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1.  Inferred miRNA activity identifies miRNA-mediated regulatory networks underlying multiple cancers 
Bioinformatics  2015;32(1):96-105.
Motivation: MicroRNAs (miRNAs) play a key role in regulating tumor progression and metastasis. Identifying key miRNAs, defined by their functional activities, can provide a deeper understanding of biology of miRNAs in cancer. However, miRNA expression level cannot accurately reflect miRNA activity.
Results: We developed a computational approach, ActMiR, for identifying active miRNAs and miRNA-mediated regulatory mechanisms. Applying ActMiR to four cancer datasets in The Cancer Genome Atlas (TCGA), we showed that (i) miRNA activity was tumor subtype specific; (ii) genes correlated with inferred miRNA activities were more likely to enrich for miRNA binding motifs; (iii) expression levels of these genes and inferred miRNA activities were more likely to be negatively correlated. For the four cancer types in TCGA we identified 77–229 key miRNAs for each cancer subtype and annotated their biological functions. The miRNA-target pairs, predicted by our ActMiR algorithm but not by correlation of miRNA expression levels, were experimentally validated. The functional activities of key miRNAs were further demonstrated to be associated with clinical outcomes for other cancer types using independent datasets. For ER−/HER2− breast cancers, we identified activities of key miRNAs let-7d and miR-18a as potential prognostic markers and validated them in two independent ER−/HER2− breast cancer datasets. Our work provides a novel scheme to facilitate our understanding of miRNA. In summary, inferred activity of key miRNA provided a functional link to its mediated regulatory network, and can be used to robustly predict patient’s survival.
Availability and implementation: the software is freely available at http://research.mssm.edu/integrative-network-biology/Software.html.
Contact: jun.zhu@mssm.edu
Supplementary information: Supplementary data are available at Bioinformatics online.
doi:10.1093/bioinformatics/btv531
PMCID: PMC5006235  PMID: 26358730
2.  Global, regional, and national causes of under-5 mortality in 2000–15: an updated systematic analysis with implications for the Sustainable Development Goals 
Lancet (London, England)  2016;388(10063):3027-3035.
Summary
Background
Despite remarkable progress in the improvement of child survival between 1990 and 2015, the Millennium Development Goal (MDG) 4 target of a two-thirds reduction of under-5 mortality rate (U5MR) was not achieved globally. In this paper, we updated our annual estimates of child mortality by cause to 2000–15 to reflect on progress toward the MDG 4 and consider implications for the Sustainable Development Goals (SDG) target for child survival.
Methods
We increased the estimation input data for causes of deaths by 43% among neonates and 23% among 1–59-month-olds, respectively. We used adequate vital registration (VR) data where available, and modelled cause-specific mortality fractions applying multinomial logistic regressions using adequate VR for low U5MR countries and verbal autopsy data for high U5MR countries. We updated the estimation to use Plasmodium falciparum parasite rate in place of malaria index in the modelling of malaria deaths; to use adjusted empirical estimates instead of modelled estimates for China; and to consider the effects of pneumococcal conjugate vaccine and rotavirus vaccine in the estimation.
Findings
In 2015, among the 5·9 million under-5 deaths, 2·7 million occurred in the neonatal period. The leading under-5 causes were preterm birth complications (1·055 million [95% uncertainty range (UR) 0·935–1·179]), pneumonia (0·921 million [0·812 −1·117]), and intrapartum-related events (0·691 million [0·598 −0·778]). In the two MDG regions with the most under-5 deaths, the leading cause was pneumonia in sub-Saharan Africa and preterm birth complications in southern Asia. Reductions in mortality rates for pneumonia, diarrhoea, neonatal intrapartum-related events, malaria, and measles were responsible for 61% of the total reduction of 35 per 1000 livebirths in U5MR in 2000–15. Stratified by U5MR, pneumonia was the leading cause in countries with very high U5MR. Preterm birth complications and pneumonia were both important in high, medium high, and medium child mortality countries; whereas congenital abnormalities was the most important cause in countries with low and very low U5MR.
Interpretation
In the SDG era, countries are advised to prioritise child survival policy and programmes based on their child cause-of-death composition. Continued and enhanced efforts to scale up proven life-saving interventions are needed to achieve the SDG child survival target.
