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The enteric nervous system (ENS) forms a versatile sensory system along the gastrointestinal tract that interacts with most cell types in the bowel. Herein, we portray host-environment interactions at the intestinal mucosal surface through the lens of the enteric nervous system. We describe local cellular interactions as well as long-range circuits between the enteric, central, and peripheral nervous systems. Additionally, we discuss recently discovered mechanisms by which enteric neurons and glia respond to biotic and abiotic environmental changes and how they regulate intestinal immunity and inflammation. The enteric nervous system emerges as an integrative sensory system with manifold immunoregulatory functions under both homeostatic and pathophysiological conditions.

Granulocyte-colony stimulating factor (GCSF) is a widely used therapeutic protein to treat neutropenia. GCSF has an increased propensity to aggregate if the pH is increased above 5.0. Although GCSF is very well experimentally characterized, the exact pH-dependent aggregation mechanism of GCSF is still under debate. This study aimed to model the complex pH-dependent aggregation behavior of GCSF using state-of-the-art simulation techniques. The conformational stability of GCSF was investigated by performing metadynamics simulations, while the protein-protein interactions were investigated using coarse-grained (CG) simulations of multiple GCSF monomers. The CG simulations were directly compared with small-angle X-ray (SAXS) data. The metadynamics simulations demonstrated that the orientations of Trp residues in GCSF are dependent on pH. The conformational change of Trp residues is due to the loss of Trp-His interactions at the physiological pH, which in turn may increase protein flexibility. The helical structure of GCSF was not affected by the pH conditions of the simulations. Our CG simulations indicate that at pH 4.0, the colloidal stability may be more important than the conformational stability of GCSF. The electrostatic potential surface and CG simulations suggested that the basic residues are mainly responsible for colloidal stability as deprotonation of these residues causes a reduction of the highly positively charged electrostatic barrier close to the aggregation-prone long loop regions.

Mineralocorticoid receptor antagonists have beneficial effects on left ventricular remodeling, cardiac fibrosis, and arrhythmia in heart failure, but efficacy and safety in dialysis patients is less clear. We evaluated the effect of spironolactone on left ventricular mass (LVM), an independent predictor of all-cause and cardiovascular mortality, in hemodialysis patients. In this placebo-controlled, parallel-group trial, 97 hemodialysis patients (23% female; mean age 60.3 years) were randomized to spironolactone 50 mg once daily (n=50) or placebo (n=47). The primary efficacy endpoint was change in LVM index (LVMi) from baseline to 40 weeks as determined by cardiac magnetic resonance imaging. Safety endpoints were development of hyperkalemia and change in residual renal function. There was no significant change in LVMi in participants randomized to spironolactone compared to placebo (-2.86±11.87 vs. 0.41±10.84 g/m2). There was also no difference in the secondary outcomes of mean 24-hour systolic or diastolic ambulatory blood pressure, left ventricular ejection fraction, 6-minute walk test distance, or New York Heart Association functional class. Moderate hyperkalemia (pre-dialysis potassium levels of 6.0-6.5 mmol/L) was more frequent with spironolactone treatment (155 vs. 80 events), but severe hyperkalemia (≥6.5 mmol/L) was not (14 vs. 24 events). Changes in residual urine volume and measured glomerular filtration rate did not differ between groups. There were no deaths in the spironolactone group and 4 deaths in the placebo group. Thus, treatment with 50 mg spironolactone did not change left ventricular mass index, cardiac function, or blood pressure in hemodialysis patients. Spironolactone increased the frequency of moderate hyperkalemia, but did not increase severe hyperkalemia.

