All-or-none amyloid disassembly via chaperone-triggered fibril unzipping favors clearance of α-synuclein toxic species.

α-synuclein aggregation is present in Parkinson's disease and other neuropathologies. Among the assemblies that populate the amyloid formation process, oligomers and short fibrils are the most cytotoxic. The human Hsc70-based disaggregase system can resolve α-synuclein fibrils, but its ability to target other toxic assemblies has not been studied. Here, we show that this chaperone system preferentially disaggregates toxic oligomers and short fibrils, while its activity against large, less toxic amyloids is severely impaired. Biochemical and kinetic characterization of the disassembly process reveals that this behavior is the result of an all-or-none abrupt solubilization of individual aggregates. High-speed atomic force microscopy explicitly shows that disassembly starts with the destabilization of the tips and rapidly progresses to completion through protofilament unzipping and depolymerization without accumulation of harmful oligomeric intermediates. Our data provide molecular insights into the selective processing of toxic amyloids, which is critical to identify potential therapeutic targets against increasingly prevalent neurodegenerative disorders.

Digital use and socioeconomic inequalities in adolescent well-being: Longitudinal evidence on socioemotional and educational outcomes.

INTRODUCTION: Despite a growing body of research on associations between adolescent digital use and well-being, few studies have investigated these associations a) longitudinally and b) across socioeconomic status. The present study uses high-quality longitudinal data to examine how digital engagement shapes socioemotional and educational outcomes from early to late adolescence across socioeconomic status (SES). METHODS: Participants are 7685 individuals (49.0% female) from the 1998 birth cohort of the longitudinal Growing Up In Ireland (GUI) survey. The survey was administered to Irish parents and children between 2007 and 2016 (at ages 9, 13, and 17/18). Fixed-effects regression modeling was used to establish associations between digital engagement and socioemotional and educational outcomes. Further Fixed-Effects models were analyzed separately by SES, to assess how associations between digital use and adolescent outcomes differ by socioeconomic groups. RESULTS: Results show that digital screen time increases markedly from early to late adolescence, but to a higher extent among low-SES versus high-SES groups. Heavy levels of digital screen time (i.e., 3+ hours daily) are associated with declines in well-being, particularly for external and prosocial functioning, while engagement in learning-oriented digital activities and gaming is associated with better adolescent outcomes. Yet, low-SES adolescents are globally more harmed than high-SES adolescents by their digital engagement, and high-SES adolescents benefit more from moderate levels of digital use and from engaging in learning-oriented digital activities. CONCLUSIONS: This study suggests that digital engagement is associated with socioeconomic inequalities in adolescents' socioemotional well-being and, to a lesser extent, educational outcomes.

A programme for early diagnosis of atrial fibrillation: a multi-centre study in primary care.

BACKGROUND: Atrial fibrillation (AF) is a morbid disease whose complications can be prevented if prompt and correctly treated. OBJECTIVE: To assess the usefulness of an early AF diagnosis programme in at-risk individuals in primary care centres. METHODS: In an open-label, multi-centre, controlled interventional study, individuals with one or more risk factors for AF but without known AF were enrolled. They were allocated to intervention and control groups in a 1:2 ratio. Participants in the intervention group had three clinical and educational visits (0, 6 and 12 months). In intervention subgroup A, an electrocardiogram (ECG) was performed at each visit and in subgroup B, only if arrhythmia was detected on auscultation. After 2 years, the medical records of all participants were reviewed. Participants diagnosed with AF were followed for two additional years. RESULTS: Of the total 2231 participants enrolled, 1503 (67.36%) were allocated to the control group and 728 (32.63%) to the intervention groups (355 in subgroup A, 373 subgroup B). The groups showed similar clinical characteristics. New-onset AF was diagnosed in 38 patients. Early detection in subgroup B was similar to subgroup A and superior to control group (3.2% versus 1.2%, hazard ratio 3.149, 95% confidence interval 1.503-6.597, P = 0.002). AF patients in subgroups A and B had similar long-term complications and a tendency for fewer complications than AF patients in the control group. CONCLUSIONS: An intervention programme consisting of health education, systematic auscultation and opportunistic ECG by a primary care provider is a useful method for the early diagnosis of AF.

Evaluation of Two Strategies for Alleviating the Impact on the Circadian Cycle of Smartphone Screens.

