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1.  Selection occurs within linear fruit and during the early stages of reproduction in Robinia pseudoacacia 
Background
Pollen donor compositions differ during the early stages of reproduction due to various selection mechanisms. In addition, ovules linearly ordered within a fruit have different probabilities of reaching maturity. Few attempts, however, have been made to directly examine the magnitude and timing of selection, as well as the mechanisms during early life stages and within fruit. Robinia pseudoacacia, which contains linear fruit and non-random ovule maturation and abortion patterns, has been used to study the viability of selection within fruit and during the early stages of reproduction. To examine changes in the pollen donor composition during the early stages of reproduction and of progeny originating from different positions within fruit, paternity analyses were performed for three early life stages (aborted seeds, mature seeds and seedlings) in the insect-pollinated tree R. pseudoacacia.
Results
Selection resulted in an overall decrease in the level of surviving selfed progeny at each life stage. The greatest change was observed between the aborted seed stage and mature seed stage, indicative of inbreeding depression (the reduced fitness of a given population that occurs when related individual breeding was responsible for early selection). A selective advantage was detected among paternal trees. Within fruits, the distal ends showed higher outcrossing rates than the basal ends, indicative of selection based on the order of seeds within the fruit.
Conclusions
Our results suggest that selection exists both within linear fruit and during the early stages of reproduction, and that this selection can affect male reproductive success during the early life stages. This indicates that tree species with mixed-mating systems may have evolved pollen selection mechanisms to increase the fitness of progeny and adjust the population genetic composition. The early selection that we detected suggests that inbreeding depression caused the high abortion rate and low seed set in R. pseudoacacia.
doi:10.1186/1471-2148-14-53
PMCID: PMC3998051  PMID: 24655746
Pollen donor composition; Inbreeding depression; Paternity analysis; Robinia pseudoacacia; Viability selection
2.  BETASEQ: a powerful novel method to control type-I error inflation in partially sequenced data for rare variant association testing 
Bioinformatics  2013;30(4):480-487.
Summary: Despite its great capability to detect rare variant associations, next-generation sequencing is still prohibitively expensive when applied to large samples. In case-control studies, it is thus appealing to sequence only a subset of cases to discover variants and genotype the identified variants in controls and the remaining cases under the reasonable assumption that causal variants are usually enriched among cases. However, this approach leads to inflated type-I error if analyzed naively for rare variant association. Several methods have been proposed in recent literature to control type-I error at the cost of either excluding some sequenced cases or correcting the genotypes of discovered rare variants. All of these approaches thus suffer from certain extent of information loss and thus are underpowered. We propose a novel method (BETASEQ), which corrects inflation of type-I error by supplementing pseudo-variants while keeps the original sequence and genotype data intact. Extensive simulations and real data analysis demonstrate that, in most practical situations, BETASEQ leads to higher testing powers than existing approaches with guaranteed (controlled or conservative) type-I error.
Availability and implementation: BETASEQ and associated R files, including documentation, examples, are available at http://www.unc.edu/∼yunmli/betaseq
Contact: songyan@unc.edu or yunli@med.unc.edu
Supplementary information: Supplementary data are available at Bioinformatics online.
doi:10.1093/bioinformatics/btt719
PMCID: PMC3928526  PMID: 24336643
3.  Prestimulus alpha power predicts fidelity of sensory encoding in perceptual decision making 
NeuroImage  2013;87:242-251.
Pre-stimulus α power has been shown to correlate with the behavioral accuracy of perceptual decisions. In most cases, these correlations have been observed by comparing α power for different behavioral outcomes (e.g. correct vs incorrect trials). In this paper we investigate such covariation within the context of behaviorally-latent fluctuations in task-relevant post-stimulus neural activity. Specially we consider variations of pre-stimulus α power with post-stimulus EEG components in a two alternative forced choice visual discrimination task. EEG components, discriminative of stimulus class, are identified using a linear multivariate classifier and only the variability of the components for correct trials (regardless of stimulus class, and for nominally identical stimuli) are correlated with the corresponding pre-stimulus α power. We find a significant relationship between the mean and variance of the pre-stimulus α power and the variation of the trial-to-trial magnitude of an early post-stimulus EEG component. This relationship is not seen for a later EEG component that is also discriminative of stimulus class and which has been previously linked to the quality of evidence driving the decision process. Our results suggest that early perceptual representations, rather than temporally later neural correlates of the perceptual decision, are modulated by pre-stimulus state.
