Publications by authors named "Ruyang Zhang"

84 Publications

Global COVID-19 pandemic waves: Limited lessons learned worldwide over the past year.

Engineering (Beijing) 2021 Sep 14. Epub 2021 Sep 14.

Department of Epidemiology and Biostatistics, School of Public Health, Nanjing Medical University, Nanjing 211166, China.

The occurrence of coronavirus disease 2019 (COVID-19) was followed by a small burst of cases around the world; afterward, due to a series of emergency non-pharmaceutical interventions (NPIs), the increasing number of confirmed cases slowed down in many countries. However, the subsequent gradual easing of governance led to a sudden increase in cases in late July 2020, arousing deep concern across the globe. This study evaluates the situation of the COVID-19 pandemic in countries and territories worldwide from January 2020 to February 2021. According to the time-varying reproduction number (()) of each country or territory, the results show that almost half of the countries and territories in the world have never controlled the epidemic. Among the countries and territories that had once contained the occurrence, nearly half failed to maintain their prevention and control, causing the COVID-19 pandemic to rebound across the world-resulting in even higher waves in half of the rebounding countries or territories. This work also proposes and uses a time-varying country-level transmission risk score (CTRS), which takes into account both () and daily new cases, to demonstrate country-level or territory-level transmission potential and trends. Time-varying hierarchical clustering of time-varying CTRS values was used to successfully reveal the countries and territories that contributed to the recent aggravation of the global pandemic in the last quarter of 2020 and the beginning of 2021, and to identify countries and territories with an increasing risk of COVID-19 transmission in the near future. Furthermore, a regression analysis indicated that the introduction and relaxation of NPIs, including workplace closure policies and stay-at-home requirements, appear to be associated with recent global transmission changes. In conclusion, a systematic evaluation of the global COVID-19 pandemic over the past year indicates that the world is now in an unexpected situation, with limited lessons learned. Summarizing the lessons learned could help in designing effective public responses for constraining future waves of COVID-19 worldwide.
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http://dx.doi.org/10.1016/j.eng.2021.07.015DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8438800PMC
September 2021

Comprehensive estimation for the length and dispersion of COVID-19 incubation period: a systematic review and meta-analysis.

Infection 2021 Aug 18. Epub 2021 Aug 18.

Department of Epidemiology and Biostatistics, School of Public Health, Nanjing Medical University, 101 Longmian Avenue, Nanjing, 211166, China.

Purpose: To estimate the central tendency and dispersion for incubation period of COVID-19 and, in turn, assess the effect of a certain length of quarantine for close contacts in active monitoring.

Methods: Literature related to SARS-CoV-2 and COVID-19 was searched through April 26, 2020. Quality was assessed according to Agency for Healthcare Research and Quality guidelines. Log-normal distribution for the incubation period was assumed to estimate the parameters for each study. Incubation period median and dispersion were estimated, and distribution was simulated.

Results: Fifty-six studies encompassing 4095 cases were included in this meta-analysis. The estimated median incubation period for general transmissions was 5.8 days [95% confidence interval (95% CI): 5.3, 6.2]. Incubation period was significantly longer for asymptomatic transmissions (median: 7.7 days; 95% CI 6.3, 9.4) than for general transmissions (P = 0.0408). Median and dispersion were higher for SARS-CoV-2 incubation compared to other viral respiratory infections. Furthermore, about 12 in 10,000 contacts in active monitoring would develop symptoms after 14 days, or below 1 in 10,000 for asymptomatic transmissions. Meta-regression suggested that each 10-year increase in age resulted in an average 16% increment in length of median incubation (incubation period ratio, 1.16, 95% CI 1.01, 1.32; P = 0.0250).

Conclusion: This study estimated the median and dispersion of the SARS-CoV-2 incubation period more precisely. A 14-day quarantine period is sufficient to trace and identify symptomatic infections.
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http://dx.doi.org/10.1007/s15010-021-01682-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8372687PMC
August 2021

Genome-wide gene-smoking interaction study identified novel susceptibility loci for non-small cell lung cancer in Chinese populations.

Carcinogenesis 2021 Oct;42(9):1154-1161

Department of Epidemiology, Center for Global Health, School of Public Health, Nanjing Medical University, Nanjing 211166, China.

Gene-smoking interactions play important roles in the development of non-small cell lung cancer (NSCLC). To identify single-nucleotide polymorphisms (SNPs) that modify the association of smoking behavior with NSCLC risk, we conducted a genome-wide gene-smoking interaction study in Chinese populations. The genome-wide interaction analysis between SNPs and smoking status (ever- versus never-smokers) was carried out using genome-wide association studies of NSCLC, which included 13 327 cases and 13 328 controls. Stratified analysis by histological subtypes was also conducted. We used a genome-wide significance threshold of 5 × 10-8 for identifying significant gene-smoking interactions and 1 × 10-6 for identifying suggestive results. Functional annotation was performed to identify potential functional SNPs and target genes. We identified three novel loci with significant or suggestive gene-smoking interaction. For NSCLC, the interaction between rs2746087 (20q11.23) and smoking status reached genome-wide significance threshold [odds ratio (OR) = 0.63, 95% confidence interval (CI): 0.54-0.74, P = 3.31 × 10-8], and the interaction between rs11912498 (22q12.1) and smoking status reached suggestive significance threshold (OR = 0.72, 95% CI: 0.63-0.82, P = 8.10 × 10-7). Stratified analysis by histological subtypes identified suggestive interactions between rs459724 (5q11.2) and smoking status (OR = 0.61, 95% CI: 0.51-0.73, P = 7.55 × 10-8) in the risk of lung squamous cell carcinoma. Functional annotation indicated that both classic and novel biological processes, including nicotine addiction and airway clearance, may modulate the susceptibility to NSCLC. These novel loci provide new insights into the biological mechanisms underlying NSCLC risk. Independent replication in large-scale studies is needed and experimental studies are warranted to functionally validate these associations.
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http://dx.doi.org/10.1093/carcin/bgab064DOI Listing
October 2021

Natural variations in the P-type ATPase heavy metal transporter gene ZmHMA3 control cadmium accumulation in maize grains.

J Exp Bot 2021 09;72(18):6230-6246

Beijing Key Laboratory of Maize DNA Fingerprinting and Molecular Breeding, Maize Research Center, Beijing Academy of Agriculture and Forestry Sciences, Beijing 100097, China.

