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Abstract Background This study of the oropharyngeal microbiome complements the previously published AZIthromycin in Severe ASThma (AZISAST) clinical trial, where the use of azithromycin was assessed in subjects with exacerbation-prone severe asthma. Here, we determined the composition of the oropharyngeal microbial community by means of deep sequencing of the amplified 16S rRNA gene in oropharyngeal swabs from patients with exacerbation-prone severe asthma, at baseline and during and after 6 months treatment with azithromycin or placebo. Results A total of 1429 OTUs were observed, of which only 59 were represented by more than 0.02% of the reads. Firmicutes, Bacteroidetes, Fusobacteria, Proteobacteria and Actinobacteria were the most abundant phyla and Streptococcus and Prevotella were the most abundant genera in all the samples. Thirteen species only accounted for two thirds of the reads and two species only, i.e. Prevotella melaninogenica and Streptococcus mitis/pneumoniae, accounted for one fourth of the reads. We found that the overall composition of the oropharyngeal microbiome in patients with severe asthma is comparable to that of the healthy population, confirming the results of previous studies. Long term treatment (6 months) with azithromycin increased the species Streptococcus salivarius approximately 5-fold and decreased the species Leptotrichia wadei approximately 5-fold. This was confirmed by Boruta feature selection, which also indicated a significant decrease of L. buccalis/L. hofstadtii and of Fusobacterium nucleatum. Four of the 8 treated patients regained their initial microbial composition within one month after cessation of treatment. Conclusions Despite large diversity of the oropharyngeal microbiome, only a few species predominate. We confirm the absence of significant differences between the oropharyngeal microbiomes of people with and without severe asthma. Possibly, long term azithromycin treatment may have long term effects on the composition of the oropharygeal microbiome in half of the patients.

The pro-inflammatory cytokine thymic stromal lymphopoietin (TSLP) is a promising therapeutic target. Here the authors characterize the assembly mechanism of the receptor complex driven by human TSLP, and its antagonism by the monoclonal antibody Tezepelumab and a fusion protein comprising the TSLP receptors.

Abstract Background The fourth round of the Critical Assessment of Small Molecule Identification (CASMI) Contest ( www.casmi-contest.org ) was held in 2016, with two new categories for automated methods. This article covers the 208 challenges in Categories 2 and 3, without and with metadata, from organization, participation, results and post-contest evaluation of CASMI 2016 through to perspectives for future contests and small molecule annotation/identification. Results The Input Output Kernel Regression (CSI:IOKR) machine learning approach performed best in “Category 2: Best Automatic Structural Identification—In Silico Fragmentation Only”, won by Team Brouard with 41% challenge wins. The winner of “Category 3: Best Automatic Structural Identification—Full Information” was Team Kind (MS-FINDER), with 76% challenge wins. The best methods were able to achieve over 30% Top 1 ranks in Category 2, with all methods ranking the correct candidate in the Top 10 in around 50% of challenges. This success rate rose to 70% Top 1 ranks in Category 3, with candidates in the Top 10 in over 80% of the challenges. The machine learning and chemistry-based approaches are shown to perform in complementary ways. Conclusions The improvement in (semi-)automated fragmentation methods for small molecule identification has been substantial. The achieved high rates of correct candidates in the Top 1 and Top 10, despite large candidate numbers, open up great possibilities for high-throughput annotation of untargeted analysis for “known unknowns”. As more high quality training data becomes available, the improvements in machine learning methods will likely continue, but the alternative approaches still provide valuable complementary information. Improved integration of experimental context will also improve identification success further for “real life” annotations. The true “unknown unknowns” remain to be evaluated in future CASMI contests. Graphical abstract .

Over the last few years, there has been rapid development in demonstrating stimulated Brillouin scattering in chip-integrated optical waveguides. Most of the work has focused on finding good materials for achieving net gain, however, rather than on exploring novel waveguide designs. In this paper, we have used genetic algorithms to explore a wide range of possible waveguide shapes to achieve high gain in silicon and silicon oxide based integrated platforms. The result is a range of novel waveguide designs operating over a wide range of mechanical frequencies. Several of the waveguides found have a simulated gain in excess of 108 (Wm)−1, far above anything previously demonstrated.

A mechanically flexible textile antenna-backed sensor node is designed and manufactured, providing accurate personal localization functionality by application of Decawave’s DW1000 Impulse Radio Ultra-Wideband (IR-UWB) Integrated Circuit (IC). All components are mounted on a flexible polyimide foil, which is integrated on the backplane of a wearable cavity-backed slot antenna designed for IR-UWB localization in Channels 2 and 3 of the IEEE 802.15.4-2011 standard (3744 MHz–4742.4 MHz). The textile antenna’s radiation pattern is optimized to mitigate body effects and to minimize absorption by body tissues. Furthermore, its time-domain characteristics are measured to be adequate for localization. By combining the antenna and the bendable Printed Circuit Board (PCB), a mechanically supple sensor system is realized, for which the performance is validated by examining it as a node used in a complete localization system. This shows that six nodes around the body must be deployed to provide system coverage in all directions around the wearer. Even without using sleep mode functionalities, the measurements indicate that the system’s autonomy is 13.3 h on a 5 V 200 mAh battery. Hence, this system acts as a proof of concept for the joining of localization electronics and other sensors with a full-textile antenna into a mechanically flexible sensor system.

Glycolytic regulator PFKFB3 is a key player in vessel sprouting. Here the authors develop a computational model predicting that PFKFB3 drives endothelial cell rearrangement during vessel sprouting by promoting filopodia formation and reducing intercellular adhesion, and empirically validate this prediction.

A six-channel wavelength-division-multiplexed optical transceiver with a compact footprint of 1.5 × 0.65 mm2 for off-chip and on-chip interconnects is demonstrated on a single silicon-on-insulator chip. An arrayed waveguide grating is used as the (de)multiplexer, and III-V electroabsorption sections fabricated by hybrid integration technology are used as both modulators and detectors, which also enable duplex links. The 30-Gb/s capacity for each of the six wavelength channels for the off-chip transceiver is demonstrated. For the on-chip interconnect, an electrical-to-electrical 3-dB bandwidth of 13 GHz and a data rate of 30 Gb/s per wavelength are achieved.

