Survival and disease burden analyses of occupational pneumoconiosis during 1958-2021 in Huangshi city, China: a retrospective cohort study.

BACKGROUND: Pneumoconiosis, a chronic disease stemming from prolonged inhalation of dust particles, stands as a significant global burden of occupational diseases. This study aims to investigate the survival outcomes of pneumoconiosis patients in Huangshi city, China, while also evaluating the disease burden on afflicted patients. METHODS: Data for this study were sourced from the Huangshi Center for Disease Control and Prevention. Survival analyses of pneumoconiosis patients were conducted employing life tables and the Kaplan-Meier method. The Cox proportional hazards models were deployed to identify factors influencing pneumoconiosis patients' survival duration. Competing risks models were employed to confirm the validity of the model outcomes. Additionally, in the disease burden assessment, disability-adjusted life years (DALYs) were computed for various demographic groups and time frames. RESULTS: A total of 5,641 pneumoconiosis cases, diagnosed in Huangshi City, Hubei Province between 1958 and 2021, were incorporated into the cohort analysis. The probability of mortality and the risk ratio increased with advancing age. Notably, the median survival time of stage III pneumoconiosis patients was significantly shorter compared with those in stages I and II. The Cox proportional hazards model and competing risks analyses underscored several significant factors influencing survival time, including dust exposure duration (HR = 1.197, 95% CI: 1.104-1.298), age at first diagnosis (HR = 3.149, 95% CI: 2.961-3.349), presence of silicosis (HR = 1.378, 95% CI: 1.254-1.515), and stage II-III pneumoconiosis (HR = 1.456, 95% CI: 1.148-1.848). Cumulatively, DALYs amounted to 7,974.35 person-years, with an average of 1.41 person-years. The period between 2000 and 2019 witnessed the highest disease burden. CONCLUSION: Our findings highlight the urgent need for improved prevention, earlier detection, and more effective management strategies for the occupational pneumoconiosis population. This study not only underscores the persistent issue of pneumoconiosis in industrial environments but also serves as a crucial call to action for policymakers and healthcare providers.

The Impact of Customized Short Message Service on High-Risk Behaviors Among MSM in China, a Randomized Controlled Trial Study.

An individual based randomized controlled trial (RCT) was designed to evaluate the impact of a customized short message service (SMS) intervention on HIV-related high-risk behaviors among Men who have sex with men (MSM). In total, 631 HIV-negative MSM were enrolled at baseline and divided into intervention and control groups randomly. Nine months later, the intervention group who received additional customized SMS intervention reported significantly lower rates of multiple partners, unclear partner infection status and condomless anal intercourse compared to the control group who received the routine intervention only. Six months post stopping the SMS intervention, the rates of unclear partner infection status and condomless anal intercourse still remained lower report in the intervention group. Our study shown that the customized SMS interventions can significantly reduce the HIV-related high-risk behaviors among MSM and with sustained effects over a period of time.

Cost-effectiveness analysis of antiretroviral drugs for treatment-naive HIV infection in China.

INTRODUCTION: Dolutegravir (DTG)-based regimen was included in the expanded formulary of China's National Free Antiretroviral Treatment Program at the end of 2021. Yet high price of DTG and lack of health economic evaluation in China present barriers for implementation of the regimen. The study aims to investigate the lifetime cost-effectiveness of DTG-based regimen for treatment-naive HIV infection in China. METHODS: A decision-analytic Markov model was used to obtain the costs and effectiveness of four regimens: Arm A, efavirenz (EFV)-based regimen; Arm B, DTG-based regimen; Arm C, elvitegravir/cobicistat/tenofovir alafenamide/emtricitabine (EVG/c/FTC/TAF) regimen; Arm D, abacavir/lamivudine/dolutegravir (ABC/3TC/DTG) regimen. The potential impact of national centralized drug procurement policy was assessed in scenario analysis. The results were further validated through sensitivity analysis. RESULTS: Compared with other three regimens, DTG-based regimen led to the fewest cumulative adverse reactions, opportunistic infections and deaths. Compared with EFV-based regimen, the base-case ICERs for DTG-based regimen were 13,357 (USD/QALY) and 13,424 (USD/QALY) from the healthcare system and societal perspective respectively. In the policy scenario analysis with the procurement price of DTG equal to that of LPV/r, DTG-based regimen would be dominant. The model results remained robust in sensitivity analyses. CONCLUSIONS: DTG-based regimen for treatment-naive patients is likely to be cost-effective and deserve wider implementation in China. This study strongly suggests the centralized procurement of DTG to minimize cost and maximize cost-effectiveness.

