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1.  Solution-phase-peptide synthesis via the Group-Assisted Purification (GAP) chemistry without using chromatography and recrystallization† 
The solution phase synthesis of N-protected amino acids and peptides has been achieved through the Group-Assisted Purification (GAP) chemistry by avoiding disadvantages of other methods in regard to the difficult scale-up, expenses of solid and soluble polymers, etc. The GAP synthesis can reduce the use of solvents, silica gels, energy and manpower. In addition, the GAP auxiliary can be conveniently recovered for re-use and is of environmentally friendly benign by substantially reducing waste production in academic labs and industry.
doi:10.1039/c3cc48509a
PMCID: PMC3929111  PMID: 24336500
2.  Metal-Free Preparation of Cycloalkyl Aryl Sulfides via Di-tert-butyl Peroxide-Promoted Oxidative C(sp3)[BOND]H Bond Thiolation of Cycloalkanes 
Advanced synthesis & catalysis  2014;356(11-12):2719-2724.
A concise thiolation of C(sp3)–H bond of cycloalkanes with diaryl disulfides in the presence of oxidant of di-tert-butylperoxide (DTBP) has been developed. This reaction without using any of metal catalyst, tolerates varieties of disulfides and cycloalkanes substrates, giving good to excellent chemical yields, which provides a useful approach to cycloalkyl aryl sulfides from unactivated cycloalkanes.
doi:10.1002/adsc.201400032
PMCID: PMC4260410  PMID: 25505857
metal-free; thiolation; oxidative; C(sp3)–H activation; cycloalkane
3.  Hemodynamic Factors May Play a Critical Role in Neurological Deterioration Occurring within 72 hrs after Lacunar Stroke 
PLoS ONE  2014;9(10):e108395.
Background
Whether a perfusion defect exists in lacunar infarct and whether it is related to early neurological deterioration (END) is still under debate. The aim of this study was to evaluate whether END in lacunar infarct is related to a perfusion defect using diffusion-weighted imaging (DWI), diffusion tensor imaging (DTI) and perfusion MR imaging.
Methods
One hundred and forty-one consecutive patients had an MRI scan within 30 hours after onset of symptoms and 43 patients with acute lacunar infarct and classic lacunar syndrome were recruited. The MRI sequences included DWI, DTI and cerebral blood flow (CBF) maps to respectively represent the topographic locations of acute infarcts, the corticospinal tract and perfusion defects. The END was defined in reference to the National Institute of Health Stroke Scale (NIHSS) as an increase ≧2 within 72 hours. Cohen's Kappa coefficient was used to examine the reliability between the 2 image readers. A multivariate logistic regression model was constructed adjusting for baseline variables.
Results
Ten out of the 43 patients had END. Patients having END was significantly associated with lower chances of favorable and good outcomes at 3 months (p = 0.01 and p = 0.002, respectively). END was predicted when the non-core hypoperfused area overlapped on the corticospinal tract, which is defined as the expected END profile. Cohen's Kappa coefficient between the 2 image readers to define images of expected END profiles was 0.74. In 15 patients with expected END profile, 9 had END clinically, whereas 28 patients had no expected END profile, and only 1 patient had END (p<0.0001). After adjusting for sex, the expected END profile was still associated with END (odds ratio, 42.2; p = 0.002).
Conclusion
Our study demonstrated that the END in acute lacunar stroke is likely related to the transformation of non-core hypoperfused area into infarction in the anatomy of corticospinal tracts.
doi:10.1371/journal.pone.0108395
PMCID: PMC4207695  PMID: 25340713
4.  Asymmetric C-C Bond Formation between Chiral N-Phosphonyl Imines and Ni(II)-Complex of Glycine Schiff Base Provides a GAP Synthesis of α,β-syn-Diamino Acid Derivatives 
European journal of organic chemistry  2013;2013(22):4744-4747.
The GAP asymmetric synthesis of α,β-diamino acid derivatives has been achieved by reacting chiral N-phosphonyl imines with Ni(II)-complex of glycine ester-based enolate without the use of traditional purifications of chromatography and recrystallization. The successful control of synstereochemistry of vicinal diamino products complements our previous methods which afforded anti stereoisomers and enables all four individual isomers to be synthesized by simply changing enolate geometry. In contrast to our previous synthesis where required at least 5 equiv of glycine Schiff base enolate for complete conversion, the new synthesis only needs 1.1 equiv of glycine Schiff base enolate to give complete diastereoselectivity (>99% de) and yields (91% – 97%). The absolute stereochemistry has been unambiguously determined by X-ray structural analysis.
