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Ewing sarcoma has recently been reported to be sensitive to poly(ADP)-ribose polymerase (PARP) inhibitors. Searching for synergistic drug combinations, we tested several PARP inhibitors (talazoparib, niraparib, olaparib, veliparib) together with chemotherapeutics. Here, we report that PARP inhibitors synergize with temozolomide (TMZ) or SN-38 to induce apoptosis and also somewhat enhance the cytotoxicity of doxorubicin, etoposide, or ifosfamide, whereas actinomycin D and vincristine show little synergism. Furthermore, triple therapy of olaparib, TMZ, and SN-38 is significantly more effective compared with double or monotherapy. Mechanistic studies revealed that the mitochondrial pathway of apoptosis plays a critical role in mediating the synergy of PARP inhibition and TMZ. We show that subsequent to DNA damage-imposed checkpoint activation and G2 cell-cycle arrest, olaparib/TMZ cotreatment causes downregulation of the antiapoptotic protein MCL-1, followed by activation of the proapoptotic proteins BAX and BAK, mitochondrial outer membrane permeabilization (MOMP), activation of caspases, and caspase-dependent cell death. Overexpression of a nondegradable MCL-1 mutant or BCL-2, knockdown of NOXA or BAX and BAK, or the caspase inhibitor N-benzyloxycarbonyl-Val-Ala-Asp-fluoromethylketone (zVAD.fmk) all significantly reduce olaparib/TMZ-mediated apoptosis. These findings emphasize the role of PARP inhibitors for chemosensitization of Ewing sarcoma with important implications for further (pre)clinical studies. Mol Cancer Ther; 14(12); 2818–30. ©2015 AACR.

Cytotoxicity of PARP inhibitors and chemotherapeutics.

Olaparib/TMZ-induced G2 arrest.

Screening for synergistic drug interactions of PARP inhibitors and chemotherapeutic drugs.

Combination values of PARP inhibitors and chemotherapeutic drugs.

Olaparib synergizes with TMZ to induce cell death and to reduce viability in TC-32 and TC-71 cells.

Legends to supplemental Figures and Tables

Supplementary Table 1 from Lack of T-Cell Receptor–Induced Signaling Is Crucial for CD95 Ligand Up-regulation and Protects Cutaneous T-Cell Lymphoma Cells from Activation-Induced Cell Death

Summary:Stochastic origin activation gives rise to significant cell-to-cell variability in the pattern of genome replication. The molecular basis for heterogeneity in efficiency and timing of individual origins is a long-standing question. Here, we developedMethylationAccessibility ofTArgetedChromatin domain Sequencing (MATAC-Seq) to determine single-molecule chromatin accessibility of specific genomic loci after targeted purification in their native chromatin context. Applying MATAC-Seq to selected early-efficient (EE) and late-inefficient (LI) budding yeast replication origins revealed large heterogeneity of chromatin states. Disruption of INO80 or ISW2 chromatin remodeling complexes leads to changes at individual nucleosomal positions that correlate with changes in their replication efficiency. We found a chromatin state with an optimal 100-115bp nucleosome-free region in combination with surrounding well-positioned nucleosomes and open +2 linker region is a strong predictor for efficient origin activation. Thus, MATAC-Seq identifies the large spectrum of alternative chromatin states that co-exist on a given locus previously masked in population-based experiments and provides a mechanistic basis for origin activation heterogeneity during DNA replication of eukaryotic cells. Consequently, our single-molecule assay for chromatin accessibility will be ideal to define single-molecule heterogeneity across many fundamental biological processes such as transcription, replication, or DNA repairin vitroandex vivo.

SummaryShort tracts of trinucleotide repeats with less than 10 repeats are found frequently throughout the genome without any apparent negative impact on DNA replication fork progression or transcription elongation. CGG binding protein 1 (CGGBP1) binds to CGG triplet repeats and has been implicated in multiple cellular processes such as transcription, replication and DNA damage. Here, we show that CGGBP1 binds to human gene promoter sites prone to G-quadruplex and R-loop secondary structure formation. Altering CGGBP1 levels results in the accumulation of R-loops and causes a defect in transcriptional elongation by RNA polymerase II, which subsequently leads to replication fork stalling and transcription-replication conflicts. Together, our work shows that short trinucleotide repeats are a source of genome-destabilizing secondary structures and cells rely on specific DNA-binding factors to maintain proper transcription and replication progression at short trinucleotide repeats.

Objective Early decompression after acute spinal cord injury (SCI) is recommended. Acute care is crucial, but optimal management is unclear. The aim of this study was to investigate the role of preoperative magnetic resonance imaging (MRI) in addition to computed tomography (CT) in surgical decision making for acute cervical SCI. Methods All patients with cervical SCI between 2008 and 2016 who had preoperative CT and MRI (n = 63) at the Trauma Center Murnau, Germany, were included. We administered a survey to 10 experienced spine surgeons (5 neurosurgeons, 5 trauma surgeons) regarding the surgical management. First, the surgeons were shown clinical information and CT scans. Two months later, the survey was repeated with additional MRI. Corresponding percentages of change and agreement were obtained for each rater and survey item. Finally, results from both parts of the survey were compared with the definitive treatment option (i.e., real-world decision). Results MRI modified surgical timing in a median of 41% of patients (interquartile range 38%–56%). In almost every fifth patient (17%), no surgery would have been indicated with CT alone. The advocated surgical approach was changed in almost half of patients (median 48%, interquartile range 33%–49%). Surgically addressed levels were changed in a median of 57% of patients (interquartile range 56%–60%). MRI led to higher agreement with the real-world decision concerning addressed levels (median 35% vs. 73%), timing (median 51% vs. 57%), and approach (median 44% vs. 65%). Conclusions Preoperative MRI influenced surgical decision making substantially in our cohort and has become a new standard for patients with cervical SCI in our institution if medically possible.