Assessment of low-dose paranasal sinus CT imaging using a new deep learning image reconstruction technique in children compared to adaptive statistical iterative reconstruction V (ASiR-V).

PURPOSE: To compare the effects of deep learning image reconstruction (DLIR) and adaptive statistical iterative reconstruction V (ASiR-V) on image quality in low-dose computed tomography (CT) of paranasal sinuses in children. METHODS: Low-dose CT scans of the paranasal sinuses in 25 pediatric patients were retrospectively evaluated. The raw data were reconstructed with three levels of DLIR (high, H; medium, M; and low, L), filtered back projection (FBP), and ASiR-V (30% and 50%). Image noise was measured in both soft tissue and bone windows, and the signal-to-noise ratios (SNRs) and contrast-to-noise ratios (CNRs) of the images were calculated. Subjective image quality at the ethmoid sinus and nasal cavity levels of the six groups of reconstructed images was assessed by two doctors using a five-point Likert scale in a double-blind manner. RESULTS: The patients' mean dose-length product and effective dose were 36.65 ± 2.44 mGy·cm and 0.17 ± 0.03 mSv, respectively. (1) Objective evaluation: 1. Soft tissue window: The difference among groups in each parameter was significant (P < 0.05). Pairwise comparisons showed that the H group' s parameters were significantly better (P < 0.05) than those of the 50% post-ASiR-V group. 2. Bone window: No significant between-group differences were found in the noise of the petrous portion of the temporal bone or its SNR or in the noise of the pterygoid processes of the sphenoids or their SNRs (P > 0.05). Significant differences were observed in the background noise and CNR (P < 0.05). As the DLIR intensity increased, image noise decreased and the CNR improved. The H group exhibited the best image quality. (2) Subjective evaluation: Scores for images of the ethmoid sinuses were not significantly different among groups (P > 0.05). Scores for images of the nasal cavity were significantly different among groups (P < 0.05) and were ranked in descending order as follows: H, M, L, 50% post-ASiR-V, 30% post-ASiR-V, and FBP. CONCLUSION: DLIR was superior to FBP and post-ASiR-V in low-dose CT scans of pediatric paranasal sinuses. At high intensity (H), DLIR provided the best reconstruction effects.

Comparison of different obesity indices associated with type 2 diabetes mellitus among different sex and age groups in Nantong, China: a cross-section study.

BACKGROUND: Obesity is associated with type 2 diabetes mellitus (T2DM). However, the obesity index that is most closely related to type 2 diabetes remains controversial. Therefore, the aim of this study was to compare the associations of five anthropometric indices (body mass index [BMI], body adiposity index, waist circumference [WC], waist-to-hip ratio, and waist-to-height ratio [WHtR]) with T2DM among Chinese adults divided into four groups according to sex and age. METHODS: A total of 4007 adult participants (1669 men and 2338 women) were included in the study. Odds ratios (ORs) and 95% confidence intervals were used with binary logistic regression models to estimate the risk of T2DM for each obesity index. Furthermore, we compared the area under the receiver operating characteristic curve (AUC) of each obesity index for the criterion of T2DM under the influence of risk factors. RESULTS: WC had the highest OR (3.211 and 1.452) and AUC (0.783 and 0.614) in both age groups of men. However, WHtR (OR = 2.366, AUC = 0.771) and BMI (OR = 1.596, AUC = 0.647) were the optimal criteria for predicting T2DM among females in the 18-59 and ≥ 60 years age groups, respectively. CONCLUSIONS: This study suggests that there is a positive association between obesity-related anthropometric indices and T2DM in different sex and age groups. WC appears to be the optimal anthropometric index for predicting T2DM in men. The optimal obesity indices related to T2DM were WHtR and BMI for women aged 18-59 and ≥ 60 years, respectively.

Comparison of different obesity indices related with hypertension among different sex and age groups in China.

