Simulation zur Verbesserung der Logistikprozesse eines Pharmagroßhandels

Gehe Pharma Handel GmbH is one of Germany's biggest pharmaceutical wholesalers. This paper describes the development and application of a simulation software representing their logistic processes, built in cooperation with Gehe's Troisdorf branch. We start with an outline of the Gehe facility, describe the process of implementing and validating the software application, and show some sample results

Anharmonic force fields of perchloric acid, HClO4_4, and perchloric anhydride, Cl2_2O7_7. An extreme case of inner polarization

DFT (density functional theory) anharmonic force fields with basis sets near the Kohn-Sham limit have been obtained for perchloric acid, HClO$_4$, and perchloric anhydride, Cl$_2$O$_7$. Calculated fundamental frequencies are in very good agreement with available experimental data. Some reassignments in the vibrational spectra of Cl$_2$O$_7$ are proposed based on our calculations. HClO$_4$ and Cl$_2$O$_7$ are particularly severe examples of the `inner polarization' phenomenon. The polarization consistent basis sets pc-1 and pc-2 (as well as their augmented counterparts) should be supplemented with two (preferably three) and one (preferably two) high-exponent $d$ functions, respectively, on second-row atoms. Complete anharmonic force fields are available as electronic supporting information.Comment: J. Mol. Struct., in press (special issue); Electronic Supporting Information at http://theochem.weizmann.ac.il/web/papers/Cl2O7.htm

Laser Guide Stars for Extremely Large Telescopes: Efficient Shack-Hartmann Wavefront Sensor Design using Weighted center-of-gravity algorithm

Over the last few years increasing consideration has been given to the study of Laser Guide Stars (LGS) for the measurement of the disturbance introduced by the atmosphere in optical and near-infrared astronomical observations from the ground. A possible method for the generation of a LGS is the excitation of the Sodium layer in the upper atmosphere at approximately 90 km of altitude. Since the Sodium layer is approximately 10 km thick, the artificial reference source looks elongated, especially when observed from the edge of a large aperture. The spot elongation strongly limits the performance of the most common wavefront sensors. The centroiding accuracy in a Shack-Hartmann wavefront sensor, for instance, decreases proportionally to the elongation (in a photon noise dominated regime). To compensate for this effect a straightforward solution is to increase the laser power, i.e. to increase the number of detected photons per subaperture. The scope of the work presented in this paper is twofold: an analysis of the performance of the Weighted Center of Gravity algorithm for centroiding with elongated spots and the determination of the required number of photons to achieve a certain average wavefront error over the telescope aperture.Comment: 10 pages, 14 figure

miR-34a is upregulated inAIP-mutated somatotropinomas and promotes octreotide resistance

Pituitary adenomas (PAs) are intracranial tumors associated with significant morbidity due to hormonal dysregulation, mass effects and have a heavy treatment burden. Growth hormone (GH)-secreting PAs (somatotropinomas) cause acromegaly-gigantism. Genetic forms of somatotropinomas due to germlineAIPmutations (AIPmut+) have an early onset and are aggressive and resistant to treatment with somatostatin analogs (SSAs), including octreotide. The molecular underpinnings of these clinical features remain unclear. We investigated the role of miRNA dysregulation inAIPmut+ vsAIPmut- PA samples by array analysis. miR-34a and miR-145 were highly expressed inAIPmut+ vsAIPmut- somatotropinomas. Ectopic expression ofAIPmut (p.R271W) inAip(-/-)mouse embryonic fibroblasts (MEFs) upregulated miR-34a and miR-145, establishing a causal link betweenAIPmut and miRNA expression. In PA cells (GH3), miR-34a overexpression promoted proliferation, clonogenicity, migration and suppressed apoptosis, whereas miR-145 moderately affected proliferation and apoptosis. Moreover, high miR-34a expression increased intracellular cAMP, a critical mitogenic factor in PAs. Crucially, high miR-34a expression significantly blunted octreotide-mediated GH inhibition and antiproliferative effects. miR-34a directly targetsGnai2encoding G alpha i2, a G protein subunit inhibiting cAMP production. Accordingly, G alpha i2 levels were significantly lower inAIPmut+ vsAIPmut- PA. Taken together, somatotropinomas withAIPmutations overexpress miR-34a, which in turn downregulates G alpha i2 expression, increases cAMP concentration and ultimately promotes cell growth. Upregulation of miR-34a also impairs the hormonal and antiproliferative response of PA cells to octreotide. Thus, miR-34a is a novel downstream target of mutantAIPthat promotes a cellular phenotype mirroring the aggressive clinical features ofAIPmut+ acromegaly.Peer reviewe

Compartmentalised expression of Delta-like 1 in epithelial somites is required for the formation of intervertebral joints

