Reactive oxygen species, such as H2O2, can damage cells but also promote fundamental processes, including growth, differentiation and migration. The mechanisms allowing cells to differentially respond to toxic or signaling H2O2 levels are poorly defined. Here we reveal that increasing external H2O2 produces a bi-phasic response in intracellular H2O2. Peroxiredoxins (Prx) are abundant peroxidases which protect against genome instability, ageing and cancer. We have developed a dynamic model simulating in vivo changes in Prx oxidation. Remarkably, we show that the thioredoxin peroxidase activity of Prx does not provide any significant protection against external rises in H2O2. Instead, our model and experimental data are consistent with low levels of extracellular H2O2 being efficiently buffered by other thioredoxin-dependent activities, including H2O2-reactive cysteines in the thiol-proteome. We show that when extracellular H2O2 levels overwhelm this buffering capacity, the consequent rise in intracellular H2O2 triggers hyperoxidation of Prx to thioredoxin-resistant, peroxidase-inactive form/s. Accordingly, Prx hyperoxidation signals that H2O2 defenses are breached, diverting thioredoxin to repair damage.

Several systematic reviews have reported mixed associations between access to parks and physical activity, and suggest that this is due to inconsistencies in the study methods or differences across countries. An international study using consistent methods is needed to investigate the association between access to parks and physical activity. The International Physical Activity and Environment Network (IPEN) Adult Study is a multi-country cross-sectional study using a common design and consistent methods. Accelerometer, survey and Geographic Information Systems (GIS) data for 6,181 participants from 12 cities in 8 countries (Belgium, Brazil, Czech Republic, Denmark, Mexico, New Zealand, UK, USA) were used to estimate the strength and shape of associations of 11 measures of park access (1 perceived and 10 GIS-based measures) with accelerometer-based moderate-to-vigorous physical activity (MVPA) and four types of self-reported leisure-time physical activity. Associations were estimated using generalized additive mixed models. More parks within 1 km from participants' homes were associated with greater leisure-time physical activity and accelerometer-measured MVPA. Respondents who lived in the neighborhoods with the most parks did on average 24 minutes more MVPA per week than those living in the neighborhoods with the lowest number of parks. Perceived proximity to a park was positively associated with multiple leisure-time physical activity outcomes. Associations were homogeneous across all cities studied. Living in neighborhoods with many parks could contribute with up to 1/6 of the recommended weekly Having multiple parks nearby was the strongest positive correlate of PA. To increase comparability and validity of park access measures, we recommend that researchers, planners and policy makers use the number of parks within 1 km travel distance of homes as an objective indicator for park access in relation to physical activity.

BACKGROUND: Neutralizing autoantibodies (Abs) against granulocyte-macrophage colony-stimulating factor (GM-CSF Ab) have been associated with stricturing ileal Crohns disease (CD) in a largely pediatric patient cohort (total 394, adult CD 57). The aim of this study was to examine this association in 2 independent predominantly adult inflammatory bowel disease patient cohorts. METHODS: Serum samples from 742 subjects from the NIDDK IBD Genetics Consortium and 736 subjects from Australia were analyzed for GM-CSF Ab and genetic markers. We conducted multiple regression analysis with backward elimination to assess the contribution of GM-CSF Ab levels and established CD risk alleles and smoking on ileal disease location in the 477 combined CD subjects from both cohorts. We also determined associations of GM-CSF Ab levels with complications requiring surgical intervention in combined CD subjects in both cohorts. RESULTS: Serum samples from patients with CD expressed significantly higher concentrations of GM-CSF Ab when compared with ulcerative colitis or controls in each cohort. Nonsmokers with ileal CD expressed significantly higher GM-CSF Ab concentrations in the Australian cohort (P = 0.002). Elevated GM-CSF Ab, ileal disease location, and disease duration more than 3 years were independently associated with stricturing/penetrating behavior and intestinal resection for CD. CONCLUSIONS: The expression of high GM-CSF Ab is a risk marker for aggressive CD behavior and complications including surgery. Modifying factors include environmental exposure to smoking and genetic risk markers.

