Showing papers by "DSM published in 2012"

Recurrent mutation of the ID3 gene in Burkitt lymphoma identified by integrated genome, exome and transcriptome sequencing

Abstract: Burkitt lymphoma is a mature aggressive B-cell lymphoma derived from germinal center B cells(1). Its cytogenetic hallmark is the Burkitt translocation t(8;14)(q24;q32) and its variants, which juxtapose the MYC oncogene with one of the three immunoglobulin loci(2). Consequently, MYC is deregulated, resulting in massive perturbation of gene expression(3). Nevertheless, MYC deregulation alone seems not to be sufficient to drive Burkitt lymphomagenesis. By whole-genome, whole-exome and transcriptome sequencing of four prototypical Burkitt lymphomas with immunoglobulin gene (IG)-MYC translocation, we identified seven recurrently mutated genes. One of these genes, ID3, mapped to a region of focal homozygous loss in Burkitt lymphoma(4). In an extended cohort, 36 of 53 molecularly defined Burkitt lymphomas (68%) carried potentially damaging mutations of ID3. These were strongly enriched at somatic hypermutation motifs. Only 6 of 47 other B-cell lymphomas with the IG-MYC translocation (13%) carried ID3 mutations. These findings suggest that cooperation between ID3 inactivation and IG-MYC translocation is a hallmark of Burkitt lymphomagenesis.

Self-regulated growth of supermassive black holes by a dual jet-heating active galactic nucleus feedback mechanism: methods, tests and implications for cosmological simulations

Abstract: We develop a subgrid model for the growth of supermassive black holes (BHs) and their associated active galactic nucleus (AGN) feedback in hydrodynamical cosmological simulations. This model transposes previous attempts to describe BH accretion and AGN feedback with the smoothed particle hydrodynamics (SPH) technique to the adaptive mesh refinement framework. It also furthers their development by implementing a new jet-like outflow treatment of the AGN feedback which we combine with the heating mode traditionally used in the SPH approach. Thus, our approach allows one to test the robustness of the conclusions derived from simulating the impact of self-regulated AGN feedback on galaxy formation vis-a-vis the numerical method. Assuming that BHs are created in the early stages of galaxy formation, they grow by mergers and accretion of gas at a Eddington-limited Bondi accretion rate. However this growth is regulated by AGN feedback which we model using two different modes: a quasar-heating mode when accretion rates on to the BHs are comparable to the Eddington rate, and a radio-jet mode at lower accretion rates which not only deposits energy, but also deposits mass and momentum on the grid. In other words, our feedback model deposits energy as a succession of thermal bursts and jet outflows depending on the properties of the gas surrounding the BHs. We assess the plausibility of such a model by comparing our results to observational measurements of the co-evolution of BHs and their host galaxy properties, and check their robustness with respect to numerical resolution. We show that AGN feedback must be a crucial physical ingredient for the formation of massive galaxies as it appears to be able to efficiently prevent the accumulation of and/or expel cold gas out of haloes/galaxies and significantly suppress star formation. Our model predicts that the relationship between BHs and their host galaxy mass evolves as a function of redshift, because of the vigorous accretion of cold material in the early Universe that drives Eddington-limited accretion on to BHs. Quasar activity is also enhanced at high redshift. However, as structures grow in mass and lose their cold material through star formation and efficient BH feedback ejection, the AGN activity in the low-redshift Universe becomes more and more dominated by the radio mode, which powers jets through the hot circumgalactic medium.

The Contribution of Starbursts and Normal Galaxies to Infrared Luminosity Functions at z < 2

Abstract: We present a parameterless approach to predict the shape of the infrared (IR) luminosity function (LF) at redshifts z <= 2. It requires no tuning and relies on only three observables: (1) the redshift evolution of the stellar mass function for star-forming galaxies, (2) the evolution of the specific star formation rate (sSFR) of main-sequence galaxies, and (3) the double-Gaussian decomposition of the sSFR distribution at fixed stellar mass into a contribution (assumed redshift- and mass-invariant) from main-sequence and starburst activity. This self-consistent and simple framework provides a powerful tool for predicting cosmological observables: observed IR LFs are successfully matched at all z <= 2, suggesting a constant or only weakly redshift-dependent contribution (8%-14%) of starbursts to the SFR density. We separate the contributions of main-sequence and starburst activity to the global IR LF at all redshifts. The luminosity threshold above which the starburst component dominates the IR LF rises from log(LIR/Lsun) = 11.4 to 12.8 over 0 < z < 2, reflecting our assumed (1+z)^2.8-evolution of sSFR in main-sequence galaxies.