Funding
Bill & Melinda Gates Foundation, WHO.
doi:10.1016/S0140-6736(16)31593-8
PMCID: PMC5161777  PMID: 27839855
3.  EXPLORING THE REPRODUCIBILITY OF PROBABILISTIC CAUSAL MOLECULAR NETWORK MODELS 
Network reconstruction algorithms are increasingly being employed in biomedical and life sciences research to integrate large-scale, high-dimensional data informing on living systems. One particular class of probabilistic causal networks being applied to model the complexity and causal structure of biological data is Bayesian networks (BNs). BNs provide an elegant mathematical framework for not only inferring causal relationships among many different molecular and higher order phenotypes, but also for incorporating highly diverse priors that provide an efficient path for incorporating existing knowledge. While significant methodological developments have broadly enabled the application of BNs to generate and validate meaningful biological hypotheses, the reproducibility of BNs in this context has not been systematically explored. In this study, we aim to determine the criteria for generating reproducible BNs in the context of transcription-based regulatory networks. We utilize two unique tissues from independent datasets, whole blood from the GTEx Consortium and liver from the Stockholm-Tartu Atherosclerosis Reverse Network Engineering Team (STARNET) study. We evaluated the reproducibility of the BNs by creating networks on data subsampled at different levels from each cohort and comparing these networks to the BNs constructed using the complete data. To help validate our results, we used simulated networks at varying sample sizes. Our study indicates that reproducibility of BNs in biological research is an issue worthy of further consideration, especially in light of the many publications that now employ findings from such constructs without appropriate attention paid to reproducibility. We find that while edge-to-edge reproducibility is strongly dependent on sample size, identification of more highly connected key driver nodes in BNs can be carried out with high confidence across a range of sample sizes.
PMCID: PMC5161348  PMID: 27896968
4.  Molecular mechanism: the human dopamine transporter histidine 547 regulates basal and HIV-1 Tat protein-inhibited dopamine transport 
Scientific Reports  2016;6:39048.
Abnormal dopaminergic transmission has been implicated as a risk determinant of HIV-1-associated neurocognitive disorders. HIV-1 Tat protein increases synaptic dopamine (DA) levels by directly inhibiting DA transporter (DAT) activity, ultimately leading to dopaminergic neuron damage. Through integrated computational modeling prediction and experimental validation, we identified that histidine547 on human DAT (hDAT) is critical for regulation of basal DA uptake and Tat-induced inhibition of DA transport. Compared to wild type hDAT (WT hDAT), mutation of histidine547 (H547A) displayed a 196% increase in DA uptake. Other substitutions of histidine547 showed that DA uptake was not altered in H547R but decreased by 99% in H547P and 60% in H547D, respectively. These mutants did not alter DAT surface expression or surface DAT binding sites. H547 mutants attenuated Tat-induced inhibition of DA transport observed in WT hDAT. H547A displays a differential sensitivity to PMA- or BIM-induced activation or inhibition of DAT function relative to WT hDAT, indicating a change in basal PKC activity in H547A. These findings demonstrate that histidine547 on hDAT plays a crucial role in stabilizing basal DA transport and Tat-DAT interaction. This study provides mechanistic insights into identifying targets on DAT for Tat binding and improving DAT-mediated dysfunction of DA transmission.
doi:10.1038/srep39048
PMCID: PMC5155291  PMID: 27966610
5.  The Sex Ratio at Birth for 5,338,853 Deliveries in China from 2012 to 2015: A Facility-Based Study 
PLoS ONE  2016;11(12):e0167575.
Objective
The accuracy of a population-based sex ratio at birth (SRB) in China has long been questioned. To depict a more accurate profile, the present study used data from a national surveillance system for health facility births to explore the characteristics of SRB in China.
Methods
Data from China’s National Maternal Near Miss Surveillance System between 2012 and 2015 were used. We restricted the analysis to live births of ≥28 completed gestational weeks or ≥1000 g birth weight. The strength of association between obstetric characteristics and SRB was examined using logistic regression, taking into account the sampling strategy and clustering of births within health facilities.
Results
There were 2,785,513 boys and 2,549,269 girls born alive between 2012 and 2015 in 441 health facilities. The SRB was 111.04 in 2012, 110.16 in 2013, 108.79 in 2014, and 109.53 in 2015. The SRB was high in the eastern region, especially in rural areas. The SRBs increased with mother’s age and decreased with mother’s education. The SRB in women who were pregnant for the first time was 104.30. The SRB in primipara was normal (104.35), but it was extremely high in non-primipara, especially for women with three or more parities (141.76); only 5.26% of live births fell within this group. The SRBs increased significantly by the number of parities, especially in the rural areas of the central region. After adjustment for sociodemographic factors, women with three or more parities were 1.39 (95% CI 1.34, 1.43) times more likely to give birth to a boy compared with primiparae who were pregnant for the first time.
