Publications

Mitochondrial DNA (mtDNA) escaping stressed mitochondria provokes inflammation via cGAS-STING pathway activation and, when oxidized (Ox-mtDNA), it binds cytosolic NLRP3, thereby triggering inflammasome activation. However, it is unknown how and in which form Ox-mtDNA exits stressed mitochondria in non-apoptotic macrophages. We found that diverse NLRP3 inflammasome activators rapidly stimulated uniporter-mediated calcium uptake to open mitochondrial permeability transition pores (mPTP) and trigger VDAC oligomerization. This occurred independently of mtDNA or reactive oxygen species, which induce Ox-mtDNA generation. Within mitochondria, Ox-mtDNA was either repaired by DNA glycosylase OGG1 or cleaved by the endonuclease FEN1 to 500-650 bp fragments that exited mitochondria via mPTP- and VDAC-dependent channels to initiate cytosolic NLRP3 inflammasome activation. Ox-mtDNA fragments also activated cGAS-STING signaling and gave rise to pro-inflammatory extracellular DNA. Understanding this process will advance the development of potential treatments for chronic inflammatory diseases, exemplified by FEN1 inhibitors that suppressed interleukin-1β (IL-1β) production and mtDNA release in mice.

We examined the relationships of objectively-measured walkability with accelerometer-measured activity patterns including bout-specific moderate-to-vigorous physical activity (MVPA), light-intensity physical activity (LPA) and sedentary behavior in older Japanese adults.This cross-sectional study included 450 men and women (mean age 74 years) who were randomly selected from a resident registry of each municipality (Bunkyo, Fuchu and Oyama city). Neighborhood walkability was assessed using geographic information system data and activity patterns by a validated accelerometer (Active style Pro HJA-350IT). MVPA was assessed as overall (all minutes), short-bout (<10 min) and long-bout (≥10 min). We used analysis of covariance to examine environmental relationships with the three MVPA measures, LPA and sedentary behavior by quartiles of walkability, adjusting for accelerometer wear time and sociodemographic, behavioral and health-related factors.In total, 27% of participants achieved ≥150 min/week of long-bout MVPA. Walkability was not associated with overall MVPA (Q1 = 35.0, Q2 = 31.9, Q3 = 31.4, Q4 = 34.2 min/day) Older adults living in low-walkability areas significantly accumulated more short-bout MVPA (Q1 = 27.2, Q2 = 22.1, Q3 = 20.1, Q4 = 20.5 min/day) and LPA (Q1 = 346, Q2 = 311, Q3 = 289, Q4 = 284 min/day), but less sedentary behavior (Q1 = 479, Q2 = 520, Q3 = 544, Q4 = 544 min/day) than those living in high-walkability areas.Those living in low-walkability areas accumulated more LPA and short-bout MVPA. These activities might be helpful targets for initiatives to promote physical activity among older adult residents of low-walkability areas. Geriatr Gerontol Int 2019; 19: 861-867.

This study investigated the impact of renovation and redesign of a university preschool’s outdoor space on children’s sedentary behavior, light activity, and moderate-to-vigorous-physical-activity (MVPA) during unstructured recess. Physical activity was measured by accelerometry and direct observation in two independent samples of 50 (baseline) and 57 (postintervention) children ( M age =4.4 yrs ± 0.5). Controlling for gender, age, BMI and recess length, observational data, but not accelerometry, revealed a significant decrease in intervals spent sedentary (-26.5%) and increases in light physical activity (+11.6%) and MVPA (+14.9%). Higher levels of MVPA were associated with specific environmental changes (new looping cycle path, OR = 2.18; increased playground open space, OR = 7.62; and new grass hill, OR = 3.27). Decreased sedentary behavior and increased light activity and MVPA may be realized with environmental changes that promote continuous and novel movement experiences in more expansive spaces.