doi:10.1016/j.neuroimage.2013.10.041
PMCID: PMC3946902  PMID: 24185020
decision-making; sensory encoding; single-trial; alpha power; electroencephalogram (EEG)
4.  An abundance of rare functional variants in 202 drug target genes sequenced in 14,002 people 
Science (New York, N.Y.)  2012;337(6090):100-104.
Rare genetic variants contribute to complex disease risk; however, the abundance of rare variants in human populations remains unknown. We explored this spectrum of variation by sequencing 202 genes encoding drug targets in 14,002 individuals. We find rare variants are abundant (one every 17 bases) and geographically localized, such that even with large sample sizes, rare variant catalogs will be largely incomplete. We used the observed patterns of variation to estimate population growth parameters, the proportion of variants in a given frequency class that are putatively deleterious, and mutation rates for each gene. Overall we conclude that, due to rapid population growth and weak purifying selection, human populations harbor an abundance of rare variants, many of which are deleterious and have relevance to understanding disease risk.
doi:10.1126/science.1217876
PMCID: PMC4319976  PMID: 22604722
5.  Deferoxamine attenuates lipopolysaccharide-induced neuroinflammation and memory impairment in mice 
Background
Neuroinflammation often results in enduring cognitive impairment and is a risk factor for postoperative cognitive dysfunction. There are currently no effective treatments for infection-induced cognitive impairment. Previous studies have shown that the iron chelator deferoxamine (DFO) can increase the resistance of neurons to injury and disease by stimulating adaptive cellular stress responses. However, the impact of DFO on the cognitive sequelae of neuroinflammation is unknown.
Methods
A mouse model of lipopolysaccharide (LPS)-induced cognitive impairment was established to evaluate the neuroprotective effects of DFO against LPS-induced memory deficits and neuroinflammation. Adult C57BL/6 mice were treated with 0.5 μg of DFO 3 days prior to intracerebroventricular microinjection of 2 μg of LPS. Cognitive function was assessed using a Morris water maze from post-injection days 1 to 3. Animal behavioral tests, as well as pathological and biochemical assays were performed to evaluate the LPS-induced hippocampal damage and the neuroprotective effect of DFO.
Results
Treatment of mice with LPS resulted in deficits in cognitive performance in the Morris water maze without changing locomotor activity, which were ameliorated by pretreatment with DFO. DFO prevented LPS-induced microglial activation and elevations of IL-1β and TNF-α levels in the hippocampus. Moreover, DFO attenuated elevated expression of caspase-3, modulated GSK3β activity, and prevented LPS-induced increases of MDA and SOD levels in the hippocampus. DFO also significantly blocked LPS-induced iron accumulation and altered expression of proteins related to iron metabolism in the hippocampus.
Conclusions
Our results suggest that DFO may possess a neuroprotective effect against LPS-induced neuroinflammation and cognitive deficits via mechanisms involving maintenance of less brain iron, prevention of neuroinflammation, and alleviation of oxidative stress and apoptosis.
doi:10.1186/s12974-015-0238-3
PMCID: PMC4323121  PMID: 25644393
Deferoxamine; Neuroinflammation; Iron; Memory impairment; Oxidative stress; Apoptosis
6.  Sexual and Reproductive Health Knowledge, Contraception Uptake, and Factors Associated with Unmet Need for Modern Contraception among Adolescent Female Sex Workers in China 
PLoS ONE  2015;10(1):e0115435.
Objective
In China, policy and social taboo prevent unmarried adolescents from accessing sexual and reproductive health (SRH) services. Research is needed to determine the SRH needs of highly disadvantaged groups, such as adolescent female sex workers (FSWs). This study describes SRH knowledge, contraception use, pregnancy, and factors associated with unmet need for modern contraception among adolescent FSWs in Kunming, China.