Background & Aims Acute liver failure (ALF) represents an unmet medical need in Western countries. Although the link between intestinal dysbiosis and chronic liver disease is well-established, there is little evidence for a functional role of gut-liver interaction during ALF. Here we hypothesized that intestinal dysbiosis may affect ALF. Methods To test this hypothesis, we assessed the association of proton pump inhibitor (PPI) or long-term antibiotics (ABx) intake, which have both been linked to intestinal dysbiosis, and occurrence of ALF in the 500,000 participants of the UK BioBank population-based cohort. For functional studies, male Nlrp6-/- mice were used as a dysbiotic mouse model and injected with a sublethal dose of acetaminophen (APAP) or lipopolysaccharide (LPS) to induce ALF. Results Multivariate Cox regression analyses revealed a significantly increased risk (odds ratio, 2.3–3) for developing ALF in UK BioBank participants with PPI or ABx. Similarly, dysbiotic Nlrp6-/- mice displayed exacerbated APAP- and LPS-induced liver injury, which was linked to significantly reduced gut and liver tissue microbiota diversity and correlated with increased intestinal permeability at baseline. Fecal microbiota transfer (FMT) from Nlrp6-/- mice into wild-type (WT) mice augmented liver injury on APAP treatment in recipient WT mice, resembling the inflammatory phenotype of Nlrp6-/- mice. Specifically, FMT skewed monocyte polarization in WT mice toward a Ly6Chi inflammatory phenotype, suggesting a critical function of these cells as sensors of gut-derived signals orchestrating the inflammatory response. Conclusions Our data show an important yet unknown function of intestinal microbiota during ALF. Intestinal dysbiosis was transferrable to healthy WT mice via FMT and aggravated liver injury. Our study highlights intestinal microbiota as a targetable risk factor for ALF., Graphical abstract

Background & Aims Previous studies have identified physical activity as an important lifestyle factor in the pathogenesis of chronic liver diseases (CLD). However, most studies were short in follow-up, and based on self-reported activity. Moreover, it is unknown whether physical activity affects the risk of liver disease development in the general population. Herein, we aimed to clarify the association between physical activity and CLD by examining the risk of liver disease and progression in relation to accelerometer-based physical activity in a large subset of prospectively recruited participants in the UK Biobank. Methods We analysed data from 96,688 participants that recorded their physical activity through the use of a wrist accelerometer. Relative risks for development of liver diseases were calculated using multivariable-adjusted Cox regression models. In a subgroup of participants without any previously diagnosed liver disease (n = 95,974), a total of 374 liver disease cases were diagnosed during follow-up (mean = 5.5 years). Results Participants in the top compared with the bottom quartile of physical activity had a reduced risk of both overall CLD (hazard ratio [HR]: 0.41 [0.29–0.59]) and NAFLD (HR: 0.39 [0.21–0.70]). An activity increase of an additional 2,500 steps per day, was associated with a 38% reduction in CLD and a 47% reduction in NAFLD development, independent of adiposity. In the subgroup of participants with previously diagnosed liver disease (n = 714), participants in the top compared with the bottom quartile of physical activity had a striking 89% risk reduction in liver-related death (HR: 0.11 [0.02–0.86]), and 85% risk reduction in all-cause mortality (adjusted HR: 0.15 [0.05–0.44]). Walking an additional 2,500 steps per day was associated with 44% reduction in liver disease progression. Conclusions Greater physical activity is associated with a dose-dependent reduction in liver disease, which appears to be independent of adiposity. Lay summary In this study, we aimed to clarify the association between accelerometer-measured physical activity and chronic liver disease by examining risk of overall and specific liver diseases and their progression in relation to accelerometer-based physical activity in 96,688 participants in the UK Biobank. Our results show a clear, dose-dependent protective association between accelerometer-measured physical activity and liver disease development and progression. The linkage of device-measured activity could therefore create a framework for using wearables for personalised prevention of liver diseases., Graphical abstract, Highlights • Physical activity is associated with a dose-dependent reduction in liver disease that appears to be independent of adiposity. • An increase of 2,500 steps per day was associated with a 38% reduction in liver disease and a 47% reduction in NAFLD. • In patients with liver disease, activity was associated with a reduction in liver disease progression and cirrhosis development. • In patients with liver disease, increased physical activity significantly reduced the risk of liver-related death.

The Technology Centre PULS (Production and Logistics Systems) operates a learning factory for application-related research and education in the areas of Lean Production, Accounting for Lean as well as Industry 4.0. The main didactic approach for teaching and training is simulation games. Lean Production is accepted as the benchmark for a high efficient production. Nevertheless, the results of Lean transformations often lack behind the expectations. Experts consider that Lean initiatives need to enlarge their focus. Therefore, the simulation game described in this paper points out the need for shopfloor management in combination with the new field of Accounting for Lean.