SIGNIFICANCE: Electronic display devices used before bed may negatively affect sleep quality through the effects of short-wavelength (blue) light on melatonin production and the circadian cycle. We quantified the efficacy of night-mode functions and blue-light-reducing lenses in ameliorating this problem. PURPOSE: The purpose of this study was to compare the radiation produced by smartphones that reaches the eye when using night-mode functions or blue-light-reducing spectacle lenses. METHODS: Radiant flux of 64 smartphones was measured with an integrating sphere. The retinal illuminance was calculated from the radiant flux of the smartphones. For the night-mode functions, the spectra produced by the smartphones were measured. The transmittance of four blue-light-reducing spectacle lenses, which filter light with either antireflective coatings or tints, was measured using a spectrometer. To determine the impact of blue-light-reducing spectacles, the radiant flux of the smartphone was weighted by the transmission spectrum of these glasses. Visual and nonvisual (circadian) parameters were calculated to compute the melatonin suppression values (MSVs) through a logistic fitting of previously published data. The MSV was used as the figure of merit to evaluate the performance of blue-light spectacles and smartphone night-mode functions. RESULTS: Night-mode functions in smartphones reduced MSVs by up to 93%. The warmest mode produced the least suppression. Blue-light-reducing spectacles reduced melatonin suppression by 33%, the coated lenses being more efficient than tinted lenses. CONCLUSIONS: All smartphones in this study emit radiant power in the short-wavelength region of the visible spectrum. Such smartphones may impair the regulation of circadian cycles at nighttime. The activation of night-mode functions was more efficient than the commercially available blue-light-reducing spectacle lenses in reducing the amount of short-wavelength light (up to 2.25 times). These results can be extrapolated to most electronic devices because they share the same type of white radiant sources with smartphones.

Multiplicity of α-Synuclein Aggregated Species and Their Possible Roles in Disease.

α-Synuclein amyloid aggregation is a defining molecular feature of Parkinson's disease, Lewy body dementia, and multiple system atrophy, but can also be found in other neurodegenerative disorders such as Alzheimer's disease. The process of α-synuclein aggregation can be initiated through alternative nucleation mechanisms and dominated by different secondary processes giving rise to multiple amyloid polymorphs and intermediate species. Some aggregated species have more inherent abilities to induce cellular stress and toxicity, while others seem to be more potent in propagating neurodegeneration. The preference for particular types of polymorphs depends on the solution conditions and the cellular microenvironment that the protein encounters, which is likely related to the distinct cellular locations of α-synuclein inclusions in different synucleinopathies, and the existence of disease-specific amyloid polymorphs. In this review, we discuss our current understanding on the nature and structure of the various types of α-synuclein aggregated species and their possible roles in pathology. Precisely defining these distinct α-synuclein species will contribute to understanding the molecular origins of these disorders, developing accurate diagnoses, and designing effective therapeutic interventions for these highly debilitating neurodegenerative diseases.

Comparing habitual and i. Scription refractions.

BACKGROUND: Many patients voice concerns regarding poor night vision, even when they see 20/20 or better in the exam room. During mesopic and scotopic conditions the pupil size increases, increasing the effects on visual performance of uncorrected (residual) refractive errors. The i.Scription refraction method claims to optimize traditional refractions for mesopic and scotopic conditions, by using the information that the Zeiss i.Profilerplus gathers of ocular aberrations (low and high order). The aim of this study was to investigate any differences between habitual and i.Scription refractions and their relationship to night vision complaints. METHODS: Habitual, subjective, and i.Scription refractions were obtained from both eyes of eighteen subjects. Low and high order aberrations of the subjects were recorded with the Zeiss i.Profilerplus. The root mean square (RMS) metric was calculated for small (3 mm) and maximum pupil sizes. Subjects rated their difficulty with driving at night on a scale of 1-10. RESULTS: There was a statistically significant difference between the habitual and i.Scription refractions on both the sphere and cylinder values [(t = 3.12, p < 0.01), (t = 5.39, p < 0.01)]. The same was found when comparing the subjective and i.Scription refractions [(t = 2.31, p = 0.03), (t = 2.54, p = 0.02)]. There were no significant differences found when comparing the sphere and cylinder values between the habitual and subjective refractions or on any combination of spherical equivalent refraction. The maximum pupil size of the subject population on this study, measured with the i.Profilerplus, was 4.8 ± 1.04 mm. Ten out of the eighteen subjects had discomfort at night with an average magnitude of 4 ± 2.7. Ratings of difficulty with night vision correlated with the change in spherical equivalent correction between the habitual and i.Scription refractions (p = 0.01). A sub-analysis of myopic subjects (n = 15) showed an increase in the significance of this relationship (p = 0.002). CONCLUSIONS: The i.Scription method improves night vision by correcting the sphere and cylinder more precisely. There was a correlation between the amount of change in the cylinder value between habitual and i.Scription prescriptions and the magnitude of the reported visual discomfort at night.