Methods
A cross-sectional study using a one-stage cluster sampling method was employed to recruit adolescents aged 15 to 20 years, and who self-reported having received money or gifts in exchange for sex in the past 6 months. A semi-structured questionnaire was administered by trained peer educators or health workers. Multivariable logistic regression was conducted to determine correlates of low knowledge and unmet need for modern contraception.
Results
SRH knowledge was poor among the 310 adolescents surveyed; only 39% had heard of any long-acting reversible contraception (implant, injection or IUD). Despite 98% reporting not wanting to get pregnant, just 43% reported consistent condom use and 28% currently used another form of modern contraception. Unmet need for modern contraception was found in 35% of adolescents, and was associated with having a current non-paying partner, regular alcohol use, and having poorer SRH knowledge. Past abortion was common (136, 44%). In the past year, 76% had reported a contraception consultation but only 27% reported ever receiving SRH information from a health service.
Conclusions
This study demonstrated a low level of SRH knowledge, a high unmet need for modern contraception and a high prevalence of unintended pregnancy among adolescent FSWs in Kunming. Most girls relied on condoms, emergency contraception, or traditional methods, putting them at risk of unwanted pregnancy. This study identifies an urgent need for Chinese adolescent FSWs to be able to access quality SRH information and effective modern contraception.
doi:10.1371/journal.pone.0115435
PMCID: PMC4307985  PMID: 25625194
7.  HMG-coenzyme A reductase inhibition, type 2 diabetes, and bodyweight: evidence from genetic analysis and randomised trials 
Swerdlow, Daniel I | Preiss, David | Kuchenbaecker, Karoline B | Holmes, Michael V | Engmann, Jorgen E L | Shah, Tina | Sofat, Reecha | Stender, Stefan | Johnson, Paul C D | Scott, Robert A | Leusink, Maarten | Verweij, Niek | Sharp, Stephen J | Guo, Yiran | Giambartolomei, Claudia | Chung, Christina | Peasey, Anne | Amuzu, Antoinette | Li, KaWah | Palmen, Jutta | Howard, Philip | Cooper, Jackie A | Drenos, Fotios | Li, Yun R | Lowe, Gordon | Gallacher, John | Stewart, Marlene C W | Tzoulaki, Ioanna | Buxbaum, Sarah G | van der A, Daphne L | Forouhi, Nita G | Onland-Moret, N Charlotte | van der Schouw, Yvonne T | Schnabel, Renate B | Hubacek, Jaroslav A | Kubinova, Ruzena | Baceviciene, Migle | Tamosiunas, Abdonas | Pajak, Andrzej | Topor-Madry, Romanvan | Stepaniak, Urszula | Malyutina, Sofia | Baldassarre, Damiano | Sennblad, Bengt | Tremoli, Elena | de Faire, Ulf | Veglia, Fabrizio | Ford, Ian | Jukema, J Wouter | Westendorp, Rudi G J | de Borst, Gert Jan | de Jong, Pim A | Algra, Ale | Spiering, Wilko | der Zee, Anke H Maitland-van | Klungel, Olaf H | de Boer, Anthonius | Doevendans, Pieter A | Eaton, Charles B | Robinson, Jennifer G | Duggan, David | Kjekshus, John | Downs, John R | Gotto, Antonio M | Keech, Anthony C | Marchioli, Roberto | Tognoni, Gianni | Sever, Peter S | Poulter, Neil R | Waters, David D | Pedersen, Terje R | Amarenco, Pierre | Nakamura, Haruo | McMurray, John J V | Lewsey, James D | Chasman, Daniel I | Ridker, Paul M | Maggioni, Aldo P | Tavazzi, Luigi | Ray, Kausik K | Seshasai, Sreenivasa Rao Kondapally | Manson, JoAnn E | Price, Jackie F | Whincup, Peter H | Morris, Richard W | Lawlor, Debbie A | Smith, George Davey | Ben-Shlomo, Yoav | Schreiner, Pamela J | Fornage, Myriam | Siscovick, David S | Cushman, Mary | Kumari, Meena | Wareham, Nick J | Verschuren, W M Monique | Redline, Susan | Patel, Sanjay R | Whittaker, John C | Hamsten, Anders | Delaney, Joseph A | Dale, Caroline | Gaunt, Tom R | Wong, Andrew | Kuh, Diana | Hardy, Rebecca | Kathiresan, Sekar | Castillo, Berta A | van der Harst, Pim | Brunner, Eric J | Tybjaerg-Hansen, Anne | Marmot, Michael G | Krauss, Ronald M | Tsai, Michael | Coresh, Josef | Hoogeveen, Ronald C | Psaty, Bruce M | Lange, Leslie A | Hakonarson, Hakon | Dudbridge, Frank | Humphries, Steve E | Talmud, Philippa J | Kivimäki, Mika | Timpson, Nicholas J | Langenberg, Claudia | Asselbergs, Folkert W | Voevoda, Mikhail | Bobak, Martin | Pikhart, Hynek | Wilson, James G | Reiner, Alex P | Keating, Brendan J | Hingorani, Aroon D | Sattar, Naveed
Lancet  2015;385(9965):351-361.
