Interleukin-1β (IL-1β) is a potent inflammatory cytokine that is usually cleaved and activated by inflammasome-associated caspase-1. To determine whether IL-1β activation is regulated by inhibitor of ...apoptosis (IAP) proteins, we treated macrophages with an IAP-antagonist “Smac mimetic” compound or genetically deleted the genes that encode the three IAP family members cIAP1, cIAP2, and XIAP. After Toll-like receptor priming, IAP inhibition triggered cleavage of IL-1β that was mediated not only by the NLRP3-caspase-1 inflammasome, but also by caspase-8 in a caspase-1-independent manner. In the absence of IAPs, rapid and full generation of active IL-1β by the NLRP3-caspase-1 inflammasome, or by caspase-8, required the kinase RIP3 and reactive oxygen species production. These results demonstrate that activation of the cell death-inducing ripoptosome platform and RIP3 can generate bioactive IL-1β and implicate them as additional targets for the treatment of pathological IL-1-driven inflammatory responses.
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► IAP inhibition induces NLRP3 inflammasome-dependent and -independent IL-1 activation ► Genetic deletion of the three IAPs (cIAP1, cIAP2, XIAP) activates IL-1 ► Inflammasome-independent IL-1 maturation is mediated by caspase-8 cleavage ► RIP3 signaling, and not cell death, activates IL-1
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Studies exploring associations between neighbourhood environment and obesity often overlook the fact that neighbourhoods are multi-dimensional and that the effects of one environmental exposure may ...be modified by another. We examine whether associations between neighbourhood density of formal physical activity (PA) facilities and body mass index (BMI) are modified by the density of neighbourhood green spaces and takeaway stores. We used cross-sectional data from the UK Biobank cohort and linked UK Biobank Urban Morphometric Platform (UKBUMP) for 345,269 urban-dwelling adults aged 40–69. We examined associations between objectively measured BMI and the number of formal PA facilities (gyms, pools, etc.) within 1 km of each individual's home, testing separately for interactions with the number of local public green spaces, and number of takeaway stores, within the same 1 km buffers. We estimated modifier-stratified associations using multivariable, multilevel models to account for a clustered sampling design and potential confounding. Likelihood ratio tests were used to assess statistical interaction. We found that the association between a greater number of local PA facilities and lower BMI was stronger among people with fewer urban green spaces in their neighbourhood than among those with more green spaces (Pinteraction = 0.021). The same relationship between PA facilities and BMI was also noticeably attenuated among those with more takeaway stores near home, compared with people with none (Pinteraction = 0.014). We conclude that formal PA facilities may buffer against a lack of informal, green resources for PA in areas where the latter are scarce. However, the potential benefits of formal PA facilities in terms of obesity risk may be undermined by an unhealthy food environment close to home. Locating formal PA facilities in places with fewer public green resources and reducing the prevalence of takeaway stores in areas with formal PA resources may maximise the health benefits to be derived from these neighbourhood resources.
•Neighbourhoods are multi-dimensional; dimensions may interact to influence health.•Stronger association of PA facility availability and lower BMI when no local parks.•Weaker association between PA facilities and BMI when more takeaways near home.•Formal PA facilities may buffer against a lack of informal, green spaces for PA.•Benefits of PA facilities may be undermined by unhealthy local food environments.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK, ZRSKP
Bacterial infection is highly prevalent in patients who have had a stroke. Despite the potential contribution of micro-aspiration in post-stroke pneumonia, we found that the majority of the ...microorganisms detected in the patients who developed infections after having a stroke were common commensal bacteria that normally reside in the intestinal tracts. In a mouse model of ischemic stroke, post-stroke infection was only observed in mice that were born and raised in specific-pathogen-free facilities; this was not seen in mice that were born and raised in germ-free facilities. Using high-throughput 16S rRNA gene amplicon sequencing and bioinformatics analyses, we provide evidence demonstrating that the source of the bacteria forming the microbial community in the lungs of post-stroke mice was indeed the host small intestine. Additionally, stroke-induced gut barrier permeability and dysfunction preceded the dissemination of orally inoculated bacteria to peripheral tissues. This study identifies a novel pathway in which stroke promotes the translocation and dissemination of selective strains of bacteria that originated from the host gut microbiota.
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IJS, NUK, SBMB, UL, UM, UPUK
Purpose
Neighborhood environments may influence cancer risk. Average population effect estimates might mask differential effects by socioeconomic position. Improving neighborhood environments could ...inadvertently widen health inequalities if important differences are overlooked.
Methods
Using linked records of hospital admissions in UK Biobank, we assessed associations between admission with a primary diagnosis of cancer (any/breast/colorectal), and exposure to neighborhood greenspace, physical activity facilities, and takeaway food stores, and whether household income and area deprivation modify these associations. We used adjusted Cox proportional hazards models, and estimated relative excess risks due to interaction (RERI) to assess effect modification.
Results
Associations between neighborhood exposures and cancer-related hospitalizations were weak to null overall, but with some evidence of effect modification. Most notably, more greenspace near home was associated with 16% lower hazard of cancer-related hospital admission in deprived areas (95% CI 2–29%). This was further pronounced for people in low-income households in deprived areas, and for breast cancer.