Conclusion
Our analysis suggests that the SRB was lower than what was reported officially but higher than normal. The government should keep strengthening supervision to prevent sex-selection, especially in the wake of the two-child policy implemented in 2015.
doi:10.1371/journal.pone.0167575
PMCID: PMC5152891  PMID: 27941978
6.  Association Between KCNQ1 Genetic Variants and Type 2 Diabetes in the Uyghur Population 
Objective: To investigate the association between KCNQ1 gene polymorphisms and type 2 diabetes (T2D) in an admixed ethnic minority, Uyghur population, living in the Northwest region of China. Materials and Methods: We genotyped three tagging single-nucleotide polymorphisms rs2283171, rs11023485, and rs2283208 of the KCNQ1 gene in 1006 T2D participants and 1004 controls and conducted association analysis. Results: The frequencies of the AG and GG genotypes and the G allele of rs2283171 were higher in the control group (51.4%, 22%, and 47.7%, respectively) than in the case group (49%, 17.6%, and 42.1%, respectively). The minor G allele decreased the risk of T2D with a per-allele odds ratio of 0.79 (95% CI: 0.70–0.90) for the additive genetic model in univariate analysis (p = 0.0001). After adjustment for the covariates of age, gender, smoking, alcohol use, systolic blood pressure (SBP), diastolic blood pressure (DBP), body mass index (BMI), triglyceride (TG), and total cholesterol (TC), the diabetic protective effect of the rs2283171-G allele remained. No difference was observed in the frequency distributions of the rs11023485 and rs2283208 genotypes between the two groups. Conclusion: We identified a novel association between rs2283171 of KCNQ1 and T2D in the Uyghur population. Further association and functional studies are required to identify the causal functional variant that is in linkage disequilibrium with this polymorphism.
doi:10.1089/gtmb.2015.0146
PMCID: PMC4677565  PMID: 26540651
7.  Cell Therapy with Human Dermal Fibroblasts Enhances Intervertebral Disk Repair and Decreases Inflammation in the Rabbit Model 
Global Spine Journal  2016;6(8):771-779.
Study Design Pilot study using the rabbit model.
Objective Low back pain is often associated with disk degeneration. Cell therapy for degenerating disks may promote tissue regeneration and repair. Human dermal fibroblasts, obtained from the patient's skin tissue or donated tissue, may be a promising cell therapy option for degenerating disks. The objective of these studies is to determine the effects of intradiscal transplantation of neonatal human dermal fibroblasts (nHDFs) on intervertebral disk (IVD) degeneration by measuring disk height, magnetic resonance imaging (MRI) signal intensity, gene expression, and collagen immunostaining.
Methods New Zealand white rabbits (n = 16) received an annular puncture to induce disk degeneration and were treated with nHDFs or saline 4 weeks later. At 2 and 8 weeks post-treatment, X-ray and MRI images were obtained. IVDs were isolated and examined for changes in collagen staining and gene expression.
Results In the nHDF-treated group, there was a 10% increase in the disk height index after 8 weeks of treatment (p ≤ 0.05), and there was no significant difference in the saline-treated group. When compared with the saline-treated disks, disks treated with nHDFs showed reduced expression of inflammatory markers, a higher ratio of collagen type II over collagen type I gene expression, and more intense immunohistochemical staining for both collagen types I and II.
Conclusions Human dermal fibroblast introduction into the disk reduced inflammation and promoted tissue rich in both type I and type II collagens. The results of this study suggest that nHDFs would be a feasible cell therapy option for disk degeneration.
doi:10.1055/s-0036-1582391
PMCID: PMC5110358  PMID: 27853661
cell therapy; human dermal fibroblast; disk degeneration; rabbit model
8.  Quorum Regulated Resistance of Vibrio cholerae against Environmental Bacteriophages 
Scientific Reports  2016;6:37956.
Predation by bacteriophages can significantly influence the population structure of bacterial communities. Vibrio cholerae the causative agent of cholera epidemics interacts with numerous phages in the aquatic ecosystem, and in the intestine of cholera patients. Seasonal epidemics of cholera reportedly collapse due to predation of the pathogen by phages. However, it is not clear how sufficient number of the bacteria survive to seed the environment in the subsequent epidemic season. We found that bacterial cell density-dependent gene expression termed “quorum sensing” which is regulated by signal molecules called autoinducers (AIs) can protect V. cholerae against predatory phages. V. cholerae mutant strains carrying inactivated AI synthase genes were significantly more susceptible to multiple phages compared to the parent bacteria. Likewise when mixed cultures of phage and bacteria were supplemented with exogenous autoinducers CAI-1 or AI-2 produced by recombinant strains carrying cloned AI synthase genes, increased survival of V. cholerae and a decrease in phage titer was observed. Mutational analyses suggested that the observed effects of autoinducers are mediated in part through the quorum sensing-dependent production of haemaglutinin protease, and partly through downregulation of phage receptors. These results have implication in developing strategies for phage mediated control of cholera.