Waste Heat Recovery at industrial processes becomes more and more important. The thermal profiles in these processes undergo high fluctuations, which pose a problem for downstream Organic Rankine Cycles. A possibility to cope with this circumstance is the implementation of storages or intermediate cycles, but in this paper, a different approach is followed. The ORC conditions should be kept constant by means of an adaptable turbine geometry. The present publication deals with the investigation of two different technologies to adjust the swallowing capacity of a cantilever ORC turbine - rotatable nozzle ring (RNR) and adjustable nozzle height (ANH). The considerations were performed on a reference turbine using pressurized air as working fluid. But a transfer of the findings to ORC application is reasonable. By performing comprehensive CFO analysis of the two technologies, the ANH technology was found to be superior. This is why a prototype of this technology was built and tested on a pressurized air test rig. Only small deteriorations of the total-to-static turbine efficiency at 50% design mass flow rate were observed. Based on this result, a ORC prototype of the ANH technology will be tested in future.

Background: Various methods exist for statistical inference about a prevalence that consider misclassifications due to an imperfect diagnostic test. However, traditional methods are known to suffer from censoring of the prevalence estimate and the confidence intervals constructed around the point estimate, as well as from under-performance of the confidence intervals' coverage. Methods: In this study, we used simulated data sets to validate a Bayesian prevalence estimation method and compare its performance to frequentist methods, i.e. the Rogan-Gladen estimate for prevalence, RGE, in combination with several methods of confidence interval construction. Our performance measures are (i) bias of the point estimate against the simulated true prevalence and (ii) coverage and length of the confidence interval, or credible interval in the case of the Bayesian method. Results: Across all data sets, the Bayesian point estimate and the RGE produced similar bias distributions with slight advanteges of the former over the latter. In addition, the Bayesian estimate did not suffer from the RGE's censoring problem at zero or unity. With respect to coverage performance of the confidence and credible intervals, all of the traditional frequentist methods exhibited strong under-coverage, whereas the Bayesian credible interval as well as a newly developed frequentist method by Lang and Reiczigel performed as desired, with the Bayesian method having a very slight advantage in terms of interval length. Conclusion: The Bayesian prevalence estimation method should be prefered over traditional frequentist methods. An acceptable alternative is to combine the Rogan-Gladen point estimate with the Lang-Reiczigel confidence interval.

The effect of low energy plasma immersion ion implantation and deposition of titanium on microstructure, defect structure and hydrogen trapping in zirconium alloy Zr-1Nb was studied. Defect structure and distribution were analyzed by Doppler broadening using slow positron beam. The surface microstructure after modification is represented by nanostructured Ti grains with random orientation. The gradient distribution of titanium as well as vacancy type defects were analyzed. The concentration of vacancy type defects is rising with increasing bias voltage. Gas-phase hydrogenation of the Ti-modified Zr-1Nb alloy was performed at 400 °C for 60 min. The strong interaction of hydrogen with vacancy type defects was demonstrated. Two different changes in the defect structure after hydrogenation were observed: when a titanium film is formed on the surface (after deposition at 500 V) hydrogen trapping occurs with the formation of titanium hydride phases, while in the implanted layer (deposition at 1000 and 1500 V) hydrogen is trapped due to interaction with vacancy type defects. The physical basis of Ti diffusion and its influence on the evolution of defect structure after surface modification and hydrogenation were discussed.

Solid electrolytes are the core components for many next generation lithium battery concepts such as all-solid-state batteries (ASSB) or batteries based on metallic lithium anodes protected by a ceramic or composite passivation layer. Therefore, the search for new solid state Li-ion conductors with superior properties and improved electrochemical stabilities remains of high interest. In this work, the synthesis of a new class of silicon-containing, sulfide-based lithium-ion conductors is reported. Very good conductivities of up to ∼2.0–3.0·10 −3 S/cm could be achieved for compositions such as Li 22 SiP 2 S 18 , among the highest for silicon sulfide containing materials. Based on the recorded powder XRD diffraction patterns and simulations it could be confirmed that they constitute novel members of the argyrodite family of sulfide lithium-ion conductors. The cubic high-temperature modification of such argyrodites with high lithium-ion conductivity can therefore be stabilized by implementation of silicon into the lattice, while additional doping with halogen atoms is not necessary.

Purpose To systematically evaluate image characteristics of simultaneous-multislice (SMS)-accelerated diffusion-weighted imaging (DWI) of the liver using different breathing schemes in comparison to standard sequences. Materials and Methods DWI of the liver was performed in 10 healthy volunteers and 12 patients at 1.5T using an SMS-accelerated echo planar imaging sequence performed with respiratory-triggering and free breathing (SMS-RT, SMS-FB). Standard DWI sequences served as reference (STD-RT, STD-FB). Reduction of scan time by SMS-acceleration was measured. Image characteristics of SMS-DWI and STD-DWI with both breathing schemes were analyzed quantitatively (apparent diffusion coefficient [ADC], signal-to-noise ratio [SNR]) and qualitatively (5-point Likert scale, 5 = excellent). Qualitative and quantitative parameters were compared using Friedman test and Dunn-Bonferroni post-hoc method with P-values < 0.05 considered statistically significant. Results SMS-DWI provided diagnostic image quality in volunteers and patients both with RT and FB with a reduction of scan time of 70% (0:56 vs. 3:20 min in FB). Overall image quality did not significantly differ between FB and RT acquisition in both STD and SMS sequences (median STD-RT 5.0, STD-FB 4.5, SMS-RT: 4.75; SMS-FB: 4.5; P = 0.294). SNR in the right hepatic lobe was comparable between the four tested sequences. ADC values were significantly lower in SMS-DWI compared to STD-DWI irrespective of the breathing scheme (1.2 ± 0.2 × 10-3 mm2/s vs. 1.0 ± 0.2 × 10-3 mm2/s; P < 0.001). Conclusion SMS-acceleration provides considerable scan time reduction for hepatic DWI with equivalent image quality compared to the STD technique both using RT and FB. Discrepancies in ADC between STD-DWI and SMS-DWI need to be considered when transferring the SMS technique to clinical routine reading. J. MAGN. RESON. IMAGING 2016;44:865–879.

