TonB-Dependent Transport Across the Bacterial Outer Membrane.

TonB-dependent transporters (TBDTs) are present in all gram-negative bacteria and mediate energy-dependent uptake of molecules that are too scarce or large to be taken up efficiently by outer membrane (OM) diffusion channels. This process requires energy that is derived from the proton motive force and delivered to TBDTs by the TonB-ExbBD motor complex in the inner membrane. Together with the need to preserve the OM permeability barrier, this has led to an extremely complex and fascinating transport mechanism for which the fundamentals, despite decades of research, are still unclear. In this review, we describe our current understanding of the transport mechanism of TBDTs, their potential role in the delivery of novel antibiotics, and the important contributions made by TBDT-associated (lipo)proteins.

P-type ATPases: Many more enigmas left to solve.

P-type ATPases constitute a large ancient super-family of primary active pumps that have diverse substrate specificities ranging from H+ to phospholipids. The significance of these enzymes in biology cannot be overstated. They are structurally related, and their catalytic cycles alternate between high- and low-affinity conformations that are induced by phosphorylation and dephosphorylation of a conserved aspartate residue. In the year 1988, all P-type sequences available by then were analyzed and five major families, P1 to P5, were identified. Since then, a large body of knowledge has accumulated concerning the structure, function, and physiological roles of members of these families, but only one additional family, P6 ATPases, has been identified. However, much is still left to be learned. For each family a few remaining enigmas are presented, with the intention that they will stimulate interest in continued research in the field. The review is by no way comprehensive and merely presents personal views with a focus on evolution.

Low molecular weight acids and OATP1B mediated hepatic clearance: In vitro and in vivo evaluation using novel hypoxia-inducible factor prolyl hydroxylase inhibitors (Dustats).

Organic anion transporting polypeptide (OATP1B) plays a key role in the hepatic clearance of a majority of high molecular weight (MW) acids and zwitterions. Here, we evaluated the role of OATP1B-mediated uptake in the clearance of novel hypoxia-inducible factor prolyl hydroxylase inhibitors ("Dustats"), which are typically low MW (300-400 daltons) aliphatic carboxylic acids. Five acid dustats, namely daprodustat, desidustat, enarodustat, roxadustat and vadadustat, showed specific transport by OATP1B1/1B3 in transporter-transfected HEK293 cells. Neutral compound, molidustat, was not a substrate to OATP1B1/1B3. None of the dustats showed transport by other hepatic uptake transporters, including NTCP, OAT2 and OAT7. In the primary human hepatocytes, uptake of all acids was significantly reduced by rifampin (OATP1B inhibitor); with an estimated fraction transported by OATP1B (ft ,OATP1B) of up to >80% (daprodustat). Molidustat uptake was minimally inhibited by rifampin; and low permeability acids (desidustat and enarodustat) also showed biliary efflux in sandwich culture human hepatocytes. In vivo, intravenous pharmacokinetics of all 5 acids was significantly altered by a single-dose rifampin (30 mg/kg) in Cynomolgus monkey. Hepatic clearance (non-renal) was about 4-fold (vadadustat) to >11-fod (daprodustat and roxadustat) higher in control group compared to rifampin-treated subjects. In vivo ft ,OATP1B was estimated to be ~70-90%. In the case of molidustat, rifampin had a minimal effect on overall clearance. Rifampin also considerably reduced volume of distribution of daprodustat and roxadustat. Overall, OATP1B significantly contribute to the hepatic clearance and pharmacokinetics of several dustats, which are low MW carboxylic acids. OATP1B activity should therefore by evaluated in this property space. Significance Statement Our in vitro and in vivo results suggest that OATP1B-mediated hepatic uptake play a significant role in the pharmacokinetics of low MW acidic dustats, which are being developed or approved for the treatment of anemia in chronic kidney disease. Significant active uptake mechanisms are not apparent for the neutral compound, molidustat. Characterization of uptake mechanisms is therefore important in predicting human pharmacokinetics and evaluating drug-drug interactions for low MW acids.