doi:10.1038/srep37956
PMCID: PMC5124996  PMID: 27892495
9.  Genetic Algorithms Applied to Multi-Class Clustering for Gene Expression Data 
A hybrid GA (genetic algorithm)-based clustering (HGACLUS) schema, combining merits of the Simulated Annealing, was described for finding an optimal or near-optimal set of medoids. This schema maximized the clustering success by achieving internal cluster cohesion and external cluster isolation. The performance of HGACLUS and other methods was compared by using simulated data and open microarray gene-expression datasets. HGACLUS was generally found to be more accurate and robust than other methods discussed in this paper by the exact validation strategy and the explicit cluster number.
doi:10.1016/S1672-0229(03)01033-7
PMCID: PMC5172428  PMID: 15629056
genetic algorithms; gene expression; clustering; medoid
10.  Clustering Gene Expression Data Based on Predicted Differential Effects of GV Interaction 
Microarray has become a popular biotechnology in biological and medical research. However, systematic and stochastic variabilities in microarray data are expected and unavoidable, resulting in the problem that the raw measurements have inherent “noise” within microarray experiments. Currently, logarithmic ratios are usually analyzed by various clustering methods directly, which may introduce bias interpretation in identifying groups of genes or samples. In this paper, a statistical method based on mixed model approaches was proposed for microarray data cluster analysis. The underlying rationale of this method is to partition the observed total gene expression level into various variations caused by different factors using an ANOVA model, and to predict the differential effects of GV (gene by variety) interaction using the adjusted unbiased prediction (AUP) method. The predicted GV interaction effects can then be used as the inputs of cluster analysis. We illustrated the application of our method with a gene expression dataset and elucidated the utility of our approach using an external validation.
doi:10.1016/S1672-0229(05)03005-6
PMCID: PMC5172465  PMID: 16144520
gene expression; clustering analysis; predicting GV interaction effects
11.  OsACOS12, an orthologue of Arabidopsis acyl-CoA synthetase5, plays an important role in pollen exine formation and anther development in rice 
BMC Plant Biology  2016;16:256.
Background
Sporopollenin is a major component of the pollen exine pattern. In Arabidopsis, acyl-CoA synthetase5 (ACOS5) is involved in sporopollenin precursor biosynthesis. In this study, we identified its orthologue, OsACOS12, in rice (Oryza sativa) and compared the functional conservation of ACOS in rice to Arabidopsis.
Results
Sequence analysis showed that OsACOS12 shares 63.9 % amino acid sequence identity with ACOS5. The osacos12 mutation caused by a pre-mature stop codon in LOC_Os04g24530 exhibits defective sexine resulting in a male sterile phenotype in rice. In situ hybridization shows that OsACOS12 is expressed in tapetal cells and microspores at the transcript level. The localization of OsACOS12-GFP demonstrated that OsACOS12 protein is accumulated in tapetal cells and anther locules. OsACOS12 driven by the ACOS5 promoter could partially restore the male fertility of the acos5 mutant in Arabidopsis.
Conclusions
OsACOS12 is an orthologue of ACOS5 that is essential for sporopollenin synthesis in rice. ACOS5 and OsACOS12 are conserved for pollen wall formation in monocot and dicot species.
Electronic supplementary material
The online version of this article (doi:10.1186/s12870-016-0943-9) contains supplementary material, which is available to authorized users.
doi:10.1186/s12870-016-0943-9
PMCID: PMC5117612  PMID: 27871243
Oryza sativa; OsACOS12; Male sterility; Pollen exine; Anther cuticle
12.  BACH2 regulates CD8+ T cell differentiation by controlling access of AP-1 factors to enhancers 
Nature immunology  2016;17(7):851-860.
T cell antigen receptor (TCR) signaling drives distinct responses depending upon the differentiation state and context of CD8+ T cells. We hypothesized that access of signal-dependent transcription factors (TFs) to enhancers is dynamically regulated to shape transcriptional responses to TCR signaling. We found that the TF BACH2 restrains terminal differentiation to enable generation of long-lived memory cells and protective immunity following viral infection. BACH2 was recruited to enhancers where it limited expression of TCR-driven genes by attenuating the availability of activator protein 1 (AP-1) sites to Jun family signal-dependent TFs. In naïve cells, this prevented TCR-driven induction of genes associated with terminal differentiation. Upon effector differentiation, reduced expression of BACH2 and its phosphorylation enabled unrestrained induction of TCR-driven effector programs.
doi:10.1038/ni.3441
PMCID: PMC4918801  PMID: 27158840
13.  Fusobacterium nucleatum-Induced Impairment of Autophagic Flux Enhances the Expression of Proinflammatory Cytokines via ROS in Caco-2 Cells 
PLoS ONE  2016;11(11):e0165701.