Summary
Background
Statins increase the risk of new-onset type 2 diabetes mellitus. We aimed to assess whether this increase in risk is a consequence of inhibition of 3-hydroxy-3-methylglutaryl-CoA reductase (HMGCR), the intended drug target.
Methods
We used single nucleotide polymorphisms in the HMGCR gene, rs17238484 (for the main analysis) and rs12916 (for a subsidiary analysis) as proxies for HMGCR inhibition by statins. We examined associations of these variants with plasma lipid, glucose, and insulin concentrations; bodyweight; waist circumference; and prevalent and incident type 2 diabetes. Study-specific effect estimates per copy of each LDL-lowering allele were pooled by meta-analysis. These findings were compared with a meta-analysis of new-onset type 2 diabetes and bodyweight change data from randomised trials of statin drugs. The effects of statins in each randomised trial were assessed using meta-analysis.
Findings
Data were available for up to 223 463 individuals from 43 genetic studies. Each additional rs17238484-G allele was associated with a mean 0·06 mmol/L (95% CI 0·05–0·07) lower LDL cholesterol and higher body weight (0·30 kg, 0·18–0·43), waist circumference (0·32 cm, 0·16–0·47), plasma insulin concentration (1·62%, 0·53–2·72), and plasma glucose concentration (0·23%, 0·02–0·44). The rs12916 SNP had similar effects on LDL cholesterol, bodyweight, and waist circumference. The rs17238484-G allele seemed to be associated with higher risk of type 2 diabetes (odds ratio [OR] per allele 1·02, 95% CI 1·00–1·05); the rs12916-T allele association was consistent (1·06, 1·03–1·09). In 129 170 individuals in randomised trials, statins lowered LDL cholesterol by 0·92 mmol/L (95% CI 0·18–1·67) at 1-year of follow-up, increased bodyweight by 0·24 kg (95% CI 0·10–0·38 in all trials; 0·33 kg, 95% CI 0·24–0·42 in placebo or standard care controlled trials and −0·15 kg, 95% CI −0·39 to 0·08 in intensive-dose vs moderate-dose trials) at a mean of 4·2 years (range 1·9–6·7) of follow-up, and increased the odds of new-onset type 2 diabetes (OR 1·12, 95% CI 1·06–1·18 in all trials; 1·11, 95% CI 1·03–1·20 in placebo or standard care controlled trials and 1·12, 95% CI 1·04–1·22 in intensive-dose vs moderate dose trials).
Interpretation
The increased risk of type 2 diabetes noted with statins is at least partially explained by HMGCR inhibition.
Funding
The funding sources are cited at the end of the paper.
