A transformer architecture for retention time prediction in liquid chromatography mass spectrometry-based proteomics.

Accurate retention time (RT) prediction is important for spectral library-based analysis in data-independent acquisition mass spectrometry-based proteomics. The deep learning approach has demonstrated superior performance over traditional machine learning methods for this purpose. The transformer architecture is a recent development in deep learning that delivers state-of-the-art performance in many fields such as natural language processing, computer vision, and biology. We assess the performance of the transformer architecture for RT prediction using datasets from five deep learning models Prosit, DeepDIA, AutoRT, DeepPhospho, and AlphaPeptDeep. The experimental results on holdout datasets and independent datasets exhibit state-of-the-art performance of the transformer architecture. The software and evaluation datasets are publicly available for future development in the field.

Societal Adaptation to Aging and Prevalence of Depression Among Older Adults: Evidence From 20 Countries.

Policy Points Countries have adopted different strategies to support aging populations, which are broadly reflected in social, economic, and contextual environments. Referred to as "societal adaptation to aging," these factors affect countries' capacity to support older adults. Results from our study show that countries with more robust societal adaptation to aging had lower depression prevalence. Reductions in depression prevalence occurred among every investigated sociodemographic group and were most pronounced among the old-old. Findings suggest that societal factors have an underacknowledged role in shaping depression risk. Policies that improve societal approaches to aging may reduce depression prevalence among older adults. CONTEXT: Countries have adopted various formal and informal approaches to support older adults, which are broadly reflected in different policies, programs, and social environments. These contextual environments, broadly referred to as "societal adaptation to aging," may affect population health. METHODS: We used a new theory-based measure that captured societal adaptation to aging, the Aging Society Index (ASI), which we linked with harmonized individual-level data from 89,111 older adults from 20 countries. Using multi-levels models that accounted for differences in the population composition across countries, we estimated the association between country-level ASI scores and depression prevalence. We also tested if associations were stronger among the old-old and among sociodemographic groups that experience more disadvantage (i.e., women, those with lower educational attainment, unmarried adults). FINDINGS: We found that countries with higher ASI scores, indicating more comprehensive approaches to supporting older adults, had lower depression prevalence. We found especially strong reductions in depression prevalence among the oldest adults in our sample. However, we did not find stronger reductions among sociodemographic groups who may experience more disadvantage. CONCLUSIONS: Country-level strategies to support older adults may affect depression prevalence. Such strategies may become increasingly important as adults grow older. These results offer promising evidence that improvements in societal adaptation to aging-such as through adoption of more comprehensive policies and programs targeting older adults-may be one avenue to improve population mental health. Future research could investigate observed associations using longitudinal and quasi-experimental study designs, offering additional information regarding a potential causal relationship.

Exploring the dynamics of flagellar dynein within the axoneme with Fluctuating Finite Element Analysis.

Flagellar dyneins are the molecular motors responsible for producing the propagating bending motions of cilia and flagella. They are located within a densely packed and highly organised super-macromolecular cytoskeletal structure known as the axoneme. Using the mesoscale simulation technique Fluctuating Finite Element Analysis (FFEA), which represents proteins as viscoelastic continuum objects subject to explicit thermal noise, we have quantified the constraints on the range of molecular conformations that can be explored by dynein-c within the crowded architecture of the axoneme. We subsequently assess the influence of crowding on the 3D exploration of microtubule-binding sites, and specifically on the axial step length. Our calculations combine experimental information on the shape, flexibility and environment of dynein-c from three distinct sources; negative stain electron microscopy, cryo-electron microscopy (cryo-EM) and cryo-electron tomography (cryo-ET). Our FFEA simulations show that the super-macromolecular organisation of multiple protein complexes into higher-order structures can have a significant influence on the effective flexibility of the individual molecular components, and may, therefore, play an important role in the physical mechanisms underlying their biological function.

Extremes in water availability and suicide: Evidence from a nationally representative sample of rural Indian adults.