A synthesis of carbon dioxide emissions from fossil-fuel combustion

Abstract: This synthesis discusses the emissions of carbon dioxide from fossil-fuel combustion and cement production. While much is known about these emissions, there is still much that is unknown about the details surrounding these emissions. This synthesis explores our knowledge of these emissions in terms of why there is concern about them; how they are calculated; the major global efforts on inventory- ing them; their global, regional, and national totals at differ- ent spatial and temporal scales; how they are distributed on global grids (i.e., maps); how they are transported in mod- els; and the uncertainties associated with these different as- pects of the emissions. The magnitude of emissions from the combustion of fossil fuels has been almost continuously in- creasing with time since fossil fuels were first used by hu- mans. Despite events in some nations specifically designed to reduce emissions, or which have had emissions reduction as a byproduct of other events, global total emissions con- tinue their general increase with time. Global total fossil- fuel carbon dioxide emissions are known to within 10 % un- certainty (95 % confidence interval). Uncertainty on individ- ual national total fossil-fuel carbon dioxide emissions range from a few percent to more than 50 %. This manuscript con- cludes that carbon dioxide emissions from fossil-fuel com- bustion continue to increase with time and that while much is known about the overall characteristics of these emissions, much is still to be learned about the detailed characteristics of these emissions.

A global representation of vitamin D status in healthy populations.

Abstract: Purpose This paper visualizes the available data on vitamin D status on a global map, examines the existing heterogeneities in vitamin D status and identifies research gaps.

Herschel far-infrared and submillimeter photometry for the kingfish sample of nearby galaxies

Abstract: New far-infrared and submillimeter photometry from the Herschel Space Observatory is presented for 61 nearby galaxies from the Key Insights on Nearby Galaxies: A Far-Infrared Survey with Herschel (KINGFISH) sample. The spatially integrated fluxes are largely consistent with expectations based on Spitzer far-infrared photometry and extrapolations to longer wavelengths using popular dust emission models. Dwarf irregular galaxies are notable exceptions, as already noted by other authors, as their 500 μm emission shows evidence for a submillimeter excess. In addition, the fraction of dust heating attributed to intense radiation fields associated with photodissociation regions is found to be (21 ± 4)% larger when Herschel data are included in the analysis. Dust masses obtained from the dust emission models of Draine & Li are found to be on average nearly a factor of two higher than those based on single-temperature modified blackbodies, as single blackbody curves do not capture the full range of dust temperatures inherent to any galaxy. The discrepancy is largest for galaxies exhibiting the coolest far-infrared colors.

Asymmetric homogeneous hydrogenations at scale

Abstract: Asymmetric hydrogenations are increasingly being used to introduce stereogenic centres into products used in the life sciences industries. There are a number of potential pitfalls when moving from a laboratory reaction to a manufacturing process, not least of which is safety. Time-to-market pressure leads to short development times, which in the past could be a large barrier for the implementation of catalytic steps; now there are new ways to minimise this problem. The potential problems associated with impurities and other methods that can shut down the hydrogenation reactions are highlighted in this critical review (353 references).

De novo sequencing, assembly and analysis of the genome of the laboratory strain Saccharomyces cerevisiae CEN.PK113-7D, a model for modern industrial biotechnology.

Abstract: Saccharomyces cerevisiae CEN.PK 113-7D is widely used for metabolic engineering and systems biology research in industry and academia. We sequenced, assembled, annotated and analyzed its genome. Single-nucleotide variations (SNV), insertions/deletions (indels) and differences in genome organization compared to the reference strain S. cerevisiae S288C were analyzed. In addition to a few large deletions and duplications, nearly 3000 indels were identified in the CEN.PK113-7D genome relative to S288C. These differences were overrepresented in genes whose functions are related to transcriptional regulation and chromatin remodelling. Some of these variations were caused by unstable tandem repeats, suggesting an innate evolvability of the corresponding genes. Besides a previously characterized mutation in adenylate cyclase, the CEN.PK113-7D genome sequence revealed a significant enrichment of non-synonymous mutations in genes encoding for components of the cAMP signalling pathway. Some phenotypic characteristics of the CEN.PK113-7D strains were explained by the presence of additional specific metabolic genes relative to S288C. In particular, the presence of the BIO1 and BIO6 genes correlated with a biotin prototrophy of CEN.PK113-7D. Furthermore, the copy number, chromosomal location and sequences of the MAL loci were resolved. The assembled sequence reveals that CEN.PK113-7D has a mosaic genome that combines characteristics of laboratory strains and wild-industrial strains.