The PuLL® Competence Centre operates a learning factory for application-related research and education in the area of Lean Production / Lean Logistics for students and companies with the didactic approach of simulation games. The Competence Centre developed a new learning factory for “intelligent production logistics”. A new simulation game was developed with the learning focus on internal material flow, intelligently combined with Industry 4.0 components. The goal is to teach the adequate application of Industry 4.0 technology in production logistics. A survey is going to evaluate the specific problems of logistics planning in the field of “intelligent production logistics”.

Using power distance (PD) and individualism (ID), this study examines the impact of cross-functional cooperation and competition on the EO–performance link in different cultural settings. This study is the first to take departments’ cooperative and competitive behavior into account. A study of 846 firms from nine countries reconfirms the positive impact of EO and finds a negative impact of cross-functional cooperation, but does not confirm an impact of competition. When culture is taken into account, we see a significant impact of PD on the proposed relationships, with lower levels of PD increasing the impact. We find no significance for ID.

Background & Aims The hepatitis C virus (HCV) NS3-4A protease is essential for the HCV life cycle and a prime target of antiviral treatment strategies. Protease inhibitors, however, are limited by emergence of resistance-associated amino acid variants (RAVs). The capacity to cleave and inactivate mitochondrial antiviral-signaling protein (MAVS) in the RIG-I-signaling pathway is a cardinal feature of NS3-4A, by which HCV blocks induction of interferon-(IFN)-β, thereby promoting viral persistence. Here, we aimed to investigate the impact of NS3-4A RAVs on MAVS cleavage. Methods The impact of NS3-4A RAVs on MAVS cleavage was assessed using immunoblot analyses, luciferase reporter assays and molecular dynamics simulations to study the underlying molecular principles. IFN-β was quantified in serum from patients with different NS3-4A RAVs. Results We show that macrocyclic NS3-4A RAVS with substitutions at residue D168 of the protease result in an increased capacity of NS3-4A to cleave MAVS and suppress IFN-β induction compared with a comprehensive panel of RAVs and wild type HCV. Mechanistically, we show the reconstitution of a tight network of electrostatic interactions between protease and the peptide substrate that allows much stronger binding of MAVS to D168 RAVs than to the wild-type protease. Accordingly, we could show IFN-β serum levels to be lower in patients with treatment failure due to the selection of D168 variants compared to R155 RAVs. Conclusions Our data constitutes a proof of concept that the selection of RAVs against specific classes of direct antivirals can lead to the predominance of viral variants with possibly adverse pathogenic characteristics.

Many geographical applications have to deal with spatial objects that reveal an intrinsically vague or fuzzy nature. A spatial object is fuzzy if locations exist that cannot be assigned completely to the object or to its complement. Spatial database systems and Geographical Information Systems (GIS) are currently unable to cope with this kind of data. Based on an available abstract data model of fuzzy spatial data types for fuzzy points, fuzzy lines, and fuzzy regions that leverages fuzzy set theory and fuzzy point set topology, this article proposes a Spatial Plateau Algebra that provides spatial plateau data types as an implementation of fuzzy spatial data types. Each spatial plateau object consists of a finite number of crisp counterparts that are all adjacent or disjoint to each other, are associated with different membership values, and hence form different plateaus. The formal framework and the implementation are based on well known, exact models and implementations of crisp spatial data types. Spatial plateau operations as geometric operations on spatial plateau objects are expressed as a combination of geometric operations on the underlying crisp spatial objects. This article offers a conceptually clean foundation for implementing a database extension for fuzzy spatial objects and their operations, and demonstrates the embedding of these new data types as attribute data types in a database schema as well as the incorporation of fuzzy spatial operations into a database query language.

Fuzzy hashing provides the possibility to identify similar files based on their hash signatures, which is useful for forensic investigations. Current tools for fuzzy hashing, e. g. ssdeep, perform similarity search on fuzzy hashes by brute force. This is often too time-consuming for real cases. We solve this issue for ssdeep and even a larger class of fuzzy hashes, namely for piecewise hash signatures, by introducing a suitable indexing strategy. The strategy is based on n-grams contained in the piecewise hash signatures, and it allows for answering similarity queries very efficiently. The implementation of our solution is called F2S2. This tool reduces the time needed for typical investigations from many days to minutes.