BACKGROUND: Extremes in water availability, either exceptionally wet or dry conditions, can damage crops and may detrimentally affect the livelihood and well-being of people engaged in agriculture. We estimated the effect of water availability on suicide in rural India, a context where the majority of households are dependent upon agriculture. METHODS: We used data from a nationally representative sample of 8.5 million people who were monitored for causes of death from 2001 to 2013. Water availability was measured with high-resolution precipitation and temperature data (i.e., the Standardized Precipitation Evapotranspiration Index). We used a fixed effects approach that modeled changes in water availability within districts (n = 569) over time (n = 13 years) to estimate the impact on suicide deaths. We restricted our analysis to rural areas and to deaths occurring during the growing season (June-March) among adults aged 15 or older, and controlled for sex, age, region, and year. We used Poisson regression with standard errors clustered at the district level and total deaths as the offset. RESULTS: There were 9456 suicides and 249,786 total deaths in our study population between 2001 and 2013. Compared to normal growing seasons, the percent of deaths due to suicide increased by 18.7% during extremely wet growing seasons (95% CI: 6.2, 31.2) and by 3.6% during extremely dry growing seasons (95% CI: -17.9, 25.0). We found that effects varied by age. CONCLUSIONS: We found extremes is water availability associated with an increase in suicide. Abnormally wet growing conditions may play an important, yet overlooked, role in suicide among rural Indian adults.

Fluctuating Finite Element Analysis (FFEA): A continuum mechanics software tool for mesoscale simulation of biomolecules.

Fluctuating Finite Element Analysis (FFEA) is a software package designed to perform continuum mechanics simulations of proteins and other globular macromolecules. It combines conventional finite element methods with stochastic thermal noise, and is appropriate for simulations of large proteins and protein complexes at the mesoscale (length-scales in the range of 5 nm to 1 µm), where there is currently a paucity of modelling tools. It requires 3D volumetric information as input, which can be low resolution structural information such as cryo-electron tomography (cryo-ET) maps or much higher resolution atomistic co-ordinates from which volumetric information can be extracted. In this article we introduce our open source software package for performing FFEA simulations which we have released under a GPLv3 license. The software package includes a C ++ implementation of FFEA, together with tools to assist the user to set up the system from Electron Microscopy Data Bank (EMDB) or Protein Data Bank (PDB) data files. We also provide a PyMOL plugin to perform basic visualisation and additional Python tools for the analysis of FFEA simulation trajectories. This manuscript provides a basic background to the FFEA method, describing the implementation of the core mechanical model and how intermolecular interactions and the solvent environment are included within this framework. We provide prospective FFEA users with a practical overview of how to set up an FFEA simulation with reference to our publicly available online tutorials and manuals that accompany this first release of the package.

Are work demands associated with mental distress? Evidence from women in rural India.

PURPOSE: High work demands might be a determinant of poor mental health among women in low- and middle-income countries, especially in rural settings where women experience greater amounts of labor-intensive unpaid work. Research originating from such settings is lacking. METHODS: We estimated the cross-sectional association between work demands and mental distress among 3177 women living in 160 predominantly tribal communities in southern Rajasthan, India. A structured questionnaire captured the number of minutes women spent on various activities in the last 24 h, and we used this information to measure women's work demands, including the total work amount, nature of work (e.g., housework), and type of work (e.g., cooking). Mental distress was measured with the Hindi version of the 12-item General Health Questionnaire. We used negative binomial regression models to estimate the association between work demands (amount, nature, and type) and mental distress. RESULTS: On average, women spent more than 9.5 h a day on work activities. The most time, intensive work activity was caring for children, the elderly, or disabled (149 min). In adjusted models, we found a U-shaped association between work amount and mental distress. High amounts of housework were associated with higher distress, whereas paid work and farmwork amount were not. Certain types of housework, including collecting water and cleaning, were associated with increased distress scores. CONCLUSIONS: We found an association between aspects of work demands and mental distress. Research in other contexts where women perform high amounts of unpaid work, particularly within the home or farm, is warranted.