ECOSMOG : an efficient code for simulating modified gravity.

Abstract: We introduce a new code, ECOSMOG, to run N-body simulations for a wide class of modified gravity and dynamical dark energy theories. These theories generally have one or more new dynamical degrees of freedom, the dynamics of which are governed by their (usually rather nonlinear) equations of motion. Solving these non-linear equations has been a great challenge in cosmology. Our code is based on the RAMSES code, which solves the Poisson equation on adaptively refined meshes to gain high resolutions in the high-density regions. We have added a solver for the extra degree(s) of freedom and performed numerous tests for the f(R) gravity model as an example to show its reliability. We find that much higher efficiency could be achieved compared with other existing mesh/grid-based codes thanks to two new features of the present code: (1) the efficient parallelisation and (2) the usage of the multigrid relaxation to solve the extra equation(s) on both the regular domain grid and refinements, giving much faster convergence even under much more stringent convergence criteria. This code is designed for performing high-accuracy, high-resolution and large-volume cosmological simulations for modified gravity and general dark energy theories, which can be utilised to test gravity and the dark energy hypothesis using the upcoming and future deep and high-resolution galaxy surveys.

New constraints on primordial black holes abundance from femtolensing of gamma-ray bursts

Abstract: The abundance of primordial black holes is currently significantly constrained in a wide range of masses. The weakest limits are established for the small mass objects where the small intensity of the associated physical phenomenon provides a challenge for current experiments. We used gamma-ray bursts with known redshifts detected by the Fermi Gamma-ray Burst Monitor (GBM) to search for the femtolensing effects caused by compact objects. The lack of femtolensing detection in the GBM data provides new evidence that primordial black holes in the mass range ${10}^{17}--{10}^{20}\text{ }\text{ }\mathrm{g}$ do not constitute a major fraction of dark matter.

One Hundred Years of Vitamins—A Success Story of the Natural Sciences

Abstract: The discovery of vitamins as essential factors in the diet was a scientific breakthrough that changed the world. Diseases such as scurvy, rickets, beriberi, and pellagra were recognized to be curable with an adequate diet. These diseases had been prevalent for thousands of years and had a dramatic impact on societies as well as on economic development. This Review highlights the key achievements in the development of industrial processes for the manufacture of eight of the 13 vitamins.

The physics and the structure of the quasar-driven outflow in Mrk 231

Abstract: Massive AGN-driven outflows are invoked by AGN-galaxy co-evolutionary models to suppress both star formation and black hole accretion. Massive molecular outflows have been discovered in some AGN hosts. However, the physical properties and structures of these AGN-driven molecular outflows are still poorly constrained. Here we present new IRAM PdBI observations of Mrk 231, the closest quasar known, targeting both the CO(1−0) and CO(2−1) transitions. We detect broad wings in both transitions, which trace a massive molecular outflow moving with velocities of up to 800 km s −1 . The wings are spatially resolved at high significance levels (5−11σ), indicating that the molecular outflow extends to the kpc scale. The CO(2−1)/CO(1−0) ratio of the red broad wings is consistent with the ratio observed in the narrow core, while the blue broad wing is less excited than the core. The latter result suggests that quasar-driven outflow models invoking shocks (which would predict higher gas excitation) are inappropriate for describing the bulk of the outflow in Mrk 231. However, we note that within the central 700 pc the CO(2−1)/CO(1−0) ratio of the red wing is slightly, but significantly, higher than in the line core, suggesting that shocks may play a role in the central region. We also find that the average size of the outflow anticorrelates with the critical density of the transition used as a wind tracer. This indicates that, although diffuse and dense clumps coexist in the outflowing gas, dense outflowing clouds have shorter lifetimes and that they evaporate into the diffuse component along the outflow or, more simply, that diffuse clouds are more efficiently accelerated to larger distances by radiation pressure.

kT -points: short three-dimensional tailored RF pulses for flip-angle homogenization over an extended volume.