Justice-oriented climate activism is proliferating. Many scholars aspire to deliver research that supports activism. However, measures of impact for research evaluation and funding purposes place little weight on the use of research by activists. Here we consider how academics and academia might effectively support and enable climate activism. We report outcomes from a series of online deliberative workshops involving both activists and academics from several European countries. The workshops were facilitated to create space for discussion, sharing of experiences and the development of proposals for the future. The outcomes take the form of a set of principles (a “minifesta”) for academic-activist engagement generated by the group. In discussing the process and outputs, we argue that a focus on inclusion can support politically transformative change of the scale and urgency required. We suggest that this also demands a shift in attitudes toward the role of activism and activists in collaborative processes. We further discuss the inevitable incompleteness of this process, arguing that incompleteness is, itself, a feature of inclusive engagement. We conclude that scholars working on climate issues in any discipline could benefit from increasing mutually supportive collaboration with activists; and that such collaboration and inclusion could help liberate democracy from authoritarian tendencies and market influences. Collaborative engagements generate legitimate, rich, and impactful outcomes even with the limitations posed by COVID19. We, therefore, commend both the model of engagement and the principles it generated for our colleagues and peers.

This study investigated whether residential availability of natural outdoor environments (NOE) was associated with contact with NOE, overall physical activity and physical activity in NOE, in four different European cities using objective measures. A nested cross-sectional study was conducted in Barcelona (Spain); Stoke-on-Trent (United Kingdom); Doetinchem (The Netherlands); and Kaunas (Lithuania). Smartphones were used to collect information on the location and physical activity (overall and NOE) of around 100 residents of each city over seven days. We used Geographic Information Systems (GIS) to determine residential NOE availability (presence/absence of NOE within 300 m buffer from residence), contact with NOE (time spent in NOE), overall PA (total physical activity), NOE PA (total physical activity in NOE). Potential effect modifiers were investigated. Participants spent around 40 min in NOE and 80 min doing overall PA daily, of which 11% was in NOE. Having residential NOE availability was consistently linked with higher NOE contact during weekdays, but not to overall PA. Having residential NOE availability was related to NOE PA, especially for our Barcelona participants, people that lived in a city with low NOE availability.

Introduction

Growing evidence suggests that close contact with nature brings benefits to human health and well-being, but the proposed mechanisms are still not well understood and the associations with health remain uncertain. The Positive Health Effects of the Natural Outdoor environment in Typical Populations in different regions in Europe (PHENOTYPE) project investigates the interconnections between natural outdoor environments and better human health and well-being.

Aims and methods

The PHENOTYPE project explores the proposed underlying mechanisms at work (stress reduction/restorative function, physical activity, social interaction, exposure to environmental hazards) and examines the associations with health outcomes for different population groups. It implements conventional and new innovative high-tech methods to characterise the natural environment in terms of quality and quantity. Preventive as well as therapeutic effects of contact with the natural environment are being covered. PHENOTYPE further addresses implications for land-use planning and green space management. The main innovative part of the study is the evaluation of possible short-term and long-term associations of green space and health and the possible underlying mechanisms in four different countries (each with quite a different type of green space and a different use), using the same methodology, in one research programme. This type of holistic approach has not been undertaken before. Furthermore there are technological innovations such as the use of remote sensing and smartphones in the assessment of green space.

Conclusions

The project will produce a more robust evidence base on links between exposure to natural outdoor environment and human health and well-being, in addition to a better integration of human health needs into land-use planning and green space management in rural as well as urban areas.

Background & aims

Genome-wide association studies have identified 200 inflammatory bowel disease (IBD) loci, but the genetic architecture of Crohn's disease (CD) and ulcerative colitis remain incompletely defined. Here, we aimed to identify novel associations between IBD and functional genetic variants using the Illumina ExomeChip (San Diego, CA).