Cadmium (Cd) accumulation in maize grains is detrimental to human health. Developing maize varieties with low Cd content is important for safe consumption of maize grains. However, the key genes controlling maize grain Cd accumulation have not been cloned. Here, we identified one major locus for maize grain Cd accumulation (qCd1) using a genome-wide association study (GWAS) and bulked segregant RNA-seq analysis with a biparental segregating population of Jing724 (low-Cd line) and Mo17 (high-Cd line). The candidate gene ZmHMA3 was identified by fine mapping and encodes a tonoplast-localized heavy metal P-type ATPase transporter. An ethyl methane sulfonate mutant analysis and an allelism test confirmed that ZmHMA3 influences maize grain Cd accumulation. A transposon in intron 1 of ZmHMA3 is responsible for the abnormal amino acid sequence in Mo17. Based on the natural sequence variations in the ZmHMA3 gene of diverse maize lines, four PCR-based molecular markers were developed, and these were successfully used to distinguish five haplotypes with different grain Cd contents in the GWAS panel and to predict grain Cd contents of widely used maize inbred lines and hybrids. These molecular markers can be used to breed elite maize varieties with low grain Cd contents.
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http://dx.doi.org/10.1093/jxb/erab254DOI Listing
September 2021

Cord serum elementomics profiling of 56 elements depicts risk of preterm birth: Evidence from a prospective birth cohort in rural Bangladesh.

Environ Int 2021 11 28;156:106731. Epub 2021 Jun 28.

State Key Laboratory of Reproductive Medicine, Nanjing Medical University, Nanjing 211166, China; Department of Biostatistics, School of Public Health, Nanjing Medical University, Nanjing 211166, China; China International Cooperation Center for Environment and Human Health, Center of Global Health, Nanjing Medical University, Nanjing 211166, China.

Maternal exposure to some individual rare earth elements and trace elements is associated with preterm birth, but few elements have been studied and little is known about the potential effect of simultaneous exposure to multiple elements. We examined individual and mixture effects of elements on preterm birth among 745 pregnant women in a prospective birth cohort in Bangladesh (2008-2011). We measured 56 elements in umbilical cord blood collected during delivery using inductively coupled plasma-mass spectrometry. Using elastic net (ENET) regularization and multivariate logistic regression, we examined independent associations between element concentrations and preterm birth. Bayesian kernel machine regression identified mixture effects of elements most critical to preterm birth, accounting for correlated exposure and interaction. ENET identified titanium (Ti), arsenic (As), and barium (Ba) as the most important predictors of shortened gestational age and preterm birth. In adjusted models, cord blood Ti (OR = 2.52; 95% CI: 1.08-5.93; P = 0.033), As (odds ratio (OR) = 1.34; 95% CI: 1.04-1.73; P = 0.023), and Ba (OR = 1.18; 95% CI: 1.02-1.38; P = 0.029) were significantly associated with preterm birth. Bayesian kernel machine regression suggested an interaction effect between As and Ba. Further, we constructed an element risk score (ERS) using estimated weights from a multivariate regression model for Ti, As, and Ba and regressed preterm birth by this score (OR = 2.72, 95% CI: 1.57-4.69; P = 3.35 × 10). Additionally, we observed a significant modification effect of child marriage on ERS, which means marriage before the age of 18 (P = 0.0438). This study identified element exposures profiles in cord blood and constructed metal risk score that are jointly associated with the risk of preterm birth. Ti, As, and Ba exposure may adversely affect birth outcomes as well as child marriage may be a modifiable factor potentially affecting environmental element exposure and preterm birth.
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http://dx.doi.org/10.1016/j.envint.2021.106731DOI Listing
November 2021

A predictive paradigm for COVID-19 prognosis based on the longitudinal measure of biomarkers.

Brief Bioinform 2021 Jun 3. Epub 2021 Jun 3.

Department of Biostatistics, School of Public Health, Nanjing Medical University, Nanjing, Jiangsu, China, 211166.

Novel coronavirus disease 2019 (COVID-19) is an emerging, rapidly evolving crisis, and the ability to predict prognosis for individual COVID-19 patient is important for guiding treatment. Laboratory examinations were repeatedly measured during hospitalization for COVID-19 patients, which provide the possibility for the individualized early prediction of prognosis. However, previous studies mainly focused on risk prediction based on laboratory measurements at one time point, ignoring disease progression and changes of biomarkers over time. By using historical regression trees (HTREEs), a novel machine learning method, and joint modeling technique, we modeled the longitudinal trajectories of laboratory biomarkers and made dynamically predictions on individual prognosis for 1997 COVID-19 patients. In the discovery phase, based on 358 COVID-19 patients admitted between 10 January and 18 February 2020 from Tongji Hospital, HTREE model identified a set of important variables including 14 prognostic biomarkers. With the trajectories of those biomarkers through 5-day, 10-day and 15-day, the joint model had a good performance in discriminating the survived and deceased COVID-19 patients (mean AUCs of 88.81, 84.81 and 85.62% for the discovery set). The predictive model was successfully validated in two independent datasets (mean AUCs of 87.61, 87.55 and 87.03% for validation the first dataset including 112 patients, 94.97, 95.78 and 94.63% for the second validation dataset including 1527 patients, respectively). In conclusion, our study identified important biomarkers associated with the prognosis of COVID-19 patients, characterized the time-to-event process and obtained dynamic predictions at the individual level.
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http://dx.doi.org/10.1093/bib/bbab206DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8195146PMC
June 2021

A multi-omics study links TNS3 and SEPT7 to long-term former smoking NSCLC survival.

NPJ Precis Oncol 2021 May 17;5(1):39. Epub 2021 May 17.

Department of Environmental Health, Harvard T.H. Chan School of Public Health, Harvard University, Boston, MA, 02115, USA.

The genetic architecture of non-small cell lung cancer (NSCLC) is relevant to smoking status. However, the genetic contribution of long-term smoking cessation to the prognosis of NSCLC patients remains largely unknown. We conducted a genome-wide association study primarily on the prognosis of 1299 NSCLC patients of long-term former smokers from independent discovery (n = 566) and validation (n = 733) sets, and used in-silico function prediction and multi-omics analysis to identify single nucleotide polymorphisms (SNPs) on prognostics with NSCLC. We further detected SNPs with at least moderate association strength on survival within each group of never, short-term former, long-term former, and current smokers, and compared their genetic similarity at the SNP, gene, expression quantitative trait loci (eQTL), enhancer, and pathway levels. We identified two SNPs, rs34211819 at 7p12.3 (P = 3.90 × 10) and rs1143149 at 7p14.2 (P = 9.75 × 10), were significantly associated with survival of NSCLC patients who were long-term former smokers. Both SNPs had significant interaction effects with years of smoking cessation (rs34211819: P = 8.0 × 10; rs1143149: P = 0.003). In addition, in silico function prediction and multi-omics analysis provided evidence that these QTLs were associated with survival. Moreover, comparison analysis found higher genetic similarity between long-term former smokers and never-smokers, compared to short-term former smokers or current smokers. Pathway enrichment analysis indicated a unique pattern among long-term former smokers that was related to immune pathways. This study provides important insights into the genetic architecture associated with long-term former smoking NSCLC.
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http://dx.doi.org/10.1038/s41698-021-00182-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8128887PMC
May 2021

The genetic mechanism of heterosis utilization in maize improvement.

Genome Biol 2021 05 10;22(1):148. Epub 2021 May 10.

National Key Laboratory of Crop Genetic Improvement, Huazhong Agricultural University, Wuhan, 430070, China.