Abstract: With Transmit SENSE, we demonstrate the feasibility of uniformly exciting a volume such as the human brain at 7T through the use of an original minimalist transmit k-space coverage, referred to as "k(T) -points." Radio-frequency energy is deposited only at a limited number of k-space locations in the vicinity of the center to counteract transmit sensitivity inhomogeneities. The resulting nonselective pulses are short and need little energy compared to adiabatic or other B 1+-robust pulses available in the literature, making them good candidates for short-repetition time 3D sequences at high field. Experimental verification was performed on three human volunteers at 7T by means of an 8-channel transmit array system. On average, whereas the standard circularly polarized excitation resulted in a 33%-flip angle spread (standard deviation over mean) throughout the brain, and a static radio-frequency shim showed flip angle variations of 17% and up, application of k(T) -point-based excitations demonstrated excellent flip angle uniformity (8%) for a small target flip angle and with sub-millisecond durations.

Visualization and curve-parameter estimation strategies for efficient exploration of phenotype microarray kinetics.

Abstract: Background The Phenotype MicroArray (OmniLog® PM) system is able to simultaneously capture a large number of phenotypes by recording an organism's respiration over time on distinct substrates This technique targets the object of natural selection itself, the phenotype, whereas previously addressed ‘-omics’ techniques merely study components that finally contribute to it The recording of respiration over time, however, adds a longitudinal dimension to the data To optimally exploit this information, it must be extracted from the shapes of the recorded curves and displayed in analogy to conventional growth curves Methodology The free software environment R was explored for both visualizing and fitting of PM respiration curves Approaches using either a model fit (and commonly applied growth models) or a smoothing spline were evaluated Their reliability in inferring curve parameters and confidence intervals was compared to the native OmniLog® PM analysis software We consider the post-processing of the estimated parameters, the optimal classification of curve shapes and the detection of significant differences between them, as well as practically relevant questions such as detecting the impact of cultivation times and the minimum required number of experimental repeats Conclusions We provide a comprehensive framework for data visualization and parameter estimation according to user choices A flexible graphical representation strategy for displaying the results is proposed, including 95% confidence intervals for the estimated parameters The spline approach is less prone to irregular curve shapes than fitting any of the considered models or using the native PM software for calculating both point estimates and confidence intervals These can serve as a starting point for the automated post-processing of PM data, providing much more information than the strict dichotomization into positive and negative reactions Our results form the basis for a freely available R package for the analysis of PM data

The effects of baryon physics, black holes and active galactic nucleus feedback on the mass distribution in clusters of galaxies

Abstract: The spatial distribution of matter in clusters of galaxies is mainly determined by the dominant dark matter component; however, physical processes involving baryonic matter are able to modify it significantly. We analyse a set of 500 pc resolution cosmological simulations of a cluster of galaxies with mass comparable to Virgo, performed with the AMR code ramses. We compare the mass density profiles of the dark, stellar and gaseous matter components of the cluster that result from different assumptions for the subgrid baryonic physics and galaxy formation processes. First, the prediction of a gravity-only N-body simulation is compared to that of a hydrodynamical simulation with standard galaxy formation recipes, and then all results are compared to a hydrodynamical simulation which includes thermal active galactic nucleus (AGN) feedback from supermassive black holes (SMBHs). We find the usual effects of overcooling and adiabatic contraction in the run with standard galaxy formation physics, but very different results are found when implementing SMBHs and AGN feedback. Star formation is strongly quenched, producing lower stellar densities throughout the cluster, and much less cold gas is available for star formation at low redshifts. At redshift z= 0 we find a flat density core of radius 10 kpc in both the dark and stellar matter density profiles. We speculate on the possible formation mechanisms able to produce such cores and we conclude that they can be produced through the coupling of different processes: (I) dynamical friction from the decay of black hole orbits during galaxy mergers; (II) AGN-driven gas outflows producing fluctuations of the gravitational potential causing the removal of collisionless matter from the central region of the cluster; (III) adiabatic expansion in response to the slow expulsion of gas from the central region of the cluster during the quiescent mode of AGN activity.

