IAnimal: a cross-species omics knowledgebase for animals.

With the exponential growth of multi-omics data, its integration and utilization have brought unprecedented opportunities for the interpretation of gene regulation mechanisms and the comprehensive analyses of biological systems. IAnimal (https://ianimal.pro/), a cross-species, multi-omics knowledgebase, was developed to improve the utilization of massive public data and simplify the integration of multi-omics information to mine the genetic mechanisms of objective traits. Currently, IAnimal provides 61 191 individual omics data of genome (WGS), transcriptome (RNA-Seq), epigenome (ChIP-Seq, ATAC-Seq) and genome annotation information for 21 species, such as mice, pigs, cattle, chickens, and macaques. The scale of its total clean data has reached 846.46 TB. To better understand the biological significance of omics information, a deep learning model for IAnimal was built based on BioBERT and AutoNER to mine 'gene' and 'trait' entities from 2 794 237 abstracts, which has practical significance for comprehending how each omics layer regulates genes to affect traits. By means of user-friendly web interfaces, flexible data application programming interfaces, and abundant functional modules, IAnimal enables users to easily query, mine, and visualize characteristics in various omics, and to infer how genes play biological roles under the influence of various omics layers.

Ambient fine particulate matter and allergic symptoms in the middle-aged and elderly population: results from the PIFCOPD study.

BACKGROUND: The associations between short- and long-term exposure to ambient fine particulate matter with an aerodynamic diameter ≤ 2.5 µm (PM2.5) and allergic symptoms in middle-aged and elderly populations remain unclear, particularly in China, where most cities have severe air pollution. METHODS: Participants (n = 10,142; age = 40-75 years) were recruited from ten regions in China from 2018 to 2021 for the Predictive Value of Inflammatory Biomarkers and Forced Expiratory Volume in 1 s (FEV1) for Chronic Obstructive Pulmonary Disease (PIFCOPD) study. Short-term (lag0 and lag0-7 day) and long-term (1-, 3- and 5-year) PM2.5 concentrations at residences were extracted from the air pollutant database known as Tracking Air Pollution (TAP) in China. Multivariate logistic regression models were used to estimate associations for short- and long-term PM2.5 exposure concentrations and long-term exposure models were additionally adjusted for short-term deviations. RESULTS: A 10 µg/m3 increase in PM2.5 on the day the allergic symptoms questionnaire was administered (lag0 day) was associated with higher odds of allergic nasal (1.09, 95% CI 1.05, 1.12) and eye symptoms (1.08, 95% CI 1.05, 1.11), worsening dyspnea caused by allergens (1.06, 95% CI 1.02, 1.10), and ≥ 2 allergic symptoms (1.07, 95% CI 1.03, 1.11), which was similar in the lag0-7 day concentrations. A 10 µg/m3 increase in the 1-year average PM2.5 concentration was associated with an increase of 23% for allergic nasal symptoms, 22% for eye symptoms, 20% for worsening dyspnea caused by allergens, and 21% for ≥ 2 allergic symptoms, similar to the 3- and 5-year average PM2.5 concentrations. These associations between long-term PM2.5 concentration and allergic symptoms were generally unchanged after adjustment for short-term deviations. CONCLUSIONS: Short- and long-term exposure to ambient PM2.5 was associated with an increased risk of allergic nasal and eye symptoms, worsening dyspnea caused by allergens, and ≥ 2 allergic symptoms. TRIAL REGISTRATION: Clinical trial ID: NCT03532893 (29 Mar 2018).

Health Impacts of Long-Term NO2 Exposure and Inequalities among the Chinese Population from 2013 to 2020.

Nitrogen dioxide (NO2) is associated with mortality and many other adverse health outcomes. In 2021, the World Health Organization established a new NO2 air quality guideline (AQG) (annual average <10 µg/m3). However, the burden of diseases attributable to long-term NO2 exposure above the AQG is unknown in China. Nitrogen oxide is a major air pollutant in populous cities, which are disproportionately impacted by NO2; this represents a form of environmental inequality. We conducted a nationwide risk assessment of premature deaths attributable to long-term NO2 exposure from 2013 to 2020 based on the exposure-response relationship, high-resolution annual NO2 concentrations, and gridded population data (considering sex, age, and residence [urban vs rural]). We calculated health metrics including attributable deaths, years of life lost (YLL), and loss of life expectancy (LLE). Inequality in the distribution of attributable deaths and YLLs was evaluated by the Lorenz curve and Gini index. According to the health impact assessments, in 2013, long-term NO2 exposure contributed to 315,847 (95% confidence interval [CI]: 306,709-319,269) premature deaths, 7.90 (7.68-7.99) million YLLs, and an LLE of 0.51 (0.50-0.52) years. The high-risk subgroup (top 20%) accounted for 85.7% of all NO2-related deaths and 85.2% of YLLs, resulting in Gini index values of 0.81 and 0.67, respectively. From 2013 to 2020, the estimated health impact from NO2 exposure was significantly reduced, but inequality displayed a slightly increasing trend. Our study revealed a considerable burden of NO2-related deaths in China, which were disproportionally frequent in a small high-risk subgroup. Future clean air initiatives should focus not only on reducing the average level of NO2 exposure but also minimizing inequality.

