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author:("Ma, jianli")
1.  Three Independent Forms of Cardio-Respiratory Coupling: Transitions across Sleep Stages 
Computing in cardiology  2014;41:781-784.
We demonstrate that the cardiac and respiratory system exhibit three distinct forms of coupling that are independent from each other, respond differently to key physiologic parameters, and act on different time scales. We find that all three forms of coupling undergo pronounced phase transitions across sleep stages characterized by different stratification patterns, indicating markedly different response to changes in neuroautonomic control. Our analyses show that all three forms of cardio-respiratory interaction are not of constant strength but are of transient and intermittent nature with “on” and “off” periods, and that these forms of coupling, representing different aspects of physiologic regulation, can simultaneously coexist.
PMCID: PMC4319215  PMID: 25664348
2.  Effects of coarse-graining on the scaling behavior of long-range correlated and anti-correlated signals 
Physica A  2011;390(23-24):4057-4072.
We investigate how various coarse-graining (signal quantization) methods affect the scaling properties of long-range power-law correlated and anti-correlated signals, quantified by the detrended fluctuation analysis. Specifically, for coarse-graining in the magnitude of a signal, we consider (i) the Floor, (ii) the Symmetry and (iii) the Centro-Symmetry coarse-graining methods. We find that for anti-correlated signals coarse-graining in the magnitude leads to a crossover to random behavior at large scales, and that with increasing the width of the coarse-graining partition interval Δ, this crossover moves to intermediate and small scales. In contrast, the scaling of positively correlated signals is less affected by the coarse-graining, with no observable changes when Δ < 1, while for Δ > 1 a crossover appears at small scales and moves to intermediate and large scales with increasing Δ. For very rough coarse-graining (Δ > 3) based on the Floor and Symmetry methods, the position of the crossover stabilizes, in contrast to the Centro-Symmetry method where the crossover continuously moves across scales and leads to a random behavior at all scales; thus indicating a much stronger effect of the Centro-Symmetry compared to the Floor and the Symmetry method. For coarse-graining in time, where data points are averaged in non-overlapping time windows, we find that the scaling for both anti-correlated and positively correlated signals is practically preserved. The results of our simulations are useful for the correct interpretation of the correlation and scaling properties of symbolic sequences.
PMCID: PMC4226277  PMID: 25392599
Coarse-graining; Detrended fluctuation analysis; Scaling behavior
3.  Distribution of HLA-A, -B, and -C Alleles and HLA/KIR Combinations in Han Population in China 
Journal of Immunology Research  2014;2014:565296.
We investigated polymorphisms of the human leukocyte antigen (HLA) class I (A, B, and C) loci of a Han population (n, 239) from the Yunnan province, Southwest China, using high-resolution polymerase chain reaction-Luminex (PCR-Luminex) typing. We combined the HLA data from this study with the KIR genotypes from a previous study of this Han population to analyze the combination of KIR/HLA ligands. A total of 27 HLA-A, 54 HLA-B, and 31 HLA-C alleles were found in this population. The frequencies of A*11:01, A*24:02, B*40:01, B*46:01, C*01:02, C*03:04, and C*07:02 were all > 10%. The following haplotypes were common, with frequencies > 5%: 1 A-B (A*02:07-B*46:01), 2 A-C (A*02:07-C*01:02, and A*11:01-C*07:02), 4 C-B (B*13:01-C*03:04, B*40:01-C*07:02, B*46:01-C*01:02 and B*58:01-C*03:02), and 1 A-C-B (A*02:07-C*01:02-B*46:01). Analysis of KIR3D and their ligands HLA-A3/A11 and HLA-Bw4 showed that the frequencies of 3DL2+-A3/A11+ and 3DL2+-A3/A11− were 0.527 and 0.473, and the frequencies of 3DL1+-Bw4+, 3DL1+-Bw4−, 3DL1−-Bw4+, and 3DL1−-Bw4− were 0.552, 0.397, 0.038, and 0.013, respectively. The results of KIR/HLA-C combination analysis showed that all individuals had at least one inhibitory or activating KIR/HLA-C pair, and one KIR/HLA-C pair was the most frequent (157/239), followed by two pairs (46/239), three pairs (33/239), and no pairs (3/239). Comparison of KIR gene and HLA gene and their pair frequency between Yunnan Han and the isolated Han (FYDH) who also lived in Yunnan province showed no significant difference (P > 0.05) in KIR frequencies, but significant differences (P < 0.05) for some HLA allele frequencies. In addition, there was no significant difference (P > 0.05) between the two populations for KIR/HLA pairs.