Background: In maize hybrid breeding, complementary pools of parental lines with reshuffled genetic variants are established for superior hybrid performance. To comprehensively decipher the genetics of heterosis, we present a new design of multiple linked F1 populations with 42,840 F1 maize hybrids, generated by crossing a synthetic population of 1428 maternal lines with 30 elite testers from diverse genetic backgrounds and phenotyped for agronomic traits.

Results: We show that, although yield heterosis is correlated with the widespread, minor-effect epistatic QTLs, it may be resulted from a few major-effect additive and dominant QTLs in early developmental stages. Floral transition is probably one critical stage for heterosis formation, in which epistatic QTLs are activated by paternal contributions of alleles that counteract the recessive, deleterious maternal alleles. These deleterious alleles, while rare, epistatically repress other favorable QTLs. We demonstrate this with one example, showing that Brachytic2 represses the Ubiquitin3 locus in the maternal lines; in hybrids, the paternal allele alleviates this repression, which in turn recovers the height of the plant and enhances the weight of the ear. Finally, we propose a molecular design breeding by manipulating key genes underlying the transition from vegetative-to-reproductive growth.

Conclusion: The new population design is used to dissect the genetic basis of heterosis which accelerates maize molecular design breeding by diminishing deleterious epistatic interactions.
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http://dx.doi.org/10.1186/s13059-021-02370-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8108465PMC
May 2021

Genome-wide identification, characterization, and expression analysis of the monovalent cation-proton antiporter superfamily in maize, and functional analysis of its role in salt tolerance.

Genomics 2021 Jul 23;113(4):1940-1951. Epub 2021 Apr 23.

Beijing Key Laboratory of Maize DNA Fingerprinting and Molecular Breeding, Maize Research Center, Beijing Academy of Agriculture and Forestry Sciences (BAAFS), Beijing 100079, China. Electronic address:

Na, K and pH homeostasis are important for plant life and they are controlled by the monovalent cation proton antiporter (CPA) superfamily. The roles of ZmCPAs in salt tolerance are not fully elucidated. In this study, we identified 35 ZmCPAs comprising 13 Na/H exchangers (ZmNHXs), 16 cation/H exchanger (ZmCHXs), and 6 K efflux antiporters (ZmKEAs). All ZmCPAs have transmembrane domains and most of them were localized to plasma membrane or tonoplast. ZmCHXs were specifically highly expressed in anthers, while ZmNHXs and ZmKEAs showed high expression in various tissues. ZmNHX5 and ZmKEA2 were up-regulated in maize seedlings under both NaCl and KCl stresses. Yeast complementation experiments revealed the roles of ZmNHX5, ZmKEA2 in NaCl tolerance. Analysis of the maize mutants further validated the salt tolerance functions of ZmNHX5 and ZmKEA2. Our study highlights comprehensive information of ZmCPAs and provides new gene targets for salt tolerance maize breeding.
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http://dx.doi.org/10.1016/j.ygeno.2021.04.032DOI Listing
July 2021

Mendelian Randomization With Refined Instrumental Variables From Genetic Score Improves Accuracy and Reduces Bias.

Front Genet 2021 17;12:618829. Epub 2021 Mar 17.

Department of Biostatistics, Center for Global Health, School of Public Health, Nanjing Medical University, Nanjing, China.

Mendelian randomization (MR) can estimate the causal effect for a risk factor on a complex disease using genetic variants as instrument variables (IVs). A variety of generalized MR methods have been proposed to integrate results arising from multiple IVs in order to increase power. One of the methods constructs the genetic score (GS) by a linear combination of the multiple IVs using the multiple regression model, which was applied in medical researches broadly. However, GS-based MR requires individual-level data, which greatly limit its application in clinical research. We propose an alternative method called Mendelian Randomization with Refined Instrumental Variable from Genetic Score (MR-RIVER) to construct a genetic IV by integrating multiple genetic variants based on summarized results, rather than individual data. Compared with inverse-variance weighted (IVW) and generalized summary-data-based Mendelian randomization (GSMR), MR-RIVER maintained the type I error, while possessing more statistical power than the competing methods. MR-RIVER also presented smaller biases and mean squared errors, compared to the IVW and GSMR. We further applied the proposed method to estimate the effects of blood metabolites on educational attainment, by integrating results from several publicly available resources. MR-RIVER provided robust results under different LD prune criteria and identified three metabolites associated with years of schooling and additional 15 metabolites with indirect mediation effects through butyrylcarnitine. MR-RIVER, which extends score-based MR to summarized results in lieu of individual data and incorporates multiple correlated IVs, provided a more accurate and powerful means for the discovery of novel risk factors.
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http://dx.doi.org/10.3389/fgene.2021.618829DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8044958PMC
March 2021

Comprehensive analyses of m6A regulators and interactive coding and non-coding RNAs across 32 cancer types.

Mol Cancer 2021 04 13;20(1):67. Epub 2021 Apr 13.

State Key Laboratory of Reproductive Medicine, Nanjing Medical University, Nanjing, 211166, China.

N6-Methyladenosine (m6A) is an RNA modification that interacts with numerous coding and non-coding RNAs and plays important roles in the development of cancers. Nonetheless, the clinical impacts of m6A interactive genes on these cancers largely remain unclear since most studies focus only on a single cancer type. We comprehensively evaluated m6A modification patterns, including 23 m6A regulators and 83 interactive coding and non-coding RNAs among 9,804 pan-cancer samples. We used clustering analysis to identify m6A subtypes and constructed the m6A signature based on an unsupervised approach. We used the signatures to identify potential m6A modification targets across the genome. The prognostic value of one target was further validated in 3,444 samples from six external datasets. We developed three distinct m6A modification subtypes with different tumor microenvironment cell infiltration degrees: immunological, intermediate, and tumor proliferative. They were significantly associated with overall survival in 24 of 27 cancer types. Our constructed individual-level m6A signature was associated with survival, tumor mutation burden, and classical pathways. With the signature, we identified 114 novel genes as potential m6A targets. The gene shared most commonly between cancer types, BCL9L, is an oncogene and interacts with m6A patterns in the Wnt signaling pathway. In conclusion, m6A regulators and their interactive genes impact the outcome of various cancers. Evaluating the m6A subtype and the signature of individual tumors may inform the design of adjuvant treatments.
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http://dx.doi.org/10.1186/s12943-021-01362-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8045265PMC
April 2021

Child marriage, maternal serum metal exposure, and risk of preterm birth in rural Bangladesh: evidence from mediation analysis.

J Expo Sci Environ Epidemiol 2021 05 6;31(3):571-580. Epub 2021 Apr 6.

State Key Laboratory of Reproductive Medicine, Nanjing Medical University, Nanjing, China.

Background: The prevalence of preterm birth in Bangladesh is estimated to be 19.1%, the highest in the world. Although prenatal exposure to several metals has been linked with preterm birth, fewer prospective studies have investigated the socioeconomic factors that affect metal exposure, leading to preterm birth risk.