A fundamental part of the immune response to infection or injury is leukocyte migration. Matrix metalloproteinases (MMPs) are a class of secreted or cell-bound endopeptidases, implicated in every step of the process of inflammatory cell migration. Hence, specific inhibition of MMPs is an interesting approach to control inflammation. We evaluated the potential of a bivalent carboxylate inhibitor to selectively inhibit the trimeric proteoform of MMP-9 and compared this with a corresponding monovalent inhibitor. The bivalent inhibitor efficiently inhibited trimeric MMP-9 (IC50 = 0.1 nM), with at least 500-fold selectivity for MMP-9 trimers over monomers. Surprisingly, in a mouse model for chemotaxis, the bivalent inhibitor amplified leukocyte influxes towards lipopolysaccharide-induced inflammation. We verified by microscopic and flow cytometry analysis increased amounts of neutrophils. In a mouse model for endotoxin shock, mice treated with the bivalent inhibitor had significantly increased levels of MMP-9 in plasma and lungs, indicative for increased inflammation. In conclusion, we propose a new role for MMP-9 trimers in tempering excessive neutrophil migration. In addition, we have identified a small molecule inhibitor with a high selectivity for the trimeric proteoform of MMP-9, which will allow further research on the functions of MMP-9 proteoforms.

This study aims to define the perspectives taken by single mothers when combining work and motherhood in a stressful work–life constellation. One of the challenges for single mothers after divorce is to find a work–life balance in their single-parent family system. Regarding work-life balance, we take a General Strain Perspective, describing the work-life conflict as a combination of financial strain and role strain. We argue that both strains are the most problematic for single mothers in comparison to their married and/or male counterparts, as both finances and parenthood ideologies are more under pressure. For this reason, we explore how single mothers coped with this strain, answering the question: ‘Which perspectives on the combination motherhood and work do single mothers take in their attempt to balance role strain and financial strain after divorce?’ To answer this research question, we used a qualitative approach, based on 202 in-depth interviews with single mothers in Belgium. These interviews involved two groups: A primary research population of 13 single mothers and an elaborative research population of 189 single mothers. Timelines were used to structure the single mothers’ narratives. The analysis resulted in the contruction of a typology of four different perspectives based on how single mothers dealt with maternal role strain and financial strain: the re-invented motherhood perspective, the work-family symbiosis perspective, the work-centered motherhood perspective and the work-family conflicted perspective. We found that perspective of single mothers in their work-life strain can be described by the flexibility and/or strictness in either their motherhood ideology and/or their work context. These results point at the needs for policymakers, employers, and practitioners to focus on initiatives improving the work–life balance of single mothers by reducing financial and role strains.

Nano-ridge engineering (NRE) is a novel heteroepitaxial approach for the monolithic integration of lattice-mismatched III-V devices on Si substrates. It has been successfully applied to GaAs for the realization of nano-ridge (NR) laser diodes and heterojunction bipolar transistors on 300 mm Si wafers. In this report we extend NRE to GaSb for the integration of narrow bandgap heterostructures on Si. GaSb is deposited by selective area growth in narrow oxide trenches fabricated on 300 mm Si substrates to reduce the defect density by aspect ratio trapping. The GaSb growth is continued and the NR shape on top of the oxide pattern is manipulated via NRE to achieve a broad (001) NR surface. The impact of different seed layers (GaAs and InAs) on the threading dislocation and planar defect densities in the GaSb NRs is investigated as a function of trench width by using transmission electron microscopy (TEM) as well as electron channeling contrast imaging (ECCI), which provides significantly better defect statistics in comparison to TEM only. An InAs/GaSb multi-layer heterostructure is added on top of an optimized NR structure. The high crystal quality and low defect density emphasize the potential of this monolithic integration approach for infrared optoelectronic devices on 300 mm Si substrates.

For possible applications of colloidal nanocrystals in optoelectronics and nanophotonics, it is of high interest to study their response at low excitation intensity with high repetition rates, as switching energies in the pJ/bit to sub-pJ/bit range are targeted. We develop a sensitive pump-probe method to study the carrier dynamics in colloidal PbS/CdS quantum dots deposited on a silicon nitride waveguide after excitation by laser pulses with an average energy of few pJ/pulse. We combine an amplitude modulation of the pump pulse with phase-sensitive heterodyne detection. This approach permits to use co-linearly propagating co-polarized pulses. The method allows resolving transmission changes of the order of 10−5 and phase changes of arcseconds. We find a modulation on a sub-nanosecond time scale caused by Auger processes and biexciton decay in the quantum dots. With ground state lifetimes exceeding 1 μs, these processes become important for possible realizations of opto-electronic switching and modulation based on colloidal quantum dots emitting in the telecommunication wavelength regime.

In the paper, we review our work on heterogeneous III-V-on-silicon photonic components and circuits for applications in optical communication and sensing. We elaborate on the integration strategy and describe a broad range of devices realized on this platform covering a wavelength range from 850 nm to 3.85 μm.

In this study, zeolite was employed for the separation and recovery of P from synthetic wastewater and its use as phosphorus (P) source for the cultivation of the green microalga Chlorella vulgaris and the cyanobacterium Arthrospira (Spirulina) platensis. At P-loaded zeolite concentration of 0.15–1 g/L, in which P was limited, the two species displayed quite different behavior regarding their growth and biomass composition. C. vulgaris preferred to increase the intracellular P and did not synthesize biomass, while A. platensis synthesized biomass keeping the intracellular P as low as possible. In addition under P limitation, C. vulgaris did display some little alteration of the biomass composition, while A. platensis did it significantly, accumulating carbohydrates around 70% from about 15%–20% (control). Both species could desorb P from zeolite biologically. A. platensis could recover over 65% and C. vulgaris 25% of the P bounded onto zeolite. When P-loaded zeolite concentration increased to 5 g/L, P was adequate to support growth for both species. Especially in the case of C. vulgaris, growth was stimulated from the presence of P-loaded zeolite and produced more biomass compared to the control.