PMCID: PMC4068047  PMID: 24995346
4.  Disease knowledge level is a noteworthy risk factor of anxiety and depression in patients with chronic obstructive pulmonary disease: a cross-sectional study 
Risk factors of anxiety and depression symptoms in patients with chronic obstructive pulmonary disease (COPD) have been widely researched, but most of them cannot be addressed clinically. The aim of this study was to investigate whether COPD knowledge level is a risk factor of anxiety and/or depression in COPD patients in addition to functional capacity and quality of life, and to determine the key topics of COPD knowledge.
A total of 364 COPD patients from four centers were recruited into this cross-sectional survey. Subjects’ general medical information, assessments of lung function, dyspnea, quality of life, and exercise capacity, and responses to the Hospital Anxiety and Depression Scale (HAD) and the Bristol COPD Knowledge Questionnaire (BCKQ) were collected. Partial correlation analysis was performed, and a multivariable model testing risk factors of anxiety and depression as well as a multivariable model of 13 topics of knowledge derived from BCKQ were constructed.
Subjects with anxiety or depression were more likely to have less COPD knowledge. Partial correlation analysis revealed that HAD score was negatively correlated with BCKQ score (rho = −0.153, P = 0.004). BCKQ score was significant in the multivariable model that tested risk factors of anxiety and depression (P = 0.001, OR = 0.944). Topics of epidemiology (P < 0.001, OR = 0.653) and infections (P = 0.006, OR = 0.721) were significant in the multivariable model evaluating 13 topics.
The level of patients’ disease knowledge is a significant risk factor of anxiety and depression in COPD patients. Epidemiology and infections are key topics of COPD knowledge to target in the Chinese population.
Trial registration
PMCID: PMC4041907  PMID: 24884452
COPD; Knowledge; Anxiety; Depression; Comorbidities
5.  Surgical techniques and results of the pulmonary artery reconstruction for patients with central non-small cell lung cancer 
It is difficult to achieve a margin-negative resection (R0) for non-small cell lung cancer (NSCLC) patients with infiltration of the pulmonary artery. We report our experience of the pulmonary artery reconstruction with regard to long-term survival.
Clinical records of 118 patients with NSCLC who underwent partial or circumferential pulmonary artery resection during a 21-year period were reviewed retrospectively. Techniques and survival outcomes were analyzed.
We performed 22 pulmonary artery sleeve resections, 51 reconstructions by autologous pericardial patch, 36 tangential resections, 3 left main pulmonary artery (PA) angioplasties during pneumonectomy without cardiopulmonary bypass, and 6 by only preserving the apical and anterior (1st) branch of pulmonary arterial trunk. In 41 patients, bronchial sleeve resection was associated; in 7 cases, superior vena cava reconstruction was also required. Thirty-one patients received induction therapy. Thirteen patients had stage IB disease, 41 stage II, 53 IIIA, and 11 IIIB. Ninety-three patients had squamous cell carcinoma, 22 adenocarcinoma, 2 mixed and 1 large cell carcinoma. Negative vascular margins were achieved in all. 5 positive bronchial margins were due to limited lung function. The analysis of 118 cases yielded follow-up data in 94 cases. The mean follow-up was 70 months (range 1–156 months). There was no in hospital death, and the overall 5-year survival was 50.2%. Five-year survivals for stages I and II versus III were 63.9% versus 37.0% (p = 0.0059). Multivariate analysis yielded non-squamous cell carcinoma, stage III and patch pulmonary arterioplasty as negative prognosis factors. PA reconstruction associated with bronchial sleeve resection was the positive prognostic factor.