Associations between transport modes and site-specific cancers: a systematic review and meta-analysis.

BACKGROUND: Physical inactivity is a global public health problem. A practical solution would be to build physical activity into the daily routine by using active modes of transport. Choice of transport mode can influence cancer risk through their effects on levels of physical activity, sedentary time, and environmental pollution. This review synthesizes existing evidence on the associations of specific transport modes with risks of site-specific cancers. METHODS: Relevant literature was searched in PubMed, Embase, and Scopus from 1914 to 17th February 2023. For cancer sites with effect measures available for a specific transport mode from two or more studies, random effects meta-analyses were performed to pool relative risks (RR) comparing the highest vs. lowest activity group as well as per 10 Metabolic Equivalent of Task (MET) hour increment in transport-related physical activity per week (∼150 min of walking or 90 min of cycling). RESULTS: 27 eligible studies (11 cohort, 15 case-control, and 1 case-cohort) were identified, which reported the associations of transport modes with 10 site-specific cancers. In the meta-analysis, 10 MET hour increment in transport-related physical activity per week was associated with a reduction in risk for endometrial cancer (RR: 0.91, 95% CI: 0.83-0.997), colorectal cancer (RR: 0.95, 95% CI: 0.91-0.99) and breast cancer (RR: 0.99, 95% CI: 0.89-0.996). The highest level of walking only or walking and cycling combined modes, compared to the lowest level, were significantly associated with a 12% and 30% reduced risk of breast and endometrial cancers respectively. Cycling, compared to motorized modes, was associated with a lower risk of overall cancer incidence and mortality. CONCLUSION: Active transport appears to reduce cancer risk, but evidence for cancer sites other than colorectum, breast, and endometrium is currently limited.

Promoting children's health through community-led street interventions: analyzing sustained voluntarism in Canadian School Streets.

BACKGROUND: Active School Travel (AST) initiatives align with the Ottawa Charter for Health Promotion, which calls for 'creating supportive environments' and 'strengthening community action.' However, their reliance on volunteers poses sustainability challenges. The main objectives of this study were to document the motivations, satisfaction, and experiences of volunteers involved in sustaining two AST initiatives in Ontario for an entire school year. METHODS: Two volunteer-led School Street initiatives in Kingston, Ontario successfully operated during pick-up and drop-off times of each school day. The first initiative operated for the entire 2021-2022 school year, and the second operated for the entire 2022-2023 school year. These initiatives were the first of their kind in the province of Ontario, Canada. Volunteers from both sites (n = 56) participated in online surveys and their motivations, satisfaction, and experiences of their role were compared using the 2-sided Fisher's Exact Test. RESULTS: Over 80% of volunteers were highly motivated to promote safety and over 70% of volunteers were highly motivated to disrupt the status quo of unsupportive, car-centric urban environments by reimagining how streets can be used. By taking collective action to re-shape the environment around these public schools to support healthy, active living, our findings reveal that over 90% of volunteers were highly satisfied. Of the volunteers, 87% felt they contributed to child safety and 85% felt they had developed stronger community connections. They appreciated the short (i.e., 40 minute) time commitment of each shift, weekly email communications by the community organization leading the initiative, and the volunteer schedule. They also appreciated the positive social interactions during volunteer shifts, which they felt outweighed the minimal resistance they experienced. CONCLUSIONS: This research demonstrates the importance of logistical, motivational, and social factors in recruiting and retaining volunteers for community-led School Streets. Our findings support appealing to prospective volunteers' influence in achieving School Street objectives (e.g., improved safety) in recruitment efforts, as well as highlighting School Streets' innovative approach. Communicating with volunteers throughout School Street planning and implementation processes and limiting traffic in the closed street zone (i.e., by excluding the school staff parking lot and private driveways from the scope) are additional recommendations based on the findings of this study.

Experimental and Computational Methods to Assess Central Nervous System Penetration of Small Molecules.

