98 research outputs found

    Quantitative characterization of metabolism and metabolic shifts during growth of the new human cell line AGE1.HN using time resolved metabolic flux analysis

    Get PDF
    For the improved production of vaccines and therapeutic proteins, a detailed understanding of the metabolic dynamics during batch or fed-batch production is requested. To study the new human cell line AGE1.HN, a flexible metabolic flux analysis method was developed that is considering dynamic changes in growth and metabolism during cultivation. This method comprises analysis of formation of cellular components as well as conversion of major substrates and products, spline fitting of dynamic data and flux estimation using metabolite balancing. During batch cultivation of AGE1.HN three distinct phases were observed, an initial one with consumption of pyruvate and high glycolytic activity, a second characterized by a highly efficient metabolism with very little energy spilling waste production and a third with glutamine limitation and decreasing viability. Main events triggering changes in cellular metabolism were depletion of pyruvate and glutamine. Potential targets for the improvement identified from the analysis are (i) reduction of overflow metabolism in the beginning of cultivation, e.g. accomplished by reduction of pyruvate content in the medium and (ii) prolongation of phase 2 with its highly efficient energy metabolism applying e.g. specific feeding strategies. The method presented allows fast and reliable metabolic flux analysis during the development of producer cells and production processes from microtiter plate to large scale reactors with moderate analytical and computational effort. It seems well suited to guide media optimization and genetic engineering of producing cell lines

    Big data-driven fuzzy cognitive map for prioritising IT service procurement in the public sector

    Get PDF
    YesThe prevalence of big data is starting to spread across the public and private sectors however, an impediment to its widespread adoption orientates around a lack of appropriate big data analytics (BDA) and resulting skills to exploit the full potential of big data availability. In this paper, we propose a novel BDA to contribute towards this void, using a fuzzy cognitive map (FCM) approach that will enhance decision-making thus prioritising IT service procurement in the public sector. This is achieved through the development of decision models that capture the strengths of both data analytics and the established intuitive qualitative approach. By taking advantages of both data analytics and FCM, the proposed approach captures the strength of data-driven decision-making and intuitive model-driven decision modelling. This approach is then validated through a decision-making case regarding IT service procurement in public sector, which is the fundamental step of IT infrastructure supply for publics in a regional government in the Russia federation. The analysis result for the given decision-making problem is then evaluated by decision makers and e-government expertise to confirm the applicability of the proposed BDA. In doing so, demonstrating the value of this approach in contributing towards robust public decision-making regarding IT service procurement.EU FP7 project Policy Compass (Project No. 612133

    The Spectacular Ultraviolet Flash from the Peculiar Type Ia Supernova 2019yvq

    Get PDF
    Early observations of Type Ia supernovae (SNe Ia) provide essential clues for understanding the progenitor system that gave rise to the terminal thermonuclear explosion. We present exquisite observations of SN 2019yvq, the second observed SN Ia, after iPTF 14atg, to display an early flash of emission in the ultraviolet (UV) and optical. Our analysis finds that SN 2019yvq was unusual, even when ignoring the initial flash, in that it was moderately underluminous for an SN Ia (Mg18.5{M}_{g}\approx -18.5 mag at peak) yet featured very high absorption velocities (v15,000v\approx 15{\rm{,0}}00 km s−1 for Si ii λ6355 at peak). We find that many of the observational features of SN 2019yvq, aside from the flash, can be explained if the explosive yield of radioactive 56Ni is relatively low (we measure M56Ni=0.31±0.05M{M}_{{56}_{\mathrm{Ni}}}=0.31\pm 0.05\,{M}_{\odot }) and it and other iron-group elements are concentrated in the innermost layers of the ejecta. To explain both the UV/optical flash and peak properties of SN 2019yvq we consider four different models: interaction between the SN ejecta and a nondegenerate companion, extended clumps of 56Ni in the outer ejecta, a double-detonation explosion, and the violent merger of two white dwarfs. Each of these models has shortcomings when compared to the observations; it is clear additional tuning is required to better match SN 2019yvq. In closing, we predict that the nebular spectra of SN 2019yvq will feature either H or He emission, if the ejecta collided with a companion, strong [Ca ii] emission, if it was a double detonation, or narrow [O i] emission, if it was due to a violent merger

    Inhaled tolafentrine reverses pulmonary vascular remodeling via inhibition of smooth muscle cell migration

