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Surface nuclear magnetic resonance (NMR) provides information not only on the lithology and water transport characteristics of aquifer systems but also on the state of iron mineralization within the pore space. This feature makes surface NMR a potential tool for the observation of changing redox conditions in the aquifer, which control the type and oxidation state of iron minerals and, relatedly, the buffering or release of pollutants that may pose a threat to drinking water resources. Our study aims on testing this potential and focuses on pyrite contained in the matrix of a sandy aquifer that serves as a natural denitrification buffer in a drinking water catchment area with intensive agricultural use. We observe a significant change in the surface-NMR relaxation times related to the pyrite content in the subsurface, which is most obvious at the transition from the pyrite-free oxic zone and the pyrite-bearing reducing zone. Complementary laboratory experiments using core material from the study site, including laboratory NMR and geochemical analyses, verify that the influence of pyrite content predominates the NMR relaxation behavior rather than pore size, porosity, or carbon content. The mean relaxation times measured in the sediment without pyrite exceed those with pyrite by approximately 20%–100%. We conclude that surface NMR can serve as a capable tool to locate and monitor the pyrite-based denitrification buffer. However, for general applicability within the given framework, more research is needed to address the natural ambiguity among iron content, its redox state and speciation, and pore size.

In this study, we report for the first time the use of the American oil palm (Elaeis oleifera) as roost by the Neotropical Pacific tent-making bat (Uroderma convexum). Palms with tent roosts consisting of modified leaves were found within the semi-deciduous lowland rainforest in Panama. We present detailed information on a new style of leaf modifications and compare these to tent architectures in other palm species used by U. convexum.

A safe and effective vaccine against COVID-19 is urgently needed in quantities that are sufficient to immunize large populations. Here we report the preclinical development of two vaccine candidates (BNT162b1 and BNT162b2) that contain nucleoside-modified messenger RNA that encodes immunogens derived from the spike glycoprotein (S) of SARS-CoV-2, formulated in lipid nanoparticles. BNT162b1 encodes a soluble, secreted trimerized receptor-binding domain (known as the RBD–foldon). BNT162b2 encodes the full-length transmembrane S glycoprotein, locked in its prefusion conformation by the substitution of two residues with proline (S(K986P/V987P); hereafter, S(P2) (also known as P2 S)). The flexibly tethered RBDs of the RBD–foldon bind to human ACE2 with high avidity. Approximately 20% of the S(P2) trimers are in the two-RBD ‘down’, one-RBD ‘up’ state. In mice, one intramuscular dose of either candidate vaccine elicits a dose-dependent antibody response with high virus-entry inhibition titres and strong T-helper-1 CD4+ and IFNγ+CD8+ T cell responses. Prime–boost vaccination of rhesus macaques (Macaca mulatta) with the BNT162b candidates elicits SARS-CoV-2-neutralizing geometric mean titres that are 8.2–18.2× that of a panel of SARS-CoV-2-convalescent human sera. The vaccine candidates protect macaques against challenge with SARS-CoV-2; in particular, BNT162b2 protects the lower respiratory tract against the presence of viral RNA and shows no evidence of disease enhancement. Both candidates are being evaluated in phase I trials in Germany and the USA1–3, and BNT162b2 is being evaluated in an ongoing global phase II/III trial (NCT04380701 and NCT04368728). BNT162b1 and BNT162b2 are two candidate mRNA vaccines against COVID-19 that elicit high virus-entry inhibition titres in mice, elicit high virus-neutralizing titres in rhesus macaques and protect macaques from SARS-CoV-2 challenge.

Hesperomyces virescens (Ascomycota, Laboulbeniales), a fungal ectoparasite, is thus far reported on Harmonia axyridis from five continents: North and South America, Europe, Africa, and Asia. While it is known that He. virescens can cause mortality of Ha. axyridis under laboratory conditions, the role of biotic and abiotic factors in influencing the distribution of He. virescens in the field is unknown. We collected and screened 3,568 adult Ha. axyridis from 23 locations in seven countries in Central Europe between October and November 2018 to test the effect of selected host characters and climate and landscape variables on the infection probability with He. virescens. Mean parasite prevalence of He. virescens on Ha. axyridis was 17.9%, ranging among samples from 0 to 46.4%. Host sex, climate, and landscape composition did not have any significant effect on the infection probability of He. virescens on Ha. axyridis. Two color forms, f. conspicua and f. spectabilis, had a significantly lower parasite prevalence compared to the common Ha. axyridis f. novemdecimsignata.

Zusammenfassung Ziel der Studie Untersuchung der Perspektive von Medizinischen Fachangestellten (MFA) bezüglich der Mitwirkung in verhaltenstherapeutisch orientierten Interventionen in der Hausarztpraxis. Methode 15 MFA (w, 39,5 Jahre), Case-Manager in einem hausarztpraxis-unterstützten Übungsprogramm für Patienten mit Panik- und Angststörung (ICD-10: F41.0), wurden mittels semistrukturiertem Interviewleitfaden zur Rekrutierung von und Interaktion mit Patienten, Vermittlung der Übungen und der Implementierung in den Praxisalltag befragt. Die Interviews (n = 14) wurden dokumentiert, transkribiert und inhaltsanalytisch nach Mayring qualitativ analysiert. Ergebnisse MFA empfanden ihren Anteil an der Intervention im Rahmen der Rekrutierung und Bindung von Patienten ans Projekt durch Telefonkontakte als positiv. Schlussfolgerung Das Einbinden der MFA kann dazu beitragen, im Rahmen einer niedrigschwelligen Intervention Patienten mit psychischen Beschwerden in der hausärztlichen Versorgung gezielt zu unterstützen und den Hausarzt zu entlasten.

Parasites represent a large fraction of the world's biodiversity. They control host population sizes and contribute to ecosystem functioning. However, surveys on species diversity rarely include parasitic species. Bats often present traits favoring parasite diversity, such as large home ranges, long life spans, and large colonies. The most conspicuous bat parasites are the highly host‐specific, blood‐sucking bat flies (Diptera: Streblidae, Nycteribiidae). Recent studies have found a direct effect of habitat alteration on the abundance of bat species. We expected, therefore, that changes in the host community in response to anthropogenic habitat modification will also result in changes in the associated parasite community. We captured bats in three different habitats in Central Panama between 2013 and 2015. We recorded information on prevalence and intensity of bat fly parasitization of the seven most commonly captured bat species. Prevalence and intensity were both significantly influenced by roost type, abundance, and host sex and age. We found that habitat variables and matrix type significantly influenced the prevalence and intensity of parasitization, while the direction of the responses was host species‐ and parasite species‐specific. In general, roosting conditions and behavior of host bats appear to be fundamental in explaining changes in prevalence and intensity of parasitization between different habitat types, as bat flies are bound to the roost during their reproductive cycle. Habitat alterations affect next to the host community composition also the availability of possible roost structures as well as microclimatic conditions, which all three reflect in parasitization. Abstract in Spanish is available with online material.