In CNS drug discovery, the estimation of brain exposure to lead compounds is critical for their optimization. Compounds need to cross the blood-brain barrier (BBB) to reach the pharmacological targets in the CNS. The BBB is a complex system involving passive and active mechanisms of transport and efflux transporters such as P-glycoproteins (P-gp) and breast cancer resistance protein (BCRP), which play an essential role in CNS penetration of small molecules. Several in vivo, in vitro, and in silico methods are available to estimate human brain penetration. Preclinical species are used as in vivo models to understand unbound brain exposure by deriving the Kp,uu parameter and the brain/plasma ratio of exposure corrected with the plasma and brain free fraction. The MDCK-mdr1 (Madin Darby canine kidney cells transfected with the MDR1 gene encoding for the human P-gp) assay is the commonly used in vitro assay to estimate compound permeability and human efflux. The in silico methods to predict brain exposure, such as CNS MPO, CNS BBB scores, and various machine learning models, help save costs and speed up compound discovery and optimization at all stages. These methods enable the screening of virtual compounds, building of a CNS penetrable compounds library, and optimization of lead molecules for CNS penetration. Therefore, it is crucial to understand the reliability and ability of these methods to predict CNS penetration. We review the in silico, in vitro, and in vivo data and their correlation with each other, as well as assess published experimental and computational approaches to predict the BBB penetrability of compounds.

My Way to School Through a Camera Lens: Involving Children to Inform a Policy Recommendation on Active School Travel.

Active school travel (AST) is an effective approach for increasing children's physical activity and independent mobility, but policy supporting AST is lacking. This study aims to explore children's experiences of AST to inform a policy recommendation. Photovoice methodology with a qualitative approach was applied, with children taking pictures on their way to school. This was followed by focus groups where the children explored their experiences of AST based on their photos. The data were analyzed using qualitative content analysis. The results show that the children valued independent mobility and wanted to be involved in decisions about their travels; they also expressed feelings of increased responsibility and personal growth as a consequence. Although the children recognized areas of improvement regarding infrastructure, especially regarding heavy traffic that jeopardized travel safety, they continued using AST. Finally, the children talked about the value of the health and environmental benefits of AST. Opportunities for friendship, play, and making decisions about their own time were highlighted as important incentives. The benefits from AST are many for children, as well as for society. The result has informed policy recommendations for AST, and the children's input will be used to communicate the recommendations. Listening to the voices of children could be a steppingstone toward forming future healthy mobility initiatives. In that process, it is key to include children's perspectives when formulating the AST policy for successful adoption and implementation.

Results from Ireland North and South's 2022 report card on physical activity for children and adolescents.

Background: The Ireland North and South Report Card on Physical Activity (PA) for Children and Adolescents aims to monitor progress in PA participation across a range of internationally established indicators. Methods: Data were collated for 11 indicators and graded following the harmonised Active Healthy Kids Global Alliance report card process. Six representative studies (sample size range n = 898 to n = 15,557) were primarily used in the grading, with many indicators supplemented with additional studies and reports. Data collected since the implementation of COVID-19 public health measures in March 2020 were excluded. Results: Grades were awarded as follows: 'Overall physical activity', C-; 'Organised Sport and Physical Activity', C; 'Active Play', INC; 'Sedentary Behaviours', C-; 'Physical Fitness', INC; 'Family and Peers', D+; 'School', C-; 'Physical Education', D; 'Community and Environment', B+ and 'Government', B. Separate grades were awarded for disability as follows; 'Overall physical activity', F; 'Organised Sport and Physical Activity', D; 'Sedentary Behaviours', C-; 'Family and Peers', C; 'School', C- and 'Government', B. 'Active Play', 'Physical Fitness', 'Physical Education' and 'Community and Environment' were all graded INC for disability. Since the last report card in 2016, four grades remained the same, three increased ('Overall physical activity', 'School' and 'Physical Education') and two ('Family and Peers,' and 'Government') were awarded grades for the first time. Conclusion: Grades specific to children and adolescents with disability were generally lower for each indicator. While small improvements have been shown across a few indicators, PA levels remain low across many indicators for children and adolescents.

