Publications by authors named "Zhanghua Chen"

42 Publications

In utero exposure to near-roadway air pollution and autism spectrum disorder in children.

Environ Int 2021 Oct 6;158:106898. Epub 2021 Oct 6.

Department of Research & Evaluation, Kaiser Permanente Southern California, Pasadena, CA, USA. Electronic address:

Importance: Previous studies have reported associations between in utero exposure to regional air pollution and autism spectrum disorders (ASD). In utero exposure to components of near-roadway air pollution (NRAP) has been linked to adverse neurodevelopment in animal models, but few studies have investigated NRAP association with ASD risk.

Objective: To identify ASD risk associated with in utero exposure to NRAP in a large, representative birth cohort.

Design, Setting, And Participants: This retrospective pregnancy cohort study included 314,391 mother-child pairs of singletons born between 2001 and 2014 at Kaiser Permanente Southern California (KPSC) hospitals. Maternal and child data were extracted from KPSC electronic medical records. Children were followed until: clinical diagnosis of ASD, non-KPSC membership, death, or December 31, 2019, whichever came first. Exposure to the complex NRAP mixture during pregnancy was assessed using line-source dispersion models to estimate fresh vehicle emissions from freeway and non-freeway sources at maternal addresses during pregnancy. Vehicular traffic load exposure was characterized using advanced telematic models combining traditional traffic counts and travel-demand models with cell phone and vehicle GPS data. Cox proportional-hazard models estimated hazard ratios (HR) of ASD associated with near-roadway traffic load and dispersion-modeled NRAP during pregnancy, adjusted for covariates. Non-freeway NRAP was analyzed using quintile distribution due to nonlinear associations with ASD.

Exposures: Average NRAP and traffic load exposure during pregnancy at maternal residential addresses.

Main Outcomes: Clinical diagnosis of ASD.

Results: A total of 6,291 children (5,114 boys, 1,177 girls) were diagnosed with ASD. The risk of ASD was associated with pregnancy-average exposure to total NRAP [HR(95% CI): 1.03(1.00,1.05) per 5 ppb increase in dispersion-modeled NOx] and to non-freeway NRAP [HR(95% CI) comparing the highest to the lowest quintile: 1.19(1.11, 1.27)]. Total NRAP had a stronger association in boys than in girls, but the association with non-freeway NRAP did not differ by sex. The association of freeway NRAP with ASD risk was not statistically significant. Non-freeway traffic load exposure demonstrated associations with ASD consistent with those of NRAP and ASD.

Conclusions: In utero exposure to near-roadway air pollution, particularly from non-freeway sources, may increase ASD risk in children.
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http://dx.doi.org/10.1016/j.envint.2021.106898DOI Listing
October 2021

The Role of Childhood Asthma in Obesity Development: A Nationwide U.S. Multi-cohort Study.

Epidemiology 2021 Sep 20. Epub 2021 Sep 20.

Department of Preventive Medicine, University of Southern California, Los Angeles, CA Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD Department of Civil and Environmental Engineering, Northeastern University, Boston, MA Department of Population Medicine, Harvard Medical School and Harvard Pilgrim Health Care Institute, Boston MA Department of Pediatrics, Hackensack Meridian School of Medicine, Nutley NJ and the Albert Einstein College of Medicine, Bronx, NY Department of Pediatrics, University of North Carolina School of Medicine, Chapel Hill, NC Department of Emergency Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, MA Department of Pediatrics, Vanderbilt University Medical Center, Nashville, TN Departments of Pediatrics and Medicine, The University of Chicago, Chicago, IL University of Colorado, Anschutz Medical Campus, Aurora, CO Nell Hodgson Woodruff School of Nursing and Department of Family & Preventive Medicine, Emory University, Atlanta, GA Avera Research Institute, Sioux Falls, SD Kaiser Permanente Northern California Division of Research Department of Psychology The George Washington University, Washington, DC Department of Pediatrics, University of Wisconsin School of Medicine and Public Health, Madison, WI Harvard T.H. Chan School of Public Health, Harvard University, Boston, Massachusetts, United States; Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, USA University of California, Davis, School of Medicine, CA Geisel School of Medicine, Dartmouth College, Hanover, NH Department of Pediatrics & Environmental and Occupational Health Sciences, University of Washington, WA Department of Psychiatry and Human Behavior and Department of Pediatrics, Brown Alpert Medical School and Women and Infants Hospital, Providence, RI. Department of Education, University of Oregon, Eugene, OR Division of Pediatric Pulmonary Medicine, Department of Pediatrics, University of Rochester Medical Center, Rochester, NY Department of Pediatrics, Oregon Health and Science University, Portland, OR Division of Clinical Immunology, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY Departments of Psychiatry, Psychology, Neuroscience and Obstetrics and Gynecology, University of Rochester, NY Department of Environmental Health Sciences, Mailman School of Public Health, Columbia University, New York, NY Department of Family and Preventive Medicine, University of Utah, Salt Lake City, UT Division of Allergy, Immunology, and Pulmonary Medicine, Department of PediatricsSt. Louis Children's Hospital, Washington University School of Medicine St. Louis, MO Departments of Pediatrics, Environmental Medicine and Population Health, New York University School of Medicine, NY Department of Environmental Medicine and Public Health, Icahn School of Medicine at Mount Sinai, New York, NY Department of Internal Medicine, University of Utah, Salt Lake City, UT Department of Biostatistics, Mailman School of Public Health, Columbia University, New York, NY.

Rationale: Asthma and obesity often co-occur. It has been hypothesized that asthma may contribute to childhood obesity onset.

Objectives: To determine if childhood asthma is associated with incident obesity and examine the role of asthma medication in this association.

Methods: We studied 8716 children between ages 6-18.5 years who were non-obese at study entry participating in 18 U.S. cohorts of the Environmental influences on Child Health Outcomes program (among 7299 children with complete covariate data mean [SD] study entry age=7.2 [1.6] years and follow-up=5.3 [3.1] years).

Measurements And Main Results: We defined asthma based on caregiver report of provider diagnosis. Incident obesity was defined as the first documented body mass index ≥95th percentile for age and sex following asthma status ascertainment. Over the study period, 26% of children had an asthma diagnosis and 11% developed obesity. Cox proportional hazards models with sex-specific baseline hazards were fitted to assess the association of asthma diagnosis with obesity incidence. Children with asthma had a 23% (95%CI: 4%, 44%) higher risk for subsequently developing obesity compared to those without asthma. A novel mediation analysis was also conducted to decompose the total asthma effect on obesity into pathways mediated and not mediated by asthma medication use. Use of asthma medication attenuated the total estimated effect of asthma on obesity by 64% (excess HR:-0.64 [95%CI:-1.05,-0.23]).

Conclusions: This nationwide study supports the hypothesis that childhood asthma is associated with later risk of obesity. Asthma medication may reduce this association and merits further investigation as a potential strategy for obesity prevention among children with asthma.
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http://dx.doi.org/10.1097/EDE.0000000000001421DOI Listing
September 2021

Near-roadway air pollution associated with COVID-19 severity and mortality - Multiethnic cohort study in Southern California.

Environ Int 2021 12 4;157:106862. Epub 2021 Sep 4.

