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Rationale & Objective: It is unclear whether the effect of canagliflozin on adverse kidney and cardiovascular events in those with diabetic kidney disease varies by age and sex. We assessed the effects of canagliflozin among age group categories and between sexes in the Canagliflozin and Renal Endpoints in Diabetes with Established Nephropathy Clinical Evaluation (CREDENCE) study.Study Design: Secondary analysis of a randomized controlled trial.Setting & Participants: Participants in the CREDENCE trial.Intervention: Participants were randomly assigned to receive canagliflozin 100 mg/d or placebo.Outcomes: Primary composite outcome of kidney failure, doubling of serum creatinine concentration, or death due to kidney or cardiovascular disease. Prespecified secondary and safety outcomes were also analyzed. Outcomes were evaluated by age at baseline (Results: The mean age of the cohort was 63.0 ± 9.2 years, and 34% were female. Older age and female sex were independently associated with a lower risk of the composite of adverse kidney outcomes. There was no evidence that the effect of canagliflozin on the primary outcome (a composite of kidney failure, a doubling of serum creatinine concentration, or death from kidney or cardiovascular causes) differed between age groups (HRs, 0.67 [95% CI, 0.52-0.87], 0.63 [0.48-0.82], and 0.89 [0.61-1.29] for ages Limitations: This was a post hoc analysis with multiple comparisons.Conclusions: Canagliflozin consistently reduced the relative risk of kidney events in people with diabetic kidney disease in both sexes and across age subgroups. As a result of greater background risk, the absolute reduction in adverse kidney outcomes was greater in younger participants.Funding: This post hoc analysis of the CREDENCE trial was not funded. The CREDENCE study was sponsored by Janssen Research and Development and was conducted collaboratively by the sponsor, an academic-led steering committee, and an academic research organization, George Clinical.Trial Registration: The original CREDENCE trial was registered at ClinicalTrials.gov with study number NCT02065791.

Neural Network Coding and Representation (NNR) is the first international standard for efficient compression of neural networks (NNs). The standard is designed as a toolbox of compression methods, which can be used to create coding pipelines. It can be either used as an independent coding framework (with its own bitstream format) or together with external neural network formats and frameworks. For providing the highest degree of flexibility, the network compression methods operate per parameter tensor in order to always ensure proper decoding, even if no structure information is provided. The NNR standard contains compression-efficient quantization and deep context-adaptive binary arithmetic coding (DeepCABAC) as core encoding and decoding technologies, as well as neural network parameter pre-processing methods like sparsification, pruning, low-rank decomposition, unification, local scaling and batch norm folding. NNR achieves a compression efficiency of more than 97% for transparent coding cases, i.e. without degrading classification quality, such as top-1 or top-5 accuracies. This paper provides an overview of the technical features and characteristics of NNR.

Shorter product innovation cycles, high variant products, and demand fluctuation, as well as equipment life cycles and technology life cycles force manufacturing companies to regularly change their manufacturing system. In order to address this challenge, an efficient and structured change management is required. As change causes and factory elements are connected via a complex network of relations and flows, an essential step in change management is the evaluation of considered adjustments with regard to their effects on the current production system. Depending on the context of the application, change impact analysis must process specific inputs and deliver different results. Current approaches, however, each focus only on selected aspects of the versatility of change effects. To address this challenge, this paper presents a modular approach for the individual design of change impact analysis.

The transcription factor STAT6 regulates gene expression in response to IL-4 and IL-13. To further investigate how activated STAT6 modulates B cells development and function in vivo, we characterized mice that express a constitutively active version specifically in B cells. CD19Cre_STAT6vt mice show spontaneous phosphorylation and nuclear translocation of STAT6 in B cells. About 80 genes were more than twofold up- or downregulated in splenic B cells from CD19Cre_STAT6vt as compared to control mice. B cell development, tissue localization, and populations of follicular and marginal zone B cells, B1 B cells, GC B cells, and plasma cells (PCs) appeared to be normal. However, the number of IgE+ and IgG1+ GC B cells and PCs as well as serum IgE and IgG1 levels were increased in CD19Cre_STAT6vt mice. Infection with Lymphocytic choriomeningitis virus associated with high levels of TNF and IFN-γ did not prevent the development of a significantly increased IgE and IgG1 response against the virus in CD19Cre_STAT6vt mice. These results suggest that prolonged STAT6 activation during chronic allergic inflammation may result in IgE responses during subsequent viral or bacterial infection that could further stimulate mast cell activation even in the absence of the initial allergic response.