A novel fiber Bragg grating (FBG) interrogator is demonstrated based on an optimized arrayed waveguide grating (AWG) filter. The AWG response is optimized to achieve large crosstalk between the output channels, which allows simultaneous detection of multiple FBG peaks, using centroid signal processing techniques, without constraints on the minimum FBG peak spectral width. The measured interrogator resolution is 2.5 pm, and the total measurement range is 50 nm. The device is fabricated in a silicon-on-insulator platform and has a footprint of only 2.2 × 1.5 mm. A novel approach to minimize the polarization dependence of the device is proposed and experimentally demonstrated.

Graphene-based electrical components are inherently multiscale, which poses a real challenge for finite-difference time-domain (FDTD) solvers due to the stringent time step upper bound. Here, a unidirectionally collocated hybrid implicit-explicit (UCHIE) FDTD method is put forward that exploits the planar structure of graphene to increase the time step by implicitizing the critical dimension. The method replaces the traditional Yee discretization by a partially collocated scheme that allows a more accurate numerical description of the material boundaries. Moreover, the UCHIE-FDTD method preserves second-order accuracy even for nonuniform discretization in the direction of collocation. The auxiliary differential equation (ADE) approach is used to implement the graphene sheet as a dispersive Drude medium. The finite grid is terminated by a uniaxial perfectly matched layer (UPML) to permit open-space simulations. Special care is taken to elaborate on the efficient implementation of the implicit update equations. The UCHIE-FDTD method is validated by computing the shielding effectiveness of a typical graphene sheet.

Dissolved organic C (DOC) plays an important role in the cycling and distribution of energy and nutrients. However, factors controlling the transport of DOC both within and between ecosystems are not clear. The aim of this work was to identify the contributing pathways for transport of DOC to surface water in catchments contrasting in land use and hydrogeology and during different flow regimes. Stream water was sampled to observe temporal variation of DOC concentrations and quality both seasonally and at the time scale of a rain event. Major cation and silica concentrations in stream water, groundwater, soil pore water, precipitation/throughfall, and riparian zone water samples were combined in an end‐member mixing analysis to determine the contributing end‐members for DOC delivery at the catchment outlet. Results show that the change in DOC concentrations and quality observed in the stream water during a rain event can be explained by a change in contribution of the different end‐members. In the forested catchments with deep groundwater tables, the main pathway for DOC transport from the soil to the surface water during base flow was via the groundwater. Rising stream DOC concentrations during rainfall events were attributed to additional throughfall and riparian zone transport pathways. In the grassland catchments with shallow groundwater tables, DOC in the stream mainly originated from seeps. During rain events, contributions from a surficial transport pathway and riparian zone water gained importance. The importance of contributing pathways changed seasonally and highly depended on the degree of saturation of the vadose zone.

The Boltzmann equation is applied to fit data of volume loss for evaporation (in %) during spirit ageing in northern white oak (Quercus Alba) standard barrels of 205 L (+/− 10 L) using a temperature and humidity controlled cellar. The Boltzmann equation satisfactory fitted to the experimental data of the volume loss against temperature at constant humidity. Two parameters of the Boltzmann equation showed a linear dependency on the relative humidity of the air, while the other two parameters exhibited a constant value independently of the air humidity. The found empirical mathematical model can be used to calculate the volume loss for evaporation of spirits (40% v/v of ethanol) during ageing in terms of relative humidity (range: 40%−95%) and temperature (range: 10−30 °C) with significant accuracy.

The co-occurrence of non-toxic phytoplankton alongside cyanobacteria adds to the challenge of treating source waters with harmful algal blooms. The non-toxic species consume the oxidant and, thereby, reduce the efficacy of oxidation of both the extracellular and intracellular cyanotoxins. In this work, a 3D printed mini-hydrocyclone was used to separate a mixture of non-toxic green algae, Scenedesmus obliquus, from a toxic species of cyanobacteria, Microcystis aeruginosa. When water is pumped through the mini-hydrocyclone, cells exit through an overflow or underflow port depending on their size, shape, and density relative to the other cells and particles in the water matrix. The overflow port contains the cells that are smaller and less dense since these particles move toward the center of the hydrocyclone. In this work, the majority (>93%) of Microcystis cells were found in the overflow while the underflow contained primarily the Scenedesmus (>80%). This level of separation efficiency was maintained over the 30-min experiment and the majority of both cells (>86%) remained viable following the separation, which indicates that the pumping combined with forces exerted within the mini-hydrocyclone were not sufficient to cause cell death. The impact of free chlorine on the cells both pre-separation and post-separation was evaluated at two doses (1 and 2 mg/L). After separation, the overflow, which contained primarily Microcystis, had at least a 24% reduction in the free chlorine decay rate as compared to the feed water, which contained both species. This reduction in chlorine consumption shows that the cells separated via mini-hydrocyclone would likely require lower doses of oxidant to produce a similar level of degradation of the cyanotoxins present in either the extracellular or intracellular form. However, future work should be undertaken to evaluate this effect in natural bloom samples.

Although semi-crystalline polymers are associated with considerably better mechanical properties and thermal stability compared to their amorphous counterparts, using them as feedstock for Fused Filament Fabrication still poses some major challenges. Hence, the development of printed part crystallinity during printing should be fully understood in order to control the developed weld strength, as well as part shrinkage and warpage. Infrared thermography was utilized to record the thermal history of deposited layers while printing a single-layer wall geometry, employing two PA 6/66 copolymers with distinct molecular weights as feedstock. Print settings were varied to establish which settings are essential to effectively monitor final part crystallinity. The resulting temperature profiles were simulated in a Fast Scanning Chip Calorimetry device that allows for the rapid heating and cooling rates experienced by the printed polymer. Both liquefier temperature and print speed were found to have very little influence on the total attained crystallinity. It became apparent that the build plate, set at a temperature above the polymer’s glass transition temperature, imposes a considerable annealing effect on the printed part. A reduced molecular weight was observed to enhance crystallinity even more strongly. The presented methodology proves that Fast Scanning Chip Calorimetry is an effective tool to assess the impact of both print parameters and feedstock characteristics on the crystallization behavior of semi-crystalline polymers over the course of printing.