Taxonomic revision of the family closteroviridae with special reference to the grapevine leafroll-associated members of the genus ampelovirus and the putative species unassigned to the family

Abstract: New insights into the genetic structure and variability of grapevine leafroll-associated viruses (GLRaVs) gained through worldwide efforts in the last decade or so, and the production and use of new sets of serological reagents, have provided the solid foundation on which the present revision of the taxonomic structure of the family Closteroviridae, and the genus Ampelovirus in particular, is based. A comparative examination of the amino acid sequence divergence of three taxonomically relevant genes [RNA-dependent RNA polymerase (polymerase), heat shock protein 70 homologue (HSP70h) and coat protein (CP)] disclosed a difference among Grapevine leafroll-associated virus 4 (GLRaV-4), -5, -6 and -9 and a group of more recently described viruses (GLRaV-Pr, GLRaV-De and GLRaV-Car) below the 25% limit recently set by the International Committee on Taxonomy of Viruses (ICTV) as a discriminating criterion for the identification of species in the family Closteroviridae. This, plus the recognition that GLRaV-4, -5, -6 and -9 are serologically related, have similar biological and epidemiological traits, and that these viruses and GLRaV-Pr, GLRaV-De, GLRaV-Car have a genome with the same structure and size, supports the notion that they are all genetically divergent variants of a single species, GLRaV-4. The genus Ampelovirus is split into two subgroups designated I and II in recognition of the wide difference in the size and structure of the genome of the present members. Finally, the establishment of a fourth genus within the family Closteroviridae, comprising the unassigned putative species Grapevine leafroll-associated virus 7 (GLRaV-7), Little cherry virus 1 (LChV-1) and Cordyline virus 1 (CoV-1), is justified based on their molecular and biological characteristics that differ from those of members of the other three genera of the family.

Modeling Dust and Starlight in Galaxies Observed by Spitzer and Herschel: NGC?628 and NGC?6946

Abstract: We characterize the dust in NGC 628 and NGC 6946, two nearby spiral galaxies in the KINGFISH sample. With data from 3.6 μm to 500 μm, dust models are strongly constrained. Using the Draine & Li dust model (amorphous silicate and carbonaceous grains), for each pixel in each galaxy we estimate (1) dust mass surface density, (2) dust mass fraction contributed by polycyclic aromatic hydrocarbons, (3) distribution of starlight intensities heating the dust, (4) total infrared (IR) luminosity emitted by the dust, and (5) IR luminosity originating in regions with high starlight intensity. We obtain maps for the dust properties, which trace the spiral structure of the galaxies. The dust models successfully reproduce the observed global and resolved spectral energy distributions (SEDs). The overall dust/H mass ratio is estimated to be 0.0082 ± 0.0017 for NGC 628, and 0.0063 ± 0.0009 for NGC 6946, consistent with what is expected for galaxies of near-solar metallicity. Our derived dust masses are larger (by up to a factor of three) than estimates based on single-temperature modified blackbody fits. We show that the SED fits are significantly improved if the starlight intensity distribution includes a (single intensity) "delta function" component. We find no evidence for significant masses of cold dust (T ≲ 12 K). Discrepancies between PACS and MIPS photometry in both low and high surface brightness areas result in large uncertainties when the modeling is done at PACS resolutions, in which case SPIRE, MIPS70, and MIPS160 data cannot be used. We recommend against attempting to model dust at the angular resolution of PACS.

Diet supplementation with green tea extract epigallocatechin gallate prevents progression to glucose intolerance in db/db mice.

Abstract: Background Green tea was suggested as a therapeutic agent for the treatment of diabetes more than 70 years ago, but the mechanisms behind its antidiabetic effect remains elusive. In this work, we address this issue by feeding a green tea extract (TEAVIGO™) with a high content of epigallocatechin gallate (EGCG) or the thiazolidinedione PPAR-γ agonist rosiglitazone, as positive control, to db/db mice, an animal model for diabetes.

Dietary surveys indicate vitamin intakes below recommendations are common in representative Western countries

Abstract: Vitamins play a crucial role in health, but modern lifestyles may lead to suboptimal intakes even in affluent countries The aim of the present study is to review vitamin intakes in Germany, the UK, The Netherlands and the USA and to compare them with respective national recommendations Data on adults from the most recently published national dietary intake surveys for the first three countries and data for adults from the US National Health and Nutrition Examination Survey from 2003 to 2008 for the USA were used as a basis for the analysis The proportions of the populations with intakes below recommendations were categorised as 25-50, >50-75 and >75 % for each vitamin The data generated are presented in a 'traffic light display', using colours from green to red to indicate degrees of sufficiency The trends found were compared with the results from the European Nutrition and Health Report 2009, even though in that report, only information on mean intakes in the different countries was available We showed that, although inter-country differences exist, intakes of several vitamins are below recommendations in a significant part of the population in all these countries The most critical vitamin appears to be vitamin D and the least critical niacin The variation between the countries is most probably due to differences in recommendations, levels of fortification and local dietary habits We show that a gap exists between vitamin intakes and requirements for a significant proportion of the population, even though diverse foods are available Ways to correct this gap need to be investigated