Objective: We aim to identify novel metal biomarkers and their critical exposure windows, as well as the upstream socioeconomic risk factors for preterm birth in rural Bangladeshi, to shed light for future interventional strategies.

Methods: This study included data from 780 mother-offspring pairs, who were recruited to participate in a prospective birth cohort in Bangladesh (2008-2011). Serum concentrations of 19 metals were measured in the first and second trimesters using inductively coupled plasma mass spectrometry. Mediation analysis was performed to explore the upstream socioeconomic factors that affect the risk of preterm birth mediated via metal exposure concentrations.

Results: Early pregnancy exposure to serum zinc, arsenic, and strontium and mid-pregnancy exposure to barium were significantly associated with risk of preterm birth. Furthermore, younger marriage age was associated with an exponential increase in the risk of preterm birth, and women who married after 18 years old had a considerably lower risk of preterm birth. Mediation analysis indicated that these four elements mediated 30.2% of the effect of marriage age on preterm birth.

Conclusion: This study indicated that maternal serum metal exposure mediates the impact of child marriage on the increased risk of preterm birth via metal exposures. The findings shed light on the mechanisms underlying such association and provide insights into future interventional strategies.
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http://dx.doi.org/10.1038/s41370-021-00319-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8134042PMC
May 2021

Association between aspirin use and lung cancer incidence depends on high-frequency use, bodyweight, and age in U.S. adults.

Transl Lung Cancer Res 2021 Jan;10(1):392-401

Department of Environmental Health, Harvard T.H. Chan School of Public Health, Boston, MA, USA.

Background: Chemoprevention of cancer with aspirin is controversial as a primary prevention strategy. We sought to investigate the association between aspirin frequency and risk of lung cancer in The Prostate, Lung, Colorectal and Ovarian (PLCO) Cancer Screening Trial.

Methods: Using data from 101,722 participants in PLCO, we used a Cox regression model coupling with propensity score to detect the association between aspirin frequency and lung cancer risk.

Results: High-frequency aspirin use significantly increased risk of lung cancer by 28% compared to no use (HR =1.28; 95% CI, 1.14-1.45; P=3.37×10), especially for current smoker (HR =1.30; 95% CI, 1.07-1.57; P=6.82×10). However, the increased lung cancer risk due to high-frequency aspirin use significantly decreased with increasing bodyweight (HR =0.96; 95% CI, 0.94-0.99; P=1.26×10). Further, for participants with bodyweight <80 kg, high-frequency aspirin use showed an elevated risk at <76 years of age (HR =1.47; 95% CI, 1.25-1.73; P=3.81×10). Our study used propensity score under various confounding and stratification analyses by cardio-cerebrovascular status, which all presented similar evidences.

Conclusions: High-frequency aspirin use is associated with the increased risk of lung cancer. Current smoker or people with age <76 years and bodyweight <80 kg should be more cautious to high-frequency aspirin use for lung cancer chemoprevention. This study provides a new insight for lung cancer chemoprevention.
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http://dx.doi.org/10.21037/tlcr-20-414DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7867785PMC
January 2021

Association of Serum Mannose With Acute Respiratory Distress Syndrome Risk and Survival.

JAMA Netw Open 2021 01 4;4(1):e2034569. Epub 2021 Jan 4.

Department of Environmental Health, Harvard T.H. Chan School of Public Health, Boston, Massachusetts.

Importance: Acute respiratory distress syndrome (ARDS) confers high mortality risk among critically ill patients. Identification of biomarkers associated with ARDS risk may guide clinical diagnosis and prognosis.

Objective: To systematically evaluate the association of blood metabolites with ARDS risk and survival.

Design, Setting, And Participants: In this cohort study, data from the Molecular Epidemiology of ARDS (MEARDS) study, a prospective cohort of 403 patients with ARDS and 1227 non-ARDS controls, were analyzed. Patients were recruited in intensive care units (ICUs) at Massachusetts General Hospital and Beth Israel Deaconess Medical Center, both in Boston, Massachusetts, from January 1, 1998, to December 31, 2014. Data analysis was performed from December 9, 2018, to January 4, 2019.

Main Outcomes And Measures: Participants were followed up daily for ARDS development defined by Berlin criteria, requiring fulfillment of chest radiograph and oxygenation criteria on the same calendar day during invasive ventilatory assistance. A 2-stage study design was used to explore novel metabolites associated with ARDS risk and survival.

Results: Of the 1630 participants from MEARDS who were admitted to the ICU , 403 (24.7%) were diagnosed with ARDS (mean [SD] age, 63.0 [17.0] years; 251 [62.3%] male) and 1227 (75.3%) were at-risk but did not have ARDS (mean [SD] age, 62.3 [16.9] years; 753 [61.4%] male). Mendelian randomization suggested that genetically regulated serum mannose was associated with ARDS risk (odds ratio [OR], 0.64; 95% CI, 0.53-0.78; P = 7.46 × 10-6) in the discovery stage. In the functional validation stage incorporating 83 participants with ARDS and matched at-risk participants in the control group from the ICU, the protective association of mannose with ARDS risk was validated (OR, 0.67; 95% CI, 0.46-0.97; P = .03). Furthermore, serum mannose was associated with 28-day (OR, 0.25; 95% CI, 0.11-0.56; P = 6.95 × 10-4) and 60-day (OR, 0.36; 95% CI, 0.19-0.71; P = 3.12 × 10-3) mortality and 28-day (hazard ratio, 0.49; 95% CI, 0.32-0.74; P = 6.41 × 10-4) and 60-day (hazard ratio, 0.55; 95% CI, 0.37-0.80; P = 2.11 × 10-3) survival.

Conclusions And Relevance: In this study, genetically regulated serum mannose appeared to be associated with ARDS risk and outcome, and increased serum mannose at admission was associated with reduced ARDS risk and better survival. These findings could inform prevention and clinical intervention in ARDS cases, which have increased with the expansion of the coronavirus disease 2019 pandemic.
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http://dx.doi.org/10.1001/jamanetworkopen.2020.34569DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7841460PMC
January 2021

Epigenetic-smoking interaction reveals histologically heterogeneous effects of TRIM27 DNA methylation on overall survival among early-stage NSCLC patients.

Mol Oncol 2020 11 3;14(11):2759-2774. Epub 2020 Sep 3.

Department of Environmental Health, Harvard T.H. Chan School of Public Health, Boston, MA, USA.