The dynamic fragmentation of planetary materials during impact into finite targets has been examined. A particle tracking algorithm was implemented to estimate the size and velocity of fragments ejected from the rear of the target. A total of 76 experiments were performed for four materials, target thicknesses of 7 mm–55 mm, and impact energies of 10 J–6810 J. Semi-empirical models were developed from non-dimensional groups to predict key experimental results. This includes the transformation of incoming projectile kinetic energy to the ejecta kinetic energy. The amount of impact energy converted to kinetic energy of ejecta was found to increase from 2% to 18% over the range of test conditions. Energy dissipated into expanding the field laterally was found to be small in comparison to the streamwise direction (∑KEy/∑KEx = 4%). Percentiles of the distribution of mass, momentum and kinetic energy with respect to ejecta lengths were also examined. Percentile ejecta lengths decrease for increasing normalized impact energy. Fits of the non-dimensional ejecta lengths provide reasonable collapse for the percentile values. Lastly, the cumulative distributions of mass, momentum and kinetic energy among normalized 50% length values were quantified. Exponential function forms were found to fit all of the data over the range over normalized length scales of 0.3–4. When integrated, this predicts the probability density distribution of mass, momentum, and kinetic energy among ejecta lengths for the range of experimental conditions in this study. This data is important in the development and validation of numerical models.

Ejecta velocity measurements were made during impacts into solid planetary materials. Ejecta velocity fields overlie each other when normalized by v max , v 50 % mass , and v 50 % KE ; these correspond to the maximum velocity and median values of mass and kinetic energy among ejecta velocities. Semi-empirical models were developed to provide predictive capabilities of 10th, 50th, and 90th percentiles of the distributions of mass, momentum and kinetic energy with respect to ejecta velocity. Lastly, a functional equation describing the probability density distribution of mass, momentum and kinetic energy among ejecta velocities was derived. Data and predictive models are valuable in the development and validation of numerical models, where comparison between experiments and simulations rely on well characterized measurements.

Velocity and size measurements of ejecta derived from impacts of railgun-launched projectiles into 10 mm thick gabbro tiles are examined. Fragmentation of the target and the ejecta velocity field are found to be governed by Hertzian fracture and the transfer of kinetic energy to the target. Over 90% of the total kinetic energy is contained above the average ejecta velocity and greater than 95% in angles bounded by Hertzian fracture. Log-normal distributions of the ejecta reveal that the kinetic energy transfer from projectile to ejecta is an organized process that spans over four orders of magnitude. The ejection angle that contains the most total kinetic energy coincides with the primary ejection angle, indicating the importance of larger plate-like fragments in the fragmentation process. Approximately 11–16% of energy to the target (initial − final kinetic energy of the projectile) is converted to the kinetic energy of fragments when the projectile does not perforate the target (≤52 J). The conversion to fragment kinetic energy increases near-linearly to ∼50% at an incoming projectile energy of 305 J. This reveals the importance of this energy conversion mechanism under these experimental conditions.

This paper investigates the effects of CSR performance and the amount of CSR material information disclosed on analysts’ forecast accuracy. Both independent variables were operationalized matching the indicators of the GRI sector guidelines with those of ASSET4. Regression analysis was used on 43,273 observations related to 359 firms from 22 countries sectors during the period 2011–2014. Data was collected from the Datastream’s ASSET4, Worldscope, and I/B/E/S databases. Results indicate that it is the amount of CSR material information disclosed and not the CSR performance which reduces analysts’ forecast error. They also show that the amount of CSR material information disclosed has more explanatory power over forecasts error than the CSR performance. The paper contributes to the literature by helping to explain the mechanism through which CSR disclosures help to reduce analysts’ forecast error. According to the results, signaling theory is more helpful than the stakeholder-risk mitigation hypothesis with regard to explaining the relationship between CSR disclosures and analysts’ forecast accuracy. These findings have implications for firms, data providers, and non-financial disclosures frameworks.