Background Primary care is the main treatment setting for panic disorder and should be supplemented by collaborative care programs. However, shortage of mental health professionals prevents collaborative care programs from being effectively implemented. The PARADISE study showed the efficacy of a self-managed, cognitive-behavioural therapy (CBT)-oriented exposure training for patients with panic disorder with or without agoraphobia in primary care delivered by the family practice team. Objective To assess the cost-effectiveness of the PARADISE intervention. Design Cost-effectiveness analysis from the societal perspective based on data from a cluster-randomized controlled trial over a time horizon of 12 months. Participants Four hundred nineteen adult panic disorder patients with or without agoraphobia. Interventions A self-managed, CBT-oriented exposure training for patients with panic disorder with or without agoraphobia in primary care delivered by the primary care practice team in comparison to routine care. Main Measures Total costs from the societal perspective. Direct costs and disease-specific costs. Quality-adjusted life years based on the EQ-5D-3L. Incremental cost-effectiveness ratios and cost-effectiveness acceptability curves. Key Results Patients in the intervention group caused lower costs (mean, €1017; 95% confidence interval [-€3306; €1272]; p = 0.38) and gained on average more QALY (mean, 0.034 QALY (95% confidence interval [0.005; 0.062]; p = 0.02). Therefore, the intervention dominated the control treatment. The probability of cost-effectiveness of the intervention at a willingness-to-pay margin of €50,000 per QALY was 96%. Results from supplementary analyses considering direct or disease-specific costs instead of total costs showed comparable results. Conclusion The PARADISE intervention is cost effective. This conclusion is valid for total costs, generic health care (direct) costs, disease-specific health care costs. Trial Registration German Clinical Trials Register: DRKS00004386 Current Controlled Trials: ISRCTN64669297

Lung cancer still has one of the highest morbidity and mortality rates among all types of cancer. Its incidence continues to increase, especially in developing countries. Although the medical field has witnessed the development of targeted therapies, new treatment options need to be developed urgently. For the discovery of new drugs, human cancer models are required to study drug efficiency in a relevant setting. Here, we report the generation of a non-small cell lung cancer model with a perfusion system. The bioprinted model was produced by digital light processing (DLP). This technique has the advantage of including simulated human blood vessels, and its simple assembly and maintenance allow for easy testing of drug candidates. In a proof-of-concept study, we applied gemcitabine and determined the IC50 values in the 3D models and 2D monolayer cultures and compared the response of the model under static and dynamic cultivation by perfusion. As the drug must penetrate the hydrogel to reach the cells, the IC50 value was three orders of magnitude higher for bioprinted constructs than for 2D cell cultures. Compared to static cultivation, the viability of cells in the bioprinted 3D model was significantly increased by approximately 60% in the perfusion system. Dynamic cultivation also enhanced the cytotoxicity of the tested drug, and the drug-mediated apoptosis was increased with a fourfold higher fraction of cells with a signal for the apoptosis marker caspase-3 and a sixfold higher fraction of cells positive for PARP-1. Altogether, this easily reproducible cancer model can be used for initial testing of the cytotoxicity of new anticancer substances. For subsequent in-depth characterization of candidate drugs, further improvements will be necessary, such as the generation of a multi-cell type lung cancer model and the lining of vascular structures with endothelial cells.

Because of its mobility and ability to investigate exposed surfaces, single-sided (SiS) nuclear magnetic resonance (NMR) technology enables new application fields in geosciences. To test and assess its corresponding potential, we compare longitudinal (T 1) and transverse (T 2) data measured by SiS NMR with those of conventional geoscientific laboratory NMR. We use reference sandstone samples covering a broad range of pore sizes. Our study demonstrates that the lower signal-to-noise ratio of SiS NMR data generally tends to slightly overestimated widths of relaxation time distributions and consequently pore size distributions. While SiS and conventional NMR produce very similar T 1 relaxation data, unbiased SiS NMR results for T 2 measurements can only be expected for fine material, i.e. clayey or silty sediments and soils with main relaxation times below 0.05 s . This limit is given by the diffusion relaxation rate due to the gradient in the primary magnetic field associated with the SiS NMR. Above that limit, i.e. for coarse material, the relaxation data is strongly attenuated. If considering the diffusion relaxation time of 0.2 s in the numerical data inversion process, the information content > 0.2 s is blurred over a range larger than that of conventional NMR. However, our results show that principle range and magnitudes of the relaxation time distributions are reconstructed to some extent. Regarding these findings, SiS NMR can be helpful to solve geoscientific issues, e.g. to assess the hydro-mechanical properties of the walls of underground facilities or to provide local soil moisture data sets for calibrating indirect remote techniques on the regional scale. The greatest opportunity provided by the SiS NMR technology is the acquisition of profile relaxation data for rocks with significant bedding structures at the μm scale. With this unique feature, SiS NMR can support the understanding and modeling of hydraulic and diffusional anisotropy behavior of sedimentary rocks.

Summary Small-scale investigations of the unsaturated zone has gained increasing interest in the hydro-geophysical research community. The technique of surface-NMR (SNMR), while providing valuable data on water content and permeability in the saturated zone, has difficulties to reliably detect and interpret signals from partly-saturated soils due to low signal amplitudes. Recently, SNMR using prepolarization (SNMR-PP) has gained interest to overcome this limitation. Here, a strong prepolarization field enhances the SNMR signal of coils with a footprint of below 1m up to a level that promises to enable soil moisture measurements in the upper two meters of the subsurface in the near future. We present the first SNMR-PP measurements on a real soil and demonstrate the general feasibility of this technique to qualitatively and quantitatively detect soil moisture. Our soil moisture measurements are validated by independent time domain reflectometry (TDR) data.