Cryo-EM of the ATP11C flippase reconstituted in Nanodiscs shows a distended phospholipid bilayer inner membrane around transmembrane helix 2.

ATP11C is a member of the P4-ATPase flippase family that mediates translocation of phosphatidylserine (PtdSer) across the lipid bilayer. In order to characterize the structure and function of ATP11C in a model natural lipid environment, we revisited and optimized a quick procedure for reconstituting ATP11C into Nanodiscs using methyl-ß-cyclodextrin as a reagent for the detergent removal. ATP11C was efficiently reconstituted with the endogenous lipid, or the mixture of endogenous lipid and synthetic dioleoylphosphatidylcholine (DOPC)/dioleoylphosphatidylserine (DOPS), all of which retained the ATPase activity. We obtained 3.4 Å and 3.9 Å structures using single-particle cryo-electron microscopy (cryo-EM) of AlF- and BeF-stabilized ATP11C transport intermediates, respectively, in a bilayer containing DOPS. We show that the latter exhibited a distended inner membrane around ATP11C transmembrane helix 2, possibly reflecting the perturbation needed for phospholipid release to the lipid bilayer. Our structures of ATP11C in the lipid membrane indicate that the membrane boundary varies upon conformational changes of the enzyme and is no longer flat around the protein, a change that likely contributes to phospholipid translocation across the membrane leaflets.

Allosteric gate modulation confers K+ coupling in glutamate transporters.

Excitatory amino acid transporters (EAATs) mediate glial and neuronal glutamate uptake to terminate synaptic transmission and to ensure low resting glutamate concentrations. Effective glutamate uptake is achieved by cotransport with 3 Na+ and 1 H+ , in exchange with 1 K+ . The underlying principles of this complex transport stoichiometry remain poorly understood. We use molecular dynamics simulations and electrophysiological experiments to elucidate how mammalian EAATs harness K+ gradients, unlike their K+ -independent prokaryotic homologues. Glutamate transport is achieved via elevator-like translocation of the transport domain. In EAATs, glutamate-free re-translocation is prevented by an external gate remaining open until K+  binding closes and locks the gate. Prokaryotic GltPh contains the same K+ -binding site, but the gate can close without K+ . Our study provides a comprehensive description of K+ -dependent glutamate transport and reveals a hitherto unknown allosteric coupling mechanism that permits adaptions of the transport stoichiometry without affecting ion or substrate binding.

When Moving Is the Only Option: The Role of Necessity Versus Choice for Understanding and Promoting Physical Activity in Low- and Middle-Income Countries.

Given its origins in high-income countries, the field of physical activity and public health research and promotion has broadly followed a choice-based model. However, a substantial amount of the physical activity occurring routinely in many settings, particularly in low- and middle-income countries (LMICs), is the result of economic necessity and is not due to true, free choices. We propose the "necessity- versus choice-based physical activity models" framework as a conceptual tool to ground physical activity and public health research and promotion efforts in LMICs, helping ensurethat these efforts are relevant, ethical, responsive, and respectful to local contexts. Identifying ways to ensure that LMIC populations can maintain high levels of active transport while increasing opportunities for active leisure must be prioritized. To promote equity, physical activity research, programs, and policies in LMICs must focus on improving the conditions under which necessity-driven physical activity occurs for a vast majority of the population.

School-based physical activity in relation to active travel - a cluster randomized controlled trial among adolescents enrolled in the school in motion study in Norway.