The conjugacy problem asks whether two words over generators of a fixed group G are conjugated, i.e., it is the problem to decide on input words x, y whether there exists z such that $$zx z^{-1} =y$$zxz-1=y in G. The conjugacy problem is more difficult than the word problem, in general. We investigate the conjugacy problem for two prominent groups: the Baumslag---Solitar group $$\mathbf{{BS}}_{1,2}$$BS1,2 and the Baumslag group $${\mathbf{{G}}}_{1,2}$$G1,2 (also known as Baumslag---Gersten group). The conjugacy problem in $${\mathbf{{BS}}}_{1,2}$$BS1,2 is complete for the circuit class $$\mathsf {TC}^0$$TC0. To the best of our knowledge $${\mathbf{{BS}}}_{1,2}$$BS1,2 is the first natural infinite non-commutative group where such a precise and low complexity is shown. The Baumslag group $${\mathbf{{G}}}_{1,2}$$G1,2 is an HNN-extension of $${\mathbf{{BS}}}_{1,2}$$BS1,2. Hence, decidability of the conjugacy problem in $$\mathbf{{G}}_{1,2}$$G1,2 outside the so-called "black hole" follows from Borovik et al. (Int J Algebra Comput 17(5/6):963---997, 2007). Decidability everywhere is due to Beese. Moreover, he showed exponential time for the set of elements which cannot be conjugated into $$\mathbf{{BS}}_{1,2}$$BS1,2 (Beese 2012). Here we improve Beese's result in two directions by showing that the conjugacy problem in $${\mathbf{{G}}}_{1,2}$$G1,2 can be solved in polynomial time in a strongly generic setting. This means that essentially for all inputs, conjugacy in $${\mathbf{{G}}}_{1,2}$$G1,2 can be decided efficiently. In contrast, we show that under a plausible assumption the average case complexity of the same problem is non-elementary. Moreover, we provide a lower bound for the conjugacy problem in $${\mathbf{{G}}}_{1,2}$$G1,2 by reducing the divisibility problem in power circuits to the conjugacy problem in $${\mathbf{{G}}}_{1,2}$$G1,2. The complexity of the divisibility problem in power circuits is an open and interesting problem in integer arithmetic. We conjecture that it cannot be solved in elementary time because we can show that it cannot be solved in elementary time by calculating modulo values in power circuits.

Ewing sarcoma has recently been reported to be sensitive to poly(ADP)-ribose polymerase (PARP) inhibitors. Searching for synergistic drug combinations, we tested several PARP inhibitors (talazoparib, niraparib, olaparib, veliparib) together with chemotherapeutics. Here, we report that PARP inhibitors synergize with temozolomide (TMZ) or SN-38 to induce apoptosis and also somewhat enhance the cytotoxicity of doxorubicin, etoposide, or ifosfamide, whereas actinomycin D and vincristine show little synergism. Furthermore, triple therapy of olaparib, TMZ, and SN-38 is significantly more effective compared with double or monotherapy. Mechanistic studies revealed that the mitochondrial pathway of apoptosis plays a critical role in mediating the synergy of PARP inhibition and TMZ. We show that subsequent to DNA damage-imposed checkpoint activation and G2 cell-cycle arrest, olaparib/TMZ cotreatment causes downregulation of the antiapoptotic protein MCL-1, followed by activation of the proapoptotic proteins BAX and BAK, mitochondrial outer membrane permeabilization (MOMP), activation of caspases, and caspase-dependent cell death. Overexpression of a nondegradable MCL-1 mutant or BCL-2, knockdown of NOXA or BAX and BAK, or the caspase inhibitor N-benzyloxycarbonyl-Val-Ala-Asp-fluoromethylketone (zVAD.fmk) all significantly reduce olaparib/TMZ-mediated apoptosis. These findings emphasize the role of PARP inhibitors for chemosensitization of Ewing sarcoma with important implications for further (pre)clinical studies. Mol Cancer Ther; 14(12); 2818–30. ©2015 AACR.

QuickHeapsort is a combination of Quicksort and Heapsort. We show that the expected number of comparisons for QuickHeapsort is always better than for Quicksort if a usual median-of-constant strategy is used for choosing pivot elements. In order to obtain the result we present a new analysis for QuickHeapsort splitting it into the analysis of the partition-phases and the analysis of the heap-phases. This enables us to consider samples of non-constant size for the pivot selection and leads to better theoretical bounds for the algorithm. Furthermore, we introduce some modifications of QuickHeapsort. We show that for every input the expected number of comparisons is at most nlog2nź0.03n+o(n)$n\log _{2}n - 0.03n + o(n)$ for the in-place variant. If we allow n extra bits, then we can lower the bound to nlog2nź0.997n+o(n)$ n\log _{2} n -0.997 n+ o (n)$. Thus, spending n extra bits we can save more that 0.96n comparisons if n is large enough. Both estimates improve the previously known results. Moreover, our non-in-place variant does essentially use the same number of comparisons as index based Heapsort variants and Relaxed-Weak-Heapsort which use nlog2nź0.9n+o(n)$ n\log _{2}n -0.9 n+ o (n)$ comparisons in the worst case. However, index based Heapsort variants and Relaxed-Weak-Heapsort require ź(nlogn)${\Theta }(n\log n)$ extra bits whereas we need n bits only. Our theoretical results are upper bounds and valid for every input. Our computer experiments show that the gap between our bounds and the actual values on random inputs is small. Moreover, the computer experiments establish QuickHeapsort as competitive with Quicksort in terms of running time.

Current systems for enacting scientific experiments, and simulation workflows in particular, do not support multi-scale and multi-field problems if they are not coupled on the level of the mathematical model. To address this deficiency, we present an approach enabling the trial-and-error modeling and execution of multi-scale and/or multi-field simulations in a top-down and bottom-up manner which is based on the notion of choreographies. The approach defines techniques for composing data-intensive, scientific workflows in more complex simulations in a generic, domain-independent way and thus provides means for collaborative and integrated data management using the workflow/process-based paradigm. We contribute a life cycle definition of such simulations and present in detail concepts and techniques that support all life cycle phases. Furthermore, requirements on a respective software system and choreography language supporting multi-scale and/or multi-field simulations are identified, and an architecture and its realization are presented.

