Fibroblast senescence-associated extracellular matrix promotes heterogeneous lung niche.

Senescent cell accumulation in the pulmonary niche is associated with heightened susceptibility to age-related disease, tissue alterations, and ultimately a decline in lung function. Our current knowledge of senescent cell-extracellular matrix (ECM) dynamics is limited, and our understanding of how senescent cells influence spatial ECM architecture changes over time is incomplete. Herein is the design of an in vitro model of senescence-associated extracellular matrix (SA-ECM) remodeling using a senescent lung fibroblast-derived matrix that captures the spatiotemporal dynamics of an evolving senescent ECM architecture. Multiphoton second-harmonic generation microscopy was utilized to examine the spatial and temporal dynamics of fibroblast SA-ECM remodeling, which revealed a biphasic process that established a disordered and heterogeneous architecture. Additionally, we observed that inhibition of transforming growth factor-ß signaling during SA-ECM remodeling led to improved local collagen fiber organization. Finally, we examined patient samples diagnosed with pulmonary fibrosis to further tie our results of the in vitro model to clinical outcomes. Moreover, we observed that the senescence marker p16 is correlated with local collagen fiber disorder. By elucidating the temporal dynamics of SA-ECM remodeling, we provide further insight on the role of senescent cells and their contributions to pathological ECM remodeling.

Automated brightfield layerwise evaluation in three-dimensional micropatterning via two-photon polymerization.

Two-photon polymerization (TPP) is an advanced 3D fabrication technique capable of creating features with submicron precision. A primary challenge in TPP lies in the facile and accurate characterization of fabrication quality, particularly for structures possessing complex internal features. In this study, we introduce an automated brightfield layerwise evaluation technique that enables a simple-to-implement approach for in situ monitoring and quality assessment of TPP-fabricated structures. Our approach relies on sequentially acquired brightfield images during the TPP writing process and using background subtraction and image processing to extract layered spatial features. We experimentally validate our method by printing a fibrous tissue scaffold and successfully achieve an overall system-adjusted fidelity of 87.5% in situ. Our method is readily adaptable in most TPP systems and can potentially facilitate high-quality TPP manufacturing of sophisticated microstructures.

Single-wavelength, single-shot pulse oximetry using an LED-generated vector beam.

Photoplethysmography (PPG) is an optical technique that monitors blood oxygen saturation levels, typically with the use of pulse oximeters. Conventional pulse oximetry estimates the ratio of light absorbed at two wavelengths. Attempts have been made to improve the precision of these measurements by using polarized light, with the tradeoff of requiring multiple sequential measurements. We demonstrate a novel PPG technique that uses radially polarized light generated by a light-emitting diode (LED) to obtain single-shot, blood oxygen-saturation measurements using a single wavelength at a rate of 50 fps. Our work, to the best of our knowledge, presents both a novel use of a vector beam and a first demonstration of vector-beam generation using LEDs.

Quantifying Cell-Derived Changes in Collagen Synthesis, Alignment, and Mechanics in a 3D Connective Tissue Model.

Dysregulation of extracellular matrix (ECM) synthesis, organization, and mechanics are hallmark features of diseases like fibrosis and cancer. However, most in vitro models fail to recapitulate the three-dimensional (3D) multi-scale hierarchical architecture of collagen-rich tissues and as a result, are unable to mirror native or disease phenotypes. Herein, using primary human fibroblasts seeded into custom fabricated 3D non-adhesive agarose molds, a novel strategy is proposed to direct the morphogenesis of engineered 3D ring-shaped tissue constructs with tensile and histological properties that recapitulate key features of fibrous connective tissue. To characterize the shift from monodispersed cells to a highly-aligned, collagen-rich matrix, a multi-modal approach integrating histology, multiphoton second-harmonic generation, and electron microscopy is employed. Structural changes in collagen synthesis and alignment are then mapped to functional differences in tissue mechanics and total collagen content. Due to the absence of an exogenously added scaffolding material, this model enables the direct quantification of cell-derived changes in 3D matrix synthesis, alignment, and mechanics in response to the addition or removal of relevant biomolecular perturbations. To illustrate this, the effects of nutrient composition, fetal bovine serum, rho-kinase inhibitor, and pro- and anti-fibrotic compounds on ECM synthesis, 3D collagen architecture, and mechanophenotype are quantified.