Proton–nucleus collisions at the LHC: scientific opportunities and requirements

Abstract: Proton–nucleus (p+A) collisions have long been recognized as a crucial component of the physics program with nuclear beams at high energies, in particular for their reference role to interpret and understand nucleus–nucleus data as well as for their potential to elucidate the partonic structure of matter at low parton fractional momenta (small-x). Here, we summarize the main motivations that make a proton–nucleus run a decisive ingredient for a successful heavy-ion program at the Large Hadron Collider (LHC) and we present unique scientific opportunities arising from these collisions. We also review the status of ongoing discussions about operation plans for the p+A mode at the LHC.

The Highly Energetic Expansion of SN 2010bh Associated with GRB 100316D

Abstract: Wepresentthespectroscopicandphotometricevolutionofthenearby(z = 0.059)spectroscopicallyconfirmedType Ic supernova, SN 2010bh, associated with the soft, long-duration gamma-ray burst (X-ray flash) GRB 100316D. Intensive follow-up observations of SN 2010bh were performed at the ESO Very Large Telescope (VLT) using the X-shooter and FORS2 instruments. Thanks to the detailed temporal coverage and the extended wavelength range (3000‐24800 A), we obtained an unprecedentedly rich spectral sequence among the hypernovae, making SN 2010bh one of the best studied representatives of this SN class. We find that SN 2010bh has a more rapid rise to maximum brightness (8.0 ± 1.0 rest-frame days) and a fainter absolute peak luminosity (Lbol ≈ 3 × 10 42 ergs −1 ) than previously observed SN events associated with GRBs. Our estimate of the ejected 56 Ni mass is 0.12±0.02 M� . From the broad spectral features, we measure expansion velocities up to 47,000 km s −1 , higher than those of SNe 1998bw (GRB 980425) and 2006aj (GRB 060218). Helium absorption lines Hei λ5876 and Hei 1.083 μm, blueshifted by ∼20,000‐30,000 km s −1 and ∼28,000‐38,000 km s −1 , respectively, may be present in the optical spectra. However, the lack of coverage of the Hei 2.058 μm line prevents us from confirming such identifications. The nebular spectrum, taken at ∼186 days after the explosion, shows a broad but faint [Oi] emission at 6340 A. The light curve shape and photospheric expansion velocities of SN 2010bh suggest that we witnessed a highly energetic

Submillimetre photometry of 323 nearby galaxies from the Herschel Reference Survey

Abstract: The Herschel Reference Survey (HRS) is a guaranteed time Herschel key project aimed at studying the physical properties of the interstellar medium in galaxies of the nearby universe. This volume limited, K-band selected sample is composed of galaxies spanning the whole range of morphological types (from ellipticals to late-type spirals) and environments (from the field to the centre of the Virgo Cluster). We present flux density measurements of the whole sample of 323 galaxies of the HRS in the three bands of the Spectral and Photometric Imaging Receiver (SPIRE), at 250 μm, 350 μm and 500 μm. Aperture photometry is performed on extended galaxies and point spread function (PSF) fitting on timeline data for unresolved objects; we carefully estimate errors and upper limits. The flux densities are found to be in good agreement with those of the HeViCS and KINGFISH key projects in all SPIRE bands, and of the Planck consortium at 350 μm and 550 μm, for the galaxies in common. This submillimetre catalogue of nearby galaxies is a benchmark for the study of the dust properties in the local universe, giving the zero redshift reference for any cosmological survey.