This article considers the modeling of count data time series with a finite range having extra-binomial variation. We propose a beta-binomial autoregressive model using the concept of random coefficient thinning. We discuss the stationarity conditions, derive the moments and autocovariance function and consider approaches for parameter estimation. Furthermore, we develop two new tests for detecting extra-binomial variation, and we derive the asymptotic distributions of the test statistics under the null hypothesis of a binomial autoregressive model. The size and power performance of the two tests are analyzed under various alternatives taken from a beta-binomial autoregressive model with Monte Carlo experiments. The article ends with a real-data example about the Harmonised Index of Consumer Prices of the European Union. Copyright © 2013 John Wiley & Sons, Ltd.

The aim of this study was to evaluate whether a computer-based 3-item version (Alcohol Use Disorders Identification Test–Consumption [AUDIT-C]) of the Alcohol Use Disorders Identification Test (AUDIT) identifies alcohol use disorder (AUD) in the same patients as the full 10-item version in 809 women and 747 men in an anesthesiology preoperative assessment clinic. According to cutoffs used (AUDIT: 5–8 points, AUDIT-C: 4–6 points), rate of disagreement (AUDIT-positive and AUDIT-C-negative or vice versa) ranged between 4% and 31% (men) and between 4% and 19% (women). In male patients, 15% were positive for both the AUDIT (≥8 points) and the AUDIT-C (≥6 points), 7% were positive for AUDIT-C only, and 4% were positive for AUDIT only. In female patients, using cutoffs of 5 more points (AUDIT) and 4 or more points (AUDIT-C), 16% were positive for both versions, 9% were positive for AUDIT-C only, and 2% were positive for AUDIT only. The AUDIT and AUDIT-C seem to identify AUD in differing patients.

Procedures for continuously monitoring binary attribute data processes are of utmost relevance for fields like electrical engineering, chemical production, software quality engineering, healthcare monitoring, and many more. In this article, new approaches are proposed, where kth order runs in a binary process are monitored. We derive methods for evaluating the performance of the new control charts, discuss computational issues of these methods and give design recommendations for the control charts. A real-data example demonstrates the successful application of the new control procedures.

The purpose of this study was to determine the diagnostic power of a newly available assay for amino-terminal pro-brain natriuretic peptide (NT-proBNP) to identify patients with acute heart failure. In addition, the influence of initial NT-proBNP measurements on economic consequences, diagnostic procedures and staff involvement was evaluated.401 patients presenting with acute dyspnea or peripheral edema in the emergency department were enrolled. NT-proBNP was measured after initial clinical evaluation. Clinical routine care and diagnostic assessment were blinded to NT-proBNP results. Two cardiologists independently validated the period of hospitalization, clinical examinations and medical therapies of each patient considering NT-proBNP results. The median NT-proBNP level among patients with acute congestive heart failure (CHF) (n=122) was 3497 pg/ml as compared to 320 pg/ml in patients without (n=279) (p0.0001). An NT-proBNP cutoff level300 pg/ml was optimal to rule out acute CHF (negative predictive value 96%; sensitivity 96%). NT-proBNPor=300 pg/ml could strongly predict acute CHF when compared to patients' history or physical examination (odds ratio 9.5; p0.0001) and diagnostic technical findings (odds ratio 14.7; p0.05). In patients with NT-proBNP300 pg/ml, 14% of the period of hospitalization could be saved, corresponding to savings of US $481 per patient. In addition, 9% of the number and time of staff involvement of clinical examinations and therapies could be saved, 10% of the costs of clinical examinations. Chest X-rays were saved in 34%, echocardiography in 9%.Measurement of NT-proBNP leads to multiple saving amounts and optimizes diagnostic pathways and resource allocation.

River/floodplain restoration programs are often based on type-specific reference conditions of the respective river section. Most large rivers in the industrialized world are heavily degraded and lack near-natural reference sites. For that reason, historical analyses of the pre-channelization state have been used to define adequate restoration targets at the Austrian Danube section in the Alluvial Zone National Park downstream from Vienna. This study compares new reference data derived from 3D-reconstructions in the form of digital terrain models from two historical Danube river landscapes: the Machland floodplain in 1812 and the former floodplain in Vienna in 1849. The focus is on the original hydrological surface and subsurface connectivity of the river-floodplain systems related to different flow situations. Here, we use water cover, shorelines, depth of the groundwater table and inundation depth as surrogates for measuring connectivity. The results show that the two study sites naturally constituted extreme formations of the Austrian anabranching Danube sections. The Machland section was one of the narrowest floodplains but highly dynamic, and the Vienna/Lobau section was one of the broadest, whereby only the central part close to the main channel originally showed high morphological turnover. The analyses of hydrological surface connectivity relative to total floodplain extension reveal significant differences due to their basic geological and geographical conditions. Despite these basic differences, both study sites – in absolute numbers – showed similar extensions of the water bodies at low and mean flow. The depths of the groundwater table related to mean flow were also comparable. Prior to channelization, the groundwater conditions in both floodplains favored the formation of wet to moist alluvial forest communities. Up until today, the two river landscapes continue to undergo different developments: both river sections are impounded, but the Machland floodplain still represents a rural site while the Vienna site has been utilized more intensively as building land and for urban infrastructure. As a consequence of the diverse human interventions in the 19th and 20th century, river bed degradation and aggradation of sediments in the floodplains have significantly truncated fluvial dynamics and hydrological connectivity. In addition, these phenomena have substantially deepened the groundwater table in both study sites. The results contribute to the identification of river/floodplain-type-specific reference conditions and provide an additional decision basis for discussing appropriate management strategies in the degraded riverine ecosystems.