Cognitively bounded rational analyses and the crucial role of theories of subjective utility.

We agree that combining rational analysis with cognitive bounds, what we previously introduced as Cognitively Bounded Rational Analysis, is a promising and under-used methodology in psychology. We further situate the framework in the literature, and highlight the important issue of a theory of subjective utility, which is not addressed sufficiently clearly in the framework or related previous work.

Ageing, frailty and resilience in Botswana: rapid ageing, rapid change. Findings from a national working group meeting and literature review.

BACKGROUND: The demography of Botswana is rapidly changing. Successes in tackling communicable diseases and economic development increased life expectancy from 53.7 years in 2006 to 66.8 years in 2016. The prevalence of diseases associated with older age, especially chronic non-communicable diseases including diabetes, hypertension and cerebrovascular disease are suspected to have increased but accurate data are lacking. The country has high youth unemployment and national retirement is at the age of 60, which limits the opportunity to build pensions for prosperity in older age. Changes across health, social care and economic policy are needed to prepare for a future ageing population. METHODS: This article reports on the national working group meeting outputs on issues that face older people, their families, healthcare providers, and policy makers in Botswana. A collaborative working group meeting was convened in Gaborone, Botswana on 25th September 2018 by the University of Botswana and University of Birmingham, UK, to identify key challenges and opportunities for an ageing Batswana population. RESULTS: There was agreement across diverse stakeholders of a need for effective and rapid policy formation to prepare and protect the future health and economy of an ageing Batswana population with a high burden of NCDs. The main priorities for policy-makers must be social care, poverty reduction and healthcare provision, conducted in an evidence-based manner, as far as practicable. To effectively achieve this, research and high-quality data collection mechanisms are required. CONCLUSIONS: Future policy in Botswana must focus on the challenges that an ageing population brings, and development of health and care system resilience for the demographic change could be a model for healthcare policy across Southern Africa.

Parameter Inference for Computational Cognitive Models with Approximate Bayesian Computation.

This paper addresses a common challenge with computational cognitive models: identifying parameter values that are both theoretically plausible and generate predictions that match well with empirical data. While computational models can offer deep explanations of cognition, they are computationally complex and often out of reach of traditional parameter fitting methods. Weak methodology may lead to premature rejection of valid models or to acceptance of models that might otherwise be falsified. Mathematically robust fitting methods are, therefore, essential to the progress of computational modeling in cognitive science. In this article, we investigate the capability and role of modern fitting methods-including Bayesian optimization and approximate Bayesian computation-and contrast them to some more commonly used methods: grid search and Nelder-Mead optimization. Our investigation consists of a reanalysis of the fitting of two previous computational models: an Adaptive Control of Thought-Rational model of skill acquisition and a computational rationality model of visual search. The results contrast the efficiency and informativeness of the methods. A key advantage of the Bayesian methods is the ability to estimate the uncertainty of fitted parameter values. We conclude that approximate Bayesian computation is (a) efficient, (b) informative, and (c) offers a path to reproducible results.

4-Hydroxy-7-oxo-5-heptenoic Acid Lactone Is a Potent Inducer of the Complement Pathway in Human Retinal Pigmented Epithelial Cells.