Department of Research & Evaluation, Kaiser Permanente Southern California, Pasadena, CA, United States. Electronic address:

Background: Air pollution exposure has been associated with increased risk of COVID-19 incidence and mortality by ecological analyses. Few studies have investigated the specific effect of traffic-related air pollution on COVID-19 severity.

Objective: To investigate the associations of near-roadway air pollution (NRAP) exposure with COVID-19 severity and mortality using individual-level exposure and outcome data.

Methods: The retrospective cohort includes 75,010 individuals (mean age 42.5 years, 54% female, 66% Hispanic) diagnosed with COVID-19 at Kaiser Permanente Southern California between 3/1/2020-8/31/2020. NRAP exposures from both freeways and non-freeways during 1-year prior to the COVID-19 diagnosis date were estimated based on residential address history using the CALINE4 line source dispersion model. Primary outcomes include COVID-19 severity defined as COVID-19-related hospitalizations, intensive respiratory support (IRS), intensive care unit (ICU) admissions within 30 days, and mortality within 60 days after COVID-19 diagnosis. Covariates including socio-characteristics and comorbidities were adjusted for in the analysis.

Result: One standard deviation (SD) increase in 1-year-averaged non-freeway NRAP (0.5 ppb NO) was associated with increased odds of COVID-19-related IRS and ICU admission [OR (95% CI): 1.07 (1.01, 1.13) and 1.11 (1.04, 1.19) respectively] and increased risk of mortality (HR = 1.10, 95% CI = 1.03, 1.18). The associations of non-freeway NRAP with COVID-19 outcomes were largely independent of the effect of regional fine particulate matter and nitrogen dioxide exposures. These associations were generally consistent across age, sex, and race/ethnicity subgroups. The associations of freeway and total NRAP with COVID-19 severity and mortality were not statistically significant.

Conclusions: Data from this multiethnic cohort suggested that NRAP, particularly non-freeway exposure in Southern California, may be associated with increased risk of COVID-19 severity and mortality among COVID-19 infected patients. Future studies are needed to assess the impact of emerging COVID-19 variants and chemical components from freeway and non-freeway NRAP.
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http://dx.doi.org/10.1016/j.envint.2021.106862DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8416551PMC
December 2021

Exposure to Perfluoroalkyl Substances and Glucose Homeostasis in Youth.

Environ Health Perspect 2021 Sep 1;129(9):97002. Epub 2021 Sep 1.

Department of Population and Public Health Sciences, University of Southern California, Los Angeles, California, USA.

Background: Exposure to per- and polyfluoroalkyl substances (PFAS), a prevalent class of persistent pollutants, may increase the risk of type 2 diabetes.

Objective: We examined associations between PFAS exposure and glucose metabolism in youth.

Methods: Overweight/obese adolescents from the Study of Latino Adolescents at Risk of Type 2 Diabetes (SOLAR; ) participated in annual visits for an average of . Generalizability of findings were tested in young adults from the Southern California Children's Health Study (CHS; ) who participated in a clinical visit with a similar protocol. At each visit, oral glucose tolerance tests were performed to estimate glucose metabolism and function via the insulinogenic index. Four PFAS were measured at baseline using liquid chromatography-high-resolution mass spectrometry; high levels were defined as concentrations percentile.

Results: In females from the SOLAR, high perfluorohexane sulfonate (PFHxS) levels () were associated with the development of dysregulated glucose metabolism beginning in late puberty. The magnitude of these associations increased postpuberty and persisted through 18 years of age. For example, postpuberty, females with high PFHxS levels had higher 60-min glucose (95% CI: ; ), higher 2-h glucose (95% CI: ; ), and 25% lower function () compared with females with low levels. Results were largely consistent in the CHS, where females with elevated PFHxS levels had higher 60-min glucose (95% CI: ; ) and higher 2-h glucose, which did not meet statistical significance (95% CI: ; ). In males, no consistent associations between PFHxS and glucose metabolism were observed. No consistent associations were observed for other PFAS and glucose metabolism.

Discussion: Youth exposure to PFHxS was associated with dysregulated glucose metabolism in females, which may be due to changes in function. These associations appeared during puberty and were most pronounced postpuberty. https://doi.org/10.1289/EHP9200.
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http://dx.doi.org/10.1289/EHP9200DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8409228PMC
September 2021

Asthma Disease Status, COPD, and COVID-19 Severity in a Large Multiethnic Population.

J Allergy Clin Immunol Pract 2021 10 10;9(10):3621-3628.e2. Epub 2021 Aug 10.

Department of Research and Evaluation, Kaiser Permanente Southern California, Pasadena, Calif. Electronic address:

Background: Current studies of asthma history on coronavirus disease 2019 (COVID-19) outcomes are limited and lack consideration of disease status.

Objective: To conduct a population-based study to assess asthma disease status and chronic obstructive pulmonary disease (COPD) in relation to COVID-19 severity.

Methods: Patients diagnosed with COVID-19 (n = 61,338) in a large, diverse integrated health care system were identified. Asthma/COPD history, medication use, and covariates were extracted from electronic medical records. Asthma patients were categorized into those with and without clinical visits for asthma 12 or fewer months prior to COVID-19 diagnosis and labeled as active and inactive asthma, respectively. Primary outcomes included COVID-19-related hospitalizations, intensive respiratory support (IRS), and intensive care unit admissions within 30 days, and mortality within 60 days after COVID-19 diagnosis. Logistic and Cox regression were used to relate COVID-19 outcomes to asthma/COPD history.

Results: The cohort was 53.9% female and 66% Hispanic and had a mean age of 43.9 years. Patients with active asthma had increased odds of hospitalization, IRS, and intensive care unit admission (odds ratio 1.47-1.66; P < .05) compared with patients without asthma or COPD. No increased risks were observed for patients with inactive asthma. Chronic obstructive pulmonary disease was associated with increased risks of hospitalization, IRS, and mortality (odds ratio and hazard ratio 1.27-1.67; P < .05). Among active asthma patients, those using asthma medications had greater than 25% lower odds for COVID-19 outcomes than those without medication.

Conclusions: Patients with asthma who required clinical care 12 or fewer months prior to COVID-19 or individuals with COPD history are at increased risk for severe COVID-19 outcomes. Proper medication treatment for asthma may lower this risk.
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http://dx.doi.org/10.1016/j.jaip.2021.07.030DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8353223PMC
October 2021

COVID-19 mortality in California based on death certificates: disproportionate impacts across racial/ethnic groups and nativity.

Ann Epidemiol 2021 06 18;58:69-75. Epub 2021 Mar 18.

Department of Preventive Medicine, University of Southern California, Los Angeles, CA.

Purpose: To examine characteristics of coronavirus disease 2019 (COVID-19) decedents in California (CA) and evaluate for disproportionate mortality across race/ethnicity and ethnicity/nativity.

Methods: COVID-19 deaths were identified from death certificates. Age-adjusted mortality rate ratios (MRR) were compared across race/ethnicity. Proportionate mortality rates (PMR) were compared across race/ethnicity and by ethnicity/nativity.