PMCID: PMC4192728  PMID: 25309122
5.  let-7b/g silencing activates AKT signaling to promote gastric carcinogenesis 
Background
Aberrant AKT activation contributes to gastric cancer cell survival and chemotherapy resistance, however its regulation is poorly understood. microRNAs have been established to be important regulators in gastric carcinogenesis. Here, we showed the functional role and putative target of let-7b and let-7g (let-7b/g) in gastric carcinogenesis.
Methods
The expression of let-7b/g in gastric cancer cell lines and primary tumors were evaluated by miRNA qRT-PCR. The putative target gene of let-7b/g was explored by TargetScan followed by further validation. Functional analyses including MTT proliferation, monolayer colony formation, cell invasion assays and in vivo study were performed in both ectopic expression and knockdown approaches.
Results
let-7b/g was found down-regulated in gastric cancer and its downregulation was associated with poor survival and correlated with lymph node metastasis. let-7b/g inhibited AKT2 expression by directly binding to its 3’UTR, reduced p-AKT (S473) activation and suppressed expression of the downstream effector pS6. AKT2 mRNA expression showed negative correlation with the expression of let-7b/g in primary tumors. Short interfering RNA (siRNA) mediated knockdown of AKT2 phenocopied the tumor-suppressive effects of let-7b/g. Moreover, AKT2 re-expression partly abrogated the growth-inhibitory effect of let-7b/g.
Conclusion
In conclusion, our findings reveal decreased let-7b/g contributes to aberrant AKT activation in gastric tumorigenesis and provide a potential therapeutic strategy for gastric cancer.
Electronic supplementary material
The online version of this article (doi:10.1186/s12967-014-0281-3) contains supplementary material, which is available to authorized users.
doi:10.1186/s12967-014-0281-3
PMCID: PMC4196013  PMID: 25288334
let-7b; let-7g; AKT2; Gastric cancer; Tumor suppressor
6.  EARLY CHILDHOOD INVESTMENTS SUBSTANTIALLY BOOST ADULT HEALTH 
Science (New York, N.Y.)  2014;343(6178):1478-1485.
High-quality early childhood programs have been shown to have substantial benefits in reducing crime, raising earnings, and promoting education. Much less is known about their benefits for adult health. We report the long-term health impacts of one of the oldest and most heavily cited early childhood interventions with long-term follow-up evaluated by the method of randomization: the Carolina Abecedarian Project (ABC). Using recently collected biomedical data, we find that disadvantaged children randomly assigned to treatment have significantly lower prevalence of risk factors for cardiovascular and metabolic diseases in their mid-30s. The evidence is especially strong for males. The mean systolic blood pressure among the control males is 143, while only 126 among the treated. One in four males in the control group is affected by metabolic syndrome, while none in the treatment group is. To reach these conclusions, we address several statistical challenges. We use exact permutation tests to account for small sample sizes and conduct a parallel bootstrap confidence interval analysis to confirm the permutation analysis. We adjust inference to account for the multiple hypotheses tested and for nonrandom attrition. Our evidence shows the potential of early life interventions for preventing disease and promoting health.
doi:10.1126/science.1248429
PMCID: PMC4028126  PMID: 24675955
7.  Comparison of Brain Transcriptome of the Greater Horseshoe Bats (Rhinolophus ferrumequinum) in Active and Torpid Episodes 
PLoS ONE  2014;9(9):e107746.
Hibernation is an energy-saving strategy which is widely adopted by heterothermic mammals to survive in the harsh environment. The greater horseshoe bat (Rhinolophus ferrumequinum) can hibernate for a long period in the hibernation season. However, the global gene expression changes between hibernation and non-hibernation season in the greater horseshoe bat remain largely unknown. We herein reported a comprehensive survey of differential gene expression in the brain between winter hibernating and summer active greater horseshoe bats using next-generation sequencing technology. A total of 90,314,174 reads were generated and we identified 1,573 differentially expressed genes between active and torpid states. Interestingly, we found that differentially expressed genes are over-represented in some GO categories (such as metabolic suppression, cellular stress responses and oxidative stress), which suggests neuroprotective strategies might play an important role in hibernation control mechanisms. Our results determined to what extent the brain tissue of the greater horseshoe bats differ in gene expression between summer active and winter hibernating states and provided comprehensive insights into the adaptive mechanisms of bat hibernation.
doi:10.1371/journal.pone.0107746
PMCID: PMC4174523  PMID: 25251558
8.  Dietary Sources of Methylated Arsenic Species in Urine of the United States Population, NHANES 2003–2010 
PLoS ONE  2014;9(9):e108098.