BACKGROUND: Active travel and school settings are considered ideal for promoting physical activity. However, previous research suggests limited effect of school-based interventions on overall physical activity levels among adolescents. The relationship between physical activity in different domains remains inconclusive. In this study, we examined the effects of adding two weekly hours of school-based physical activity on active travel rates. METHOD: We analyzed data from 1370 pupils in the 9th-grade participating in the cluster RCT; the School In Motion (ScIM) project. Intervention schools (n = 19) implemented 120 min of class-scheduled physical activity and physical education, in addition to the normal 2 hours of weekly physical education in the control schools (n = 9), for 9 months. Active travel was defined as pupils who reported walking or cycling to school, while motorized travel was defined as pupils who commuted by bus or car, during the spring/summer half of the year (April-September), or autumn/winter (October-February). The participants were categorized based on their travel mode from pretest to posttest as; maintained active or motorized travel ("No change"), changing to active travel (motorized-active), or changing to motorized travel (active-motorized). Multilevel logistic regression was used to analyze the intervention effect on travel mode. RESULTS: During the intervention period, most participants maintained their travel habits. In total, 91% of pupils maintained their travel mode to school. Only 6% of pupils switched to motorized travel and 3% switched to active travel, with small variations according to season and trip direction. The intervention did not seem to influence the likelihood of changing travel mode. The odds ratios for changing travel habits in spring/summer season were from active to motorized travel 1.19 [95%CI: 0.53-2.15] and changing from motorized to active travel 1.18 [0.30-2.62], compared to the "No change" group. These findings were consistent to and from school, and for the autumn/winter season. CONCLUSION: The extra school-based physical activity does not seem to affect rates of active travel among adolescents in the ScIM project. TRIAL REGISTRATION: Clinicaltrials.gov ID nr: NCT03817047. Registered 01/25/2019' retrospectively registered'.

Determinants of physical activity in community-dwelling older adults: an umbrella review.

INTRODUCTION: Physical activity (PA) is critical for disease prevention and maintaining functional ability with aging. Despite this, as many as 50% of older adults in populations worldwide are considered insufficiently active. There is a recognized need to mobilize policies targeted toward modifiable determinants of healthy aging like PA. This umbrella review aimed to summarize the evidence for determinants of PA in community-dwelling older adults. METHODS: A research librarian searched six databases. Systematic and scoping reviews were included if they investigated community-dwelling people with a mean age of 60 + years and examined a relationship between a determinant and any type of PA. Two independent reviewers screened and extracted data from all reviews. JBI methodology and Critical Appraisal Checklist for Systematic Reviews and Research Syntheses were followed and information on the quality of the evidence was extracted. RESULTS: From 17,277 records screened,11 reviews representing > 300 unique primary papers were ultimately included. Only 6% of studies included in all reviews had longitudinal designs. Included studies used a large variety of PA measures, with 76% using only self-report, 15% using only direct measures (e.g., accelerometry), 3% using both types, and 6% with no outcome measure reported. Only four reviews provided a definition of PA and there was substantial inconsistency in the way PA was categorised. Community level influences, which only included the physical environment, were the most commonly assessed (6/11) with more than 70% of the summarized relationships demonstrating null associations. Three out of four reviews reported a positive relationship between walkability and PA in general community-dwelling older adults. There was also evidence supporting relationships between presence of social support for PA, younger age, and men having higher PA from a single systematic review. None of the included reviews assessed the quality of evidence but over 60% performed a risk of bias assessment. CONCLUSIONS: Walkability, age, gender, and social support for PA were the most supported PA determinants identified. Further research should focus on interpersonal and intrapersonal influences and incorporate direct measures of PA with clear operational definitions. There is a need for longitudinal study designs to further understand determinants of PA behaviour trajectories.

Mode of transport, genetic susceptibility, and incidence of coronary heart disease.