Results: We identified 10,200 COVID-19 deaths in CA occurring February 1 through July 31, 2020. The most frequently observed characteristics among decedents were age 65 years or above, male, Hispanic, foreign-born, and educational attainment of High School or below. MRR indicated elevated COVID-19 morality rates among Asian/Pacific Islander, Black, and Hispanic groups compared with the White group, with Black and Hispanic groups having the highest MRR at 2.75 (95%CI: 2.54-2.97) and 4.18 (95%CI: 3.99-4.37), respectively. Disparities were larger at younger ages. Similar results were observed with PMR, and patterns of age-racial/ethnic disparities remained in analyses stratified by education. Elevated PMR were observed in all ethnicity/nativity groups, especially foreign-born Hispanic individuals, relative to U.S.-born non-Hispanic individuals. These were generally larger at younger ages and persisted after stratifying by education.

Conclusions: Differential COVID-19 mortality was observed in California across racial/ethnic groups and by ethnicity/nativity groups with evidence of greater disparities among younger age groups. Identifying COVID-19 disparities is an initial step toward mitigating disease impacts in vulnerable communities.
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http://dx.doi.org/10.1016/j.annepidem.2021.03.006DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8005258PMC
June 2021

COVID-19 Mortality in California Based on Death Certificates: Disproportionate Impacts Across Racial/Ethnic Groups and Nativity.

medRxiv 2021 Mar 3. Epub 2021 Mar 3.

Purpose: To examine characteristics of coronavirus disease 2019 (COVID-19) decedents in California (CA) and evaluate for disproportionate mortality across race/ethnicity and ethnicity/nativity.

Methods: COVID-19 deaths were identified from death certificates. Age-adjusted mortality rate ratios (MRR) were compared across race/ethnicity. Proportionate mortality rates (PMR) were compared across race/ethnicity and by ethnicity/nativity.

Results: We identified 10,200 COVID-19 deaths in CA occurring February 1 through July 31, 2020. Decedents tended to be older, male, Hispanic, foreign-born, and have lower educational attainment. MRR indicated elevated COVID-19 morality rates among Asian/Pacific Islander, Black, and Hispanic groups compared with the White group, with Black and Hispanic groups having the highest MRR at 2.75 (95%CI:2.54-2.97) and 4.18 (95%CI: 3.99-4.37), respectively. Disparities were larger at younger ages. Similar results were observed with PMR, which remained in analyses stratified by education. Elevated PMR were observed in all ethnicity/nativity groups, especially foreign-born Hispanic individuals, relative to U.S.-born non-Hispanic individuals, were generally larger at younger ages, and persisted after stratifying by education.

Conclusions: Differential COVID-19 mortality was observed in California across racial/ethnic groups and by ethnicity/nativity groups with evidence of greater disparities among younger age groups. Identifying COVID-19 disparities is an initial step towards mitigating disease impacts in vulnerable communities.
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http://dx.doi.org/10.1101/2021.03.01.21252678DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7941651PMC
March 2021

Liver Immune Profiling Reveals Pathogenesis and Therapeutics for Biliary Atresia.

Cell 2020 12 27;183(7):1867-1883.e26. Epub 2020 Nov 27.

Walter and Eliza Hall Institute of Medical Research and Department of Medical Biology, University of Melbourne, Parkville, Melbourne, VIC 3052, Australia.

Biliary atresia (BA) is a severe cholangiopathy that leads to liver failure in infants, but its pathogenesis remains to be fully characterized. By single-cell RNA profiling, we observed macrophage hypo-inflammation, Kupffer cell scavenger function defects, cytotoxic T cell expansion, and deficiency of CX3CR1effector T and natural killer (NK) cells in infants with BA. More importantly, we discovered that hepatic B cell lymphopoiesis did not cease after birth and that tolerance defects contributed to immunoglobulin G (IgG)-autoantibody accumulation in BA. In a rhesus-rotavirus induced BA model, depleting B cells or blocking antigen presentation ameliorated liver damage. In a pilot clinical study, we demonstrated that rituximab was effective in depleting hepatic B cells and restoring the functions of macrophages, Kupffer cells, and T cells to levels comparable to those of control subjects. In summary, our comprehensive immune profiling in infants with BA had educed that B-cell-modifying therapies may alleviate liver pathology.
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http://dx.doi.org/10.1016/j.cell.2020.10.048DOI Listing
December 2020

Macroscopic somatic clonal expansion in morphologically normal human urothelium.

Science 2020 10;370(6512):82-89

Biomedical Pioneering Innovation Center (BIOPIC), School of Life Sciences, Peking University, Beijing, China.

Knowledge of somatic mutation accumulation in normal cells, which is essential for understanding cancer development and evolution, remains largely lacking. In this study, we investigated somatic clonal events in morphologically normal human urothelium (MNU; epithelium lining the bladder and ureter) and identified macroscopic clonal expansions. Aristolochic acid (AA), a natural herb-derived compound, was a major mutagenic driving factor in MNU. AA drastically accelerates mutation accumulation and enhances clonal expansion. Mutations in MNU were widely observed in chromatin remodeling genes such as and but rarely in , , and mutations were found to be common in urothelial cells, regardless of whether the cells experience exogenous mutagen exposure. Copy number alterations were rare and largely confined to small-scale regions, along with copy-neutral loss of heterozygosity. Single AA-associated clones in MNU expanded to a scale of several square centimeters in size.
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http://dx.doi.org/10.1126/science.aba7300DOI Listing
October 2020

Excessive deubiquitination of NLRP3-R779C variant contributes to very-early-onset inflammatory bowel disease development.

J Allergy Clin Immunol 2021 01 15;147(1):267-279. Epub 2020 Sep 15.

MOE Key Laboratory of Gene Function and Regulation, Department of Gastroenterology and Guangzhou Institute of Pediatrics, Guangzhou Women and Children's Medical Center, School of Life Sciences, Sun Yat-sen University, Guangzhou, China. Electronic address:

Background: Very-early-onset inflammatory bowel disease (VEOIBD) is a chronic inflammatory disease of the gastrointestinal tract occurring during infancy or early childhood. NOD-like receptor family, pyrin domain containing 3 (NLRP3) inflammasome has emerged as a crucial regulator of intestinal homeostasis; however, whether NLRP3 variants may modify VEOIBD risk is unknown.

Objective: We sought to investigate whether and how a rare NLRP3 variant, found in 3 patients with gastrointestinal symptoms, contributes to VEOIBD development.

Methods: Whole-exome sequencing and bioinformatic analysis were performed to screen disease-associated NLRP3 variants from a cohort of children with VEOIBD. Inflammasome activation was determined in reconstituted HEK293T human embryonic kidney cells with NLRP3 inflammasome components, doxycycline-inducible NLRP3 macrophages, as well as PBMCs and biopsies from patients with NLRP3 variants. Pathogenesis of the variants was determined using a dextran sulfate sodium-induced acute colitis model.

Results: We identified a dominant gain-of-function missense variant of NLRP3, encoded by rs772009059 (R779C), in 3 patients with gastrointestinal symptoms. Functional analysis revealed that R779C increased NLRP3 inflammasome activation and pyroptosis in macrophages. This was mediated by enhanced deubiquitination of NLRP3 via binding with deubiquitinases BRCC3 and JOSD2, which are highly expressed in myeloid cells. In a dextran sulfate sodium-induced acute colitis model, NLRP3-R779C in hematopoietic cells resulted in more severe colitis, which can be ameliorated via knockdown of BRCC3 or JOSD2.