Background
Arsenic is an ubiquitous element linked to carcinogenicity, neurotoxicity, as well as adverse respiratory, gastrointestinal, hepatic, and dermal health effects.
Objective
Identify dietary sources of speciated arsenic: monomethylarsonic acid (MMA), and dimethylarsinic acid (DMA).
Methods
Age-stratified, sample-weighted regression of NHANES (National Health and Nutrition Examination Survey) 2003–2010 data (∼8,300 participants ≥6 years old) characterized the association between urinary arsenic species and the additional mass consumed of USDA-standardized food groups (24-hour dietary recall data), controlling for potential confounders.
Results
For all arsenic species, the rank-order of age strata for median urinary molar concentration was children 6–11 years > adults 20–84 years > adolescents 12–19 years, and for all age strata, the rank-order was DMA > MMA. Median urinary molar concentrations of methylated arsenic species ranged from 0.56 to 3.52 µmol/mol creatinine. Statistically significant increases in urinary arsenic species were associated with increased consumption of: fish (DMA); fruits (DMA, MMA); grain products (DMA, MMA); legumes, nuts, seeds (DMA); meat, poultry (DMA); rice (DMA, MMA); rice cakes/crackers (DMA, MMA); and sugars, sweets, beverages (MMA). And, for adults, rice beverage/milk (DMA, MMA). In addition, based on US (United States) median and 90th percentile consumption rates of each food group, exposure from the following food groups was highlighted: fish; fruits; grain products; legumes, nuts, seeds; meat, poultry; and sugars, sweets, beverages.
Conclusions
In a nationally representative sample of the US civilian, noninstitutionalized population, fish (adults), rice (children), and rice cakes/crackers (adolescents) had the largest associations with urinary DMA. For MMA, rice beverage/milk (adults) and rice cakes/crackers (children, adolescents) had the largest associations.
doi:10.1371/journal.pone.0108098
PMCID: PMC4176478  PMID: 25251890
9.  miR-203 Suppresses the Proliferation and Migration and Promotes the Apoptosis of Lung Cancer Cells by Targeting SRC 
PLoS ONE  2014;9(8):e105570.
SRC, also known as proto-oncogene c-Src, is a non-receptor tyrosine kinase that plays an important role in cancer progression by promoting survival, angiogenesis, proliferation, and invasion pathways. In this study, we found that SRC protein levels were consistently upregulated in lung cancer tissues, but that SRC mRNA levels varied randomly, suggesting that a post-transcriptional mechanism was involved in SRC regulation. Because microRNAs (miRNAs) are powerful post-transcriptional regulators of gene expression, we used bioinformatic analyses to search for miRNAs that potentially target SRC. We identified specific targeting sites for miR-203 in the 3′-untranslated region (3′-UTR) of SRC. We then experimentally validated miR-203 as a direct regulator of SRC using cell transfection and luciferase assays and showed that miR-203 inhibited SRC expression and consequently triggered suppression of the SRC/Ras/ERK pathway. Finally, we demonstrated that the repression of SRC by miR-203 suppressed the proliferation and migration and promoted the apoptosis of lung cancer cells. In summary, this study provides the first clues regarding the role of miR-203 as a tumor suppressor in lung cancer cells through the inhibition of SRC translation.
doi:10.1371/journal.pone.0105570
PMCID: PMC4139332  PMID: 25140799
10.  Molecular Characterization of Putative Virulence Determinants in Burkholderia pseudomallei 
The Scientific World Journal  2014;2014:590803.