Fusobacterium nucleatum (F. nucleatum) plays a critical role in gastrointestinal inflammation. However, the exact mechanism by which F. nucleatum contributes to inflammation is unclear. In the present study, it was revealed that F. nucleatum could induce the production of proinflammatory cytokines (IL-8, IL-1β and TNF-α) and reactive oxygen species (ROS) in Caco-2 colorectal) adenocarcinoma cells. Furthermore, ROS scavengers (NAC or Tiron) could decrease the production of proinflammatory cytokines during F. nucleatum infection. In addition, we observed that autophagy is impaired in Caco-2 cells after F. nucleatum infection. The production of proinflammatory cytokines and ROS induced by F. nucleatum was enhanced with either autophagy pharmacologic inhibitors (3-methyladenine, bafilomycin A1) or RNA interference in essential autophagy genes (ATG5 or ATG12) in Caco-2 cells. Taken together, these results indicate that F. nucleatum-induced impairment of autophagic flux enhances the expression of proinflammatory cytokines via ROS in Caco-2 Cells.
doi:10.1371/journal.pone.0165701
PMCID: PMC5102440  PMID: 27828984
14.  The OsmiR396c‐OsGRF4‐OsGIF1 regulatory module determines grain size and yield in rice 
Plant Biotechnology Journal  2016;14(11):2134-2146.
Summary
Grain weight is the most important component of rice yield and is mainly determined by grain size, which is generally controlled by quantitative trait loci (QTLs). Although numerous QTLs that regulate grain weight have been identified, the genetic network that controls grain size remains unclear. Herein, we report the cloning and functional analysis of a dominant QTL, grain length and width 2 (GLW2), which positively regulates grain weight by simultaneously increasing grain length and width. The GLW2 locus encodes OsGRF4 (growth‐regulating factor 4) and is regulated by the microRNA miR396c in vivo. The mutation in OsGRF4 perturbs the OsmiR396 target regulation of OsGRF4, generating a larger grain size and enhanced grain yield. We also demonstrate that OsGIF1 (GRF‐interacting factors 1) directly interacts with OsGRF4, and increasing its expression improves grain size. Our results suggest that the miR396c‐OsGRF4‐OsGIF1 regulatory module plays an important role in grain size determination and holds implications for rice yield improvement.
doi:10.1111/pbi.12569
PMCID: PMC5095787  PMID: 27107174
rice; grain size; growth‐regulating factor; miR396; GRF‐interacting factors
15.  Tcf1 and Lef1 transcription factors establish CD8+ T cell identity through intrinsic HDAC activity 
Nature immunology  2016;17(6):695-703.
The CD4+ and CD8+ T cell dichotomy is essential for effective cellular immunity. How the individual T cell identity is established remains poorly understood. Here we show that the high mobility group (HMG) transcription factors Tcf1 and Lef1 are essential for repressing CD4+ lineage-associated genes including Cd4, Foxp3 and Rorc in CD8+ T cells. Tcf1- and Lef1-deficient CD8+ T cells exhibit histone hyperacetylation, which is ascribed to an unexpected intrinsic histone deacetylase (HDAC) activity in Tcf1 and Lef1. Mutating five conserved amino acids in the Tcf1 HDAC domain diminishes the HDAC activity and the ability to suppress CD4+ lineage genes in CD8+ T cells. These findings reveal that sequence-specific transcription factors can utilize intrinsic HDAC activity to guard cell identity by repressing lineage-inappropriate genes.
doi:10.1038/ni.3456
PMCID: PMC4873337  PMID: 27111144
16.  Inconceivable Hypokalemia: A Case Report of Acute Severe Barium Chloride Poisoning 
Case Reports in Medicine  2016;2016:2743134.