Tripartite motif containing 27 (TRIM27) is highly expressed in lung cancer, including non-small-cell lung cancer (NSCLC). Here, we profiled DNA methylation of lung adenocarcinoma (LUAD) and lung squamous cell carcinoma (LUSC) tumours from 613 early-stage NSCLC patients and evaluated associations between CpG methylation of TRIM27 and overall survival. Significant CpG probes were confirmed in 617 samples from The Cancer Genome Atlas. The methylation of the CpG probe cg05293407 was significantly associated with overall survival in patients with LUSC (HR = 1.65, 95% CI: 1.30-2.09, P = 4.52 × 10), but not in patients with LUAD (HR = 1.08, 95% CI: 0.87-1.33, P = 0.493). As incidence of LUSC is associated with higher smoking intensity compared to LUAD, we investigated whether smoking intensity impacted on the prognostic effect of cg05293407 methylation in NSCLC. LUSC patients had a higher average pack-year of smoking (37.49 vs 54.79, P = 1.03 × 10) and included a higher proportion of current smokers than LUAD patients (28.24% vs 34.09%, P = 0.037). cg05293407 was significantly associated with overall survival only in NSCLC patients with medium-high pack-year of smoking (HR = 1.58, 95% CI: 1.26-1.96, P = 5.25 × 10). We conclude that cg05293407 methylation is a potential predictor of LUSC prognosis, and smoking intensity may impact on its prognostic value across the various types of NSCLC.
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http://dx.doi.org/10.1002/1878-0261.12785DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7607178PMC
November 2020

Plasma Insulin-like Growth Factor Binding Protein 7 Contributes Causally to ARDS 28-Day Mortality: Evidence From Multistage Mendelian Randomization.

Chest 2021 03 12;159(3):1007-1018. Epub 2020 Nov 12.

Department of Environmental Health, Harvard T.H. Chan School of Public Health, Boston, MA; Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA; Pulmonary and Critical Care Division, Department of Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, MA. Electronic address:

Background: ARDS is a devastating syndrome with heterogeneous subtypes, but few causal biomarkers have been identified.

Research Question: Would multistage Mendelian randomization identify new causal protein biomarkers for ARDS 28-day mortality?

Study Design And Methods: Three hundred moderate to severe ARDS patients were selected randomly from the Molecular Epidemiology of ARDS cohort for proteomics analysis. Orthogonal projections to latent structures discriminant analysis was applied to detect the association between proteins and ARDS 28-day mortality. Candidate proteins were analyzed using generalized summary data-based Mendelian randomization (GSMR). Protein quantitative trait summary statistics were retrieved from the Efficiency and safety of varying the frequency of whole blood donation (INTERVAL) study (n = 2,504), and a genome-wide association study for ARDS was conducted from the Identification of SNPs Predisposing to Altered Acute Lung Injury Risk (iSPAAR) consortium study (n = 534). Causal mediation analysis detected the role of platelet count in mediating the effect of protein on ARDS prognosis.

Results: Plasma insulin-like growth factor binding protein 7 (IGFBP7) moderately increased ARDS 28-day mortality (OR, 1.11; 95% CI, 1.04-1.19; P = .002) per log2 increase. GSMR analysis coupled with four other Mendelian randomization methods revealed IGFBP7 as a causal biomarker for ARDS 28-day mortality (OR, 2.61; 95% CI, 1.33-5.13; P = .005). Causal mediation analysis indicated that the association between IGFBP7 and ARDS 28-day mortality is mediated by platelet count (OR, 1.03; 95% CI, 1.02-1.04; P = .01).

Interpretation: We identified plasma IGFBP7 as a novel causal protein involved in the pathogenesis of ARDS 28-day mortality and platelet function in ARDS, a topic for further experimental and clinical investigation.
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http://dx.doi.org/10.1016/j.chest.2020.10.074DOI Listing
March 2021

Stalk architecture, cell wall composition, and QTL underlying high stalk flexibility for improved lodging resistance in maize.

BMC Plant Biol 2020 Nov 11;20(1):515. Epub 2020 Nov 11.

Beijing Key Laboratory of Maize DNA Fingerprinting and Molecular Breeding, Maize Research Center, Beijing Academy of Agriculture & Forestry Sciences (BAAFS), Shuguang Garden Middle Road No. 9, Haidian District, Beijing, 100097, China.

Background: Stalk fracture caused by strong wind can severely reduce yields in maize. Stalks with higher stiffness and flexibility will exhibit stronger lodging resistance. However, stalk flexibility is rarely studied in maize. Stalk fracture of the internode above the ear before tasseling will result in the lack of tassel and pollen, which is devastating for pollination in seed production. In this study, we focused on stalk lodging before tasseling in two maize inbred lines, JING724 and its improved line JING724A1 and their F population.

Results: JING724A1 showed a larger stalk fracture angle than JING724, indicating higher flexibility. In addition, compared to JING724, JING724A1 also had longer and thicker stalks, with a conical, frustum-shaped internode above the ear. Microscopy and X-ray microcomputed tomography of the internal stalk architecture revealed that JING724A1 had more vascular bundles and thicker sclerenchyma tissue. Furthermore, total soluble sugar content of JING724A1, especially the glucose component, was substantially higher than in JING724. Using an F population derived from a JING724 and JING724A1 cross, we performed bulk segregant analysis for stalk fracture angle and detected one QTL located on Chr3: 14.00-19.28 Mb. Through transcriptome data analysis and ∆ (SNP-index), we identified two candidate genes significantly associated with high stalk fracture angle, which encode a RING/U-box superfamily protein (Zm00001d039769) and a MADS-box transcription factor 54 (Zm00001d039913), respectively. Two KASP markers designed from these two candidate genes also showed significant correlations with stalk fracture angle.

Conclusions: The internode shape and glucose content are possibly correlated with stalk flexibility in maize. Two genes in the detected QTL are potentially associated with stalk fracture angle. These novel phenotypes and associated loci will provide a theoretical foundation for understanding the genetic mechanisms of lodging, and facilitate the selection of maize varieties with improved flexibility and robust lodging resistance.
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http://dx.doi.org/10.1186/s12870-020-02728-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7659129PMC
November 2020

Effects of zero-valent iron nanoparticles and quinclorac coexposure on the growth and antioxidant system of rice (Oryza sativa L.).

Ecotoxicol Environ Saf 2020 Oct 28;203:111054. Epub 2020 Jul 28.

College of Resources and Environment, Hunan Agricultural University, Changsha, 410128, PR China. Electronic address:

Quinclorac (3,7-dichloroquinoline-8-carboxylic acid, QNC) is a highly selective auxin herbicide that is typically applied to paddy rice fields. Its residue is a serious problem in crop rotations. In this study, Oryza sativa L. seedlings was used as a model plant to explore its biochemical response to abiotic stress caused by QNC and nZVI coexposure, as well as the interactions between QNC and nZVI treatments. Exposure to 5 and 10 mg/L QNC reduced the fresh biomass by 26.6% and 33.9%, respectively, compared to the control. The presence of 50 and 250 mg/L nZVI alleviated the QNC toxicity, but the nZVI toxicity was aggravated by the coexist of QNC. Root length was enhanced upon exposure to low or medium doses of both QNC and nZVI, whereas root length was inhibited under high-dose coexposure. Both nZVI and QNC, either alone or in combination, significantly inhibited the biosynthesis of chlorophyll, and the inhibition rate increased with elevated nZVI and QNC concentration. It was indicated that nZVI or QNC can affect the plant photosynthesis, and there was a significant interaction between the two treatments. Effects of QNC on the antioxidant response of Oryza sativa L. differed in the shoots and roots; generally, the introduction of 50 and 250 mg/L nZVI alleviated the oxidative stress (POD in shoots, SOD and MDA in roots) induced by QNC. However, 750 mg/kg nZVI seriously damaged Oryza sativa L. seedlings, which likely resulted from active iron deficiency. QNC could be removed from the culture solution by nZVI; as a result, nZVI suppressed QNC uptake by 20%-30%.
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http://dx.doi.org/10.1016/j.ecoenv.2020.111054DOI Listing
October 2020

Identification and Fine Mapping of , a Southern Corn Rust Resistance Gene in Maize.

