Cardiac-Specific Expression of the Tetracycline Transactivator Confers Increased Heart Function and Survival Following Ischemia Reperfusion Injury

Mice expressing the tetracycline transactivator (tTA) transcription factor driven by the rat α-myosin heavy chain promoter (α-MHC-tTA) are widely used to dissect the molecular mechanisms involved in cardiac development and disease. However, these α-MHC-tTA mice exhibit a gain-of-function phenotype consisting of robust protection against ischemia/reperfusion injury in both in vitro and in vivo models in the absence of associated cardiac hypertrophy or remodeling. Cardiac function, as assessed by echocardiography, did not differ between α-MHC-tTA and control animals, and there were no noticeable differences observed between the two groups in HW/TL ratio or LV end-diastolic and end-systolic dimensions. Protection against ischemia/reperfusion injury was assessed using isolated perfused hearts where α-MHC-tTA mice had robust protection against ischemia/reperfusion injury which was not blocked by pharmacological inhibition of PI3Ks with LY294002. Furthermore, α-MHC-tTA mice subjected to coronary artery ligation exhibited significantly reduced infarct size compared to control animals. Our findings reveal that α-MHC-tTA transgenic mice exhibit a gain-of-function phenotype consisting of robust protection against ischemia/reperfusion injury similar to cardiac pre- and post-conditioning effects. However, in contrast to classical pre- and post-conditioning, the α-MHC-tTA phenotype is not inhibited by the classic preconditioning inhibitor LY294002 suggesting involvement of a non-PI3K-AKT signaling pathway in this phenotype. Thus, further study of the α-MHC-tTA model may reveal novel molecular targets for therapeutic intervention during ischemic injury

Staphylococcal Panton-Valentine Leucocidin as a Major Virulence Factor Associated to Furuncles

Panton-Valentine Leucocidin (PVL), one of the β-barrel pore-forming staphylococcal leucotoxins, is known to be associated to furuncles and some severe community pneumonia. However, it is still uncertain how many other virulence factors are also associated to furuncles and what the risk factors of furuncles are in immuno-compromised status of patients, especially the HIV (+) patients. In this paper, we use antigen immunoprecipitation and multiplex PCR approach to determine the presence of 19 toxins, 8 adhesion factors and the PFGE profiles associated to furuncles in three independent patient study groups of S. aureus (SA) isolates collected from the Cayenne General Hospital (French Guiana). The patient groups were made of: 16 isolates from HIV (−) patients, 9 from HIV (+) patients suffering from furuncles, and 30 control isolates from patients with diverse secondary infected dermatitis. Our data reveals that the majority (96%) of SA strains isolated from HIV patient-derived furuncles significantly produced PVL (p<10−7), whereas only 10% of SA strains produced this toxin in secondary infected dermatosis. A high prevalence of LukE-LukD-producing isolates (56 to 78%) was recorded in patient groups. Genes encoding clumping factor B, collagen- and laminin-binding proteins (clfB, cna, lbp, respectively) were markedly frequent (30 to 55%), without being associated to a specific group. Pulse field gel electrophoresis evidenced 24 overall pulsotypes, whereas the 25 PVL-producing isolates were distributed into 15 non clonal fingerprints. These pulsotypes were not specific PVL-producing isolates. PVL appears to be the major virulence factor associated to furuncles in Europe and in South America regardless of the immune status of the HIV patients

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

Cardiomyopathy and Response to Enzyme Replacement Therapy in a Male Mouse Model for Fabry Disease