Pulmonary artery resection and reconstruction is feasible and safe, with favorable long-term survival. Our results support this technique as an effective alternative to selected patients with infiltration of the pulmonary artery, such as stage I and II and those who proved down-staged from stage III. Accurate preoperative evaluation, precise and suitable surgical techniques are crucial to achieve good results. Only preserving the anterior and apical pulmonary arteries and reconstruction of the main pulmonary artery by using the artery conduit technique without cardiopulmonary bypass in association with left pneumonectomy can be performed successfully. Postoperative anticoagulation is unnecessary.
PMCID: PMC4222057  PMID: 24289720
Lung cancer; Pulmonary artery; Reconstruction; Surgery
6.  DGKα DNA vaccine relieves airway allergic inflammation in asthma model possibly via induction of T cell anergy 
Induction of T cell immune tolerance is thought to be a good method for treatment of asthma. Diacylglycerol kinases alpha (DGKα), enzymes that catalyze phosphorylation of diacylglycerol to produce phosphatidic acid, could inhibit diacylglycerol (DAG)-mediated signaling following T-cell receptor engagement and prevent T cell hyperactivation, thus playing important roles in the induction of T cell anergy. In the present study, we aimed to investigate the effects of DNA vaccine encoding DGKα gene administration on allergen-induced airway allergic inflammation in the murine model of asthma. Animal models were created and plasmid containing DGKα were constructed. Cytokine production was detected after the administration of DGKα gene plasmid. Immunization of mice with alum-adsorbed ovalbumin (OVA) followed by challenged with inhalation of aerosolized OVA resulted in the development of airway allergic inflammation. Administration of DGKα gene before the aerosolized OVA challenge significantly decreased the allergic airway inflammation and eosinophil infiltration in bronchoalveolar lavage fluid (BALF). Immunization with DGKα DNA vaccine decreased OVA-specific IgE and interleukin 13 (IL-13) levels in sera, and increased the IFN-γ level in BALF. The results of the present study provide evidence for the potential utility of the administration of DGKα DNA vaccine as an approach to gene therapy for asthma.
PMCID: PMC3816809  PMID: 24228102
Asthma; diacylglycerol kinases alpha; airway inflammation; DNA vaccine
7.  Effect of extreme data loss on long-range correlated and anticorrelated signals quantified by detrended fluctuation analysis 
Detrended fluctuation analysis (DFA) is an improved method of classical fluctuation analysis for nonstationary signals where embedded polynomial trends mask the intrinsic correlation properties of the fluctuations. To better identify the intrinsic correlation properties of real-world signals where a large amount of data is missing or removed due to artifacts, we investigate how extreme data loss affects the scaling behavior of long-range power-law correlated and anticorrelated signals. We introduce a segmentation approach to generate surrogate signals by randomly removing data segments from stationary signals with different types of long-range correlations. The surrogate signals we generate are characterized by four parameters: (i) the DFA scaling exponent α of the original correlated signal u(i), (ii) the percentage p of the data removed from u(i), (iii) the average length μ of the removed (or remaining) data segments, and (iv) the functional form P(l) of the distribution of the length l of the removed (or remaining) data segments. We find that the global scaling exponent of positively correlated signals remains practically unchanged even for extreme data loss of up to 90%. In contrast, the global scaling of anticorrelated signals changes to uncorrelated behavior even when a very small fraction of the data is lost. These observations are confirmed on two examples of real-world signals: human gait and commodity price fluctuations. We further systematically study the local scaling behavior of surrogate signals with missing data to reveal subtle deviations across scales. We find that for anticorrelated signals even 10% of data loss leads to significant monotonic deviations in the local scaling at large scales from the original anticorrelated to uncorrelated behavior. In contrast, positively correlated signals show no observable changes in the local scaling for up to 65% of data loss, while for larger percentage of data loss, the local scaling shows overestimated regions (with higher local exponent) at small scales, followed by underestimated regions (with lower local exponent) at large scales. Finally, we investigate how the scaling is affected by the average length, probability distribution, and percentage of the remaining data segments in comparison to the removed segments. We find that the average length μr of the remaining segments is the key parameter which determines the scales at which the local scaling exponent has a maximum deviation from its original value. Interestingly, the scales where the maximum deviation occurs follow a power-law relationship with μr. Whereas the percentage of data loss determines the extent of the deviation. The results presented in this paper are useful to correctly interpret the scaling properties obtained from signals with extreme data loss.