Slow Interconversion in a Heterogeneous Unfolded-State Ensemble of Outer-Membrane Phospholipase A.

Structural and dynamic investigations of unfolded proteins are important for understanding protein-folding mechanisms as well as the interactions of unfolded polypeptide chains with other cell components. In the case of outer-membrane proteins (OMPs), unfolded-state properties are of particular physiological relevance, because these proteins remain unfolded for extended periods of time during their biogenesis and rely on interactions with binding partners to support proper folding. Using a combination of ensemble and single-molecule spectroscopy, we have scrutinized the unfolded state of outer-membrane phospholipase A (OmpLA) to provide a detailed view of its structural dynamics on timescales from nanoseconds to milliseconds. We find that even under strongly denaturing conditions and in the absence of residual secondary structure, OmpLA populates an ensemble of slowly (>100 ms) interconverting and conformationally heterogeneous unfolded states that lack the fast chain-reconfiguration motions expected for an unstructured, fully unfolded chain. The drastically slowed sampling of potentially folding-competent states, as compared with a random-coil polypeptide, may contribute to the slow in vitro folding kinetics observed for many OMPs. In vivo, however, slow intramolecular long-range dynamics might be advantageous for entropically favored binding of unfolded OMPs to chaperones and, by facilitating conformational selection after release from chaperones, for preserving binding-competent conformations before insertion into the outer membrane.

Optimal orientation for angularly segmented multifocal corrections.

PURPOSE: Evaluate the importance of orientation of multifocal lens designs with angular increments of addition. METHODS: Optical properties of one monofocal and three multifocal designs were analysed with the visual Strehl ratio (VSOTF) metric through-focus (-1 to 5 D). Designs were tested in combination with the higher-order aberrations (HOAs) of 782 subjects (1564 eyes). Simulations included one monofocal, one bifocal (eight orientations), one trifocal (four orientations), and a 4-foci design (four orientations). Monocular and binocular performances of all designs were assessed by computing the area under the through-focus VSOTF plots, the through-focus range of acceptable optical performance, and, for binocular combinations, optical disparity between left and right eyes. RESULTS: Under monocular conditions, bifocal designs generated larger areas under the through focus VSOTF than trifocal designs and 4-foci designs. Specifically, bifocal designs divided vertically were optimal for 48% of eyes. Trifocal designs and 4-foci designs offered longer intervals of acceptable through-focus vision. Coma and spherical aberration values were correlated with the optimal orientation of multifocal corrections. The best binocular combination was achieved with a monofocal and a trifocal lens. The orientation of a multifocal design with angular areas affected the final optical properties of the combination (lens plus eye). CONCLUSIONS: The optical aberration distributions for our population of physiologically normal eyes demonstrated improved performance for some lens design orientations (i.e., left-right segments for 2-zone bifocals). Taking into account the HOAs of healthy patients, with special attention to coma and spherical aberration, will increase the optical quality of angularly divided multifocal solutions.

Educational inequalities in parental care time: Cross-national evidence from Belgium, Denmark, Spain, and the United Kingdom.

This study uses time-diary data for dual-earner couples from Belgium, Denmark, Spain, and the United Kingdom to analyze educational inequalities in parental care time in different national contexts. For mothers, education is significantly associated with parenting involvement only in Spain and the United Kingdom. In Spain these differences are largely explained by inequalities in mothers' time and monetary resources, but not in the United Kingdom, where less-educated mothers disproportionally work in short part-time jobs. For fathers, education is associated with parenting time in Denmark, and particularly in Spain, while the wife's resources substantially drive these associations. On weekends, the educational gradient in parental care time applies only to Spain and the United Kingdom, two countries with particularly large inequalities in parents' opportunities to engage in parenting. The study shows country variations in educational inequalities in parenting, suggesting that socioeconomic resources, especially from mothers, shape important variations in parenting involvement.