<p>Abstract</p> <p>Background</p> <p>Expression of the mouse <it>Delta-like 1 </it>(<it>Dll1</it>) gene in the presomitic mesoderm and in the caudal halves of somites of the developing embryo is required for the formation of epithelial somites and for the maintenance of caudal somite identity, respectively. The rostro-caudal polarity of somites is initiated early on within the presomitic mesoderm in nascent somites. Here we have investigated the requirement of restricted <it>Dll1 </it>expression in caudal somite compartments for the maintenance of rostro-caudal somite polarity and the morphogenesis of the axial skeleton. We did this by overexpressing a functional copy of the <it>Dll1 </it>gene throughout the paraxial mesoderm, in particular in anterior somite compartments, during somitogenesis in transgenic mice.</p> <p>Results</p> <p>Epithelial somites were generated normally and appeared histologically normal in embryos of two independent <it>Dll1 </it>over-expressing transgenic lines. Gene expression analyses of rostro-caudal marker genes suggested that over-expression of <it>Dll1 </it>without restriction to caudal compartments was not sufficient to confer caudal identity to rostral somite halves in transgenic embryos. Nevertheless, <it>Dll1 </it>over-expression caused dysmorphologies of the axial skeleton, in particular, in morphological structures that derive from the articular joint forming compartment of vertebrae. Accordingly, transgenic animals exhibited missing or reduced intervertebral discs, rostral and caudal articular processes as well as costal heads of ribs. In addition, the midline of the vertebral column did not develop normally. Transgenic mice had open neural arches and split vertebral bodies with ectopic pseudo-growth plates. Endochondral bone formation and ossification in the developing vertebrae were delayed.</p> <p>Conclusion</p> <p>The mice overexpressing <it>Dll1 </it>exhibit skeletal dysmorphologies that are also evident in several mutant mice with defects in somite compartmentalisation. The <it>Dll1 </it>transgenic mice demonstrate that vertebral dysmorphologies such as bony fusions of vertebrae and midline vertebral defects can occur without apparent changes in somitic rostro-caudal marker gene expression. Also, we demonstrate that the over-expression of the <it>Dll1 </it>gene in rostral epithelial somites is not sufficient to confer caudal identity to rostral compartments. Our data suggest that the restricted <it>Dll1 </it>expression in caudal epithelial somites may be particularly required for the proper development of the intervertebral joint forming compartment.</p

Investigation of Molecular Iridium Fluorides IrFn (n=1–6): A Combined Matrix-Isolation and Quantum-Chemical Study

The photo-initiated defluorination of iridium hexafluoride (IrF6) was investigated in neon and argon matrices at 6 K, and their photoproducts are characterized by IR and UV-vis spectroscopies as well as quantum-chemical calculations. The primary photoproducts obtained after irradiation with λ=365 nm are iridium pentafluoride (IrF5) and iridium trifluoride (IrF3), while longer irradiation of the same matrix with λ=278 nm produced iridium tetrafluoride (IrF4) and iridium difluoride (IrF2) by Ir−F bond cleavage or F2 elimination. In addition, IrF5 can be reversed to IrF6 by adding a F atom when exposed to blue-light (λ=470 nm) irradiation. Laser irradiation (λ=266 nm) of IrF4 also generated IrF6, IrF5, IrF3 and IrF2. Alternatively, molecular binary iridium fluorides IrFn (n=1–6) were produced by co-deposition of laser-ablated iridium atoms with elemental fluorine in excess neon and argon matrices under cryogenic conditions. Computational studies up to scalar relativistic CCSD(T)/triple-ζ level and two-component quasirelativistic DFT computations including spin-orbit coupling effects supported the formation of these products and provided detailed insights into their molecular structures by their characteristic Ir−F stretching bands. Compared to the Jahn-Teller effect, the influence of spin-orbit coupling dominates in IrF5, leading to a triplet ground state with C4v symmetry, which was spectroscopically detected in solid argon and neon matrices

Impaired resolution of inflammatory response in the lungs of JF1/Msf mice following carbon nanoparticle instillation

<p>Abstract</p> <p>Background</p> <p>Declined lung function is a risk factor for particulate matter associated respiratory diseases like asthma and chronic obstructive pulmonary disease (COPD). Carbon nanoparticles (CNP) are a prominent component of outdoor air pollution that causes pulmonary toxicity mainly through inflammation. Recently we demonstrated that mice (C3H/HeJ) with higher than normal pulmonary function resolved the elicited pulmonary inflammation following CNP exposure through activation of defense and homeostasis maintenance pathways. To test whether CNP-induced inflammation is affected by declined lung function, we exposed JF1/Msf (JF1) mice with lower than normal pulmonary function to CNP and studied the pulmonary inflammation and its resolution.</p> <p>Methods</p> <p>5 μg, 20 μg and 50 μg CNP (Printex 90) were intratracheally instilled in JF1 mice to determine the dose response and the time course of inflammation over 7 days (20 μg dosage). Inflammation was assessed using histology, bronchoalveolar lavage (BAL) analysis and by a panel of 62 protein markers.</p> <p>Results</p> <p>24 h after instillation, 20 μg and 50 μg CNP caused a 25 fold and 19 fold increased polymorphonuclear leucocytes (PMN) respectively while the 5 μg represented the 'no observable adverse effect level' as reflected by PMN influx (9.7 × 10E3 vs 8.9 × 10E3), and BAL/lung concentrations of pro-inflammatory cytokines. Time course assessment of the inflammatory response revealed that compared to day1 the elevated BAL PMN counts (246.4 × 10E3) were significantly decreased at day 3 (72.9 × 10E3) and day 7 (48.5 × 10E3) but did not reach baseline levels indicating slow PMN resolution kinetics. Strikingly on day 7 the number of macrophages doubled (455.0 × 10E3 vs 204.7 × 10E3) and lymphocytes were 7-fold induced (80.6 × 10E3 vs 11.2 × 10E3) compared to day1. At day 7 elevated levels of IL1B, TNF, IL4, MDC/CCL22, FVII, and vWF were detected in JF1 lungs which can be associated to macrophage and lymphocyte activation.</p> <p>Conclusion</p> <p>This explorative study indicates that JF1 mice with impaired pulmonary function also exhibits delayed resolution of particle mediated lung inflammation as evident from elevated PMN and accumulation of macrophages and lymphocytes on day7. It is plausible that elevated levels of IL1B, IL4, TNF, CCL22/MDC, FVII and vWF counteract defense and homeostatic pathways thereby driving this phenomenon.</p

