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[This corrects the article DOI: 10.1371/journal.pone.0217185.].

ObjectivesNon-communicable diseases (NCDs) have become the main cause of mortality in China. In 2009, the Chinese government introduced the Basic Public Health Service (BPHS) program to relieve the rising burden of NCDs through public health measures and delivery of essential medical care. The primary aim of this study was to evaluate the impact of the BPHS program on hypertension control.MethodsThe China National Health Development Research Center (CNHDRC) undertook a Cross-sectional Health Service Interview Survey (CHSIS) of 62,097 people from primary healthcare reform pilot areas across 17 provinces from eastern, central, and western parts of China in 2014. The current study is based on responses to the CHSIS survey from 7,867 participants, who had been diagnosed with hypertension. Multi-variable mixed logit regression analysis was used to estimate the association between BPHS management and uncontrolled hypertension. In a follow-up analysis, generalized structural equation modelling (GSEM) was used to test for mediation of the BPHS program effect through patient compliance with medication.FindingsThe estimated proportion of patients with uncontrolled hypertension was 30% lower (23.2% vs 31.5%) in those participants who were adequately managed under the BPHS program. Other predictors of hypertension control included compliance with medication, self-reported wellbeing, income, educational attainment and exercise; smoking was associated with reduced hypertension control. The significant inverse association between uncontrolled hypertension and age indicates poor outcomes for younger patients. Additional testing suggested that nearly 40% of the effect of BPHS management (95% CI: 28.2 to 51.7) could be mediated by improved compliance with medication; there was also an indication that the effect of management was 30% stronger in districts/counties with established digital information management systems (IMS).ConclusionHypertension control improved markedly following active management through the BPHS program. Some of that improvement could be explained by greater compliance with medication among program participants. This study also identified the need to tailor the BPHS program to the needs of younger patients to achieve higher levels of control in this population. Future investigations should explore ways in which existing healthcare management influences the success of the BPHS program.

Epstein-Barr virus (EBV) infection is closely linked to several human malignancies including endemic Burkitt's lymphoma, Hodgkin's lymphoma and nasopharyngeal carcinomas (NPC). Latent membrane protein 2 (LMP-2) of EBV plays a pivotal role in pathogenesis of EBV-related tumors and thus, is a potential target for diagnosis and targeted therapy of EBV LMP-2+ malignant cancers. Affibody molecules are developing as imaging probes and tumor-targeted delivery of small molecules. In this study, four EBV LMP-2-binding affibodies (ZEBV LMP-212, ZEBV LMP-2132, ZEBV LMP-2137, and ZEBV LMP-2142) were identified by screening a phage-displayed LMP-2 peptide library for molecular imaging and targeted therapy in EBV xenograft mice model. ZEBV LMP-2 affibody has high binding affinity for EBV LMP-2 and accumulates in mouse tumor derived from EBV LMP-2+ xenografts for 24 h after intravenous (IV) injection. Subsequent fusion of Pseudomonas exotoxin PE38KDEL to the ZEBV LMP-2 142 affibody led to production of Z142X affitoxin. This fused Z142X affitoxin exhibits high cytotoxicity specific for EBV+ cells in vitro and significant antitumor effect in mice bearing EBV+ tumor xenografts by IV injection. The data provide the proof of principle that EBV LMP-2-speicifc affibody molecules are useful for molecular imaging diagnosis and have potentials for targeted therapy of LMP-2-expressing EBV malignancies.

BackgroundThe cesarean section (CS) rate has risen globally during the last two decades. Effective and feasible strategies are needed to reduce it. The aim of this study was to assess the CS rate change after a two-stage intervention package that was designed to reduce the overall CS rate in Guangzhou, China.Methods and findingsThis intervention package was implemented by the Health Commission of Guangzhou Municipality in 2 stages (October 2010-September 2014 and October 2014-December 2016) and included programs for population health education, skills training for healthcare professionals, equipment and technical support for local healthcare facilities, and capacity building for the maternal near-miss care system. A retrospective repeated cross-sectional study was conducted to evaluate influences of the intervention on CS rates. A pre-intervention period from January 2008 to September 2010 served as the baseline. The primary outcome was the CS rate, and the secondary outcomes included maternal mortality ratio (MMR) and perinatal mortality rate (PMR), all obtained from the Guangzhou Perinatal Health Care and Delivery Surveillance System (GPHCDSS). The Cochran-Armitage test was used to examine the trends of the overall CS rate, MMR, and PMR across different stages. Segmented linear regression analysis was used to assess the change of the CS rate over the intervention period. A total of 1,921,932 records of births and 108 monthly CS rates from 2008 to 2016 were analyzed. The monthly CS rate declined across the intervention stages (Z = 75.067, p < 0.001), with an average rate of 42.4% at baseline, 39.8% at Stage 1, and 35.0% at Stage 2. The CS rate declined substantially among nulliparous women who delivered term singletons, with an accelerating decreasing trend observed across Stage 1 and Stage 2 (the difference in slopes: -0.09 [95% CI -0.16 to -0.02] between Stage 1 and baseline, p = 0.014; -0.11 [95% CI -0.20 to -0.02] between Stage 1 and Stage 2, p = 0.017). The CS rate in the remaining population increased during baseline and Stage 1 and subsequently decreased during Stage 2. The sensitivity analysis suggested no immediate impact of the universal two-child policy on the trend of the CS rate. The MMR (Z = -4.368, p < 0.001) and PMR (Z = -13.142, p < 0.001) declined by stage over the intervention period. One of the main limitations of the study is the lack of a parallel control group. Moreover, the influence of temporal changes in the study population on the CS rate was unknown. Given the observational nature of the present study, causality cannot be confirmed.ConclusionsApparent decline in the overall CS rate was observed in Guangzhou, China, after the implementation of a two-stage intervention package. The decline was most evident among nulliparous women who delivered term singletons. Despite some limitations for causal inference, Guangzhou's experience in controlling the CS rate by implementing composite interventions with public health education and perinatal healthcare service improvement could have implications for other similar areas with high rates of CS.