BACKGROUND: Car use has been associated with higher risk of coronary heart disease (CHD). However, whether the associations of transport modes with CHD vary by genetic susceptibility to CHD are unknown. This study aims to investigate the associations of genetic susceptibility and modes of transport with incidence of CHD. METHODS: We included 339,588 white British participants from UK Biobank with no history of CHD or stroke at baseline or within two years of follow-up (52.3% in work). Genetic susceptibility to CHD was quantified through weighted polygenic risk scores derived from 300 single-nucleotide polymorphisms related to CHD risk. Categories of transport mode included exclusive car use and alternatives to the car (e.g., walking, cycling and public transport), separately for non-commuting (e.g., getting about [n=339,588] excluding commuting for work), commuting (in the sub-set in work [n=177,370] who responded to the commuting question), and overall transport (transport mode for both commuting and non-commuting [n=177,370]). We used Cox regression with age as the underlying timescale to estimate hazard ratios (HR) of CHD (n=13,730; median 13.8-year follow-up) and tested the interaction between genetic susceptibility and travel modes with adjustment for confounders. RESULTS: Compared to those using alternatives to the car, hazards of CHD were higher for exclusive use of cars for overall transport (HR: 1.16, 95% confidence interval (CI): 1.08-1.25), non-commuting (HR: 1.08, 95% CI: 1.04-1.12) and commuting (HR: 1.16, 95% CI: 1.09-1.23), after adjusting for confounders plus genetic susceptibility. HRs of CHD were 1.45 (95% CI: 1.38-1.52) and 2.04 (95% CI: 1.95-2.12) for the second and third tertile of genetic susceptibility to CHD, respectively, compared to the first. There was, in general, no strong evidence of interactions between genetic susceptibility and categories of overall, non-commuting and commuting transport. Estimated 10-year absolute risk of CHD was lower for the alternatives to the car across strata of genetic susceptibility, compared with exclusive use of cars for overall, non-commuting and commuting transport. CONCLUSION: Exclusive use of cars was associated with a relatively higher risk of CHD across all strata of genetic susceptibility. Using alternatives to the car should be encouraged for prevention of CHD for the general population including individuals at high genetic risk.

Cross-sectional and longitudinal associations of domain-specific physical activity composition with health-related quality of life in childhood and adolescence in Australia.

BACKGROUND: Health benefits have been linked with physical activity (PA), as well as some domains of PA among youth (e.g. organized PA and active transport). However, less is known about whether some PA domains are more beneficial than others. There is also a lack of evidence about whether health outcomes are related to the composition of PA (i.e. the share of PA spent in different domains). This study aimed to identify: (1) how the absolute durations of organized PA, non-organized PA, active transport and active chores/work at 10-11y are individually associated with physical, psychosocial and total health-related quality of life (HRQOL) at 10-11y and 12-13y; and (2) how the domain-specific composition of PA at 10-11y is associated with HRQOL at 10-11y and 12-13y. METHODS: Data from the Longitudinal Study of Australian Children were used in cross-sectional (n ≥ 2730) and longitudinal analyses (n ≥ 2376). Measurement included the Pediatric Quality of Life Inventory (PedsQL™) for HRQOL domains and one-day time-use diaries (TUDs) for PA domains. Robust linear regression models were used, controlling for age, sex, pubertal status, socioeconomic position, body mass index and TUD context (season and school attendance). Compositional models additionally adjusted for total PA duration and longitudinal models controlled for baseline PedsQL™ scores. RESULTS: Non-compositional models indicated that the duration of organized PA, and to a lesser extent non-organized PA, were positively but weakly associated with some HRQOL outcomes at 10-11y. These trends were not reflected in longitudinal models, although a 30-min increase in non-organized PA per day did predict marginally better psychosocial HRQOL at 12-13y (+ 0.17%; 95%CI = + 0.03%, + 0.32%). Compositional models revealed that a 30-min increase in organized PA relative to other domains was positively but weakly associated with physical (+ 0.32%; 95%CI = + 0.01%, + 0.63%), psychosocial (+ 0.41%; 95%CI = + 0.11%, + 0.72%) and total HRQOL (+ 0.39%; 95%CI = + 0.12%, + 0.66%) at 10-11y. However, the overall PA composition at 10-11y was not related to HRQOL at 12-13y. CONCLUSIONS: Non-compositional and compositional models generally concurred on the direction of cross-sectional and longitudinal relationships (and lack thereof) between PA domains and HRQOL outcomes. The strongest associations were cross-sectional between organized PA and HRQOL at 10-11y. However, all associations between PA domains and HRQOL outcomes were weak and may not be clinically meaningful.