Barium is a heavy divalent alkaline earth metal that has been known as a muscle poison. Barium can cause human toxicity, which may lead to significant hypokalemia and have serious consequences. This paper reports a case of unprecedented barium intoxication in which the patient, who suffered from depression, swallowed at least 3.0 g barium chloride to commit suicide. On admission, the patient presented with nausea, vomiting, stomach burning feeling, dizziness, and weakness. Emergency biochemical testing showed that the patient was suffering from severe hypokalemia (K+ 1.7 mmol/L). His electrocardiogram (ECG) prompted atrioventricular blocking, ventricular tachycardia, prolongation of PR interval, ST segment depression with U waves, and T wave inversion. Intravenous potassium supplements were given immediately to correct hypokalemia and regular monitoring of vital signs and fluid balance was arranged. After all-out rescue of our hospital personnel, the condition of the patient is currently stable and he is gradually recovering. This case exemplifies the weaknesses of the management of toxic substances and the lack of mental health education for young people. We hope to get more attention for the supervision of toxic substances and the healthy development of young people.
doi:10.1155/2016/2743134
PMCID: PMC5093257  PMID: 27840643
17.  Amniotic fluid embolism as a cause of maternal mortality in China between 1996 and 2013: a population-based retrospective study 
Background
To analyse the maternal mortality ratio, demographic and pregnancy related details in women who suffered a fatal amniotic fluid embolism (AFE) in China.
Methods
A retrospective population based study using data collected as part of the National Maternal Mortality Surveillance System between 1996 and 2013. Data were collected onto a standardised form from women whose cause of death was listed as being secondary to AFE.
Results
Records were available for 640 deaths. Over the 17 year period the maternal mortality ratio for AFE decreased from 4.4 per 100,000 births (95 % confidence interval (CI):2.72–6.12) to 1.9 per 100,000 births (95 % CI:1.35–2.54). Over the same period the proportion of maternal deaths secondary to AFE increased from 6.8 to 12.5 %. The mean age of women who died was 30.1 years and the onset of the AFE occurred prior to delivery in 39 %. The most prominent presenting features included premonitory symptoms (29 %), acute fetal compromise (28 %), maternal haemorrhage (16 %) and shortness of breath (15 %).
Conclusions
Maternal mortality secondary to AFE has decreased in China, however at a slower rate than mortality secondary to other conditions. Active surveillance is recommended to assess case fatality rates, risk factors and other lessons specific to this population.
doi:10.1186/s12884-016-1106-6
PMCID: PMC5069862  PMID: 27760522
Amniotic fluid embolism; Maternal mortality ratio; Maternal mortality; Maternal death; Pregnancy; China
18.  Stacking sequence and interlayer coupling in few-layer graphene revealed by in situ imaging 
Nature Communications  2016;7:13256.
In the transition from graphene to graphite, the addition of each individual graphene layer modifies the electronic structure and produces a different material with unique properties. Controlled growth of few-layer graphene is therefore of fundamental interest and will provide access to materials with engineered electronic structure. Here we combine isothermal growth and etching experiments with in situ scanning electron microscopy to reveal the stacking sequence and interlayer coupling strength in few-layer graphene. The observed layer-dependent etching rates reveal the relative strength of the graphene–graphene and graphene–substrate interaction and the resulting mode of adlayer growth. Scanning tunnelling microscopy and density functional theory calculations confirm a strong coupling between graphene edge atoms and platinum. Simulated etching confirms that etching can be viewed as reversed growth. This work demonstrates that real-time imaging under controlled atmosphere is a powerful method for designing synthesis protocols for sp2 carbon nanostructures in between graphene and graphite.
Controlled preparation of few-layer graphene is a promising, yet challenging technological protocol. Here, the authors perform real-time imaging during chemical vapour deposition growth and hydrogen etching, to gain insight into layer-dependent growth mechanisms and graphene-substrate interaction.
doi:10.1038/ncomms13256
PMCID: PMC5075831  PMID: 27759024
19.  In Situ Graphene Growth Dynamics on Polycrystalline Catalyst Foils 
Nano Letters  2016;16(10):6196-6206.
The dynamics of graphene growth on polycrystalline Pt foils during chemical vapor deposition (CVD) are investigated using in situ scanning electron microscopy and complementary structural characterization of the catalyst with electron backscatter diffraction. A general growth model is outlined that considers precursor dissociation, mass transport, and attachment to the edge of a growing domain. We thereby analyze graphene growth dynamics at different length scales and reveal that the rate-limiting step varies throughout the process and across different regions of the catalyst surface, including different facets of an individual graphene domain. The facets that define the domain shapes lie normal to slow growth directions, which are determined by the interfacial mobility when attachment to domain edges is rate-limiting, as well as anisotropy in surface diffusion as diffusion becomes rate-limiting. Our observations and analysis thus reveal that the structure of CVD graphene films is intimately linked to that of the underlying polycrystalline catalyst, with both interfacial mobility and diffusional anisotropy depending on the presence of step edges and grain boundaries. The growth model developed serves as a general framework for understanding and optimizing the growth of 2D materials on polycrystalline catalysts.
doi:10.1021/acs.nanolett.6b02459
PMCID: PMC5064306  PMID: 27576749
Graphene; platinum; chemical vapor deposition; growth dynamics; modeling; domain shape
20.  Metabolic Risk Factors of Type 2 Diabetes Mellitus and Correlated Glycemic Control/Complications: A Cross-Sectional Study between Rural and Urban Uygur Residents in Xinjiang Uygur Autonomous Region 
PLoS ONE  2016;11(9):e0162611.