Conclusions: BRCC3 and JOSD2 mediate NLRP3-R779C deubiquitination, which promotes NLRP3 inflammasome activation and the risk of developing VEOIBD.
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http://dx.doi.org/10.1016/j.jaci.2020.09.003DOI Listing
January 2021

Dysregulated lipid and fatty acid metabolism link perfluoroalkyl substances exposure and impaired glucose metabolism in young adults.

Environ Int 2020 12 3;145:106091. Epub 2020 Sep 3.

Division of Environmental Health, Department of Preventive Medicine, Keck School of Medicine of the University of Southern California, Los Angeles, CA, USA.

Background: Per- and polyfluoroalkyl substances (PFASs) exposure is ubiquitous among the US population and has been linked to adverse health outcomes including cardiometabolic diseases, immune dysregulation and endocrine disruption. However, the metabolic mechanism underlying the adverse health effect of PFASs exposure is unknown.

Objective: The aim of this project is to investigate the association between PFASs exposure and altered metabolic pathways linked to increased cardiometabolic risk in young adults.

Methods: A total of 102 young adults with 82% overweight or obese participants were enrolled from Southern California between 2014 and 2017. Cardiometabolic outcomes were assessed including oral glucose tolerance test (OGTT) measures, body fat and lipid profiles. High-resolution metabolomics was used to quantify plasma exposure levels of three PFAS congeners and intensity profiles of the untargeted metabolome. Fasting concentrations of 45 targeted metabolites involved in fatty acid and lipid metabolism were used to verify untargeted metabolomics findings. Bayesian Kernel Machine Regression (BKMR) was used to examine the associations between PFAS exposure mixture and cardiometabolic outcomes adjusting for covariates. Mummichog pathway enrichment analysis was used to explore PFAS-associated metabolic pathways. Moreover, the effect of PFAS exposure on the metabolic network, including metabolomic profiles and cardiometabolic outcomes, was investigated.

Results: Higher exposure to perfluorooctanoic acid (PFOA) was associated with higher 30-minute glucose levels and glucose area under the curve (AUC) during the OGTT (p < 0.001). PFAS exposure was also associated with altered lipid pathways, which contributed to the metabolic network connecting PFOA and higher glucose levels following the OGTT. Targeted metabolomics analysis indicated that higher PFOA exposure was associated with higher levels of glycerol (p = 0.006), which itself was associated with higher 30-minute glucose (p = 0.006).

Conclusions: Increased lipolysis and fatty acid oxidation could contribute to the biological mechanisms linking PFAS exposure and impaired glucose metabolism among young adults. Findings of this study warrants future experimental studies and epidemiological studies with larger sample size to replicate.
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http://dx.doi.org/10.1016/j.envint.2020.106091DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8009052PMC
December 2020

Lung Function in African American Children with Asthma Is Associated with Novel Regulatory Variants of the KIT Ligand and Gene-By-Air-Pollution Interaction.

Genetics 2020 07 23;215(3):869-886. Epub 2020 Apr 23.

Department of Medicine, University of California, San Francisco, California 94143.

Baseline lung function, quantified as forced expiratory volume in the first second of exhalation (FEV), is a standard diagnostic criterion used by clinicians to identify and classify lung diseases. Using whole-genome sequencing data from the National Heart, Lung, and Blood Institute Trans-Omics for Precision Medicine project, we identified a novel genetic association with FEV on chromosome 12 in 867 African American children with asthma ( = 1.26 × 10, β = 0.302). Conditional analysis within 1 Mb of the tag signal (rs73429450) yielded one major and two other weaker independent signals within this peak. We explored statistical and functional evidence for all variants in linkage disequilibrium with the three independent signals and yielded nine variants as the most likely candidates responsible for the association with FEV Hi-C data and expression QTL analysis demonstrated that these variants physically interacted with (KIT ligand, also known as ), and their minor alleles were associated with increased expression of the gene in nasal epithelial cells. Gene-by-air-pollution interaction analysis found that the candidate variant rs58475486 interacted with past-year ambient sulfur dioxide exposure ( = 0.003, β = 0.32). This study identified a novel protective genetic association with FEV, possibly mediated through , in African American children with asthma. This is the first study that has identified a genetic association between lung function and , which has established a role in orchestrating allergic inflammation in asthma.
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http://dx.doi.org/10.1534/genetics.120.303231DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7337089PMC
July 2020

Potential therapeutic effects of dipyridamole in the severely ill patients with COVID-19.

Acta Pharm Sin B 2020 Jul 20;10(7):1205-1215. Epub 2020 Apr 20.

Guangdong Provincial Key Laboratory of New Drug Design and Evaluation, School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou 510006, China.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection can cause acute respiratory distress syndrome, hypercoagulability, hypertension, and multiorgan dysfunction. Effective antivirals with safe clinical profile are urgently needed to improve the overall prognosis. In an analysis of a randomly collected cohort of 124 patients with COVID-19, we found that hypercoagulability as indicated by elevated concentrations of D-dimers was associated with disease severity. By virtual screening of a U.S. FDA approved drug library, we identified an anticoagulation agent dipyridamole (DIP) , which suppressed SARS-CoV-2 replication . In a proof-of-concept trial involving 31 patients with COVID-19, DIP supplementation was associated with significantly decreased concentrations of D-dimers ( < 0.05), increased lymphocyte and platelet recovery in the circulation, and markedly improved clinical outcomes in comparison to the control patients. In particular, all 8 of the DIP-treated severely ill patients showed remarkable improvement: 7 patients (87.5%) achieved clinical cure and were discharged from the hospitals while the remaining 1 patient (12.5%) was in clinical remission.
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http://dx.doi.org/10.1016/j.apsb.2020.04.008DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7169892PMC
July 2020

Air pollution exposure is associated with the gut microbiome as revealed by shotgun metagenomic sequencing.

Environ Int 2020 05 2;138:105604. Epub 2020 Mar 2.

University of Colorado Boulder, Boulder, CO, USA. Electronic address:

Animal work indicates exposure to air pollutants may alter the composition of the gut microbiota. This study examined relationships between air pollutants and the gut microbiome in young adults residing in Southern California. Our results demonstrate significant associations between exposure to air pollutants and the composition of the gut microbiome using whole-genome sequencing. Higher exposure to 24-hour O was associated with lower Shannon diversity index, higher Bacteroides caecimuris, and multiple gene pathways, including L-ornithine de novo biosynthesis as well as pantothenate and coenzyme A biosynthesis I. Among other pollutants, higher NO exposure was associated with fewer taxa, including higher Firmicutes. The percent variation in gut bacterial composition that was explained by air pollution exposure was up to 11.2% for O concentrations, which is large compared to the effect size for many other covariates reported in healthy populations. This study provides the first evidence of significant associations between exposure to air pollutants and the compositional and functional profile of the human gut microbiome. These results identify O as an important pollutant that may alter the human gut microbiome.
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http://dx.doi.org/10.1016/j.envint.2020.105604DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7181344PMC
May 2020

Mucosal Profiling of Pediatric-Onset Colitis and IBD Reveals Common Pathogenics and Therapeutic Pathways.

Cell 2019 11;179(5):1160-1176.e24

Department of Gastroenterology, Guangzhou Institute of Pediatrics, Guangzhou Women and Children's Medical Center, Guangzhou Medical University, Guangzhou, 510623, China.

