Interaction with ErbB4 promotes hypoxia-inducible factor-1α signaling

The receptor-tyrosine kinase ErbB4 was identified as a direct regulator of hypoxia-inducible factor-1α (HIF-1α) signaling. Cleaved intracellular domain of ErbB4 directly interacted with HIF-1α in the nucleus, and stabilized HIF-1α protein in both normoxic and hypoxic conditions by blocking its proteasomal degradation. The mechanism of HIF stabilization was independent of VHL and proline hydroxylation but dependent on RACK1. ErbB4 activity was necessary for efficient HRE-driven promoter activity, transcription of known HIF-1α target genes, and survival of mammary carcinoma cells in vitro. In addition, mammary epithelial specific targeting of Erbb4 in the mouse significantly reduced the amount of HIF-1α protein in vivo. ERBB4 expression also correlated with the expression of HIF-regulated genes in a series of 4552 human normal and cancer tissue samples. These data demonstrate that soluble ErbB4 intracellular domain promotes HIF-1α stability and signaling via a novel mechanism

Geographical Variations of the Minimum Mortality Temperature at a Global Scale

Background: Minimum mortality temperature (MMT) is an important indicator to assess the temperature-mortality association, indicating long-term adaptation to local climate. Limited evidence about the geographical variability of the MMT is available at a global scale. Methods: We collected data from 658 communities in 43 countries under different climates. We estimated temperature-mortality associations to derive the MMT for each community using Poisson regression with distributed lag nonlinear models. We investigated the variation in MMT by climatic zone using a mixed-effects meta-analysis and explored the association with climatic and socioeconomic indicators. Results: The geographical distribution of MMTs varied considerably by country between 14.2 and 31.1 ºC decreasing by latitude. For climatic zones, the MMTs increased from alpine (13.0 ºC) to continental (19.3 ºC), temperate (21.7 ºC), arid (24.5 ºC), and tropical (26.5 ºC). The MMT percentiles (MMTPs) corresponding to the MMTs decreased from temperate (79.5th) to continental (75.4th), arid (68.0th), tropical (58.5th), and alpine (41.4th). The MMTs indreased by 0.8 ºC for a 1 ºC rise in a community's annual mean temperature, and by 1 ºC for a 1 ºC rise in its SD. While the MMTP decreased by 0.3 centile points for a 1 ºC rise in a community's annual mean temperature and by 1.3 for a 1 ºC rise in its SD. Conclusions: The geographical distribution of the MMTs and MMTPs is driven mainly by the mean annual temperature, which seems to be a valuable indicator of overall adaptation across populations. Our results suggest that populations have adapted to the average temperature, although there is still more room for adaptation. Copyright © 2021 The Authors

Coarse particulate air pollution and daily mortality: A global study in 205 cities.

RATIONALE: The associations between ambient coarse particulate matter (PM2.5-10) and daily mortality is not fully understood at a global scale. OBJECTIVES: To evaluate the short-term associations between PM2.5-10 and total, cardiovascular, and respiratory mortality across multiple countries/regions worldwide. METHODS: We collected daily mortality (total, cardiovascular, respiratory) and air pollution data from 205 cities in 20 countries/regions. Concentrations of PM2.5-10 were computed as the difference between inhalable and fine particulate matter. A two-stage time-series analytic approach was applied, with over-dispersed generalized linear models and multilevel meta-analysis. We fitted two-pollutant models to test the independent effect of PM2.5-10 from co-pollutants (fine particulate matter, nitrogen dioxide, sulfur dioxide, ozone, and carbon monoxide). Exposure-response relationship curves were pooled and regional analyses were conducted. MEASUREMENTS AND MAIN RESULTS: A 10 μg/m3 increase in PM2.5-10 concentration on lag 0-1 day was associated with increments of 0.51% (95% confidence interval [CI]: 0.18%, 0.84%), 0.43% (95%CI: 0.15%, 0.71%) and 0.41% (95%CI: 0.06%, 0.77%) in total, cardiovascular, and respiratory mortality, respectively. The associations varied by country and region. These associations were robust to adjustment by all co-pollutants in two-pollutant models, especially for PM2.5. The exposure-response curves for total, cardiovascular, and respiratory mortality were positive, with steeper slopes at lower exposure ranges and without discernible thresholds. CONCLUSIONS: This study provides novel global evidence on the robust and independent associations between short-term exposure to ambient PM2.5-10 and total, cardiovascular and respiratory mortality, suggesting the need to establish a unique guideline or regulatory limit for daily concentrations of PM2.5-10