The Gram-negative saprophyte Burkholderia pseudomallei is the causative agent of melioidosis, an infectious disease which is endemic in Southeast Asia and northern Australia. This bacterium possesses many virulence factors which are thought to contribute to its survival and pathogenicity. Using a virulent clinical isolate of B. pseudomallei and an attenuated strain of the same B. pseudomallei isolate, 6 genes BPSL2033, BP1026B_I2784, BP1026B_I2780, BURPS1106A_A0094, BURPS1106A_1131, and BURPS1710A_1419 were identified earlier by PCR-based subtractive hybridization. These genes were extensively characterized at the molecular level, together with an additional gene BPSL3147 that had been identified by other investigators. Through a reverse genetic approach, single-gene knockout mutants were successfully constructed by using site-specific insertion mutagenesis and were confirmed by PCR. BPSL2033::Km and BURPS1710A_1419::Km mutants showed reduced rates of survival inside macrophage RAW 264.7 cells and also low levels of virulence in the nematode infection model. BPSL2033::Km demonstrated weak statistical significance (P = 0.049) at 8 hours after infection in macrophage infection study but this was not seen in BURPS1710A_1419::Km. Nevertheless, complemented strains of both genes were able to partially restore the gene defects in both in vitro and in vivo studies, thus suggesting that they individually play a minor role in the virulence of B. pseudomallei.
doi:10.1155/2014/590803
PMCID: PMC4158159  PMID: 25215325
11.  Iodine Status in Pregnant Women in the National Children's Study and in U.S. Women (15–44 Years), National Health and Nutrition Examination Survey 2005–2010 
Thyroid  2013;23(8):927-937.
Background
This report presents iodine data from National Health and Nutrition Examination Survey (NHANES) and from a sample of pregnant women in the National Children's Study (NCS) Vanguard Study.
Methods
Urinary iodine (UI) was measured in a one third subsample of NHANES 2005–2006 and 2009–2010 participants and in all 2007–2008 participants age 6 years and older. These measurements are representative of the general U.S. population. UI was also measured in a convenience sample of 501 pregnant women enrolled in the NCS initial Vanguard Study from seven study sites across the United States.
Results
NHANES median UI concentration in 2009–2010 (144 μg/L) was significantly lower than in 2007–2008 (164 μg/L). Non-Hispanic blacks had the lowest UI concentrations (131 μg/L) compared with non-Hispanic whites or Hispanics (147 and 148 μg/L, respectively). The median for all pregnant women in NHANES 2005–2010 was less than adequate (129 μg/L), while third trimester women had UI concentrations that were adequate (median UI 172 μg/L). Third trimester women participating in the NCS similarly had an adequate level of iodine intake, with a median UI concentration of 167 μg/L. Furthermore, NCS median UI concentrations varied by geographic location.
Conclusions
Dairy, but not salt, seafood, or grain consumption, was significantly positively associated with median UI concentration in women of childbearing age. Pregnant women in their third trimester in the NHANES 2005–2010 had adequate median UI concentrations, but pregnant women in NHANES who were in their first or second trimesters had median UI concentrations that were less than adequate. Non-Hispanic black pregnant women from both the NHANES 2005–20010 and the NCS consistently had lower UI median concentrations than non-Hispanic whites or Hispanics.
doi:10.1089/thy.2013.0012
PMCID: PMC3752509  PMID: 23488982
12.  N,N-Diisopropyl-N-phosphonyl Imines Lead to Efficient Asymmetric Synthesis of Aziridine-2-Carboxylic Esters 
Organic & biomolecular chemistry  2013;11(20):3400-3408.
Highly diastereoselective asymmetric synthesis of chiral aziridine-2-carboxylic esters is reported for 20 examples with good yields (51–87%) and excellent diastereoselectivities (>99:1 dr for most cases). The modified N-phosphonyl imines are proven to be superior to previous imine auxiliaries for the aza Darzens reaction by using secondary isopropyl to replace primary benzyl group for N,N-diamino protection. In the meanwhile, a special operation by slowly adding the pre-cooled imine solution at −78 °C into the preformed β-bromo lithium enolate mixture at this temperature in the presence of 4 Å molecular sieves was found to be crucial in terms of yields and diastereoselectivity. The present method can provide an easy and general access to β-hydroxy α-amino acids and other important amino building blocks.
doi:10.1039/c3ob40251g
PMCID: PMC3653188  PMID: 23563304
13.  Identifying Dynamic Protein Complexes Based on Gene Expression Profiles and PPI Networks 
BioMed Research International  2014;2014:375262.