Parent-child leisure activities and cultural capital in the United Kingdom: The gendered effects of education and social class.

This article uses data on couples from the 2000 UK Time Use Survey (N=610) to analyze how social position influences parents' leisure activities with children. The study is the first using representative data to investigate this fundamental question to understand social inequalities in family life and children's life chances. Results reveal that social position intersects with gender in influencing parent-child leisure activities with implications on children's cultural capital. Three are the main findings: (1) social position has significant positive effects on cultural activities with children and negative on parent-child television watching among mothers, but moderate differences are observed for fathers; (2) father-child leisure is strongly influenced by the spouse's social position, but not mother-child leisure; (3) education and social class show complex differences in affecting parent-child leisure, suggesting that future studies should include these two variables when analyzing parent-child time and family life.

Correction: Gender differences in time use across age groups: A study of ten industrialized countries, 2005-2015.

[This corrects the article DOI: 10.1371/journal.pone.0264411.].

Genomic deletions explain the generation of alternative BRAF isoforms conferring resistance to MAPK inhibitors in melanoma.

Resistance to MAPK inhibitors (MAPKi), the main cause of relapse in BRAF-mutant melanoma, is associated with the production of alternative BRAF mRNA isoforms (altBRAFs) in up to 30% of patients receiving BRAF inhibitor monotherapy. These altBRAFs have been described as being generated by alternative pre-mRNA splicing, and splicing modulation has been proposed as a therapeutic strategy to overcome resistance. In contrast, we report that altBRAFs are generated through genomic deletions. Using different in vitro models of altBRAF-mediated melanoma resistance, we demonstrate the production of altBRAFs exclusively from the BRAF V600E allele, correlating with corresponding genomic deletions. Genomic deletions are also detected in tumor samples from melanoma and breast cancer patients expressing altBRAFs. Along with the identification of altBRAFs in BRAF wild-type and in MAPKi-naive melanoma samples, our results represent a major shift in our understanding of mechanisms leading to the generation of BRAF transcripts variants associated with resistance in melanoma.

Multiple zone multifocal phase designs.

New multifocal phase designs aiming at expanding depth of focus in the presbyopic eye are presented. The designs consist of multiple radial or angular zones of different powers or of combined low- and high-order aberrations. Multifocal performance was evaluated in terms of the dioptric range for which the optical quality is above an appropriate threshold, as well as in terms of the area under the through-focus optical quality curves. For varying optical power designs optimal through-focus performance was found for a maximum of three to four zones. Furthermore adding more zones decreased the optical performance of the solution. Angular zone designs provided better multifocal performance (1.95 times on average) than radial zone designs with identical number of zones and the same power range. The optimal design (angular design with three zones) surpassed by 33% the multifocal performance of a bifocal angular zone design and by 32% a standard multifocal phase plate with induced spherical aberration only. By using combinations of low- and high-order aberrations the through-focus range can be extended further by another 0.5 D beyond that of the best design of varying optical power. These designs can be implemented in adaptive optics systems for testing their visual performance in subjects and converted into multifocal contact lenses, intraocular lenses, or presbyopic corneal laser ablation profiles.

Astigmatism impact on visual performance: meridional and adaptational effects.