Gestational age modifies the association between exposure to fine particles and fetal death: findings from a nationwide epidemiological study in the contiguous United States.

BACKGROUNDS: The vulnerability of fetuses differs at different developmental stages, in response to environmental stressors such as fine particulate matter (PM2.5), a ubiquitous air pollutant. Whether gestational age (GA) modifies the association between prenatal fine particulate matter (PM2.5) exposure and fetal death remains unclear. METHODS: We selected approximately 47.8 million eligible United States (US) livebirth and fetal death (defined as a termination at a GA of 20-43 weeks) records from 1989 to 2004. For each record, we took the level of prenatal exposure to PM2.5 as the average concentration in the mother's residential county during the entire gestational period, or a specific trimester (i.e., GA-specific exposure), according to well-established estimates of monthly levels across the contiguous US. First, we evaluated the associations between PM2.5 exposure and fetal death at a specific GA (i.e., GA-specific outcome) using five different logit models (unadjusted, covariate-adjusted, propensity-score, double robust, and diagnostic-score models). Double robust model was selected as the main model due to its advantages in causal inference. Then, we conducted meta-analyses to pool the estimated GA-specific associations, and explored how the pooled estimates varied with GA. RESULTS: According to the meta-analysis, all models suggested gestational PM2.5 exposure was associated with fetal death. However, there was slight heterogeneity in the estimated effects, as different models revealed a range of 3.6-10.7% increase in the odds of fetal death per 5-µg/m3 increment of PM2.5. Each 5-µg/m3 increase in PM2.5 exposure during the entire gestation period significantly increased the odds of fetal death, by 8.1% (95% confidence interval [CI]: 5.1-11.2%). In terms of GA-specific outcomes, the odds of fetal death at a GA of 20-27, 28-36, or ≥ 37 weeks increased by 11.0% (5.9-16.4%), 5.2% (0.4-10.1%), and 8.3% (2.5-14.5%), respectively. In terms of GA-specific exposure, the odds of fetal death increased by 6.0% (3.9-8.2%), 4.1% (3.9-8.2%), and 4.3% (0.5-8.2%) with 5-µg/m3 increases in PM2.5 exposure during the first, second, and third trimester, respectively. The association had the largest effect size (odds ratio = 1.098, 95% CI: 1.061-1.137) between PM2.5 exposure during early gestation (i.e., first trimester) and early fetal death (i.e., 20-27 weeks). CONCLUSIONS: Prenatal exposure to PM2.5 was significantly associated with an increased risk of fetal death. The association was varied by gestational-age-specific exposures or outcomes, suggesting gestation age as a potential modifier on the effect of PM2.5. The fetus was most vulnerable during the early stage of development to death associated with PM2.5 exposure.

Air pollution attenuated the benefits of physical activity on blood pressure: Evidence from a nationwide cross-sectional study.