Conclusion
In deprived neighborhoods, increasing the amount of greenspace may help reduce cancer-related hospitalizations. Examining effect modification by multiple socioeconomic indicators can yield greater insight into how social and environmental factors interact to influence cancer incidence. This may help avoid perpetuating cancer inequalities when designing neighborhood environment interventions.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, VSZLJ, ZAGLJ
There is increasing evidence of a direct association between unaffordable housing and poor mental health, over and above the effects of general financial hardship. Type of housing tenure may be an ...important factor in determining how individuals experience and respond to housing affordability problems. This study investigated whether a relationship exists between unaffordable housing and mental health that differs for home purchasers and private renters among low-income households. Data from 2001 to 2010 of the longitudinal Household, Income and Labour Dynamics in Australia (HILDA) survey were analysed using fixed-effects linear regression to examine change in the SF-36 Mental Component Summary (MCS) score of individuals aged 25–64 years, associated with changes in housing affordability, testing for an interaction with housing tenure type. After adjusting for age, survey year and household income, among individuals living in households in the lower 40% of the national income distribution, private renters in unaffordable housing experienced somewhat poorer in mental health than when their housing was affordable (difference in MCS = −1.18 or about 20% of one S.D. of the MCS score; 95% CI: -1.95,-0.41; p = 0.003) while home purchasers experienced no difference on average. The statistical evidence for housing tenure modifying the association between unaffordable housing and mental health was moderate (p = 0.058). When alternatives to 40% were considered as income cut-offs for inclusion in the sample, evidence of a difference between renters and home purchasers was stronger amongst households in the lowest 50% of the income distribution (p = 0.020), and between the 30th and 50th percentile (p = 0.045), with renters consistently experiencing a decline in mental health while mean MCS scores of home purchasers did not change. In this study, private renters appeared to be more vulnerable than home purchasers to mental health effects of unaffordable housing. Such a modified effect suggests that tenure-differentiated policy responses to poor housing affordability may be appropriate.
•Housing costs impact on health and wellbeing, but do effects differ by tenure type?•We used data from a large, nationally representative Australian panel survey.•Only for renters did we observe poorer mental health when housing was unaffordable.•Unaffordable housing differentially affects mental health of renters and owners.•It may be appropriate to tailor policy responses according to housing tenure type.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK, ZRSKP
The built environment might be associated with development of obesity and related disorders. We examined whether neighbourhood exposure to fast-food outlets and physical activity facilities were ...associated with adiposity in UK adults.
We used cross-sectional observational data from UK Biobank. Participants were aged 40–70 years and attended 21 assessment centres between 2006 and 2010. Using linked data on environments around each participant's residential address, we examined whether density of physical activity facilities and proximity to fast-food outlets were associated with waist circumference, body-mass index (BMI), and body fat percentage. We used multilevel linear regression models adjusted for potential confounders, and conducted several sensitivity analyses.
Complete case sample sizes were 401 917 (waist circumference models), 401 435 (BMI), and 395 640 (body fat percentage). Greater density of physical activity facilities within 1000 m of home was independently associated with smaller waist circumference and lower BMI and body fat percentage. Compared with people with no nearby facilities, those with at least six facilities close to home had 1·22 cm smaller waist circumference (95% CI −1·64 to −0·80), 0·57 kg/m2 lower BMI (−0·74 to −0·39), and 0·81 percentage points lower body fat (−1·03 to −0·59). Living further from a fast-food outlet was weakly associated with waist circumference and BMI, mostly among women. Compared with people living fewer than 500 m from a fast-food outlet, those living at least 2000 m away had 0·26 cm smaller waist circumference (−0·52 to 0·01).
This study shows strong associations between high densities of physical activity facilities and lower adiposity for adults in mid-life. We observed weaker associations for access to fast food, but these are likely to be underestimated owing to limitations of the food environment measure. Policy makers should consider interventions aimed at tackling the obesogenic built environment.
Commonwealth Scholarship Commission, Wellcome Trust Institutional Strategic Support Fund.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Housing insecurity is an escalating problem in the UK but there is limited evidence about its health impacts. Using nationally representative panel data and causally focussed methods, we examined the ...effect of insecure housing on mental health, sleep and blood pressure, during a period of government austerity.
We used longitudinal survey data (2009–2019, n = 11,164 individuals with annual data) from the UK Household Longitudinal Study. Outcomes were probable common mental disorder (GHQ-12), sleep disturbance due to worry, and new diagnoses of hypertension. The primary exposure was housing payment problems in the past year. Using doubly robust marginal structural models with inverse probability of treatment weights, we estimated absolute and relative health effects of housing payment problems, and population attributable fractions. In stratified analyses we assessed potentially heterogeneous impacts across the population, and potential modifying effects of government austerity measures. A negative control analysis was conducted to detect bias due to unmeasured confounding.