Recent approaches to compression of deep neural networks, like the emerging standard on compression of neural networks for multimedia content description and analysis (MPEG-7 part 17), apply scalar quantization and entropy coding of the quantization indexes. In this paper we present an advanced method for quantization of neural network parameters, which applies dependent scalar quantization (DQ) or trellis-coded quantization (TCQ), and an improved context modeling for the entropy coding of the quantization indexes. We show that the proposed method achieves 5.778% bitrate reduction and virtually no loss (0.37%) of network performance in average, compared to the baseline methods of the second test model (NCTM) of MPEG-7 part 17 for relevant working points.

The type 2 immune response is associated with helminth infections and allergic inflammation where antibody production of the IgG1 and IgE isotypes can elicit protective or proinflammatory functions. Studies over the past few years revealed important new insights regarding the regulatory mechanisms orchestrating the humoral type 2 immune response. This includes investigations on B-cell extrinsic signals, such IL-4 and IL-21, derived from different T-helper cell subsets or discovery of new follicular helper T cells with regulatory or IgE-promoting activities. In addition, studies on B-cell intrinsic factors required for germinal center formation and class switch recombination, including the transcription factors STAT3, STAT6, and BCL-6, led to a better understanding of these processes in type 2 immune responses. Here, we review the current understanding of mechanisms controlling humoral type 2 immunity in vivo including the generation of IgE-producing plasma cells and the memory IgE response.

Background Allergic inflammation is driven by IgE-producing plasma cells (PCs), which are required for IgE-mediated activation of mast cells and basophils. Repeated antigen encounter elicits a memory IgE response with elevated serum IgE titers and accumulation of IgE-producing PCs. However, the cellular compartment and molecular signals that underlie the immunologic memory of IgE responses remain unclear. Objective With this study we aimed at clarifying whether inactivation of the cytoplasmic immunoglobulin tail tyrosine (ITT) motif in transmembrane IgE (mIgE) impairs the memory IgE response in mice. Methods We generated mice with an inactivated mIgE-ITT motif and analyzed serum IgE levels as well as the generation of IgE-producing germinal center B cells and PCs subsequent to primary and secondary infection with helminths. In vitro cultures were used to study the mIgE-ITT–controlled expression of mIgE on the surface of PCs. Systemic mast cell activation was determined by serum Mcpt1 ELISA in response to ovalbumin challenge. Results mIgE-ITT–mutant mice showed an impaired memory IgE response subsequent to helminth infection. Furthermore, sensitization and challenge of mIgE-ITT–mutant mice with ovalbumin resulted in diminished serum IgE titers and reduced mast cell activation. The mIgE-ITT motif was required for optimal cell surface expression of mIgE B-cell antigen receptors but not for intracellular IgE expression in PCs. Conclusion These results indicate that the mIgE B-cell antigen receptor plays a critical role in establishing or maintaining the population of IgE-producing PCs during memory IgE responses.