INTRODUCTION: Although physical activity (PA) has multiple health benefits, the inhaled dose of fine particulate matter (PM2.5) during PA may increase. The trade-off between harmful effects of PM2.5 exposure and protective effects of PA remain unclear. Our study aims to examine the joint effects of PA and PM2.5 exposure on blood pressure (BP) in Chinese adults. METHODS: A total of 203,108 adults aged ≥ 18 years from the China Hypertension Survey study (2012-2015) were included. Individual-level PA was assessed as minutes of metabolic equivalent tasks per week (MET-min/week). The average weekly PM2.5 exposures were estimated by using a spatial resolution of 10 km, integrating multiple data sources, including monitoring values, satellite measurements and model simulations. BP was measured with a professional portable BP monitor. Generalized linear regressions were used to estimate joint associations and to further explore two-dimensional nonlinear associations. RESULTS: The median PA and 4-week PM2.5 average exposures were 3213.0 MET-min/week and 47.8 µg/m3, respectively. PA was negatively associated with BP, while PM2.5 exposure was positively with BP. The associations between PA and systolic BP were significantly modified by PM2.5 exposure (Pinteraction < 0.001). Compared with inactive participants under low PM2.5 exposure, those with highest level of PA under low PM2.5 exposure had a 0.90 (95 % CI: 0.53, 1.26) mmHg decrease in systolic BP, whereas they had a 0.48 (95 % CI: 0.07, 0.89) mmHg increase under high PM2.5 exposure. When PM2.5 exposure was approximately > 25 µg/m3, the joint exposure to total PA and PM2.5 was associated with an increase in systolic BP. CONCLUSIONS: The benefits of PA on BP were counteracted by high PM2.5 levels.

Gestational exposure to landscape fire increases under-5 child death via reducing birthweight: A risk assessment based on mediation analysis in low- and middle-income countries.

BACKGROUND: Exposure to landscape fire smoke (LFS) is linked to child mortality and birthweight. It is unknown whether gestational exposure to LFS affects child survival rate. We aimed to link under-five death (U5D) to gestational LFS exposure by performing a causal mediation analysis based on birthweight. METHOD: We conducted a sibling-matched case-control study of children under 5 years of age who were affiliated with the same mothers from Demographic and Health Surveys in 54 low- and middle-income countries, during the period from 2000 to 2014. LFS exposure was quantified as the surface concentration of fine particulate matter (PM2.5) attributable to landscape fires, estimated using a global atmospheric model. Three pairwise associations between fire-sourced PM2.5, birthweight, and U5D were assessed using fixed-effects regressions. We used a bootstrap-based mediation test of regression coefficients to examine whether the LFS-birthweight-U5D pathway was statistically significant. We also conducted three pairwise exposure-response functions using nonlinear models and used them to estimate the pathway-specific disease burden from 2000 to 2014. RESULTS: After adjustments for multiple confounders, each 1-µg/m3 increase in gestational exposure to fire-sourced PM2.5 was associated with a reduction of 2.179 (95% confidence interval [CI]: -3.777, -0.580) g in birthweight. Each 1-g birthweight reduction was associated with a 0.072% (95% CI: 0.065%, 0.078%) increase in U5D. Furthermore, each increase in exposure to fire-sourced PM2.5 was associated with a 2.853% (95% CI: 0.835%, 4.911%) increase in U5D; 7.294% (95% CI: 0.710%, 24.254%) of the linkage was explained by LFS-attributable birthweight reduction. Based on the estimated exposure-response functions, from 2000 to 2014, global exposure to fire-sourced PM2.5 contributed a mean birthweight reduction of 10.30 (95% CI: 2.93, 19.47) g, contributing to 60,350 (18,111, 106,619) premature U5Ds annually. CONCLUSION: In low- and middle-income countries, gestational exposure to LFS can increase mortality during infancy; appropriate interventions are needed to promote health in childhood.

Greenspace exposure and poststroke disability: A nationwide longitudinal study.

INTRODUCTION: Exposure to greenspace has been reported to reduce stroke mortality, but there is a lack of evidence regarding poststroke disability. This study aimed to investigate the association between long-term greenspace exposure and the risk of poststroke disability. METHODS: Based on the China National Stroke Screening Survey from 2013 to 2019, a total of 65,892 visits from 28,085 stroke survivors with ≥ 2 visits were included in this longitudinal study. Long-term greenspace exposure was assessed by a 3-year average of the Normalized Difference Vegetation Index (NDVI) and the proportion of green land cover according to participants' residential communities. Poststroke functional status was assessed with the modified Ranking Score (mRS) at each visit; a cutoff score > 2 indicated disability. Fixed effects regressions were used to examine the association of greenspace exposure with continuous mRS scores or binary indicators for disability. RESULTS: The annual mean NDVI value was 0.369 (standard deviation = 0.120) for all visits among stroke survivors. With full adjustments, each 0.05 increase in NDVI was associated with a 0.056-unit (95 % confidence interval (CI): 0.034, 0.079) decrease in the mRS score and a 46.6 % (95 % CI: 10.0 %, 68.3 %) lower risk of poststroke disability. An L-shaped curve was observed for the nonlinear associations between NDVI and mRS score or disability. Additionally, each 1 % increase in grasslands, savannas, forest, and croplands was associated with 0.008- (95 % CI: 0.002, 0.014), 0.003- (95 % CI: 0.001, 0.005), 0.001- (95 % CI: -0.015, 0.018), and 0.002-unit (95 % CI: -0.003, 0.007) decreases in the mRS score, respectively. CONCLUSIONS: Increasing greenspace was inversely associated with mRS score. Greenspace planning can be a potential intervention to prevent poststroke disability.