Interactions between objects inside living cells are often investigated by looking for colocalization between fluorescence microscopy images that are recorded in separate colours corresponding to the fluorescent label of each object. The fundamental limitation of this approach in the case of dynamic objects is that coincidental colocalization cannot be distinguished from true interaction. Instead, correlation between motion trajectories obtained by dual colour single particle tracking provides a much stronger indication of interaction. However, frequently occurring phenomena in living cells, such as immobile phases or transient interactions, can limit the correlation to small parts of the trajectories. The method presented here, developed for the detection of interaction, is based on the correlation inside a window that is scanned along the trajectories, covering different subsets of the positions. This scanning window method was validated by simulations and, as an experimental proof of concept, it was applied to the investigation of the intracellular trafficking of polymeric gene complexes by endosomes in living retinal pigment epithelium cells, which is of interest to ocular gene therapy.

BACKGROUND:Bovine Taenia saginata cysticercus infections (also called bovine cysticercosis or beef measles) is usually diagnosed in cattle only during post-mortem meat inspection. The aim of this study was to investigate the identification rates of these infections in and to identify predictors/determinants of variations in the identification rates in abattoirs in Gauteng province, South Africa. METHODS:Retrospective data for over 1.4 million cattle carcasses inspected in 26 abattoirs between January 2010 and December 2013 were used for the study. The identification rates (proportion of bovine Taenia saginata cysticercus positive carcasses) were computed and generalized estimating equations used to identify predictors/determinants of identification rates. RESULTS:The overall identification rate was 0.70% (95% CI: 0.45, 0.95). Significantly (p< 0.05) lower rates were reported during summer (0.55%) than other seasons. Some geographic areas reported significantly (p0.05) association was identified between identification rates and either the number of meat inspectors per abattoir or the provider of inspection services. CONCLUSION:Although no significant association was found between identification rates and provider of inspection services, follow-up studies will need to be done to specifically investigate the potential conflict of interest arising from the fact that abattoir owners hire meat inspection services directly. Capture of abattoir surveillance data needs to include farm address and for each case to be reported separately. Finally, information on the type of identified cysts (alive or calcified) need to be collected to help better estimate risk to consumers. This study provides useful baseline data to guide future studies, surveillance and control efforts.

Aerothermoelasticity plays a vital role in the design and optimisation of hypersonic aircraft. Furthermore, the transient and nonlinear effects of the harsh thermal and aerodynamic environment a lifting surface is in cannot be ignored. This article investigates the effects of transient temperatures on the flutter behavior of a three-dimensional wing with a control surface and compares results for transient and steady-state temperature distributions. The time-varying temperature distribution is applied through the unsteady heat conduction equation coupled to nonlinear aerodynamics calculated using 3rd order piston theory. The effect of a transient temperature distribution on the flutter velocity is investigated and the results are compared with a steady-state heat distribution. The steady-state condition proves to over-compensate the effects of heat on the flutter response, whereas the transient case displays the effects of a constantly changing heat load by varying the response as time progresses.

A novel manufacturing procedure for the fabrication of ultra-wideband cavity-backed substrate integrated waveguide antennas on textile substrates is proposed. The antenna cavity is constructed using a single laser-cut electrotextile patch, which is folded around the substrate. Electrotextile slabs protruding from the laser-cut patch are then vertically folded and glued to form the antenna cavity instead of rigid metal tubelets to implement the vertical cavity walls. This approach drastically improves mechanical flexibility, decreases the antenna weight to slightly more than 1 g and significantly reduces alignment errors. As a proof of concept, a cavity-backed substrate integrated waveguide antenna is designed and realized for ultra-wideband operation in the [5.15–5.85] GHz band. Antenna performance is validated in free space as well as in two on body measurement scenarios. Furthermore, the antenna’s figures of merit are characterized when the prototype is bent at different curvature radii, as commonly encountered during deployment on the human body. Also the effect of humidity content on antenna performance is studied. In all scenarios, the realized antenna covers the entire operating frequency band, meanwhile retaining a stable radiation pattern with a broadside gain above 5 dBi, and a radiation efficiency of at least 70%.

This article tries to chart the developing of an ancient building technique which might be the oldest constructual technique imported to Brazil, the rammed earth technique, and a variety of aspects in relation to the cultural heritage and other buildings of cultural significance. It does not pretend a total inventarisation of whole heritage that is constructed totally or partially by this building technique but a careful study about the origin of this remote building technique and its antecedents, and an indication where in Brazil this technique can be found. The term "formigão", often incorrectly used, will be clarified and the essential function of the aggregate lime for its conservation. At the end follows an explanation why the state of São Paulo had used the rammed earth technique much longer than other regions of Brazil and the reasons behind its disappearing.

Sugarcane interacts with particular types of beneficial nitrogen-fixing bacteria that provide fixed-nitrogen and plant growth hormones to host plants, promoting an increase in plant biomass. Other benefits, as enhanced tolerance to abiotic stresses have been reported to some diazotrophs. Here we aim to study the effects of the association between the diazotroph Gluconacetobacter diazotrophicus PAL5 and sugarcane cv. SP70-1143 during water depletion by characterizing differential transcriptome profiles of sugarcane. RNA-seq libraries were generated from roots and shoots of sugarcane plants free of endophytes that were inoculated with G. diazotrophicus and subjected to water depletion for 3 days. A sugarcane reference transcriptome was constructed and used for the identification of differentially expressed transcripts. The differential profile of non-inoculated SP70-1143 suggests that it responds to water deficit stress by the activation of drought-responsive markers and hormone pathways, as ABA and Ethylene. qRT-PCR revealed that root samples had higher levels of G. diazotrophicus 3 days after water deficit, compared to roots of inoculated plants watered normally. With prolonged drought only inoculated plants survived, indicating that SP70-1143 plants colonized with G. diazotrophicus become more tolerant to drought stress than non-inoculated plants. Strengthening this hypothesis, several gene expression responses to drought were inactivated or regulated in an opposite manner, especially in roots, when plants were colonized by the bacteria. The data suggests that colonized roots would not be suffering from stress in the same way as non-inoculated plants. On the other hand, shoots specifically activate ABA-dependent signaling genes, which could act as key elements in the drought resistance conferred by G. diazotrophicus to SP70-1143. This work reports for the first time the involvement of G. diazotrophicus in the promotion of drought-tolerance to sugarcane cv. SP70-1143, and it describes the initial molecular events that may trigger the increased drought tolerance in the host plant.