BACKGROUND AND AIMS: To compare the relationships of five obesity-related routine anthropometric indicators (body mass index (BMI), body adiposity index (BAI), waist circumference (WC), waist-to-hip ratio (WHR), waist-to-height ratio (WHtR)) for hypertension in both sexes and among different age groups of the Chinese population. METHODS AND RESULTS: A total of 12,064 adult participants (5638 males and 6426 females) were included. Odds ratios (OR) and 95% confidence intervals were used with binary logistic regression models to estimate the risk of hypertension for each obesity index. For the males, WHtR had the highest OR value in all age groups. The degrees of correlation between hypertension and the obesity indices for different age groups were different among the females. WC, BMI, and WHtR were the highest in the 18-44, 45-59, and ≥60 years age groups, respectively. Furthermore, we compared the area under the ROC curve (AUC) of each obesity index for the criterion of hypertension under the influence of risk factors. For the males, the AUC of WHtR was the largest (0.814, 0.710, and 0.662). WC (AUC = 0.820), BMI (AUC = 0.765), and WHtR (AUC = 0.668) tended to be the best criteria for hypertension among females in the 18-44, 45-59, and ≥60 years age groups respectively. In addition, BAI, as an obesity indicator proposed in recent years, has a positive association with hypertension except in 18-44 years women, which was not stronger than other obesity indicators. CONCLUSIONS: For males, WHtR appears to be the best obesity index related with hypertension. For young, middle-aged, and elderly women, the best obesity indices related with hypertension are WC, BMI, and WHtR, respectively.

A novel regQTL-SNP and the risk of lung cancer: a multi-dimensional study.

RegQTL, a novel concept, indicates that different genotypes of some SNPs have differential effects on the expression patterns of miRNAs and their target mRNAs. We aimed to identify the association between regQTL-SNPs and lung cancer risk and to explore the underlying mechanisms. The two-stage case-control study included the first stage in a Chinese population (626 lung cancer cases and 667 healthy controls) and the second stage in a European population (18,082 lung cancer cases and 13,780 healthy controls). Functional annotations were conducted based on the GTEx and the TCGA databases. Functional experiments were performed to explore the underlying biological mechanisms in vitro and vivo. After strict screening, five candidate regQTL-SNPs (rs7110737, rs273957, rs6593210, rs3768617, and rs6836432) were selected. Among them, the variant T allele of rs3768617 in LAMC1 was found to significantly increase the risk of lung cancer (first stage: P = 0.044; second stage: P = 0.007). The eQTL analysis showed that LAMC1 expression level was significantly higher in subjects with the variant T allele of rs3768617 (P = 1.10 × 10-14). In TCGA paired database, the regQTL annotation indicated the different expression patterns between LAMC1 and miRNA-548b-3p for the distinct genotypes of rs3768617. Additionally, LAMC1 knockdown significantly inhibited malignant phenotypes in lung cancer cell lines and suppressed tumor growth. A novel regQTL-SNP, rs3768617, might affect lung cancer risk by modulating the expression patterns of miRNA-548b-3p and LAMC1. RegQTL-SNPs could provide a new perspective for evaluating the regulatory function of SNPs in lung cancer development.

A national survey of HIV knowledge, sexual practices and attitude towards homosexuality for HIV elimination among young people in China.

Background Elimination of HIV is a public health priority in China, but there has been reports of an upsurge in HIV among young people. A nationwide cross-sectional survey was conducted to assess the awareness of HIV knowledge, attitudes towards homosexuality and practice of sexual behaviours among Chinese aged 15-24 years. METHODS: The face-to-face survey was conducted from June to August 2017, collecting data on sociodemographic characteristics, HIV-related knowledge, attitudes towards homosexuality and practice of sexual behaviours among Chinese senior high school and university students. A generalised linear model (GLM) was used to assess the different levels of HIV knowledge between groups, and identify the key contributors to HIV knowledge scores. RESULTS: The survey was completed by 73.6% (1355/1840) of the students approached. The overall level of HIV-related knowledge was low (58.9%, 10.6/18); 48.0% (650/1355) supported same-sex marriage; and 6.9% (93/1355) self-identified as homosexual or bisexual. The major factors associated with higher scores [mean ± standard deviation (s.d.)] in HIV knowledge among students included: having received school-based HIV education (11.47 ± 3.51 vs 9.02 ± 4.14, P < 0.05); support for same-sex marriage (11.69 ± 3.33 vs 9.49 ± 4.29, P < 0.05) and older age (11.61 ± 2.78 vs 9.87 ± 4.17, P < 0.05). Compared with females, males were significantly more likely (all P < 0.05) to report masturbation (60.7% vs 7.6%), pornography experiences (77.4% vs 35.3%), sexual encounters (24.6% vs 12.3%), casual sex (37.0% vs 18.1%) and sex under the influence of alcohol (29.5% vs 12.8%). CONCLUSIONS: There is is still much room for improvement in terms of HIV/AIDS prevention and health education for Chinese young people, and more comprehensive and diverse models of education for HIV prevention are urgently needed.