Effect of Different Filler Contents and Printing Directions on the Mechanical Properties for Photopolymer Resins.

Photopolymer resins are widely used in the production of dental prostheses, but their mechanical properties require improvement. We evaluated the effects of different zirconia filler contents and printing directions on the mechanical properties of photopolymer resin. Three-dimensional (3D) printing was used to fabricate specimens using composite photopolymers with 0 (control), 3, 5, and 10 wt.% zirconia filler. Two printing directions for fabricating rectangular specimens (25 mm × 2 mm × 2 mm) and disk-shaped specimens (φ10 mm × 2 mm) were used, 0° and 90°. Three-point bending tests were performed to determine the flexural strengths and moduli of the specimens. The Vickers hardness test was performed to determine the hardness of the specimens. Tukey's multiple comparison tests were performed on the average values of the flexural strengths, elastic moduli, and Vickers hardness after one-way ANOVA (α = 0.05). The flexural strengths and elastic moduli at 0° from high to low were in the order of 0, 3, 10, and 5 wt.%, and those at 90° were in the order of 3, 0, 10, and 5 wt.% (p < 0.05). For 5 and 10 wt.%, no significant differences were observed in mechanical properties at 0° and 90° (p < 0.05). The Vickers hardness values at 0° and 90° from low to high were in the order of 0, 3, 5, and 10 wt.% (p < 0.05). Within the limits of this study, the optimal zirconia filler content in the photopolymer resin for 3D printing was 0 wt.% at 0° and 3 wt.% at 90°.

Association of maternal exposure to ambient particulate pollution with incident spontaneous pregnancy loss.

BACKGROUND: Maternal exposure to ambient fine particulate matter (PM2.5) is a potential risk factor for pregnancy loss, but the extant findings are inconsistent. One reason for the inconsistency is the difficulty of distinguishing spontaneous from induced pregnancy losses, particularly in countries with planning policies. OBJECTIVE: To examine the association between maternal PM2.5 exposure and spontaneous incident pregnancy loss in China. METHODS: A total of 18,513 women of reproductive age was recruited from Jiangsu Province, China, in 2007. Among them, 2451 women reported 2613 valid records of incident pregnancies from 2007 to 2010. We used Cox regression to link the outcomes (live birth, spontaneous pregnancy loss, or induced abortion) of those incident pregnancies with maternal PM2.5 exposures, assessed using well-developed estimates of historical concentrations at the county level. RESULTS: Among the 2613 incident pregnancies, 69 spontaneous pregnancy losses, 596 induced abortions, and 1948 live births occurred. According to the adjusted model, each 10-µg/m3 increment in the average PM2.5 concentration during pregnancy was associated with a 43.3% (95% confidence interval, 6.6-92.5%) increased probability of spontaneous pregnancy loss. Advanced maternal age, a potential competing risk factor, weakened the association between PM2.5 and spontaneous pregnancy loss. The association was nonsignificant for unintended pregnancies. CONCLUSION: Maternal PM2.5 exposure was associated significantly with incident spontaneous pregnancy loss. Our findings provide insight into the harmful effect of air pollution on human reproduction.

Difference in diet quality trends between children and adults in the United States: A serial cross-sectional study from 1999 to 2018.

