Random walks - a sequential approach

In this paper sequential monitoring schemes to detect nonparametric drifts are studied for the random walk case. The procedure is based on a kernel smoother. As a by-product we obtain the asymptotics of the Nadaraya-Watson estimator and its as- sociated sequential partial sum process under non-standard sampling. The asymptotic behavior differs substantially from the stationary situation, if there is a unit root (random walk component). To obtain meaningful asymptotic results we consider local nonpara- metric alternatives for the drift component. It turns out that the rate of convergence at which the drift vanishes determines whether the asymptotic properties of the monitoring procedure are determined by a deterministic or random function. Further, we provide a theoretical result about the optimal kernel for a given alternative

Mutual Ionization in 200-keV H⁻+ He Collisions

We studied mutual ionization in 200-keV H-+He collisions in a kinematically complete experiment by measuring the fully momentum-analyzed recoil ions and both active electrons in coincidence. Comparison of the data to our calculations, based on various theoretical models, show that mutual ionization proceeds predominantly through the interaction between both electrons. The post-collision interaction between the outgoing ejected electrons as well as higher order processes involving the interaction between the core of both collision partners are also important

Triple-Differential Cross Sections for Target Ionization with Simultaneous Projectile Detachment in 200-keV H⁻ + He Collisions

We have performed a kinematically complete experiment for target ionization with simultaneous projectile detachment (TIPD) in 200-keV H− + He collisions. From the data we extracted triple-differential cross sections (TDCSs) for each electron separately. These TDCSs closely resemble corresponding data for single ionization by charged-particle impact. Surprisingly, the contributions from higher-order processes to TIPD, proceeding through two independent interactions of each electron with the core of the respective other collision partner, are found to be somewhat larger than the first-order process proceeding through the electron-electron interaction

Interactions of variously coated gold and silver nanoparticles with a bis(triarylborane) photodyanmic therapy (PDT)-dye; their cellular uptake, cytotoxicity and photo-activity

Background and purpose: Diethynylarene-linked bis(triarylborane) tetracations can be used as probes for fluorimetric and Raman sensing of biomacromolecules, as well as promising theragnostic agents. Among them, bis(triarylborane) fluorophore (TAB3), when bonded to Ag nanoparticles (NP), stood out with specific properties such as Raman signal enhancemen of the TAB3 dye in a cuvette. However, TAB3 dye - nanoparticle composites have not been studied in biological systems. For this reason, questions arose as to whether different types of metal nanoparticles (Au or Ag-based) with different coatings (negatively charged citrate or neutral PVP) could be efficiently stained with the TAB3 dye in a cuvette. The aim of this research was to examine Au and Ag nanoparticles of similar size (20-25 nm) with different stabilizers for their cellular uptake, cytotoxicity in the dark and under visible light radiation, to characterize the interactions of nanoparticles with the TAB3 fluorophore, and to study NP-TAB3 composites in cells, evaluate their intracellular staining, as well as possible photoinduced release and biological activity. Materials and methods: The binding constants of Au- and Ag- based nanoparticles with TAB3 were determined by fluorimetric titrations. The cytotoxic effect of NPs was determined by the survival of A549 cells (MTT assay). Cellular uptake of both NP and NP-TAB3 composites were performed by live cell imaging experiments. Results: The Au- or Ag-based NPs with different coatings bind to the TAB3 with high affinity. These NPs, as well as TAB3-NP complexes, efficiently enter living human cells, accumulating in cytoplasm with no apparent selectivity for a particular organelle. Even prolonged 3-day treatment with the NPs studied did not show any toxic effect on the cells. Bioimaging studies in cells revealed that the TAB3-NP complex does not intracellularly dissociate; the previously reported photo-bioactivity of TAB3 is completely inhibited by binding to NPs. Conclusion: Au- and Ag NPs were non-covalently stained by TAB3, irrespective of the different coatings, with similar binding affinities. Emission from TAB3 is strongly quenched by the NPs, but not completely. Experiments on living human cells revealed that neither free NPs, nor their composites with TAB3, were toxic. Bioimaging studies by confocal microscopy revealed that all NPs efficiently enter living cells within 90 min. Colocalization experiment with simultaneous collection of data in the reflection and fluorescence modes demonstrated that the TAB3 dye remained bound to NPs inside cells. Strong irradiation of TAB3-NP inside cells with a 457 nm laser did not yield any damage to the cells, at variance with our previously shown very strong photo-bioactivity of the TAB3 dye alone. Thus, binding of a chromophore to a nanoparticle can inhibit the chromophore’s ability to undergo photo-induced singlet oxygen production, consequently blocking its photo-bioactivity

