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1.  Transcriptome analysis during seed germination of elite Chinese bread wheat cultivar Jimai 20 
BMC Plant Biology  2014;14:20.
Background
Wheat seed germination directly affects wheat yield and quality. Although transcriptome and proteome analyses during seed germination have been reported in some crop plant species, dynamic transcriptome characterization during wheat seed germination has not been conducted. We performed the first comprehensive dynamic transcriptome analysis during different seed germination stages of elite Chinese bread wheat cultivar Jimai 20 using the Affymetrix Wheat Genome Array.
Results
A total of 61,703 probe sets representing 51,411 transcripts were identified during the five seed germination stages of Jimai 20, of which 2,825 differential expression probe sets corresponding to 2,646 transcripts with different functions were declared by ANOVA and a randomized variance model. The seed germination process included a rapid initial uptake phase (0–12 hours after imbibition [HAI]), a plateau phase (12–24 HAI), and a further water uptake phase (24–48 HAI), corresponding to switches from the degradation of small-molecule sucrose to the metabolism of three major nutrients and to photosynthesis. Hierarchical cluster and MapMan analyses revealed changes in several significant metabolism pathways during seed germination as well as related functional groups. The signal pathway networks constructed with KEGG showed three important genes encoding the phosphofructokinase family protein, with fructose-1, 6-bisphosphatase, and UTP-glucose-1-phosphate uridylyltransferase located at the center, indicating their pivotal roles in the glycolytic pathway, gluconeogenesis, and glycogenesis, respectively. Several significant pathways were selected to establish a metabolic pathway network according to their degree value, which allowed us to find the pathways vital to seed germination. Furthermore, 51 genes involved in transport, signaling pathway, development, lipid metabolism, defense response, nitrogen metabolism, and transcription regulation were analyzed by gene co-expression network with a k-core algorithm to determine which play pivotal roles in germination. Twenty-three meaningful genes were found, and quantitative RT-PCR analysis validated the expression patterns of 12 significant genes.
Conclusions
Wheat seed germination comprises three distinct phases and includes complicated regulation networks involving a large number of genes. These genes belong to many functional groups, and their co-regulations guarantee regular germination. Our results provide new insight into metabolic changes during seed germination and interactions between some significant genes.
doi:10.1186/1471-2229-14-20
PMCID: PMC3923396  PMID: 24410729
Bread wheat; Seed germination; Transcriptome; qRT-PCR
2.  Vehicle Scheduling Schemes for Commercial and Emergency Logistics Integration 
PLoS ONE  2013;8(12):e82866.
In modern logistics operations, large-scale logistics companies, besides active participation in profit-seeking commercial business, also play an essential role during an emergency relief process by dispatching urgently-required materials to disaster-affected areas. Therefore, an issue has been widely addressed by logistics practitioners and caught researchers' more attention as to how the logistics companies achieve maximum commercial profit on condition that emergency tasks are effectively and performed satisfactorily. In this paper, two vehicle scheduling models are proposed to solve the problem. One is a prediction-related scheme, which predicts the amounts of disaster-relief materials and commercial business and then accepts the business that will generate maximum profits; the other is a priority-directed scheme, which, firstly groups commercial and emergency business according to priority grades and then schedules both types of business jointly and simultaneously by arriving at the maximum priority in total. Moreover, computer-based simulations are carried out to evaluate the performance of these two models by comparing them with two traditional disaster-relief tactics in China. The results testify the feasibility and effectiveness of the proposed models.
doi:10.1371/journal.pone.0082866
PMCID: PMC3877009  PMID: 24391724
3.  Proteome and Phosphoproteome Characterization Reveals New Response and Defense Mechanisms of Brachypodium distachyon Leaves under Salt Stress* 
Salinity is a major abiotic stress affecting plant growth and development. Understanding the molecular mechanisms of salt response and defense in plants will help in efforts to improve the salt tolerance of crops. Brachypodium distachyon is a new model plant for wheat, barley, and several potential biofuel grasses. In the current study, proteome and phosphoproteome changes induced by salt stress were the focus. The Bd21 leaves were initially treated with salt in concentrations ranging from 80 to 320 mm and then underwent a recovery process prior to proteome analysis. A total of 80 differentially expressed protein spots corresponding to 60 unique proteins were identified. The sample treated with a median salt level of 240 mm and the control were selected for phosphopeptide purification using TiO2 microcolumns and LC-MS/MS for phosphoproteome analysis to identify the phosphorylation sites and phosphoproteins. A total of 1509 phosphoproteins and 2839 phosphorylation sites were identified. Among them, 468 phosphoproteins containing 496 phosphorylation sites demonstrated significant changes at the phosphorylation level. Nine phosphorylation motifs were extracted from the 496 phosphorylation sites. Of the 60 unique differentially expressed proteins, 14 were also identified as phosphoproteins. Many proteins and phosphoproteins, as well as potential signal pathways associated with salt response and defense, were found, including three 14-3-3s (GF14A, GF14B, and 14-3-3A) for signal transduction and several ABA signal-associated proteins such as ABF2, TRAB1, and SAPK8. Finally, a schematic salt response and defense mechanism in B. distachyon was proposed.
doi:10.1074/mcp.M113.030171
PMCID: PMC3916659  PMID: 24335353
4.  Factors Affecting Regional Per-Capita Carbon Emissions in China Based on an LMDI Factor Decomposition Model 
PLoS ONE  2013;8(12):e80888.