Background. Participant recruitment is an understudied part of health research. It can be a limiting factor and can affect the external validity of a study. This study compares two recruitment methods, active and passive, used to recruit university seniors into a health promotion study. Methods. During active recruitment, 3,787 seniors were telephoned and asked to participate. During passive recruitment, 5,644 seniors were mailed literature and asked to respond if interested. Results. During active recruitment, 1,680 h were spent on the phone, 341 participants were measured, and 161 entered the study, at a cost of $79 per participant. During passive recruitment, 970 h were spent on the phone, 238 participants were measured, and 178 entered the study, at a cost of $45 per participant. The active method had a higher recruitment rate (9% vs 4%) and attrition rate (53% vs 25%) than the passive method. Conclusions. In conclusion, neither recruitment method was ideal. Those recruited with the passive method reported more physical activity and had lower blood pressures, suggesting a self-selection bias. Active recruitment produced a more representative sample and a higher recruitment rate. Passive recruitment was less expensive and led to a lower attrition rate. Conclusions are limited because these are uncontrolled comparisons, not a controlled study.

The 3 new Lancet series papers on physical activity1–3 build on the evidence presented in 2 previous series that underlined the pandemic magnitude of physical inactivity, its health, social, environmental and economic global consequences, and the urgency to take immediate multisectoral actions to make active living an affordable and accessible choice for all population groups. These messages were based on unquestionable evidence of the beneficial effects of physical activity on virtually every system of the body, supporting it as a “best buy in public health.” Increasing physical activity could save 5.3 million lives per year,4 and it is critical for the prevention and control of multiple noncommunicable diseases (NCDs) that account for 74% of deaths globally. However, an estimated 1 in 3 adults and 3 in 4 adolescents worldwide did not meet the physical activity guidelines before the pandemic. Now in 2021, the failure to take seriously evidence-based recommendations to increase physical activity has contributed to the estimated 4.2 million COVID-19 deaths worldwide. It is clear that the inactivity pandemic is foundational in the global explosion of NCDs that have collided so tragically with the COVID-19 pandemic.

The present study extended the results of previous research in applying the “stages of acquisition” model to the onset of smokeless tobacco as well as cigarette use. Three expert judges classified an initial pool of items as to whether they represented “precontemplation,” “contemplation,” “action,” or “maintenance” stages of smokeless tobacco acquisition. Fifty items with adequate inter-rater reliability were combined with 21 previously developed items pertaining to cigarette smoking acquisition in an overall tobacco acquisition questionnaire, which in turn was administered to 358 junior and senior high public school students. Three distinct components labeled precontemplation, action, and maintenance were delineated through principal component analyses. Coefficient alphas and discriminant analyses according to self-reported use demonstrated adequate reliability and validity for the new smokeless tobacco- and previously developed smoking-acquisition scale.

Many bacterial toxins act on conserved components of essential host-signaling pathways. One consequence of this conservation is that genetic model organisms such as Drosophila melanogaster can be used for analyzing the mechanism of toxin action. In this study, we characterize the activities of two anthrax virulence factors, lethal factor (LF) and edema factor, in transgenic Drosophila. LF is a zinc metalloprotease that cleaves and inactivates most human mitogen-activated protein kinase (MAPK) kinases (MAPKKs). We found that LF similarly cleaves the Drosophila MAPK kinases Hemipterous (Hep) and Licorne in vitro. Consistent with these observations, expression of LF in Drosophila inhibited the Hep/c-Jun N-terminal kinase pathway during embryonic dorsal closure and the related process of adult thoracic closure. Epistasis experiments confirmed that LF acts at the level of Hep. We also found that LF inhibits Ras/MAPK signaling during wing development and that LF acts upstream of MAPK and downstream of Raf, consistent with LF acting at the level of Dsor. In addition, we found that edema factor, a potent adenylate cyclase, inhibits the hh pathway during wing development, consistent with the known role of cAMP-dependent PKA in suppressing the Hedgehog response. These results demonstrate that anthrax toxins function in Drosophila as they do in mammalian cells and open the way to using Drosophila as a multicellular host system for studying the in vivo function of diverse toxins and virulence factors.