Insufficiently protected mobile devices present a ubiquitous threat. Due to severe hardware constraints, such as limited printed circuit board area, hardware-based security as proposed by the Trusted Computing Group is usually not part of mobile devices, yet. We present the design and implementation of seTPM, a secure element based TPM, utilizing Java Card technology. seTPM establishes trust in mobile devices by enabling Trusted Computing based integrity measurement services, such as IMA for Linux. Our prototype emulates TPM functionality on a GlobalPlatform secure element, which allows seamless integration into the Trusted Software Stack of Linux-based mobile operating systems like Android. With our work, we provide a solution to run Trusted Computing based security protocols while supplying a similar security level as provided by hardware TPM chips. In addition, due to the flexible design of the seTPM, we further increase the security level as we are able to selectively replace the outdated SHA-1 hash algorithm of TPM 1.2 specification by the present Keccak algorithm. Further, our architecture comprises hybrid support for the TPM 1.2 and TPM 2.0 specifications to simplify the transition towards the TPM 2.0 standard.

This article utilizes stochastic ideas for reasoning about association rule mining, and provides a formal statistical view of this discipline. A simple stochastic model is proposed, based on which support and confidence are reasonable estimates for certain probabilities of the model. Statistical properties of the corresponding estimators, like moments and confidence intervals, are derived, and items and itemsets are observed for correlations. After a brief review of measures of interest of association rules, with the main focus on interestingness measures motivated by statistical principles, two new measures are described. These measures, called ?- and ?-precision, respectively, rely on statistical properties of the estimators discussed before. Experimental results demonstrate the effectivity of both measures.

Many methods for the identification of key variables in movement patterns have the problem that direct transferability back to coaches or players is not easy; this is because the variables used are not presented in the language of most sport participants. Using a research strategy—from the coaches back to the coaches—proposed by Roth (1996), this study tries to identify discriminative variables by an expert rating. The statistical problem was to analyze the reliability between three coaches. A new, weighted Kappa coefficient for multiple observers is introduced as an extension of what Fleiss proposed in 1971, which takes into account the different types of disagreement. It is concluded that the high variability among different variables´ reliability can be considered as a measurement of the difficulty for the expert ratings. The results also indicate that simple movement features could be identified and transferred as instructions for goalkeepers back to the coaches.

To systematically evaluate image characteristics of simultaneous-multislice (SMS)-accelerated diffusion-weighted imaging (DWI) of the liver using different breathing schemes in comparison to standard sequences.DWI of the liver was performed in 10 healthy volunteers and 12 patients at 1.5T using an SMS-accelerated echo planar imaging sequence performed with respiratory-triggering and free breathing (SMS-RT, SMS-FB). Standard DWI sequences served as reference (STD-RT, STD-FB). Reduction of scan time by SMS-acceleration was measured. Image characteristics of SMS-DWI and STD-DWI with both breathing schemes were analyzed quantitatively (apparent diffusion coefficient [ADC], signal-to-noise ratio [SNR]) and qualitatively (5-point Likert scale, 5 = excellent). Qualitative and quantitative parameters were compared using Friedman test and Dunn-Bonferroni post-hoc method with P-values0.05 considered statistically significant.SMS-DWI provided diagnostic image quality in volunteers and patients both with RT and FB with a reduction of scan time of 70% (0:56 vs. 3:20 min in FB). Overall image quality did not significantly differ between FB and RT acquisition in both STD and SMS sequences (median STD-RT 5.0, STD-FB 4.5, SMS-RT: 4.75; SMS-FB: 4.5; P = 0.294). SNR in the right hepatic lobe was comparable between the four tested sequences. ADC values were significantly lower in SMS-DWI compared to STD-DWI irrespective of the breathing scheme (1.2 ± 0.2 × 10(-3) mm(2) /s vs. 1.0 ± 0.2 × 10(-3) mm(2) /s; P0.001).SMS-acceleration provides considerable scan time reduction for hepatic DWI with equivalent image quality compared to the STD technique both using RT and FB. Discrepancies in ADC between STD-DWI and SMS-DWI need to be considered when transferring the SMS technique to clinical routine reading. J. MAGN. RESON. IMAGING 2016;44:865-879.

Background The immunosuppressant cyclosporin A has been used with success in the treatment of chronic plaque-type psoriasis; little is known about its effect on palmoplantar psoriasis. Subjects and methods Thirty-three patients (12 women, 21 men; mean age = 44.2 years, range 22-68 years) with palmoplantar psoriasis were treated with oral cyclosporin A, (CyA), 2.5 mg/kg/day, which could be increased to 5 mg/kg/day, for 12 weeks. Patients were followed up for a further 4 weeks without CyA treatment. A total of 26 patients completed the 12-week treatment course, an additional six patients were followed up during 4 weeks after premature withdrawal. Efficacy was assessed by calculating the Psoriasis Area and Severity Index (PASl). a Local Psoriasis Severity Index (LPS1), and estimation of the area involved. Results Clinical response, being defined as at least 50% reduction of these parameters at the end of the therapeutic phase compared to baseline before treatment, was reached in 84% of the patients; 61% of the patients showed clinical response after only 6 weeks of treatment. No signs of severe hepatic or renal toxicity were noted during the study period; mild hypertension, which developed in one case, resolved after termination of the treatment. Relapses after treatment never reached the pretreatment baseline levels. Conclusions It is concluded that palmoplantar psoriasis can be treated effectively and safely with oral CyA at the low-dose range of 2.5-5 mg/kg/day. The results demonstrate the necessity for evaluation of a maintenance treatment in this special form of psoriasis, the doses and safety of which remain to be determined in future controlled clinical trials.

The simple-septate basidiomycetes comprise more than 8,000 species that show a high morphological and ecological heterogeneity. To gain insight in the phylogenetic relationships within this group, we compared several ultrastructural features such as septal pore apparatus, form, and behavior of the spindle pole bodies, types of host–parasite interaction, presence or absence of colacosomes, symplechosomes, atractosomes, and cystosomes as well as nuclear rDNA sequences coding for small- and large-subunit rRNA. Based on our integrated analysis, we propose a new classification system for the simple-septate basidiomycetes with the subphylum Pucciniomycotina and the classes Agaricostilbomycetes, Atractiellomycetes, Classiculomycetes, Cryptomycocolacomycetes, Cystobasidiomycetes, Microbotryomycetes, Mixiomycetes, and Pucciniomycetes. We also propose the pucciniomycotinous taxa Cystobasidiales, Erythrobasidiales, Helicobasidiales, Mixiales, Naohideales, Pachnocybales, Spiculogloeales, and Kondoaceae and the new subphyla Agaricomycotina (equivalent to the current Hymenomycetes) and Ustilaginomycotina (equivalent to the current Ustilaginomycetes).