China is considered to be the main carbon producer in the world. The per-capita carbon emissions indicator is an important measure of the regional carbon emissions situation. This study used the LMDI factor decomposition model–panel co-integration test two-step method to analyze the factors that affect per-capita carbon emissions. The main results are as follows. (1) During 1997, Eastern China, Central China, and Western China ranked first, second, and third in the per-capita carbon emissions, while in 2009 the pecking order changed to Eastern China, Western China, and Central China. (2) According to the LMDI decomposition results, the key driver boosting the per-capita carbon emissions in the three economic regions of China between 1997 and 2009 was economic development, and the energy efficiency was much greater than the energy structure after considering their effect on restraining increased per-capita carbon emissions. (3) Based on the decomposition, the factors that affected per-capita carbon emissions in the panel co-integration test showed that Central China had the best energy structure elasticity in its regional per-capita carbon emissions. Thus, Central China was ranked first for energy efficiency elasticity, while Western China was ranked first for economic development elasticity.
doi:10.1371/journal.pone.0080888
PMCID: PMC3865993  PMID: 24353753
5.  Prenatal exposure to lipopolysaccharide results in myocardial remodelling in adult murine offspring 
Background
The epigenetic plasticity hypothesis indicates that pregnancy exposure may result in adult-onset diseases, including hypertension, diabetes and cardiovascular disease, in offspring. In a previous study, we discovered that prenatal exposure to inflammatory stimulants, such as lipopolysaccharides (LPS), could lead to hypertension in adult rat offspring. In the present study, we further demonstrate that maternal inflammation induces cardiac hypertrophy and dysfunction via ectopic over-expression of nuclear transcription factor κB (NF- κB), and pyrrolidine dithiocarbamate (PDTC) can protect cardiac function by reducing maternal inflammation.
Methods
Pregnant SD rats were randomly divided into three groups and intraperitoneally injected with a vehicle, LPS (0.79 mg/kg), or LPS (0.79 mg/kg) plus PDTC (100 mg/kg) at 8 to 12 days of gestation. The offspring were raised until 4 and 8 months old, at which point an echocardiographic study was performed. The left ventricular (LV) mass index and apoptosis were examined.
Results
At 4 months of age, the LPS offspring exhibited augmented posterior wall thickness. These rats displayed left ventricle (LV) hypertrophy and LV diastolic dysfunction as well as a higher apoptotic index, a higher level of Bax and a lower level of Bcl-2 at 8 months of age. The protein levels of NF-κB (p65) in the myocardium of the offspring were measured at this time. NF-κB protein levels were higher in the myocardium of LPS offspring. The offspring that were prenatally treated with PDTC displayed improved signs of blood pressure (BP) and LV hypertrophy.
Conclusions
Maternal inflammation can induce cardiac hypertrophy in offspring during aging accompanied with hypertension emergence and can be rescued by the maternal administration of PDTC (the inhibitor of NF-κB).
doi:10.1186/1476-9255-10-35
PMCID: PMC3874617
Foetal development; Maternal inflammation; Myocardial remodelling; Inhibitor of NF-κB
6.  Genetic Association of COL5A1 Variants in Keratoconus Patients Suggests a Complex Connection between Corneal Thinning and Keratoconus 
Purpose.
Single nucleotide polymorphisms (SNPs) located near or within the COL5A1 gene, at 9q34.2-q34.3 chromosomal region have been reported in association with central corneal thickness (CCT). Using family linkage analysis, we identified a keratoconus susceptibility locus at 9q34. These findings led us to perform an association study between COL5A1 variation and keratoconus susceptibility.
Methods.
A Caucasian case–control cohort of 222 keratoconus patients and 3324 controls was selected as the discovery panel. An independent case–control panel of 304 cases and 518 controls and a family panel of 186 subjects were replicated for genotyping and association. Forty-four SNPs (21 for discovery and 23 for fine-mapping) spanning 300 kilobases in and around COL5A1 were genotyped and tested for genetic association. Logistic regression models implemented in PLINK were used to test for association in case controls. Generalized estimating equation models accounting for familial correlations implemented in genome-wide interaction analyses with family data were used for association testing in families.
Results.
Two CCT associated SNPs (rs1536482 and rs7044529 near and within COL5A1) were identified in the keratoconus discovery cohort (P values of 6.5 × 10−3 and 7.4 × 10−3). SNP rs1536482 was replicated in the second case–control sample (P = 0.02), and SNP rs7044529 was replicated in a keratoconus family panel (P = 0.03). Meta P values of rs1536482 and rs7044529 in the keratoconus cohorts were 1.5 × 10−4 (odds ratio [OR] = 1.30) and 2.9 × 10−3 (OR = 1.39). After Bonferroni correction, the association of SNP rs1536482 remained significant (P = 6.5 × 10−3).
Conclusions.
SNPs in the COL5A1 region, which regulate normal variation in CCT, may play a role in the thinning associated with keratoconus.
Variants in the COL5A1 gene may contribute to genetic susceptibility to corneal thinning associated with keratoconus, in addition to their role in genetic regulation of normal variation in central corneal thickness.
doi:10.1167/iovs.13-11601
PMCID: PMC3630822  PMID: 23513063
keratoconus; association; COL5A1
7.  Keratoconus: Classification scheme based on videokeratography and clinical signs 
PURPOSE
To determine in a longitudinal study whether there is correlation between videokeratography and clinical signs of keratoconus that might be useful to practicing clinicians.
