Two years of monitoring Supergiant Fast X-ray Transients with Swift

We present two years of intense Swift monitoring of three SFXTs, IGR J16479-4514, XTE J1739-302, and IGR J17544-2619 (since October 2007). Out-of-outburst intensity-based X-ray (0.3-10keV) spectroscopy yields absorbed power laws with by hard photon indices (G~1-2). Their outburst broad-band (0.3-150 keV) spectra can be fit well with models typically used to describe the X-ray emission from accreting NSs in HMXBs. We assess how long each source spends in each state using a systematic monitoring with a sensitive instrument. These sources spend 3-5% of the total in bright outbursts. The most probable flux is 1-2E-11 erg cm^{-2} s^{-1} (2-10 keV, unabsorbed), corresponding to luminosities in the order of a few 10^{33} to 10^{34} erg s^{-1} (two orders of magnitude lower than the bright outbursts). The duty-cycle of inactivity is 19, 39, 55%, for IGR J16479-4514, XTE J1739-302, and IGR J17544-2619, respectively. We present a complete list of BAT on-board detections further confirming the continued activity of these sources. This demonstrates that true quiescence is a rare state, and that these transients accrete matter throughout their life at different rates. X-ray variability is observed at all timescales and intensities we can probe. Superimposed on the day-to-day variability is intra-day flaring which involves variations up to one order of magnitude that can occur down to timescales as short as ~1ks, and whichcan be explained by the accretion of single clumps composing the donor wind with masses M_cl~0.3-2x10^{19} g. (Abridged)Comment: Accepted for publication in MNRAS. 17 pages, 11 figures, 8 table

Orbital parameters of supergiant fast X-ray transients

Supergiant fast X-ray transient (SFXT) is a new class of the high mass X-ray binary that shows short X-ray flares. The physical mechanism of SFXT short flares is still open for discussion. The accretion process of dense clumps in stellar wind onto neutron star (NS) has been proposed as the origin of such short flares. In order to examine the applicability of the clumpy wind scenario, we focus on the accretion mode that depends on orbital parameters. Our goal is to impose restrictions on the orbital parameters of SFXT. Assuming a simple analytic model of clumpy wind, we investigate the condition where the size of accretion cylinder overcomes the clump size. The allowed parameter region for SFXT is restricted in a relatively narrow window in $P_{\rm{orb}} - e$ diagram. Binary systems with large eccentricities (e \ga 0.4) and moderate orbital periods ($P_{\rm{orb}} \sim 10$ d) are prone to show periodic X-ray outbursts which are characteristic for SFXT. We confirm that systems with a long orbital period of more than 100 days cannot produce bright X-ray flares in the simple clumpy wind scenario.Comment: 6 pages, accepted for publication in A&

Methadone maintenance treatment, criminality and overdose‐related deaths: An ecological study, 1983-1999

Background: Methadone maintenance treatments (MMTs) are the commonest substitution treatments offered to opiate addiction in Switzerland, in order to reduce criminal behaviour, infectious disease transmission and overdose death. Method: To investigate the relationship between the increase in the number of methadone maintenance treatments, criminal activity of addicts and overdose‐related deaths, an ecological study was undertaken in the Canton of Geneva, from 1983 to 1999. Results: The regular and extensive increase in the number of MMTs is not significantly associated, during the 1983-1999 period, with a fall either in drug addict incarcerations or in overdose‐related deaths. However, a slight decrease is observed in the number of imprisoned opiate addicts since 1994, and a marked decrease is seen in overdose deaths from 1997 on. An important and stable number of these deaths is due to methadone itself. Conclusion: Public health objectives to diminish delinquency and overdose deaths cannot solely be fulfilled by extensive use of MMTs. A positive result could appear when access to MMT is highly favoured. This hypothesis must be proved correct by observational studies conducted on a general populatio

Mitotic cell death induction by targeting the mitotic spindle with tubulin-inhibitory indole derivative molecules

Tubulin-targeting molecules are widely used cancer therapeutic agents. They inhibit microtubule-based structures, including the mitotic spindle, ultimately preventing cell division. The final fates of microtubule-inhibited cells are however often heterogeneous and difficult to predict. While recent work has provided insight into the cell response to inhibitors of microtubule dynamics (taxanes), the cell response to tubulin polymerization inhibitors remains less well characterized. Arylthioindoles (ATIs) are recently developed tubulin inhibitors. We previously identified ATI members that effectively inhibit tubulin polymerization in vitro and cancer cell growth in bulk cell viability assays. Here we characterise in depth the response of cancer cell lines to five selected ATIs. We find that all ATIs arrest mitotic progression, yet subsequently yield distinct cell fate profiles in time-lapse recording assays, indicating that molecules endowed with similar tubulin polymerization inhibitory activity in vitro can in fact display differential efficacy in living cells. Individual ATIs induce cytological phenotypes of increasing severity in terms of damage to the mitotic apparatus. That differentially triggers MCL-1 down-regulation and caspase-3 activation, and underlies the terminal fate of treated cells. Collectively, these results contribute to define the cell response to tubulin inhibitors and pinpoint potentially valuable molecules that can increase the molecular diversity of tubulin-targeting agents