Within the growing body of research linking neighbourhood environmental attributes with physical activity, associations between recreational destinations and non-walking leisure-time physical activity (LTPA) are rarely studied, and to date, not across multiple cities. We examined six potential associations of objectively-measured access to private recreational facilities (e.g., fitness centres, swimming pools) and parks with adults’ non-walking LTPA (e.g., swimming, cycling, tennis), using data gathered with consistent methods from adults living in international cities with a range of environment attributes. The potential effects of socio-demographic moderators and between-city variations were also examined. Data from 6725 adults from 10 cities (6 countries) were gathered. Adults were more likely to engage in non-walking LTPA if they had a greater number of private recreational facilities within 0.5 or 1 km of the home, particularly in women, and if they lived closer to a park. The amount of non-zero LTPA was only associated (positively) with the number of recreational facilities within 1 km. Relationships between amount of LTPA and park proximity appear complex, with likely contextual and cultural differences. Improving access to private recreational facilities could promote non-walking LTPA, especially in women.

Anorexia and weight loss are prevalent in infectious diseases. To investigate the molecular mechanisms underlying these phenomena, we established animal models of infection-associated anorexia by administrating bacterial and viral products, lipopolysaccharide (LPS) and human immunodeficiency virus-1 transactivator protein (Tat). In these models, we found that the nuclear factor-kappaB (NF-kappaB), a pivotal transcription factor for inflammation-related proteins, was activated in the hypothalamus. In parallel, administration of LPS and Tat increased hypothalamic pro-inflammatory cytokine production, which was abrogated by inhibition of hypothalamic NF-kappaB. In vitro, NF-kappaB activation directly stimulated the transcriptional activity of pro-opiomelanocortin (POMC), a precursor of anorexigenic melanocortin, and mediated the stimulatory effects of LPS, Tat, and pro-inflammatory cytokines on POMC transcription, implying the involvement of NF-kappaB in controlling feeding behavior. Consistently, hypothalamic injection of LPS and Tat caused a significant reduction in food intake and body weight, which was prevented by blockade of NF-kappaB and melanocortin. Furthermore, disruption of I kappaB kinase-beta, an upstream kinase of NF-kappaB, in POMC neurons attenuated LPS- and Tat-induced anorexia. These findings suggest that infection-associated anorexia and weight loss are mediated via NF-kappaB activation in hypothalamic POMC neurons. In addition, hypothalamic NF-kappaB was activated by leptin, an important anorexigenic hormone, and mediates leptin-stimulated POMC transcription, indicating that hypothalamic NF-kappaB also serves as a downstream signaling pathway of leptin.

Intestinal epithelial cell (IEC) death is a common feature of inflammatory bowel disease (IBD) that triggers inflammation by compromising barrier integrity. In many patients with IBD, epithelial damage and inflammation are TNF-dependent. Elevated TNF production in IBD is accompanied by increased expression of the <i>TNFAIP3</i> gene, which encodes A20, a negative feedback regulator of NF-κB. A20 in intestinal epithelium from patients with IBD coincided with the presence of cleaved caspase-3, and A20 transgenic (Tg) mice, in which A20 is expressed from an IEC-specific promoter, were highly susceptible to TNF-induced IEC death, intestinal damage, and shock. A20-expressing intestinal organoids were also susceptible to TNF-induced death, demonstrating that enhanced TNF-induced apoptosis was a cell-autonomous property of A20. This effect was dependent on Receptor Interacting Protein Kinase 1 (RIPK1) activity, and A20 was found to associate with the Ripoptosome complex, potentiating its ability to activate caspase-8. A20-potentiated RIPK1-dependent apoptosis did not require the A20 deubiquitinase (DUB) domain and zinc finger 4 (ZnF4), which mediate NF-κB inhibition in fibroblasts, but was strictly dependent on ZnF7 and A20 dimerization. We suggest that A20 dimers bind linear ubiquitin to stabilize the Ripoptosome and potentiate its apoptosis-inducing activity.