Background
Diabetes is a major global public health problem driven by a high prevalence of metabolic risk factors.
Objective
To describe the differences of metabolic risk factors of type 2 diabetes, as well as glycemic control and complicated diabetic complications between rural and urban Uygur residents in Xinjiang Uygur Autonomous Region of China.
Methods
This comparative cross-sectional study, conducted among 2879 urban and 918 rural participants in Xinjiang, China, assessed the metabolic risk factors of diabetes and related complications differences between urban and rural settlements.
Results
Compared to rural areas, urban participants had higher education level and more average income, little physical activity, less triglycerides and higher HDL-c (p < 0.05 respectively). Differences in metabolic risk factors by urban/rural residence included overweight or obesity, triglycerides (≥1.71mmol/l), HDL-c (< 1.04 mmol/l), alcohol intake, and physical inactivity (p < 0.01 respectively). There was significant difference regarding the prevalence of HbA1c >8% (48.1% versus 54.5%, p = 0.019) between rural and urban diabetic participants. No significant difference in the prevalence of type 2 diabetic complications between urban and rural participants (74.9% versus 72.2%; p = 0.263) was detected. Compared to rural participants, the most prevalent modifiable risk factors associated with diabetic complications in urban participants were obesity (BMI ≥ 28 Kg/m2), HDL-c (< 1.04 mmol/l), physical inactivity and irregular eating habits (p = 0.035, p = 0.001, p < 0.001, and p = 0.013, respectively).
Conclusions
Urban settlers were significantly more likely to have metabolic risk factors highlighting the need for public health efforts to improve health outcomes for these vulnerable populations. Diabetes related complications risk factors were prevalent amongst rural and urban diabetes settlers.
doi:10.1371/journal.pone.0162611
PMCID: PMC5021360  PMID: 27622506
21.  Disease-specific classification using deconvoluted whole blood gene expression 
Scientific Reports  2016;6:32976.
Blood-based biomarker assays have an advantage in being minimally invasive. Diagnostic and prognostic models built on peripheral blood gene expression have been reported for various types of disease. However, most of these studies focused on only one disease type, and failed to address whether the identified gene expression signature is disease-specific or more widely applicable across diseases. We conducted a meta-analysis of 46 whole blood gene expression datasets covering a wide range of diseases and physiological conditions. Our analysis uncovered a striking overlap of signature genes shared by multiple diseases, driven by an underlying common pattern of cell component change, specifically an increase in myeloid cells and decrease in lymphocytes. These observations reveal the necessity of building disease-specific classifiers that can distinguish different disease types as well as normal controls, and highlight the importance of cell component change in deriving blood gene expression based models. We developed a new strategy to develop blood-based disease-specific models by leveraging both cell component changes and cell molecular state changes, and demonstrate its superiority using independent datasets.
doi:10.1038/srep32976
PMCID: PMC5011717  PMID: 27596246
22.  Discover the network mechanisms underlying the connections between aging and age-related diseases 
Scientific Reports  2016;6:32566.
Although our knowledge of aging has greatly expanded in the past decades, it remains elusive why and how aging contributes to the development of age-related diseases (ARDs). In particular, a global mechanistic understanding of the connections between aging and ARDs is yet to be established. We rely on a network modelling named “GeroNet” to study the connections between aging and more than a hundred diseases. By evaluating topological connections between aging genes and disease genes in over three thousand subnetworks corresponding to various biological processes, we show that aging has stronger connections with ARD genes compared to non-ARD genes in subnetworks corresponding to “response to decreased oxygen levels”, “insulin signalling pathway”, “cell cycle”, etc. Based on subnetwork connectivity, we can correctly “predict” if a disease is age-related and prioritize the biological processes that are involved in connecting to multiple ARDs. Using Alzheimer’s disease (AD) as an example, GeroNet identifies meaningful genes that may play key roles in connecting aging and ARDs. The top modules identified by GeroNet in AD significantly overlap with modules identified from a large scale AD brain gene expression experiment, supporting that GeroNet indeed reveals the underlying biological processes involved in the disease.
doi:10.1038/srep32566
PMCID: PMC5007654  PMID: 27582315
23.  CCCCC pentadentate chelates with planar Möbius aromaticity and unique properties 
Science Advances  2016;2(8):e1601031.