A safe and effective vaccine against COVID-19 is urgently needed in quantities sufficient to immunise large populations. We report the preclinical development of two BNT162b vaccine candidates, which contain lipid-nanoparticle (LNP) formulated nucleoside-modified mRNA encoding SARS-CoV-2 spike glycoprotein-derived immunogens. BNT162b1 encodes a soluble, secreted, trimerised receptor-binding domain (RBD-foldon). BNT162b2 encodes the full-length transmembrane spike glycoprotein, locked in its prefusion conformation (P2 S). The flexibly tethered RBDs of the RBD-foldon bind ACE2 with high avidity. Approximately 20% of the P 2S trimers are in the two-RBD ‘down,’ one-RBD ‘up’ state. In mice, one intramuscular dose of either candidate elicits a dose-dependent antibody response with high virus-entry inhibition titres and strong TH1 CD4+ and IFNγ+ CD8+ T-cell responses. Prime/boost vaccination of rhesus macaques with BNT162b candidates elicits SARS-CoV-2 neutralising geometric mean titres 8.2 to 18.2 times that of a SARS-CoV-2 convalescent human serum panel. The vaccine candidates protect macaques from SARS-CoV-2 challenge, with BNT162b2 protecting the lower respiratory tract from the presence of viral RNA and with no evidence of disease enhancement. Both candidates are being evaluated in phase 1 trials in Germany and the United States. BNT162b2 is being evaluated in an ongoing global, pivotal Phase 2/3 trial (NCT04380701, NCT04368728).

Parasitism is one of the most diverse and abundant modes of life, and of great ecological and evolutionary importance. Notwithstanding, large groups of parasites remain relatively understudied. One particularly unique form of parasitism is hyperparasitism, where a parasite is parasitized itself. Bats (Chiroptera) may be parasitized by bat flies (Diptera: Hippoboscoidea), obligate blood-sucking parasites, which in turn may be parasitized by hyperparasitic fungi, Laboulbeniales (Ascomycota: Laboulbeniomycetes). In this study, we present the global tritrophic associations among species within these groups and analyze their host specificity patterns. Bats, bat flies, and Laboulbeniales fungi are shown to form complex networks, and sixteen new associations are revealed. Bat flies are highly host-specific compared to Laboulbeniales. We discuss possible future avenues of study with regard to the dispersal of the fungi, abiotic factors influencing the parasite prevalence, and ecomorphology of the bat fly parasites., publishedVersion

Summary We investigate the effect of the length scale of wetting heterogeneities, close to the length scale of a pore, on capillary pressure saturation (CPS) curves and the United States Bureau of Mines (USBM) and Amott-Harvey (AH) wettability indices. These macroscopic wettability indices are used to describe bulk rock wettability, because the local contact angle (the standard physical measure of wettability) in a sample is difficult to access and might vary within and between pores caused by changes in mineralogy and the surface coverage of organic materials. Our study combines laboratory experiments and full-scale fluid-dynamics simulations using the multiphase stochastic-rotation dynamics (SRDmc) model. Four model systems were created using monodisperse glass beads. The surface properties of the beads were modified so that one-half of the surface area in each system was strongly hydrophilic and the other half was hydrophobic. However, each system had a different length scale of wetting heterogeneity, ranging from a fraction of a bead diameter to two bead diameters. There is excellent agreement between the experimental and simulation results. All systems are classified as intermediate-wet on the basis of their AH and USBM indices. An examination of the capillary pressure curves shows that the opening of the stable hysteresis loop decreases monotonically as the length scale of the wetting heterogeneities is increased. Thus, our results suggest that macroscopic wettability indices could be used as indicators of ultimate recovery, but they are not suited to discriminate between the different flows that occur earlier in a mixed-wettability displacement process.

The tent-making bat hepatitis B virus (TBHBV) is a hepadnavirus closely related to human hepatitis B virus. The ecology of TBHBV is unclear. We show that it is widespread and highly diversified in Peters’ tent-making bats (Uroderma bilobatum) within Panama, while local prevalence varied significantly between sample sites, ranging from 0 to 14.3%. Females showed significantly higher prevalence than males, and pregnant females were more often acutely infected than non-reproductive ones. The distribution of TBHBV in bats was significantly affected by forest cover, with higher infection rates in areas with lower forest cover. Our data indicate that loss of natural habitat may lead to positive feedback on the biotic factors driving infection possibility. These results underline the necessity of multidisciplinary studies for a better understanding of mechanisms in pathogen–host relationships and for predictions in disease ecology. Electronic supplementary material The online version of this article (10.1007/s10393-018-1387-5) contains supplementary material, which is available to authorized users.

Bats are parasitized by numerous lineages of arthropods, of which bat flies (Diptera, Nycteribiidae and Streblidae) are the most conspicuous. Bat flies themselves can be parasitized by Laboulbeniales, fungal biotrophs of arthropods. This is known as hyperparasitism, a severely understudied phenomenon. Three genera of Laboulbeniales occur on bat flies: Arthrorhynchus on Nycteribiidae, Gloeandromyces and Nycteromyces on Streblidae. In this review we introduce the parasitic partners in this tripartite system and discuss their diversity, ecology, and specificity patterns, alongside some important life history traits. Furthermore, we cover recent advances in the study of the associations between bat flies and Laboulbeniales, which were neglected for decades. Among the most immediate needs for further studies are detailed tripartite field surveys. The vermin only teaze and pinch Their foes superior by an inch So, naturalists observe, a flea Has smaller fleas that on him prey; And these have smaller still to bite 'em, And so proceed ad infinitum. Jonathan Swift (On Poetry: A Rhapsody, 1733).

Bats and their ectoparasites are excellent model organisms to assess the conservation status of protected areas because both groups are speciose, and bats can be particularly affected by land use changes. The majority of bat studies conducted in Panama are clustered in protected areas around the Isthmus of Panama, while protected areas outside the Isthmus have not been studied in depth or remain largely unexplored. Coiba National Park is located on the Pacific coast of the country and is the fourth largest national park in Panama. Despite its distinct isolation from the mainland and the periodic dry spells it has undergone during the last 25,000 years, Coiba National Park has highly preserved forests. We provide the first study that assesses the structure of the bat assemblage of Coiba National Park, describe echolocation calls of some of its aerial insectivorous species, and contribute the first species list of ectoparasitic bat flies (Diptera: Streblidae). Using mist nets and acoustic monitoring techniques, we identified 30 bat species from 904 captures and 751 recordings. Artibeus jamaicensis and Carollia perspicillata were the most abundant species captured, while Myotis nigricans, Saccopteryx leptura and Molossus bondae were the most frequently recorded aerial insectivores. Associated with the bats we also identified 22 species of streblid flies, all representing new records for Coiba National Park. The host specificity was 98.2%, a high value compared to studies in other areas of Latin America. In total, we found eight new bat species for Coiba National Park, increasing the species list to 39, making it, with a rather limited study effort, the National Park with the fourth highest bat species richness recorded in Panama. We reckon that such levels of richness are correlated with the highly preserved forests of Coiba National Park.