Bonds governed under German law would normally not contain collective action clauses, ie provisions dealing with majority decisions by bondholders by which certain bond terms may be altered or waived. This is because it is uncertain whether, in the absence of a statutory basis, a decision taken by a majority of bondholders would be binding upon a dissenting minority. For certain circumstances, however, a statutory basis exists in the form of a law enacted in 1899 which, during the last decades, has been very rarely used. This paper discusses in what cases the law may be invoked, what decisions can be made by bondholders and what procedural requirements must be observed for getting to a binding and unchallengeable decision.

Virtualization has become one of the most important security enhancing techniques for embedded systems during the last years, both for mobile devices and cyber-physical system CPS. One of the major security threats in this context is posed by side channel attacks. In this work, Bernstein's time-driven cache-based attack against AES is revisited in a virtualization scenario based on an actual CPS using the PikeOS microkernel virtualization framework. The attack is conducted in the context of the implemented virtualization scenario using different scheduler configurations. We provide experimental results which show that using dedicated cores for crypto routines will have a high impact on the vulnerability of such systems. We also compare the results to previous work in that field and our visualization directly shows the differences between cache architectures of the ARM Cortex-A8 and Cortex-A9. Further, a non-invasive countermeasure against timing attacks based on the scheduler of PikeOS is devised, which in fact increases the system's security against cache timing attacks.

Scientists that use the workflow paradigm for the enactment of scientific experiments need support for trial-and-error modeling, as well as flexibility mechanisms that enable the ad hoc repetition of workflow logic for the convergence of results or error handling. Towards this goal, in this paper we introduce the facilities to repeat partially or completely running choreographies on demand. Choreographies are interesting for the scientific workflow community because so-called multi-scale/field multi-* experiments can be modeled and enacted as choreographies of scientific workflows. A prerequisite for choreography repetition is the rewinding of the involved participant instances to a previous state. For this purpose, we define a formal model representing choreography models and their instances as well as a concept to repeat choreography logic. Furthermore, we provide an algorithm for determining the rewinding points in each involved participant instance.

Starting from Marco Conci's presentation of the personal letters between Bion and Rickman, this paper tries to explore possible links between Rickman's and Bion's thinking that go beyond both authors’ interest in group dynamics in the 1940s. Such links can be seen in the psychodynamic of psychosis, the theory of institutions/organizations, the concept of containment, the role of the here-and-now, and the analyst's attitude of receptiveness. Discussing these areas, the author supposes that Rickman's personality and style of thinking may have had a longer lasting influence on Bion's work.

An Elastomerbauteile werden immer hohere Anforderungen bezuglich Funktionalitat und Lebensdauer gestellt. Daher wird in modernen Entwicklungsstrukturen der Berechnungs-Ingenieur verstarkt in die Bauteilentwicklung einbezogen. Mit numerischen Methoden wird die Bauteilauslegung hoch effektiv. Allerdings ist der Aufwand, der bei der numerischen Analyse von Elastomerbauteilen betrieben werden muss, wesentlich hoher als bei Metallen, denn in aller Regel liegen neben dem nichtlinearen Werkstoffverhalten auch geometrische Nichtlinearitaten vor. Freudenberg hat dennoch auch fur Elastomerbauteile moderne Berechnungs- und Simulationswerkzeuge entwickelt.

Die Berichterstattung der deutschen Medien uber den Irak-Krieg im Fruhjahr 2003 loste eine breite mediale Selbstreolexion journalistischer Qualitatsstandards aus, die insbesondere auo das Fernsehen ookussiert war (ugl. Eilders 2005a, 2005b; Vogele 2004). Eines der zentralen Themen der Medienkritik war die Erorterung der Parteilichkeit und mangelnden Objektiuitat der Kriegsberichterstattung. Bezogen auo die deutschen Medien wurde der Vorwuro oormuliert, die Berichterstattung uber den Irak-Krieg wurde sich einseitig gegen die USA richten: „Die deutschen Medien haben die amerikanischen Militaraktionen im Irak in den uergangenen Wochen besonders kritisch begleitet, wahrend der Terror des irakischen Diktators Saddam Hussein our sie kaum ein Thema war.“2 Die empirische Auotragsstudie, die dieser exemplarischen Medienkritik der Frankourter Allgemeinen Zeitung (FAZ) zugrunde lag, untersuchte allerdings nicht „die deutschen Medien“, sondern lediglich die Berichterstattung der Hauptnachrichtensendungen von ARD, ZDF und RTL.3 Der Intendant des our die Kriegsberichterstattung im Ersten Programm der ARD zustandigen Sudwestrundounks, Peter Vos, kritisierte die eigenen Journalistinnen und Journalisten mit den Worten: „bei einigen Sendungen konnte man wohl eher den Eindruck haben, im Hinblick auo das amerikanische Vorgehen werde stets die negativste Interpretationsvariante gewahlt.

The evaporation process of zirconia powders injected in a thermal RF plasma is investigated. Both model calculations and experimental techniques such as Optical Emission Spectroscopy (OES) and Laser Doppler Anemometry (LDA) are used to study the evaporation behaviour. Gas temperatures and velocity distributions are determined numerically from conservation laws and Maxwell equations. The influence of plasma and particle parameters on the thermal interaction of injected particles is discussed. Asymmetric Abel inversion is applied to detect asymmetric emission profiles in the plasma source. Spectroscopic measurements reveal that evaporated zirconia is concentrated near the axis of the plasma. Numerical calculations show that line-integrated emission profiles can be used to distinguish the cases of complete and incomplete evaporation. LDA measurements of the particle velocity distribution show good agreement with the results achieved with modelling.