doi:10.1016/S0140-6736(14)61183-1
PMCID: PMC4322187  PMID: 25262344
8.  Inhibited biofilm formation and improved antibacterial activity of a novel nanoemulsion against cariogenic Streptococcus mutans in vitro and in vivo 
The aim of this study was to prepare a novel nanoemulsion loaded with poorly water-soluble chlorhexidine acetate (CNE) to improve its solubility, and specifically enhance the antimicrobial activity against Streptococcus mutans in vitro and in vivo. In this study, a novel CNE nanoemulsion with an average size of 63.13 nm and zeta potential of −67.13 mV comprising 0.5% CNE, 19.2% Tween 80, 4.8% propylene glycol, and 6% isopropyl myristate was prepared by the phase inversion method. Important characteristics such as the content, size, zeta potential, and pH value of CNE did not change markedly, stored at room temperature for 1 year. Also, compared with chlorhexidine acetate water solution (CHX), the release profile results show that the CNE has visibly delayed releasing effect in both phosphate-buffered saline and artificial saliva solutions (P<0.005). The minimum inhibitory concentration and minimum bactericidal concentration of CHX for S. mutans (both 0.8 μg/mL) are both two times those of CNE (0.4 μg/mL). Besides, CNE of 0.8 μg/mL exhibited fast-acting bactericidal efficacy against S. mutans, causing 95.07% death within 5 minutes, compared to CHX (73.33%) (P<0.01). We observed that 5 mg/mL and 2 mg/mL CNE were both superior to CHX, significantly reducing oral S. mutans numbers and reducing the severity of carious lesions in Sprague Dawley rats (P<0.05), in an in vivo test. CNE treatment at a concentration of 0.2 μg/mL inhibited biofilm formation more effectively than CHX, as indicated by the crystal violet staining method, scanning electron microscopy, and atomic force microscopy. The cell membrane of S. mutans was also severely disrupted by 0.2 μg/mL CNE, as indicated by transmission electron microscopy. These results demonstrated that CNE greatly improved the solubility and antimicrobial activity of this agent against S. mutans both in vitro and in vivo. This novel nanoemulsion is a promising medicine for preventing and curing dental caries.
Video abstract
doi:10.2147/IJN.S72920
PMCID: PMC4296965  PMID: 25624759
nanoemulsion; chlorhexidine acetate; Streptococcus mutans; antibacterial
9.  Insulin Resistance Is an Important Risk Factor for Cognitive Impairment in Elderly Patients with Primary Hypertension 
Yonsei Medical Journal  2014;56(1):89-94.
Purpose
Insulin resistance plays a role in the development of dementia and hypertension. We investigated a possible relationship between cognitive impairment and insulin resistance in elderly Chinese patients with primary hypertension.
Materials and Methods
One hundred and thirty-two hypertensive elderly patients (>60 years) were enrolled in this study, and assigned into either the cognitive impairment group (n=61) or the normal cognitive group (n=71). Gender, age, education, body mass index (BMI), waist hip ratio (WHR), total cholesterol (TC), triglyceride (TG), C-reactive protein (CRP), high density lipoprotein cholesterol (HDL-C), low density lipoprotein cholesterol (LDL-C), creatinine (Cr), fasting plasma glucose (FPG), fasting insulin (FINS), homeostasis model of assessment for insulin resistance index (HOMA-IR), systolic blood pressure, diastolic blood pressure, smoking history, atherosclerosis and the proportion of uncontrolled hypertension were compared between the two groups. Multi-factorial logistic regression analysis was performed.
Results
No significant differences were found in gender, age, TC, CRP, HDL-C, LDL-C, Cr, BP, smoking history, atherosclerosis and the proportion of uncontrolled hypertension between the two groups. The cognitive impairment group had lower education levels, and higher BMI, WHR, TG, FPG, FINS, and HOMA-IR levels than the control group. Logistic regression analysis revealed the levels of education, BMI, WHR, and HOMA-IR as independent factors that predict cognitive impairment in patients.
Conclusion
Our study demonstrates that poor education and increased BMI, WHR, and HOMA-IR are independent risk factors for cognitive impairment in elderly patients with hypertension. Insulin resistance plays an important role in the development of cognitive impairment in primary elderly hypertensive patients.
doi:10.3349/ymj.2015.56.1.89
PMCID: PMC4276782  PMID: 25510751
Hypertension; insulin resistance; cognitive impairment; elderly; risk factor
10.  Left-sided approach video-assisted thymectomy for the treatment of thymic diseases 
Background
Video-assisted thoracoscopic thymectomy was developed more than 10 years ago and has become a widely accepted surgical approach. Most published reports regarding this procedure have focused on the right-sided approach. Since left-sided approach chest surgery is the first choice in cases of right pleural adhesion, large left thymus tumors, and tumors in close contact with the great vessels of the left pericardium, we performed thoracoscopic thymectomy using the left-sided approach in 52 cases and summarize herein its technical feasibility, indications, and operative steps.
