A Two-Photon Probe Based on Naphthalimide-Styrene Fluorophore for the In Vivo Tracking of Cellular Senescence

Cellular senescence is a state of stable cell cycle arrest that can negatively affect the regenerative capacities of tissues and can contribute to inflammation and the progression of various aging-related diseases. Advances in the in vivo detection of cellular senescence are still crucial to monitor the action of senolytic drugs and to assess the early onset or accumulation of senescent cells. Here, we describe a naphthalimide-styrene-based probe (HeckGal) for the detection of cellular senescence both in vitro and in vivo. HeckGal is hydrolyzed by the increased lysosomal β-galactosidase activity of senescent cells, resulting in fluorescence emission. The probe was validated in vitro using normal human fibroblasts and various cancer cell lines undergoing senescence induced by different stress stimuli. Remarkably, HeckGal was also validated in vivo in an orthotopic breast cancer mouse model treated with senescence-inducing chemotherapy and in a renal fibrosis mouse model. In all cases, HeckGal allowed the unambiguous detection of senescence in vitro as well as in tissues and tumors in vivo. This work is expected to provide a potential technology for senescence detection in aged or damaged tissues

Monitoring the antimicrobial susceptibility of Gramnegative organisms involved in intraabdominal and urinary tract infections recovered during the SMART study (Spain, 2016 and 2017)

OBJECTIVE: Continuous antimicrobial resistance surveillance is recommended by Public Health authorities. We up-dated data from the SMART (Study for Monitoring Antimicrobial Resistance Trends) surveillance study in Spain. METHODS: The antimicrobial susceptibility data and extended-spectrum beta-lactamase (ESBL) production in isolates recovered from intra-abdominal (IAI) (n=1,429) and urinary tract (UTI) (n=937) infections during the 2016- 2017 SMART study in 10 Spanish hospitals were analysed. RESULTS: Escherichia coli was the most frequently microorganism isolated (48.3% and 53.7%) followed by Klebsiella spp. (11.5% and 21.9%) in IAIs and UTIs, respectively. Figures for Pseudomonas aeruginosa were 9.0% and 6.1%, being more frequently recovered from patients with nosocomial infections. Overall, 9.9% (IAI) and 14.0% (UTI) of E. coli, Klebsiella spp. and Proteus mirabilis isolates were ESBL-producers, being Klebsiella pneumoniae (34.5%) from UTI of nosocomial origin the most frequent. ESBL-producers were higher in patients >60 years in both IAIs and UTIs. As in previous years, amikacin (96.3%-100% susceptibility), ertapenem (84.2%-100%) and imipenem (70.3%- 100%) were the most active antimicrobials tested among Enterobacterales species. The activity of amoxicillin-clavulanic, piperacillin-tazobactam, and ciprofloxacin susceptibility was lower, particularly among ESBL-producers. Ertapenem susceptibility (88.9%-100%) was retained in ESBL-E. coli isolates that were resistant to these antimicrobials but decreased (28.6%-100%) in similar isolates of K. pneumoniae. CONCLUSIONS: Continuous antimicrobial resistance surveillance from the SMART study reveals overall maintenance of ESBL-producers in Spain, although with higher presence in isolates from UTIs than from IAIs. Moreover, ertapenem activity was high in E. coli irrespective of ESBL production but decreased in K. pneumoniae, particularly among ESBL-producers

First broadband characterization and redshift determination of the VHE blazar MAGIC J2001+439

We aim to characterize the broadband emission from 2FGL J2001.1+4352, which has been associated with the unknown-redshift blazar MG4 J200112+4352. Based on its gamma-ray spectral properties, it was identified as a potential very high energy (VHE; E > 100 GeV) gamma-ray emitter. The source was observed with MAGIC first in 2009 and later in 2010 within a multi-instrument observation campaign. The MAGIC observations yielded 14.8 hours of good quality stereoscopic data. The object was monitored at radio, optical and gamma-ray energies during the years 2010 and 2011. The source, named MAGIC J2001+439, is detected for the first time at VHE with MAGIC at a statistical significance of 6.3 {\sigma} (E > 70 GeV) during a 1.3-hour long observation on 2010 July 16. The multi-instrument observations show variability in all energy bands with the highest amplitude of variability in the X-ray and VHE bands. We also organized deep imaging optical observations with the Nordic Optical Telescope in 2013 to determine the source redshift. We determine for the first time the redshift of this BL Lac object through the measurement of its host galaxy during low blazar activity. Using the observational evidence that the luminosities of BL Lac host galaxies are confined to a relatively narrow range, we obtain z = 0.18 +/- 0.04. Additionally, we use the Fermi-LAT and MAGIC gamma-ray spectra to provide an independent redshift estimation, z = 0.17 +/- 0.10. Using the former (more accurate) redshift value, we adequately describe the broadband emission with a one-zone SSC model for different activity states and interpret the few-day timescale variability as produced by changes in the high-energy component of the electron energy distribution.Comment: 17 pages, 15 figures, Accepted for publication in A&