Sintered metals have found wide applications in mechanical design for their low manufacturing costs. The present paper deals with a sintered iron powder material (ASC 100.29) which is specially manufactured for experimental and computational investigations. The material has been tested under both monotonic and cyclic loading conditions. Fully reversed fatigue tests have been performed with different material porosities, strain loading ratios and loading amplitudes. Cyclic stress–strain curves and corresponding fatigue life curves are identified. Experiments confirm that the cyclic loading reduces material fracture strain dramatically and the mean strain does not influence fatigue life, regardless of material porosities. The resulting hysteresis loops have been investigated concerning the hardening mechanism. The computational simulations show that the superposition of a nonlinear kinematic and isotropic hardening model can describe experiments reasonably. Computational verification reveals that the identified material model will hardly predict ratcheting behavior of the material.

The dynamic fracture of natural polyphase ceramic (granite) blocks by high-speed impact at 207 m/s, 420 m/s and 537 m/s has been investigated. An electromagnetic railgun was used as the launch system. Results reveal that the number of fragments increases substantially, and the dominant length scale in their probability distributions decreases, as the impact energy is increased. Micro-scale studies of the fracture surfaces reveals evidence of localized temperatures in excess of 2000 K brought on by frictional melting via fracturing and slip along grain boundaries in orthoclase and plagioclase, and via transgranular fracture (micro-cracking) in quartz. The formation of SiO2- and TiO2-rich spheroids on fracture surfaces indicates that temperatures in excess of 3500 K are reached during fracture.

Many geographical applications deal with objects in space that cannot be adequately described by determinate, crisp spatial concepts because of their intrinsically indeterminate and vague nature. Geographical information systems and spatial database systems are currently unable to cope with this kind of data. To support the efficient representation, querying, and manipulation of vague spatial data in a database context, we present a formal data model called vague spatial algebra (VASA). This algebra comprises a set of vague spatial data types for vague points, vague lines, and vague regions together with a comprehensive collection of vague spatial operations and vague topological predicates. One of VASA's main benefits is that its formal framework is based on well known, general, and exact models of crisp spatial data types. This enables an exact definition of the vague spatial model since we can build upon an already existing theory of spatial data types. In particular, crisp spatial data types turn out to be a special case of their vague counterparts. In addition, our approach enables executable specifications for the operations, which can be immediately used as implementations. The article offers a precise and conceptually clean foundation for implementing a DBMS extension for vague spatial data and demonstrates the embedding of these new data types as attribute data types in a database schema as well as the incorporation of vague spatial operations and predicates into queries formulated in an SQL-like query language. All concepts have been verified in a prototype implementation.

Wireless sensor networks can be used in various security-critical applications. The most challenging security problems are insider attacks. In this article we present security strategies to cope with insider attacks and a classification of mechanisms which apply the strategies. We show that strategies and mechanisms for wireless sensor networks have different characteristics and realizations than in classic computer systems because of the special requirements and conditions.

The paper examines relationships between law and technology and focuses on the legal aspects of copyright and centers on the new EU Copyright Directive specifically with respect to DRMS. It, furthermore, examines the relationships between DRMS and the Trusted Computer Platform (TCP) initiative. In order to illustrate the complex relationships between laws, licenses, and DRMS, the paper presents a model, illustrating that copyright holders will not rely exclusively on law or technology but on the interplay between the two.

Queries about objects that change their spatial attributes over time become particularly interesting when they ask for changes in the spatial relationships between different objects. We propose a visual notation that is able to describe scenarios of changing object relationships. The visual language is based on the idea to analyze two-dimensional traces of moving objects to infer a temporal development of their mutual spatial relationships. We motivate the language design by successively simplifying object traces to their intrinsic properties. The notation can be effectively translated into a calculus of spatio-temporal predicates that formally characterizes the evolution of spatial relationships. We also outline a user interface that supports specifications by menus and a drawing editor. The visual notation can be used directly as a visual query interface to spatio-temporal databases, or it can provide predicate specifications that can be integrated into textual query languages leading to heterogeneous languages.