Upscaling permeability of grid blocks is crucial for groundwater models. A novel upscaling method for three-dimensional fractured porous rocks is presented. The objective of the study was to compare this method with the commonly used Oda upscaling method and the volume averaging method. First, the multiple boundary method and its computational framework were defined for three-dimensional stochastic fracture networks. Then, the different upscaling methods were compared for a set of rotated fractures, for tortuous fractures, and for two discrete fracture networks. The results computed by the multiple boundary method are comparable with those of the other two methods and fit best the analytical solution for a set of rotated fractures. The errors in flow rate of the equivalent fracture model decrease when using the multiple boundary method. Furthermore, the errors of the equivalent fracture models increase from well-connected fracture networks to poorly connected ones. Finally, the diagonal components of the equivalent permeability tensors tend to follow a normal or log-normal distribution for the well-connected fracture network model with infinite fracture size. By contrast, they exhibit a power-law distribution for the poorly connected fracture network with multiple scale fractures. The study demonstrates the accuracy and the flexibility of the multiple boundary upscaling concept. This makes it attractive for being incorporated into any existing flow-based upscaling procedures, which helps in reducing the uncertainty of groundwater models.

Zusammenfassung Ziel Beschreibung der hausärztlichen Standardtherapie (Therapy As Usual, TAU) bei Panikstörung mit/ohne Agoraphobie (PDA). Methoden Schriftliche Befragung von 38 Hausärzten, die in einer Interventionsstudie 189 Patienten mit PDA behandelten. Ergebnisse TAU beinhaltete eine Mischung aus psychosozialen (Besprechung psychosozialer Probleme, 83 %) und pharmakologischen (SSRI, 62 %) Interventionen. Schlussfolgerung TAU erscheint weitgehend leitliniengerecht. Die Generalisierbarkeit der Ergebnisse ist studienbedingt eventuell eingeschränkt.

Multiphase flows in porous media are important in many natural and industrial processes. Pore-scale models for multiphase flows have seen rapid development in recent years and are becoming increasingly useful as predictive tools in both academic and industrial applications. However, quantitative comparisons between different pore-scale models, and between these models and experimental data, are lacking. Here, we perform an objective comparison of a variety of state-of-the-art pore-scale models, including lattice Boltzmann, stochastic rotation dynamics, volume-of-fluid, level-set, phase-field, and pore-network models. As the basis for this comparison, we use a dataset from recent microfluidic experiments with precisely controlled pore geometry and wettability conditions, which offers an unprecedented benchmarking opportunity. We compare the results of the 14 participating teams both qualitatively and quantitatively using several standard metrics, such as fractal dimension, finger width, and displacement efficiency. We find that no single method excels across all conditions and that thin films and corner flow present substantial modeling and computational challenges.

Summary Since several years, surface nuclear magnetic resonance (SNMR) is a well-established method for the hydrogeological characterization of the subsurface up to depths of 150m. When used with small surface loops of only a few square meters, SNMR suffers from low signal-to-noise ratios. This limits the methods applicability in urban areas or areas with low water content (vadose zone). Recently, the SNMR method has been extended by the application of prepolarization (PP) pulses prior to the classical spin excitation, to amplify the measured response signal. Depending on the applied PP-current, the amplification can reach up to two orders of magnitude very close to the PP-loop. This theoretically achievable amplification crucially depends on the assumption of perfect adiabatic switch-off of the corresponding PP-pulse. To study the effect of non-adiabatic switch-off, which is most likely always the case in practical applications, we implement the full spin dynamics simulation of the PP switch-off into the SNMR forward modelling. We show, that depending on the shape and duration of the PP-switch-off ramp, the resulting sounding curves can have decreased signal amplitudes of up to 45%. Neglecting this effect would yield an underestimation of the corresponding subsurface water content of similar magnitude.

Summary Measurements of surface nuclear magnetic resonance (NMR) combined with a prepolarisation previous to the conventional spin excitation are expected to enable non-invasive soil moisture investigations even in urban areas with high environmental noise. To test this expectation, we conducted prepolarised surface NMR using a very small coil (figure-of-eight coil with a diameter of 0.5 m) on a water-filled basin in the city area of Berlin. Using an additional prepolarisation coil with a diameter of 2 m, the NMR signal amplitudes could be amplified by factors up to ten. These NMR signals from depths up to 1 m could be measured and quantified despite the high urban noise level in contrast to those without prepolarisation. Significant Earth’s magnetic field heterogeneities due to the reinforcement of a near-by building yielded a shortened relaxation time for the bulk water (about 40 ms) and correspondingly a broad distribution of Larmor frequencies. We conclude that for the general applicability of surface NMR in urban areas, field heterogeneity and corresponding off-resonance effects must be considered in the forward operator. Our future research will combine prepolarisation with adiabatic spin excitation and will include the exact spin dynamics in the forward calculation.

Primary human hepatocytes (PHH) are still considered as gold standard for investigation of in vitro metabolism and hepatotoxicity in pharmaceutical research. It has been shown that the three-dimensional (3D) cultivation of PHH in a sandwich configuration between two layers of extracellular matrix (ECM) enables the hepatocytes to adhere three dimensionally leading to formation of in vivo like cell-cell contacts and cell-matrix interactions. The aim of the present study was to investigate the influence of different ECM compositions on morphology, cellular arrangement and bile canaliculi formation as well as bile excretion processes in PHH sandwich cultures systematically. Freshly isolated PHH were cultured for 6 days between two ECM layers made of collagen and/or Matrigel in four different combinations. The cultures were investigated by phase contrast microscopy and immunofluorescence analysis with respect to cell-cell connections, repolarization as well as bile canaliculi formation. The influence of the ECM composition on cell activity and viability was measured using the XTT assay and a fluorescent dead or alive assay. Finally, the bile canalicular transport was analyzed by live cell imaging to monitor the secretion and accumulation of the fluorescent substance CDF in bile canaliculi. Using collagen and Matrigel in different compositions in sandwich cultures of hepatocytes, we observed differences in morphology, cellular arrangement and cell activity of PHH in dependence of the ECM composition. Sandwich-cultured hepatocytes with an underlay of collagen seem to represent the best in vivo tissue architecture in terms of formation of trabecular cell arrangement. Cultures overlaid with collagen were characterized by the formation of abundant bile canaliculi, while the bile canaliculi network in hepatocytes cultured on a layer of Matrigel and overlaid with collagen showed the most branched and stable canalicular network. All cultures showed a time-dependent leakage of CDF from the bile canaliculi into the culture supernatant with variations in dependence on the used matrix combination. In conclusion, the results of this study show that the choice of ECM has an impact on the morphology, cell assembly and bile canaliculi formation in PHH sandwich cultures. The morphology and the multicellular arrangement were essentially influenced by the underlaying matrix, while bile excretion and leakage of sandwich-cultured hepatocytes were mainly influenced by the overlay matrix. Leaking and damaged bile canaliculi could be a limitation of the investigated sandwich culture models in long-term excretion studies.