Identification of protein complexes from protein-protein interaction networks has become a key problem for understanding cellular life in postgenomic era. Many computational methods have been proposed for identifying protein complexes. Up to now, the existing computational methods are mostly applied on static PPI networks. However, proteins and their interactions are dynamic in reality. Identifying dynamic protein complexes is more meaningful and challenging. In this paper, a novel algorithm, named DPC, is proposed to identify dynamic protein complexes by integrating PPI data and gene expression profiles. According to Core-Attachment assumption, these proteins which are always active in the molecular cycle are regarded as core proteins. The protein-complex cores are identified from these always active proteins by detecting dense subgraphs. Final protein complexes are extended from the protein-complex cores by adding attachments based on a topological character of “closeness” and dynamic meaning. The protein complexes produced by our algorithm DPC contain two parts: static core expressed in all the molecular cycle and dynamic attachments short-lived. The proposed algorithm DPC was applied on the data of Saccharomyces cerevisiae and the experimental results show that DPC outperforms CMC, MCL, SPICi, HC-PIN, COACH, and Core-Attachment based on the validation of matching with known complexes and hF-measures.
doi:10.1155/2014/375262
PMCID: PMC4052612  PMID: 24963481
14.  Intermittent hypoxia-induced protein phosphatase 2A activation reduces PC12 cell proliferation and differentiation 
Background
Intermittent hypoxia (IH) plays a critical role in sleep breathing disorder-associated hippocampus impairments, including neurocognitive deficits, irreversible memory and learning impairments. IH-induced neuronal injury in the hippocampus may result from reduced precursor cell proliferation and the relative numbers of postmitotic differentiated neurons. However, the mechanisms underlying IH-induced reactive oxygen species (ROS) generation effects on cell proliferation and neuronal differentiation remain largely unknown.
Results
ROS generation significantly increased after 1–4 days of IH without increased pheochromocytoma-12 (PC12) cell death, which resulted in increased protein phosphatase 2A (PP2A) mRNA and protein levels. After 3–4 days of IH, extracellular signal-regulated kinases 1/2 (ERK1/2) protein phosphorylation decreased, which could be reversed by superoxide dismutase (SOD), 1,10-phenanthroline (Phe), the PP2A phosphorylation inhibitors, okadaic acid (OKA) and cantharidin, and the ERK phosphorylation activator nicotine (p < 0.05). In particular, the significantly reduced cell proliferation and increased proportions of cells in the G0/G1 phase after 1–4 days of IH (p < 0.05), which resulted in decreased numbers of PC12 cells, could be reversed by treatment with SOD, Phe, PP2A inhibitors and an ERK activator. In addition, the numbers of nerve growth factor (NGF)-induced PC12 cells with neurite outgrowths after 3–4 days of IH were less than those after 4 days of RA, which was also reversed by SOD, Phe, PP2A inhibitors and an ERK activator.
Conclusions
Our results suggest that IH-induced ROS generation increases PP2A activation and subsequently downregulates ERK1/2 activation, which results in inhibition of PC12 cell proliferation through G0/G1 phase arrest and NGF-induced neuronal differentiation.
doi:10.1186/1423-0127-21-46
PMCID: PMC4058715  PMID: 24885237
Oxidative stress; Apoptosis; Cell viability; Cell cycle; Neurite outgrowth
15.  Intraneural perineurioma affecting multiple nerves: a case report and literature review 
Intraneural perineurioma is a neoplasm of perineurial cells, corresponding to WHO grade I. We present a case of intraneural perineurioma affecting multiple nerves, which usually involved one or two of major nerve trunks in one patient. We describe the clinical presentation, magnetic resonance (MR) neurography characteristics, and pathological characteristics. The differential diagnosis with other diseases, such as neurofibroma, Schwannomatosis and HNPP, will also be discussed. We also review the literature in efforts to highlight recent studies on intraneural perineurioma and heighten and awareness for the possible presentations of this disorder.
PMCID: PMC4097238  PMID: 25031759
Intraneural perineurioma; neuropathology; pseudo-onion bulbs; MR
16.  Adult Outcomes as a Function of an Early Childhood Educational Program: An Abecedarian Project Follow-Up 
Developmental psychology  2012;48(4):1033-1043.
