Exploration of GH94 Sequence Space for Enzyme Discovery Reveals a Novel Glucosylgalactose Phosphorylase Specificity

The substantial increase in DNA sequencing efforts has led to a rapid expansion of available sequences in glycoside hydrolase families. The ever-increasing sequence space presents considerable opportunities for the search for enzymes with novel functionalities. In this work, the sequence-function space of glycoside hydrolase family 94 (GH94) was explored in detail, using a combined approach of phylogenetic analysis and sequence similarity networks. The identification and experimental screening of unknown clusters led to the discovery of an enzyme from the soil bacterium Paenibacillus polymyxa that acts as a 4-O-β-d -glucosyl-d -galactose phosphorylase (GGalP), a specificity that has not been reported to date. Detailed characterization of GGalP revealed that its kinetic parameters were consistent with those of other known phosphorylases. Furthermore, the enzyme could be used for production of the rare disaccharides 4-O-β-d -glucosyl-d -galactose and 4-O-β-d -glucosyl-l -arabinose. Our current work highlights the power of rational sequence space exploration in the search for novel enzyme specificities, as well as the potential of phosphorylases for rare disaccharide synthesis.     

Color evolution during a coating process of pharmaceutical tablet cores by random spraying

Placebo white tablet cores (lactose anhydrous [47.6%], corn starch [23.8%], microcrystalline cellulose [19.1%], polyvinylpyrrolidone [7.9%], magnesium stearate [0.8%], and talcum powder [0.8%]) were coated with a colorant (hydroxypropyl methylcellulose [8% w/v], titanium dioxide [0.2% w/v], FD&C yellow No. 6 with aluminum lacquer [0.8% w/v], polyethylene glycol 4000 [0.4% w/v], and purified water [q.s.p. 100 mL]) using a random spraying method during 130 minutes. During the coating process, batches of 21 samples were extracted every 10 minutes and measured with a DigiEye imaging system. The initial cores showed very similar and uniform colors (Mean Color Difference from the Mean [MCDM] of 0.8 CIELAB units), but partially coated tablets showed lower uniformity (MCDM below 2.0 CIELAB units). There was a high color variability (MCDM about 4.0 CIELAB units) among tablets of the same batch in the period between 10 and 30 minutes, which decreased as the coating process progressed, until achieving a final acceptable value (MCDM below 2.0 CIELAB units). During the coating process, L^* decreased, C^*_ab strongly increased, and h _ab remained nearly constant (disregarding results at 0 and 10 minutes). CIELAB and CIEDE2000 color differences (mainly chroma differences) with respect to the initial color of the tablets were modeled as a function of time by exponential functions with three coefficients. The color change in the interval from 90 to 130 minutes (4.3 CIELAB units, or 2.6 CIEDE2000 units), may be considered negligible bearing in mind the color variability in the batches of 21 samples and typical values of visual color thresholds.     

BET-Inhibitor I-BET762 and PARP-Inhibitor Talazoparib Synergy in Small Cell Lung Cancer Cells

Small cell lung cancer (SCLC) is an aggressive type of lung cancer with high mortality that is caused by frequent relapses and acquired resistance. Despite that several target-based approaches with potential therapeutic impact on SCLC have been identified, numerous targeted drugs have not been successful in providing improvements in cancer patients when used as single agents. A combination of targeted therapies could be a strategy to induce maximum lethal effects on cancer cells. As a starting point in the development of new drug combination strategies for the treatment of SCLC, we performed a mid-throughput screening assay by treating a panel of SCLC cell lines with BETi or AKi in combination with PARPi or EZH2i. We observed drug synergy between I-BET762 and Talazoparib, BETi and PARPi, respectively, in SCLC cells. Combinatorial efficacy was observed in MYCs-amplified and MYCs-wt SCLC cells over SCLC cells with impaired MYC signaling pathway or non-tumor cells. We indicate that drug synergy between I-BET762 and Talazoparib is associated with the attenuation HR-DSBR process and the downregulation of various players of DNA damage response by BET inhibition, such as CHEK2, PTEN, NBN, and FANCC. Our results provide a rationale for the development of new combinatorial strategies for the treatment of SCLC.     