SETTING
Cornea-Genetic Eye Institute, Cedars-Sinai Medical Center, Los Angeles, California, USA.
METHODS
Eyes grouped as keratoconus, early keratoconus, keratoconus suspect, or normal based on clinical signs and videokeratography were examined at baseline and followed for 1 to 8 years. Differences in quantitative videokeratography indices and the progression rate were evaluated. The quantitative indices were central keratometry (K), the inferior–superior (I–S) value, and the keratoconus percentage index (KISA). Discriminant analysis was used to estimate the classification rate using the indices.
RESULTS
There were significant differences at baseline between the normal, keratoconus-suspect, and early keratoconus groups in all indices; the respective means were central K: 44.17 D, 45.13 D, and 45.97 D; I–S: 0.57, 1.20, and 4.44; log(KISA): 2.49, 2.94, and 5.71 (all P<.001 after adjusting for covariates). Over a median follow-up of 4.1 years, approximately 28% in the keratoconus-suspect group progressed to early keratoconus or keratoconus and 75% in the early keratoconus group progressed to keratoconus. Using all 3 indices and age, 86.9% in the normal group, 75.3% in the early keratoconus group, and 44.6% in the keratoconus-suspect group could be classified, yielding a total classification rate of 68.9%.
CONCLUSIONS
Cross-sectional and longitudinal data showed significant differences between groups in the 3 indices. Use of this classification scheme might form a basis for detecting subclinical keratoconus.
doi:10.1016/j.jcrs.2009.03.050
PMCID: PMC3712873  PMID: 19683159
8.  Correction: Molecular Mechanisms of HMW Glutenin Subunits from 1Sl Genome of Aegilops longissima Positively Affecting Wheat Breadmaking Quality 
PLoS ONE  2013;8(6):10.1371/annotation/d86a2c61-0953-4555-95bc-1ae9b8e3452c.
doi:10.1371/annotation/d86a2c61-0953-4555-95bc-1ae9b8e3452c
PMCID: PMC3734319
9.  Metabolic and cardiovascular genes in polycystic ovary syndrome: A candidate-wide association study (CWAS) 
Steroids  2011;77(4):317-322.
The role of metabolic disturbance in polycystic ovary syndrome (PCOS) has been well established, with insulin resistance and the resulting compensatory hyperinsulinemia thought to promote hyperandrogenemia. Genome-wide association studies (GWAS) have established a large number of loci for metabolic conditions such as type 2 diabetes and obesity. A subset of these loci has been investigated for a role in PCOS; these studies generally have not revealed a confirmed role for these loci in PCOS risk. However, a large scale investigation of genes related to these pathways has not previously been performed. We conducted a two stage case control association study of 121,715 single nucleotide polymorphisms (SNPs) selected to represent susceptibility loci associated with traits such as type 2 diabetes, obesity measures, lipid levels and cardiovascular function using the Cardio-Metabochip in 847 PCOS cases and 845 controls. Several hypothesis-generating associations with PCOS were observed (top SNP rs2129107, P = 3.8 × 10−6). We did not find any loci definitively associated with PCOS after strict correction for multiple testing, suggesting that cardio-metabolic loci are not major risk factors underlying the susceptibility to PCOS.
doi:10.1016/j.steroids.2011.12.005
PMCID: PMC3689580  PMID: 22178785
Candidate-wide association study; Polycystic ovary syndrome; Cardio-Metabochip; Single nucleotide polymorphism; Genetic association
10.  Genetic Loci for Retinal Arteriolar Microcirculation 
PLoS ONE  2013;8(6):e65804.
Narrow arterioles in the retina have been shown to predict hypertension as well as other vascular diseases, likely through an increase in the peripheral resistance of the microcirculatory flow. In this study, we performed a genome-wide association study in 18,722 unrelated individuals of European ancestry from the Cohorts for Heart and Aging Research in Genomic Epidemiology consortium and the Blue Mountain Eye Study, to identify genetic determinants associated with variations in retinal arteriolar caliber. Retinal vascular calibers were measured on digitized retinal photographs using a standardized protocol. One variant (rs2194025 on chromosome 5q14 near the myocyte enhancer factor 2C MEF2C gene) was associated with retinal arteriolar caliber in the meta-analysis of the discovery cohorts at genome-wide significance of P-value <5×10−8. This variant was replicated in an additional 3,939 individuals of European ancestry from the Australian Twins Study and Multi-Ethnic Study of Atherosclerosis (rs2194025, P-value = 2.11×10−12 in combined meta-analysis of discovery and replication cohorts). In independent studies of modest sample sizes, no significant association was found between this variant and clinical outcomes including coronary artery disease, stroke, myocardial infarction or hypertension. In conclusion, we found one novel loci which underlie genetic variation in microvasculature which may be relevant to vascular disease. The relevance of these findings to clinical outcomes remains to be determined.
doi:10.1371/journal.pone.0065804
PMCID: PMC3680438  PMID: 23776548
11.  Molecular Mechanisms of HMW Glutenin Subunits from 1Sl Genome of Aegilops longissima Positively Affecting Wheat Breadmaking Quality 
PLoS ONE  2013;8(4):e58947.