Siemens Corporate Technology has developed a methodology for formal verification. This methodology allows to prove or falsify the correctness of programs for a PLC (programmable logical controller) fully automatically and exactly in a strongly mathematical sense. A program is correct, if eveiy possible execution trace of the program fulfils a set of required properties specified by the user. For instance, a property for a traffic light control at some given intersection could be 'traffic lights never all show green at the same time' or 'when a car stops at a red traffic light that traffic light will eventually switch to green'. For this verification method a tool has been developed that checks properties fully automatically and completely. In case a given property is not satisfied by the PLC-program, the verification tool generates an execution trace of the program (a so-called countersequence) that illustrates its erroneous behaviour. In a pilot application, tool machine manufacturers used and evaluated the verification tool with respect to specification, error detection, cost/benefit-estimation and other criteria for verification. The verification tool was received very well.

We demonstrate a selective deposition of ultrathin gold layers via OMCVD (organometallic chemical vapor deposition) onto self-assembled dithiols. Dithiols have been self-assembled to produce a thiolated surface. The gold layer deposited from a gold precursor, present in the vapor around the sample, is bound to the exposed thiol groups. We demonstrate that it is possible to deposit gold only onto the areas where the binding thiol groups are located, and investigate the growth process with spontaneous desorption time-of-flight mass spectrometry, Rutherford backscattering spectroscopy, atomic absorption spectroscopy and atomic force microscopy.

Nanophase composites based on Zr-and Mg-base easy glass forming alloys were prepared by partial crystallization of melt-quenched amorphous alloys or by mechanical alloying of elemental powder mixtures blended with oxide particles. The amorphous phases exhibit a wide supercooled liquid region before crystallization, even in the presence of second phase particles. This allows an easy consolidation of powders or shaping of bulk samples due to viscous flow. Room temperature mechanical properties will be presented and discussed with respect to the potential of the nanoscale microstructure for mechanical strengthening.

For the first time large single-crystals of taranakite K3Al5(HPO4)6(PO4)2·18H2O were grown by gel crystallization. An X-ray structure determination showed taranakite to be the mineral with the longest crystallographic axis described hitherto. X-ray crystal data are: space group R3c, a = 870.25 (11), c = 9505(1)_pm, Z = 6, Rg = 0.028. A neutron scattering experiment with subsequent Rietveld refinement of the powder pattern of deuterated taranakite elucidated the D-atom positions. Neutron crystal data are: a=868.82(3), c=9498(2) pm, Rwp=0.061. Taranakite is a layer structure mineral having six layers of composition [K3Al5(HPO4)6(PO4)2(H2O)12] separated from each other by water layers. The rigid layer is formed by columns of corner sharing hydrogen phosphate tetrahedra and Al octahedra which are interconnected by additional six-coordinated Al ions. In trigonal holes of the layer orthophosphate ions are situated. Non-exchangeable K ions are trapped within the layers. Hydrogen bonds in taranakite are formed between building units within the rigid layer, within the water interlayer, and between layer and interlayer. Similarities and differences between the coordination of interlayer water in taranakite and ice Ih are discussed. 31P solid-state MAS NMR spectra show two isotropic lines at σ180 = −17.2 and 5.2 ppm. The intensity ratio 3:1 of the two sideband systems corresponds to the molar ratio of HPO42− and PO43− units in the structure of taranakite. The P(1) atom of hydrogen phosphate has a larger anisotropy in agreement with the more different PO bond lengths of HPO42− compared to PO43−. The 31P nuclear magnetic shielding tensor of HPO42− is characterized by larger shielding values σ22 and σ33.

Pure cobalt indium alloy thin films of the nominal compositions Co0.50In0.50, Co0.66In0.33 and Co0.75In0.25 were grown by OMCVD using volatile organometallic precursors of the general formula [( CO ) 4 Co ] a - InR 3-a [ R = CH 2 CH 2 CH 2 N ( CH 3 ) 2 ; 1 : a = 1 ; 2 : a = 2 ; 3 : a = 3] . These organometallic compounds contain direct CoIn bonds and allow molecular control of the metal ratio of the grown films. The distribution of the metals were uniform throughout the films. The films were examined by AES depth profiling, SEM-EDX and X-ray diffraction. The phase composition of the films follows the phase diagram of the Co/In system, e.g. reflections of the crystalline phase Co, CoIn2 and CoIn3 were detected. Due to the multi-phase nature of the films, the coatings were unstable with respect to interfacial reactions with InP, e.g. the formation of CoP was observed by X-ray diffraction.

Treatment of Cp * Fe(dppe)C ≡ CH (dppe = Ph2PCH2CH2PPh2), 1, with an equimolar quantity of t-BuLi or with 2.5 equivalents of MeLi, followed by addition of ClPPh2, yielded Cp * Fe(dppe)C ≡ CPPh2, 2. With excess t- or n-BuLi, the ethylene bridge of the dppe ligand in 1 was also metallated, and further reaction with ClPPh2 resulted in Cp * Fe(tppe)C ≡ CPPh2 (tppe = Ph2PCH(PPh2)CH2PPh2), 3. Quaternization of 3 by Mel smoothly produced the phosphoniumethynyl derivative [Cp * Fe(tppe)C ≡ CPPh2me]I, 4. Reactions of cis-Ru(dppm)2Cl2 (dppm = Ph2PCH2PPh2) with LiC ≡ CC ≡ CSiMe3, in situ generated from Me3SiC ≡ CC ≡ CSiMe3 and MeLi/LiBr in THF, gave cis-Ru(dppm)2(C ≡ CC ≡ CSiMe3)2, 5, trans-Ru(dppm)2(C ≡ CC ≡ CSiMe3)2, 6, and trans-Ru(dppm)2(Cl)C ≡ CC ≡ CSiMe3, 7, depending on the solvent (ether or THF) and the molar ratios of the reactants. According to an X-ray structure analysis, the ethynyl ligand of 1 is structurally characterized by d(Fe-C), 1.876(13) and d(C ≡ C), 1.206(15) A, the value of the angle Fe-C≡C being 176.3(11)°.

