A multi‐omics approach identifies key regulatory pathways induced by long‐term zinc supplementation in human primary retinal pigment epithelium

In age-related macular degeneration (AMD), both systemic and local zinc levels decline. Elevation of zinc in clinical studies delayed the progression to end-stage AMD. However, the molecular pathways underpinning this beneficial effect are not yet identified. In this study, we used differentiated primary human fetal retinal pigment epithelium (RPE) cultures and long-term zinc supplementation to carry out a combined transcriptome, proteome and secretome analysis from three genetically different human donors. After combining significant differences, we identified the complex molecular networks using Database for Annotation, Visualization and Integrated Discovery (DAVID) and Ingenuity Pathway Analysis (IPA). The cell cultures from the three donors showed extensive pigmentation, development of microvilli and basal infoldings and responded to zinc supplementation with an increase in transepithelial electrical resistance (TEER) (apical supplementation: 443.2 ± 79.3%, basal supplementation: 424.9 ± 116.8%, compared to control: 317.5 ± 98.2%). Significant changes were observed in the expression of 1044 genes, 151 cellular proteins and 124 secreted proteins. Gene set enrichment analysis revealed changes in specific molecular pathways related to cell adhesion/polarity, extracellular matrix organization, protein processing/transport, and oxidative stress response by zinc and identified a key upstream regulator effect similar to that of TGFB1

Velocity-space sensitivity of the time-of-flight neutron spectrometer at JET

The velocity-space sensitivities of fast-ion diagnostics are often described by so-called weight functions. Recently, we formulated weight functions showing the velocity-space sensitivity of the often dominant beam-target part of neutron energy spectra. These weight functions for neutron emission spectrometry (NES) are independent of the particular NES diagnostic. Here we apply these NES weight functions to the time-of-flight spectrometer TOFOR at JET. By taking the instrumental response function of TOFOR into account, we calculate time-of-flight NES weight functions that enable us to directly determine the velocity-space sensitivity of a given part of a measured time-of-flight spectrum from TOFOR

Relationship of edge localized mode burst times with divertor flux loop signal phase in JET

A phase relationship is identified between sequential edge localized modes (ELMs) occurrence times in a set of H-mode tokamak plasmas to the voltage measured in full flux azimuthal loops in the divertor region. We focus on plasmas in the Joint European Torus where a steady H-mode is sustained over several seconds, during which ELMs are observed in the Be II emission at the divertor. The ELMs analysed arise from intrinsic ELMing, in that there is no deliberate intent to control the ELMing process by external means. We use ELM timings derived from the Be II signal to perform direct time domain analysis of the full flux loop VLD2 and VLD3 signals, which provide a high cadence global measurement proportional to the voltage induced by changes in poloidal magnetic flux. Specifically, we examine how the time interval between pairs of successive ELMs is linked to the time-evolving phase of the full flux loop signals. Each ELM produces a clear early pulse in the full flux loop signals, whose peak time is used to condition our analysis. The arrival time of the following ELM, relative to this pulse, is found to fall into one of two categories: (i) prompt ELMs, which are directly paced by the initial response seen in the flux loop signals; and (ii) all other ELMs, which occur after the initial response of the full flux loop signals has decayed in amplitude. The times at which ELMs in category (ii) occur, relative to the first ELM of the pair, are clustered at times when the instantaneous phase of the full flux loop signal is close to its value at the time of the first ELM

Prevalence of Age-Related Macular Degeneration in Europe: The Past and the Future

Purpose Age-related macular degeneration (AMD) is a frequent, complex disorder in elderly of European ancestry. Risk profiles and treatment options have changed considerably over the years, which may have affected disease prevalence and outcome. We determined the prevalence of early and late AMD in Europe from 1990 to 2013 using the European Eye Epidemiology (E3) consortium, and made projections for the future. Design Meta-analysis of prevalence data. Participants A total of 42 080 individuals 40 years of age and older participating in 14 population-based cohorts from 10 countries in Europe. Methods AMD was diagnosed based on fundus photographs using the Rotterdam Classification. Prevalence of early and late AMD was calculated using random-effects meta-analysis stratified for age, birth cohort, gender, geographic region, and time period of the study. Best-corrected visual acuity (BCVA) was compared between late AMD subtypes; geographic atrophy (GA) and choroidal neovascularization (CNV). Main Outcome Measures Prevalence of early and late AMD, BCVA, and number of AMD cases. Results Prevalence of early AMD increased from 3.5% (95% confidence interval [CI] 2.1%–5.0%) in those aged 55–59 years to 17.6% (95%

Mapping local patterns of childhood overweight and wasting in low- and middle-income countries between 2000 and 2017