PURPOSE: Astigmatic subjects are adapted to their astigmatism and perceptually recalibrate upon its correction. However, the extent to which prior adaptation to astigmatism affects visual performance, whether this effect is axis dependent, and the time scale of potential changes in visual performance after astigmatism correction are not known. Moreover, the effect of possible positive interactions of aberrations (astigmatism and coma) might be altered after recalibration to correction of astigmatism. METHODS: Visual acuity (VA) was measured in 25 subjects (astigmats and non-astigmats, corrected and uncorrected) under induction of astigmatism and combinations of astigmatism and coma while controlling subject aberrations. Astigmatism (1.00 diopter) was induced at three different orientations, the natural axis, the perpendicular orientation, and 45 degrees for astigmats and at 0, 90, and 45 degrees for non-astigmats. Experiments were also performed, adding coma (0.41 µm at a relative angle of 45 degrees) to the same mentioned astigmatism. Fourteen different conditions were measured using an 8-Alternative Forced Choice procedure with Tumbling E letters and a QUEST algorithm. Longitudinal measurements were performed up to 6 months. Uncorrected astigmats were provided with proper astigmatic correction after the first session. RESULTS: In non-astigmats, inducing astigmatism at 90 degrees, produced a statistically lower reduction in VA than at 0 or 45 degrees, whereas in astigmats, the lower decrease in VA occurred for astigmatism induced at the natural axis. Six months of astigmatic correction did not reduce the insensitivity to astigmatic induction along the natural axis. Differences after orientation of astigmatism were also found when adding coma to astigmatism. CONCLUSIONS: The impact of astigmatism on VA is greatly dependent on the orientation of the induced astigmatism, even in non-astigmats. Previous experience to astigmatism plays a significant role on VA, with a strong bias toward the natural axis. In contrast to perceived isotropy, the correction of astigmatism does not shift the bias in VA from the natural axis of astigmatism.

Fourier tools for the evaluation of refractive multifocal designs.

This paper presents innovative tools and methodologies for the theoretical assessment of optical properties in refractive multifocal designs. Utilizing lens segmentation techniques and classical Fourier optics, these tools can be of help evaluating multifocal contact lenses, intraocular lenses, small aperture designs, and corneal inlays. As an example of their utility, this study presents the through-focus Visual Strehl ratios in the frequency domain of 12 multifocal contact lenses from four companies, derived from the sagittal power profiles obtained with a NIMO equipment (LAMBDA-X) for three base prescriptions (- 6.00 D, - 3.00 D, and + 1.00 D). The contact lenses are also assessed alongside higher-order aberrations obtained from 65 eyes, measured using a Wavefront Sciences Complete Ophthalmic Analysis System (AMO). Diameter variations, corresponding to individual pupil sizes (2.45-6.27 mm), were considered in the evaluation. These novel tools enable the theoretical evaluation of multifocal solutions without the need for prototypes. In the case examples presented, they differentiate between lenses tailored for different presbyopic age groups, offer guidance on optimizing hyperfocal distance in contact lens design, and underscore the relevance of the effective aperture effect. Notably, this paper introduces the pioneering conversion of sagittal powers of multifocal solutions into an equivalent wavefront and optical quality metric, with potential applications in myopia control assessments. The author hopes that readers recognize and utilize these tools to advance the field of refractive multifocality.

Gender differences in mental health following the transition into parenthood: Longitudinal evidence from the UK.

Previous studies have largely omitted a dynamic analysis of how the transition into parenthood shapes gender differences in mental health trajectories. This study adopts a life course approach to examine how transitioning into parenthood affects men's and women's mental health across multiple domains over time, using large-scale panel data from the 'UK Household Longitudinal Study' (2009-2020). Results from fixed effects models with discrete-time trends show that: (1) women's mental health is more largely affected by parenthood than men's; (2) women's overall mental health shows stable improvements following childbirth, while men's shows mostly insignificant changes; (3) role and social functioning are largely improved among women following childbirth, but only marginally among men; (4) emotional functioning and vitality demonstrate the counteracting effects of parenthood for both genders, with increases in feeling happy but a deterioration in feeling calm and having energy, particularly during care-intensive years; (5) women show larger variations by socioeconomic characteristics than men, with women from higher socioeconomic backgrounds and working full-time experiencing smaller mental health benefits from parenthood compared to less privileged women or having lower paid work constraints. Overall, transitioning to parenthood leads to distinct changes in mental health domains with heterogeneous effects across genders and socioeconomic groups.

Single-Particle Analysis of the Interaction Between Molecules and Protein Aggregated Species by Dual-Color Time-Resolved Fluorescence Spectroscopy.

Amyloid protein aggregation is widely involved in a number of neurodegenerative diseases for which novel therapeutic and diagnostic strategies are still needed. Owing to the complex and heterogeneous nature of the aggregated species responsible for toxicity in these disorders, a detailed characterization of the interaction of molecules of interest with the amyloid aggregates is a challenging endeavor. Here, we present the experimental and analytical steps of a protocol which combines dual-color fluorescence cross-correlation spectroscopy and dual-color single-particle fluorescence spectroscopy to quantify the binding affinity and stoichiometry of an inhibitor of α-synuclein amyloid aggregation. This approach allows studying the interaction in detail and through two independent analytical methods, thus yielding a remarkably robust tool that could be extended to investigating the interaction of molecules of interest to other pathogenic protein aggregates as well as multi-ligand/multi-receptor complexes.