Stimulation of GSH synthesis to prevent oxidative stress-induced apoptosis by hydroxytyrosol in human retinal pigment epithelial cells: activation of Nrf2 and JNK-p62/SQSTM1 pathways

Abstract: The Nrf2-Keap1 pathway is believed to be a critical regulator of the phase II defense system against oxidative stress. By activation of Nrf2, cytoprotective genes such as heme oxygenase-1 (HO-1), NAD(P)H:quinone oxidoreductase (NQO-1) and γ-glutamyl-cysteine ligase (GCL) are induced. GCL-induced glutathione (GSH) production is believed to affect redox signaling, cell proliferation and death. We here report that tert-butyl hydroperoxide (t-BHP)-induced GSH reduction led to mitochondrial membrane potential loss and apoptosis in cultured human retinal pigment epithelial cells from the ARPE-19 cell line. Hydroxytyrosol (HT), a natural phytochemical from olive leaves and oil, was found to induce phase II enzymes and GSH, thus protect t-BHP-induced mitochondrial dysfunction and apoptosis. Depletion of GSH by buthionine-[S,R]-sulfoximine enhanced t-BHP toxicity and abolished HT protection. Overexpression of Nrf2 increased GSH content and efficiently protected t-BHP-induced mitochondrial membrane potential loss. Meanwhile, HT-induced GSH enhancement and induction of Nrf2 target gene (GCLc, GCLm, HO-1, NQO-1) messenger RNA (mRNA) were inhibited by Nrf2 knockdown, suggesting that HT increases GSH through Nrf2 activation. In addition, we found that HT was able to activate the PI3/Akt and mTOR/p70S6-kinase pathways, both of which contribute to survival signaling in stressed cells. However, the effect of HT was not inhibited by the PI3K inhibitor LY294002. Rather, c-Jun N-terminal kinase (JNK) activation was found to induce p62/SQSTM1 expression, which is involved in Nrf2 activation. Our study demonstrates that Nrf2 activation induced by the JNK pathway plays an essential role in the mechanism behind HT's strengthening of the antiapoptotic actions of the endogenous antioxidant system.

The carbon starvation response of Aspergillus niger during submerged cultivation: insights from the transcriptome and secretome

Abstract: Filamentous fungi are confronted with changes and limitations of their carbon source during growth in their natural habitats and during industrial applications. To survive life-threatening starvation conditions, carbon from endogenous resources becomes mobilized to fuel maintenance and self-propagation. Key to understand the underlying cellular processes is the system-wide analysis of fungal starvation responses in a temporal and spatial resolution. The knowledge deduced is important for the development of optimized industrial production processes. This study describes the physiological, morphological and genome-wide transcriptional changes caused by prolonged carbon starvation during submerged batch cultivation of the filamentous fungus Aspergillus niger. Bioreactor cultivation supported highly reproducible growth conditions and monitoring of physiological parameters. Changes in hyphal growth and morphology were analyzed at distinct cultivation phases using automated image analysis. The Affymetrix GeneChip platform was used to establish genome-wide transcriptional profiles for three selected time points during prolonged carbon starvation. Compared to the exponential growth transcriptome, about 50% (7,292) of all genes displayed differential gene expression during at least one of the starvation time points. Enrichment analysis of Gene Ontology, Pfam domain and KEGG pathway annotations uncovered autophagy and asexual reproduction as major global transcriptional trends. Induced transcription of genes encoding hydrolytic enzymes was accompanied by increased secretion of hydrolases including chitinases, glucanases, proteases and phospholipases as identified by mass spectrometry. This study is the first system-wide analysis of the carbon starvation response in a filamentous fungus. Morphological, transcriptomic and secretomic analyses identified key events important for fungal survival and their chronology. The dataset obtained forms a comprehensive framework for further elucidation of the interrelation and interplay of the individual cellular events involved.

Clinical, immunophenotypic, cytogenetic, and molecular genetic features in 117 adult patients with mixed-phenotype acute leukemia defined by WHO-2008 classification

Abstract: Among 4,780 consecutive adult acute lymphoblastic/myeloblastic leukemia patients, we identified 117 (2.4%) patients with mixed-phenotype acute leukemia fulfilling WHO 2008 criteria; these were classified as: Blymphoid+ myeloid (n=64), T-lymphoid+myeloid (n=38), B+T-lymphoid (n=14) and trilineage (n=1). Of 92 patients karyotyped, 59 were abnormal and were classified as: complex (22 of 92), t(9;22)(q34;q11) (14 of 92), monosomy 7 (7 of 92), polysomy 21 (7 of 92), t(v;11q23) (4 of 92), t(10;11)(p15;q21) (3 of 92), while STIL-TAL1 fusion was detected in one (T+My) patient. After investigating common acute leukemia-related mutations in 17 genes, 12 of 31 (39%) patients were found to have at least one mutation, classified with: IKZF1 deletion (4 of 31), and EZH2 (3 of 31), ASXL1 (3 of 31), ETV6 (2 of 31), NOTCH1 (1 of 31), and TET2 (1 of 31) mutations. Array-CGH revealed genomic deletions of CDKN2A (4 of 12), IKZF1 (3 of 12), MEF2C (2 of 12), BTG1 (2 of 12), together with BCOR, EBF1, K-RAS, LEF1, MBNL1, PBX3, and RUNX1 (one of 12 each). Our results indicate that mixed-phenotype acute leukemia is a complex entity with heterogeneous clinical, immunophenotypic, cytogenetic, and molecular genetic features.