Short term associations of ambient nitrogen dioxide with daily total, cardiovascular, and respiratory mortality: multilocation analysis in 398 cities.

OBJECTIVE: To evaluate the short term associations between nitrogen dioxide (NO2) and total, cardiovascular, and respiratory mortality across multiple countries/regions worldwide, using a uniform analytical protocol. DESIGN: Two stage, time series approach, with overdispersed generalised linear models and multilevel meta-analysis. SETTING: 398 cities in 22 low to high income countries/regions. MAIN OUTCOME MEASURES: Daily deaths from total (62.8 million), cardiovascular (19.7 million), and respiratory (5.5 million) causes between 1973 and 2018. RESULTS: On average, a 10 μg/m3 increase in NO2 concentration on lag 1 day (previous day) was associated with 0.46% (95% confidence interval 0.36% to 0.57%), 0.37% (0.22% to 0.51%), and 0.47% (0.21% to 0.72%) increases in total, cardiovascular, and respiratory mortality, respectively. These associations remained robust after adjusting for co-pollutants (particulate matter with aerodynamic diameter ≤10 μm or ≤2.5 μm (PM10 and PM2.5, respectively), ozone, sulfur dioxide, and carbon monoxide). The pooled concentration-response curves for all three causes were almost linear without discernible thresholds. The proportion of deaths attributable to NO2 concentration above the counterfactual zero level was 1.23% (95% confidence interval 0.96% to 1.51%) across the 398 cities. CONCLUSIONS: This multilocation study provides key evidence on the independent and linear associations between short term exposure to NO2 and increased risk of total, cardiovascular, and respiratory mortality, suggesting that health benefits would be achieved by tightening the guidelines and regulatory limits of NO2

Short term associations of ambient nitrogen dioxide with daily total, cardiovascular, and respiratory mortality: Multilocation analysis in 398 cities

AbstractObjective To evaluate the short term associations between nitrogen dioxide (NO 2) and total, cardiovascular, and respiratory mortality across multiple countries/regions worldwide, using a uniform analytical protocol. Design Two stage, time series approach, with overdispersed generalised linear models and multilevel meta-analysis. Setting 398 cities in 22 low to high income countries/regions. Main outcome measures Daily deaths from total (62.8 million), cardiovascular (19.7 million), and respiratory (5.5 million) causes between 1973 and 2018. Results On average, a 10 μg/m 3 increase in NO 2 concentration on lag 1 day (previous day) was associated with 0.46% (95% confidence interval 0.36% to 0.57%), 0.37% (0.22% to 0.51%), and 0.47% (0.21% to 0.72%) increases in total, cardiovascular, and respiratory mortality, respectively. These associations remained robust after adjusting for co-pollutants (particulate matter with aerodynamic diameter ≤10 μm or ≤2.5 μm (PM 10 and PM 2.5, respectively), ozone, sulfur dioxide, and carbon monoxide). The pooled concentration-response curves for all three causes were almost linear without discernible thresholds. The proportion of deaths attributable to NO 2 concentration above the counterfactual zero level was 1.23% (95% confidence interval 0.96% to 1.51%) across the 398 cities. Conclusions This multilocation study provides key evidence on the independent and linear associations between short term exposure to NO 2 and increased risk of total, cardiovascular, and respiratory mortality, suggesting that health benefits would be achieved by tightening the guidelines and regulatory limits of NO 2.