Methods

Genotyping was performed in 10,523 IBD cases and 5726 non-IBD controls. There were 91,713 functional single-nucleotide polymorphism loci in coding regions analyzed. A novel identified association was replicated further in 2 independent cohorts. We further examined the association of the identified single-nucleotide polymorphism with microbiota from 338 mucosal lavage samples in the Mucosal Luminal Interface cohort measured using 16S sequencing.

Results

We identified an association between CD and a missense variant encoding alanine or threonine at position 391 in the zinc transporter solute carrier family 39, member 8 protein (SLC39A8 alanine 391 threonine, rs13107325) and replicated the association with CD in 2 replication cohorts (combined meta-analysis P = 5.55 × 10(-13)). This variant has been associated previously with distinct phenotypes including obesity, lipid levels, blood pressure, and schizophrenia. We subsequently determined that the CD risk allele was associated with altered colonic mucosal microbiome composition in both healthy controls (P = .009) and CD cases (P = .0009). Moreover, microbes depleted in healthy carriers strongly overlap with those reduced in CD patients (P = 9.24 × 10(-16)) and overweight individuals (P = 6.73 × 10(-16)).

Conclusions

Our results suggest that an SLC39A8-dependent shift in the gut microbiome could explain its pleiotropic effects on multiple complex diseases including CD.

The Large Synoptic Survey Telescope (LSST) will enable revolutionary studies of galaxies, dark matter, and black holes over cosmic time. The LSST Galaxies Science Collaboration has identified a host of preparatory research tasks required to leverage fully the LSST dataset for extragalactic science beyond the study of dark energy. This Galaxies Science Roadmap provides a brief introduction to critical extragalactic science to be conducted ahead of LSST operations, and a detailed list of preparatory science tasks including the motivation, activities, and deliverables associated with each. The Galaxies Science Roadmap will serve as a guiding document for researchers interested in conducting extragalactic science in anticipation of the forthcoming LSST era.

From 2005 to 2018, among 32013 adults with human immunodeficiency virus entering care, median time to antiretroviral therapy (ART) prescription declined from 69 to 6 days, CD4 count at entry into care increased from 300 to 362 cells/μL, and CD4 count at ART prescription increased from 160 to 364 cells/μL.

Background

The updated Veterans Aging Cohort Study (VACS) Index 2.0 combines general and human immunodeficiency virus (HIV)-specific biomarkers to generate a continuous score that accurately discriminates risk of mortality in diverse cohorts of persons with HIV (PWH), but a score alone is difficult to interpret. Using data from the North American AIDS Cohort Collaboration (NA-ACCORD), we translate VACS Index 2.0 scores into validated probability estimates of mortality.

Methods

Because complete mortality ascertainment is essential for accurate calibration, we restricted analyses to cohorts with mortality from the National Death Index or equivalent sources. VACS Index 2.0 components were ascertained from October 1999 to April 2018. Mortality was observed up to March 2019. Calibration curves compared predicted (estimated by fitting a gamma model to the score) to observed mortality overall and within subgroups: cohort (VACS/NA-ACCORD subset), sex, age <50 or ≥50 years, race/ethnicity, HIV-1 RNA ≤500 or >500 copies/mL, CD4 count <350 or ≥350 cells/µL, and years 1999-2009 or 2010-2018. Because mortality rates have decreased over time, the final model was limited to 2010-2018.

Results

Among 37230 PWH in VACS and 8061 PWH in the NA-ACCORD subset, median age was 53 and 44 years; 3% and 19% were women; and 48% and 39% were black. Discrimination in NA-ACCORD (C-statistic = 0.842 [95% confidence interval {CI}, .830-.854]) was better than in VACS (C-statistic = 0.813 [95% CI, .809-.817]). Predicted and observed mortality largely overlapped in VACS and the NA-ACCORD subset, overall and within subgroups.

Conclusions

Based on this validation, VACS Index 2.0 can reliably estimate probability of all-cause mortality, at various follow-up times, among PWH in North America.