Supplemental Digital Content is available in the text., Background: Canagliflozin reduces the risk of kidney failure in patients with type 2 diabetes mellitus and chronic kidney disease, but effects on specific cardiovascular outcomes are uncertain, as are effects in people without previous cardiovascular disease (primary prevention). Methods: In CREDENCE (Canagliflozin and Renal Events in Diabetes With Established Nephropathy Clinical Evaluation), 4401 participants with type 2 diabetes mellitus and chronic kidney disease were randomly assigned to canagliflozin or placebo on a background of optimized standard of care. Results: Primary prevention participants (n=2181, 49.6%) were younger (61 versus 65 years), were more often female (37% versus 31%), and had shorter duration of diabetes mellitus (15 years versus 16 years) compared with secondary prevention participants (n=2220, 50.4%). Canagliflozin reduced the risk of major cardiovascular events overall (hazard ratio [HR], 0.80 [95% CI, 0.67–0.95]; P=0.01), with consistent reductions in both the primary (HR, 0.68 [95% CI, 0.49–0.94]) and secondary (HR, 0.85 [95% CI, 0.69–1.06]) prevention groups (P for interaction=0.25). Effects were also similar for the components of the composite including cardiovascular death (HR, 0.78 [95% CI, 0.61–1.00]), nonfatal myocardial infarction (HR, 0.81 [95% CI, 0.59–1.10]), and nonfatal stroke (HR, 0.80 [95% CI, 0.56–1.15]). The risk of the primary composite renal outcome and the composite of cardiovascular death or hospitalization for heart failure were also consistently reduced in both the primary and secondary prevention groups (P for interaction >0.5 for each outcome). Conclusions: Canagliflozin significantly reduced major cardiovascular events and kidney failure in patients with type 2 diabetes mellitus and chronic kidney disease, including in participants who did not have previous cardiovascular disease. Clinical Trial Registration: URL: https://www.clinicaltrials.gov. Unique identifier: NCT02065791.

Benzoic acid esterases and ferulic acid esterases (FAE) are enzymes with different profiles of substrate specificity. An extracellular esterase (EstBC) from culture supernatants of the edible basidiomycete fungus Auricularia auricula-judae was purified by anion exchange chromatography, followed by preparative isoelectric focusing and hydrophobic interaction chromatography. EstBC showed a molecular mass of 36 kDa and an isoelectric point of 3.2 along with broad pH and temperature windows similar to fungal FAEs. However, EstBC exhibited also characteristics of a benzoic acid esterase acting on both benzoates and cinnamates, and most efficiently on methyl and ethyl benzoate, methyl 3-hydroxybenzoate and methyl salicylate. Feruloyl saccharides as well as lipase substrates, such as long chain fatty acids esterified with glycerol, polyethoxylated sorbitan and p -nitrophenol were not hydrolyzed. Protein database analyses with tryptic peptides of EstBC solely yielded hits regarding hypothetical proteins belonging to the alpha/beta hydrolase family. The uncommon substrate specificity of EstBC concomitant with a lack of sequence homology to known enzymes suggests a new type of enzyme.

Halogenated natural products (HNPs) have been increasingly reported to occur in marine wild life from all oceans. Several HNPs, such as 2,3,3',4,4',5,5'-heptachloro-1'-methyl-1,2'-bipyrrole (1) and 4,6-dibromo-2-(2',4'-dibromo)phenoxyanisole (2'-MeO-BDE 68 or BC-2), were detected at particularly high concentrations in dolphins from Queensland/Australia. About half of the coastline of Queensland (approximately 2500 km) is covered by the Great Barrier Reef, a rich ecosystem hosting a huge variety of species, many of which are known to produce natural compounds. In this study, semipermeable membrane devices (SPMDs) were deployed as passive samplers for about 30 days at 12 marine and 2 nonmarine sites (i.e., rivers) along the Great Barrier Reef as part of a routine monitoring program during November 2007 and May 2008. Q1 and 2'-MeO-BDE 68 were detected at the marine sites with frequencies of about 65% but not in any sample from the two rivers. Further HNPs (2,4,6-tribromophenol, TBP; 2,4,6-tribromoanisole, TBA; 2,2'-dimethoxy-3,3'5,5'-tetrabromobiphenyl, 2,2'-diMeO-BB 80 or BC-1; 3,5-dibromo-2-(2',4'-dibromo)phenoxyanisole, 6-MeO-BDE 47 or BC-3; and 3,5-dibromo-2-(3',5'-dibromo,2'-methoxy)phenoxyanisole, 2',6-diMeO-BDE 68 or BC-11) were detected as well with frequencies of 18-97% in the marine samples, but no polybrominated flame retardants were detected. The highest amount of a single HNP, 2.3 microg/SPMD, was determined for TBP, which had a frequency of detection of only 46%. The maximum (average) amount in the SPMDs from marine sites was 44 ng (12 ng) for (1 and 115 ng (20 ng) for 2'-MeO-BDE 68. A first order kinetic model was used to estimate concentrations of the HNPs in the water phase. Based on the depuration of performance reference compounds obtained at one of the sites, we assumed a sampling rate of 16 L/day. We used this sampling rate to estimate that the highest and average available concentrations of Q1 in the water during the deployment of the SPMD were 97 and 25 pg/L, respectively. The estimated maximum water concentrations of 2'-MeO-BDE 68, 2,2'-diMeO-BB 80, 6-MeO-BDE 47, and 2',6-diMeO-BDE 68 were on average 2-5.5 fold higher than that of Q1. The results confirm that the HNPs are produced throughout the Great Barrier Reef, which appears to be a significant source of these compounds.