Extragalactic Background Light Inferred from AEGIS Galaxy SED-type Fractions

The extragalactic background light (EBL) is of fundamental importance both for understanding the entire process of galaxy evolution and for gamma-ray astronomy, but the overall spectrum of the EBL between 0.1-1000 microns has never been determined directly from galaxy spectral energy distribution (SED) observations over a wide redshift range. The evolving, overall spectrum of the EBL is derived here utilizing a novel method based on observations only. This is achieved from the observed evolution of the rest-frame K-band galaxy luminosity function up to redshift 4 (Cirasuolo et al. 2010), combined with a determination of galaxy SED-type fractions. These are based on fitting SWIRE templates to a multiwavelength sample of about 6000 galaxies in the redshift range from 0.2 to 1 from the All-wavelength Extended Groth Strip International Survey (AEGIS). The changing fractions of quiescent galaxies, star-forming galaxies, starburst galaxies and AGN galaxies in that redshift range are estimated, and two alternative extrapolations of SED-types to higher redshifts are considered. This allows calculation of the evolution of the luminosity densities from the UV to the IR, the evolving star formation rate density of the universe, the evolving contribution to the bolometric EBL from the different galaxy populations including AGN galaxies and the buildup of the EBL. Our EBL calculations are compared with those from a semi-analytic model, from another observationally-based model and observational data. The EBL uncertainties in our modeling based directly on the data are quantified, and their consequences for attenuation of very high energy gamma-rays due to pair production on the EBL are discussed. It is concluded that the EBL is well constrained from the UV to the mid-IR, but independent efforts from infrared and gamma-ray astronomy are needed in order to reduce the uncertainties in the far-IR.Comment: 25 pages, 18 figures, 4 tables; accepted for publication in MNRAS on September 3, 2010. Online material available at http://side.iaa.es/EB

The 2009 multiwavelength campaign on Mrk 421: Variability and correlation studies

We performed a 4.5-month multi-instrument campaign (from radio to VHE gamma rays) on Mrk421 between January 2009 and June 2009, which included VLBA, F-GAMMA, GASP-WEBT, Swift, RXTE, Fermi-LAT, MAGIC, and Whipple, among other instruments and collaborations. Mrk421 was found in its typical (non-flaring) activity state, with a VHE flux of about half that of the Crab Nebula, yet the light curves show significant variability at all wavelengths, the highest variability being in the X-rays. We determined the power spectral densities (PSD) at most wavelengths and found that all PSDs can be described by power-laws without a break, and with indices consistent with pink/red-noise behavior. We observed a harder-when-brighter behavior in the X-ray spectra and measured a positive correlation between VHE and X-ray fluxes with zero time lag. Such characteristics have been reported many times during flaring activity, but here they are reported for the first time in the non-flaring state. We also observed an overall anti-correlation between optical/UV and X-rays extending over the duration of the campaign. The harder-when-brighter behavior in the X-ray spectra and the measured positive X-ray/VHE correlation during the 2009 multi-wavelength campaign suggests that the physical processes dominating the emission during non-flaring states have similarities with those occurring during flaring activity. In particular, this observation supports leptonic scenarios as being responsible for the emission of Mrk421 during non-flaring activity. Such a temporally extended X-ray/VHE correlation is not driven by any single flaring event, and hence is difficult to explain within the standard hadronic scenarios. The highest variability is observed in the X-ray band, which, within the one-zone synchrotron self-Compton scenario, indicates that the electron energy distribution is most variable at the highest energies.Comment: Accepted for publication in A&A, 18 pages, 14 figures (v2 has a small modification in the acknowledgments, and also corrects a typo in the field "author" in the metadata

Costs and benefits of automation for astronomical facilities

The Observatorio Astrof\'isico de Javalambre (OAJ{\dag}1) in Spain is a young astronomical facility, conceived and developed from the beginning as a fully automated observatory with the main goal of optimizing the processes in the scientific and general operation of the Observatory. The OAJ has been particularly conceived for carrying out large sky surveys with two unprecedented telescopes of unusually large fields of view (FoV): the JST/T250, a 2.55m telescope of 3deg field of view, and the JAST/T80, an 83cm telescope of 2deg field of view. The most immediate objective of the two telescopes for the next years is carrying out two unique photometric surveys of several thousands square degrees, J-PAS{\dag}2 and J-PLUS{\dag}3, each of them with a wide range of scientific applications, like e.g. large structure cosmology and Dark Energy, galaxy evolution, supernovae, Milky Way structure, exoplanets, among many others. To do that, JST and JAST are equipped with panoramic cameras under development within the J-PAS collaboration, JPCam and T80Cam respectively, which make use of large format (~ 10k x 10k) CCDs covering the entire focal plane. This paper describes in detail, from operations point of view, a comparison between the detailed cost of the global automation of the Observatory and the standard automation cost for astronomical facilities, in reference to the total investment and highlighting all benefits obtained from this approach and difficulties encountered. The paper also describes the engineering development of the overall facilities and infrastructures for the fully automated observatory and a global overview of current status, pinpointing lessons learned in order to boost observatory operations performance, achieving scientific targets, maintaining quality requirements, but also minimizing operation cost and human resources.Comment: Global Observatory Control System GOC