Genome-Wide Multiple Sclerosis Association Data and Coagulation

The emerging concept of a crosstalk between hemostasis, inflammation, and immune system prompt recent works on coagulation cascade in multiple sclerosis (MS). Studies on MS pathology identified several coagulation factors since the beginning of the disease pathophysiology: fibrin deposition with breakdown of blood brain barrier, and coagulation factors within active plaques may exert pathogenic role, especially through the innate immune system. Studies on circulating coagulation factors showed complex imbalance involving several components of hemostasis cascade (thrombin, factor X, factor XII). To analyze the role of the coagulation process in connection with other pathogenic pathways, we implemented a systematic matching of genome-wide association studies (GWAS) data with an informative and unbiased network of coagulation pathways. Using MetaCore (version 6.35 build 69300, 2018) we analyzed the connectivity (i.e., direct and indirect interactions among two networks) between the network of the coagulation process and the network resulting from feeding into MetaCore the MS GWAS data. The two networks presented a remarkable over-connectivity: 958 connections vs. 561 expected by chance; z-score = 17.39; p-value < 0.00001. Moreover, genes coding for cluster of differentiation 40 (CD40) and plasminogen activator, urokinase (PLAU) shared both networks, pointed to an integral interplay between coagulation cascade and main pathogenic immune effectors. In fact, CD40 pathways is especially operative in B cells, that are currently a major therapeutic target in MS field. The potential interaction of PLAU with a signal of paramount importance for B cell pathogenicity, such as CD40, suggest new lines of research and pave the way to implement new therapeutic targets

Chemical abundances and radial velocities in the extremely metal-poor galaxy DDO 68

We present chemical abundances and radial velocities of six HII regions in the extremely metal-poor star-forming dwarf galaxy DDO 68. They are derived from deep spectra in the wavelength range 3500 - 10,000 {\AA}, acquired with the Multi Object Double Spectrograph (MODS) at the Large Binocular Telescope (LBT). In the three regions where the [O III]$\lambda$4363 {\AA} line was detected, we inferred the abundance of He, N, O, Ne, Ar, and S through the "direct" method. We also derived the oxygen abundances of all the six regions adopting indirect method calibrations. We confirm that DDO 68 is an extremely metal-poor galaxy, and a strong outlier in the luminosity - metallicity relation defined by star-forming galaxies. With the direct-method we find indeed an oxygen abundance of 12+log(O/H)=7.14$\pm$0.07 in the northernmost region of the galaxy and, although with large uncertainties, an even lower 12+log(O/H)=6.96$\pm$0.09 in the "tail". This is, at face value, the most metal-poor direct abundance detection of any galaxy known. We derive a radial oxygen gradient of -0.06$\pm$0.03 dex/kpc (or -0.30 dex $R_{25}^{-1}$) with the direct method, and a steeper gradient of -0.12$\pm$0.03 dex/kpc (or -0.59 dex $R_{25}^{-1}$) from the indirect method. For the $\alpha$-element to oxygen ratios we obtain values in agreement with those found in other metal-poor star-forming dwarfs. For nitrogen, instead, we infer much higher values, leading to log(N/O)$\sim-1.4$, at variance with the suggested existence of a tight plateau at $-1.6$ in extremely metal poor dwarfs. The derived helium mass fraction ranges from Y=0.240$\pm$0.005 to Y=0.25$\pm$0.02, compatible with standard big bang nucleosynthesis. Finally, we measured HII region radial velocities in the range 479$-$522 km/s from the tail to the head of the "comet", consistent with the rotation derived in the HI.Comment: Accepted for publication in MNRA

Reconsolidation or Extinction: Transcription Factor Switch in the Determination of Memory Course after Retrieval

In fear conditioning, aversive stimuli are readily associated with contextual features. A brief reexposure to the training context causes fear memory reconsolidation, whereas a prolonged reexposure induces memory extinction. The regulation of hippocampal gene expression plays a key role in contextual memory consolidation and reconsolidation. However, the mechanisms that determine whether memory will reconsolidate or extinguish are not known. Here, we demonstrate opposing roles for two evolutionarily related transcription factors in the mouse hippocampus. We found that nuclear factor-κB (NF-κB) is required for fear memory reconsolidation. Conversely, calcineurin phosphatase inhibited NF-κB and induced nuclear factor of activated T-cells (NFAT) nuclear translocation in the transition between reconsolidation and extinction. Accordingly, the hippocampal inhibition of both calcineurin and NFAT independently impaired memory extinction, whereas inhibition of NF-κB enhanced memory extinction. These findings represent the first insight into the molecular mechanisms that determine memory reprocessing after retrieval, supporting a transcriptional switch that directs memory toward reconsolidation or extinction. The precise molecular characterization of postretrieval processes has potential importance to the development of therapeutic strategies for fear memory disorders.Fil: de la Fuente, Verónica. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Ciudad Universitaria. Instituto de Fisiología, Biología Molecular y Neurociencias. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Instituto de Fisiología, Biología Molecular y Neurociencias; ArgentinaFil: Freudenthal, Ramiro A. M.. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Ciudad Universitaria. Instituto de Fisiología, Biología Molecular y Neurociencias. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Instituto de Fisiología, Biología Molecular y Neurociencias; ArgentinaFil: Romano, Arturo Gabriel. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Ciudad Universitaria. Instituto de Fisiología, Biología Molecular y Neurociencias. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Instituto de Fisiología, Biología Molecular y Neurociencias; Argentin