A Nationwide Spatiotemporal Analysis of Syphilis Over 21 Years and Implications for Prevention and Control in China.

Syphilis control programs have been scaled up due to the substantial burden in China. We analyzed syphilis incidence according to demographic, spatiotemporal, and economic factors. The increasing latent syphilis diagnoses and declining congenital syphilis suggest the effectiveness of scale-up screening. However, primary and secondary cases persist, especially in inland provinces.

Effectiveness of Lifestyle and Drug Intervention on Hypertensive Patients: a Randomized Community Intervention Trial in Rural China.

BACKGROUND: Strict medication guidance and lifestyle interventions to manage blood pressure (BP) in hypertensive patients are typically difficult to follow. OBJECTIVE: To evaluate the 1-year effectiveness of lifestyle and drug intervention in the management of rural hypertensive patients. DESIGN: Randomized community intervention trial. PARTICIPANTS: The control group comprised 967 patients who received standard antihypertensive drug intervention therapy from two communities, whereas the intervention group comprised 1945 patients who received antihypertensive drug and lifestyle intervention therapies from four communities in rural China. MAIN MEASURES: Data on lifestyle behaviors and BP measurements at baseline and 1-year follow-up were collected. A difference-in-difference logistic regression model was used to assess the effect of the intervention. KEY RESULTS: BP control after the 1-year intervention was better than that at baseline in both groups. The within-group change in BP control of 59.3% in the intervention group was much higher than the 25.2% change in the control group (P < 0.001). Along with the duration of the follow-up period, systolic and diastolic BP decreased rapidly in the early stages and then gradually after 6 months in the intervention group (P < 0.001). In the intervention group, drug therapy adherence was increased by 39.5% (from 48.1% at 1 month to 87.6% at 1 year) (P < 0.001), more in women (45.6%) than in men (31.2%; P < 0.001). The net effect of the lifestyle intervention improved the rate of BP control by 56.1% (70.8% for men and 44.7% for women). For all physiological and biochemical factors, such as body mass index, waist circumference, lipid metabolism, and glucose control, improvements were more significant in the behavioral intervention group than those in the control group (all P < 0.001). CONCLUSION: The addition of lifestyle intervention by physicians or nurses helps control BP effectively and lowers BP better than usual care with antihypertensive drug therapy alone.

Production of ent-kaurene from lignocellulosic hydrolysate in Rhodosporidium toruloides.

BACKGROUND: Rhodosporidium toruloides has emerged as a promising host for the production of bioproducts from lignocellulose, in part due to its ability to grow on lignocellulosic feedstocks, tolerate growth inhibitors, and co-utilize sugars and lignin-derived monomers. Ent-kaurene derivatives have a diverse range of potential applications from therapeutics to novel resin-based materials. RESULTS: The Design, Build, Test, and Learn (DBTL) approach was employed to engineer production of the non-native diterpene ent-kaurene in R. toruloides. Following expression of kaurene synthase (KS) in R. toruloides in the first DBTL cycle, a key limitation appeared to be the availability of the diterpene precursor, geranylgeranyl diphosphate (GGPP). Further DBTL cycles were carried out to select an optimal GGPP synthase and to balance its expression with KS, requiring two of the strongest promoters in R. toruloides, ANT (adenine nucleotide translocase) and TEF1 (translational elongation factor 1) to drive expression of the KS from Gibberella fujikuroi and a mutant version of an FPP synthase from Gallus gallus that produces GGPP. Scale-up of cultivation in a 2 L bioreactor using a corn stover hydrolysate resulted in an ent-kaurene titer of 1.4 g/L. CONCLUSION: This study builds upon previous work demonstrating the potential of R. toruloides as a robust and versatile host for the production of both mono- and sesquiterpenes, and is the first demonstration of the production of a non-native diterpene in this organism.

Direct-acting antivirals and interferon-based therapy on hepatocellular carcinoma risk in chronic hepatitis-C patients.