Fabry disease is an X-linked disorder of glycosphingolipid metabolism that results in progressive accumulation of neutral glycosphingolipids, (predominately globotriaosylceramide; GL-3) in lysosomes, as well as other cellular compartments and the extracellular space. Our aim was to characterize the cardiac phenotype of male knock-out mice that are deficient in alpha-galactosidase A activity, as a model for Fabry disease and test the efficacy of Enzyme Replacement Therapy with agalsidase-beta. Male mice (3–4 months of age) were characterized with awake blood pressure and heart rate measurements, cardiac echocardiography and electrocardiography measurements under light anesthesia, histological studies and molecular studies with real-time polymerase chain reaction. The Fabry knock-out mouse has bradycardia and lower blood pressure than control wild type (CB7BL/6J) mice. In Fabry knock-out mice, the cardiomyopathy associated mild hypertrophy at echography with normal systolic LV function and mild diastolic dysfunction. Premature atrial contractions were more frequent in without conduction defect. Heart weight normalized to tibial length was increased in Fabry knock-out mice. Ascending aorta dilatation was observed. Molecular studies were consistent with early stages of cardiac remodeling. A single dose of agalsidase-beta (3 mg/kg) did not affect the LV hypertrophy, function or heart rate, but did improve the mRNA signals of early cardiac remodeling. In conclusion, the alpha-galactosidase A deficient mice at 3 to 4 months of age have cardiac and vascular alterations similar to that described in early clinical stage of Fabry disease in children and adolescents. Enzyme replacement therapy affects cardiac molecular remodeling after a single dose

Invading Basement Membrane Matrix Is Sufficient for MDA-MB-231 Breast Cancer Cells to Develop a Stable In Vivo Metastatic Phenotype

1 - ArticleIntroduction: The poor efficacy of various anti-cancer treatments against metastatic cells has focused attention on the role of tumor microenvironment in cancer progression. To understand the contribution of the extracellular matrix (ECM) environment to this phenomenon, we isolated ECM surrogate invading cell populations from MDA-MB-231 breast cancer cells and studied their genotype and malignant phenotype. Methods: We isolated invasive subpopulations (INV) from non invasive populations (REF) using a 2D-Matrigel assay, a surrogate of basal membrane passage. INV and REF populations were investigated by microarray assay and for their capacities to adhere, invade and transmigrate in vitro, and to form metastases in nude mice. Results: REF and INV subpopulations were stable in culture and present different transcriptome profiles. INV cells were characterized by reduced expression of cell adhesion and cell-cell junction genes (44% of down regulated genes) and by a gain in expression of anti-apoptotic and pro-angiogenic gene sets. In line with this observation, in vitro INV cells showed reduced adhesion and increased motility through endothelial monolayers and fibronectin. When injected into the circulation, INV cells induced metastases formation, and reduced injected mice survival by up to 80% as compared to REF cells. In nude mice, INV xenografts grew rapidly inducing vessel formation and displaying resistance to apoptosis. Conclusion: Our findings reveal that the in vitro ECM microenvironment per se was sufficient to select for tumor cells with a stable metastatic phenotype in vivo characterized by loss of adhesion molecules expression and induction of proangiogenic and survival factors

Transit Timings Variations In The Three-Planet System: TOI-270

We present ground- and space-based photometric observations of TOI-270 (L231-32), a system of three transiting planets consisting of one super-Earth and two sub-Neptunes discovered by TESS around a bright (K-mag = 8.25) M3V dwarf. The planets orbit near low-order mean-motion resonances (5:3 and 2:1) and are thus expected to exhibit large transit timing variations (TTVs). Following an extensive observing campaign using eight different observatories between 2018 and 2020, we now report a clear detection of TTVs for planets c and d, with amplitudes of ~10 min and a super-period of ~3 yr, as well as significantly refined estimates of the radii and mean orbital periods of all three planets. Dynamical modelling of the TTVs alone puts strong constraints on the mass ratio of planets c and d and on their eccentricities. When incorporating recently published constraints from radial velocity observations, we obtain masses of Mb = 1.48 ± 0.18 M⊕, Mc = 6.20 ± 0.31 M⊕, and Md = 4.20 ± 0.16 M⊕ for planets b, c, and d, respectively. We also detect small but significant eccentricities for all three planets : eb = 0.0167 ± 0.0084, ec = 0.0044 ± 0.0006, and ed = 0.0066 ± 0.0020. Our findings imply an Earth-like rocky composition for the inner planet, and Earth-like cores with an additional He/H₂O atmosphere for the outer two. TOI-270 is now one of the best constrained systems of small transiting planets, and it remains an excellent target for atmospheric characterization