Dependence of subjective image focus on the magnitude and pattern of high order aberrations.

The image formed by the eye's optics is inherently blurred by aberrations specific to the individual's eyes. We examined to what extent judgments of perceived focus depend on the total magnitude as opposed to the specific pattern of blur introduced by the eye's high order aberrations (HOA). An Adaptive Optics system was used to simultaneously correct each subject's wave aberrations and display natural images blurred by simulated aberrations. To isolate the effects of blur magnitude, images were blurred by pure symmetric defocus, and subjects judged the level of the defocus that subjectively appeared best focused (i.e., neither too blurred nor too sharp). These settings were strongly correlated with the native blur magnitude. To isolate the effect of the HOA pattern, retinal image blur was instead maintained at a constant blur (Strehl Ratio) equal to each subject's natural blur, and subjects judged the best-focused image from pairs of images blurred by different patterns of HOA, one selected from 100 patterns, the other blurred by a reference pattern which included the subject's natural HOA, rotated HOA, or nine other HOA patterns. The percentage of images judged as best focused was not systematically higher when filtered with the subject's own HOA pattern. However, all subjects preferred their own HOA to the rotated version significantly more often (57% versus 45% on average across subjects). The representation of subjective image focus thus appears to be driven primarily by the overall amount of blur and only weakly by HOA blur orientation.

The Gendered Effects of Divorce on Mothers' and Fathers' Time with Children and Children's Developmental Activities: A Longitudinal Study.

How divorce influences parents' and children's time use has received very little scientific attention. This study uses high-quality longitudinal time-diary data across six waves from the Longitudinal Study of Australian Children to examine how parental separation shapes parent-child time and children's daily activities. Results show that separation leads to a strong increase of gender inequalities in parents' time use. After separation, mother-child time doubles, two-parent time declines by three, and father-child time remains low. Parental separation also leads to a decline in children's time allocated to educational activities (e.g., studying, reading) and an increase in children's time in unstructured activities (e.g., TV watching, video gaming, smartphone use). Additionally, the effect of separation on children's time use is twice as large for boys than for girls, with gender gaps in children's unstructured time increasing over time. Finally, mother-child time returns to similar pre-separation levels over time, but only after 4 years since separation occurred. The study findings are robust to different panel regression strategies. Overall, this study implies that parental divorce negatively affects children's developmental time use, especially among boys, and leads lone mothers to experience increasing 'time penalties' associated with gender inequalities in society.

Gender differences in time use across age groups: A study of ten industrialized countries, 2005-2015.

This study uses largescale cross-national time-diary data from the Multinational Time Use Study (MTUS) (N = 201,972) covering the period from 2005 to 2015 to examine gender differences in time use by age groups. The study compares ten industrialized countries across Asia, Europe, and North America. In all ten countries, gender differences in time use are smaller in personal care, sleeping and meals, followed by leisure time (including screen-based leisure and active leisure), and largest in housework, care work and paid work activities. Gender disparities in time use are higher in South Korea, Hungary, and Italy, followed closely by Spain, with moderate gender gaps in Western European countries like France and Netherlands, and lowest differences in Finland and Anglo-Saxon countries, including Canada, US, and the UK. Gender differences in housework and caring time increase from adolescence (10-17 years) to early adulthood (18-29 years), showing strong gender gaps in early/middle adulthood (30-44 years), but narrow again during late adulthood (65 years or older). However, the age gradient in care work and housework is most pronounced in Italy and South Korea, being less prominent in Canada and Finland. Gender gaps in paid work are larger in early/middle adulthood (30-44) and middle/late adulthood (45-64), with strongest age gradients observed in the Netherlands and weaker gradients for the US. Gender differences in active leisure increase by age, especially in Southern European countries, while screen-based leisure shows more stable gender gaps by age groups across different countries. Overall, this study shows that age and gender intersect strongly in affecting time-use patterns, but also that the national context plays an important role in shaping gender-age interactions in time use allocation.