Multi-color Stochastic Rotation Dynamics (SRDmc) has been introduced by Inoue et al. as a particle based simulation method to study the flow of emulsion droplets in non-wetting microchannels. In this work, we extend the multi-color method to also account for different wetting conditions. This is achieved by assigning the color information not only to fluid particles but also to virtual wall particles that are required to enforce proper no-slip boundary conditions. To extend the scope of the original SRDmc algorithm to e.g. immiscible two-phase flow with viscosity contrast we implement an angular momentum conserving scheme (SRDmc+). We perform extensive benchmark simulations to show that a mono-phase SRDmc fluid exhibits bulk properties identical to a standard SRD fluid and that SRDmc fluids are applicable to a wide range of immiscible two-phase flows. To quantify the adhesion of a SRDmc+ fluid in contact to the walls we measure the apparent contact angle from sessile droplets in mechanical equilibrium. For a further verification of our wettability implementation we compare the dewetting of a liquid film from a wetting stripe to experimental and numerical studies of interfacial morphologies on chemically structured surfaces., Comment: preprint submitted to Journal of Computational Physics

Deforestation and the conversion of forests to agricultural areas lead to habitat loss and often create highly fragmented landscapes. Permeability and quality of the surrounding matrix determine the connectivity of remaining forest remnants. For mobile species, such as bats, the matrix is not necessarily an entirely insurmountable obstacle. We studied the effects of fragmentation on New-World leaf-nosed bats (Phyllostomidae), a highly diverse keystone taxon in the Neotropics. Bats were assessed in two highly fragmented systems varying in matrix quality: Forested islands surrounded by the water (I) and forest fragments embedded in a matrix of small-scale agriculture (A) together with a continuous forest as control (C). In total, we recorded over 2 years 5176 captures. Observed species richness was highest in continuous forest. Fragmentation reduced in both fragmented landscapes the bat diversity and led to characteristic changes in the bat assemblage, with gleaning animalivorous phyllostomids being most affected. The responses of bats to fragmentation were found to be not only guild - but also species-specific within the guild, a fact easily overlooked or misinterpreted when focussing solely on diversity indices or the response of bat guilds alone. Forest remnants can support a relatively speciose bat fauna, due to the heterogeneity of the inter-fragment matrix. On forested islands, however, isolation processes lead to a decline in bat diversity, resulting in strongly impoverished bat assemblages favouring highly mobile species and habitat generalists. Conservation of the full local bat community of phyllostomids, including the vulnerable gleaning animalivorous phyllostomids, however, requires the protection of old-growth forests.

We present a newly developed high-pressure nuclear magnetic resonance (NMR) flow cell, which allows for the simultaneous determination of water saturation, effective gas permeability and NMR relaxation time distribution in two-phase fluid flow experiments. We introduce both the experimental setup and the experimental procedure on a tight Rotliegend sandstone sample. The initially fully water saturated sample is systematically drained by a stepwise increase of gas (Nitrogen) inlet pressure and the drainage process is continuously monitored by low field NMR relaxation measurements. After correction of the data for temperature fluctuations, the monitored changes in water saturation proved very accurate. The experimental procedure provides quantitative information about the total water saturation as well as about its distribution within the pore space at defined differential pressure conditions. Furthermore, the relationship between water saturation and relative (or effective) apparent permeability is directly determined.

Harmonia axyridis is an invasive ladybird (Coleoptera, Coccinellidae) with the potential to outcompete native ladybird species in its invasive distribution area. It was introduced as a biological control agent in many countries but has also spread unintentionally in many others. Hesperomyces virescens (Ascomycota, Laboulbeniales) is a minute (200–400 µm in size) biotrophic fungus that infects over 30 species of ladybirds. The aim of this study was to evaluate whether elytral colour pattern, size, and sex of Ha. axyridis affect infection by H. virescens. Colouration in Ha. axyridis has been linked to the presence of an antimicrobial alkaloid (harmonine). In fall 2016, we collected 763 Ha. axyridis individuals in Cambridge, Massaschusetts, of which 119 (16%) bore H. virescens fruiting bodies. We analysed 160 individuals concerning prevalence and intensity of infection by H. virescens. Elytral sizes and colouration patterns were quantified using digital photography and analytical methods. Smaller ladybirds had a higher prevalence and higher intensity of parasitism. Additionally, male ladybirds bore more thalli compared to female ladybirds. Elytral colour patterns had an effect on neither prevalence nor intensity of infection by Laboulbeniales in our dataset. This suggests that development of Laboulbeniales may be unaffected by certain insect alkaloids.

Bat flies (Streblidae) are diverse, obligate blood-feeding insects and probably the most conspicuous ectoparasites of bats. They show preferences for specific body regions on their host bat, which are reflected in behavioural characteristics. In this study, we corroborate the categorization of bat flies into three ecomorphological groups, focusing only on differences in hind leg morphology. As no detailed phylogeny of bat flies is available, it remains uncertain whether these morphological differences reflect the evolutionary history of bat flies or show convergent adaptations for the host habitat type. We show that the division of the host bat into three distinct habitats contributes to the avoidance of interspecific competition of bat fly species. Finally, we found evidence for density-dependent competition between species belonging to the same ecomorphological group.