BACKGROUND AND OBJECTIVES: Previous studies had shown that trends in diet quality between children and adults may vary but lack quantitative comparisons. We aimed to compare diet quality and its trends between US children and adults in this research. METHODS AND STUDY DESIGN: Children aged 2 to 18 and adults aged 19 to 59 years old in the US were enrolled the serial cross-sectional analysis of National Health and Nutrition Examination Survey (NHANES) cycles from 1999 to 2018. Diet quality was assessed using the Healthy Eating Index-2015 (HEI-2015), and trends were analyzed by joinpoint regression model. RESULTS: This study included 31988 children and 34317 adults. From 1999 to 2018, there was a trend-change among 5 children's components trends (including total fruits in 2011-2012, whole fruits in 2005-2006, greens and beans in 2013-2014, dairy in 2013-2014, and total protein foods in 2013-2014, p for joinpoint <0.05 for each) and overall trend in 2013-2014, whereas no significant trend-change in adults' trend. The trends of overall HEI-2015 between children (average annual percent change 0.3%; 95% CI: -0.1% to 0.8%) and adults (0.3%; 95%CI: 0.0% to 0.6%) showed no significant difference in parallelism (p for parallelism=0.60), but a significant difference in coincidence (intercept -7.7±3.7 among children; -2.3±2.5 among adults; p for coincidence <0.05). CONCLUSIONS: Children had a different trend with more trend-changes in diet quality compared with adults, and the diet quality of children was worse than that of adults during 1999-2018 in the US.

Transmission routes of SARS-CoV-2 and protective measures in dental clinics during the COVID-19 pandemic.

RESULTS: The outbreak of coronavirus disease 2019 (COVID-19) has become a primary challenging public health issue for not only China but also the world. On March 11, 2020, the World Health Organization declared that the pandemic of COVID-19 had become a public health emergency of global concern. As of May 12, 2020 COVID-19 has been reported in over 180 countries/regions, with a total of 4,178,156 confirmed cases and over 280,000 deaths. The risk of cross-infection by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) might be elevated between dental specialists and patients due to the peculiarity of dental practice. Therefore, detailed and effective infection control measures are imminently needed to prevent nosocomial coronavirus infection. This paper, based on proven effective experience, relevant guidelines, and research, not only presents the fundamental knowledge about the name, etiologic characteristics, epidemiologic characteristics and clinical manifestations of COVID-19, transmission routes and risk points of SARS-CoV-2 in dental clinics but also provides recommended protective measures for dental professionals to interdict the transmission of SARS-CoV-2 in dental clinics. Classification schemes as well as color identification according to the results of the questionnaire survey and temperature measurement in precheck and triages are innovations proposed in this paper. CLINICAL SIGNIFICANCE: This paper, based on proven effective experience, relevant guidelines, and research, not only presents the fundamental knowledge about the name, etiologic characteristics, epidemiologic characteristics and clinical manifestations of COVID-19, transmission routes and risk points of SARS-CoV-2 in dental clinics but also provides recommended protective measures for dental professionals to interdict the transmission of SARS-CoV-2 in dental clinics.

Effect of gum-chewing exercise on maintaining and improving oral function in older adults: A pilot randomized controlled trial.

Background/purpose: Gum chewing has been found to improve oral function. Nevertheless, few randomized controlled trials have investigated the effects of gum-chewing exercises on oral function in older adults. This study aimed to examine the effect of gum-chewing exercises on oral function in older adults. Materials and methods: This was a single-blind, randomized controlled trial, conducted from November 2021 to January 2022. A total of 130 participants were divided randomly into the intervention and control groups. The intervention group was told to chew experimental gums for one month, while the control group was instructed to chew experimental tablets for one month. Maximum bite force, occlusal contact areas, oral dryness, tongue pressure, tongue and lip functions (number of times each of the following syllables is pronounced per second:/pa/,/ta/, and/ka/), masticatory function, subjective masticatory function, and gum-chewing time were measured at baseline and one month following intervention to assess outcomes. Results: One month following the intervention, tongue pressure was significantly higher in the intervention group than in the control group (P = 0.027). In the within-group comparisons, maximum bite force (P < 0.001), unstimulated saliva flow (P < 0.001), tongue and lip functions (/pa/: P < 0.001;/ta/: P < 0.001;/ka/: P < 0.001), color scale value (P = 0.019), and ΔE value (P = 0.024) were significantly increased in the intervention group. Conclusion: The results suggest that gum-chewing exercises can improve oral functions in older adults, although additional increases in masticatory load may be necessary to establish a more effective oral function training method using gum-chewing exercises in older adults.

Effects of multiple firings on the translucency, crystalline phase, and mechanical strength of highly translucent zirconia.