Aim: It was controversial whether direct-acting antiviral (DAA) is better than interferon-based therapy (IBT) in preventing HCV-related hepatocellular carcinoma (HCC). Therefore, we accomplished this large, stepwise meta-analysis. Materials & methods: The PubMed, Cochrane and ScienceDirect were searched for studies published during January 2009-March 2019. Antiviral type, number of chronic hepatitis C (CHC) patients, number of HCC cases from CHC patients, sustained virological response (SVR) status and important covariate data were extracted from each study. Results & conclusion: It is demonstrated that antiviral treatment reduces the occurrence of HCC in patients with CHC; achieving SVR to antiviral treatment reduces HCC; DAA treatment is not better than IBT in the prophylaxis of HCC; DAA treatment and cirrhosis are independently associated with a higher incidence of HCC than IBT in middle-aged CHC patients who achieve SVR.

miRNA sequencing reveals miRNA-4508 from peripheral blood lymphocytes as potential diagnostic biomarker for silica-related pulmonary fibrosis: A multistage study.

BACKGROUND AND OBJECTIVE: This study aimed to identify miRNA as potential diagnostic biomarkers for silica-related pulmonary fibrosis (SPF). METHODS: We first performed a comprehensive miRNA-seq screening in PBL of eight subjects exposed to silica dust (four individuals with SPF and four healthy controls). The promising miRNA were then evaluated in the first-stage validation using an independent GEO data set (GSE80555) of 6 subjects (3 individuals with SPF and 3 healthy controls), followed by a second-stage validation using 120 subjects exposed to silica dust (60 individuals with SPF and 60 healthy controls). RESULTS: Thirty-five miRNA showed strong expression differences in miRNA-seq screening, while miRNA-4508 (P = 9.52 × 10-3 ) was retained as a candidate after the first-stage validation (GSE80555), which was further confirmed in the second-stage validation with similar and strong effect (P = 9.93 × 10-17 ). ROC analysis showed that miRNA-4508 could distinguish SPF cases from healthy controls with high AUC (0.886), with sensitivity of 81.7% and specificity of 86.7%. In addition, the miRNA-4508 upstream rs6576457 mutant A allele exhibited a strong association with susceptibility to SPF (OR = 1.64, 95% CI = 1.20-2.23, P = 0.002), while eQTL analysis revealed a potential association between different genotypes of rs6576457 and miRNA-4508 expression (P = 0.068) in 60 healthy subjects with silica dust exposure. CONCLUSION: miRNA-4508 may be a potential diagnostic marker for SPF, and rs6576457, a functional variant of miRNA-4508, may affect SPF susceptibility. The detailed mechanism of action of this miRNA remains to be elucidated.

Trans fatty acid intake among Chinese population: a longitudinal study from 1991 to 2011.

OBJECTIVE: This study was aimed to roughly describe individual Trans Fatty Acids (TFAs) intake and the percentage of energy intake(E%), and identify major food sources in the Chinese population, taking gender, age, and regional distribution into the consideration, as well as examining temporal changes over the course of 20 years. METHOD: This multi-center study, covering nine provinces among populations aged ≥ 3 in China, was conducted to collect food consumption information from 1991 to 2011. A classical assessment method was used to estimate the level of dietary TFA intake. RESULTS: Over the 20-year period, the intake of TFAs in Chinese populations had increased, but remained at a relatively lower level (from 0.25 g/d(0.11% for E%) to 0.53 g/d(0.24% for E%)) compared with that of other countries and the World Health Organization (WHO) recommended level. Collectively, males and participants aged 19-60 generally consumed more TFA-containing foods. People in eastern regions consumed more TFAs and had a higher E% than those in western area. Industrial sources of TFAs, especially vegetable oil, ranked as the principal food sources of TFAs in the Chinese population. Natural sources of TFAs have gradually increased in proportion among children and adolescents. CONCLUSIONS: TFA intake and the E% are commonly under the recommended level in the general population in China. Presently, restriction of vegetable oil could be a crucial method to reduce TFA intake. It would be critical to facilitate and promote public health that food recommendations might be based on the dietary preferences for population separated by different ages and regions.

Analysis of hospitalization expenses of 610 HIV/AIDS patients in Nantong, China.