Mesenchymal Transition and PDGFRA Amplification/Mutation Are Key Distinct Oncogenic Events in Pediatric Diffuse Intrinsic Pontine Gliomas

Diffuse intrinsic pontine glioma (DIPG) is one of the most frequent malignant pediatric brain tumor and its prognosis is universaly fatal. No significant improvement has been made in last thirty years over the standard treatment with radiotherapy. To address the paucity of understanding of DIPGs, we have carried out integrated molecular profiling of a large series of samples obtained with stereotactic biopsy at diagnosis. While chromosomal imbalances did not distinguish DIPG and supratentorial tumors on CGHarrays, gene expression profiling revealed clear differences between them, with brainstem gliomas resembling midline/thalamic tumours, indicating a closely-related origin. Two distinct subgroups of DIPG were identified. The first subgroup displayed mesenchymal and pro-angiogenic characteristics, with stem cell markers enrichment consistent with the possibility to grow tumor stem cells from these biopsies. The other subgroup displayed oligodendroglial features, and appeared largely driven by PDGFRA, in particular through amplification and/or novel missense mutations in the extracellular domain. Patients in this later group had a significantly worse outcome with an hazard ratio for early deaths, ie before 10 months, 8 fold greater that the ones in the other subgroup (p = 0.041, Cox regression model). The worse outcome of patients with the oligodendroglial type of tumors was confirmed on a series of 55 paraffin-embedded biopsy samples at diagnosis (median OS of 7.73 versus 12.37 months, p = 0.045, log-rank test). Two distinct transcriptional subclasses of DIPG with specific genomic alterations can be defined at diagnosis by oligodendroglial differentiation or mesenchymal transition, respectively. Classifying these tumors by signal transduction pathway activation and by mutation in pathway member genes may be particularily valuable for the development of targeted therapies

A pair of Sub-Neptunes transiting the bright K-dwarf TOI-1064 characterised with CHEOPS

Funding: TGW, ACC, and KH acknowledge support from STFC consolidated grant numbers ST/R000824/1 and ST/V000861/1, and UKSA grant ST/R003203/1.We report the discovery and characterization of a pair of sub-Neptunes transiting the bright K-dwarf TOI-1064 (TIC 79748331), initially detected in the Transiting Exoplanet Survey Satellite (TESS) photometry. To characterize the system, we performed and retrieved the CHaracterising ExOPlanets Satellite (CHEOPS), TESS, and ground-based photometry, the High Accuracy Radial velocity Planet Searcher (HARPS) high-resolution spectroscopy, and Gemini speckle imaging. We characterize the host star and determine Teff,⋆=4734±67K⁠, R⋆=0.726±0.007R⊙⁠, and M⋆=0.748±0.032M⊙⁠. We present a novel detrending method based on point spread function shape-change modelling and demonstrate its suitability to correct flux variations in CHEOPS data. We confirm the planetary nature of both bodies and find that TOI-1064 b has an orbital period of Pb = 6.44387 ± 0.00003 d, a radius of Rb = 2.59 ± 0.04 R⊕, and a mass of Mb=13.5+1.7−1.8 M⊕, whilst TOI-1064 c has an orbital period of Pc=12.22657+0.00005−0.00004 d, a radius of Rc = 2.65 ± 0.04 R⊕, and a 3σ upper mass limit of 8.5 M⊕. From the high-precision photometry we obtain radius uncertainties of ∼1.6 per cent, allowing us to conduct internal structure and atmospheric escape modelling. TOI-1064 b is one of the densest, well-characterized sub-Neptunes, with a tenuous atmosphere that can be explained by the loss of a primordial envelope following migration through the protoplanetary disc. It is likely that TOI-1064 c has an extended atmosphere due to the tentative low density, however further radial velocities are needed to confirm this scenario and the similar radii, different masses nature of this system. The high-precision data and modelling of TOI-1064 b are important for planets in this region of mass–radius space, and it allow us to identify a trend in bulk density–stellar metallicity for massive sub-Neptunes that may hint at the formation of this population of planets.Publisher PDFPeer reviewe