Methods
Between February 2004 and October 2014, 52 patients (24 men, 28 women, median age: 50 years, ranging from 18 to 85 years), underwent a video-assisted thoracoscopic thymectomy using the left-sided approach. All procedures were performed under general anesthesia with single-lung ventilation. Patients were placed in the right lateral decubitus position and three ports were made. The entire hemithorax was carefully examined, then mediastinal pleura was incised, and the thymus was bluntly dissected from the inferior polar extending to the superior polar. The thymic venous was clipped.
Results
All procedures were carried out safely, including simple thymectomy (n = 43) and extended thymectomy (n = 9). There were no operative deaths or serious complications, and there were seven cases of conversion to open thoracotomy. The mean operative duration was 105.3 minutes (ranging from 80 to 140 minutes). The mean blood loss was 78.5 ml (ranging from 20 to 200 ml), and there was no blood transfusion required. All patients were well throughout the follow-up period.
Conclusions
The left-sided approach for video-assisted thoracoscopic thymectomy was a safe approach and could be an alternative procedure to the right-sided approach for the same procedure.
doi:10.1186/1477-7819-12-398
PMCID: PMC4320500  PMID: 25547586
Left-sided approach; Video-assisted thoracoscopic; Thymectomy
11.  Deacetylase-Independent Function of HDAC3 in Transcription and Metabolism Requires Nuclear Receptor Corepressor 
Molecular cell  2013;52(6):10.1016/j.molcel.2013.10.022.
Histone deacetylases (HDACs) are believed to regulate gene transcription by catalyzing deacetylation reactions. HDAC3 depletion in mouse liver upregulates lipogenic genes and results in severe hepatosteatosis. Here we show that pharmacologic HDAC inhibition in primary hepatocytes causes histone hyperacetylation but does not upregulate expression of HDAC3 target genes. Meanwhile, deacetylase-dead HDAC3 mutants can rescue hepatosteatosis and repress lipogenic genes expression in HDAC3-depleted mouse liver, demonstrating that histone acetylation is insufficient to activate gene transcription. Mutations abolishing interactions with the nuclear receptor corepressor (NCOR or SMRT) render HDAC3 nonfunctional in vivo. Additionally, liver-specific knockout of NCOR, but not SMRT, causes metabolic and transcriptomal alterations resembling those of mice without hepatic HDAC3, demonstrating that interaction with NCOR is essential for deacetylase-independent function of HDAC3. These findings highlight non-enzymatic roles of a major HDAC in transcriptional regulation in vivo and warrant reconsideration of the mechanism of action of HDAC inhibitors.
doi:10.1016/j.molcel.2013.10.022
PMCID: PMC3877208  PMID: 24268577
12.  Prospective Associations of Coronary Heart Disease Loci in African Americans Using the MetaboChip: The PAGE Study 
PLoS ONE  2014;9(12):e113203.
Background
Coronary heart disease (CHD) is a leading cause of morbidity and mortality in African Americans. However, there is a paucity of studies assessing genetic determinants of CHD in African Americans. We examined the association of published variants in CHD loci with incident CHD, attempted to fine map these loci, and characterize novel variants influencing CHD risk in African Americans.
Methods and Results
Up to 8,201 African Americans (including 546 first CHD events) were genotyped using the MetaboChip array in the Atherosclerosis Risk in Communities (ARIC) study and Women's Health Initiative (WHI). We tested associations using Cox proportional hazard models in sex- and study-stratified analyses and combined results using meta-analysis. Among 44 validated CHD loci available in the array, we replicated and fine-mapped the SORT1 locus, and showed same direction of effects as reported in studies of individuals of European ancestry for SNPs in 22 additional published loci. We also identified a SNP achieving array wide significance (MYC: rs2070583, allele frequency 0.02, P = 8.1×10−8), but the association did not replicate in an additional 8,059 African Americans (577 events) from the WHI, HealthABC and GeneSTAR studies, and in a meta-analysis of 5 cohort studies of European ancestry (24,024 individuals including 1,570 cases of MI and 2,406 cases of CHD) from the CHARGE Consortium.