BACKGROUND: The goal of this study was to describe the expenses related to human immunodeficiency virus (HIV) and acquired immune deficiency syndrome (AIDS) management and care in Nantong Infectious Disease Hospital from October 2013 through June 2017. METHODS: The information of 610 HIV/AIDS inpatients were collected from the Electronic Medical Record System of the hospital. Univariate and path analysis were employed to evaluate the association between hospitalization expense and its related factors. RESULTS: The average hospitalization expenses per person was 5454 RMB (Renminbi, the currency of China, about $808 USD) and 23,555 RMB (about $3489 USD), respectively for HIV/AIDS patients. The average length of hospital stay was 10.0 ± 5.5 days for HIV patients and 21.7 ± 12.4 days for AIDS patients. For HIV patients, laboratory test fees constituted 37.46% of total expenses; while drug fees accounted for the largest proportion for AIDS patients. Path analysis indicated that the length of hospital stay was the most important factor affecting total expenses (total path coefficient = 0.563 for HIV patients and 0.649 for AIDS patients). Total expenses for HIV-infected females was higher than that of males (total path coefficient = 0.217), and the more complications led to higher expenses for AIDS patients. CONCLUSIONS: Though antiretroviral therapy (ART) is provided for free in China, associated medical care, particularly hospitalizations and fees, continue to drive up the medical costs of patients living with HIV and AIDS. Understanding the factors influencing these costs are crucial for determining policies and strategies that can reduce the economic burden of HIV/AIDS patients in China.

Correction: Population genomic screening of all young adults in a health-care system: a cost-effectiveness analysis.

In the original version of this Article, the affiliation details for Lei Zhang were given as Monash University. While working on the Article Dr. Zhang was also affiliated with the Department of Epidemiology and Biostatistics, School of Public Health, Xi'an Jiaotong University Health Science Center, Xi'an, Shaanxi, PR China. This has now been corrected in both the PDF and HTML versions of the Article.

Population genomic screening of all young adults in a health-care system: a cost-effectiveness analysis.

PURPOSE: To consider the impact and cost-effectiveness of offering preventive population genomic screening to all young adults in a single-payer health-care system. METHODS: We modeled screening of 2,688,192 individuals, all adults aged 18-25 years in Australia, for pathogenic variants in BRCA1/BRCA2/MLH1/MSH2 genes, and carrier screening for cystic fibrosis (CF), spinal muscular atrophy (SMA), and fragile X syndrome (FXS), at 71% testing uptake using per-test costs ranging from AUD$200 to $1200 (~USD$140 to $850). Investment costs included genetic counseling, surveillance, and interventions (reimbursed only) for at-risk individuals/couples. Cost-effectiveness was defined below AUD$50,000/DALY (disability-adjusted life year) prevented, using an incremental cost-effectiveness ratio (ICER), compared with current targeted testing. Outcomes were cancer incidence/mortality, disease cases, and treatment costs reduced. RESULTS: Population screening would reduce variant-attributable cancers by 28.8%, cancer deaths by 31.2%, and CF/SMA/FXS cases by 24.8%, compared with targeted testing. Assuming AUD$400 per test, investment required would be between 4 and 5 times higher than current expenditure. However, screening would lead to substantial savings in medical costs and DALYs prevented, at a highly cost-effective ICER of AUD$4038/DALY. At AUD$200 per test, screening would approach cost-saving for the health system (ICER = AUD$22/DALY). CONCLUSION: Preventive genomic screening in early adulthood would be highly cost-effective in a single-payer health-care system, but ethical issues must be considered.

Molecular Diversity of Terpene Synthases in the Liverwort Marchantia polymorpha.

Marchantia polymorpha is a basal terrestrial land plant, which like most liverworts accumulates structurally diverse terpenes believed to serve in deterring disease and herbivory. Previous studies have suggested that the mevalonate and methylerythritol phosphate pathways, present in evolutionarily diverged plants, are also operative in liverworts. However, the genes and enzymes responsible for the chemical diversity of terpenes have yet to be described. In this study, we resorted to a HMMER search tool to identify 17 putative terpene synthase genes from M. polymorpha transcriptomes. Functional characterization identified four diterpene synthase genes phylogenetically related to those found in diverged plants and nine rather unusual monoterpene and sesquiterpene synthase-like genes. The presence of separate monofunctional diterpene synthases for ent-copalyl diphosphate and ent-kaurene biosynthesis is similar to orthologs found in vascular plants, pushing the date of the underlying gene duplication and neofunctionalization of the ancestral diterpene synthase gene family to >400 million years ago. By contrast, the mono- and sesquiterpene synthases represent a distinct class of enzymes, not related to previously described plant terpene synthases and only distantly so to microbial-type terpene synthases. The absence of a Mg2+ binding, aspartate-rich, DDXXD motif places these enzymes in a noncanonical family of terpene synthases.