The wax ester fraction of various plant oils was isolated by normal-phase HPLC (NPLC) on-line coupled to GC via the on-column interface and applying concurrent eluent evaporation. The esters were analyzed by on-line NPLC-GC-MS and by comprehensive two-dimensional GC with flame ionization detection (GC x GC-FID) off-line combined with NPLC-GC. GC x GC-FID enables to group the various classes of wax esters, in particular the phytol esters, geranylgeraniol esters and the straight-chain esters of palmitic acids and the unsaturated C 18 acids. Optimization of the GC x GC columns and the conditions must take into account the limited thermostability of the diterpene esters. Chromatograms are shown for a range of oils, with particular focus on the various classes of wax esters in olive oil and the geranylgeraniol esters 22:0 and 24:0 in a variety of oils.

An extracellular chlorogenic acid esterase from Ustilago maydis (UmChlE) was purified to homogeneity by using three separation steps, including anion-exchange chromatography on a Q Sepharose FF column, preparative isoelectric focusing (IEF), and, finally, a combination of affinity chromatography and hydrophobic interaction chromatography on polyamide. SDS-PAGE analysis suggested a monomeric protein of ∼71 kDa. The purified enzyme showed maximal activity at pH 7.5 and at 37°C and was active over a wide pH range (3.5 to 9.5). Previously described chlorogenic acid esterases exhibited a comparable affinity for chlorogenic acid, but the enzyme from Ustilago was also active on typical feruloyl esterase substrates. Kinetic constants for chlorogenic acid, methyl p -coumarate, methyl caffeate, and methyl ferulate were as follows: K m values of 19.6 μM, 64.1 μM, 72.5 μM, and 101.8 μM, respectively, and k cat / K m values of 25.83 mM −1 s −1 , 7.63 mM −1 s −1 , 3.83 mM −1 s −1 and 3.75 mM −1 s −1 , respectively. UmChlE released ferulic, p -coumaric, and caffeic acids from natural substrates such as destarched wheat bran (DSWB) and coffee pulp (CP), confirming activity on complex plant biomass. The full-length gene encoding UmChlE consisted of 1,758 bp, corresponding to a protein of 585 amino acids, and was functionally produced in Pichia pastoris GS115. Sequence alignments with annotated chlorogenic acid and feruloyl esterases underlined the uniqueness of this enzyme.

The paper describes the addition of actively controlled aerodynamic appendages (flaps) attached along the length of the bridge deck to dampen wind-induced oscillations in long suspension bridges. A novel approach using control systems methods for the analysis of dynamic stability is presented. In order to make use of control analysis and design techniques, a linear model of the structural and aerodynamic motion around equilibrium is developed. The model is validated through comparison with finite element calculations and wind tunnel experimental data on the Great Belt East Bridge in Denmark. The developed active control scheme is local in that the flap control signal at a given longitudinal position along the bridge only depends on local motion measurements. The analysis makes use of the Nyquist stability criteria and an analysis of the sensitivity function for stability analysis. The analysis shows that the critical wind speed for flutter instability and divergence is increased substantially by active control.