In pursuit of an accurate spatial and temporal model of biomolecules at the atomistic level: a perspective on computer simulation.

Despite huge advances in the computational techniques available for simulating biomolecules at the quantum-mechanical, atomistic and coarse-grained levels, there is still a widespread perception amongst the experimental community that these calculations are highly specialist and are not generally applicable by researchers outside the theoretical community. In this article, the successes and limitations of biomolecular simulation and the further developments that are likely in the near future are discussed. A brief overview is also provided of the experimental biophysical methods that are commonly used to probe biomolecular structure and dynamics, and the accuracy of the information that can be obtained from each is compared with that from modelling. It is concluded that progress towards an accurate spatial and temporal model of biomacromolecules requires a combination of all of these biophysical techniques, both experimental and computational.

Understanding the apparent stator-rotor connections in the rotary ATPase family using coarse-grained computer modeling.

Advances in structural biology, such as cryo-electron microscopy (cryo-EM) have allowed for a number of sophisticated protein complexes to be characterized. However, often only a static snapshot of a protein complex is visualized despite the fact that conformational change is frequently inherent to biological function, as is the case for molecular motors. Computer simulations provide valuable insights into the different conformations available to a particular system that are not accessible using conventional structural techniques. For larger proteins and protein complexes, where a fully atomistic description would be computationally prohibitive, coarse-grained simulation techniques such as Elastic Network Modeling (ENM) are often employed, whereby each atom or group of atoms is linked by a set of springs whose properties can be customized according to the system of interest. Here we compare ENM with a recently proposed continuum model known as Fluctuating Finite Element Analysis (FFEA), which represents the biomolecule as a viscoelastic solid subject to thermal fluctuations. These two complementary computational techniques are used to answer a critical question in the rotary ATPase family; implicit within these motors is the need for a rotor axle and proton pump to rotate freely of the motor domain and stator structures. However, current single particle cryo-EM reconstructions have shown an apparent connection between the stators and rotor axle or pump region, hindering rotation. Both modeling approaches show a possible role for this connection and how it would significantly constrain the mobility of the rotary ATPase family.

Does domestic violence legislation reduce permissive attitudes about intimate partner violence? Longitudinal evidence from men and women from 61 countries.

Background: Intimate partner violence (IPV) is highly prevalent and has substantial implications for women's health. Changing IPV attitudes is one pathway to reduce IPV. While evidence suggests that interventions targeting individuals may change IPV attitudes, the effect of wider-scale interventions, such as legislation, remain unknown. Methods: We used individual-level IPV attitudes information collected between 1997 and 2020 by the Demographic and Health Surveys (DHS) and the Multiple Indicator Cluster Surveys (MICS), which we linked with national-level domestic violence (DV) legislation information. We evaluated the effect of adoption of DV legislation on changes in IPV attitudes using a difference-in-differences study design that controlled for time-varying country-level confounding and accounted for staggered timing of legislation adoption. Findings: Our sample included 2,184,047 women from 60 countries and 390,877 men from 40 countries. After controlling for country-level confounders, adoption of DV legislation reduced IPV acceptability among women (average treatment effect among treated (ATT) = -0.07, 95% CI: -0.16, 0.06) and men (ATT = -0.11, 95% CI: -0.22, 0.03) although estimates were imprecise and included the null. Interpretation: DV legislation may reduce permissive IPV attitudes, especially among men, although conclusions should be interpreted cautiously due to imprecise estimates. Funding: Eunice Kennedy Shriver National Institute of Child Health and Human Development (5R00HD104896).

Social support and intimate partner violence in rural Pakistan: A longitudinal investigation of the bi-directional relationship.