Adult (age 30) educational, economic, and social-emotional adjustment outcomes were investigated for participants in the Abecedarian Project, a randomized controlled trial of early childhood education for children from low-income families. Of the original 111 infants enrolled (98% African American), 101 took part in the age-30 follow-up. Primary indicators of educational level, economic status, and social-adjustment were examined as a function of early childhood treatment. Treated individuals attained significantly more years of education, but income-to-needs ratios and criminal involvement did not vary significantly as a function of early treatment. A number of other indicators were described for each domain. Overall, the findings provide strong evidence for educational benefits, mixed evidence for economic benefits and little evidence for social-adjustment outcomes. Implications for public policy are discussed.
doi:10.1037/a0026644
PMCID: PMC3989926  PMID: 22250997
Abecedarian Project; Early Childhood Education; Poverty; Adult Outcomes; Education; Employment
17.  Prognostic value of circulating microRNA-21 in digestive system cancers: a meta-analysis 
Circulating microRNAs show aberrant expression in patients with cancer. The aim of this study was to investigate the prognostic value of circulating microRNA-21 (miR-21) in digestive system cancers. Methods: All the eligible studies were searched by Medline and EMBASE. The hazard ratios (HRs) for overall survival (OS), which compared the expression levels of circulating miR-21 in patients with digestive cancer was extracted and estimated. Pooled HRs and 95% confidence intervals (CI) were calculated. Then a meta-analysis was performed to clarify the prognostic value of the miR-21. Results: A total of seven studies involving 907 subjects were included. The results suggested that higher circulating miR-21 could predict worse OS outcome with the pooled HR of 2.19 (95% CI 1.01-4.75, P = 0.05) in digestive system cancers. Subgroup analysis by ethnicity indicated circulating miR-21 was associated with OS in patients with digestive cancer among Asians with the pooled HR of 2.90 (95% CI 1.30-6.45, P = 0.009). However, subgroup analysis by digestive system site revealed that there is no associated with OS in patients with colorectal cancer with the pooled HR of 1.34 (95% CI 0.45-4.00, P = 0.60). Conclusion: The present findings suggest that circulating miR-21 is associated with poor survival in patients with digestive cancer and could be a prognostic biomarker for those patients.
PMCID: PMC4057835  PMID: 24955156
Digestive cancer; circulating miR-21; prognosis; biomarker; meta-analysis
18.  A Novel Algorithm for Detecting Protein Complexes with the Breadth First Search 
BioMed Research International  2014;2014:354539.
Most biological processes are carried out by protein complexes. A substantial number of false positives of the protein-protein interaction (PPI) data can compromise the utility of the datasets for complexes reconstruction. In order to reduce the impact of such discrepancies, a number of data integration and affinity scoring schemes have been devised. The methods encode the reliabilities (confidence) of physical interactions between pairs of proteins. The challenge now is to identify novel and meaningful protein complexes from the weighted PPI network. To address this problem, a novel protein complex mining algorithm ClusterBFS (Cluster with Breadth-First Search) is proposed. Based on the weighted density, ClusterBFS detects protein complexes of the weighted network by the breadth first search algorithm, which originates from a given seed protein used as starting-point. The experimental results show that ClusterBFS performs significantly better than the other computational approaches in terms of the identification of protein complexes.
doi:10.1155/2014/354539
PMCID: PMC4003846  PMID: 24818139
19.  Cloud computing for detecting high-order genome-wide epistatic interaction via dynamic clustering 
BMC Bioinformatics  2014;15:102.
Backgroud
Taking the advan tage of high-throughput single nucleotide polymorphism (SNP) genotyping technology, large genome-wide association studies (GWASs) have been considered to hold promise for unravelling complex relationships between genotype and phenotype. At present, traditional single-locus-based methods are insufficient to detect interactions consisting of multiple-locus, which are broadly existing in complex traits. In addition, statistic tests for high order epistatic interactions with more than 2 SNPs propose computational and analytical challenges because the computation increases exponentially as the cardinality of SNPs combinations gets larger.
Results
In this paper, we provide a simple, fast and powerful method using dynamic clustering and cloud computing to detect genome-wide multi-locus epistatic interactions. We have constructed systematic experiments to compare powers performance against some recently proposed algorithms, including TEAM, SNPRuler, EDCF and BOOST. Furthermore, we have applied our method on two real GWAS datasets, Age-related macular degeneration (AMD) and Rheumatoid arthritis (RA) datasets, where we find some novel potential disease-related genetic factors which are not shown up in detections of 2-loci epistatic interactions.