Tetracationic bis-triarylborane 1, 3-butadiyne as a combined fluorimetric and Raman probe for simultaneous and selective sensing of various DNA, RNA and proteins

A new bis-triarylborane tetracation (4-Ar2B-3, 5-Me2C6H2)-C≡C- C≡C-(3, 5-Me2C6H2-4-BAr2 [Ar = (2, 6-Me2-4-NMe3-C6H2)+] (24+) shows distinctly different behaviour in its fluorimetric response than that of our recently published bis-triarylborane 5- (4-Ar2B-3, 5-Me2C6H2)-2, 2’-(C4H2S)2-5’-(3, 5-Me2C6H2-4-BAr2) (34+). Single-crystal X-ray diffraction data on the neutral bis- triarylborane precursor 2N confirm its rod-like dumbbell structure, which is shown to be important for DNA/RNA targeting and also for BSA protein binding. Fluorimetric titrations with DNA/RNA/BSA revealed the very strong affinity of 24+ and indicated the importance of the properties of the linker connecting the two triarylboranes. Using the butadiyne- rather than a bithiophene linker resulted in an opposite emission effect (quenching vs enhancement), and 24+ bound to BSA 100 times stronger than 34+. Moreover, 24+ interacted strongly with ss-RNA, and circular dichroism (CD) results suggest ss- RNA chain-wrapping around the rod-like bis-triarylborane dumbbell structure like a thread around a spindle, a very unusual mode of binding of ss-RNA with small molecules. Furthermore, 24+ yielded strong Raman/SERS signals, allowing DNA or protein detection at ca. 10 nM concentrations. The above observations, combined with low cytotoxicity, efficient human cell uptake and organelle-selective accumulation make such compounds intriguing novel lead structures for bio-oriented, dual fluorescence/Raman-based applications

oA novel nonparametric approach for estimating cut-offs in continuous risk indicators with application to diabetes epidemiology

<p>Abstract</p> <p>Background</p> <p>Epidemiological and clinical studies, often including anthropometric measures, have established obesity as a major risk factor for the development of type 2 diabetes. Appropriate cut-off values for anthropometric parameters are necessary for prediction or decision purposes. The cut-off corresponding to the Youden-Index is often applied in epidemiology and biomedical literature for dichotomizing a continuous risk indicator.</p> <p>Methods</p> <p>Using data from a representative large multistage longitudinal epidemiological study in a primary care setting in Germany, this paper explores a novel approach for estimating optimal cut-offs of anthropomorphic parameters for predicting type 2 diabetes based on a discontinuity of a regression function in a nonparametric regression framework.</p> <p>Results</p> <p>The resulting cut-off corresponded to values obtained by the Youden Index (maximum of the sum of sensitivity and specificity, minus one), often considered the optimal cut-off in epidemiological and biomedical research. The nonparametric regression based estimator was compared to results obtained by the established methods of the Receiver Operating Characteristic plot in various simulation scenarios and based on bias and root mean square error, yielded excellent finite sample properties.</p> <p>Conclusion</p> <p>It is thus recommended that this nonparametric regression approach be considered as valuable alternative when a continuous indicator has to be dichotomized at the Youden Index for prediction or decision purposes.</p

Introduction to This Special Issue on Open Design at the Intersection of Making and Manufacturing

What is ‘open design’ and who gets to say what it is? In the emerging body of literature on open design, there is a clear alignment to the values and practices of free culture and open source software and hardware. Yet this same literature includes multiple, sometimes even contradictory strands of technology practice and research. These different perspectives can be traced back to free culture advocates from the 1970s to the 1990s who formulated the ideal of the internet as inherently empowering, democratizing, and countercultural. However, more recent approaches include feminist and critical interventions into hacking and making as well as corporate strategies of “open innovation” that bring end-users and consumers into the design process. What remains today seems to fall into two schools of thought. On one hand, we have the celebratory endorsements of ‘openness’ as applied to technology and design. On the other hand, we have a continuous and expanding critique of these very ideals and questions, where that critique identifies persisting forms of racial, gender, age, and class-based exclusions, and questions about the relationship between open design, labor and power remain largely unanswered