Pediatric-onset colitis and inflammatory bowel disease (IBD) have significant effects on the growth of infants and children, but the etiopathogenesis underlying disease subtypes remains incompletely understood. Here, we report single-cell clustering, immune phenotyping, and risk gene analysis for children with undifferentiated colitis, Crohn's disease, and ulcerative colitis. We demonstrate disease-specific characteristics, as well as common pathogenesis marked by impaired cyclic AMP (cAMP)-response signaling. Specifically, infiltration of PDE4B- and TNF-expressing macrophages, decreased abundance of CD39-expressing intraepithelial T cells, and platelet aggregation and release of 5-hydroxytryptamine at the colonic mucosae were common in colitis and IBD patients. Targeting these pathways by using the phosphodiesterase inhibitor dipyridamole restored immune homeostasis and improved colitis symptoms in a pilot study. In summary, comprehensive analysis of the colonic mucosae has uncovered common pathogenesis and therapeutic targets for children with colitis and IBD.
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http://dx.doi.org/10.1016/j.cell.2019.10.027DOI Listing
November 2019

The Dynamic Relationship Between Asthma and Obesity in Schoolchildren.

Am J Epidemiol 2020 06;189(6):583-591

Department of Preventive Medicine, Keck School of Medicine, University of Southern California, Los Angeles, California.

Asthma and obesity are among the most prevalent chronic health conditions in children. Although there has been compelling evidence of co-occurrence of asthma and obesity, it is uncertain whether asthma contributes to the development of obesity or obesity contributes to the onset of asthma or both. In this study, we used a joint transition modeling approach with cross-lagged structure to understand how asthma and obesity influence each other dynamically over time. Subjects for this study included 5,193 kindergarten and first-grade students enrolled from 13 communities in 2002-2003 in the Southern California Children's Health Study, with up to 10 years of follow-up. We found that nonobese children with diagnosed asthma at a study visit were at 37% higher odds of becoming obese by the next annual visit compared with children without asthma (odds ratio = 1.38; 95% credible interval: 1.12, 1.71). However, the presence of obesity at the current visit was not statistically significantly associated with asthma onset in the next visit (odds ratio = 1.25; 95% credible interval: 0.94, 1.62). In conclusion, childhood asthma appears to drive an increase in the onset of obesity among schoolchildren, while the onset of obesity does not necessarily imply the future onset of asthma, at least in the short term.
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http://dx.doi.org/10.1093/aje/kwz257DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7443205PMC
June 2020

Associations of air pollution, obesity and cardiometabolic health in young adults: The Meta-AIR study.

Environ Int 2019 12 15;133(Pt A):105180. Epub 2019 Oct 15.

Department of Preventive Medicine, Division of Environmental Health, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA. Electronic address:

Objective: Growing evidence indicates exposure to air pollution contributes to obesity and cardiometabolic disease risk in children and adults, however studies are lacking in young adulthood, an important transitional period in the life course. The aim of this study was to examine the associations of short- and long-term regional ambient and near-roadway air pollution (NRAP) exposures on adiposity and cardiometabolic health in young adults aged 17-22 years.

Methods: From 2014 to 2018, a subset of participants (n = 158) were recruited from the Children's Health Study to participate in the Meta-AIR (Metabolic and Asthma Incidence Research) study to assess obesity (body composition and abdominal adiposity) and cardiometabolic health (fasting glucose, fasting insulin and lipid profiles) measures. Prior 1-month and 1-year average air pollution exposures were calculated from residential addresses. This included nitrogen dioxide (NO), ozone (O), particulate matter with aerodynamic diameter < 10 μm (PM), particulate matter with aerodynamic diameter < 2.5 μm (PM) and NRAP (freeway, non-freeway, and total nitrogen oxides (NO)) exposures. Linear regression models examined associations of prior 1-month (short-term) and 1-year (long-term) air pollution exposures on obesity and cardiometabolic factors adjusting for covariates and past childhood air pollution exposures.

Results: In the Meta-AIR study, we conducted a comprehensive analysis with short- and long-term regional ambient and NRAP exposures (in both single- and multi-pollutant models) and obesity- and cardiometabolic-related outcomes and found associations with a few outcomes. A 1 standard deviation (SD) change in long-term NO exposure was associated with a 11.3 mg/dL higher level of total cholesterol (p = 0.04) and 9.4 mg/dL higher level of low-density lipoproteins (LDL)-cholesterol (p = 0.04). Amongst obese participants, associations between long-term NO and total cholesterol and LDL-cholesterol were 4.5 and 9 times larger than the associations in non-obese participants (p = 0.008 and 0.03, respectively). Additionally, we observed a statistically significant association with increased short-term O exposure and higher triglyceride and very-low-density lipoprotein (VLDL) cholesterol levels (p = 0.04), lower high-density lipoprotein (HDL) cholesterol levels (p = 0.03), and higher hepatic fat levels (p = 0.02). Amongst glucose-related factors, long-term PM exposure was associated with higher levels of insulin area under the curve (p = 0.03). There were no other statistically significant associations with short- or long-term air pollutants and BMI, other measures of adiposity, and cardiometabolic outcomes.

Conclusion: Higher exposure to regional air pollutants, namely prior 1-year average NO, was associated with higher fasting serum lipid measures. These associations were more pronounced in obese participants, suggesting obesity may exacerbate the effects of air pollution exposure on lipid levels in young adults. This study did not find any other associations between short- and long-term ambient and NRAP exposures across a range of other obesity and cardiometabolic indicators. Further studies in young adults are warranted as our study suggests potential deleterious associations of both short- and long-term air pollution exposures and lipid metabolism.
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http://dx.doi.org/10.1016/j.envint.2019.105180DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6884139PMC
December 2019

A trans-ancestral meta-analysis of genome-wide association studies reveals loci associated with childhood obesity.

Hum Mol Genet 2019 10;28(19):3327-3338

Unidad de Investigacion Medica en Bioquımica, Hospital de Especialidades, Centro Medico Nacional Siglo XXI, Instituto Mexicano del Seguro Social, Mexico City, Mexico.

Although hundreds of genome-wide association studies-implicated loci have been reported for adult obesity-related traits, less is known about the genetics specific for early-onset obesity and with only a few studies conducted in non-European populations to date. Searching for additional genetic variants associated with childhood obesity, we performed a trans-ancestral meta-analysis of 30 studies consisting of up to 13 005 cases (≥95th percentile of body mass index (BMI) achieved 2-18 years old) and 15 599 controls (consistently <50th percentile of BMI) of European, African, North/South American and East Asian ancestry. Suggestive loci were taken forward for replication in a sample of 1888 cases and 4689 controls from seven cohorts of European and North/South American ancestry. In addition to observing 18 previously implicated BMI or obesity loci, for both early and late onset, we uncovered one completely novel locus in this trans-ancestral analysis (nearest gene, METTL15). The variant was nominally associated with only the European subgroup analysis but had a consistent direction of effect in other ethnicities. We then utilized trans-ancestral Bayesian analysis to narrow down the location of the probable causal variant at each genome-wide significant signal. Of all the fine-mapped loci, we were able to narrow down the causative variant at four known loci to fewer than 10 single nucleotide polymorphisms (SNPs) (FAIM2, GNPDA2, MC4R and SEC16B loci). In conclusion, an ethnically diverse setting has enabled us to both identify an additional pediatric obesity locus and further fine-map existing loci.
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http://dx.doi.org/10.1093/hmg/ddz161DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6859434PMC
October 2019

Near-roadway air pollution exposure and altered fatty acid oxidation among adolescents and young adults - The interplay with obesity.