This paper describes a control method for non-linear systems based on generalized predictive control. Generalized predictive control (GPC) was developed to control linear systems, including open-loop unstable and non-minimum phase systems, but has also been proposed to be extended for the control of non-linear systems. GPC is model based and in this paper we propose the use of a neural network for the modeling of the system. Based on the neural network model, a controller with extended control horizon is developed and the implementation issues are discussed, with particular emphasis on an efficient quasi-Newton algorithm. The performance is demonstrated on a pneumatic servo system.

The possibilities of implementing an active boom suspension is investigated. Compared with a traditional passive suspension, it could improve the spraying result, and make the operators task much easier. In a simulation is compared the possible performance of both an active and a passive system. The simulated passive suspension is an advanced construction, that combines a traditional trapezoid with a spring pendulum system. The active suspension is combining a hydraulic actuator and a spring. According to the simulations, the performance is improved significantly. An attempt has been made to implement the active suspension on a full-size field sprayerboom provided with the hydraulics of a running tractor. A closed loop controlsystem with two ultrasonic sensors, a proportional valve and a hydraulic actuator has been constructed. In the article is described how the system has been build, and what changes should be made for future experiments.

An extracellular feruloyl esterase (PeFaeA) from the culture supernatant of Pleurotus eryngii was purified to homogeneity using cation exchange, hydrophobic interaction, and size exclusion chromatography. The length of the complete coding sequence of PeFaeA was determined to 1668 bp corresponding to a protein of 555 amino acids. The catalytic triad of Ser-Glu-His demonstrated the uniqueness of the enzyme compared to previously published FAEs. The purified PeFaeA was a monomer with an estimated molecular mass of 67 kDa. Maximum feruloyl esterase (FAE) activity was observed at pH 5.0 and 50 °C, respectively. Metal ions (5 mM), except Hg(2+), had no significant influence on the enzyme activity. Substrate specificity profiling characterized the enzyme as a type A FAE preferring bulky natural substrates, such as feruloylated saccharides, rather than small synthetic ones. Km and kcat of the purified enzyme for methyl ferulate were 0.15 mM and 0.85 s(-1). In the presence of 3 M NaCl activity of the enzyme increased by 28 %. PeFaeA alone released only little ferulic acid from destarched wheat bran (DSWB), whereas after addition of Trichoderma viride xylanase the concentration increased more than 20 fold.

Little is known on basidiomycete sources of feruloyl esterases (FAEs), although many wood-rotting representatives of these fungi typically grow on feruloyl-rich substrates. A major reason is that the almost ubiquitous presence of laccases interferes with the detection of FAE activity. Laccases polymerize the liberated ferulic acid (FA) in situ, thus detracting the product of enzymatic hydrolysis from its detection. A rapid HPLC-UV method was developed to detect the loss of FA, but also to quantify the hydrolysis of FA esters. The method allows at the same time to evaluate the substrate specificity of a FAE. Forty one basidiomycetes were tested for their FAE activities, and 25 out of the set were positive. The basidiomycetes hydrolyzing cinnamates with the highest conversion rates were Auricularia auricula-judae and Marasmius scorodonius. Moreover, a new FAE inducer, the nonionic detergent Tween 80, was found. This is the first comprehensive study on basidiomycete sources of FAEs.

A very fast digital control system implemented with a AT&T signalprocessor DSP32 which has been developed to the fast TUD-hydraulic test robot manipulator installed in the hydraulic laboratory at the Control Engineering Institute, the Technical University of Denmark (TUD) is presented. Results and experiences with CAD/CAE-based tools for design and implementation of digital controller algorithms for hydraulic robot manipulators and other multiaxes hydraulic machines are presented and discussed. Furthermore, a new design concept applying the AT&T-signal processor DSP32C is discussed. Finally, the paper describes and discusses the simulation results with an adaptive perturbation control scheme and the obtained experimental results with a digital PID controller.