Human cytomegalovirus is a significant agent of hepatic involvement in neonates. In this study, we investigated the polymorphisms and features of the viral genes UL144 and UL146 as well as their significance to congenital hepatic involvement. In 79 neonates with congenital cytomegalovirus infection and hepatic involvement, full length UL144 and UL146 were successfully amplified in 73.42% and 60.76% of cases, respectively. Sequencing indicated that both genes were hypervariable. Notably, UL144 genotype B was highly associated with aspartate aminotransferase (P = 0.028) and lactate dehydrogenase (P = 0.046). Similarly, UL146 genotype G1 and G13 were significantly associated with CMV IgM (P = 0.026), CMV IgG (P = 0.034), alanine aminotransferase (P = 0.019), and aspartate aminotransferase (P = 0.032). In conclusion, dominant UL144 (genotype B) and UL146 (genotype G1 and G13) genotypes are associated with elevated levels of enzymes and CMV IgM and IgG of cytomegalovirus infection.

Heavy seismic damage tends to occur in slopes when groundwater is present. The main objectives of this paper are to determine the dynamic response and failure mode of sandy slope subjected simultaneously to seismic forces and variable groundwater conditions. This paper applies the finite element method, which is a fast and efficient design tool in modern engineering analysis, to evaluate dynamic response of the slope subjected simultaneously to seismic forces and variable groundwater conditions. Shaking table test is conducted to analyze the failure mode and verify the accuracy of the finite element method results. The research results show that dynamic response values of the slope have different variation rules under near and far field earthquakes. And the damage location and pattern of the slope are different in varying groundwater conditions. The destruction starts at the top of the slope when the slope is in no groundwater, which shows that the slope appears obvious whipping effect under the earthquake. The destruction starts at the toe of the slope when the slope is in the high groundwater levels. Meanwhile, the top of the slope shows obvious seismic subsidence phenomenon after earthquake. Furthermore, the existence of the groundwater has a certain effect of damping.

Salinization is an important and increasingly prevalent issue which has broad and profound effects on plant survival and distribution pattern. To understand the patterns and potential drivers of leaf traits in saline environments, we determined the soil properties, leaf morphological traits (specific leaf area, SLA, and leaf dry matter content, LDMC), leaf chemical traits (leaf carbon, C, nitrogen, N, and phosphorus, P, stoichiometry) based on 142 observations collected from 23 sites in an arid saline environment, which is a vulnerable ecosystem in northwest China. We also explored the relationships among leaf traits, the responses of leaf traits, and plant functional groups (herb, woody, and succulent woody) to various saline environments. The arid desert halophytes were characterized by lower leaf C and SLA levels, higher N, but stable P and N:P. The leaf morphological traits were correlated significantly with the C, N, and P contents across all observations, but they differed within each functional group. Succulent woody plants had the lowest leaf C and highest leaf N levels among the three functional groups. The growth of halophytes might be more limited by N rather than P in the study area. GLM analysis demonstrated that the soil available nutrients and plant functional groups, but not salinity, were potential drivers of leaf C:N:P stoichiometry in halophytes, whereas species differences accounted for the largest contributions to leaf morphological variations. Our study provides baseline information to facilitate the management and restoration of arid saline desert ecosystem.

