhydrazones. Screening against the RAD51-BRCA2 protein-protein interaction via ELISA assay afforded 10 inhibitors in the micromolar range. Further 19F NMR experiments revealed that 7 could bind RAD51 and be displaced by BRC4, suggesting an interaction in the same binding pocket of BRCA2. These results proved not only that ptDCC could be successfully applied on full-length oligomeric RAD51, but also that it could address the need of alternative strategies toward the identification of small-molecule PPI inhibitors