A wheat cultivar “Chinese Spring” chromosome substitution line CS-1Sl(1B), in which the 1B chromosome was substituted by 1Sl from Aegilops longissima, was developed and found to possess superior dough and breadmaking quality. The molecular mechanism of its super quality conformation is studied in the aspects of high molecular glutenin genes, protein accumulation patterns, glutenin polymeric proteins, protein bodies, starch granules, and protein disulfide isomerase (PDI) and PDI-like protein expressions. Results showed that the introduced HMW-GS 1Sl×2.3* and 1Sly16* in the substitution line possesses long repetitive domain, making both be larger than any known x- and y-type subunits from B genome. The introduced subunit genes were also found to have a higher level of mRNA expressions during grain development, resulting in more HMW-GS accumulation in the mature grains. A higher abundance of PDI and PDI-like proteins was observed which possess a known function of assisting disulfide bond formation. Larger HMW-GS deposited in protein bodies were also found in the substitution line. The CS substitution line is expected to be highly valuable in wheat quality improvement since the novel HMW-GS are located on chromosome 1Sl, making it possible to combine with the known superior D×5+Dy10 subunits encoded by Glu-D1 for developing high quality bread wheat.
doi:10.1371/journal.pone.0058947
PMCID: PMC3617193  PMID: 23593125
12.  Longitudinal study of keratoconus progression 
Experimental eye research  2007;85(4):502-507.
To determine if differences in topographic progression between unaffected keratoconus relatives and normal controls can predict factors associated with the development of keratoconus in a longitudinal study.
We recruited 369 unaffected keratoconus relatives and 119 normal controls in Los Angeles. Both eyes of subjects were examined at baseline clinically and by quantitative videokeratography and at a period ranging from 1 year to 8 years. Progression to keratoconus was evaluated by quantitative videokeratography variables.
Unaffected relatives had higher Central K (CK), I-S and KISA values and were younger than normal controls (CK: 44.70 vs 44.01, P<0.01; I-S: 0.76 vs 0.58, P<0.01, KISA: 29.97 vs 23.89, P=0.02; age: 34.8 vs 41.0, P<0.01) at baseline. All three indices significantly increased with age, and CK and KISA values were associated with a positive family history for keratoconus (P<0.001 for CK and P=0.05 for KISA), however, the two groups were not statistically different in progression of keratoconus. After grouped unaffected relatives as the high risk (age<=30 or Central K>=47.2 or I-S >=1.2 or KISA>=60) and the low risk (age>30 and Central K<47.2 and I-S <1.2 and KISA<60), relatives in the high risk group had a greater increase in CK and I-S values than those in the low risk group (CK: p=0.009; I-S: p<0.001), which indicated that there were significantly different rates of progression between two groups.
Unaffected relatives had higher videokeratography indices than normal controls, but overall they did not progress to keratoconus quicker than normal controls. However, relatives in a high risk group may have a greater risk of progression to keratoconus.
doi:10.1016/j.exer.2007.06.016
PMCID: PMC3597220  PMID: 17681291
keratoconus; progression; videokeratography
13.  The Association between Subclinical Atherosclerosis and Uterine Fibroids 
PLoS ONE  2013;8(2):e57089.
Objective(s)
To explore the atherogenic hypothesis of uterine fibroids among Chinese women.
Methods
In a case-control study, 335 patients confirmed by ultrasound or hysterectomy surgery and 539 controls were enrolled between October 1, 2009 and April 1, 2012. Unconditional logistic regressions were used to calculate the odds ratios (ORs) for the associations of subclinical atherogenic and cardiovascular risk parameters with uterine fibroids in the overall case group and hysterectomy-confirmed case group, respectively.
Results
Higher level of ankle-brachial index (ABI) was independently associated with increased odds of uterine fibroids. The odds of UF among women in the highest tertile of ABI were 1.88 times higher (95%CI: 1.17, 3.02, Ptrend = 0.008) compared to those in the lowest tertile. The serum concentration of homocysteine was inversely related to fibroids (middle vs. low: OR 0.56, 95%CI: 0.36, 0.85; high vs. low: OR 0.50, 95% CI: 0.32, 0.79; Ptrend = 0.002). In the hysterectomy-confirmed group, an inverse association was suggested between high-density lipoprotein cholesterol (HDL-C) and fibroids (OR 0.46, 95% CI: 0.25, 0.84, Ptrend = 0.014). Moreover, the effect of homocysteine concentration was not observed in this group.
Conclusion(s)
These findings suggest that women with uterine fibroids might have an increased risk of subclinical atherosclerosis.
doi:10.1371/journal.pone.0057089
PMCID: PMC3579803  PMID: 23451155
14.  Genome-Wide Association Study of Retinopathy in Individuals without Diabetes 
PLoS ONE  2013;8(2):e54232.
Background
Mild retinopathy (microaneurysms or dot-blot hemorrhages) is observed in persons without diabetes or hypertension and may reflect microvascular disease in other organs. We conducted a genome-wide association study (GWAS) of mild retinopathy in persons without diabetes.