The paper describes a very fast digitally controlled hydraulic test robot manipulator which has been developed and designed by the use of CAD/CAE-methods. The robot is implemented in the hydraulic laboratory at the Control Engineering Institute, the Technical University of Denmark. The purpose of the test robot manipulator is to carry out research activities within CAD/CAE in hydraulic control system design, digital control and adaptive control design and implementation. Furthermore the test robot is used for test and evaluation of off-line and on-line systemidentification methods and digital algorithms for modelling and adaptive control of multivariable hydraulic systems such as hydraulic robots, escavators og multi-axes test equipment. The paper describes and discusses the control and mechanical design problem and CAD/CAE-methods. The special software package KISMET and ROBCAD can be used in the design and 3D-animation of the robot manipulator for investigation of the robot and the workspace. The control design of the digital control system is done with the packages MATLAB and ACSL. The digital control computer is implemented with a fast AT&T-signalprocessor. A developed adaptive geometrical compensation control scheme is proposed for control of hydraulic robot manipulators

A fast digitally controlled hydraulic test robot has been developed, designed and implemented in the hydraulic laboratory at the Control Engineering Institute, the Technical University of Denmark. The purpose of the test robot is to carry out research activities in hydraulic control system design, digital control and adaptive control and on-line systemidentification. The paper describes the test robot, design and implementation of an adaptive controller. An adaptive geometrical compensation control scheme is proposed for hydraulic robot manipulators.

This chapter has the purpose of reviewing the most important design aspects of Kalman filters as well as some of their most important properties. Heuristic derivations are given of the Kalman filter `equations for both continuous time and discrete time dynamic systems. It is shown that the state mean values propagate according to the same observer equations as given in Chap. 4. Moreover it is shown that the state noise propagates according to the time dependent Lyapunov equation derived in Chap. 6. When measurements are made on the system this equation has to be modified with a term which expresses the decrease of uncertainty which the measurements make possible. The combination of these two results yields the main stochastic design equation for Kalman filters: the Riccati equation. Solving this equation immediately gives the optimal observer gain for a Kalman filter. Combining a Kalman filter with optimal or LQR feedback results in a very robust controller design: the LQG or Linear Quadratic Gaussian regulator.

Modelling of state space models based on relevant physical laws is introduced. Linearization of nonlinear models is discussed and the connection between the transfer function model and the state space model is derived. Discrete time models are also introduced.

The purpose of this chapter is to present a brief review of the salient points of the theory of stochastic processes which are relevant to the study of stochastic optimal control and observer systems. Starting with a brief review of the main properties of random variables, this chapter goes forward to a detailed description of the main random process which is used as a model for noise in technological systems: Gaussian white noise. Both time domain and frequency domain descriptions of this important noise model are given. The main result of these considerations is the time dependent Lyapunov equation which is a compact way to express how white noise propagates through linear dynamic systems. Both continuous time and discrete time versions of this equation are given.

In this chapter an overview of the properties of the state space models will be given. A basis for the investigation of these properties is the solution of the state equation given appropriate boundary conditions. The important notions of stability, controllability and observability will be introduced and the similarity transformation discussed. This makes possible the construction of state space models with a number of useful properties.

In this chapter a review of the design of multivariable feedback controllers for linear systems will be considered. This review treats mainly deterministic control objects with deterministic disturbances. After giving an overview of the type of linear systems to be treated, this chapter will handle the basic control system design method known as pole or eigenvalue placement. First systems where measurements of all the states are available will be treated. For cases when such complete state measurements are not available the concept of deterministic observers to estimate the states which are not measured directly will be introduced. It will also be shown that it is often possible to design reduced order observers where only the unmeasured states are estimated.

In this paper an experimental system for identifying reliable and accurate steady-state characteristics of hydrostatic machines for hydraulic drives is presented. The core of the experimental system consists of two unique components: A servo controlled dynamometer for 4-quadrant operational modes and a servo controlled volume rate flowmeter. Both components have been developed at the Technical University of Denmark. First, a short review of the state-of-the-art and a discussion of analytical and experimental modelling of the steady-state characteristics for hydraulic motors and pumps are given. Then the concept, control and implementation of the developed dynamometer system are described. Further, the flowmeter principle is explained and its specifications are stated. Finally, a typical result obtained by the experimental system is presented.