The efficiency of a wireless power transfer (WPT) system in the radiative near-field is inevitably affected by the variability in the design parameters of the deployed antennas and by uncertainties in their mutual position. Therefore, we propose a stochastic analysis that combines the generalized polynomial chaos (gPC) theory with an efficient model for the interaction between devices in the radiative near-field. This framework enables us to investigate the impact of random effects on the power transfer efficiency (PTE) of a WPT system. More specifically, the WPT system under study consists of a transmitting horn antenna and a receiving textile antenna operating in the Industrial, Scientific and Medical (ISM) band at 2.45 GHz. First, we model the impact of the textile antenna’s variability on the WPT system. Next, we include the position uncertainties of the antennas in the analysis in order to quantify the overall variations in the PTE. The analysis is carried out by means of polynomial-chaos-based macromodels, whereas a Monte Carlo simulation validates the complete technique. It is shown that the proposed approach is very accurate, more flexible and more efficient than a straightforward Monte Carlo analysis, with demonstrated speedup factors up to 2500.

With a laboratory experiment, we study the impact of buy-options and the corresponding buy-price on revenues and bidding behavior in (online) proxy-auctions with independent private valuations. We show that temporary buy-options may reduce revenues for two reasons: At low buy-prices, the application of the buy-option avoids revenue-enhancing bidding; at high buy-prices, bidders are reluctant to bid above the option price (even though the option is no longer available once an auction has started). The latter suggests a particular type of anchoring, where bidders use the buy-price to update their expectations about the strengths of their opponents.

The performance of beamforming versus space-time coding using a body-worn textile antenna array is experimentally evaluated for an indoor environment, where a walking rescue worker transmits data in the 2.45 GHz ISM band, relying on a vertical textile four-antenna array integrated into his garment. The two transmission scenarios considered are static beamforming at low-elevation angles and space-time code based transmit diversity. Signals are received by a base station equipped with a horizontal array of four dipole antennas providing spatial receive diversity through maximum-ratio combining. Signal-to-noise ratios, bit error rate characteristics, and signal correlation properties are assessed for both off-body transmission scenarios. Without receiver diversity, the performance of space-time coding is generally better. In case of fourth-order receiver diversity, beamforming is superior in line-of-sight conditions. For non-line-of-sight propagation, the space-time codes perform better as soon as bit error rates are low enough for a reliable data link.

A novel high-gain textile antenna array system, fully integrated into a rescue-worker’s vest and operating in the Industrial, Scientific, and Medical wireless band (2.4–2.4835 GHz), is presented. The system comprises an array consisting of four tip-truncated equilateral triangular microstrip patch antennas (ETMPAs), a power divider, line stretchers, and coaxial cables. The array is vertically positioned on the human torso to produce a narrow beam in elevation, as such reducing fading and allowing to steer the maximum gain in a small angular sector centered around the broadside direction. To allow simple low-cost beam steering, we specifically minimize mutual coupling by using a relative large distance between the patches and by selecting the ETMPA element as the most suited topology from three potential patch geometries. Moreover, we investigate the stability of return loss and mutual coupling characteristics under different relative humidity conditions, when bending the array, when placing the system on-body, and when covering it by different textile layers. Reflection coefficient and gain patterns are simulated and measured for the antenna system in free space and placed on the human body.

A novel, low-cost, low-weight, wearable Doppler radar system composed of textile materials and capable of detecting moving objects behind a barrier is presented. The system operates at 2.35 GHz and is integrable into garments, making it well-suited for usage in difficult to access terrain, such as disaster areas or burning buildings. Wearability is maximized by relying on flexible, low-weight, and breathable materials to manufacture the key parts of the system. The low-complexity Doppler radar system makes use of an array of four textile-transmit antennas to scan the surroundings. The beam emitted by this array is right-hand circularly polarized along all scanning angles and provides a measured gain of 9.2 dBi. At the receiving end, textile materials are used to develop an active wearable receive antenna, with 15.7 dBi gain, 1.1 dB noise figure, left-hand circular polarization, and a 3 dB axial ratio beamwidth larger than 50°. Several measurement setups demonstrate that the onbody system is capable of detecting multiple moving subjects in indoor environments, including through-wall scenarios.

The century-old study of photon–phonon coupling has seen a remarkable revival in the past decade. Driven by early observations of dynamical back-action, the field progressed to ground-state cooling and the counting of individual phonons. A recent branch investigates the potential of traveling-wave, optically broadband photon–phonon interaction in silicon circuits. Here, we report continuous-wave Brillouin gain exceeding the optical losses in a series of suspended silicon beams, a step towards selective on-chip amplifiers. We obtain efficiencies up to ${10}^{4}\;{{\rm{W}}}^{-1}\;{{\rm{m}}}^{-1},$ the highest to date in the phononic gigahertz range. We also find indications that geometric disorder poses a significant challenge towards nanoscale phonon-based technologies.

Chronic infection with hepatitis C (HCV) is a major risk factor in the development of cirrhosis and hepatocellular carcinoma. Lipid metabolism plays a major role in the replication and deposition of HCV at lipid droplets (LDs). We have demonstrated the importance of LD-associated proteins of the perilipin family in steatotic liver diseases. Using a large collection of 231 human liver biopsies with HCV, perilipins 1 and 2 have been localized to LDs of hepatocytes that correlate with the degree of steatosis and specific HCV genotypes, but not significantly with the HCV viral load. Perilipin 1- and 2-positive microvesicular steatotic foci were observed in 36% of HCV liver biopsies, and also in chronic hepatitis B, autoimmune hepatitis and mildly steatotic or normal livers, but less or none were observed in normal livers of younger patients. Microvesicular steatotic foci did not frequently overlap with glycogenotic/clear cell foci as determined by PAS stain in serial sections. Steatotic foci were detected in all liver zones with slight architectural disarrays, as demonstrated by immunohistochemical glutamine synthetase staining of zone three, but without elevated Ki67-proliferation rates. In conclusion, microvesicular steatotic foci are frequently found in chronic viral hepatitis, but the clinical significance of these foci is so far not clear.