PMCID: PMC3534784  PMID: 20365691
8.  Concentration- and time-dependent response of human gingival fibroblasts to fibroblast growth factor 2 immobilized on titanium dental implants 
Titanium (Ti) implants are widely used clinically, but peri-implantitis remains one of the most common and serious complications. Healthy integration between gingival tissue and the implant surface is critical to long-term success in dental implant therapy. The objective of this study was to investigate how different concentrations of immobilized fibroblast growth factor 2 (FGF2) on the titania nanotubular surface influence the response of human gingival fibroblasts (HGFs).
Pure Ti metal was anodized at 20 V to form a vertically organized titanium dioxide nanotube array on which three concentrations of FGF2 (250 ng/mL, 500 ng/mL, or 1000 ng/mL) were immobilized by repeated lyophilization. Surface topography was observed and FGF2 elution was detected using enzyme-linked immunosorbent assay. The bioactivity changes of dissolvable immobilized FGF2 were measured by methyl-thiazolyl-tetrazolium assay. Behavior of HGFs was evaluated using adhesion and methyl-thiazolyl-tetrazolium bromide assays.
The FGF2 remained for several days on the modified surface on which HGFs were cultured. Over 90% of the dissolvable immobilized FGF2 had been eluted by Day 9, whereas the FGF2 activity was found to diminish gradually from Day 1 to Day 9. The titania nanotubular surface with an optimal preparing concentration (500 ng/mL) of FGF2 immobilization exhibited improved HGF functions such as cellular attachment, proliferation, and extracellular matrix-related gene expression. Moreover, significant bidirectional as well as concentration- and time-dependent bioactivity was observed.
Synergism of the FGF2-impregnated titanium dioxide nanotubular surface revealed good gingival-implant integration, indicating that these materials might have promising applications in dentistry and other biomedical devices.
PMCID: PMC3356224  PMID: 22619534
dental implants; titanium dioxide nanotube; fibroblast growth factor 2; extracellular matrix; real-time polymerase chain reaction
9.  Genetic modifiers of Hb E/β0 thalassemia identified by a two-stage genome-wide association study 
BMC Medical Genetics  2010;11:51.
Patients with Hb E/β0 thalassemia display remarkable variability in disease severity. To identify genetic modifiers influencing disease severity, we conducted a two-stage genome scan in groups of 207 mild and 305 severe unrelated patients from Thailand with Hb E/β0 thalassemia and normal α-globin genes.
First, we estimated and compared the allele frequencies of approximately 110,000 gene-based single nucleotide polymorphisms (SNPs) in pooled DNAs from different severity groups. The 756 SNPs that showed reproducible allelic differences at P < 0.02 by pooling were selected for individual genotyping.
After adjustment for age, gender and geographic region, logistic regression models showed 50 SNPs significantly associated with disease severity (P < 0.05) after Bonferroni adjustment for multiple testing. Forty-one SNPs in a large LD block within the β-globin gene cluster had major alleles associated with severe disease. The most significant was bthal_bg200 (odds ratio (OR) = 5.56, P = 2.6 × 10-13). Seven SNPs in two distinct LD blocks within a region centromeric to the β-globin gene cluster that contains many olfactory receptor genes were also associated with disease severity; rs3886223 had the strongest association (OR = 3.03, P = 3.7 × 10-11). Several previously unreported SNPs were also significantly associated with disease severity.
These results suggest that there may be an additional regulatory region centromeric to the β-globin gene cluster that affects disease severity by modulating fetal hemoglobin expression.
PMCID: PMC2853425  PMID: 20353593
10.  Sickle Cell Leg Ulcers: Associations with Haemolysis and SNPs in Klotho, TEK and Genes of the TGF-β/BMP Pathway 
British journal of haematology  2006;133(5):570-578.