Construction of a scientific abstract

An abstract is a brief summary of a research article, thesis, review, conference proceeding, or any in-depth analysis of a particular subject [1]. It is used to help the reader quickly ascertain the authors’ principle messages. The aim of this text is to strengthen the understanding of abstract writing, define its specific components, and to help the writer evaluate and complete their abstract with enhanced clarity and quality [2]. Typically, the academic research abstract contains four elements: objective and study design, materials and methods, results, and discussion/conclusions. During peer review, it is important that authors adhere to this format, as reviewers often evaluate these parts separately

Pathway focused protein profiling indicates differential function for IL-1B, -18 and VEGF during initiation and resolution of lung inflammation evoked by carbon nanoparticle exposure in mice

<p>Abstract</p> <p>Background</p> <p>Carbonaceous nanoparticles possess an emerging source of human exposure due to the massive release of combustion products and the ongoing revolution in nanotechnology. Pulmonary inflammation caused by deposited nanoparticles is central for their adverse health effects. Epidemiological studies suggest that individuals with favourable lung physiology are at lower risk for particulate matter associated respiratory diseases probably due to efficient control of inflammation and repair process. Therefore we selected a mouse strain C3H/HeJ (C3) with robust lung physiology and exposed it to moderately toxic carbon nanoparticles (CNP) to study the elicited pulmonary inflammation and its resolution.</p> <p>Methods</p> <p>5 μg, 20 μg and 50 μg CNP were intratracheally (i.t.) instilled in C3 mice to identify the optimal dose for subsequent time course studies. Pulmonary inflammation was assessed using histology, bronchoalveolar lavage (BAL) analysis and by a panel of 62 protein markers.</p> <p>Results</p> <p>1 day after instillation of CNP, C3 mice exhibited a typical dose response, with the lowest dose (5 μg) representing the 'no effect level' as reflected by polymorphonuclear leucocyte (PMN), and BAL/lung concentrations of pro-inflammatory proteins. Histological analysis and BAL-protein concentration did not reveal any evidence of tissue injury in 20 μg CNP instilled animals. Accordingly time course assessment of the inflammatory response was performed after 3 and 7 days with this dose (20 μg). Compared to day 1, BAL PMN counts were significantly decreased at day 3 and completely returned to normal by day 7. We have identified protein markers related to the acute response and also to the time dependent response in lung and BAL. After complete resolution of PMN influx on day 7, we detected elevated concentrations of 20 markers that included IL1B, IL18, FGF2, EDN1, and VEGF in lung and/or BAL. Biological pathway analysis revealed these factors to be involved in a closely regulated molecular cascade with IL1B/IL18 as upstream and FGF2/EDN1/VEGF as downstream molecules.</p> <p>Conclusion</p> <p>Considering the role of VEGF, FGF2 and EDN1 in lung development and morphogenesis together with the lack of any evident tissue damage we suggest a protective/homeostatic machinery to be associated in lungs of stable organisms to counter the CNP challenge as a precautionary measure.</p

Assimilation of sea surface temperature, sea ice concentration and sea ice drift in a model of the Southern Ocean

Current ocean models have relatively large errors and biases in the Southern Ocean. The aim of this study is to provide a reanalysis from 1985 to 2006 assimilating sea surface temperature, sea ice concentration and sea ice drift. In the following it is also shown how surface winds in the Southern Ocean can be improved using sea ice drift estimated from infrared radiometers. Such satellite observations are available since the late seventies and have the potential to improve the wind forcing before more direct measurements of winds over the ocean are available using scatterometry in the late nineties. The model results are compared to the assimilated data and to independent measurements (the World Ocean Database 2009 and the mean dynamic topography based on observations). The overall improvement of the assimilation is quantified, in particular the impact of the assimilation on the representation of the polar front is discussed. Finally a method to identify model errors in the Antarctic sea ice area is proposed based on Model Output Statistics techniques using a series of potential predictors. This approach provides new directions for model improvements