Alzheimer's disease (AD) is characterized by the accumulation in the brain of intraneuronal aggregates of abnormally and hyperphosphorylated tau proteins and of extracellular deposits of amyloid-β surrounded by dystrophic neurites. Numerous experimental models have shown that tau pathology develops in the brain after intracerebral injection of brain homogenates or pathological tau [paired helical filaments (PHF)-tau)] from AD brains. Further investigations are however necessary to identify or exclude potential extracerebral routes of tau pathology transmission, e.g., through the intravascular route. In this study, we have analyzed the effect of intravenous injection of PHF-tau proteins from AD brains on the formation of tau and amyloid pathologies in the brain of wild-type (WT) mice and of 5XFAD mice (an amyloid model). We observed that 5XFAD mice with a disrupted blood-brain barrier showed increased plaque-associated astrogliosis, microgliosis, and increased deposits of Aβ40 and Aβ42 after intravenous injection of PHF-tau proteins. In addition, an increased phosphotau immunoreactivity was observed in plaque-associated dystrophic neurites. These results suggest that blood products contaminated by PHF-tau proteins could potentially induce an exacerbation of neuroinflammation and AD pathologies., (Copyright © 2020 Houben, de Fisenne, Ando, Vanden Dries, Poncelet, Yilmaz, Mansour, De Decker, Brion and Leroy.)

In this study, six commercial meat starters, each consisting of a pure strain of a lactic acid-fermenting bacterium (including Lactococcus lactis , Lactobacillus curvatus , L. farciminis, L. plantarum, L. sakei , and Pediococcus acidilactici ), were tested for their ability to ferment a paste produced from the yellow mealworm ( Tenebrio molitor ). During fermentation, microbial counts, pH, and the bacterial community composition were determined. In addition, UPLC-MS was applied to monitor the consumption of glucose and the production of glutamic (Glu) and aspartic (Asp) acid. All tested starters were able to ferment the mealworm paste, judged by a pH reduction from 6.68 to 4.60-4.95 within 72 h. Illumina amplicon sequencing showed that all starters were able to colonize the substrate eciently. Moreover, the introduction of the starter cultures led to the disappearance of Bacillus and Clostridium species, which were the dominant microorganisms in un-inoculated samples. Of the six cultures tested, Lactobacillus farciminis was most promising as its application resulted in the largest increase (±25 mg/100 g of paste) in the content of free glutamic and aspartic acid. These amino acids are responsible for the appreciated umami flavour in fermented food products and might stimulate the acceptance of insects and their consumption.

Neuropathological analysis in Alzheimer's disease (AD) and experimental evidence in transgenic models overexpressing frontotemporal dementia with Parkinsonism linked to chromosome 17 (FTDP-17) mutant tau suggest that amyloid-β pathology enhances the development of tau pathology. In this work, we analyzed this interaction independently of the overexpression of an FTDP-17 mutant tau, by analyzing tau pathology in wild-type (WT), 5xFAD, APP -/- and tau -/- mice after stereotaxic injection in the somatosensory cortex of short-length native human AD-PHF. Gallyas and phosphotau-positive tau inclusions developed in WT, 5xFAD, and APP -/- but not in tau -/- mice. Ultrastructural analysis demonstrated their intracellular localization and that they were composed of straight filaments. These seeded tau inclusions were composed only of endogenous murine tau exhibiting a tau antigenic profile similar to tau aggregates in AD. Insoluble tau level was higher and ipsilateral anteroposterior and contralateral cortical spreading of tau inclusions was more important in AD-PHF-injected 5xFAD mice than in WT mice. The formation of large plaque-associated dystrophic neurites positive for oligomeric and phosphotau was observed in 5xFAD mice injected with AD-PHF but never in control-injected or in non-injected 5xFAD mice. An increased level of the p25 activator of CDK5 kinase was found in AD-PHF-injected 5xFAD mice. These data demonstrate in vivo that the presence of Aβ pathology enhances experimentally induced tau seeding of endogenous, wild-type tau expressed at physiological level, and demonstrate the fibrillar nature of heterotopically seeded endogenous tau. These observations further support the hypothesis that Aβ enhances tau pathology development in AD through increased pathological tau spreading.

Alzheimer's disease is characterized by the presence of 2 neuropathological lesions: neurofibrillary tangles, composed of tau proteins which are highly phosphorylated and phosphorylated on uncommon sites, and amyloid plaques, containing the Aß peptides generated from the amyloid precursor protein (APP). Reduction of some APP proteolytic derivatives in Alzheimer's disease such as sAPPα fragment has been reported and sAPPα has been shown to affect tau phosphorylation. To investigate in vivo the effect of absence of APP protein and its fragments on tau phosphorylation and the formation of neurofibrillary tangles, we have generated mice deleted for APP gene and overexpressing a human mutant tau protein and developing neurofibrillary tangles (APPKOTg30 mice). These APPKOTg30 mice showed more severe motor and cognitive deficits, increased tau phosphorylation, increased load of neurofibrillary tangles, and increased p25/35 ratio in the brain, compared with Tg30 mice. These data suggest that APP and/or its proteolytic derivatives interfere with the formation of neurofibrillary tangles in a transgenic mouse model that will be useful for investigating the relationship between APP and tau., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Bioavailability has been used as a key indicator in chemical risk assessment yet poorly quantified risk factor. Worldwide, the framework used to assess potentially contaminated sites is similar, and the decisions are based on threshold contaminant concentration. The uncertainty in the definition and measurement of bioavailability had limited its application to environment risk assessment and remediation. Last ten years have seen major developments in bioavailability research and acceptance. The use of bioavailability in the decision making process as one of the key variables has led to a gradual shift towards a more sophisticated risk-based approach. Now a days, many decision makers and regulatory organisations 'more readily accept' this concept. Bioavailability should be the underlying basis for risk assessment and setting remediation goals of those contaminated sites that pose risk to environmental and human health. This paper summarises the potential application of contaminant bioavailability and bioaccessibility to the assessment of sites affected by different contaminants, and the potential for this to be the underlying basis for sustainable risk assessment and remediation in Europe, North America and Australia over the coming decade.