Methods
A working group agreed on phenotype harmonization, covariate selection and analytic plans for within-cohort GWAS. An inverse-variance weighted fixed effects meta-analysis was performed with GWAS results from six cohorts of 19,411 Caucasians. The primary analysis included individuals without diabetes and secondary analyses were stratified by hypertension status. We also singled out the results from single nucleotide polymorphisms (SNPs) previously shown to be associated with diabetes and hypertension, the two most common causes of retinopathy.
Results
No SNPs reached genome-wide significance in the primary analysis or the secondary analysis of participants with hypertension. SNP, rs12155400, in the histone deacetylase 9 gene (HDAC9) on chromosome 7, was associated with retinopathy in analysis of participants without hypertension, −1.3±0.23 (beta ± standard error), p = 6.6×10−9. Evidence suggests this was a false positive finding. The minor allele frequency was low (∼2%), the quality of the imputation was moderate (r2 ∼0.7), and no other common variants in the HDAC9 gene were associated with the outcome. SNPs found to be associated with diabetes and hypertension in other GWAS were not associated with retinopathy in persons without diabetes or in subgroups with or without hypertension.
Conclusions
This GWAS of retinopathy in individuals without diabetes showed little evidence of genetic associations. Further studies are needed to identify genes associated with these signs in order to help unravel novel pathways and determinants of microvascular diseases.
doi:10.1371/journal.pone.0054232
PMCID: PMC3564946  PMID: 23393555
15.  Replication of Association of DENND1A and THADA Variants with Polycystic Ovary Syndrome in European Cohorts 
Journal of medical genetics  2011;49(2):90-95.
Background
Polycystic ovary syndrome (PCOS) is a complex endocrine disorder with a strong familial component. PCOS is characterized by hyperandrogenemia and irregular menses. A recent genome wide association study of PCOS in a Chinese cohort identified three reproducible PCOS susceptibility loci mapping to 2p16.3 (luteinizing hormone/choriogonadotropin receptor; LHCGR), 2p21 (thyroid associated protein; THADA), and 9q33.3 (DENN/MADD domain containing 1A; DENNDIA). The impact of these loci in non-Chinese PCOS cohorts remains to be determined.
Methods/Results
We tested association with PCOS of seven single nucleotide polymorphisms mapping to the three Chinese PCOS loci in two European-derived PCOS cohorts (Cohort A = 939 cases and 957 controls; Cohort B = 535 cases and 845 controls). Cases fulfilled the NICHD criteria for PCOS. Variation in DENND1A was strongly associated with PCOS in our cohort (pcombined cohorts=10−8 ); multiple variants in THADA were also associated with PCOS, while there was no significant evidence for association of LHCGR variation with PCOS. We had greater than 80% power to detect an effect of similar size as was observed by Chen et al. for DENND1A and THADA but reduced power (at <40%) for LHCGR at p=0.0001. We had sufficient power (57-88%) for LHCGR at p=0.01.
Conclusions
At least two of the PCOS susceptibility loci identified in the Chinese PCOS GWAS (DENND1A and THADA) are also associated with PCOS in European-derived populations, and therefore likely to be important in the etiology of PCOS regardless of ethnicity. Our analysis of the LHCGR gene was not sufficiently powered to detect modest effects.
doi:10.1136/jmedgenet-2011-100427
PMCID: PMC3536488  PMID: 22180642
PCOS; DENND1A; THADA; genome-wide association study
16.  A genome-wide association study identifies a potential novel gene locus for keratoconus, one of the commonest causes for corneal transplantation in developed countries 
Human Molecular Genetics  2011;21(2):421-429.
Keratoconus is a condition in which the cornea progressively thins over time, and is a major cause for cornea transplantation. To identify keratoconus susceptibility regions, we performed a comprehensive genome-wide association study (GWAS) using a discovery and replication design. A discovery panel of 222 keratoconus Caucasian patients and 3324 Caucasian controls was genotyped using Illumina 370K beadchips. Further associated and fine-mapping single nucleotide polymorphisms (SNPs) (n= 4905) were genotyped in an independent replication case–control panel of 304 cases and 518 controls and a family panel of 307 subjects in 70 families. Logistic regression models implemented in PLINK were performed to test associations in case–control samples with and without principal component (PC) adjustments. Generalized estimation equation models accounting for familial correlations implemented in GWAF were used for association testing in families. No genome-wide associations were identified in the discovery GWAS panel. From the initial testing without adjustments for PCs, the top three SNPs located at 3p26 (rs6442925), 2q21.3 (rs4954218) and 19q13.3 (rs1428642) were identified with unadjusted P-values of 6.5 × 10−8, 2.4 × 10−7 and 3.1 × 10−7, respectively. After adjustments for PCs, rs1428642 became the most significant through the genome with a P-value of 1.4 × 10−6, while rs6442925 and rs4954218 were less significant (P= 1.9 × 10−5 and 2.6 × 10−4). SNP rs4954218 was confirmed in two independent replication panels with P-values of 0.004 and 0.009, respectively. Meta-analysis revealed a highest association at rs4954218 with adjusted P= 1.6 × 10−7 (unadjusted P= 1.2 × 10−9). These findings suggest SNP rs4954218, located near the RAB3GAP1 gene, previously reported to be associated with corneal malformation, is a potential susceptibility locus for keratoconus.
doi:10.1093/hmg/ddr460
PMCID: PMC3276283  PMID: 21979947
17.  Insights into the Genetic Architecture of Early Stage Age-Related Macular Degeneration: A Genome-Wide Association Study Meta-Analysis 
PLoS ONE  2013;8(1):e53830.