Prediction model for milk transfer of drugs by primarily evaluating the area under the curve using QSAR/QSPR.

PURPOSE: Information on milk transferability of drugs is important for patients who wish to breastfeed. The purpose of this study is to develop a prediction model for milk-to-plasma drug concentration ratio based on area under the curve (M/PAUC). The quantitative structure-activity/property relationship (QSAR/QSPR) approach was used to predict compounds involved in active transport during milk transfer. METHODS: We collected M/P ratio data from literature, which were curated and divided into M/PAUC ≥ 1 and M/PAUC < 1. Using the ADMET Predictor® and ADMET Modeler™, we constructed two types of binary classification models: an artificial neural network (ANN) and a support vector machine (SVM). RESULTS: M/P ratios of 403 compounds were collected, M/PAUC data were obtained for 173 compounds, while 230 compounds only had M/Pnon-AUC values reported. The models were constructed using 129 of the 173 compounds, excluding colostrum data. The sensitivity of the ANN model was 0.969 for the training set and 0.833 for the test set, while the sensitivity of the SVM model was 0.971 for the training set and 0.667 for the test set. The contribution of the charge-based descriptor was high in both models. CONCLUSIONS: We built a M/PAUC prediction model using QSAR/QSPR. These predictive models can play an auxiliary role in evaluating the milk transferability of drugs.

Prediction of the Renal Organic Anion Transporter 1 (OAT1)- Mediated Drug Interactions for LY404039, the Active Metabolite of Pomaglumetad Methionil.

PURPOSE: The objective of this work was to demonstrate that clinical OAT1-mediated DDIs can be predicted using physiologically based pharmacokinetic (PBPK) modeling. METHODS: LY404039 is a metabotropic glutamate receptor 2/3 agonist and the active moiety of the prodrug pomaglumetad methionil (LY2140023). After oral administration, pomaglumetad methionil is rapidly taken up by enterocytes via PEPT1 and once absorbed, converted to LY404039 via membrane dehydropeptidase 1 (DPEP1). LY404039 is renally excreted by both glomerular filtration and active secretion and in vitro studies showed that the active secretion of LY404039 was mediated by the organic anion transporter 1 (OAT1). Both clinical and in vitro data were used to build a PBPK model to predict OAT1-mediated DDIs. RESULTS: In vitro inhibitory potencies (IC50) of the known OAT inhibitors, probenecid and ibuprofen, were determined to be 4.00 and 2.63 µM, respectively. Subsequently, clinical drug-drug interaction (DDI) study showed probenecid reduced the renal clearance of LY404039 by 30 to 40%. The PBPK bottom-up model, predicted a renal clearance that was approximately 20% lower than the observed one. The middle-out model, using an OAT1 relative activity factor (RAF) of 3, accurately reproduced the renal clearance of LY404039 and pharmacokinetic (PK) changes of LY404039 in the presence of probenecid. CONCLUSIONS: OAT1- mediated DDIs can be predicted using in vitro measured IC50 and PBPK modeling. The effect of ibuprofen was predicted to be minimal (AUC ratio of 1.15) and not clinically relevant.

Contribution of active commuting to and from school to device-measured physical activity levels in young people: A systematic review and meta-analysis.