Electron-Rich EDOT Linkers in Tetracationic bis-Triarylborane Chromophores: Influence on Water Stability, Biomacromolecule Sensing, and Photoinduced Cytotoxicity

Three novel tetracationic bis-triarylboranes with 3, 4-ethylenedioxythiophene (EDOT) linkers, and their neutral precursors, showed significant red-shifted absorption and emission compared to their thiophene-containing analogues, with one of the EDOT-derivatives emitting in the NIR region. Only the EDOT-linked trixylylborane tetracation was stable in aqueous solution, indicating that direct attachment of a thiophene or even 3-methylthiophene to the boron atom is insufficient to provide hydrolytic stability in aqueous solution. Further comparative analysis of the EDOT-linked trixylylborane tetracation and its bis-thiophene analogue revealed efficient photo-induced singlet oxygen production, with the consequent biological implications. Thus, both analogues bind strongly to ds-DNA and BSA, very efficiently enter living human cells, accumulate in several different cytoplasmic organelles with no toxic effect but, under intense visible light irradiation, they exhibit almost instantaneous and very strong cytotoxic effects, presumably attributed to singlet oxygen production. Thus, both compounds are intriguing theranostic agents, whose intracellular and probably intra-tissue location can be monitored by strong fluorescence, allowing switching on of the strong bioactivity by well-focused visible light

MPP+-induced toxicity in the presence of dopamine is mediated by COX-2 through oxidative stress

Accumulating evidence suggests that endogenous dopamine may act as a neurotoxin and thereby participate in the pathophysiology of Parkinson’s disease (PD). Cyclooxygenase-2 (COX-2) has been implicated in the pathogenesis of PD due to its ability to generate reactive oxygen species (ROS). Inhibition of COX-2 leads to neuroprotection by preventing the formation of dopamine-quinone. In this study, we examined whether dopamine mediates 1-methyl-4-phenylpyridinium (MPP+)-induced toxicity in primary ventral mesencephalic (VM) neurons, an in vitro model of PD, and if so, whether the protective effects of COX-2 inhibitors on dopamine mediated MPP+-induced VM neurotoxicity and VM dopaminergic cell apoptosis result from the reduction of ROS. Reserpine, a dopamine-depleting agent, significantly reduced VM neurotoxicity induced by MPP+, whereas dopamine had an additive effect on MPP+-induced VM neurotoxicity and VM dopaminergic cell apoptosis. However, inhibition of COX-2 by a selective COX-2 inhibitor (DFU) or ibuprofen significantly attenuated MPP+-induced VM cell toxicity and VM dopaminergic cell apoptosis, which was accompanied by a decrease in ROS production in VM dopaminergic neurons. These results suggest that dopamine itself mediates MPP+-induced VM neurotoxicity and VM dopaminergic cell apoptosis in the presence of COX-2

IFN-γ signaling, with the synergistic contribution of TNF-α, mediates cell specific microglial and astroglial activation in experimental models of Parkinson's disease

To through light on the mechanisms underlying the stimulation and persistence of glial cell activation in Parkinsonism, we investigate the function of IFN-γ and TNF-α in experimental models of Parkinson's disease and analyze their relation with local glial cell activation. It was found that IFN-γ and TNF-α remained higher over the years in the serum and CNS of chronic Parkinsonian macaques than in untreated animals, accompanied by sustained glial activation (microglia and astroglia) in the substantia nigra pars compacta. Importantly, Parkinsonian monkeys showed persistent and increasing levels of IFN-γR signaling in both microglial and astroglial cells. In addition, experiments performed in IFN-γ and TNF-α KO mice treated with MPTP revealed that, even before dopaminergic cell death can be observed, the presence of IFN-γ and TNF-α is crucial for microglial and astroglial activation, and, together, they have an important synergistic role. Both cytokines were necessary for the full level of activation to be attained in both microglial and astroglial cells. These results demonstrate that IFN-γ signaling, together with the contribution of TNF-α, have a critical and cell-specific role in stimulating and maintaining glial cell activation in Parkinsonism