Front Plant Sci 2020 9;11:1057. Epub 2020 Jul 9.

Maize Research Center, Beijing Academy of Agriculture and Forestry Sciences (BAAFS), Beijing Key Laboratory of Maize DNA Fingerprinting and Molecular Breeding, Beijing, China.

Southern corn rust (SCR) caused by Underw. is a major disease causing severe yield losses during maize production. Here, we identified and mapped the SCR resistance gene from the near-isogenic line Kangxiujing2416 (Jing2416K), which harbors in the genetic background of the susceptible inbred line Jing2416. In this study, the inheritance of SCR resistance was investigated in F and F populations derived from a cross between Jing2416K and Jing2416. The observed 3:1 segregation ratio of resistant to susceptible plants indicated that the SCR resistance is controlled by a single dominant gene. Using an F population, we performed bulked segregant analysis (BSA) sequencing and mapped to a 3.69-Mb region on chromosome arm 10S. To further narrow down the region harboring , we developed 13 insertion/deletion (InDel) markers based on the sequencing data. Finally, was mapped to a region spanning 110-kb using susceptible individuals from a large F population. Two genes ( and ) encoding putative CC-NBS-LRR (coiled-coiled, nucleotide-binding site, and leucine-rich repeat) proteins, a common characteristic of R genes, were located in this region (B73 RefGen_v4 reference genome). Sequencing and comparison of the two genes cloned from Jing2416K and Jing2416 revealed sequence variations in their coding regions. The relative expression levels of these two genes in Jing2416K were found to be significantly higher than those in Jing2416. and are thus potential candidates.
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http://dx.doi.org/10.3389/fpls.2020.01057DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7363983PMC
July 2020

Epigenome-wide gene-age interaction analysis reveals reversed effects of DNA methylation on survival between young and elderly early-stage NSCLC patients.

Aging (Albany NY) 2020 06 8;12(11):10642-10662. Epub 2020 Jun 8.

Department of Environmental Health, Harvard T.H. Chan School of Public Health, Boston, MA 02115, USA.

DNA methylation changes during aging, but it remains unclear whether the effect of DNA methylation on lung cancer survival varies with age. Such an effect could decrease prediction accuracy and treatment efficacy. We performed a methylation-age interaction analysis using 1,230 early-stage lung adenocarcinoma patients from five cohorts. A Cox proportional hazards model was used to investigate lung adenocarcinoma and squamous cell carcinoma patients for methylation-age interactions, which were further confirmed in a validation phase. We identified one adenocarcinoma-specific CpG probe, cg14326354, with effects significantly modified by age ( = 0.989; 95% CI: 0.986-0.994; = 9.18×10-7). The effect of low methylation was reversed for young and elderly patients categorized by the boundary of 95% CI standard ( = 2.44; 95% CI: 1.26-4.72; = 8.34×10-3; = 0.58; 95% CI: 0.42-0.82; = 1.67×10-3). Moreover, there was an antagonistic interaction between low cg14326354 methylation and elderly age ( = 0.21; 95% CI: 0.11-0.40; = 2.20×10-6). In summary, low methylation of cg14326354PRODH might benefit survival of elderly lung adenocarcinoma patients, providing new insight to age-specific prediction and potential drug targeting.
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http://dx.doi.org/10.18632/aging.103284DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7346054PMC
June 2020

Protein-altering germline mutations implicate novel genes related to lung cancer development.

Nat Commun 2020 05 11;11(1):2220. Epub 2020 May 11.

Radboud University Medical Center, Radboud Institute for Health Sciences, Nijmegen, The Netherlands.

Few germline mutations are known to affect lung cancer risk. We performed analyses of rare variants from 39,146 individuals of European ancestry and investigated gene expression levels in 7,773 samples. We find a large-effect association with an ATM L2307F (rs56009889) mutation in adenocarcinoma for discovery (adjusted Odds Ratio = 8.82, P = 1.18 × 10) and replication (adjusted OR = 2.93, P = 2.22 × 10) that is more pronounced in females (adjusted OR = 6.81 and 3.19 and for discovery and replication). We observe an excess loss of heterozygosity in lung tumors among ATM L2307F allele carriers. L2307F is more frequent (4%) among Ashkenazi Jewish populations. We also observe an association in discovery (adjusted OR = 2.61, P = 7.98 × 10) and replication datasets (adjusted OR = 1.55, P = 0.06) with a loss-of-function mutation, Q4X (rs150665432) of an uncharacterized gene, KIAA0930. Our findings implicate germline genetic variants in ATM with lung cancer susceptibility and suggest KIAA0930 as a novel candidate gene for lung cancer risk.
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http://dx.doi.org/10.1038/s41467-020-15905-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7214407PMC
May 2020

Identification of genetic features associated with fine particulate matter (PM2.5) modulated DNA damage using improved random forest analysis.

Gene 2020 May 9;740:144570. Epub 2020 Mar 9.

Department of Biostatistics, School of Public Health, Nanjing Medical University, Nanjing 211166, China; China International Cooperation Center (CICC) for Environment and Human Health, Nanjing Medical University, Nanjing 211166, China. Electronic address:

Recent studies have found multiple single nucleotide variants (SNVs) associated with DNA damage. However, previous association analysis may ignore the potential interaction effects between SNVs. Therefore, we used an improved random forest (RF) analysis to identify the SNVs related to personal DNA damage in exon-focused genome-wide association study (GWAS). A total of 301 subjects from three independent centers (Zhuhai, Wuhan, and Tianjin) were retained for analysis. An improved RF procedure was used to systematically screen key SNVs associated with DNA damage. Furthermore, we used genetic risk score (GRS) and mediation analysis to investigate the integrative effect and potential mechanism of these genetic variants on DNA damage. Besides, gene set enrichment analysis was conducted to identify the pathways enriched by key SNVs using the Data-driven Expression Prioritized Integration for Complex Traits (DEPICT). Finally, a set of 24 SNVs with the lowest mean square errors (MSE) were identified by improved RF analysis. Both weighted and unweighted GRSs were associated with increased DNA damage levels (P < 0.001 and P < 0.001). Gene set enrichment analysis indicated that these loci were significantly enriched in several biological features associated with DNA damage. These findings suggested the role of SNVs in modifying DNA damage levels. It may be convincing that this improved RF analysis can effectively identify SNVs associated with DNA damage levels.
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http://dx.doi.org/10.1016/j.gene.2020.144570DOI Listing
May 2020

Independent Validation of Early-Stage Non-Small Cell Lung Cancer Prognostic Scores Incorporating Epigenetic and Transcriptional Biomarkers With Gene-Gene Interactions and Main Effects.