Genetic factors explain a majority of risk variance for age-related macular degeneration (AMD). While genome-wide association studies (GWAS) for late AMD implicate genes in complement, inflammatory and lipid pathways, the genetic architecture of early AMD has been relatively under studied. We conducted a GWAS meta-analysis of early AMD, including 4,089 individuals with prevalent signs of early AMD (soft drusen and/or retinal pigment epithelial changes) and 20,453 individuals without these signs. For various published late AMD risk loci, we also compared effect sizes between early and late AMD using an additional 484 individuals with prevalent late AMD. GWAS meta-analysis confirmed previously reported association of variants at the complement factor H (CFH) (peak P = 1.5×10−31) and age-related maculopathy susceptibility 2 (ARMS2) (P = 4.3×10−24) loci, and suggested Apolipoprotein E (ApoE) polymorphisms (rs2075650; P = 1.1×10−6) associated with early AMD. Other possible loci that did not reach GWAS significance included variants in the zinc finger protein gene GLI3 (rs2049622; P = 8.9×10−6) and upstream of GLI2 (rs6721654; P = 6.5×10−6), encoding retinal Sonic hedgehog signalling regulators, and in the tyrosinase (TYR) gene (rs621313; P = 3.5×10−6), involved in melanin biosynthesis. For a range of published, late AMD risk loci, estimated effect sizes were significantly lower for early than late AMD. This study confirms the involvement of multiple established AMD risk variants in early AMD, but suggests weaker genetic effects on the risk of early AMD relative to late AMD. Several biological processes were suggested to be potentially specific for early AMD, including pathways regulating RPE cell melanin content and signalling pathways potentially involved in retinal regeneration, generating hypotheses for further investigation.
doi:10.1371/journal.pone.0053830
PMCID: PMC3543264  PMID: 23326517
18.  Variation in the Lysyl Oxidase (LOX) Gene Is Associated with Keratoconus in Family-Based and Case-Control Studies 
Purpose.
Keratoconus is a bilateral noninflammatory progressive corneal disorder with complex genetic inheritance and a common cause for cornea transplantation in young adults. A genomewide linkage scan in keratoconus families identified a locus at 5q23.2, overlapping the gene coding for the lysyl oxidase (LOX). LOX encodes an enzyme responsible for collagen cross-linking in a variety of tissues including the cornea. Corneal collagen cross-linking with long-wave ultraviolet light and riboflavin is a promising new treatment for keratoconus. To determine whether LOX is a genetic determinant of the pathogenesis of keratoconus, we analyzed association results of LOX polymorphisms in two independent case-control samples and in keratoconus families.
Methods.
Association results were analyzed of single-nucleotide polymorphisms (SNPs) in the LOX gene from a Genome-Wide Association Study (GWAS) investigation in two independent panels of patients with keratoconus and controls and in keratoconus families.
Results.
Evidence of association was found at SNPs rs10519694 and rs2956540 located in intron 4 of LOX in the GWAS discovery case-control panel with P values of 2.3 × 10−3 and 7 × 10−3, respectively. The same two SNPs were found to be associated with keratoconus by family-based association testing with P values of 2.7 × 10−3 and 7.7 × 10−4, respectively. Meta P values of 4.0 × 10−5 and 4.0 × 10−7 were calculated for SNPs rs10519694 and rs2956540 by analyzing case-control and family samples simultaneously. Sequencing of LOX exons in a subset of keratoconus patients identified two polymorphisms, rs1800449 and rs2288393, located in LOX transcripts I and II, associated with keratoconus in case-control and family samples with a meta P value of 0.02.
Conclusions.
Results provided strong genetic evidence that LOX variants lead to increased susceptibility to developing of keratoconus.
Keratoconus is a progressive disorder of the cornea with complex genetic inheritance, which can lead to severe visual impairment or blindness. Here we describe the association between variation in the lysyl oxidase gene and keratoconus susceptibility in case-control and family studies.
doi:10.1167/iovs.11-9268
PMCID: PMC3760233  PMID: 22661479
19.  Molecular characterization of LMW-GS genes in Brachypodium distachyon L. reveals highly conserved Glu-3 loci in Triticum and related species 
BMC Plant Biology  2012;12:221.
Background
Brachypodium distachyon L. is a newly emerging model plant system for temperate cereal crop species. However, its grain protein compositions are still not clear. In the current study, we carried out a detailed proteomics and molecular genetics study on grain glutenin proteins in B. distachyon.
Results
SDS-PAGE and RP-HPLC analysis of grain proteins showed that Brachypodium has few gliadins and high molecular weight glutenin subunits. In contrast the electrophoretic patterns for the albumin, globulin and low molecular weight glutenin subunit (LMW-GS) fractions of the grain protein were similar to those in wheat. In particular, the LMW-C type subunits in Brachypodium were more abundant than the equivalent proteins in common wheat. Southern blotting analysis confirmed that Brachypodium has 4–5 copies of LMW-GS genes. A total of 18 LMW-GS genes were cloned from Brachypodium by allele specific PCR. LMW-GS and 4 deduced amino acid sequences were further confirmed by using Western-blotting and MALDI-TOF-MS. Phylogenetic analysis indicated that Brachypodium was closer to Ae. markgrafii and Ae. umbellulata than to T. aestivum.