New Mutations in Chronic Lymphocytic Leukemia Identified by Target Enrichment and Deep Sequencing

Chronic lymphocytic leukemia (CLL) is a heterogeneous disease without a well-defined genetic alteration responsible for the onset of the disease. Several lines of evidence coincide in identifying stimulatory and growth signals delivered by B-cell receptor (BCR), and co-receptors together with NFkB pathway, as being the driving force in B-cell survival in CLL. However, the molecular mechanism responsible for this activation has not been identified. Based on the hypothesis that BCR activation may depend on somatic mutations of the BCR and related pathways we have performed a complete mutational screening of 301 selected genes associated with BCR signaling and related pathways using massive parallel sequencing technology in 10 CLL cases. Four mutated genes in coding regions (KRAS, SMARCA2, NFKBIE and PRKD3) have been confirmed by capillary sequencing. In conclusion, this study identifies new genes mutated in CLL, all of them in cases with progressive disease, and demonstrates that next-generation sequencing technologies applied to selected genes or pathways of interest are powerful tools for identifying novel mutational changes

Seguimiento de la sensibilidad antimicrobiana de microorganismos gramnegativos procedentes de infecciones intraabdominales y urinarias del estudio smart (España, 2016 y 2017)

Introducción. Las autoridades de Salud Pública recomiendan la vigilancia continua de la resistencia a los antimicrobianos. Se actualizan los datos del estudio SMART (Study for Monitoring Antimicrobial Resistance Trends) en España. Material y métodos. Se analizaron los datos de sensibilidad antimicrobiana y la producción de betalactamasas de espectro extendido (BLEE) en aislamientos obtenidos en el estudio SMART de infecciones intraabdominales (IIA) (n=1.429) y del tracto urinario (ITU) (n=937) durante 2016-2017 en 10 hospitales españoles. Resultados. Escherichia coli fue el microorganismo más frecuente (54,5% y 57,5%, respectivamente), seguido de Klebsiella spp. (18,4% y 25,4%) en IIA y en ITU. En Pseudomonas aeruginosa estas cifras fueron 9% y 6%, siendo más frecuente en la infección nosocomial. El 9,9% (IIA) y el 14% (ITU) del total de los aislados de E. coli, Klebsiella spp. y Proteus mirabilis producían BLEE, obteniéndose la tasa más alta en Klebsiella pneumoniae (34.5%) en ITU nosocomial. El mayor porcentaje de aislados con BLEE se observó en pacientes >60 años, tanto en IIA como en ITU. Como en años anteriores, amikacina (sensibilidad 96,3%-100%), ertapenem (84,2%-100%) e imipenem (70,3%-100%) fueron los antimicrobianos más activos en Enterobacterales. La sensibilidad a amoxicilina-ácido clavulánico, piperacilina-tazobactam y ciprofloxacino fue menor, en particular en los productores de BLEE. La sensibilidad a ertapenem (88,9%-100%) se mantuvo en E. coli con BLEE resistente a estos antimicrobianos, pero disminuyó (28,6%-100%) en aislados similares de K. pneumoniae. Conclusiones. La vigilancia continua de la resistencia a los antimicrobianos en el estudio SMART revela el mantenimiento de la frecuencia de aislados productores de BLEE en España, pero con mayor presencia en las ITUs que en las IIAs. Además, la sensibilidad a ertapenem fue alta en E. coli con independencia de la producción de BLEE, pero disminuyó en K. pneumoniae, sobre todo en los productores de BLEE. Introduction. Continuous antimicrobial resistance surveillance is recommended by Public Health authorities. We updated data from the SMART (Study for Monitoring Antimicrobial Resistance Trends) surveillance study in Spain. Material and methods. The antimicrobial susceptibility data and extended-spectrum beta-lactamase (ESBL) production in isolates recovered from intra-abdominal (IAI) (n=1,429) and urinary tract (UTI) (n=937) infections during the 2016-2017 SMART study in 10 Spanish hospitals were analysed. Results. Escherichia coli was the most frequently microorganism isolated (48.3% and 53.7%) followed by Klebsiella spp. (11.5% and 21.9%) in IAIs and UTIs, respectively. Figures for Pseudomonas aeruginosa were 9.0% and 6.1%, being more frequently recovered from patients with nosocomial infections. Overall, 9.9% (IAI) and 14.0% (UTI) of E. coli, Klebsiella spp. and Proteus mirabilis isolates were ESBL-producers, being Klebsiella pneumoniae (34.5%) from UTI of nosocomial origin the most frequent. ESBL-producers were higher in patients >60 years in both IAIs and UTIs. As in previous years, amikacin (96.3%-100% susceptibility), ertapenem (84.2%-100%) and imipenem (70.3%-100%) were the most active antimicrobials tested among Enterobacterales species. The activity of amoxicillin-clavulanic, piperacillin-tazobactam, and ciprofloxacin susceptibility was lower, particularly among ESBL-producers. Ertapenem susceptibility (88.9%-100%) was retained in ESBL-E. coli isolates that were resistant to these antimicrobials but decreased (28.6%-100%) in similar isolates of K. pneumoniae. Conclusions. Continuous antimicrobial resistance surveillance from the SMART study reveals overall maintenance of ESBL-producers in Spain, although with higher presence in isolates from UTIs than from IAIs. Moreover, ertapenem activity was high in E. coli irrespective of ESBL production but decreased in K. pneumoniae, particularly among ESBL-producers