Precision cut tissue slices (PCTS) represent a suitable and convenient tool for pharmacological, toxicological and morphological studies. Cryopreservation would enable to overcome the shortage of liver tissue, in particular in settings using human liver tissue. We investigated the potential of cryopreservation of porcine PCTS as a morphological tool by rapid freezing with 10% and 30% dimethyl sulfoxide as cryopreservation agents and with or without medium using a Brendel/Vitron tissue slicer. Incubation after thawing was done in a static incubation system. Slices were cultured for 3 h, 6 h, 24 h and 48 h and assessed histologically and immunohistologically for proliferation (Ki67) and spontaneous as well as induced apoptotic activity (M30Cytodeath). Vitality was tested using the Tox-8 test. After cryopreservation, morphology of PCTS was well preserved up to 24 h. A reduction of vitality rate took place. Compared to non-frozen PCTS, the rate of spontaneous proliferation of Kupffer cells and apoptosis of hepatocytes were significantly reduced independent of the freezing conditions. The reactivity of PCTS to apoptotic stimuli was significantly reduced in tissue slices after cryopreservation. Apoptotic stimuli could not induce the same amount of cell deaths compared to non-frozen sections. Thus, cryopreservation of PCTS does interfere with pathomechanisms of apoptosis in PCTS., (Copyright © 2010 Elsevier GmbH. All rights reserved.)

Unlabelled: Acute liver failure (ALF) is associated with massive short-term cell death, whereas chronic liver injury is accompanied by continuous cell death. Hepatic stellate cells (HSCs) contribute to tissue repair and liver fibrosis in chronic liver injury, although their role in ALF remains unexplained. Twenty-nine patients (median age = 43 years, 17 females and 12 males) with ALF according to the Acute Liver Failure Study Group criteria were included. Upon the diagnosis of ALF and after 7 days, we determined liver stiffness (LS) with FibroScan, standard laboratory parameters, and serum levels of matrix metalloproteinase 1 (MMP-1), MMP-2, MMP-9, tissue inhibitor of metalloproteinases 1 (TIMP-1), TIMP-2, hyaluronic acid, and markers of overall cell death (M65) and apoptosis (M30). Stellate cell activation and progenitor response were analyzed immunohistochemically in biopsy samples of 12 patients with alpha-smooth muscle actin (alpha-SMA), keratin-17, and keratin-19 staining, respectively. Cell death markers (M30 level = 2243 +/- 559.6 U/L, M65 level = 3732 +/- 839.9 U/L) and fibrosis markers (TIMP-1 level = 629.9 +/- 69.4 U/mL, MMP-2 level = 264 +/- 32.5 U/mL, hyaluronic acid level = 438.5 +/- 69.3 microg/mL) were significantly increased in patients versus healthy controls. This was paralleled by collagen deposition, elevated alpha-SMA expression, and higher LS (25.6 +/- 3.0 kPa). ALF was associated with ductular progenitor proliferation., Conclusion: Our results demonstrate HSC activation and a progenitor response in ALF. Positive correlations between LS, the degree of liver cell damage, and the intensity of HSC activation suggest that fibrosis is a response to ALF in an attempt to repair damaged tissue.

Objective: Recently, transient elastography (FibroScan) has been introduced for noninvasive staging of liver fibrosis. Here, we investigated a novel approach for noninvasive assessment of liver fibrosis using sonography-based real-time elastography, which can be performed with conventional ultrasound probes during a routine sonography examination., Materials and Methods: Real-time elastography was performed in 79 patients with chronic viral hepatitis and known fibrosis stage and in 20 healthy volunteers. A specially developed program was used for quantification of tissue elasticity. Stepwise logistic regression analysis was performed to define an elasticity score using variables with high reproducibility in a preceding analysis of data from 16 different patients. In addition, aspartate transaminase-to-platelet ratio index (APRI) and routine laboratory values were included in the analysis., Results: The Spearman's correlation coefficient between the elasticity scores obtained using real-time elastography and the histologic fibrosis stage was 0.48, which is highly significant (p < 0.001). The diagnostic accuracy expressed as areas under receiver operating characteristic (ROC) curves were 0.75 for the diagnosis of significant fibrosis (fibrosis stage according to METAVIR scoring system [F] > or = F2), 0.73 for severe fibrosis (F > or = F3), and 0.69 for cirrhosis. For a combined elasticity-laboratory score, the areas under the ROC curves were 0.93, 0.95, and 0.91, respectively., Discussion: Real-time elastography is a new and promising sonography-based noninvasive method for the assessment of liver fibrosis in patients with chronic viral hepatitis.

Metastases are the most common malignant tumors of the liver. In the files of the Institute of Pathology of the University of Cologne 12,161 liver tissue cases are registered. Of them, 1,357 cases (11.2%) showed tumors or tumor like masses. Liver metastases of solid tumors were the largest group of the neoplasias with 611 cases (5.0%) followed by hepatocellular carcinoma (380 cases; 3.1%). Other entities were rare and include cholangiolar carcinoma (0.5%), vascular tumors (0.4%), lymphomas (0.4%), focal nodular hyperplasias (0.36%) and liver cell adenomas (0.23%). Adenocarcinomaa are the largest group of metastases with 400 cases (65.5%). 48.2% of this group were metastases of colorectal cancer, 13.5% of pancreatic cancer, 13% of breast cancer, 6.2% of gastric cancer, 4.5% of lung cancer and 3.7% of esophageal cancer. Neuroendocrine carcinomas are the second largest group with 16% of liver filiae. Other entities were rarely found. Metastases in cirrhotic livers are seldom. The gross findings, the histology, the differential diagnosis including immunohistochemistry and the value of the liver biopsy is discussed.