Conclusions
Brachypodium possessed a highly conserved Glu-3 locus that is closely related to Triticum and related species. The presence of LMW-GS in B. distachyon grains indicates that B. distachyon may be used as a model system for studying wheat quality attributes.
doi:10.1186/1471-2229-12-221
PMCID: PMC3547698  PMID: 23171363
20.  Proteome characterization of developing grains in bread wheat cultivars (Triticum aestivum L.) 
BMC Plant Biology  2012;12:147.
Background
The analyses of protein synthesis, accumulation and regulation during grain development in wheat are more complex because of its larger genome size compared to model plants such as Arabidopsis and rice. In this study, grains from two wheat cultivars Jimai 20 and Zhoumai 16 with different gluten quality properties were harvested at five development stages, and were used to displayed variable expression patterns of grain proteins.
Results
Proteome characterization during grain development in Chinese bread wheat cultivars Jimai 20 and Zhoumai 16 with different quality properties was investigated by 2-DE and tandem MALDI-TOF/TOF-MS. Identification of 117 differentially accumulated protein spots representing 82 unique proteins and five main expression patterns enabled a chronological description of wheat grain formation. Significant proteome expression differences between the two cultivars were found; these included 14 protein spots that accumulated in both cultivars but with different patterns and 27 cultivar-different spots. Among the cultivar-different protein spots, 14 accumulated in higher abundance in Jimai 20 than in Zhoumai 16, and included NAD-dependent isocitrate dehydrogenase, triticin precursor, LMW-s glutenin subunit and replication factor C-like protein. These proteins are likely to be associated with superior gluten quality. In addition, some proteins such as class II chitinase and peroxidase 1 with isoforms in developing grains were shown to be phosphorylated by Pro-Q Diamond staining and phosphorprotein site prediction. Phosphorylation could have important roles in wheat grain development. qRT-PCR analysis demonstrated that transcriptional and translational expression patterns of many genes were significantly different.
Conclusions
Wheat grain proteins displayed variable expression patterns at different developmental stages and a considerable number of protein spots showed differential accumulation between two cultivars. Differences in seed storage proteins were considered to be related to different quality performance of the flour from these wheat cultivars. Some proteins with isoforms were phosphorylated, and this may reflect their importance in grain development. Our results provide new insights into proteome characterization during grain development in different wheat genotypes.
doi:10.1186/1471-2229-12-147
PMCID: PMC3480910  PMID: 22900893
Wheat; Grain proteome; Phosphorproteins; 2-DE; Tandem MS; qRT-PCR
21.  Proteomic Analysis of Bacillus thuringiensis Strain 4.0718 at Different Growth Phases 
The Scientific World Journal  2012;2012:798739.
The growth process of Bacillus thuringiensis Bt4.0718 strain was studied using proteomic technologies. The proteins of Bt whole cells at three phases—middle vegetative, early sporulation, and late sporulation—were extracted with lysis buffer, followed with separation by 2-DE and identified by MALDI-TOF/TOF MS. Bioactive factors such as insecticidal crystal proteins (ICPs) including Cry1Ac(3), Cry2Aa, and BTRX28, immune inhibitor (InhA), and InhA precursor were identified. InhA started to express at the middle vegetative phase, suggesting its contribution to the survival of Bt in the host body. At the early sporulation phase, ICPs started their expression. CotJC, OppA, ORF1, and SpoIVA related to the formation of crystals and spores were identified, the expression characteristics of which ensured the stable formation of crystals and spores. This study provides an important foundation for further exploration of the stable expression of ICPs, the smooth formation of crystals, and the construction of recombinant strains.
doi:10.1100/2012/798739
PMCID: PMC3353320  PMID: 22649324
22.  Association of Polymorphisms in the Hepatocyte Growth Factor Gene Promoter with Keratoconus 
This is a meta-analysis of two genome-wide association studies that found evidence of association of keratoconus with polymorphisms in the promoter of the HGF gene. One polymorphism is associated with higher levels of serum HGF.
Purpose.
Keratoconus is a progressive disorder of the cornea that can lead to severe visual impairment or blindness. Although several genomic regions have been linked to rare familial forms of keratoconus, no genes have yet been definitively identified for common forms of the disease.
Methods.
Two genome-wide association scans were undertaken in parallel. The first used pooled DNA from an Australian cohort, followed by typing of top-ranked single-nucleotide polymorphisms (SNPs) in individual DNA samples. The second was conducted in individually genotyped patients, and controls from the USA. Tag SNPs around the hepatocyte growth factor (HGF) gene were typed in three additional replication cohorts. Serum levels of HGF protein in normal individuals were assessed with ELISA and correlated with genotype.
Results.
The only SNP observed to be associated in both the pooled discovery and primary replication cohort was rs1014091, located upstream of the HGF gene. The nearby SNP rs3735520 was found to be associated in the individually typed discovery cohort (P = 6.1 × 10−7). Genotyping of tag SNPs around HGF revealed association at rs3735520 and rs17501108/rs1014091 in four of the five cohorts. Meta-analysis of all five datasets together yielded suggestive P values for rs3735520 (P = 9.9 × 10−7) and rs17501108 (P = 9.9 × 10−5). In addition, SNP rs3735520 was found to be associated with serum HGF level in normal individuals (P = 0.036).