Toward an execution system for self-healing workflows in cyber-physical systems

Cyber-physical systems (CPS) represent a new class of information system that also takes real-world data and effects into account. Software-controlled sensors, actuators and smart objects enable a close coupling of the cyber and physical worlds. Introducing processes into CPS to automate repetitive tasks promises advantages regarding resource utilization and flexibility of control systems for smart spaces. However, process execution systems face new challenges when being adapted for process execution in CPS: the automated processing of sensor events and data, the dynamic invocation of services, the integration of human interaction, and the synchronization of the cyber and physical worlds. Current workflow engines fulfill these requirements only to a certain degree. In this work, we present PROtEUS—an integrated system for process execution in CPS. PROtEUS integrates components for event processing, data routing, dynamic service selection and human interaction on the modeling and execution level. It is the basis for executing self-healing model-based workflows in CPS. We demonstrate the applicability of PROtEUS within two case studies from the Smart Home domain and discuss its feasibility for introducing workflows into cyber-physical systems.     

Internet use among older Europeans: an analysis based on SHARE data

Access to the Internet is becoming increasingly important for all generations. However, a digital gap in Internet use remains between younger and older individuals as well as within the elderly population itself. This study, therefore, aimed to investigate Internet use among elderly Europeans. Representative data across 17 countries from the Survey of Health, Ageing and Retirement in Europe (SHARE) were examined. Analyses were based on the responses of 61,202 Europeans aged ≥ 50. Results highlight that, on average, 49% of all respondents use the Internet. However, the situation varies widely among European countries. Alongside individual indicators, such as age, gender, and social class, results indicate that previous experience with computers during one’s time in the workplace is positively associated with Internet use in old age. Furthermore, use of the Internet among an individual’s social network positively influences their use. Wider contextual structures such as area of residence and country-specific wealth and communication technology infrastructure also tend to promote Internet use among elderly Europeans. Data from SHARE indicate that private Internet use among older Europeans is driven by personal resources, prior experiences with technology, social salience as well as contextual influences.     

Linking Hydro-Physical Variables and Landscape Metrics using Advanced Data Mining for Stream-Flow Prediction

Water Resources Management - In Streamflow prediction the most important triggering/controlling variables are related to climate, physiography, and landscape patterns. This study investigated the...     

Intrinsic flame resistance of polyurethane flexible foams: Unexpectedly low flammability without any flame retardant

Virgin polyurethane flexible foams are widely assumed to be highly flammable materials. The flammability of three model polyurethane flexible foams suggests that this may not be universally true. Two of them show unexpectedly low flammability in the limiting oxygen index test and pass flammability tests such as FMVSS 302 and FAR 25.853. Cone calorimetric measurements at 25 kW/m² and 50 kW/m² furthermore show a high resistance against ignition and demonstrate the self‐extinguishing properties of these two virgin, flame‐retardant‐free, polyurethane flexible foams.     

Positive Pressure Ventilation in Single Medium-Sized Premises

The objective of this study was to investigate the feasibility, for the fire and rescue services, of using mobile fans as a pro-active means of ventilating smoke in medium-sized premises. The efficacy of various types of such fans was therefore tested in two different-sized premises by measuring air pressures and volume flow rates in the premises. Three different types of mobile fans were used. The study was a cold exercise, i.e. the effects of heat and smoke were not considered, in view of the fact that we were primarily interested in the volume flow capacity and pressure. In order better to illustrate and understand the experimental data, simple theoretical models were developed which describe how various parameters affect the results. The parameters considered in the model were the size of the supply and exhaust openings, the primary air flow of the fan, volume flow and static pressure in the building.     

Proposed design methods for lateral torsional buckling of unrestrained steel beams in fire

The behaviour of unrestrained steel I-beams has been studied by means of numerical analysis and published experimental results. The numerical model was developed using a commercial finite element program, MSC.MARC Mentat. A series of different UB and UC sections and different spans, subjected to both uniform moment and midspan point loads, are considered. The numerical predictions of the buckling moments are then compared with published experimental results. Consequently, a new approach is proposed to provide more accurate and safe predictions of the fire resistance of unrestrained beams, as well as to overcome certain weaknesses in the EC3:1.2 [European committee for standardization (CEN). Eurocode 3: Design of steel structures, Part 1.2: General rules — structural fire design, EN 1993-1-2. Brussels (Belgium); 2005] design formula. In addition, to provide a quick and simple design approach for engineers, a straightforward and rational method known as the Rankine method is introduced to predict the LTB failure load of steel beams in fire. It is shown that the Rankine approach generally provides a good lower bound value for numerical predictions.