Environ Int 2019 09 22;130:104935. Epub 2019 Jun 22.

Division of Environmental Health, Department of Preventive Medicine, Keck School of Medicine of the University of Southern California, Los Angeles, CA, USA.

Background: Air pollution exposure has been shown to increase the risk of obesity and metabolic dysfunction in animal models and human studies. However, the metabolic pathways altered by air pollution exposure are unclear, especially in adolescents and young adults who are at a critical period in the development of cardio-metabolic diseases.

Objectives: The aim of this study was to examine the associations between air pollution exposure and indices of fatty acid and amino acid metabolism.

Methods: A total of 173 young adults (18-23 years) from eight Children's Health Study (CHS) Southern California communities were examined from 2014 to 2018. Near-roadway air pollution (NRAP) exposure (freeway and non-freeway) and regional air pollution exposure (nitrogen dioxide, ozone and particulate matter) during one year before the study visit were estimated based on participants' residential addresses. Serum concentrations of 64 targeted metabolites including amino acids, acylcarnitines, non-esterified fatty acid (NEFA) and glycerol were measured in fasting serum samples. Principal component analysis of metabolites was performed to identify metabolite clusters that represent key metabolic pathways. Mixed effects models were used to analyze the associations of air pollution exposure with metabolomic principal component (PC) scores and individual metabolite concentrations adjusting for potential confounders.

Results: Higher lagged one-year averaged non-freeway NRAP exposure was associated with higher concentrations of NEFA oxidation byproducts and higher NEFA-related PC score (all p's ≤ 0.038). The effect sizes were larger among obese individuals (interaction p = 0.047). Among females, higher freeway NRAP exposure was also associated with a higher NEFA-related PC score (p = 0.042). Among all participants, higher freeway NRAP exposure was associated with a lower PC score for lower concentrations of short- and median-chain acylcarnitines (p = 0.044).

Conclusions: Results of this study indicate that NRAP exposure is associated with altered fatty acid metabolism, which could contribute to the metabolic perturbation in obese youth.
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http://dx.doi.org/10.1016/j.envint.2019.104935DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6679991PMC
September 2019

Association of Changes in Air Quality With Incident Asthma in Children in California, 1993-2014.

JAMA 2019 05;321(19):1906-1915

Department of Preventive Medicine, University of Southern California, Los Angeles.

Importance: Exposure to air pollutants is a well-established cause of asthma exacerbation in children; whether air pollutants play a role in the development of childhood asthma, however, remains uncertain.

Objective: To examine whether decreasing regional air pollutants were associated with reduced incidence of childhood asthma.

Design, Setting, And Participants: A multilevel longitudinal cohort drawn from 3 waves of the Southern California Children's Health Study over a period of air pollution decline. Each cohort was followed up from 4th to 12th grade (8 years): 1993-2001, 1996-2004, and 2006-2014. Final follow-up for these data was June 2014. Population-based recruitment was from public elementary schools. A total of 4140 children with no history of asthma and residing in 1 of 9 Children's Health Study communities at baseline were included.

Exposures: Annual mean community-level ozone, nitrogen dioxide, and particulate matter less than 10 μm (PM10) and less than 2.5 μm (PM2.5) in the baseline year for each of 3 cohorts.

Main Outcomes And Measures: Prospectively identified incident asthma, collected via questionnaires during follow-up.

Results: Among the 4140 children included in this study (mean [SD] age at baseline, 9.5 [0.6] years; 52.6% female [n = 2 179]; 58.6% white [n = 2273]; and 42.2% Hispanic [n = 1686]), 525 incident asthma cases were identified. For nitrogen dioxide, the incidence rate ratio (IRR) for asthma was 0.80 (95% CI, 0.71-0.90) for a median reduction of 4.3 parts per billion, with an absolute incidence rate decrease of 0.83 cases per 100 person-years. For PM2.5, the IRR was 0.81 (95% CI, 0.67-0.98) for a median reduction of 8.1 μg/m3, with an absolute incidence rate decrease of 1.53 cases per 100 person-years. For ozone, the IRR for asthma was 0.85 (95% CI, 0.71-1.02) for a median reduction of 8.9 parts per billion, with an absolute incidence rate decrease of 0.78 cases per 100 person-years. For PM10, the IRR was 0.93 (95% CI, 0.82-1.07) for a median reduction of 4.0 μg/m3, with an absolute incidence rate decrease of 0.46 cases per 100 person-years.

Conclusions And Relevance: Among children in Southern California, decreases in ambient nitrogen dioxide and PM2.5 between 1993 and 2014 were significantly associated with lower asthma incidence. There were no statistically significant associations for ozone or PM10.
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http://dx.doi.org/10.1001/jama.2019.5357DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6537847PMC
May 2019

Perfluoroalkyl substances, metabolomic profiling, and alterations in glucose homeostasis among overweight and obese Hispanic children: A proof-of-concept analysis.

Environ Int 2019 05 4;126:445-453. Epub 2019 Mar 4.

Department of Preventive Medicine, University of Southern California, Los Angeles, CA, United States. Electronic address:

Objective: To examine the prospective associations between exposure to perfluoroalkyl substances (PFASs) and longitudinal measurements of glucose metabolism in high-risk overweight and obese Hispanic children.

Methods: Forty overweight and obese Hispanic children (8-14 years) from urban Los Angeles underwent clinical measures and 2-hour oral glucose tolerance tests (OGTT) at baseline and a follow-up visit (range: 1-3 years after enrollment). Baseline plasma perfluorooctanoic acid (PFOA), perfluorooctane sulfonate (PFOS), perfluorohexane sulfonic acid (PFHxS), and the plasma metabolome were measured by liquid-chromatography with high-resolution mass spectrometry. Multiple linear regression models were used to assess the association between baseline PFASs and changes in glucose homeostasis over follow-up. A metabolome-wide association study coupled with pathway enrichment analysis was performed to evaluate metabolic dysregulation associated with plasma PFASs concentrations. We performed a structural integrated analysis aiming to characterize the joint impact of all factors and to identify latent clusters of children with alterations in glucose homeostasis, based on their exposure and metabolomics profile.

Results: Each ln (ng/ml) increase in PFOA and PFHxS concentrations was associated with a 30.6 mg/dL (95% CI: 8.8-52.4) and 10.2 mg/dL (95% CI: 2.7-17.7) increase in 2-hour glucose levels, respectively. A ln (ng/ml) increase in PFHxS concentrations was also associated with 17.8 mg/dL increase in the glucose area under the curve (95% CI: 1.5-34.1). Pathway enrichment analysis showed significant alterations of lipids (e.g., glycosphingolipids, linoleic acid, and de novo lipogenesis), and amino acids (e.g., aspartate and asparagine, tyrosine, arginine and proline) in association to PFASs exposure. The integrated analysis identified a cluster of children with increased 2-h glucose levels over follow up, characterized by increased PFAS levels and altered metabolite patterns.