A large body of cross-sectional evidence finds strong and consistent associations between social support and intimate partner violence (IPV). However, the directionality of this relationship has not been firmly established due to a dearth of longitudinal evidence. Using cohort study data collected over a 3 year period from 945 women in rural Pakistan, we investigated the longitudinal relationship between IPV and social support. Friend and family social support was measured with the Multidimensional Perceived Social Support Scale, and IPV was measured with questions adopted from the World Health Organization's Violence Against Women Instrument, which was used to construct a measure of IPV severity. We estimated longitudinal associations in linear regression models that controlled for women's educational level, age at marriage, age, household composition, household assets, depressive symptoms, and Adverse Childhood Experiences. We found evidence of a bi-directional, mutually re-enforcing relationship that showed unique associations by type of social support. Specifically, we found that high social support from family, though not friends, decreased IPV severity 1 year later, and that higher IPV severity led to reductions in both friend and family social support 1 year later. Results suggest that interventions involving family members could be especially effective at reducing IPV in this context, and - given that low social support leads to many adverse health outcomes - results suggest that IPV can result in secondary harms due to diminished social support. In summary, our study confirms a bi-directional relationship between IPV and social support and suggests that IPV interventions that integrate social support may be especially effective at reducing IPV and mitigating secondary harms.

Perspectives on automated composition of workflows in the life sciences.

Scientific data analyses often combine several computational tools in automated pipelines, or workflows. Thousands of such workflows have been used in the life sciences, though their composition has remained a cumbersome manual process due to a lack of standards for annotation, assembly, and implementation. Recent technological advances have returned the long-standing vision of automated workflow composition into focus. This article summarizes a recent Lorentz Center workshop dedicated to automated composition of workflows in the life sciences. We survey previous initiatives to automate the composition process, and discuss the current state of the art and future perspectives. We start by drawing the "big picture" of the scientific workflow development life cycle, before surveying and discussing current methods, technologies and practices for semantic domain modelling, automation in workflow development, and workflow assessment. Finally, we derive a roadmap of individual and community-based actions to work toward the vision of automated workflow development in the forthcoming years. A central outcome of the workshop is a general description of the workflow life cycle in six stages: 1) scientific question or hypothesis, 2) conceptual workflow, 3) abstract workflow, 4) concrete workflow, 5) production workflow, and 6) scientific results. The transitions between stages are facilitated by diverse tools and methods, usually incorporating domain knowledge in some form. Formal semantic domain modelling is hard and often a bottleneck for the application of semantic technologies. However, life science communities have made considerable progress here in recent years and are continuously improving, renewing interest in the application of semantic technologies for workflow exploration, composition and instantiation. Combined with systematic benchmarking with reference data and large-scale deployment of production-stage workflows, such technologies enable a more systematic process of workflow development than we know today. We believe that this can lead to more robust, reusable, and sustainable workflows in the future.

Sociodemographic inequalities in depression among older adults: cross-sectional evidence from 18 countries.

BACKGROUND: Sociodemographic inequalities in depression are well established. However, less is known about variation in inequalities across countries. In this study, we describe cross-national variation in sociodemographic inequalities in depression among older adults. Comparing inequalities across countries is an important step towards understanding how the social environment shapes depression risk. METHODS: In this cross-sectional study, we harmonised data from eight large ageing cohort studies from 18 countries. We restricted our study to adults aged 55 years and older, and measured depression using established cut points in shortened Center for Epidemiologic Studies Depression or EURO-D scales. Next, we estimated prevalence ratios for each country by age, marital status, educational attainment, and gender with logistic regression. To compare estimates across countries, we standardised estimates to the mean sociodemographic distribution across our sample. FINDINGS: Between Jan 1, 2007, and May 31, 2015, 93 590 older adults completed questions related to depressive symptoms. Sociodemographic inequalities in depression varied substantially across countries. Variation was most apparent for age: prevalence ratios (adults aged 75 years or older vs adults aged 55-65 years) ranged from 2·66 (95% CI 2·13-3·20) in Israel to 0·78 (95% CI 0·72-0·84) in the USA. Heterogeneity by other factors was also apparent. Gender prevalence ratios (women vs men) ranged from 1·07 (95% CI 1·01-1·14) in Korea to 1·96 (95% CI 1·55-2·36) in Greece. Educational prevalence ratios (less than secondary education vs some post-secondary education) ranged from 1·01 (95% CI 0·88-1·14) in Japan to 2·34 (95% CI 2·14-2·55) in the USA. Marital status prevalence ratios (divorced or separated vs married) ranged from 1·11 (95% CI 1·01-1·21) in Chile to 2·01 (95% CI 1·73-2·29) in England. INTERPRETATION: Inequalities in depression among older adults vary substantially across countries, which might be due to country-specific aspects of the social environment. Future research should investigate social inequality determinants of mental health that might inform the design and evaluation of social, economic, and mental health-related policies and interventions to reduce depression. FUNDING: US National Institute of Mental Health and Chilean National Commission for Scientific and Technological Research.