Hypopigmentation disorders were reported in several bat species roosting in dark and sheltered roosts, but comparable records from open foliage roosts are rare. Here, we present three observations of non-albinistic hypopigmentation in two neotropical bat species. One extensively hypopigmented individual of

This protocol describes the generation of a three-dimensional (3D) ex vivo liver model and its application to the study and development of viral vector systems. The model is obtained by repopulating the extracellular matrix of a decellularized rat liver with a human hepatocyte cell line. The model permits studies in a vascularized 3D cell system, replacing potentially harmful experiments with living animals. Another advantage is the humanized nature of the model, which is closer to human physiology than animal models. In this study, we demonstrate the transduction of this liver model with a viral vector derived from adeno-associated viruses (AAV vector). The perfusion circuit that supplies the 3D liver model with media provides an easy means to apply the vector. The system permits monitoring of the major metabolic parameters of the liver. For final analysis, tissue samples can be taken to determine the extent of recellularization by histological techniques. Distribution of the virus vector and expression of the delivered transgene can be analyzed by quantitative PCR (qPCR), Western blotting and immunohistochemistry. Numerous applications of the vector model in basic research and in the development of gene therapeutic applications can be envisioned, including the development of novel antiviral therapeutics, cancer research, and the study of viral vectors and their potential side effects.

Background The liver is the major site for alcohol metabolism in the body and therefore, the primary target organ for ethanol-induced toxicity. In this study, we investigated the in vitro response of human liver cells to different ethanol concentrations in a perfused bioartificial liver device that mimics the complex architecture of the natural organ. Methods Primary human liver cells were cultured in the bioartificial liver device and treated for 24 hours with medium containing 150 mM (low), 300 mM (medium) or 600 mM (high) ethanol, while a control culture was kept untreated. Gene expression patterns for each ethanol concentration were monitored using Affymetrix Human Gene 1.0 ST Genechips. Scaled expression profiles of differentially expressed genes (DEGs) were clustered using Fuzzy c-means algorithm. In addition, functional classification methods, KEGG pathway mapping and also a machine learning approach (Random Forest) were utilized. Results A number of 966 (150 mM ethanol), 1,334 (300 mM ethanol), or 4,132 (600 mM ethanol) genes were found to be differentially expressed. Dose-response relationships of the identified clusters of co-expressed genes showed a monotonic, threshold or non-monotonic (hormetic) behavior. Functional classification of DEGs revealed that low or medium ethanol concentrations operate adaptation processes, while alterations observed for the high ethanol concentration reflect the response to cellular damage. The genes displaying a hormetic response were functionally characterized by over-represented ‘cellular ketone metabolism’ and ‘carboxylic acid metabolism’. Altered expression of the genes BAHD1 and H3F3B was identified as sufficient to classify the samples according to the applied ethanol doses. Conclusions Different pathways of metabolic and epigenetic regulation are affected by ethanol exposition and partly undergo hormetic regulation in the bioartificial liver device. Gene expression changes observed at high ethanol concentrations reflect in some aspects the situation of alcoholic hepatitis in humans This article is protected by copyright. All rights reserved.

The impact, caused by a construction of a dam site on the Birs river close to Basel (Switzerland), on the evolution of a gypsum-karst aquifer in the vicinity of the hydraulic building, is studied. Several sinkholes provoked subsidence of the dam and the highway nearby. Extensive technical measures had to be conducted in order to prevent further karstification. The numerous geophysical and geological field studies executed in the area, together with a 3D hydrogeological model of the aquifer, provide a very detailed information about the boundary conditions, and the local properties determining the karstification. In this work, we present a 2D karst evolution model of the aquifer in the vicinity of the dam structure. In contrast to older studies, this time the focus of the research is not the basic processes governing the karst evolution, but modeling the temporal development of the real aquifer. Using the large amount of information about the location, we demonstrate that a detailed knowledge of the local properties of the rock (hydraulic conductivity, solubility) is of crucial importance when modeling real aquifers. From a wide range of possible evolution scenarios, we deduce a warning that solutional features, such as sinkholes, can develop far away from the hydraulic structure and endanger facilities at the surface. Our model is able to reproduce and successfully explain the main geological features revealed by field studies. We suggest a workflow to combine the data from field observations, groundwater modeling, and karst evolution modeling and to study the karstification of real aquifers. We propose a scenario for the evolution of the aquifer and a reasonable range for the values of the basic parameters governing the karstification.

We present a three-dimensional model describing the evolution of a gypsum karst aquifer along the Birs river near Basel in Switzerland. Here, a small dam-site was built in 1890 to generate hydro-electric power. After subsidence of a nearby highway, geophysical and geological field studies have been carried out and a detailed hydrogeological model has been developed. These observations identified a karstified weathered zone as the reason for the subsidence. To prevent any further damage, remedial construction measures have been carried out. We employ our numerical model KARSTAQUIFER, which simulates the temporal evolution of a karst system by dissolution, increasing the porosity in the aquifer. We used results from geological and geophysical investigations as a priori information for implementing the initial boundary conditions into our three-dimensional numerical model. Our model accounts for topography, precipitation and geology and especially for the anisotropy of the local bedrock. It can successfully reproduce the weathered zone in its current horizontal and vertical extent. We cm also simulate the possible evolution of the aquifer following a remedial construction phase. Therefore, taken together with the geophysical and geological observations and the groundwater model, our three-dimensional karst aquifer evolution model enhances the understanding of the development of this heterogeneous karst aquifer system. (C) 2012 Elsevier B.V. All rights reserved. Hydrogeologie der Nordwestschweiz, Grundwasser

Summary Dam-sites and reservoirs located above soluble rock are often damaged by increased leakage through the sub-surface within the life-time of the structure. The high hydraulic gradients driving the water through the fracture and fissure system of the bedrock have a strong impact on the aquifer evolution. The increased permeability, if not prevented, leads to an imminent danger of high leakage rates (breakthrough) as well. As a result, the structural safety of the dam-site itself is at risk. Past experience has shown that this may have large environmental and economical consequences. For a better understanding of the evolution of karst aquifer systems in the vicinity of dam-sites, a three-dimensional conceptual model is presented. We show the evolution of the karst aquifer for simple three-dimensional dam-site setups. Keeping the symmetry and simplicity of the models we can relate our results to the two- and one-dimensional scenarios presented in the past. Implementing a statistical fracture network and topographic information to this basic setup we show that these complex three-dimensional properties of the real aquifers, have a significant influence on the karstification, and cannot always be addressed by two -and one-dimensional models.