Evolutionary winners are ecological losers among oceanic island plants

Aim Adaptive radiation, in which successful lineages proliferate by exploiting untapped niche space, provides a popular but potentially misleading characterization of evolution on oceanic islands. Here we analyse the respective roles of members of in situ diversified vs. non-diversified lineages in shaping the main ecosystems of an archipelago to explore the relationship between evolutionary and ecological ‘success’. Location Canary Islands. Taxon Vascular plants. Methods We quantified the abundance/rarity of the native flora according to the geographical range (number of islands where present and geographical extent of the range), habitat breadth (climatic niche) and local abundance (cover) using species distribution data based on 500 × 500 m grid cells and 2000 vegetation inventories located all over the archipelago. Results Species of diversified lineages have significantly smaller geographic ranges, narrower climatic niches and lower local abundances than those of non-diversified lineages. Species rarity increased with the degree of diversification. The diversified Canarian flora is mainly comprised by shrubs. At both archipelagic and island level, the four core ecosystems (Euphorbia scrub, thermophilous woodlands, laurel forest and pine forest) were dominated by non-diversified lineages species, with diversified lineages species providing <25% cover. Species of diversified lineages, although constituting 54% of the archipelagic native flora, were only abundant in two rare ecosystems: high mountain scrub and rock communities. Main conclusions Radiated species, endemic products of in situ speciation, are mostly rare in all three rarity axes and typically do not play an important role in structuring plant communities on the Canaries. The vegetation of the major ecosystem types is dominated by plants representing non-diversified lineages (species that derive from immigration and accumulation), while species of evolutionarily successful lineages are abundant only in marginal habitats and could, therefore, be considered ecological losers. Within this particular oceanic archipelago, and we posit within at least some others, evolutionary success in plants is accomplished predominantly at the margins.publishedVersio

Discovery of very high energy γ-ray emission from the blazar 1ES0033+595 by the MAGIC telescopes

The number of known very high energy (VHE) blazars is ∼50, which is very small in comparison to the number of blazars detected in other frequencies. This situation is a handicap for population studies of blazars, which emit about half of their luminosity in the γ-ray domain. Moreover, VHE blazars, if distant, allow for the study of the environment that the high-energy γ-rays traverse in their path towards the Earth, like the extragalactic background light (EBL) and the intergalactic magnetic field (IGMF), and hence they have a special interest for the astrophysics community. We present the first VHE detection of 1ES0033+595 with a statistical significance of 5.5σ. The VHE emission of this object is constant throughout the MAGIC observations (2009 August and October), and can be parametrized with a power law with an integral flux above 150GeV of (7.1 ± 1.3) × 10−12 photons cm−2 s−1 and a photon index of (3.8±0.7). We model its spectral energy distribution (SED) as the result of inverse Compton scattering of synchrotron photons. For the study of the SED, we used simultaneous optical R-band data from the KVA telescope, archival X-ray data by Swift as well as INTEGRAL, and simultaneous high-energy (HE, 300MeV-10GeV) γ-ray data from the Fermi Large Area Telescope (LAT) observatory. Using the empirical approach of Prandini etal. (2010) and the Fermi LAT and MAGIC spectra for this object, we estimate the redshift of this source to be 0.34±0.08±0.05. This is a relevant result because this source is possibly one of the 10 most distant VHE blazars known to date, and with further (simultaneous) observations could play an important role in blazar population studies, as well as future constraints on the EBL andIGM