Conclusions
Our findings suggest that some CHD loci previously identified in individuals of European ancestry may be relevant to incident CHD in African Americans.
doi:10.1371/journal.pone.0113203
PMCID: PMC4277270  PMID: 25542012
13.  Genome-Wide Identification of Hsp40 Genes in Channel Catfish and Their Regulated Expression after Bacterial Infection 
PLoS ONE  2014;9(12):e115752.
Heat shock proteins (HSPs) consist of a large group of chaperones whose expression is induced by high temperature, hypoxia, infection and a number of other stresses. Among all the HSPs, Hsp40 is the largest HSP family, which bind to Hsp70 ATPase domain in assisting protein folding. In this study, we identified 57 hsp40s in channel catfish (Ictalurus punctatus) through in silico analysis using RNA-Seq and genome databases. These genes can be classified into three different types, Type I, II and III, based on their structural similarities. Phylogenetic and syntenic analyses provided strong evidence in supporting the orthologies of these HSPs. Meta-analyses of RNA-Seq datasets were conducted to analyze expression profile of Hsp40s following bacterial infection. Twenty seven hsp40s were found to be significantly up- or down-regulated in the liver after infection with E. ictaluri; 19 hsp40s were found to be significantly regulated in the intestine after infection with E. ictaluri; and 19 hsp40s were found to be significantly regulated in the gill following infection with F. columnare. Altogether, a total of 42 Hsp40 genes were regulated under disease situations involving three tissues and two bacterial infections. The significant regulated expression of Hsp40 genes after bacterial infection suggested their involvement in disease defenses in catfish.
doi:10.1371/journal.pone.0115752
PMCID: PMC4277396  PMID: 25542027
14.  Differential expression of glycoprotein non-metastatic melanoma protein B (GPNMB) involved in trichostatin A-induced apoptosis in gastric cancer 
In this study, we investigated the effect of trichostatin A (TSA) on the gastric cancer cell line BGC-823. The effect of TSA on growth inhibition and apoptosis of BGC-823 cells was examined. The gene expression profile was determined by microarray. Western blotting was used to study the levels of acetylated histone H4 and Glycoprotein non-metastatic melanoma protein B (GPNMB) proteins. GPNMB gene expression was measured by real-time PCR. GPNMB protein levels in gastric adenocarcinoma tissues and adjoining normal tissues were detected by immunohistochemistry. The results showed that a significant decrease in cell population following treatment with 75 ng/mL TSA for 48 h (0.87 ± 0.04) as compared to control (1.14 ± 0.06) (P = 0.02). Apoptotic cells were increased in TSA (75 ng/mL for 48 h) treated group as compared to the control group (from 2.02% to 19.74%) by flow cytometry. The expression of acetylated histone H4 was increased in TSA treated (75 ng/mL for 48 h) group (from 1.00 ± 0.26 to 1.87 ± 0.33, F = 5.862, P = 0.0038) as compared to the control group by Western blotting. After 48 h TSA treatment (75 ng/mL), BGC-823 cells showed decrease in GPNMB gene expression (from 1.00 ± 0.21 to 0.59 ± 0.11, F = 6.214, P = 0.0018). Immunohistochemistry showed that GPNMB expression in gastric adenocarcinoma was significantly higher than the adjoining normal tissues (P = 0.000). To conclusion, our results support that TSA can induce apoptosis, and increase acetylated histone H4 in BGC-823 cells. GPNMB expression is decreased in BGC-823 cells after TSA treatment. GPNMB is overexpressed in gastric adenocarcinoma tissue. GPNMB involved in TSA-induced apoptosis might participate in gastric cancer.
PMCID: PMC4307429  PMID: 25663982
Trichostatin A; BGC-823; apoptosis; GPNMB; histone H4
15.  Mesothelin expression is associated with poor outcomes in breast cancer 
Background
Mesothelin, previously shown to be expressed in triple negative breast cancer (TNBC), is a potential therapeutic target and prognostic marker in breast cancer.