To investigate the performance of microengineered fluid channels in liquid dosing applications, flow-rate measurements have been performed with various channel geometries in a range from 0.01 to 1000 μl min -1 . An optical flow-measurement technique has been developed to enhance the measurement range into the desired low flow range (10 -3 to 1 μl min -1 ), and is compared to a standard gravimetric method, which is preferably used for flow rates above 1 μl min -1 . In addition, influences of the temperture-dependent viscosity and effects arising from fluidmechanical characteristics are studied. These influences are also calculated from laminar flow theory and semi-emprical models to obtain a theoretical model. It is found that the theoretical model is able to describe the measurement results well in the whole flow range. The model is implemented on a PC-based system, which measures the pressure drop across the microchannel and the fluid temperature and calculates the flow. In a temperature range from 20 to 50°C excellent agreement is found.

Treatment of Cp * RuL 2 Cl (Cp * = C 5 Me 5 ; L = PPh 3 , PMe 3 ) with Me 3 SiC≡CH in the presence of NH 4 [PF 6 ] in CH 2 Cl 2 yielded the expected vinylidene compounds [Cp * RuL 2 =C=CH 2 ][PF 6 ] with L = PPh 3 ( 1 ) and PMe 3 ( 1a ), which were deprotonated by KOBu t in THF to give the corresponding ethynyl complexes Cp * Ru(PPh 3 ) 2 C≡CH ( 2 ) and Cp * Ru(PMe 3 ) 2 C≡CH ( 2a ). Metalation of 2 using n -BuLi or t -BuLi in THF—hexane, followed by reaction of the lithio intermediate Cp * Ru(PPh 3 ) 2 C≡CLi with ClER 3 (E = Si, Ge, Sn) or ClPR 2 , resulted in the formation of substituted derivatives, Cp * Ru(PPh 3 ) 2 C≡CER 3 [ER 3 = SiMe 3 ( 3 ), GeMe 3 ( 4 ), SnBu 3 n ( 5 )] and Cp * Ru(PPh 3 ) 2 C≡CPR 2 [PR 2 = PPh 2 ( 6 ), PBu 2 t ( 7 )] respectively. Quatemization of 6 and 7 by alkyl iodides in toluene smoothly produced phosphonioethynyl complexes, [Cp * Ru(PPh 3 ) 2 C≡CPR 2 R′]I [PR 2 R′ = PPh 2 Me ( 8 ), PBu 2 t Me ( 9 ), PPh 2 Pr n ( 10 ), PBu 2 t Pr n ( 11 )], the cations of which may be regarded as donor/acceptor-stabilized derivatives of dicarbon, C 2 .

Pakaraimaea dipterocarpacea, a member of the Dipterocarpaceae endemic in the Guayana region, is associated with a diverse community of ectomycorrhizal (ECM) fungi. Amongst the 41 ECM fungal species detected in a 400 m2 P. dipterocarpacea ssp. nitida plot in Southern Venezuela, three species belonged to the Sebacinales. We tested whether ECM anatomotype characterization can be used as a feasible element in an integrative taxonomy in this diverse fungal group, where the relevance of fruitbody morphology for species delimitation seems limited. Using a combination of ECM morpho-anatomical characterizations and phylogenetic analyses based on nuclear ITS and LSU sequences, we report three new species. The main distinguishing features of Sebacina guayanensis are the yellowish cell walls together with conspicuous undifferentiated, uniform compact (type B) rhizomorphs. Staghorn-like hyphae are characteristic of S. tomentosa. The combination of clusters of thick-walled emanating hyphae, including hyphae similar to awl-shaped cystidia with basal dichotomous or trichotomous ramifications, and the presence of type B rhizomorphs were characteristic of a third, yet unnamed species. The three species belong to three different, possibly specifically tropical clades in Sebacinales Group A. The geographic distribution of phylogenetically related strains was wide, including a Dicymbe forest in Guyana and an Ecuadorian rainforest with Coccoloba species. We show that ECM morpho-anatomy can be used, in combination with other analyses, to delineate species within Sebacinales Group A. In addition to phylogenetic information, type B rhizomorphs observed in different Sebacinales clades have important ecological implications for this fungal group. The phylogeography of Sebacinales suggests that dispersion and host jump are important radiation mechanisms that shaped P. dipterocarpacea ECM fungal community. This study emphasizes the need for more sequence data to evaluate the hypothesis that phylogeographic relationships between neo- and paleotropical ECM fungal species could be attributed to the vicariance of cross-continental hosts such as the Dipterocarpacae.

Irradiation scenarios were simulated in order to evaluate different technology and design options for silicon strip detectors exposed to a high luminosity environment. Two-dimensional process and device simulations were performed to get an insight into the device behaviour. The boundary condition of the free oxide regions between the strips was evaluated thoroughly to obtain correct field distributions. Using these results the formation of electron accumulation layers on the surface of the p-side and the depletion voltage dependence on the strip geometry can be explained. We investigated the “blocking implant” and the “spray implant” techniques as promising candidates for the n-side isolation of irradiated detectors. The main drawback of the “blocking implanted” devices is the increase of the electric field with increasing oxide charges. This implies the danger of impact ionization in irradiated devices. A “spray implanted” isolation layer leads to the highest electric field in the non-irradiated state which has the advantage of a better testability. Small gaps between strips as used in charge division readout reduce electric fields and leakage currents.

Neben den aktuell im Blickpunkt der Bundesraumordnung stehenden, dynamischen Metropolregionen existieren in der Bundesrepublik Deutschland zahlreiche landliche bzw. peripher gelegene Raume, die ausgesprochen positive Entwicklungstendenzen in demographischer wie auch okonomischer Hinsicht aufweisen und damit dem verbreiteten Bild landlicher „Schrumpfungs- und Entleerungsraume“ widersprechen. Der Frage, wie solche Wachstumsmotoren entstehen, aber auch gefordert und ausgebaut sowie ahnliche Entwicklungen in anderen Regionen angestoβen werden konnen widmete sich der Lehrstuhl Regionalentwicklung und Raumordnung der Technischen Universitat Kaiserslautern zwischen 2006 und 2011 im Rahmen zweier Forschungsprojekte auf Ebene des Bundes sowie des Landes Rheinland-Pfalz.