OBJECTIVE: To analyze the contribution of active commuting to and from school (ACS) to device-measured light physical activity (LPA) and moderate-to-vigorous physical activity (MVPA) levels in young people aged 6 to 18 years old, as well as, in both trip directions (i.e., home-school, school-home). METHODS: This systematic review was conducted according to the PRISMA statement, and five different databases were used for the systematic search (PubMed, Web of Science, SPORTdiscuss, Cochrane Library, and National Transportation Library) using PECO strategy. RESULTS: A total of 14 studies met all the eligibility criteria, which compile 7127 participants. The overall ACS weighted LPA was 19.55 min (95% CI: 3.84-35.26; I2 = 99.9%, p < 0.001) and 68.74 min (95% CI: 6.09-131.39; z = 2.15, p = 0.030) during the home-school and school-home trips, respectively. For MVPA, the overall ACS weighted MVPA was 8.98 min (95% CI: 5.33-12.62; I2 = 99.95%, p < 0.001) during the home-school trip and 20.07 min (95% CI: 13.62-26.53; I2 = 99.62%, p < 0.001) during the school-home trip. CONCLUSION: ACS may contribute about 48% of the PA recommendations in young people on school days if both trip directions are actively performed. Therefore, future studies aimed at increasing daily PA levels in young population should focus on promoting students' ACS. PROSPERO registration number: CRD42020162004A.

Impact of structural-level environmental interventions on physical activity: a systematic review.

OBJECTIVE: To determine the effectiveness of structural-level environmental interventions on the changes in PA levels in the populations examined. METHODS: Natural experiments that involve environmental intervention with structural modification were included. The primary outcome PA levels with consideration of both objective and subjective measurements. An electronic search was carried out in Medline/Pubmed, SCIENCE DIRECT, WEB OF SCIENCE, and CINAHL up to January 2022. Two reviewers screened titles and abstracts, selected studies, extracted relevant data, and examined study quality. A qualitative synthesis was performed. RESULTS: Twenty-six articles were included. The structural-level environmental interventions included 4 fundamental areas: schools, work environments, streets or cities, and neighborhoods or parks. Of the 26 studies, 21 examined outdoor environments like parks, cities, pedestrian walkways, or steps, while 5 examined indoor or closed environments like schools and workplaces revealing that structural-level environmental interventions improve PA levels with the greatest effect in parks and active transportation. A risk of bias is inherent in natural experiments which is a limitation of this study. In schools and work areas, there is evidence of both decrease in sedentary time and an increase in PA related to environmental modifications. CONCLUSION: Structural-level environmental modifications in parks and active transportation demonstrated greater effects in promoting PA. Environmental modifications can impact physical activity in the population. Given that the economic and cultural setting is a key variable when considering the effectiveness of structural interventions, and since only 1 of the 26 reviewed articles included such data, more studies examining economic factors are needed especially in low- and middle-income countries like in South America. TRIAL REGISTRATION: PROSPERO CRD42021229718.

Effects of major urban redesign on sedentary behavior, physical activity, active transport and health-related quality of life in adults.

BACKGROUND: The built environment is increasingly recognized as a determinant for health and health behaviors. Existing evidence regarding the relationship between environment and health (behaviors) is varying in significance and magnitude, and more high-quality longitudinal studies are needed. The aim of this study was to evaluate the effects of a major urban redesign project on physical activity (PA), sedentary behavior (SB), active transport (AT), health-related quality of life (HRQOL), social activities (SA) and meaningfulness, at 29-39 months after opening of the reconstructed area. METHODS: PA and AT were measured using accelerometers and GPS loggers. HRQOL and sociodemographic characteristics were assessed using questionnaires. In total, 241 participants provided valid data at baseline and follow-up. We distinguished three groups, based on proximity to the intervention area: maximal exposure group, minimal exposure group and no exposure group. RESULTS: Both the maximal and minimal exposure groups showed significantly different trends regarding transport-based PA levels compared to the no exposure group. In the exposure groups SB decreased, while it increased in the no exposure group. Also, transport-based light intensity PA remained stable in the exposure groups, while it significantly decreased in the no exposure group. No intervention effects were found for total daily PA levels. Scores on SA and meaningfulness increased in the maximal exposure group and decreased in the minimal and no exposure group, but changes were not statistically significant. CONCLUSION: The results of this study emphasize the potential of the built environment in changing SB and highlights the relevance of longer-term follow-up measurements to explore the full potential of urban redesign projects. TRIAL REGISTRATION: This research was retrospectively registered at the Netherlands Trial Register (NL8108).