Conclusions
Experimental results on simulated data demonstrate that our method is more powerful than some recently proposed methods on both two- and three-locus disease models. Our method has discovered many novel high-order associations that are significantly enriched in cases from two real GWAS datasets. Moreover, the running time of the cloud implementation for our method on AMD dataset and RA dataset are roughly 2 hours and 50 hours on a cluster with forty small virtual machines for detecting two-locus interactions, respectively. Therefore, we believe that our method is suitable and effective for the full-scale analysis of multiple-locus epistatic interactions in GWAS.
doi:10.1186/1471-2105-15-102
PMCID: PMC4021249  PMID: 24717145
Cloud computing; Genome-wide association studies; Dynamic clustering
20.  In vivo analysis of DNA binding and ligand interaction of BlcR, an IclR-type repressor from Agrobacterium tumefaciens 
Microbiology  2013;159(Pt 4):814-822.
Agrobacterium tumefaciens BlcR represses transcription of the blcABC operon, which is involved in metabolism of γ-butyrolactone, and this repression is alleviated by succinate semialdehyde (SSA). BlcR exists as a homodimer, and the blcABC promoter DNA contains two BlcR-binding sites (IR1 and IR2) that correspond to two BlcR dimers. In this study, we established an in vivo system to examine the SSA-responsive control of BlcR transcriptional regulation. The endogenous blcR, encoded in the pAtC58 plasmid of A. tumefaciens C58, was not optimal for investigating the effect of SSA on BlcR repression, probably due to the SSA degradation mediated by the pAt-encoded blcABC. We therefore introduced blcR (and the blcABC promoter DNA, separately) exogenously into a strain of C58 cured of pAtC58 (and pTiC58). We applied this system to interrogate BlcR–DNA interactions and to test predictions from our prior structural and biochemical studies. This in vivo analysis confirmed the previously mapped SSA-binding site and supported a model by which DNA coordinates formation of a BlcR tetramer. In addition, we identified a specific lysine residue (K59) as an important determinant for DNA binding. Moreover, based on isothermal titration calorimetry analysis, we found IR1 to play the dominant role in binding to BlcR, relative to IR2. Together, these in vivo results expand the biochemical findings and provide new mechanistic insights into BlcR–DNA interactions.
doi:10.1099/mic.0.065680-0
PMCID: PMC4083662  PMID: 23449918
21.  Nutrition and physical activity randomized control trial in child care centers improves knowledge, policies, and children’s body mass index 
BMC Public Health  2014;14:215.
Background
To address the public health crisis of overweight and obese preschool-age children, the Nutrition And Physical Activity Self Assessment for Child Care (NAP SACC) intervention was delivered by nurse child care health consultants with the objective of improving child care provider and parent nutrition and physical activity knowledge, center-level nutrition and physical activity policies and practices, and children’s body mass index (BMI).
Methods
A seven-month randomized control trial was conducted in 17 licensed child care centers serving predominantly low income families in California, Connecticut, and North Carolina, including 137 child care providers and 552 families with racially and ethnically diverse children three to five years old. The NAP SACC intervention included educational workshops for child care providers and parents on nutrition and physical activity and consultation visits provided by trained nurse child care health consultants. Demographic characteristics and pre - and post-workshop knowledge surveys were completed by providers and parents. Blinded research assistants reviewed each center’s written health and safety policies, observed nutrition and physical activity practices, and measured randomly selected children’s nutritional intake, physical activity, and height and weight pre- and post-intervention.
Results
Hierarchical linear models and multiple regression models assessed individual- and center-level changes in knowledge, policies, practices and age- and sex-specific standardized body mass index (zBMI), controlling for state, parent education, and poverty level. Results showed significant increases in providers’ and parents’ knowledge of nutrition and physical activity, center-level improvements in policies, and child-level changes in children’s zBMI based on 209 children in the intervention and control centers at both pre- and post-intervention time points.
Conclusions
The NAP SACC intervention, as delivered by trained child health professionals such as child care health consultants, increases provider knowledge, improves center policies, and lowers BMI for children in child care centers. More health professionals specifically trained in a nutrition and physical activity intervention in child care are needed to help reverse the obesity epidemic.
Trial registration
National Clinical Trials Number NCT01921842
doi:10.1186/1471-2458-14-215
PMCID: PMC3945995  PMID: 24580983
Child care; Nutrition; Physical activity; Body mass index; Child care health consultants; Obesity; Overweight
22.  PAQR3 Modulates Insulin Signaling by Shunting Phosphoinositide 3-Kinase p110α to the Golgi Apparatus 
Diabetes  2013;62(2):444-456.