Conclusions: This proof-of-concept analysis shows that higher PFAS exposure was associated with dysregulation of several lipid and amino acid pathways and longitudinal alterations in glucose homeostasis in Hispanic youth. Larger studies are needed to confirm these findings and fully elucidate the underlying biological mechanisms.
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http://dx.doi.org/10.1016/j.envint.2019.02.047DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6555482PMC
May 2019

Regional and traffic-related air pollutants are associated with higher consumption of fast food and trans fat among adolescents.

Am J Clin Nutr 2019 01;109(1):99-108

Division of Environmental Health and Preventive Medicine.

Background: Air pollution exposures are novel contributors to the growing childhood obesity epidemic. One possible mechanism linking air pollution exposures and obesity is through changes in food consumption patterns.

Objective: The aim of this study was to examine the longitudinal association between childhood exposure to air pollutants and changes in diet among adolescents.

Design: School-age children were enrolled in the Southern California Children's Health Study during 1993-1994 (n = 3100) and were followed for 4-8 y. Community-level regional air pollutants [e.g., nitrogen dioxide (NO2), elemental carbon (EC), and fine particles with aerodynamic diameter <2.5 µm (PM2.5)] were measured at central monitoring stations. Line dispersion modeling was used to estimate concentrations of traffic-related air pollutants based on nitrogen oxides (NOx) at participants' residential addresses. In addition, self-reported diet information was collected annually using a structured youth/adolescent food-frequency questionnaire during 1997-2001. Generalized linear mixed-effects models were used in the association analyses.

Results: Higher exposures to regional and traffic-related air pollutants were associated with intake of a high-trans-fat diet, after adjusting for confounders including socioeconomic status and access to fast food in the community. A 2-SD (12.2 parts per billion) increase in regional NO2 exposure was associated with a 34% increased risk of consuming a high-trans-fat diet compared with a low-trans-fat diet (OR: 1.34; 95% CI: 1.05, 1.72). In addition, higher exposures to acid vapor, EC, PM2.5, and non-freeway NOx were all associated with higher consumption of dietary trans fat (all P < 0.04). Notably, higher exposures to regional NO2, acid vapor, and EC were also associated with a higher consumption of fast food (all P < 0.05).

Conclusions: Childhood exposures to regional and traffic-related air pollutants were associated with increased consumption by adolescents of trans fat and fast foods. Our results indicate that air pollution exposures may contribute to obesogenic behaviors. This study was registered at clinicaltrials.gov as NCT03379298.
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http://dx.doi.org/10.1093/ajcn/nqy232DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6358030PMC
January 2019

ATP-Dependent Dynamic Protein Aggregation Regulates Bacterial Dormancy Depth Critical for Antibiotic Tolerance.

Mol Cell 2019 01 21;73(1):143-156.e4. Epub 2018 Nov 21.

Biomedical Pioneering Innovation Center (BIOPIC), School of Life Sciences, Peking University, Beijing 100871, China. Electronic address:

Cell dormancy is a widespread mechanism used by bacteria to evade environmental threats, including antibiotics. Here we monitored bacterial antibiotic tolerance and regrowth at the single-cell level and found that each individual survival cell shows different "dormancy depth," which in return regulates the lag time for cell resuscitation after removal of antibiotic. We further established that protein aggresome-a collection of endogenous protein aggregates-is an important indicator of bacterial dormancy depth, whose formation is promoted by decreased cellular ATP level. For cells to leave the dormant state and resuscitate, clearance of protein aggresome and recovery of proteostasis are required. We revealed that the ability to recruit functional DnaK-ClpB machineries, which facilitate protein disaggregation in an ATP-dependent manner, determines the lag time for bacterial regrowth. Better understanding of the key factors regulating bacterial regrowth after surviving antibiotic attack could lead to new therapeutic strategies for combating bacterial antibiotic tolerance.
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http://dx.doi.org/10.1016/j.molcel.2018.10.022DOI Listing
January 2019

Gene Coexpression Networks in Whole Blood Implicate Multiple Interrelated Molecular Pathways in Obesity in People with Asthma.

Obesity (Silver Spring) 2018 12 25;26(12):1938-1948. Epub 2018 Oct 25.

Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, USA.

Objective: Asthmatic children who develop obesity through adolescence have poorer disease outcomes compared with those who do not. This study aimed to characterize the biology of childhood asthma complicated by adult obesity.

Methods: Gene expression networks are powerful statistical tools for characterizing human disease that leverage the putative coregulatory relationships of genes to infer relevant biological pathways. Weighted gene coexpression network analysis of gene expression data was performed in whole blood from 514 adult asthmatic subjects. Then, module preservation and association replication analyses were performed in 418 subjects from two independent asthma cohorts (one pediatric and one adult).

Results: A multivariate model was identified in which three gene coexpression network modules were associated with incident obesity in the discovery cohort (each P < 0.05). Two module memberships were enriched for genes in pathways related to platelets, integrins, extracellular matrix, smooth muscle, NF-κB signaling, and Hedgehog signaling. The network structures of each of the obesity modules were significantly preserved in both replication cohorts (permutation P = 9.999E-05). The corresponding module gene sets were significantly enriched for differential expression in subjects with obesity in both replication cohorts (each P < 0.05).

Conclusions: The gene coexpression network profiles thus implicate multiple interrelated pathways in the biology of an important endotype of asthma with obesity.
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http://dx.doi.org/10.1002/oby.22341DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6262830PMC
December 2018

Ambient and Traffic-Related Air Pollution Exposures as Novel Risk Factors for Metabolic Dysfunction and Type 2 Diabetes.

Curr Epidemiol Rep 2018 Jun 10;5(2):79-91. Epub 2018 Apr 10.

University of Southern California, Department of Preventive Medicine, Division of Environmental Health, Los Angeles, California, USA.

Purpose Of Review: Diabetes mellitus is a top contributor to the global burden of mortality and disability in adults. There has also been a slow, but steady rise in prediabetes and type 2 diabetes in youth. The current review summarizes recent findings regarding the impact of increased exposure to air pollutants on the type 2 diabetes epidemic.

Recent Findings: Human and animal studies provide strong evidence that exposure to ambient and traffic-related air pollutants such as particulate matter (PM), nitrogen dioxide (NO), and nitrogen oxides (NO) play an important role in metabolic dysfunction and type 2 diabetes etiology. This work is supported by recent findings that have observed similar effect sizes for increased exposure to air pollutants on clinical measures of risk for type 2 diabetes in children and adults. Further, studies indicate that these effects may be more pronounced among individuals with existing risk factors, including obesity and prediabetes.

Summary: Current epidemiological evidence suggests that increased air pollution exposure contributes to alterations in insulin signaling, glucose metabolism, and beta (β)-cell function. Future work is needed to identify the specific detrimental pollutants that alter glucose metabolism. Additionally, advanced tools and new areas of investigation present unique opportunities to study the underlying mechanisms, including intermediate pathways, that link increased air pollution exposure with type 2 diabetes onset.
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http://dx.doi.org/10.1007/s40471-018-0140-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6178230PMC
June 2018

Longitudinal associations of in utero and early life near-roadway air pollution with trajectories of childhood body mass index.

Environ Health 2018 09 14;17(1):64. Epub 2018 Sep 14.

Department of Preventive Medicine, Division of Environmental Health, Keck School of Medicine, Southern California Environmental Health Sciences Center, University of Southern California, 2001 N. Soto Street, Los Angeles, CA, 90032, USA.