The biosynthesis pathway of carotenoids in cyanobacteria is partly described. However, the subcellular localization of individual steps is so far unknown. Carotenoid analysis of different membrane subfractions in Synechocystis sp. PCC6803 shows that "light" plasma membranes have a high carotenoid/protein ratio, when compared to "heavier" plasma membranes or thylakoids. The localization of CrtQ and CrtO, two well-defined carotenoid synthesis pathway enzymes in Synechocystis, was studied by epitope tagging and western blots. Both enzymes are locally more abundant in plasma membranes than in thylakoids, implying that the plasma membrane has higher synthesis rates of β-carotene precursor molecules and echinenone.

Synthesis of monogalactosyldiacylglycerol (GalDAG) and digalactosyldiacylglycerol (GalGalDAG), the major membrane lipids in cyanobacteria, begins with production of the intermediate precursor monoglucosyldiacylglycerol (GlcDAG), by monoglucosyldiacylglycerol synthase (MGS). In Synechocystis sp. PCC6803 (Synechocystis) this activity is catalyzed by an integral membrane protein, Sll1377 or MgdA. In silico sequence analysis revealed that cyanobacterial homologues of MgdA are highly conserved and comprise a distinct group of lipid glycosyltransferases. Global regulation of lipid synthesis in Synechocystis and, more specifically, the influence of the lipid environment on MgdA activity have not yet been fully elucidated. Therefore, we purified membrane subfractions from this organism and assayed MGS activity in vitro, with and without different lipids and other potential effectors. Sulfoquinovosyldiacylglycerol (SQDAG) potently stimulates MgdA activity, in contrast to other enzymes of a similar nature, which are activated by phosphatidylglycerol instead. Moreover, the final products of galactolipid synthesis, GalDAG and GalGalDAG, inhibited this activity. Western blotting revealed the presence of MgdA both in plasma and thylakoid membranes, with a high specific level of the MgdA protein in the plasma membrane but highest MGS activity in the thylakoid membrane. This discrepancy in the subcellular localization of enzyme activity and protein may indicate the presence of either an unknown regulator and/or an as yet unidentified MGS-type enzyme. Furthermore, the stimulation of MgdA activity by SQDAG observed here provides a new insight into regulation of the biogenesis of both sulfolipids and galactolipids in cyanobacteria.

The constitutive expression of the high-risk HPV E6 and E7 viral oncogenes is the major cause of cervical cancer. To comprehensively explore the composition of HPV16 early transcripts and their genomic annotation, cervical squamous epithelial tissues from 40 HPV16-infected patients were collected for analysis of papillomavirus oncogene transcripts (APOT). We observed different transcription patterns of HPV16 oncogenes in progression of cervical lesions to cervical cancer and identified one novel transcript. Multiple-integration events in the tissues of cervical carcinoma (CxCa) are significantly more often than those of low-grade squamous intraepithelial lesions (LSIL) and high-grade squamous intraepithelial lesions (HSIL). Moreover, most cellular genes within or near these integration sites are cancer-associated genes. Taken together, this study suggests that the multiple-integrations of HPV genome during persistent viral infection, which thereby alters the expression patterns of viral oncogenes and integration-related cellular genes, play a crucial role in progression of cervical lesions to cervix cancer.

Parkinson's disease (PD) and amyotrophic lateral sclerosis (ALS) share several clinical and neuropathologic features, and studies suggest that several gene mutations and polymorphisms are involved in both conditions. Matrix metalloproteinase-9 (MMP-9) is implicated in the pathogenesis of PD and ALS, and the C(-1562)T polymorphism in the MMP-9 gene leads to higher promoter activity. We therefore investigated whether this polymorphism predisposes to both PD and sporadic ALS (sALS). Samples from 351 subjects with PD and 351 healthy controls from two major cities in China were compared, while samples from 226 subjects with sALS were compared to the same number of controls from three centers in China. A possible association between the C(-1562)T polymorphism in the MMP-9 gene and PD or sALS was assessed by restriction fragment length polymorphism (RFLP) analysis. Our results show a significant association between the C(-1562)T polymorphism in the MMP-9 gene and risk of PD (odds ratio = 2.268, 95% CI 1.506-3.416, p

Waterlogging of plants leads to low oxygen levels (hypoxia) in the roots and causes a metabolic switch from aerobic respiration to anaerobic fermentation that results in rapid changes in gene transcription and protein synthesis. Our research seeks to characterize the microRNA-mediated gene regulatory networks associated with short-term waterlogging. MicroRNAs (miRNAs) are small non-coding RNAs that regulate many genes involved in growth, development and various biotic and abiotic stress responses. To characterize the involvement of miRNAs and their targets in response to short-term hypoxia conditions, a quantitative real time PCR (qRT-PCR) assay was used to quantify the expression of the 24 candidate mature miRNA signatures (22 known and 2 novel mature miRNAs, representing 66 miRNA loci) and their 92 predicted targets in three inbred Zea mays lines (waterlogging tolerant Hz32, mid-tolerant B73, and sensitive Mo17). Based on our studies, miR159, miR164, miR167, miR393, miR408 and miR528, which are mainly involved in root development and stress responses, were found to be key regulators in the post-transcriptional regulatory mechanisms under short-term waterlogging conditions in three inbred lines. Further, computational approaches were used to predict the stress and development related cis-regulatory elements on the promoters of these miRNAs; and a probable miRNA-mediated gene regulatory network in response to short-term waterlogging stress was constructed. The differential expression patterns of miRNAs and their targets in these three inbred lines suggest that the miRNAs are active participants in the signal transduction at the early stage of hypoxia conditions via a gene regulatory network; and crosstalk occurs between different biochemical pathways.