Cutaneous leg ulcers are common in sickle cell anaemia and their risk might be genetically determined. We studied sickle cell anaemia patients to examine the relationship of leg ulcers with haemolysis and with SNPs in candidate genes that could affect sickle vasoocclusion. Leg ulcer patients had lower haemoglobin levels and higher levels of lactate dehydrogenase, bilirubin, aspartate aminotransferase and reticulocytes than did control patients with sickle cell anaemia but without leg ulcers. Age-adjusted comparisons showed that sickle cell anaemia-α thalassaemia was more frequent among controls than cases. These results strongly suggested that the likelihood of having leg ulcers was related to the intensity of haemolysis. Two-hundred fifteen SNPs in more than 100 candidate genes were studied. Associations were found with SNPs in Klotho, TEK and several genes in the TGF-β/BMP signaling pathway by genotypic association analyses. KL directly or indirectly promotes endothelial NO production and the TEK receptor tyrosine kinase is involved in angiogenesis. The TGF-β/BMP signaling pathway modulates wound healing and angiogenesis, among its other functions. Haemolysis-driven phenotypes like leg ulcers could be improved by agents that reduce sickle erythrocyte density or increase NO bioavailability.
PMCID: PMC1679888  PMID: 16681647
Polymorphisms; hemolytic anemia; genotype; phenotype; genetic association
11.  Multifactor-dimensionality reduction versus family-based association tests in detecting susceptibility loci in discordant sib-pair studies 
BMC Genetics  2005;6(Suppl 1):S146.
Complex diseases are generally thought to be under the influence of multiple, and possibly interacting, genes. Many association methods have been developed to identify susceptibility genes assuming a single-gene disease model, referred to as single-locus methods. Multilocus methods consider joint effects of multiple genes and environmental factors. One commonly used method for family-based association analysis is implemented in FBAT. The multifactor-dimensionality reduction method (MDR) is a multilocus method, which identifies multiple genetic loci associated with the occurrence of complex disease. Many studies of late onset complex diseases employ a discordant sib pairs design. We compared the FBAT and MDR in their ability to detect susceptibility loci using a discordant sib-pair dataset generated from the simulated data made available to participants in the Genetic Analysis Workshop 14. Using FBAT, we were able to identify the effect of one susceptibility locus. However, the finding was not statistically significant. We were not able to detect any of the interactions using this method. This is probably because the FBAT test is designed to find loci with major effects, not interactions. Using MDR, the best result we obtained identified two interactions. However, neither of these reached a level of statistical significance. This is mainly due to the heterogeneity of the disease trait and noise in the data.
PMCID: PMC1866789  PMID: 16451606
12.  Whole-genome variance components linkage analysis using single-nucleotide polymorphisms versus microsatellites on quantitative traits of derived phenotypes from factor analysis of electroencephalogram waves 
BMC Genetics  2005;6(Suppl 1):S15.
Alcohol dependence is a serious public health problem. We studied data from families participating in the Collaborative Study on the Genetics of Alcoholism (COGA) and made available to participants in the Genetic Analysis Workshop 14 (GAW14) in order to search for genes predisposing to alcohol dependence. Using factor analysis, we identified four factors (F1, F2, F3, F4) related to the electroencephalogram traits. We conducted variance components linkage analysis with each of the factors. Our results using the Affymetrix single-nucleotide polymorphism dataset showed significant evidence for a novel linkage of F3 (factor comprised of the three midline channel EEG measures from the target case of the Visual Oddball experiment ttdt2, 3, 4) to chromosome 18 (LOD = 3.45). This finding was confirmed by analyses of the microsatellite data (LOD = 2.73) and Illumina SNP data (LOD = 3.30). We also demonstrated that, in a sample like the COGA data, a dense single-nucleotide polymorphism map provides better linkage signals than low-resolution microsatellite map with quantitative traits.
PMCID: PMC1866785  PMID: 16451610
13.  Genome-wide linkage analysis for alcohol dependence: a comparison between single-nucleotide polymorphism and microsatellite marker assays 
BMC Genetics  2005;6(Suppl 1):S8.