Chest 2020 08 28;158(2):808-819. Epub 2020 Feb 28.

Department of Environmental Health, Harvard T. H. Chan School of Public Health, Boston, MA; Pulmonary and Critical Care Division, Department of Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, MA.

Background: DNA methylation and gene expression are promising biomarkers of various cancers, including non-small cell lung cancer (NSCLC). Besides the main effects of biomarkers, the progression of complex diseases is also influenced by gene-gene (G×G) interactions.

Research Question: Would screening the functional capacity of biomarkers on the basis of main effects or interactions, using multiomics data, improve the accuracy of cancer prognosis?

Study Design And Methods: Biomarker screening and model validation were used to construct and validate a prognostic prediction model. NSCLC prognosis-associated biomarkers were identified on the basis of either their main effects or interactions with two types of omics data. A prognostic score incorporating epigenetic and transcriptional biomarkers, as well as clinical information, was independently validated.

Results: Twenty-six pairs of biomarkers with G×G interactions and two biomarkers with main effects were significantly associated with NSCLC survival. Compared with a model using clinical information only, the accuracy of the epigenetic and transcriptional biomarker-based prognostic model, measured by area under the receiver operating characteristic curve (AUC), increased by 35.38% (95% CI, 27.09%-42.17%; P = 5.10 × 10) and 34.85% (95% CI, 26.33%-41.87%; P = 2.52 × 10) for 3- and 5-year survival, respectively, which exhibited a superior predictive ability for NSCLC survival (AUC, 0.88 [95% CI, 0.83-0.93]; and AUC, 0.89 [95% CI, 0.83-0.93]) in an independent Cancer Genome Atlas population. G×G interactions contributed a 65.2% and 91.3% increase in prediction accuracy for 3- and 5-year survival, respectively.

Interpretation: The integration of epigenetic and transcriptional biomarkers with main effects and G×G interactions significantly improves the accuracy of prognostic prediction of early-stage NSCLC survival.
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http://dx.doi.org/10.1016/j.chest.2020.01.048DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7417380PMC
August 2020

An endophytic strain of the genus Bacillus isolated from the seeds of maize (Zea mays L.) has antagonistic activity against maize pathogenic strains.

Microb Pathog 2020 Feb 24;142:104074. Epub 2020 Feb 24.

School of Chemistry and Biological Engineering, University of Science and Technology Beijing, Beijing, 100083, China. Electronic address:

Plant endophytes are microbes that colonize plant internal tissues and are ubiquitously associated with plants. In this study, seven endophytic bacterial strains, 665L2, 725L2, 725R2, 92R2, 728R3, 728R4 and 2416T3, were isolated from seeds of five healthy maize varieties (Zea mays L.) and all identified as Bacillus velezensis by polyphasic taxonomy based on 16S rRNA and gyrA gene phylogenetic analysis. In addition, according to the genotyping results from random amplified polymorphic DNA (RAPD), 665L2, 725L2, 725R2 and 92R2 belonged to the same strain, while 728R3 and 2416T3 belonged to another strain. Pathogenic fungal strains 4, 5 and 6 were isolated from three diseased maize varieties (Zea mays L.), and they were identified as Talaromyces funiculosus, Penicillium oxalicum and Fusarium verticillioides, respectively, by polyphasic taxonomy based on morphological identification, ITS rDNA and bio-control gene phylogenetic analyses. Seven endophytic bacterial Bacillus velezensis strains had favourable antagonistic activity, and antagonistic testing was carried out against the three pathogenic strains, Talaromyces funiculosus 4, Penicillium oxalicum 5 and Fusarium verticillioides 6. Biological control lipopeptide antibiotic genes (bioA, bmyB, ituC, fenD, srfAA, srfAB, yngG and yndJ) were amplified using specific primers, and they were found in the seven endophytic bacterial Bacillus velezensis strains. This study provides a scientific basis for future research on the use of resistant endophytic bacterial resources to enhance crop production.
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http://dx.doi.org/10.1016/j.micpath.2020.104074DOI Listing
February 2020

CUBIC: an atlas of genetic architecture promises directed maize improvement.

Genome Biol 2020 01 24;21(1):20. Epub 2020 Jan 24.

National Key Laboratory of Crop Genetic Improvement, Huazhong Agricultural University, Wuhan, 430070, China.

Background: Identifying genotype-phenotype links and causative genes from quantitative trait loci (QTL) is challenging for complex agronomically important traits. To accelerate maize gene discovery and breeding, we present the Complete-diallel design plus Unbalanced Breeding-like Inter-Cross (CUBIC) population, consisting of 1404 individuals created by extensively inter-crossing 24 widely used Chinese maize founders.

Results: Hundreds of QTL for 23 agronomic traits are uncovered with 14 million high-quality SNPs and a high-resolution identity-by-descent map, which account for an average of 75% of the heritability for each trait. We find epistasis contributes to phenotypic variance widely. Integrative cross-population analysis and cross-omics mapping allow effective and rapid discovery of underlying genes, validated here with a case study on leaf width.

Conclusions: Through the integration of experimental genetics and genomics, our study provides useful resources and gene mining strategies to explore complex quantitative traits.
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http://dx.doi.org/10.1186/s13059-020-1930-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6979394PMC
January 2020

Investigating the endophytic bacterial diversity and community structures in seeds of genetically related maize ( L.) genotypes.

3 Biotech 2020 Jan 4;10(1):27. Epub 2020 Jan 4.

3Maize Research Center, Beijing Academy of Agriculture and Forestry Sciences, Beijing, 100097 China.

This research aimed to investigate the composition and diversity of endophytic bacterial community in seeds of four hybrid maize and their parental lines, which was used to reveal the potential relationship and association of endophytic bacteria between maize genotypes and their genetic relevance. High-throughput sequencing (HTS) technology showed that a total of 1419 OTUs (46.6%) were parental lines unique and 1052 OTUs (34.5%) were hybrid varieties unique, with only 575 core OTUs revealed in all the samples. Most OTUs belonged to . (23.2%), (21.2%), (15.8%) and (10.1%) were the major genera; the bacterial community composition and diversity of endophytic bacteria were inconsistent among different seed genotypes. Based on principal component analysis (PCA), the results referred that the endophytic composition of hybrid sample showed obvious correlation with their female parental lines, and in 'Jingke968' and 'MC738' with the same female line the endophytic community was more similar than other hybrid samples. This was the first ever use of HTS technology for investigating the endophytic bacterial diversity and community structures in seeds of genetically related maize genotypes, it was shown that, there were core microbes shared among all genotypes of seed samples, and the female parental line was more significant to impact on the composition of their hybrid seeds than male parental line. This study would provide scientific clues for the future research on the vertical transmission of endophytes among maize generations.
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http://dx.doi.org/10.1007/s13205-019-2034-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6942555PMC
January 2020

shinyBN: an online application for interactive Bayesian network inference and visualization.