This study aimed to clarify the effects of multiple firings on the translucency, crystal structure, and mechanical strength of highly translucent zirconia. Four types of highly translucent zirconia (LAVA Esthetic, LAVA Plus, KATANA Zirconia STML, and KATANA Zirconia HTML) were fired three times at three different temperatures, and the translucency, crystal structure, and flexural strength were evaluated before and after firing. The translucency was statistically compared using repeated-measures analysis of variance; the zirconia phase composition was assessed using X-ray diffraction followed by Rietveld analysis; and the biaxial flexural strength was assessed using Weibull analysis. The translucency of LAVA Esthetic and KATANA Zirconia HTML decreased significantly after firing, and the crystal composition of LAVA Plus and KATANA Zirconia HTML changed after multiple firings, whereas multiple firings did not affect the biaxial flexural strength of any samples. Thus, multiple firings may affect the optical properties of highly translucent zirconia.

Health benefits from the rapid reduction in ambient exposure to air pollutants after China's clean air actions: progress in efficacy and geographic equality.

Clean air actions (CAAs) in China have been linked to considerable benefits in public health. However, whether the beneficial effects of CAAs are equally distributed geographically is unknown. Using high-resolution maps of the distributions of major air pollutants (fine particulate matter [PM2.5] and ozone [O3]) and population, we aimed to track spatiotemporal changes in health impacts from, and geographic inequality embedded in, the reduced exposures to PM2.5 and O3 from 2013 to 2020. We used a method established by the Global Burden of Diseases Study. By analyzing the changes in loss of life expectancy (LLE) attributable to PM2.5 and O3, we calculated the gain of life expectancy (GLE) to quantify the health benefits of the air-quality improvement. Finally, we assessed the geographic inequality embedded in the GLE using the Gini index (GI). Based on risk assessments of PM2.5 and O3, during the first stage of CAAs (2013 to 2017), the mean GLE was 1.87 months. Half of the sum of the GLE was disproportionally distributed in about one quarter of the population exposed (GI 0.44). During the second stage of CAAs (2017 to 2020), the mean GLE increased to 3.94 months and geographic inequality decreased (GI 0.18). According to our assessments, CAAs were enhanced, from the first to second stages, in terms of not only preventing premature mortality but also ameliorating health inequalities. The enhancements were related to increased sensitivity to the health effects of air pollution and synergic control of PM2.5 and O3 levels. Our findings will contribute to optimizing future CAAs.

A Chinese longitudinal maternity cohort study (2013-2021) on intrahepatic cholestasis phenotypes: Risk associations from environmental exposure to adverse pregnancy outcomes.

Intrahepatic cholestasis of pregnancy (ICP) is an idiopathic disease that occurs during mid-to-late pregnancy and is associated with various adverse pregnancy outcomes, including intrauterine fetal demise. However, since the underlying cause of ICP remains unclear, there is an ongoing debate on the phenotyping criteria used in the diagnostic process. Here, we identified single- and multi-symptomatic ICP (ICP-S and ICP-M) in 104,221 Chinese females from the ZEBRA maternity cohort, with the objective of exploring the risk implications of the two phenotypes on pregnancy outcomes and from environmental exposures. We employed multivariate binary logistic regression to estimate confounder-adjusted odds ratios and found that ICP-M was more strongly associated with preterm birth and low birth weight compared to ICP-S. Throughout pregnancy, incremental exposure to PM2.5, O3, and greenness could alter ICP risks by 17.3%, 12.5%, and -2.3%, respectively, with more substantial associations observed with ICP-M than with ICP-S. The major scientific advancements lie in the elucidation of synergistic risk interactions between pollutants and the protective antagonistic effects of greenness, as well as highlighting the risk impact of preconceptional environmental exposures. Our study, conducted in the context of the "three-child policy" in China, provides epidemiological evidence for policy-making to safeguard maternal and neonatal health.

Osteosarcoma PDX-Derived Cell Line Models for Preclinical Drug Evaluation Demonstrate Metastasis Inhibition by Dinaciclib through a Genome-Targeted Approach.

PURPOSE: Models to study metastatic disease in rare cancers are needed to advance preclinical therapeutics and to gain insight into disease biology. Osteosarcoma is a rare cancer with a complex genomic landscape in which outcomes for patients with metastatic disease are poor. As osteosarcoma genomes are highly heterogeneous, multiple models are needed to fully elucidate key aspects of disease biology and to recapitulate clinically relevant phenotypes. EXPERIMENTAL DESIGN: Matched patient samples, patient-derived xenografts (PDX), and PDX-derived cell lines were comprehensively evaluated using whole-genome sequencing and RNA sequencing. The in vivo metastatic phenotype of the PDX-derived cell lines was characterized in both an intravenous and an orthotopic murine model. As a proof-of-concept study, we tested the preclinical effectiveness of a cyclin-dependent kinase inhibitor on the growth of metastatic tumors in an orthotopic amputation model. RESULTS: PDXs and PDX-derived cell lines largely maintained the expression profiles of the patient from which they were derived despite the emergence of whole-genome duplication in a subset of cell lines. The cell lines were heterogeneous in their metastatic capacity, and heterogeneous tissue tropism was observed in both intravenous and orthotopic models. Single-agent dinaciclib was effective at dramatically reducing the metastatic burden. CONCLUSIONS: The variation in metastasis predilection sites between osteosarcoma PDX-derived cell lines demonstrates their ability to recapitulate the spectrum of the disease observed in patients. We describe here a panel of new osteosarcoma PDX-derived cell lines that we believe will be of wide use to the osteosarcoma research community.