Background: Evidence suggests that childhood near-roadway air pollution (NRAP) exposures contribute to increased body mass index (BMI); however, effects of NRAP exposure during the vulnerable periods including in utero and first year of life have yet to be established. In this study, we examined whether exposure to elevated concentrations of NRAP during in utero and/or first year of life increase childhood BMI growth.

Methods: Participants in the Children's Health Study enrolled from 2002 to 2003 with annual visits over a four-year period and who changed residences before study entry were included (n = 2318). Annual height and weight were measured and lifetime residential NRAP exposures including in utero and first year of life periods were estimated by nitrogen oxides (NO) using the California line-source dispersion model. Linear mixed effects models assessed in utero or first year near-road freeway and non-freeway NO exposures and BMI growth after adjusting for age, sex, race/ethnicity, parental education, Spanish questionnaire, and later childhood near-road NO exposure.

Results: A two-standard deviation difference in first year of life near-road freeway NO exposure was associated with a 0.1 kg/m (95% confidence interval (CI): 0.03, 0.2) faster increase in BMI growth per year and a 0.5 kg/m (95% CI: 0.02, 0.9) higher attained BMI at age 10 years.

Conclusions: Higher exposure to early life NRAP increased the rate of change of childhood BMI and resulted in a higher attained BMI at age 10 years that were independent of later childhood exposures. These findings suggest that elevated early life NRAP exposures contribute to increased obesity risk in children.
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http://dx.doi.org/10.1186/s12940-018-0409-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6137930PMC
September 2018

Does early onset asthma increase childhood obesity risk? A pooled analysis of 16 European cohorts.

Eur Respir J 2018 09 27;52(3). Epub 2018 Sep 27.

Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, Utrecht, The Netherlands.

The parallel epidemics of childhood asthma and obesity over the past few decades have spurred research into obesity as a risk factor for asthma. However, little is known regarding the role of asthma in obesity incidence. We examined whether early-onset asthma and related phenotypes are associated with the risk of developing obesity in childhood.This study includes 21 130 children born from 1990 to 2008 in Denmark, France, Germany, Greece, Italy, The Netherlands, Spain, Sweden and the UK. We followed non-obese children at 3-4 years of age for incident obesity up to 8 years of age. Physician-diagnosed asthma, wheezing and allergic rhinitis were assessed up to 3-4 years of age.Children with physician-diagnosed asthma had a higher risk for incident obesity than those without asthma (adjusted hazard ratio (aHR) 1.66, 95% CI 1.18-2.33). Children with active asthma (wheeze in the last 12 months and physician-diagnosed asthma) exhibited a higher risk for obesity (aHR 1.98, 95% CI 1.31-3.00) than those without wheeze and asthma. Persistent wheezing was associated with increased risk for incident obesity compared to never wheezers (aHR 1.51, 95% CI 1.08-2.09).Early-onset asthma and wheezing may contribute to an increased risk of developing obesity in later childhood.
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http://dx.doi.org/10.1183/13993003.00504-2018DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6443037PMC
September 2018

Author Correction: Genome-wide association and HLA fine-mapping studies identify risk loci and genetic pathways underlying allergic rhinitis.

Nat Genet 2018 09;50(9):1343

Allergy and Lung Health Unit, Melbourne School of Population and Global Health, University of Melbourne, Melbourne, Victoria, Australia.

In the version of this article initially published, in Fig. 3, the y-axis numbering did not match the log scale indicated in the axis label. The error has been corrected in the HTML and PDF version of the article.
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http://dx.doi.org/10.1038/s41588-018-0197-6DOI Listing
September 2018

Genome-wide association and HLA fine-mapping studies identify risk loci and genetic pathways underlying allergic rhinitis.

Nat Genet 2018 08 16;50(8):1072-1080. Epub 2018 Jul 16.

Allergy and Lung Health Unit, Melbourne School of Population and Global Health, University of Melbourne, Melbourne, Victoria, Australia.

Allergic rhinitis is the most common clinical presentation of allergy, affecting 400 million people worldwide, with increasing incidence in westernized countries. To elucidate the genetic architecture and understand the underlying disease mechanisms, we carried out a meta-analysis of allergic rhinitis in 59,762 cases and 152,358 controls of European ancestry and identified a total of 41 risk loci for allergic rhinitis, including 20 loci not previously associated with allergic rhinitis, which were confirmed in a replication phase of 60,720 cases and 618,527 controls. Functional annotation implicated genes involved in various immune pathways, and fine mapping of the HLA region suggested amino acid variants important for antigen binding. We further performed genome-wide association study (GWAS) analyses of allergic sensitization against inhalant allergens and nonallergic rhinitis, which suggested shared genetic mechanisms across rhinitis-related traits. Future studies of the identified loci and genes might identify novel targets for treatment and prevention of allergic rhinitis.
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http://dx.doi.org/10.1038/s41588-018-0157-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7068780PMC
August 2018

Exposure to traffic-related air pollution and the composition of the gut microbiota in overweight and obese adolescents.

Environ Res 2018 02;161:472-478

Department of Preventive Medicine, Diabetes and Obesity Research Institute, University of Southern California, Los Angeles, CA, USA; Department of Physiology and Biophysics, University of Southern California, Los Angeles, CA, USA.

Background: Traffic-related air pollution (TRAP) exposure has been linked to type 2 diabetes and metabolic dysfunction in humans. Animal studies suggest that air pollutants may alter the composition of the gut microbiota, which may negatively impact metabolic health through changes in the composition and/or function of the gut microbiome.

Objectives: The primary aim of this study was to determine whether elevated TRAP exposure was correlated with gut bacterial taxa in overweight and obese adolescents from the Meta-AIR (Metabolic and Asthma Incidence Research) study. The secondary aim was to examine whether gut microbial taxa correlated with TRAP were also correlated with risk factors for type 2 diabetes (e.g., fasting glucose levels). We additionally explored whether correlations between TRAP and these metabolic risk factors could be explained by the relative abundance of these taxa.

Methods: Participants (17-19 years; n=43) were enrolled between 2014 and 2016 from Southern California. The CALINE4 line dispersion model was used to model prior year residential concentrations of nitrogen oxides (NOx) as a marker of traffic emissions. The relative abundance of fecal microbiota was characterized by 16S rRNA sequencing and spearman partial correlations were examined after adjusting for body fat percent.

Results: Freeway TRAP was correlated with decreased Bacteroidaceae (r=-0.48; p=0.001) and increased Coriobacteriaceae (r=0.48; p<0.001). These same taxa were correlated with fasting glucose levels, including Bacteroidaceae (r=-0.34; p=0.04) and Coriobacteriaceae (r=0.41; p<0.01). Further, freeway TRAP was positively correlated fasting glucose (r=0.45; p=0.004) and Bacteroidaceae and Coriobacteriaceae explained 24% and 29% of the correlation between TRAP and fasting glucose levels.

Conclusions: Increased TRAP exposure was correlated with gut microbial taxa and fasting glucose levels. Gut microbial taxa that were correlated with TRAP partially explained the correlation between TRAP and fasting glucose levels. These results suggest that exposure to air pollutants may negatively impact metabolic health via alterations in the gut microbiota.
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http://dx.doi.org/10.1016/j.envres.2017.11.046DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5747978PMC
February 2018
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