HPV16 E6 and E7, two viral oncogenes, are expressed from a single bicistronic pre-mRNA. In this report, we provide the evidence that the bicistronic pre-mRNA intron 1 contains three 5' splice sites (5' ss) and three 3' splice sites (3' ss) normally used in HPV16(+) cervical cancer and its derived cell lines. The choice of two novel alternative 5' ss (nt 221 5' ss and nt 191 5' ss) produces two novel isoforms of E6E7 mRNAs (E6*V and E6*VI). The nt 226 5' ss and nt 409 3' ss is preferentially selected over the other splice sites crossing over the intron to excise a minimal length of the intron in RNA splicing. We identified AACAAAC as the preferred branch point sequence (BPS) and an adenosine at nt 385 (underlined) in the BPS as a branch site to dictate the selection of the nt 409 3' ss for E6*I splicing and E7 expression. Introduction of point mutations into the mapped BPS led to reduced U2 binding to the BPS and thereby inhibition of the second step of E6E7 splicing at the nt 409 3' ss. Importantly, the E6E7 bicistronic RNA with a mutant BPS and inefficient splicing makes little or no E7 and the resulted E6 with mutations of (91)QYNK(94) to (91)PSFW(94) displays attenuate activity on p53 degradation. Together, our data provide structural basis of the E6E7 intron 1 for better understanding of how viral E6 and E7 expression is regulated by alternative RNA splicing. This study elucidates for the first time a mapped branch point in HPV16 genome involved in viral oncogene expression.

Most of our understanding of plant genome structure and evolution has come from the careful annotation of small (e.g., 100 kb) sequenced genomic regions or from automated annotation of complete genome sequences. Here, we sequenced and carefully annotated a contiguous 22 Mb region of maize chromosome 4 using an improved pseudomolecule for annotation. The sequence segment was comprehensively ordered, oriented, and confirmed using the maize optical map. Nearly 84% of the sequence is composed of transposable elements (TEs) that are mostly nested within each other, of which most families are low-copy. We identified 544 gene models using multiple levels of evidence, as well as five miRNA genes. Gene fragments, many captured by TEs, are prevalent within this region. Elimination of gene redundancy from a tetraploid maize ancestor that originated a few million years ago is responsible in this region for most disruptions of synteny with sorghum and rice. Consistent with other sub-genomic analyses in maize, small RNA mapping showed that many small RNAs match TEs and that most TEs match small RNAs. These results, performed on approximately 1% of the maize genome, demonstrate the feasibility of refining the B73 RefGen_v1 genome assembly by incorporating optical map, high-resolution genetic map, and comparative genomic data sets. Such improvements, along with those of gene and repeat annotation, will serve to promote future functional genomic and phylogenomic research in maize and other grasses.

MicroRNAs (miRNAs) are small, non-coding RNAs that play essential roles in plant growth, development, and stress response. We conducted a genome-wide survey of maize miRNA genes, characterizing their structure, expression, and evolution. Computational approaches based on homology and secondary structure modeling identified 150 high-confidence genes within 26 miRNA families. For 25 families, expression was verified by deep-sequencing of small RNA libraries that were prepared from an assortment of maize tissues. PCR-RACE amplification of 68 miRNA transcript precursors, representing 18 families conserved across several plant species, showed that splice variation and the use of alternative transcriptional start and stop sites is common within this class of genes. Comparison of sequence variation data from diverse maize inbred lines versus teosinte accessions suggest that the mature miRNAs are under strong purifying selection while the flanking sequences evolve equivalently to other genes. Since maize is derived from an ancient tetraploid, the effect of whole-genome duplication on miRNA evolution was examined. We found that, like protein-coding genes, duplicated miRNA genes underwent extensive gene-loss, with approximately 35% of ancestral sites retained as duplicate homoeologous miRNA genes. This number is higher than that observed with protein-coding genes. A search for putative miRNA targets indicated bias towards genes in regulatory and metabolic pathways. As maize is one of the principal models for plant growth and development, this study will serve as a foundation for future research into the functional roles of miRNA genes.