The measurements of nuclear magnetic resonance (NMR) parameters to investigate petrophysical properties related to fluid (e.g., water) storage and transport processes provide unique insights compared to other geophysical methods and have become a very useful tool for geophysicists during the last decades at the laboratory scale and as a borehole tool. We investigated, at a groundwater test site in the desert of Abu Dhabi, the reliability and limitation of surface NMR, a new but establishing technique that measures the NMR parameter from the surface by comparing its results to borehole NMR logs. Surface NMR or magnetic resonance sounding measurements (MRS) were conducted along a profile, close to several boreholes. The available borehole NMR logs were used to i) evaluate the potential of surface NMR derived results comparing them with borehole NMR measurements and to ii) extend the hydrogeological knowledge of the groundwater site. Firstly, we show how to carefully handle short relaxation signals of surface NMR data. The most significant steps during this process are: i) broad-band filtering to preserve the short decaying NMR signals, ii) correction for relaxation during pulse effects and iii) QT-inversion to extract reliable subsurface parameter distribution. By comparing surface NMR results with borehole NMR logs we found the following limitations: i) surface NMR is not able to detect borehole NMR measured water content related to T2 decay times lower than ≈80 ms T2 decay time. This reduced detectable water content of surface NMR is due to an instrumental dead time of 40 ms, measured T2* relaxation times and a lower Larmor frequency of 2 kHz and ii) borehole NMR has significantly higher vertical resolution. Taking this into account, surface NMR is in good agreement with borehole NMR. Secondly, on a profile of 1.3 km length 11 MRS measurements were carried out to map the lateral aquifer structure. The obtained results show that surface NMR provides unique lateral information of demanded aquifer properties complementary to e.g., transient electromagnetic.

We have developed a numerical model able to describe the karstification of aquifers in fractured rocks containing soluble (limestone or gypsum) and insoluble layers. When water is flowing along fractures crossing the soluble layers, it is able to dissolve the material there, to increase the aperture width of the conduit, and consequently to increase the local hydraulic conductivity. Depending on the thickness and the distribution of these layers, the dissolution can be active only for limited periods, or during the whole evolution time. Fractures located in insoluble layers do not change at all. We are interested in the integral effect of these local processes and study four simplified scenarios of karstification along a prominent wide conduit crossing a fractured limestone block. We keep the initial and the boundary conditions the same for all scenarios and vary only in the amount and the distribution of the soluble material. We demonstrate that aquifers in 100% limestone, without any insoluble layers, develop along areas with high hydraulic conductivities and high hydraulic gradients, creating channel like pathways. On the other hand aquifers containing soluble layers with limited thickness develop faster and exhibit diffuse patterns determined by the chemical properties of the rock. The second part of the paper is a step towards modeling of real karst systems. We present the evolution of an aquifer located in the vicinity of a large hydraulic structure. All initial and boundary conditions, except the amount and the distribution of the soluble rock, remain the same for all scenarios. As a material example for the bedrock, we chose Gipskeuper from an aquifer along the Birs river in Switzerland. This rock consists of soluble gypsum layers and insoluble clays and marls, with typical layer thickness in the range of millimeters to centimeters. The basic processes discussed in the first part of the paper remain valid. We demonstrate that large insoluble zones can impair the karstification process and even completely block it, while areas with thin soluble layers can provide a preferential pathway and decrease the evolution times considerably. Finally we show that the evolution of the leakage rates and the head distribution within the aquifer can sometimes reveal misleading information about the stage of karstification and the safeness of the dam. Our model can be used not only to study simplified geological settings and basic processes, but also to address some of the complications arising when modeling real aquifers.

Summary We have developed the program package KARSTAQUIFER, which simulates flow and transport in a three-dimensional transient karst aquifer consisting of fractures and matrix elements. The fractures can be enlarged by chemical dissolution of calcite, increasing the secondary permeability of the karst aquifer. Boundary conditions for our model setup are guided by published benchmark models for karst aquifer evolution in two dimensions (length and width), with a 100 m high hydraulic head difference across the model domain responsible for relatively fast evolution of the aquifer. We are interested in the effect of the third dimension on the evolution of the karst aquifer, especially the effect of matrix flow, with a matrix defined either as porous medium or as fine fracture system, or both. We first discuss our model results using a pseudo-3D setup to be able to directly compare results to the 2D benchmark scenarios published. We then discuss real-3D models with a prominent fault located in the central part of the aquifer, connecting input and output regions. Finally, we replace the prominent fault with a statistical fracture diameter distribution. Our results compare well with existing 2D scenarios, and the additional third dimension offers new insights into the evolution of karst aquifers. Especially the role of matrix flow under fixed-head boundary conditions in their early phases can be studied in more detail.

Human papillomaviruses (HPVs) cause cervical cancer and are associated with the development of non-melanoma skin cancer. A suitable animal model for papillomavirus-associated skin carcinogenesis is the infection of domestic rabbits with the cottontail rabbit papillomavirus (CRPV). As the immortalizing activity of CRPV genes in the natural target cells remains unknown, we investigated the properties of CRPV E6 and E7 in rabbit keratinocytes (RK) and their influence on the cell cycle. Interestingly, CRPV E7 immortalized RK after a cellular crisis but showed no such activity in human keratinocytes. Co-expressed CRPV E6 prevented cellular crisis. The HPV16 or CRPV E7 protein reduced rabbit pRb levels thereby causing rabbit p19ARF induction and accumulation of p53 without affecting cellular proliferation. Both CRPV E6 proteins failed to degrade rabbit p53 in vitro or to bind E6AP; however, p53 was still inducible by mitomycin C. In summary, CRPV E7 immortalizes rabbit keratinocytes in a species-specific manner and E6 contributes to immortalization without directly affecting p53.

XRCC1 protein is required for the repair of DNA single-strand breaks and genetic stability, and is essential for viability in mammals. XRCC1 functions as a scaffold protein by interacting and modulating polypeptide components of the single-strand break repair machinery, including AP endonuclease-1, DNA ligase IIIalpha, poly (ADP-ribose) polymerase, DNA polymerase beta and human polynucleotide kinase. We show here that the E6 protein of human papillomavirus type 1, 8 and 16 directly binds XRCC1. When tested in CHO derived XRCC1 'knock out' EM9 cells, co-expression of human papillomavirus 16 E6 with human XRCC1 reduced the ability of the latter protein to correct the methyl methane sulfate sensitivity of XRCC1 mutant CHO cell line EM9. These data identify a novel link between small DNA tumour viruses and DNA repair pathways, and suggest a novel explanation for the development of genomic instability in tissue cells persistently infected with papillomaviruses.