Source sectors underlying PM2.5-related deaths among children under 5 years of age in 17 low- and middle-income countries.

BACKGROUND: Fine particulate matter (PM2.5) from different source sectors might differ in toxicity. However, data from large-scale studies on vulnerable children in low- and middle-income countries (LMICs) are insufficient. OBJECTIVE: To analyze the association of under-five death (U5D) with long-term exposure to PM2.5 from different sources. METHOD: We evaluated demographic and health survey data for 79,995 babies born in 2017 in 16 Asian and African LMICs (AA-LMICs) and a Latin America low-income country (i.e., Haiti). Long-term exposure to PM2.5 was assessed by a well-established product that attributed the annual concentration to 20 source sectors in 2017. The associations of survival during < 5-year periods with each source-specific concentration of PM2.5 were analyzed by Cox regression with multiple adjustments. We derived a multiple-pollutant ridge regression model to estimate the joint exposure-response function (JERF) between U5D and PM2.5 mixtures. To evaluate how sources affected PM2.5 toxicity, we evaluated the number of U5Ds attributable to PM2.5 based on the source profiles for 88 AA-LMICs. RESULTS: According to the single-pollutant model, the risk of U5D increased by 7% (95% confidence interval [CI]: 5%, 9%) for each 10 µg/m3 increment in total PM2.5 concentration. The model performance was lower than that of the multiple-pollutant ridge regression model. For each 10 µg/m3 increment in PM2.5, the excess risk of U5D ranged from 6% (95% CI: 4%, 9%) in Nepal to 10% (95% CI: 6%, 14%) in Mauritania. Based on the JERF, PM2.5 contributed to 817,647 (95% CI: 585,729, 1,050,439), i.e., 28.0% (95% CI: 20.1%, 35.8%), of all U5Ds across the 88 AA-LMICs. The PM2.5-related U5Ds were mostly attributable to PM2.5 produced by desert dust, followed by solid biofuel combustion and open fires. CONCLUSION: The average toxicity of PM2.5 varied by source profile, which should be taken into consideration when planning public health interventions. For some AA LMICs, natural sources of PM2.5 had the most significant health effects, and should not be ignored to ensure the protection of child health.

Evaluation of digestate-derived biochar to alleviate ammonia inhibition during long-term anaerobic digestion of food waste.

The feasibility of using food waste anaerobic digestate-derived biochar (FWDB) to mitigate ammonia toxicity in an anaerobic digester was evaluated. The optimal conditions for preparing and adding the activated FWDB were explored using response surface experiments, and the long-term effects of adding activated FWDB on digester performance under optimum conditions were verified in semi-continuous experiments. The results showed that the optimal preparation and addition conditions for activated FWDB were pyrolysis temperature of 565 °C, particle size of 0-0.30 mm, and dosage of 15.52 g·L-1. During the long-term operation of the digesters, when the total ammonia nitrogen (TAN) concentration was higher than 2000 mg·L-1, the control and experimental digesters showed deteriorated reactor performance. Volatile fatty acids in the control digester accumulated to 20,306 mg·L-1 after the TAN concentration increased to 3391 mg·L-1, the methane yield decreased to 31 mL·g VS-1, and the digester experienced process failure. In contrast, the experimental digester with added activated FWDB only suffered a slight short-term accumulation of acetate and a slight decline in methane yield. This may be attributed to the adsorption of NH4+/NH3 by activated FWDB, which reduced the TAN concentration in the anaerobic digestion (AD) system and mitigated ammonia toxicity. Microbial analysis and metagenome predictions demonstrated that the community richness, diversity, and evenness, as well as the abundance of acetogens and related key genes (ACSM1, paaF, and acdA) were higher in the experimental digester than in the control digester. This study provides a closed-loop AD enhancement strategy by pyrolysis of digestate and in-situ supplementation into the digester.