BMC Bioinformatics 2019 Dec 16;20(1):711. Epub 2019 Dec 16.

Department of Biostatistics, School of Public Health, State Key Laboratory of Reproductive Medicine, Nanjing Medical University, Nanjing, China.

Background: High-throughput technologies have brought tremendous changes to biological domains, and the resulting high-dimensional data has also posed enormous challenges to computational science. A Bayesian network is a probabilistic graphical model represented by a directed acyclic graph, which provides concise semantics to describe the relationship between entities and has an independence assumption that is suitable for sparse omics data. Bayesian networks have been broadly used in biomedical research fields, including disease risk assessment and prognostic prediction. However, the inference and visualization of Bayesian networks are unfriendly to the users lacking programming skills.

Results: We developed an R/Shiny application, shinyBN, which is an online graphical user interface to facilitate the inference and visualization of Bayesian networks. shinyBN supports multiple types of input and provides flexible settings for network rendering and inference. For output, users can download network plots, prediction results and external validation results in publication-ready high-resolution figures.

Conclusion: Our user-friendly application (shinyBN) provides users with an easy method for Bayesian network modeling, inference and visualization via mouse clicks. shinyBN can be used in the R environment or online and is compatible with three major operating systems, including Windows, Linux and Mac OS. shinyBN is deployed at https://jiajin.shinyapps.io/shinyBN/. Source codes and the manual are freely available at https://github.com/JiajinChen/shinyBN.
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http://dx.doi.org/10.1186/s12859-019-3309-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6916222PMC
December 2019

Trans-omics biomarker model improves prognostic prediction accuracy for early-stage lung adenocarcinoma.

Aging (Albany NY) 2019 08 21;11(16):6312-6335. Epub 2019 Aug 21.

Department of Environmental Health, Harvard T.H. Chan School of Public Health, Boston, MA 02115, USA.

Limited studies have focused on developing prognostic models with trans-omics biomarkers for early-stage lung adenocarcinoma (LUAD). We performed integrative analysis of clinical information, DNA methylation, and gene expression data using 825 early-stage LUAD patients from 5 cohorts. Ranger algorithm was used to screen prognosis-associated biomarkers, which were confirmed with a validation phase. Clinical and biomarker information was fused using an iCluster plus algorithm, which significantly distinguished patients into high- and low-mortality risk groups ( = 0.01 and = 2.71×10). Further, potential functional DNA methylation-gene expression-overall survival pathways were evaluated by causal mediation analysis. The effect of DNA methylation level on LUAD survival was significantly mediated through gene expression level. By adding DNA methylation and gene expression biomarkers to a model of only clinical data, the AUCs of the trans-omics model improved by 18.3% (to 87.2%) and 16.4% (to 85.3%) in discovery and validation phases, respectively. Further, concordance index of the nomogram was 0.81 and 0.77 in discovery and validation phases, respectively. Based on systematic review of published literatures, our model was superior to all existing models for early-stage LUAD. In summary, our trans-omics model may help physicians accurately identify patients with high mortality risk.
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http://dx.doi.org/10.18632/aging.102189DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6738411PMC
August 2019

Biomass fuel as a risk factor for esophageal squamous cell carcinoma: a systematic review and meta-analysis.

Environ Health 2019 07 1;18(1):60. Epub 2019 Jul 1.

Harvard Medical School, Boston, MA, USA.

Background: The link between use of solid biomass fuel (wood, charcoal, coal, dung, and crop residues) for cooking and/or heating and esophageal squamous cell carcinoma (ESCC) is inconclusive.

Objective: We systematically reviewed the literature and performed a meta-analysis to determine whether cooking fuel type influences esophageal squamous cell carcinoma.

Methods: We searched MEDLINE, EMBASE, Web of Knowledge and Cochrane Database of Systematic Reviews for studies investigating cooking fuel and ESCC from 2000 until March 2019. We performed random effects meta-analysis stratified by the continent, World Bank's country income classifications and fuel type and calculated pooled odds ratios and 95% CIs for the risk of esophageal squamous cell carcinoma in biomass fuel users compared with non-users.

Results: Our analysis included 16 studies (all case-control) with 16,189 participants (5233 cases and 10,956 controls) that compared risk of ESCC among those using nonsolid fuels and biomass fuels. We found use of biomass fuel was associated with Esophageal squamous cell carcinoma with a pooled odds ratio (OR) 3.02 (95% CI 2.22, 4.11, heterogeneity (I) = 79%). In sub-group analyses by continent, Africa (OR 3.35, 95%CI 2.34, 4.80, I = 73.4%) and Asia (OR 3.08, 95%CI 1.27, 7.43, I = 81.7%) had the highest odds of ESCC. Use of wood as fuel had the highest odds of 3.90, 95% CI 2.25, 6.77, I = 63.5%). No significant publication bias was detected.

Conclusions: Biomass fuel is associated with increased risk of Esophageal squamous cell carcinoma. Biomass fuel status should be considered in the risk assessment for Esophageal squamous cell carcinoma.
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http://dx.doi.org/10.1186/s12940-019-0496-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6604279PMC
July 2019

Multi-omics analysis of the development and fracture resistance for maize internode.

Sci Rep 2019 06 3;9(1):8183. Epub 2019 Jun 3.

Beijing Key Laboratory of Maize DNA Fingerprinting and Molecular Breeding, Maize Research Center, Beijing Academy of Agriculture and Forestry Sciences, Shuguang Huayuan Middle Road, Haidian District, No. 9, Beijing, 100097, China.

The maize stalk is an important mechanical supporting tissue. The stalk fracture resistance is closely related to lodging resistance, and thus the yield. In this study, we showed that the basal zone (BZ) was more fragile than the middle zone (MZ) of the stalk internode before tasseling. In order to clarify the relationship between the different zones and fragile resistance between the internodes, we systematically analyzed the phenotypic, metabolomic and transcriptomic differences. The results indicated that the BZ zone had lower stalk strength, which corresponded to the results of less lignin, cellulose and hemicellulose than that of the MZ. The 27 highly enriched metabolites and 4430 highly expressed genes in the BZ mainly participated in pentose phosphate, and in ribosome and sterol synthesis pathways, respectively. In addition, the BZ had higher vascular bundles density but smaller size compared with the MZ. By contrast, the 28 highly enriched known metabolites and 4438 highly expressed genes in the MZ were mainly involved in lignin synthesis, and secondary metabolites synthesis, respectively, especially the phenylpropanoid synthesis. The results provide a deeper understanding of the relationship between development and fracture differences in stalk, and may facilitate the improvement of field management practice to reduce lodging.
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http://dx.doi.org/10.1038/s41598-019-44690-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6547879PMC
June 2019
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