Conclusions.
Taken together, these results implicate genetic variation at the HGF locus with keratoconus susceptibility.
doi:10.1167/iovs.11-8261
PMCID: PMC3208191  PMID: 22003120
23.  An open-label, phase 1 study evaluating safety, tolerability, and pharmacokinetics of linifanib (ABT-869) in Japanese patients with solid tumors 
Cancer Chemotherapy and Pharmacology  2012;69(6):1477-1486.
Purpose
This phase 1 study assessed the safety, tolerability, pharmacokinetics, and preliminary antitumor activity of linifanib in Japanese patients with advanced solid tumors.
Methods
Patients were assigned to one of four sequential cohorts (0.05, 0.10, 0.20, or 0.25 mg/kg) of oral, once-daily linifanib on a 21-day cycle. Adverse events (AEs) were assessed per common terminology criteria for adverse events v3.0; tumor responses were assessed by response evaluation criteria in solid tumors.
Results
Eighteen patients were enrolled. Eleven (61%) received ≥3 prior therapies. Dose-limiting toxicities were Grade 3 ALT increase (0.10 mg/kg linifanib) and Grade 1 T-wave inversion (0.25 mg/kg linifanib) requiring dose interruption for >7 days and discontinuation on day 29. The most common linifanib-related AE was hypertension. Other significant treatment-related AEs included proteinuria, fatigue, and palmar-plantar erythrodysaesthesia. Linifanib pharmacokinetics were dose-proportional across 0.10–0.25 mg/kg. Two patients (11.1%) had confirmed partial responses, 12 had a best response of stable disease (11 had stable disease for ≥12 weeks), and four patients were not evaluable due to incomplete data. Four patients (lung cancer, breast cancer, thymic cancer, sarcoma) have continued linifanib for ≥48 weeks (range, 48–96+ weeks).
Conclusion
Linifanib was well tolerated with promising preliminary clinical activity in Japanese patients. Later-phase global studies examining linifanib efficacy will include Japanese patients.
doi:10.1007/s00280-012-1846-6
PMCID: PMC3362725  PMID: 22382879
Angiogenesis; Linifanib (ABT-869); PDGFR; Solid tumors; VEGFR; Japanese
24.  DNA breakage induced by piceatannol and copper(II): Mechanism and anticancer properties 
Oncology Letters  2012;3(5):1087-1094.
Piceatannol (3,3′,4,5′-tetrahydroxy-trans-stilbene; Pice), found in a variety of plant sources including grapes, red wine, peanuts and rhubarb, is known as a metabolite and analog of Resveratrol (3,5,4′-trihydroxy-trans-stilbene; Res) and has higher bioactivity than Res. To explore the mechanism of DNA damage induced by Pice in the presence of copper (Cu)(II), gel electrophoresis, UV-visible spectroscopy, fluorescence spectroscopy and Fourier transform infrared spectroscopy were used. The results of gel electrophoresis demonstrated that the hydroxyl radical played a critical role in DNA cleavage. Spectroscopy confirmed that the mechanism of DNA cleavage induced by Pice-Cu(II) involves the Haber Weiss and Fenton reactions. Pice chelates with Cu(II) as a bidentate ligand, and the Pice-Cu(II) complex undergoes intramolecular electron transfer to form the semiquinone radical anion and Cu(I), which may be reoxidated by O2 to form Cu(II) with hydroxyl radical generation. In brief, the formation of the hydroxyl radical and the Cu(II)/Cu(I) redox cycle play a key role in inducing DNA damage. In this process, Pice demonstrated pro-oxidant properties. Oxidative product(s) of Pice, semiquinone, was formed and Cu(I) was reoxidized to Cu(II). The redox cycling of copper generated reactive oxygen species, which induced DNA cleavage, the hallmark of cell apoptosis. The mechanism of DNA breakage induced by Pice-Cu(II) may be a significant pathway through which cancer cells are killed.
doi:10.3892/ol.2012.597
PMCID: PMC3389628  PMID: 22783397
piceatannol; anticancer; pro-oxidant; polyphenols; copper
25.  Application of Bayesian regression with singular value decomposition method in association studies for sequence data 
BMC Proceedings  2011;5(Suppl 9):S57.
Genetic association studies usually involve a large number of single-nucleotide polymorphisms (SNPs) (k) and a relative small sample size (n), which produces the situation that k is much greater than n. Because conventional statistical approaches are unable to deal with multiple SNPs simultaneously when k is much greater than n, single-SNP association studies have been used to identify genes involved in a disease’s pathophysiology, which causes a multiple testing problem. To evaluate the contribution of multiple SNPs simultaneously to disease traits when k is much greater than n, we developed the Bayesian regression with singular value decomposition (BRSVD) method. The method reduces the dimension of the design matrix from k to n by applying singular value decomposition to the design matrix. We evaluated the model using a Markov chain Monte Carlo simulation with Gibbs sampler constructed from the posterior densities driven by conjugate prior densities. Permutation was incorporated to generate empirical p-values. We applied the BRSVD method to the sequence data provided by Genetic Analysis Workshop 17 and found that the BRSVD method is a practical method that can be used to analyze sequence data in comparison to the single-SNP association test and the penalized regression method.
doi:10.1186/1753-6561-5-S9-S57
PMCID: PMC3287895  PMID: 22373181

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