Monoterpene production by the carotenogenic yeast Rhodosporidium toruloides.

BACKGROUND: Due to their high energy density and compatible physical properties, several monoterpenes have been investigated as potential renewable transportation fuels, either as blendstocks with petroleum or as drop-in replacements for use in vehicles (both heavy and light-weight) or in aviation. Sustainable microbial production of these biofuels requires the ability to utilize cheap and readily available feedstocks such as lignocellulosic biomass, which can be depolymerized into fermentable carbon sources such as glucose and xylose. However, common microbial production platforms such as the yeast Saccharomyces cerevisiae are not naturally capable of utilizing xylose, hence requiring extensive strain engineering and optimization to efficiently utilize lignocellulosic feedstocks. In contrast, the oleaginous red yeast Rhodosporidium toruloides is capable of efficiently metabolizing both xylose and glucose, suggesting that it may be a suitable host for the production of lignocellulosic bioproducts. In addition, R. toruloides naturally produces several carotenoids (C40 terpenoids), indicating that it may have a naturally high carbon flux through its mevalonate (MVA) pathway, providing pools of intermediates for the production of a wide range of heterologous terpene-based biofuels and bioproducts from lignocellulose. RESULTS: Sixteen terpene synthases (TS) originating from plants, bacteria and fungi were evaluated for their ability to produce a total of nine different monoterpenes in R. toruloides. Eight of these TS were functional and produced several different monoterpenes, either as individual compounds or as mixtures, with 1,8-cineole, sabinene, ocimene, pinene, limonene, and carene being produced at the highest levels. The 1,8-cineole synthase HYP3 from Hypoxylon sp. E74060B produced the highest titer of 14.94 ± 1.84 mg/L 1,8-cineole in YPD medium and was selected for further optimization and fuel properties study. Production of 1,8-cineole from lignocellulose was also demonstrated in a 2L batch fermentation, and cineole production titers reached 34.6 mg/L in DMR-EH (Deacetylated, Mechanically Refined, Enzymatically Hydorlized) hydrolysate. Finally, the fuel properties of 1,8-cineole were examined, and indicate that it may be a suitable petroleum blend stock or drop-in replacement fuel for spark ignition engines. CONCLUSION: Our results demonstrate that Rhodosporidium toruloides is a suitable microbial platform for the production of non-native monoterpenes with biofuel applications from lignocellulosic biomass.

Functional variant of the carboxypeptidase M (CPM) gene may affect silica-related pneumoconiosis susceptibility by its expression: a multistage case-control study.

OBJECTIVES: In a genome-wide association study, we discovered chromosome 12q15 (defined as rs73329476) as a silica-related pneumoconiosis susceptibility region. However, the causal variants in this region have not yet been reported. METHODS: We systematically screened eight potentially functional single-neucleotide polymorphism (SNPs) in the genes near rs73329476 (carboxypeptidase M (CPM) and cleavage and polyadenylation specific factor 6 (CPSF6)) in a case-control study including 177 cases with silicosis and 204 healthy controls, matched to cases with years of silica dust exposure. We evaluated the associations between these eight SNPs and the development of silicosis. Luciferase reporter gene assays were performed to test the effects of selected SNP on the activity of CPM in the promoter. In addition, a two-stage case-control study was performed to investigate the expression differences of the two genes in peripheral blood leucocytes from a total of 64 cases with silicosis and 64 healthy controls with similar years of silica dust exposure as the cases. RESULTS: We found a strong association between the mutant rs12812500 G allele and the susceptibility of silicosis (OR=1.45, 95% CI 1.03 to 2.04, p=0.034), while luciferase reporter gene assays indicated that the mutant G allele of rs12812500 is strongly associated with increased luciferase levels compared with the wild-type C allele (p<0.01). Moreover, the mRNA (peripheral blood leucocytes) expression of the CPM gene was significantly higher in subjects with silicosis compared with healthy controls. CONCLUSIONS: The rs12812500 variant of the CPM gene may increase silicosis susceptibility by affecting the expression of CPM, which may contribute to silicosis susceptibility with biological plausibility.