Phosphoinositide 3-kinase (PI3K) mediates insulin actions by relaying signals from insulin receptors (IRs) to downstream targets. The p110α catalytic subunit of class IA PI3K is the primary insulin-responsive PI3K implicated in insulin signaling. We demonstrate here a new mode of spatial regulation for the p110α subunit of PI3K by PAQR3 that is exclusively localized in the Golgi apparatus. PAQR3 interacts with p110α, and the intracellular targeting of p110α to the Golgi apparatus is reduced by PAQR3 downregulation and increased by PAQR3 overexpression. Insulin-stimulated PI3K activity and phosphoinositide (3,4,5)-triphosphate production are enhanced by Paqr3 deletion and reduced by PAQR3 overexpression in hepatocytes. Deletion of Paqr3 enhances insulin-stimulated phosphorylation of AKT and glycogen synthase kinase 3β, but not phosphorylation of IR and IR substrate-1 (IRS-1), in hepatocytes, mouse liver, and skeletal muscle. Insulin-stimulated GLUT4 translocation to the plasma membrane and glucose uptake are enhanced by Paqr3 ablation. Furthermore, PAQR3 interacts with the domain of p110α involved in its binding with p85, the regulatory subunit of PI3K. Overexpression of PAQR3 dose-dependently reduces the interaction of p85α with p110α. Thus, PAQR3 negatively regulates insulin signaling by shunting cytosolic p110α to the Golgi apparatus while competing with p85 subunit in forming a PI3K complex with p110α.
doi:10.2337/db12-0244
PMCID: PMC3554364  PMID: 23086038
23.  An Approach to Vicinal t-Boc-Amino Dibromides via Catalytic Aminobromination of Nitrostyrenes without using Chromatography and Recrystallization 
The Journal of organic chemistry  2013;78(3):1171-1175.
1.0 % Mol of K3PO4·3H2O was found to catalyze aminohalogenation reaction of nitrostyrenes with N,N-dibromo-tert-butylcarbamate (t-Boc-NBr2) in dichloroethane system. Good to excellent yields and complete regioselectivity have been achieved by taking advantage of the GAP work-up without using traditional purification techniques such as column chromatography and recrystallization. New mechanism was proposed involving radical and ionic catalytic cycles and an intramolecular migration.
doi:10.1021/jo302727v
PMCID: PMC3568972  PMID: 23311641
Aminohalogenation; bromoamine; Group-Assistant-Purification (GAP) chemistry; N,N-dibromo-tert-butylcarbamate; nitrostyrenes
24.  A Randomized, Double-Blind, Controlled Trial of the 17D Yellow Fever Virus Vaccine Given in Combination with Immune Globulin or Placebo: Comparative Viremia and Immunogenicity 
We evaluated whether coadministration of the yellow fever (YF) virus vaccine with human immunoglobulin (Ig) that contained YF virus-neutralizing antibodies would reduce post-vaccination viremia without compromising immunogenicity and thus, potentially mitigate YF vaccine-associated adverse events. We randomized 80 participants to receive either YF vaccine and Ig or YF vaccine and saline placebo. Participants were followed for 91 days for safety and assessments of viremia and immunogenicity. There were no differences found between the two groups in the proportion of vaccinated participants who developed viremia, seroconversion, cluster of differentiation (CD)-8+ and CD4+ T-cell responses, and cytokine responses. These results argue against one putative explanation for the increased reporting of YF vaccine side effects in recent years (i.e., a change in travel clinic practice after 1996 when hepatitis A prophylaxis with vaccine replaced routine use of pre-travel Ig, thus potentially removing an incidental YF vaccine-attenuating effect of anti-YF virus antibodies present in Ig) (ClinicalTrials.gov identifier: NCT00254826).
doi:10.4269/ajtmh.2012.12-0179
PMCID: PMC3541731  PMID: 23208880
25.  Asymmetric synthesis of α-alkenyl homoallylic primary amines via 1,2-addition of Grignard reagent to α,β-unsaturated phosphonyl imines 
RSC advances  2013;3(36):15820-15826.
A series of chiral N-phosphonyl protected α-alkenyl homoallylic primary amines were synthesized by asymmetric addition of allylmagnesium bromide Grignard reagent towards chiral α,β-unsaturated imines. Only 1,2-adduct was obtained for all the imines with good yields and excellent diastereoselectivities. The chiral auxiliary could be easily removed under simple conditions, giving free multiple functionalized primary amines.
doi:10.1039/C3RA42927J
PMCID: PMC3804338  PMID: 24159373

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