We previously discovered that oxidative cleavage of docosahexaenoate (DHA), which is especially abundant in the retinal photoreceptor rod outer segments and retinal pigmented endothelial (RPE) cells, generates 4-hydroxy-7-oxo-5-heptenoate (HOHA) lactone, and that HOHA lactone can enter RPE cells that metabolize it through conjugation with glutathione (GSH). The consequent depletion of GSH results in oxidative stress. We now find that HOHA lactone induces upregulation of the antioxidant transcription factor Nrf2 in ARPE-19 cells. This leads to expression of GCLM, HO1, and NQO1, three known Nrf2-responsive antioxidant genes. Besides this protective response, HOHA lactone also triggers a countervailing inflammatory activation of innate immunity. Evidence for a contribution of the complement pathway to age-related macular degeneration (AMD) pathology includes the presence of complement proteins in drusen and Bruch's membrane from AMD donor eyes, and the identification of genetic susceptibility loci for AMD in the complement pathway. In eye tissues from a mouse model of AMD, accumulation of complement protein in Bruch's membrane below the RPE suggested that the complement pathway targets this interface, where lesions occur in the RPE and photoreceptor rod outer segments. In animal models of AMD, intravenous injection of NaIO3 to induce oxidative injury selectively destroys the RPE and causes secretion of factor C3 from the RPE into areas directly adjacent to sites of RPE damage. However, a molecular-level link between oxidative injury and complement activation remained elusive. We now find that sub-micromolar concentrations of HOHA lactone foster expression of C3, CFB, and C5 in ARPE-19 cells and induce a countervailing upregulation of CD55, an inhibitor of C3 convertase production and complement cascade amplification. Ultimately, HOHA lactone causes membrane attack complex formation on the plasma membrane. Thus, HOHA lactone provides a molecular-level connection between free-radical-induced oxidative cleavage of DHA and activation of the complement pathway in AMD pathology.

The relevance of formal and nonformal primary education in relation to health, well-being and environmental awareness: Bangladeshi pupils' perspectives in the rural contexts.

PURPOSE: This article reports part of a study focusing on young people's transition from the nonformal to the formal education sector, and explores how the experiences of children and young people in remote formal and nonformal schools affect their awareness of issues of health, well-being and the environment. One of the main objectives of Bangladeshi extensive nonformal primary education, run by nongovernmental organizations (NGOs) in parallel with the formal system, is to prepare children outside schools to enter or re-enter the formal education sector. The study addresses the issue of educational relevance from pupils' perspectives and looking at the implications for pupil transition between these two sectors. METHOD: Interviews and observations of students and their classes were conducted in two contrasting rural high schools in different areas of Bangladesh, and their feeder primary schools. RESULTS: Where formal primary graduates focus more in high school on learning from their textbooks, nonformal primary graduates aim to put their knowledge into practice in their day-to-day life on a range of critical issues. CONCLUSION: The results suggest an important contrast between nonformal and formal education sectors regarding students' agency and knowledge of health and well-being, hygiene and environmental awareness in rural Bangladesh.

The role of (bounded) optimization in theory testing and prediction.

We argue that a radically increased emphasis on (bounded) optimality can contribute to cognitive science by supporting prediction. Bounded optimality (computational rationality), an idea that borrowed from artificial intelligence, supports a priori behavioral prediction from constrained generative models of cognition. Bounded optimality thereby addresses serious failings with the logic and testing of descriptive models of perception and action.

The Effect of Expected Value on Attraction Effect Preference Reversals.

The attraction effect shows that adding a third alternative to a choice set can alter preference between the original two options. For over 30 years, this simple demonstration of context dependence has been taken as strong evidence against a class of parsimonious value-maximising models that evaluate alternatives independently from one another. Significantly, however, in previous demonstrations of the attraction effect alternatives are approximately equally valuable, so there was little consequence to the decision maker irrespective of which alternative was selected. Here we vary the difference in expected value between alternatives and provide the first demonstration that, although extinguished with large differences, this theoretically important effect persists when choice between alternatives has a consequence. We use this result to clarify the implications of the attraction effect, arguing that although it robustly violates the assumptions of value-maximising models, it does not eliminate the possibility that human decision making is optimal.

Games for Psychological Science.

How does the cognitive system, as a whole, act to generate behaviour? A crucial requirement for science aimed at answering this question is that any empirical paradigm is developed hand in hand with robust theoretical models that explain the emergence of behavioural strategies. Complex games have the potential to be one such paradigm.

Workflows and individual differences during visually guided routine tasks in a road traffic management control room.

Road traffic control rooms rely on human operators to monitor and interact with information presented on multiple displays. Past studies have found inconsistent use of available visual information sources in such settings across different domains. In this study, we aimed to broaden the understanding of observer behaviour in control rooms by analysing a case study in road traffic control. We conducted a field study in a live road traffic control room where five operators responded to incidents while wearing a mobile eye tracker. Using qualitative and quantitative approaches, we investigated the operators' workflow using ergonomics methods and quantified visual information sampling. We found that individuals showed differing preferences for viewing modalities and weighting of task components, with a strong coupling between eye and head movement. For the quantitative analysis of the eye tracking data, we propose a number of metrics which may prove useful to compare visual sampling behaviour across domains in future.