A double burden of malnutrition occurs when individuals, household members or communities experience both undernutrition and overweight. Here, we show geospatial estimates of overweight and wasting prevalence among children under 5 years of age in 105 low- and middle-income countries (LMICs) from 2000 to 2017 and aggregate these to policy-relevant administrative units. Wasting decreased overall across LMICs between 2000 and 2017, from 8.4 (62.3 (55.1�70.8) million) to 6.4 (58.3 (47.6�70.7) million), but is predicted to remain above the World Health Organization�s Global Nutrition Target of <5 in over half of LMICs by 2025. Prevalence of overweight increased from 5.2 (30 (22.8�38.5) million) in 2000 to 6.0 (55.5 (44.8�67.9) million) children aged under 5 years in 2017. Areas most affected by double burden of malnutrition were located in Indonesia, Thailand, southeastern China, Botswana, Cameroon and central Nigeria. Our estimates provide a new perspective to researchers, policy makers and public health agencies in their efforts to address this global childhood syndemic. © 2020, The Author(s)

Author Correction: Mapping local patterns of childhood overweight and wasting in low- and middle-income countries between 2000 and 2017 (Nature Medicine, (2020), 26, 5, (750-759), 10.1038/s41591-020-0807-6)

An amendment to this paper has been published and can be accessed via a link at the top of the paper. © 2020, The Author(s)

Author Correction: Mapping local patterns of childhood overweight and wasting in low- and middle-income countries between 2000 and 2017 (Nature Medicine, (2020), 26, 5, (750-759), 10.1038/s41591-020-0807-6)

An amendment to this paper has been published and can be accessed via a link at the top of the paper. © 2020, The Author(s)

Effects of Target Signal Shape and System Dynamics on Feedforward in Manual Control

The human controller (HC) in manual control of a dynamical system often follows a visible and predictable reference path (target). The HC can adopt a control strategy combining closed-loop feedback and an open-loop feedforward response. The effects of the target signal waveform shape and the system dynamics on the human feedforward dynamics are still largely unknown, even for common, stable, vehicle-like dynamics. This paper studies the feedforward dynamics through computer model simulations and compares these to system identification results from human-in-the-loop experimental data. Two target waveform shapes are considered, constant velocity ramp segments and constant acceleration parabola segments. Furthermore, three representative vehicle-like system dynamics are considered: 1) a single integrator (SI); 2) a second-order system; and 3) a double integrator. The analyses show that the HC utilizes a combined feedforward/feedback control strategy for all dynamics with the parabola target, and for the SI and second-order system with the ramp target. The feedforward model parameters are, however, very different between the two target waveform shapes, illustrating the adaptability of the HC to task variables. Moreover, strong evidence of anticipatory control behavior in the HC is found for the parabola target signal. The HC anticipates the future course of the parabola target signal given extensive practice, reflected by negative feedforward time delay estimates.</p

Constraints in Identification of Multi-Loop Feedforward Human Control Models

The human controller (HC) can greatly improve target-tracking performance by utilizing a feedforward operation on the target signal, in addition to a feedback response. System identification methods are used to determine the correct HC model structure: purely feedback or a combined feedforward/feedback model. In this paper, we investigate three central issues that complicate this objective. First, the identification method should not require prior assumptions regarding the dynamics of the feedforward and feedback components. Second, severe biases might be introduced by high levels of noise in the data measured under closed-loop conditions. To address the first two issues, we will consider two identification methods that make use of linear ARX models: the classic direct method and the two-stage indirect method of van den Hof and Schrama (1993). Third, model complexity should be considered in the selection of the ‘best’ ARX model to prevent ‘false-positive’ feedforward identification. Various model selection criteria, that make an explicit trade-off between model quality and model complexity, are considered. Based on computer simulations with a HC model, we conclude that 1) the direct method provides more accurate estimates in the frequency range of interest, and 2) existing model selection criteria do not prevent false-positive feedforward identification.Control & OperationsControl & Simulatio

Objective ARX Model Order Selection for Multi-Channel Human Operator Identification

In manual control, the human operator primarily responds to visual inputs but may elect to make use of other available feedback paths such as physical motion, adopting a multi-channel control strategy. Hu- man operator identification procedures generally require a priori selection of the model structure, which can be problematic as the exact feedback organization operators adopt is not always clear in advance. This pa- per evaluates a novel method for objectively detecting the presence of additional human operator feedback responses in control tasks with multiple inputs. The approach makes use of linear-time invariant ARX mod- els for system identification, combined with an objective model selection criterion. To test the method, an experiment was conducted in which participants performed a compensatory yaw attitude tracking task in a moving-base flight simulator, with varying motion cueing settings. In addition, a pursuit tracking condition without motion feedback was tested. For all conditions, the objective ARX model-based identification method was used to verify the presence of a possible additional human operator output feedback response. With ap- propriate tuning of the penalty on model complexity in the model selection criterion, the methodology proved successful in correctly identifying the additional operator responses in experimental conditions that contained no motion or high-quality motion feedback. With low-fidelity motion feedback or a pursuit display, the results suggest that no consistent feedback response is achieved by the participants. The approach was substantiated with offline Monte Carlo simulations, which show strong correlation with the obtained experiment results.Control & Simulatio