Aims: The mechanisms of binding and uptake of hepatitis C-virus (HCV) are critical determinants of the infection-reinfection cycle but due to ongoing absence of a robust cell culture system, these mechanisms are still largely hypothetical. Cryoglobulins are atypical immunoglobulins, present in 40% of HCV patients. The aim of this study was to determine the role of these HCV-containing cryoglobulins as carrier molecules for viral uptake into primary human hepatocytes., Methodology: Cryoglobulins were precipitated from serum of chronically HCV-infected patients, labeled with biotin and incubated with freshly prepared hepatocytes from human liver tissue. Binding and endocytosis of HCV-cryoglobulins were studied by specific assays, ligand blot analysis and electron microscopy on hepatocellar plasma membranes., Results: Biotinylated HCV-cryoglobulins specifically bound to hepatocytes and inhibitors of homotypic endosomal fusion reduced their uptake and intracellular trafficking, Ligand-blot and electron microscopy analysis revealed adhesion to hepatocellular plasma membranes. Inoculation of human hepatocytes with HCV-cryoglobulins but not serum from the same patients induced HCV infection in vitro., Conclusions: HCV may enter hepatocytes in conjunction with cryoglobulins via immunoglobulin or related receptors. We hypothesize, that this mechanism plays a role in chronic hepatitis to support the infection-reinfection cycle of the virus.

Background: Transcription mediated amplification (TMA) is known to be one of the most sensitive detection assays for hepatitis C virus (HCV) RNA in serum but has not yet been evaluated in liver tissue. It is unknown whether the higher sensitivity of TMA in comparison with polymerase chain reaction (PCR)-based assays is related to a higher efficiency of the extraction and/or amplification step., Objectives: The sensitivity of a TMA-based assay (Versant HCV RNA Qualitative assay, Bayer Diagnostics) and a standard RT-PCR-based assay (Cobas Amplicor HCV 2.0, Roche Diagnostics) was compared in formalin-fixed paraffin-embedded liver biopsy specimens of patients with chronic hepatitis C., Study Design: After deparaffinization of 7.5 microm liver sections HCV RNA was extracted by standard phenol/chloroform. HCV RNA dilution panels were transferred in parallel to cDNA synthesis and amplification steps of PCR and TMA. Furthermore, TMA amplification from stepwise diluted HCV sera was performed following RNA extraction by either microcentrifuge colums (QIAmp Viral RNA spin Kit, Qiagen, Hilden, Germany) or magnetic microparticles (VERSANT HCV RNA Qualitative assay)., Results: The total number of HCV RNA positive liver specimens detected by TMA was higher compared with those detected by RT-PCR (P=0.032). The total number of TMA positive serum samples was higher when HCV RNA was extracted using magnetic microparticles in comparison with multicentrifuge column extraction (P=0.019)., Conclusion: Our results suggest that both the extraction and amplification step of the TMA-based assay contribute to the higher sensitivity compared with standard RT-PCR.

Background: Apoptosis, programmed cell death, is involved in a broad range of pathological processes. Dysregulation of apoptosis plays a key role in the pathogenesis of hepatitis, toxic liver disease and also liver tumor development. For the study of apoptosis in liver diseases, different in vivo models and different in vitro approaches have been developed. They include cell culture models based on hepatocellular carcinoma cell lines or isolated primary hepatocytes., Materials and Methods: We have established precision cut tissue slices (PCTS) of the liver as a morphological tool for the study of apoptosis. From porcine livers, PCTS were prepared and incubated in a static system with different types and amounts of media. Viability, morphology, spontaneous apoptosis and proliferation were investigated. Apoptosis was induced with actinomycin D and tumor necrosis factor (TNF) alpha., Results: Morphology and viability was well preserved for at least 24 h. After 48 h, deterioration with single and group cell autolysis was seen. There was a low rate of spontaneous apoptosis and proliferation. Using a combination of TNF alpha and actinomycin D, a significant amount of apoptosis occurred., Conclusion: PCTS can be used to directly analyse apoptosis at the tissue level in a qualitative and quantitative manner.

The cutaneous human papillomavirus (HPV) 8 is clearly involved in skin cancer development in epidermodysplasia verruciformis patients and its early genes E2, E6, and E7 have been implicated in cell transformation in vitro. To examine the functions of these genes in vivo we integrated the complete early region of HPV8 into the genome of DBA/Bl6 mice. To target their expression to the basal layer of the squamous epithelia the transgenes were put under the control of the keratin-14 promoter. Transgenic mice were back-crossed for up to six generations into both FVB/N and Bl6 mouse strains. Whereas none of the HPV8 transgene-negative littermates developed lesions in the skin or any other organ, 91% of HPV8-transgenic mice developed single or multifocal benign tumors, characterized by papillomatosis, acanthosis, hyperkeratosis, and varying degrees of epidermal dysplasia. Squamous cell carcinomas developed in 6% of the transgenic FVB/N mice. Real-time reverse transcription-PCR showed highest expression levels for HPV8-E2, followed by E7 and E6. There was no consistent difference in relative viral RNA levels between healthy or dysplastic skin and malignant skin tumors. Whereas UV-induced mutations in the tumor suppressor gene p53 are frequently detected in human skin carcinomas, mutations in p53 were not observed either in the benign or malignant mouse tumors. Nonmelanoma skin cancer developed in HPV8-transgenic mice without any treatment with physical or chemical carcinogens. This is the first experimental proof of the carcinogenic potential of an epidermodysplasia verruciformis-associated HPV-type in vivo.

We report on successful adjuvant tamoxifen therapy for a metastasizing sweat gland adenocarcinoma of the scalp in a 64-year-old woman. Before the antihormonal therapy, the patient had undergone repeated surgery for ipsilateral intraparotid, soft tissue, and lymph node metastases and had had disease-free intervals of less than 5 months. As the immunohistochemical analysis of the tumor tissue revealed a 100% nuclear reactivity to estrogen and progesterone receptors, we started empirical tamoxifen citrate therapy, which dramatically changed the course of the disease. The patient has been in complete remission for 3 years. This is the third report in the literature of substantial therapeutic benefit of antiestrogen therapy in metastasizing eccrine gland adenocarcinoma with positive hormone receptor immunohistochemistry. We suggest examining the hormone receptor expression in these neoplasms regularly. A prospective study should be commenced to assess the benefit of adjuvant antihormonal therapy in eccrine gland adenocarcinomas.