Why contextual preference reversals maximize expected value.

Contextual preference reversals occur when a preference for one option over another is reversed by the addition of further options. It has been argued that the occurrence of preference reversals in human behavior shows that people violate the axioms of rational choice and that people are not, therefore, expected value maximizers. In contrast, we demonstrate that if a person is only able to make noisy calculations of expected value and noisy observations of the ordinal relations among option features, then the expected value maximizing choice is influenced by the addition of new options and does give rise to apparent preference reversals. We explore the implications of expected value maximizing choice, conditioned on noisy observations, for a range of contextual preference reversal types-including attraction, compromise, similarity, and phantom effects. These preference reversal types have played a key role in the development of models of human choice. We conclude that experiments demonstrating contextual preference reversals are not evidence for irrationality. They are, however, a consequence of expected value maximization given noisy observations. (PsycINFO Database Record

Predicting Short-Term Remembering as Boundedly Optimal Strategy Choice.

It is known that, on average, people adapt their choice of memory strategy to the subjective utility of interaction. What is not known is whether an individual's choices are boundedly optimal. Two experiments are reported that test the hypothesis that an individual's decisions about the distribution of remembering between internal and external resources are boundedly optimal where optimality is defined relative to experience, cognitive constraints, and reward. The theory makes predictions that are tested against data, not fitted to it. The experiments use a no-choice/choice utility learning paradigm where the no-choice phase is used to elicit a profile of each participant's performance across the strategy space and the choice phase is used to test predicted choices within this space. They show that the majority of individuals select strategies that are boundedly optimal. Further, individual differences in what people choose to do are successfully predicted by the analysis. Two issues are discussed: (a) the performance of the minority of participants who did not find boundedly optimal adaptations, and (b) the possibility that individuals anticipate what, with practice, will become a bounded optimal strategy, rather than what is boundedly optimal during training.

4-Hydroxy-7-oxo-5-heptenoic Acid (HOHA) Lactone is a Biologically Active Precursor for the Generation of 2-(ω-Carboxyethyl)pyrrole (CEP) Derivatives of Proteins and Ethanolamine Phospholipids.

2-(ω-Carboxyethyl)pyrrole (CEP) derivatives of proteins were previously shown to have significant pathological and physiological relevance to age-related macular degeneration, cancer and wound healing. Previously, we showed that CEPs are generated in the reaction of ε-amino groups of protein lysyl residues with 1-palmityl-2-(4-hydroxy-7-oxo-5-heptenoyl)-sn-glycero-3-phosphatidylcholine (HOHA-PC), a lipid oxidation product uniquely generated by oxidative truncation of docosahexanenate-containing phosphatidylcholine. More recently, we found that HOHA-PC rapidly releases HOHA-lactone and 2-lyso-PC (t1/2 = 30 min at 37 °C) by nonenzymatic transesterification/deacylation. Now we report that HOHA-lactone reacts with Ac-Gly-Lys-OMe or human serum albumin to form CEP derivatives in vitro. Incubation of human red blood cell ghosts with HOHA-lactone generates CEP derivatives of membrane proteins and ethanolamine phospholipids. Quantitative analysis of the products generated in the reaction HOHA-PC with Ac-Gly-Lys-OMe showed that HOHA-PC mainly forms CEP-dipeptide that is not esterified to 2-lysophosphatidycholine. Thus, the HOHA-lactone pathway predominates over the direct reaction of HOHA-PC to produce the CEP-PC-dipeptide derivative. Myleoperoxidase/H2O2/NO2(-) promoted in vitro oxidation of either 1-palmityl-2-docosahexaneoyl-sn-glycero-3-phosphatidylcholine (DHA-PC) or docosahexaenoic acid (DHA) generates HOHA-lactone in yields of 0.45% and 0.78%, respectively. Lipid oxidation in human red blood cell ghosts also releases HOHA-lactone. Oxidative injury of ARPE-19 human retinal pigmented epithelial cells by exposure to H2O2 generated CEP derivatives. Treatment of ARPE-19 cells with HOHA-lactone generated CEP-modified proteins. Low (submicromolar), but not high, concentrations of HOHA-lactone promote increased vascular endothelial growth factor (VEGF) secretion by ARPE-19 cells. Therefore, HOHA-lactone not only serves as an intermediate for the generation of CEPs but also is a biologically active oxidative truncation product from docosahexaenoate lipids.