Uncertainty management for geometric data is currently an important problem in spatial databases, image databases, and geographic information systems. Spatial entities do not always have homogeneous interiors and sharply defined boundaries but frequently their interiors and boundaries are partially or totally indeterminate and vague. For an important kind of spatial vagueness called spatial fuzziness this paper provides a conceptual and an implementation model of fuzzy spatial objects that also incorporates fuzzy geometric union, intersection, and difference operations as well as fuzzy topological predicates. In particular, this model is not based on Euclidean space and not on an infinite-precision arithmetic which lead to lacking numerical robustness and to topological inconsistency of implementations on a computer; it rests on a finite, discrete geometric domain called grid partition which takes into account finite-precision number systems available in computers. Last but not least, this paper is a contribution to achieve a uniform treatment of vector and raster data.

The linear complexity and the linear complexity profile of sequences are used as unpredictability criteria in stream cipher applications. In this context, sequences with perfect linear complexity profile (PLCP) are of special interest. Further unpredictability requirements are given by the distribution properties of the sequence elements that should be similar to the distribution properties of a real random sequence. In this paper, the distribution of binary symbols for the class of PLCP-sequences is given by means of statistical moments. These moments are compared with the corresponding moments of real random sequences.

Crystalline fresnoite (Ba 2 TiSi 2 O 8 ), attributed glasses and glass ceramics of the systems Ba 2 TiSi 2 O 8 + x SiO 2 ( x =0, 0.75) and Sr 2 TiSi 2 O 8 have been studied by X-ray photoelectron spectroscopy (XPS). To understand the process of crystallization, changes in coordination of the constituting elements have been studied in glassy and crystalline samples. It was observed that changes in coordination took place at the Ti-sites. It is shown that in fresnoite glass (Ba 2 TiSi 2 O 8 ), fivefold coordinated Ti predominates (≈60%) while fourfold (≈25%) and sixfold (≈15%) coordinated Ti is present as well. In another series of experiments, the effect of reducing Ti(IV) to Ti(III) by adding carbon to the glass batches was studied. It was shown that XPS could resolve the two valency states and gave Ti(IV)/Ti(III) ratios equal to that obtained from thermogravimetry. By comparison of all samples measured, XPS-line positions for different coordinations and valencies of Ti in these samples are given.

X-ray photoelectron spectroscopic studies on Ca-Mg-Si-Al-O-N oxynitride glasses have been carried out. The nitrogen was incorporated into the glass by means of substituting AlN by Al 2 O 3 achieving nitrogen contents up to 10.0 at.%. Our results confirm the model that nitrogen tends to substitute non-bridging oxygen and at low concentration is solely bonded to silicon. The increase in the nitrogen content produces additional binding states for nitrogen, which are related to ‘non-crosslinked’ nitrogen. Despite the presence of 11.6 at.% network modifiers (Ca, Mg) in the glass system studied, non-bridging oxygen could not be observed in the O1s signal. This was checked by preparing the samples in three different ways: fracturing in situ, fracturing under atmosphere and ion gun sputtering and also by comparison with results obtained from oxidic sodium silicate glasses.

Batch cultures of a mouse/mouse hybridoma cell line secreting a dimeric IgA were performed in combination with a membrane process for the continuous removal of ammonia from the culture medium. The latter involves hydrophobic porous membranes with an associated pH gradient. The process was shown to be efficient reducing the ammonia concentration by approximately 50% by comparison to control experiments. Two series of experiments were performed with an initial glutamine concentration of 4 m m and 10 m m , respectively. The growth characteristics, antibody productivity, and quality of antibody assayed by Western blotting were not changed by ammonia removal; however, the cellular energy metabolism was affected by reduction of ammonia levels. At the lower initial glutamine concentration, ammonia removal caused an increased glutamine consumption and reduced lactate production. No effect upon glucose uptake was observed, thus resulting in a considerably reduced yield of lactate from glucose. At the high initial glutamine concentration, the reduced ammonia concentration led to a decrease in glucose and glutamine consumption as well as lactate production. This resulted in only a slight increase in the yield of lactate from glucose. Despite the abundance of literature concerning ammonia inhibition of mammalian cell cultures, little has been reported concerning the effect of continuous ammonia removal from such cultures.

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