Both theoretical and applied studies have proven that the utility of single nucleotide polymorphism (SNP) markers in linkage analysis is more powerful and cost-effective than current microsatellite marker assays. Here we performed a whole-genome scan on 115 White, non-Hispanic families segregating for alcohol dependence, using one 10.3-cM microsatellite marker set and two SNP data sets (0.33-cM, 0.78-cM spacing). Two definitions of alcohol dependence (ALDX1 and ALDX2) were used. Our multipoint nonparametric linkage analysis found alcoholism was nominal linked to 12 genomic regions. The linkage peaks obtained by using the microsatellite marker set and the two SNP sets had a high degree of correspondence in general, but the microsatellite marker set was insufficient to detect some nominal linkage peaks. The presence of linkage disequilibrium between markers did not significantly affect the results. Across the entire genome, SNP datasets had a much higher average linkage information content (0.33 cM: 0.93, 0.78 cM: 0.91) than did microsatellite marker set (0.57). The linkage peaks obtained through two SNP datasets were very similar with some minor differences. We conclude that genome-wide linkage analysis by using approximately 5,000 SNP markers evenly distributed across the human genome is sufficient and might be more powerful than current 10-cM microsatellite marker assays.
PMCID: PMC1866701  PMID: 16451694
14.  Search for genetic factors predisposing to atherogenic dyslipidemia 
BMC Genetics  2003;4(Suppl 1):S100.
Atherogenic dyslipidemia (AD) is a common feature in persons with premature coronary heart disease. While several linkage studies have been carried out to dissect the genetic etiology of lipid levels, few have investigated the AD lipid triad comprising elevated serum triglyceride, small low density lipoprotein (LDL) particles, and reduced high density lipoprotein (HDL) cholesterol levels. Here we report the results of a whole-genome screen for AD using the Framingham Heart Study population.
Our analyses provide some evidence for linkage to AD on chromosomes 1q31, 3q29, 10q26, 14p12, 14q13, 16q24, 18p11, and 19q13.
AD susceptibility is modulated by multiple genes in different chromosomes. Our study confirms results from other populations and suggests new areas of potential importance.
PMCID: PMC1866438  PMID: 14975168
15.  Empirically derived phenotypic subgroups – qualitative and quantitative trait analyses 
BMC Genetics  2003;4(Suppl 1):S15.
The Framingham Heart Study has contributed a great deal to advances in medicine. Most of the phenotypes investigated have been univariate traits (quantitative or qualitative). The aims of this study are to derive multivariate traits by identifying homogeneous groups of people and assigning both qualitative and quantitative trait scores; to assess the heritability of the derived traits; and to conduct both qualitative and quantitative linkage analysis on one of the heritable traits.
Multiple correspondence analysis, a nonparametric analogue of principal components analysis, was used for data reduction. Two-stage clustering, using both k-means and agglomerative hierarchical clustering, was used to cluster individuals based upon axes (factor) scores obtained from the data reduction. Probability of cluster membership was calculated using binary logistic regression. Heritability was calculated using SOLAR, which was also used for the quantitative trait analysis. GENEHUNTER-PLUS was used for the qualitative trait analysis.
We found four phenotypically distinct groups. Membership in the smallest group was heritable (38%, p < 1 × 10-6) and had characteristics consistent with atherogenic dyslipidemia. We found both qualitative and quantitative LOD scores above 3 on chromosomes 11 and 14 (11q13, 14q23, 14q31). There were two Kong & Cox LOD scores above 1.0 on chromosome 6 (6p21) and chromosome 11 (11q23).
This approach may be useful for the identification of genetic heterogeneity in complex phenotypes by clarifying the phenotype definition prior to linkage analysis. Some of our findings are in regions linked to elements of atherogenic dyslipidemia and related diagnoses, some may be novel, or may be false positives.
PMCID: PMC1866449  PMID: 14975083
16.  Genome-wide screen for heavy alcohol consumption 
BMC Genetics  2003;4(Suppl 1):S106.
To find specific genes predisposing to heavy alcohol consumption (self-reported consumption of 24 grams or more of alcohol per day among men and 12 grams or more among women), we studied 330 families collected by the Framingham Heart Study made available to participants in the Genetic Analysis Workshop 13 (GAW13).
Parametric and nonparametric methods of linkage analysis were used. No significant evidence of linkage was found; however, weak signals were identified in several chromosomal regions, including 1p22, 4q12, 4q25, and 11q24, which are in the vicinity of those reported in other similar studies.
Our study did not reveal significant evidence of linkage to heavy alcohol use; however, we found weak confirmation of studies carried out in other populations.
PMCID: PMC1866444  PMID: 14975174

Results 1-16 (16)