Quantitative Proteomic Approach Reveals Altered Metabolic Pathways in Response to the Inhibition of Lysine Deacetylases in A549 Cells under Normoxia and Hypoxia

Growing evidence is showing that acetylation plays an essential role in cancer, but studies on the impact of KDAC inhibition (KDACi) on the metabolic profile are still in their infancy. Here, we analyzed, by using an iTRAQ-based quantitative proteomics approach, the changes in the proteome of KRAS-mutated non-small cell lung cancer (NSCLC) A549 cells in response to trichostatin-A (TSA) and nicotinamide (NAM) under normoxia and hypoxia. Part of this response was further validated by molecular and biochemical analyses and correlated with the proliferation rates, apoptotic cell death, and activation of ROS scavenging mechanisms in opposition to the ROS production. Despite the differences among the KDAC inhibitors, up-regulation of glycolysis, TCA cycle, oxidative phosphorylation and fatty acid synthesis emerged as a common metabolic response underlying KDACi. We also observed that some of the KDACi effects at metabolic levels are enhanced under hypoxia. Furthermore, we used a drug repositioning machine learning approach to list candidate metabolic therapeutic agents for KRAS mutated NSCLC. Together, these results allow us to better understand the metabolic regulations underlying KDACi in NSCLC, taking into account the microenvironment of tumors related to hypoxia, and bring new insights for the future rational design of new therapies.     

Photoactivable Elimination of Tumorigenic Human Induced Pluripotent Stem Cells by Using a Lectin–Doxorubicin Prodrug Conjugate

Human pluripotent stem cells (hPSCs) are attractive resources for regenerative medicine, but medical applications are hindered by their tumorigenic potential. Previously, a hPSC-specific lectin probe, rBC2LCN, was identified through comprehensive glycome analysis by using high-density lectin microarrays. Herein, a lectin–doxorubicin (DOX) prodrug conjugate, with controllable photolysis activation for the elimination of tumorigenic human induced pluripotent stem cells, has been developed. rBC2LCN was fused with a biotin-binding protein, tamavidin (BC2Tama), and the fusion protein was expressed in Escherichia coli and purified by means of affinity chromatography. BC2Tama was then conjugated with doxorubicin-photocleavable biotin (DOXPCB). The BC2Tama–DOXPCB conjugates were observed to bind to hPSCs followed by internalization. Upon exposure to ultraviolet light, DOX was released inside the cells, which allowed specific killing of the hPSCs. Thus, BC2Tama–DOXPCB should be useful for the targeted elimination of hPSCs contained in hPSC-derived cell therapy products. This is the first report of the generation of lectin–prodrug conjugates. BC2Tama should be applicable for the targeted delivery of various types of biotinylated compounds into hPSCs.     

Crack initiation,propagation, and arrest in sintering powder aggregates

Cracking during sintering is a common problem in powder processing and is usually caused by constraint that prevents the sintering material from shrinking in one or more directions. Different factors influence sintering-induced cracking, including temperature schedule, packing density, and specimen geometry. Here we use the discrete element method to directly observe the stress distribution and sinter-cracking behavior in edge notched panels sintered under a uniaxial restraint. This geometry allows an easy comparison with traditional fracture mechanics parameters, facilitating analysis of sinter-cracking behavior. We find that cracking caused by self-stress during sintering resembles the growth of creep cracks in fully dense materials. By deriving the constrained densification rate from the appropriate constitutive equations, we discover that linear shrinkage transverse to the loading axis is accelerated by a contribution from the effective Poisson's ratio of a sintering solid. Simulation of different notch geometries and initial relative densities reveals conditions that favor densification and minimize crack growth, alluding to design methods for avoiding cracking in actual sintering processes. We combine the far-field stress and crack length to compute the net section stress, finding that it characterizes the stress profile between the notches and correlates with the sinter-crack growth rate, demonstrating its potential to quantitatively describe sinter-cracking.     

Rechnerische Beurteilung der Schubtragfähigkeit einer Spannbetonbrücke mit geringem Querkraft bewehrungsgrad

Assessment of the shear strength of an existing post‐tensioned concrete bridge with a low amount of shear reinforcement – First application of the ”Flexural Shear Crack“ model in practice In recent years it was reported several times, that within a static assessment according to current standards the shear strength of post‐tensioned bridges, which were built in Austria before 1989, cannot be fulfilled any more. However, test results prove, that especially prestressed structures have additional load bearing capacities, which cannot be reproduced with current calculation models. In the framework of a pilot project a new developed shear model (Flexural Shear Crack Model) was used. In this paper the approach as well as the main results of a statical reevaluation of an existing post‐tensioned road bridge at the Tauern Autobahn A10 will be presented.     