Planar Möbius aromatic metallacycles show NIR absorption spectrum and the highest carbon coordination number for a metal atom.
The coordinating atoms in polydentate chelates are primarily heteroatoms. We present the first examples of pentadentate chelates with all binding atoms of the chelating agent being carbon atoms, denoted as CCCCC chelates. Having up to five metal-carbon bonds in the equatorial plane has not been previously observed in transition metal chemistry. Density functional theory calculations showed that the planar metallacycle has extended Craig-Möbius aromaticity arising from 12-center–12-electron dπ-pπ π-conjugation. These planar chelates have broad absorption in the ultraviolet-visible–near-infrared region and, thus, notable photothermal performance upon irradiation by an 808-nm laser, indicating that these chelates have potential applications in photothermal therapy. The combination of facile synthesis, high stability, and broad absorption of these complexes could make the polydentate carbon chain a novel building block in coordination chemistry.
doi:10.1126/sciadv.1601031
PMCID: PMC5001811  PMID: 27574707
Metallacycles; Möbius Aromaticity; Carbon Chain; Pentadentate Chelate
24.  A parameter estimation algorithm for LFM/BPSK hybrid modulated signal intercepted by Nyquist folding receiver 
Nyquist folding receiver (NYFR) is a novel ultra-wideband receiver architecture which can realize wideband receiving with a small amount of equipment. Linear frequency modulated/binary phase shift keying (LFM/BPSK) hybrid modulated signal is a novel kind of low probability interception signal with wide bandwidth. The NYFR is an effective architecture to intercept the LFM/BPSK signal and the LFM/BPSK signal intercepted by the NYFR will add the local oscillator modulation. A parameter estimation algorithm for the NYFR output signal is proposed. According to the NYFR prior information, the chirp singular value ratio spectrum is proposed to estimate the chirp rate. Then, based on the output self-characteristic, matching component function is designed to estimate Nyquist zone (NZ) index. Finally, matching code and subspace method are employed to estimate the phase change points and code length. Compared with the existing methods, the proposed algorithm has a better performance. It also has no need to construct a multi-channel structure, which means the computational complexity for the NZ index estimation is small. The simulation results demonstrate the efficacy of the proposed algorithm.
doi:10.1186/s13634-016-0387-2
PMCID: PMC4990610  PMID: 27594883
Nyquist folding receiver; LFM/BPSK hybrid modulated signal; Parameter estimation; Signal characteristics
25.  Clinical characteristics and one year outcomes in Chinese atrial fibrillation patients with stable coronary artery disease: a population-based study 
Background
Atrial fibrillation (AF) and coronary artery disease (CAD) often coexist, however, the clinical characteristics and the impact of stable CAD on the outcomes in Chinese patients with AF has not been well understood.
Methods
Consecutive AF patients in 20 hospitals in China from November 2008 to October 2011 were enrolled. The primary endpoints included 1-year all-cause mortality, stroke, non-central nervous system (non-CNS) embolism, and major bleeding.
Results
A total of 1947 AF patients were analyzed, of whom 40.5% had stable CAD. The mean CHADS2 scores in CAD patients were significantly higher than that of non-CAD patients (2.4 ± 1.4 vs. 1.4 ± 1.2, P < 0.001). During follow-up period, warfarin use is low in both groups, with relatively higher proportion in non-CAD patients compared with CAD patients (22.3% vs. 10.7%, P < 0.001). Compared with non-CAD patients, CAD patients had higher one-year all-cause mortality (16.8% vs. 12.9%, P = 0.017) and incidence of stroke (9.0% vs. 6.4%, P = 0.030), while the non-CNS embolism and major bleeding rates were comparable between the two groups. After multivariate adjustment, stable CAD was independently associated with increased risk of 1-year all-cause mortality (HR = 1.35, 95% CI: 1.01−1 .80, P = 0.040), but not associated with stroke (HR = 1.07, 95% CI: 0.72–1.58, P = 0.736).
Conclusions
Stable CAD was prevalent in Chinese AF patients and was independently associated with increased risk of 1-year all-cause mortality. Chinese AF patients with stable CAD received inadequate antithrombotic therapy and this grim status of antithrombotic therapy needed to be improved urgently.
doi:10.11909/j.issn.1671-5411.2016.08.004
PMCID: PMC5067427  PMID: 27781056
Antithrombotic therapy; Atrial fibrillation; CHADS2 score; Stable coronary artery disease

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