We present a 3D numerical karst evolution model describing mechanisms governing the evolution of collapse dolines. The results confirm the current state of the art of the knowledge about the conditions necessary for a collapse doline to grow. We demonstrate that these geological features develop in karst aquifers, above subsurface rivers flowing through active cave systems or mechanically unstable zones. The mechanisms of growth of single/isolated collapse dolines are generally two dimensional and can be modeled with very dense numerical models. On the other hand, our results demonstrate that there can be more than one location, within a karst system, where the conditions allow the development of a collapse doline. For such complex scenarios a 3D modeling approach and a detailed knowledge of the hydro-geological situation is required in order to correctly predict and describe the development of collapse dolines.

Splicing is an essential cellular process to generate mature transcripts from pre-mRNA. It requires the splice factor U1 small nuclear ribonucleoprotein (U1), which promotes exon recognition by base-pairing interaction with the splice donor site (SD). After U1 dissociation, exon recognition is maintained by U6 small nuclear ribonucleoproteins (U6). It has been shown that SD mutations lower the binding affinity of U1 and cause splice defects in about 10% of patients with monogenetic diseases. U1 isoforms specifically designed to bind the mutated SD with increased affinity can correct these splice defects. We investigated the applicability of this gene therapeutic approach for different mutated SD positions. A minigene-based splicing assay was established to study a typical SD derived from the gene BBS1. We found that mutations at seven SD positions caused splice defects. In four cases, mutation-adapted U1 isoforms completely corrected these splice defects. Partial correction was found for splice defects induced by the mutation at SD position +5. The limited therapeutic efficacy at this position was alleviated by applying a combined treatment with mutation-adapted U1 and U6. The sequence complementarity between U6 and three SD positions (+4, +5,and +6) was relevant for the outcome of the therapy. Between 30 and 100% of the normal transcripts can be restored. The treatment significantly decreased both exon skipping and intron retention. Massive missplicing of off-target transcripts was not detected. Our study helps to assess the therapeutic efficacy of mutation-adapted U snRNAs in gene therapy and illustrates their strong potential to correct splice defects, which cause many different inherited conditions.

Small, man-portable AUVs now carry out engineering and geophysical survey tasks where previously boat-mount, towed or ROV-mounted sonars would have been required. The commercial use of low-logistics AUVs in the offshore survey industry is expanding rapidly, with several companies now operating small survey AUVs worldwide. This paper describes some of the advances in vehicle and payload technology which have enabled the uptake in commercial survey roles such as pipeline inspections, rig move surveys, harbor inspections and environmental work. Modular AUV design has enabled the continued expansion of the small-AUV envelope of operations: extending time on-site with field-swappable batteries; enhancing deliverables with multi-sensor configurations such as swath bathymetry and sub-bottom profiler; and enabling longer mission durations with multiple battery configurations. One limitation to AUV operations has been the accuracy of navigation during extended submerged missions. This has led to the development of subsea position aiding techniques such as inverted USBL to improve in the accuracy of longer missions and deeper water surveys (up to 1000m). Current AUV system performance and capabilities are illustrated using examples of side scan, swath bathymetry and sub-bottom data from a widely used low-logistics survey AUV, the Gavia Surveyor.

Strategies for antibody-mediated cancer immunotherapy, such as active immunization with virus-like particle (VLP)-based vaccines, are gaining increasing attention. We developed chimeric hepatitis B virus core antigen (HBcAg)-VLPs that display a surface epitope of the highly selective tumor-associated cell lineage marker claudin-18 isoform 2 (CLDN18.2) flanked by a mobility-increasing linker. Auto-antibodies elicited by immunization with these chimeric HBcAg-VLPs in 2 relevant species (mouse and rabbit) bind with high precision to native CLDN18.2 at physiologic densities on the surface of living cells but not to the corresponding epitope of the CLDN18.1 splice variant that differs by merely one amino acid. The induced auto-antibodies are capable of efficiently killing CLDN18.2 expressing cells in vitro by complement-dependent and antibody-dependent cell-mediated cytotoxicity. Moreover, they provide partial protective immunity against the challenge of mice with syngeneic tumor cells stably expressing CLDN18.2. Our study provides a first proof-of-concept that immunization combining VLPs as antigen carriers with specific conformational epitopes of a highly selective differentiation antigen may elicit auto-antibodies with high cytocidal and tumoricidal potential. Cancer Res; 71(2); 516–27. ©2011 AACR.

We have analyzed E6 proteins of 19 papillomaviruses able to infect genital tissue with regard to their ability to degrade p53 and the thus far unknown immortalization potential of the genomes of human papillomaviruses (HPV) 53, 56, 58, 61, 66, and 82 in primary human keratinocytes. E6 proteins of HPV types 16, 18, 33, 35, 39, 45, 51, 52, 56, 58, and 66, defined as high-risk types, were able to induce p53 degradation in vitro, and HPV18-, HPV56-, and HPV58-immortalized keratinocytes revealed markedly reduced levels of p53. In contrast, the E6 proteins of HPV6 and 11 and HPV44, 54, and 61, regarded as possible carcinogenic or low-risk HPV types, respectively, did not degrade p53. Interestingly, the E6 proteins of HPV 53, 70, and 82 inconsistently risk classified in the literature were also found to induce p53 degradation. The genomes of HPV53 and 82 immortalized primary human keratinocytes that revealed almost absent nuclear levels of p53. These data suggest a strict correlation between the biological properties of certain HPV types with conserved nucleotide sequence (phylogeny), which is largely coherent with epidemiologic risk classification. HPV types 16, 18, 33, 35, 39, 45, 51, 52, 56, 58, and 66, generally accepted as high-risk types, behaved in our assays biologically different from HPV types 6, 11, 44, 54, and 61. In contrast, HPV70, regarded as low-risk type, and HPV53 or HPV82, with inconsistent described risk status, were indistinguishable with respect to p53 degradation and immortalization from prototype high-risk HPV types. This could imply that other important functional differences exist between phylogenetically highly related viruses displaying similar biological properties in tissue culture that may affect their carcinogenicity in vivo. (Cancer Epidemiol Biomarkers Prev 2006;15(7):1262–7)

An new approach in the field of process control programming is the usage of graphical objects. This new conception tries to concentrate on the process itself and not on special languages used by different PCU's. The main idea is that pictures nowadays used only for process supervision are used at programming time. The problem itself is solved by dividing it in small function units. Every unit has a graphical equivalent associated to it. These objects are now used for programming. A synthesis phase delivers the final control program in the desired PCU language.