    Get PDF
    BACKGROUND: The aim of the study was to assess the chronic effects of combined phosphodiesterase 3/4 inhibitor tolafentrine, administered by inhalation, during monocrotaline-induced pulmonary arterial hypertension (PAH) in rats. METHODS: CD rats were given a single subcutaneous injection of monocrotaline to induce PAH. Four weeks after, rats were subjected to inhalation of tolafentrine or sham nebulization in an unrestrained, whole body aerosol exposure system. In these animals (i) the acute pulmonary vasodilatory efficacy of inhaled tolafentrine (ii) the anti-remodeling effect of long-term inhalation of tolafentrine (iii) the effects of tolafentrine on the expression profile of 96 genes encoding cell adhesion and extracellular matrix regulation were examined. In addition, the inhibitory effect of tolafentrine on ex vivo isolated pulmonary artery SMC cell migration was also investigated. RESULTS: Monocrotaline injection provoked severe PAH (right ventricular systolic pressure increased from 25.9 ± 4.0 to 68.9 ± 3.2 after 4 weeks and 74.9 ± 5.1 mmHg after 6 weeks), cardiac output depression and right heart hypertrophy. The media thickness of the pulmonary arteries and the proportion of muscularization of small precapillary resistance vessels increased dramatically, and the migratory response of ex-vivo isolated pulmonary artery smooth muscle cells (PASMC) was increased. Micro-arrays and subsequent confirmation with real time PCR demonstrated upregulation of several extracellular matrix regulation and adhesion genes, such as matrixmetalloproteases (MMP) 2, 8, 9, 10, 11, 12, 20, Icam, Itgax, Plat and serpinb2. When chronically nebulized from day 28 to 42 (12 daily aerosol maneuvers), after full establishment of severe pulmonary hypertension, tolafentrine reversed about 60% of all hemodynamic abnormalities, right heart hypertrophy and monocrotaline-induced structural lung vascular changes, including the proportion of pulmonary artery muscularization. The upregulation of extracellular matrix regulation and adhesion genes was reduced by nearly 80% by inhalation of the tolafentrine. When assessed in vitro, tolafentrine blocked the enhanced PASMC migratory response. CONCLUSION: In conclusion, we demonstrate for the first time that inhalation of combined PDE3/4 inhibitor reverses pulmonary hypertension fully developed in response to monocrotaline in rats. This "reverse-remodeling" effect includes structural changes in the lung vascular wall and key molecular pathways of matrix regulation, concomitant with 60% normalization of hemodynamics

    Super-resolution:A comprehensive survey

    Get PDF

    SN 2018fif: The Explosion of a Large Red Supergiant Discovered in Its Infancy by the Zwicky Transient Facility

    Get PDF
    High-cadence transient surveys are able to capture supernovae closer to their first light than ever before. Applying analytical models to such early emission, we can constrain the progenitor stars' properties. In this paper, we present observations of SN 2018fif (ZTF 18abokyfk). The supernova was discovered close to first light and monitored by the Zwicky Transient Facility (ZTF) and the Neil Gehrels Swift Observatory. Early spectroscopic observations suggest that the progenitor of SN 2018fif was surrounded by relatively small amounts of circumstellar material compared to all previous cases. This particularity, coupled with the high-cadence multiple-band coverage, makes it a good candidate to investigate using shock-cooling models. We employ the SOPRANOS code, an implementation of the model by Sapir & Waxman and its extension to early times by Morag et al. Compared with previous implementations, SOPRANOS has the advantage of including a careful account of the limited temporal validity domain of the shock-cooling model as well as allowing usage of the entirety of the early UV data. We find that the progenitor of SN 2018fif was a large red supergiant with a radius of R=744.0128.0+183.0RR={744.0}_{-128.0}^{+183.0}\,{R}_{\odot } and an ejected mass of Mej=9.35.8+0.4M{M}_{\mathrm{ej}}={9.3}_{-5.8}^{+0.4}\,{M}_{\odot }. Our model also gives information on the explosion epoch, the progenitor's inner structure, the shock velocity, and the extinction. The distribution of radii is double-peaked, with smaller radii corresponding to lower values of the extinction, earlier recombination times, and a better match to the early UV data. If these correlations persist in future objects, denser spectroscopic monitoring constraining the time of recombination, as well as accurate UV observations (e.g., with ULTRASAT), will help break the extinction/radius degeneracy and independently determine both

    The Zwicky Transient Facility Census of the Local Universe. I. Systematic Search for Calcium-rich Gap Transients Reveals Three Related Spectroscopic Subclasses

    Get PDF
    Using the Zwicky Transient Facility alert stream, we are conducting a large spectroscopic campaign to construct a complete, volume-limited sample of transients brighter than 20 mag, and coincident within 100'' of galaxies in the Census of the Local Universe catalog. We describe the experiment design and spectroscopic completeness from the first 16 months of operations, which have classified 754 supernovae. We present results from a systematic search for calcium-rich gap transients in the sample of 22 low-luminosity (peak absolute magnitude M > −17), hydrogen-poor events found in the experiment. We report the detection of eight new events, and constrain their volumetric rate to gsim15% ± 5% of the SN Ia rate. Combining this sample with 10 previously known events, we find a likely continuum of spectroscopic properties ranging from events with SN Ia–like features (Ca-Ia objects) to those with SN Ib/c–like features (Ca-Ib/c objects) at peak light. Within the Ca-Ib/c events, we find two populations distinguished by their red (g − r ≈ 1.5 mag) or green (gr0.5g-r\approx 0.5 mag) colors at the r-band peak, wherein redder events show strong line blanketing features and slower light curves (similar to Ca-Ia objects), weaker He lines, and lower [Ca ii]/[O i] in the nebular phase. We find that all together the spectroscopic continuum, volumetric rates, and striking old environments are consistent with the explosive burning of He shells on low-mass white dwarfs. We suggest that Ca-Ia and red Ca-Ib/c objects arise from the double detonation of He shells, while green Ca-Ib/c objects are consistent with low-efficiency burning scenarios like detonations in low-density shells or deflagrations
    corecore