Lattice-Boltzmann interactive blood flow simulation pipeline.

PURPOSE: Cerebral aneurysms are one of the prevalent cerebrovascular disorders in adults worldwide and caused by a weakness in the brain artery. The most impressive treatment for a brain aneurysm is interventional radiology treatment, which is extremely dependent on the skill level of the radiologist. Hence, accurate detection and effective therapy for cerebral aneurysms still remain important clinical challenges. In this work, we have introduced a pipeline for cerebral blood flow simulation and real-time visualization incorporating all aspects from medical image acquisition to real-time visualization and steering. METHODS: We have developed and employed an improved version of HemeLB as the main computational core of the pipeline. HemeLB is a massive parallel lattice-Boltzmann fluid solver optimized for sparse and complex geometries. The visualization component of this pipeline is based on the ray marching method implemented on CUDA capable GPU cores. RESULTS: The proposed visualization engine is evaluated comprehensively and the reported results demonstrate that it achieves significantly higher scalability and sites updates per second, indicating higher update rate of geometry sites' values, in comparison with the original HemeLB. This proposed engine is more than two times faster and capable of 3D visualization of the results by processing more than 30 frames per second. CONCLUSION: A reliable modeling and visualizing environment for measuring and displaying blood flow patterns in vivo, which can provide insight into the hemodynamic characteristics of cerebral aneurysms, is presented in this work. This pipeline increases the speed of visualization and maximizes the performance of the processing units to do the tasks by breaking them into smaller tasks and working with GPU to render the images. Hence, the proposed pipeline can be applied as part of clinical routines to provide the clinicians with the real-time cerebral blood flow-related information.

The effect of agency on women's mental distress: A prospective cohort study from rural Rajasthan, India.

Agency, the ability to identify goals and then act upon them, is a core component of women's empowerment and has important implications for the rights and well-being of women and girls. However, inadequate measurement of agency impedes empirical investigation, and few studies have investigated the relation between agency and health. Using a theory-based measure of women's agency, we investigated the longitudinal association between agency and mental distress among women living in rural Rajasthan, India. Women completed baseline interviews between June and October 2016 and follow-up interviews between June and November 2017 (n = 2859). We measured mental distress with the Hindi version of the 12 item General Health Questionnaire, which asked women 12 questions about symptoms of mental distress (score range: 0-12). We measured agency using a measurement model which was composed of 23 indicators tapping into four domains of agency and validated in a prior research study. We modeled the relation between women's agency and mental distress using Poisson regression and an individual-level fixed effects approach to account for time-fixed characteristics of individuals. In models that controlled for time-varying confounding (e.g., household wealth, number of sons), a one standard deviation increase in agency was associated with a reduction of 0.21 distress symptoms (95% CI: -0.32, -0.09), which corresponds to a 7% reduction (95% CI: 3%, 11%) relative to the mean. We found that specific domains of agency varied in their association with mental distress; namely, an increase in women's agency regarding her attitudes about gender norms corresponded to a reduction in mental distress, whereas an increase in women's agency regarding speaking up in public corresponded to an increase in mental distress. Our research demonstrates that agency may be a determinant of mental health and that comprehensive measurement can reveal nuanced relationships.

The effect of affordable daycare on women's mental health: Evidence from a cluster randomized trial in rural India.