Utility maximization and bounds on human information processing.

Utility maximization is a key element of a number of theoretical approaches to explaining human behavior. Among these approaches are rational analysis, ideal observer theory, and signal detection theory. While some examples of these approaches define the utility maximization problem with little reference to the bounds imposed by the organism, others start with, and emphasize approaches in which bounds imposed by the information processing architecture are considered as an explicit part of the utility maximization problem. These latter approaches are the topic of this issue of the journal.

Computational rationality: linking mechanism and behavior through bounded utility maximization.

We propose a framework for including information-processing bounds in rational analyses. It is an application of bounded optimality (Russell & Subramanian, 1995) to the challenges of developing theories of mechanism and behavior. The framework is based on the idea that behaviors are generated by cognitive mechanisms that are adapted to the structure of not only the environment but also the mind and brain itself. We call the framework computational rationality to emphasize the incorporation of computational mechanism into the definition of rational action. Theories are specified as optimal program problems, defined by an adaptation environment, a bounded machine, and a utility function. Such theories yield different classes of explanation, depending on the extent to which they emphasize adaptation to bounds, and adaptation to some ecology that differs from the immediate local environment. We illustrate this variation with examples from three domains: visual attention in a linguistic task, manual response ordering, and reasoning. We explore the relation of this framework to existing "levels" approaches to explanation, and to other optimality-based modeling approaches.

Spectral assignments and NMR parameter-structure relationships in borates using high-resolution 11B NMR and density functional theory.

High-resolution, solid-state (11)B NMR spectra have been obtained at high magnetic fields for a range of polycrystalline borates using double-rotation (DOR), multiple-quantum magic angle spinning and isotopic dilution. DOR linewidths can be less than 0.2 ppm in isotopically diluted samples, allowing highly accurate values for the isotropic chemical shift, δiso, and electric field gradient to be obtained. The experimental values are used as a test of density functional calculations using both projector augmented wave based CASTEP and WIEN2k. The CASTEP calculations of δiso are generally in very good agreement with experiment, having r.m.s. deviation 0.40 ppm. WIEN2k calculations of electric field gradient magnitude, CQ, and asymmetry, η, are also in excellent agreement with experiment, with r.m.s. deviations 0.038 MHz and 0.042 respectively. However, whilst CASTEP gives a similar deviation for η (0.043) it overestimates CQ by ∼15%. After scaling of the calculated electric field gradient by 0.842 the deviation in CQ is practically identical to that of the WIEN2k calculations. The spectral assignments that follow from the experimental and computational results allow identification of correlations between δiso and (a) the average B-O-B bond angle, θ[combining overline], for both three and four coordinated boron, giving δiso(B(III)) = (185.1 -θ[combining overline])/3.42 ppm and δiso(B(IV)) = (130.2 -θ[combining overline])/5.31 ppm; and (b) the ring-site T(3) unit trigonal planar angular deviation, Stri, giving δiso(T(3)(ring)) = (1.642 × 10(-2)-Stri)/(8.339 × 10(-4)) ppm.

The consequences of virtual embodiment for the mental representation of proximity.

There is evidence that knowledge about space will reflect the details of how that space is experienced and how people interact with it. In two experiments we demonstrate that memory for items is spatially structured after their locations were learnt in a desktop virtual environment (DVE). The structure was measured using interitem priming of recognition. By comparison in Experiment 2, after the same layout had been learnt using a map display, there was no evidence of spatial structuring in memory. It is concluded that the limited view of space afforded by navigation through an environment, as contrasted with the overview afforded by a map, explains the observed differences in the spatial structuring of interitem associations. Navigation through an environment leads to spatial structuring in memory whereas using a map does not.