Spatially resolved stellar, dust, and gas properties of the post-interacting whirlpool galaxy system

Abstract: Using infrared imaging from the Herschel Space Observatory, observed as part of the Very Nearby Galaxies Survey, we investigate the spatially resolved dust properties of the interacting Whirlpool galaxy system (NGC 5194 and NGC 5195), on physical scales of ~1 kpc. Spectral energy distribution modeling of the new infrared images in combination with archival optical and near- through mid-infrared images confirms that both galaxies underwent a burst of star formation ~370-480 Myr ago and provides spatially resolved maps of the stellar and dust mass surface densities. The resulting average dust-to-stellar mass ratios are comparable to other spiral and spheroidal galaxies studied with Herschel, with NGC 5194 at log (M dust/M sstarf) = –2.5 ± 0.2 and NGC 5195 at log (M dust/M sstarf) = –3.5 ± 0.3. The dust-to-stellar mass ratio is constant across NGC 5194 suggesting the stellar and dust components are coupled. In contrast, the mass ratio increases with radius in NGC 5195 with decreasing stellar mass density. Archival mass surface density maps of the neutral and molecular hydrogen gas are also folded into our analysis, revealing a fairly constant gas-to-dust mass ratio, 94 ± 17 across the system. Somewhat surprisingly, we find the dust in NGC 5195 is heated by a strong interstellar radiation field (ISRF), over 20 times that of the ISRF in the Milky Way, resulting in relatively high characteristic dust temperatures (~30 K). This post-starburst galaxy contains a substantial amount of low-density molecular gas and displays a gas-to-dust ratio (73 ± 35) similar to spiral galaxies. It is unclear why the dust in NGC 5195 is heated to such high temperatures as there is no star formation in the galaxy and its active galactic nucleus is 5-10 times less luminous than the one in NGC 5194, which exhibits only a modest enhancement in the amplitude of its ISRF.

Resolving the Far-IR Line Deficit: Photoelectric Heating and Far-IR Line Cooling in NGC 1097 and NGC 4559

Abstract: The physical state of interstellar gas and dust is dependent on the processes which heat and cool this medium. To probe heating and cooling of the interstellar medium over a large range of infrared surface brightness, on sub-kiloparsec scales, we employ line maps of [C II] 158 μm, [O I] 63 μm, and [N II] 122 μm in NGC 1097 and NGC 4559, obtained with the Photodetector Array Camera & Spectrometer on board Herschel. We matched new observations to existing Spitzer Infrared Spectrograph data that trace the total emission of polycyclic aromatic hydrocarbons (PAHs). We confirm at small scales in these galaxies that the canonical measure of photoelectric heating efficiency, ([C II] + [O I])/TIR, decreases as the far-infrared (far-IR) color, ν_f ν(70 μm) νf_ν(100 μm), increases. In contrast, the ratio of far-IR cooling to total PAH emission, ([C II] + [O I])/PAH, is a near constant ~6% over a wide range of far-IR color, 0.5 < νf_ν(70 μm) νf_ν(100 μm) ≾ 0.95. In the warmest regions, where νf_ν(70 μm) νf_ν(100 μm) ≳ 0.95, the ratio ([C II] + [OI])/PAH drops rapidly to 4%. We derived representative values of the local ultraviolet radiation density, G_0, and the gas density, n_H, by comparing our observations to models of photodissociation regions. The ratio G_0/n_H, derived from fine-structure lines, is found to correlate with the mean dust-weighted starlight intensity, langUrang, derived from models of the IR spectral energy distribution. Emission from regions that exhibit a line deficit is characterized by an intense radiation field, indicating that small grains are susceptible to ionization effects. We note that there is a shift in the 7.7/11.3 μm PAH ratio in regions that exhibit a deficit in ([C II] + [O I])/PAH, suggesting that small grains are ionized in these environments.