Access to affordable daycare might improve population mental health. However, evidence is sparse and restricted to middle- and high-income country settings. We conducted a cluster-randomized controlled trial in one low-income setting, rural Rajasthan, India. Communities lacking daycare facilities were identified (n = 160) and randomly selected for assistance in setting up a community-based daycare program (n = 80) or not (n = 80). Women eligible for the daycare program living in these communities completed structured interviews before the intervention (participation rate = 89%) and approximately one year after rollout of the intervention (participation rate = 96%), resulting in a final analytic sample of 3041. Mental distress was measured with the Hindi version of the 12-item General Health Questionnaire (score range: 0-12). We modeled the relation between access to daycare and number of mental distress symptoms (GHQ-12 score) with negative binomial regression using an intention-to-treat approach, which groups women according to if they lived in communities randomized to affordable daycare. We also evaluated the effect of access to daycare on secondary outcomes that may be related to mental distress, including women's work burden, agency, and intimate partner violence (IPV). We found that access to daycare resulted in modest reductions in symptoms of mental distress (mean difference = 0.21, 95% CI: -0.43, 0.02). We found some evidence that daycare reduced IPV, but virtually no change in women's work burden or agency. Our results provide some indication that access to affordable daycare might be one policy lever to improve population mental health.

Modeling Patient-Specific Magnetic Drug Targeting Within the Intracranial Vasculature.

Drug targeting promises to substantially enhance future therapies, for example through the focussing of chemotherapeutic drugs at the site of a tumor, thus reducing the exposure of healthy tissue to unwanted damage. Promising work on the steering of medication in the human body employs magnetic fields acting on nanoparticles made of paramagnetic materials. We develop a computational tool to aid in the optimization of the physical parameters of these particles and the magnetic configuration, estimating the fraction of particles reaching a given target site in a large patient-specific vascular system for different physiological states (heart rate, cardiac output, etc.). We demonstrate the excellent computational performance of our model by its application to the simulation of paramagnetic-nanoparticle-laden flows in a circle of Willis geometry obtained from an MRI scan. The results suggest a strong dependence of the particle density at the target site on the strength of the magnetic forcing and the velocity of the background fluid flow.

Validation of Patient-Specific Cerebral Blood Flow Simulation Using Transcranial Doppler Measurements.

We present a validation study comparing results from a patient-specific lattice-Boltzmann simulation to transcranial Doppler (TCD) velocity measurements in four different planes of the middle cerebral artery (MCA). As part of the study, we compared simulations using a Newtonian and a Carreau-Yasuda rheology model. We also investigated the viability of using downscaled velocities to reduce the required resolution. Simulations with unscaled velocities predict the maximum flow velocity with an error of less than 9%, independent of the rheology model chosen. The accuracy of the simulation predictions worsens considerably when simulations are run at reduced velocity, as is for example the case when inflow velocities from healthy individuals are used on a vascular model of a stroke patient. Our results demonstrate the importance of using directly measured and patient-specific inflow velocities when simulating blood flow in MCAs. We conclude that localized TCD measurements together with predictive simulations can be used to obtain flow estimates with high fidelity over a larger region, and reduce the need for more invasive flow measurement procedures.

A Preliminary Study Examining Nutritional Risk Factors, Body Mass Index, and Treatment Retention in Opioid-Dependent Patients.

Poor nutritional health among opioid-dependent individuals is well established, yet no nutritional screening tool exists for this specific population. The utility of "Determine Your Nutritional Health" developed by the Nutrition Screening Initiative is considered. The study examines the questionnaire's relevance in patients beginning opioid dependence treatment at a methadone-assisted treatment program (N = 140) by examining nutritional risk factor prevalence, body mass index, and association between nutritional risk level and treatment retention. The majority of patients reported at least one nutritional risk factor (89 %) and 59 % were at high nutritional risk. Body mass index was not related to nutritional risk; however, a trend was identified between increasing nutritional risk and decreased retention in treatment. These preliminary findings suggest the need for incorporation of nutritional screening at intake in opioid treatment programs, consideration of the effect of dietary risk on treatment retention, and the potential utility of this screening tool.