水化水泥颗粒表面超塑化剂吸附层分布模型

制备了钙矾石(AFt)、单硫型硫铝酸钙(AFm)和钾长石类单矿物,并研究了三聚氰胺磺酸盐甲醛缩聚物(PMS)、β-萘磺酸盐甲醛缩合物(BNS)及聚羧酸盐(PC)等几种化学成分不同的超塑化剂在其早期水化颗粒表面上的吸附行为.研究发现,zeta电位是决定水泥颗粒表面对超塑化剂吸附量的关键因素.以溶液沉淀析出法人工合成的AFt具有较高的正zeta电位,能吸附大量带负电荷的超塑化剂,AFm仅带少量正电荷,其吸附超塑化剂相对较少,钾长石、氢氧钙石和石膏的zeta电位几乎为零或负值,因而基本不吸附超塑化剂.根据实验结果,笔者认为水化水泥颗粒用马赛克结构表示为最佳,而超塑化剂主要吸附在AF表面上.     

Folgen des Globalen Wandels für das Grundwasser in Süddeutschland – Teil 2: Sozioökonomische Aspekte

In order to account for complex interactions between humans climate and the water cycle, the research consortium GLOWA-Danube (www.glowa-danube.de) has developed the simulation system DANUBIA which consists of 17 coupled models. DANUBIA was applied to investigate various impacts of global-change between 2011 and 2060 in the Upper Danube Catchment. This article describes part 2 of an article series with investigations of socio-economic aspects, while part 1 (Barthel et al. in Grundwasser 16(4), doi:10.1007/s007-011-01794, 2011) deals with natural-spatial aspects. The principles of socio-economic actor-modeling and interactions between socio-economic and natural science model components are described here. We present selected simulations that show impacts on groundwater from changes in agriculture, tourism, economy, domestic water users and water supply. Despite decreases in water consumption, the scenario simulations show significant decreases in groundwater quantity. On the other hand, groundwater quality will likely be influenced more severely by land use changes compared to direct climatic causes. However, overall changes will not be dramatic.     

Natürliche Schadstoffrückhalteprozesse für Arsen und Kupfer am Standort einer ehemaligen Buntfarbenfabrik

The sharply confined pattern of arsenic groundwater contamination at the site of a historic dye factory suggests that natural attenuation processes are active and efficient. The supporting data included sequential soil extractions combined with analyses of other soil properties like carbonate content, the loss of ignition and cation exchange capacity and the extraction characteristics of the original dye pigment. The results point to iron oxides and iron hydroxides as the most important adsorbers for copper and arsenic. The attenuation of copper can be estimated to be very efficient mainly due to its pH-controlled low solubility. Besides the specific adsorption to iron oxides, however, arsenic exhibits a rather large, loosely bound and easily exchangeable fraction. The speciation of arsenic in groundwater is dominated by As(V). The oxidation state of the original pigment is As(III). In some parts of the aquifer where suboxic conditions prevail, this oxidation state is conserved. In oxic zones of the aquifer, oxidation to the pentavalent form As(V) takes place.     

Adaptive Immune Responses in a Multiple Sclerosis Patient with Acute Varicella-Zoster Virus Reactivation during Treatment with Fingolimod

Fingolimod, an oral sphingosine 1-phosphate (S1P) receptor modulator, is approved for the treatment of relapsing forms of multiple sclerosis (MS). The interference with S1P signaling leads to retention particularly of chemokine receptor-7 (CCR7) expressing T cells in lymph nodes. The immunological basis of varicella zoster virus (VZV) infections during fingolimod treatment is unclear. Here, we studied the dynamics of systemic and intrathecal immune responses associated with symptomatic VZV reactivation including cessation of fingolimod and initiation of antiviral therapy. Key features in peripheral blood were an about two-fold increase of VZV-specific IgG at diagnosis of VZV reactivation as compared to the previous months, a relative enrichment of effector CD4+ T cells (36% versus mean 12% in controls), and an accelerated reconstitution of absolute lymphocytes counts including a normalized CD4+/CD8+ ratio and reappearance of CCR7+ T cells. In cerebrospinal fluid (CSF) the lymphocytic pleocytosis and CD4+/CD8+ ratios at diagnosis of reactivation and after nine days of fingolimod discontinuation remained unchanged. During this time CCR7+ T cells were not observed in CSF. Further research into fingolimod-associated VZV reactivation and immune reconstitution is mandatory to prevent morbidity and mortality associated with this potentially life-threatening condition.     

On the influence of gamma prime upon machining of advanced nickel based superalloy

Whilst gamma prime (γ′) phase is the strengthening phase in Ni-based superalloys its influence on machining has been seldom investigated. This paper reports for the first time on the effect of γ′ upon machining of Ni-based superalloys when cutting with parameters yielding different cutting temperature intervals which lead to strengthening/softening effects on the workpiece (sub)surface. In-depth XRD, SEM/FIB, EBSD analysis and unique micro-pillar testing in the workpiece superficial layers indicated that with the increase of γ′ fraction the grain plastic deformation significantly decreased, while specific cutting energy can switch from low to high values influenced by the real cutting temperature.