Housing payment problems were associated with a 2.5 percentage point increased risk of experiencing a common mental disorder (95% CI 1.1%, 3.8%) and 2.0% increased risk of sleep disturbance (95% CI 0.7%, 3.3%). Estimates were larger for renters, younger people, less educated, households with children, and people living in areas most affected by austerity-related cuts to housing support services. We did not find consistent evidence for an association with hypertension (risk difference = 0.4%; 95% CI -0.1%, 0.9%). The negative control analysis was not indicative of unmeasured confounding.
Housing payment problems were associated with worse mental health and sleep disturbance in a large UK sample. Households at risk of falling into rent or mortgage arrears need more support, especially in areas where housing support services have been diminished. Substantial investment is urgently needed to improve supply of social and affordable housing.
•Housing payment problems were associated with worse mental health and sleep.•We used doubly robust marginal structural models with IPTW.•No indication of bias from unmeasured confounding in a negative control analysis.•Larger estimates for renters, younger people, households with children.•Mental health effect larger in areas with disinvestment in housing support services.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Effects of residential neighbourhood environments on health may vary across geographical space, with differences in local contexts influencing how much a given neighbourhood characteristic matters ...for the health of local residents. Linking UK Biobank data from 302,952 urban-dwelling adults in England, collected between 2006 and 2010, to publicly available Local Authority-level data, we examined (a) whether cross-sectional associations between body mass index (BMI) and two characteristics of the neighbourhood built environment (availability of formal physical activity facilities near home, and fast-food proximity) vary by Local Authority (LA), and (b) whether cross-level interactions with LA-level physical features (natural landcover) and socio-cultural attributes (local obesity norms) reveal evidence of effect modification by these features of the wider contexts in which neighbourhoods are located. We found variation across urban England in the relationship between availability of neighbourhood formal physical activity facilities and BMI, and some evidence suggesting this association was stronger among people living in areas with less natural landcover, especially in areas outside of London. We also found that the relationship between proximity of fast-food stores to people's homes and BMI varied geographically across England. Local descriptive obesity norms were not an important modifier of this association. This paper highlights the importance of considering potential geographical heterogeneity in relationships between the built environment and health, and the implications for generalisability of research findings. By seeking to better understand sources of geographical heterogeneity, we may be able to better adapt and target built environment interventions for population health improvement.
•We found geographical heterogeneity in neighbourhood environment–BMI associations.•This may be explained by attributes of the wider contexts of neighbourhoods.•Less natural landcover may amplify the influence of living near formal PA facilities.•Context matters for understanding how neighbourhood characteristics affect health.•Geographical heterogeneity has implications for generalisability of single-site studies.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
A current paradigm proposes that mitochondrial damage is a critical determinant of NLRP3 inflammasome activation. Here, we genetically assess whether mitochondrial signalling represents a unified ...mechanism to explain how NLRP3 is activated by divergent stimuli. Neither co‐deletion of the essential executioners of mitochondrial apoptosis BAK and BAX, nor removal of the mitochondrial permeability transition pore component cyclophilin D, nor loss of the mitophagy regulator Parkin, nor deficiency in MAVS affects NLRP3 inflammasome function. In contrast, caspase‐8, a caspase essential for death‐receptor‐mediated apoptosis, is required for efficient Toll‐like‐receptor‐induced inflammasome priming and cytokine production. Collectively, these results demonstrate that mitochondrial apoptosis is not required for NLRP3 activation, and highlight an important non‐apoptotic role for caspase‐8 in regulating inflammasome activation and pro‐inflammatory cytokine levels.
Synopsis
Mitochondria are believed to have an important role in NLRP3 activation. Using 14 strains of knockout mice, this study finds no evidence for the involvement of mitochondrial damage in NLRP3 function, but shows that caspase‐8 is needed for inflammasome priming.
The essential mitochondrial apoptosis executioners, BAX and BAK are not required for NLRP3 activation.
Genetic deletion of the mitochondrial permeability transition pore component cyclophilin D, the mitochondrial anti‐viral signalling protein (MAVS) or the mitophagy regulator Parkin does not impact on NLRP3 activity.
Caspase‐8 expression is required for efficient inflammasome priming and Toll‐like‐receptor‐induced cytokine production.
Mitochondria are believed to have an important role in NLRP3 activation. Using 14 strains of knockout mice, this study finds no evidence for the involvement of mitochondrial damage in NLRP3 function, but shows that caspase‐8 is needed for inflammasome priming.
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FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
Remote sensing observations of Searles Lake following the 2019 moment magnitude 7.1 Ridgecrest, California, earthquake reveal an area where surface ejecta is arranged in a repeating hexagonal pattern ...that is collocated with a solution-mining operation. By analyzing geologic and geotechnical data, here we show that the hexagonal surface ejecta is likely not a result of liquefaction. Instead, we propose dissolution cavity collapse (DCC) as an alternative driving mechanism. We support this theory with pre-event Interferometric Synthetic Aperture Radar data, which reveals differential subsidence patterns and the creation of subsurface void space. We also find that DCC is likely triggered at a lower shaking threshold than classical liquefaction. This and other unknown mechanisms can masquerade as liquefaction, introducing bias into liquefaction prediction models that rely on liquefaction inventories. This paper also highlights the opportunities and drawbacks of using remote sensing data to disentangle the complex factors that influence earthquake-triggered ground failure.
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