Associations between hemoglobin levels and source-specific exposure to ambient fine particles among children aged <5 years in low- and middle-income countries.

OBJECTIVE: We investigated associations between source-specific fine particulate matter (PM2.5) exposure and hemoglobin levels among children in low- and middle-income countries (LMICs). METHOD: 36,675 children aged < 5 years were collected in 11 LMICs during 2017. We associated child hemoglobin with 20 source-specific PM2.5, and calculated changes in hemoglobin that could be attributed to different PM2.5-mixture scenarios, established using real-world data from 88 Asian and African LMICs (AA-LMICs). RESULTS: Multiple-source analysis revealed PM2.5 produced by solvents (change in hemoglobin for 1-µg/m3 increment in PM2.5: -10.34 g/L, 95% CI -14.88 to -5.91), industrial coal combustion (-0.51 g/L, 95% CI -9.25 to -0.08), road transportation (-0.50 g/L, 95% CI -6.96 to -0.29), or waste handling and disposal (-0.34 g/L, 95% CI -4.38 to -0.23) was significantly associated with a decrease in hemoglobin level. Decreases in hemoglobin attributable to the PM2.5 mixtures were co-determined by the concentrations and their source profiles. The largest PM2.5-related change in hemoglobin was -10.25 g/L (95% CI -15.54 to -5.27) for a mean exposure of 61.01 µg/m3 in India. CONCLUSION: Association between PM2.5 and a decrease in hemoglobin was affected by variations in PM2.5 source profiles. Source-oriented interventions are warranted to protect children in LMICs from air pollution.

Integrated genome-centric metagenomic and metaproteomic analyses unravel the responses of the microbial community to ammonia stress.

Ammonia is a major inhibitor in anaerobic digestion of nitrogen-rich organic wastes. In this study, integrated genome-centric metagenomic and metaproteomic analyses were used to identify the key microorganisms and metabolic links causing instability by characterizing the process performance, microbial community, and metabolic responses of key microorganisms during endogenous ammonia accumulation. The identification of 89 metagenome-assembled genomes and analysis of their abundance profile in different operational phases permitted the identification of key taxa (Firmicutes and Proteobacteria) causing poor performance. Metabolic reconstruction indicated that the key taxa had the genetic potential to participate in the metabolism of C2C5 volatile fatty acids (VFAs). Further investigation suggested that during Phase I, the total ammonia nitrogen (TAN) level was maintained below 2000 mg N/L, and the reactor showed a high methane yield (478.30 ± 33.35 mL/g VS) and low VFAs concentration. When the TAN accumulated to > 2000 mg N/L, acid accumulation, mainly of acetate, began to occur, and the methane yield gradually decreased to 330.44 mL/g VS (Phase II). During this phase, the VFA degradation functions of the community were mainly mediated by Firmicutes. Approximately 61.54% of significant differentially expressed proteins (DEPs) related to acetate metabolism in Firmicutes were down-regulated, which led to an increase in acetate concentration to 4897.91 ± 1558.96 mg/L. However, the reactor performance showed spontaneous recovery without any interference (Phase III), during which Firmicutes gradually adapted to the high ammonia conditions. Approximately 75% of the significant DEPs related to acetate metabolism of Proteobacteria were also up-regulated in Phase III compared with Phase II; thus, VFA-related metabolic functions of the community were enhanced, which resulted in a decrease in the total VFA concentration to 195.39 mg/L. When the TAN increased above 4000 mg N/L, the system gradually showed acid accumulation dominated by propionate, accompanied by a second decrease in methane yield (Phase IV). During this phase, the number of up-regulated and down-regulated proteins related to acetate metabolism of Firmicutes and butyrate/valerate metabolism of Proteobacteria was comparable with that of Phase III, indicating that the metabolic functions related to acetate, butyrate, and valerate of the microbial community were not significantly affected. However, for propionate metabolism, the expression activity of fumarate hydratase from Firmicutes and Proteobacteria was severely inhibited by ammonia, as shown by down-regulation ratios of 63.64% and 85.71%, respectively. No protein with the same function that was not inhibited by ammonia could be detected, and the fumarate degradation function of the microbial community was severely damaged, leading to blocked propionate metabolism and irreversible deterioration of reactor performance. This study has provided a new perspective on the microecological mechanisms of ammonia inhibition.