Methods
We analyzed clinical data from two cohorts comprising of 141 patients treated between 2009 and 2011 at our institution (discovery cohort) and 844 patients from The Cancer Genome Atlas (TCGA) (validation cohort). Mesothelin expression was quantified by immunohistochemistry (IHC) or by RNA transcript levels as measured by whole-transcriptome sequencing in the discovery and validation cohorts respectively.
Results
In the discovery cohort, the median follow up was 3.55 years. Univariate analyses demonstrated that tumor size (hazard ratio (HR) =1.30, 95% confidence interval (CI) 1.11–1.51), positive (+) axillary lymph nodes (HR=3.34; 95% CI 1.51–7.39), and mesothelin expression (HR = 2.03; 95% CI 1.10–3.74) were associated with overall and disease-specific survival. We used a Cox-proportional hazard (Cox-PH) model to adjust for the two independent predictors of survival, namely (+) axilla lymph nodes and tumor size, and we found a significant association between mesothelin expression and overall and disease-specific survival in the discovery cohort (HR = 3.06, 95% CI 1.40–6.68). Using the TCGA dataset, we confirmed that, over a median follow-up of 16.0 months, patients with mesothelin-expressing tumors had poorer overall survival (HR=1.46; 95% CI 1.05–2.03). On Cox-PH multivariate analysis, mesothelin-positivity was an independent predictor of worse survival, after adjusting for (+) axillary lymph nodes and tumor size (HR = 1.69; 95%CI 1.17–2.42).
Conclusions
Our results suggest that mesothelin is a prognostic breast tumor marker whose expression is highly enriched in TNBC tumors, especially in African American women. As there is no existing targeted therapy for TNBC, mesothelin may be a promising drug target for TNBC. Future work is needed to evaluate the efficacy of mesothelin directed targeted therapy in the treatment of breast cancer.
doi:10.1007/s10549-014-3077-5
PMCID: PMC4261925  PMID: 25193277
Mesothelin; breast cancer subtype; basal tumor subtype; triple negative breast cancer (TNBC); tumor marker; breast cancer outcome; targeted therapy
16.  Possible Single-Nucleotide Polymorphism Loci Associated with Systemic Sclerosis Susceptibility: A Genetic Association Study in a Chinese Han Population 
PLoS ONE  2014;9(12):e113197.
Objective
The aim of this study was to confirm the association of RHOB and FAM167A-BLK gene polymorphisms with susceptibility to systemic sclerosis (SSc) in a Chinese Han population.
Methods
A total of 248 SSc patients and 251 healthy controls of Chinese Han ethnicity, which visited the department of dermatology of Peking Union Medical College Hospital, were included in the study. Six selected single nucleotide polymorphisms (SNPs) in the RHOB and FAM167A-BLK regions were selected as markers and were genotyped using a MassARRAY system, which is based on the matrix-assisted laser desorption/ionization time of flight mass spectrometry technique.
Results
Three SNPs in the coding regions of the RHOB and FAM167A-BLK genes displayed an association with SSc: (1) rs1062292T, which is a newly discovered SNP in the RHOB gene (P = 0.03, odds ratio [OR] = 1.62, 95% confidence interval (CI) = 1.05–2.50), (2) rs2736340T (P = 0.03, OR = 1.39, 95%CI = 1.03–1.85), and (3) rs13277113A (P = 0.04, OR = 1.34, 95%CI = 1.01–1.76), both in the FAM167A-BLK gene. Our results support previous findings that vaiants in the RHOB and FAM167A-BLK genes may be associated with susceptibility to SSc. However, the loci of the SNPs in RHOB region that displayed an association with SSc are quite different from the loci which were identified in studies of Caucasian populations.
Conclusion
Our results confirm that RHOB and FAM167A-BLK polymorphisms exist in Chinese Han SSc patients. Therefore, variants of the RHOB and FAM167A-BLK genes are promising genetic markers for SSc.
doi:10.1371/journal.pone.0113197
PMCID: PMC4254283  PMID: 25470816
17.  Epidemiological Characteristics of blaNDM-1 in Enterobacteriaceae and the Acinetobacter calcoaceticus-Acinetobacter baumannii Complex in China from 2011 to 2012 
PLoS ONE  2014;9(12):e113852.
Objectives
The study aimed to investigate the prevalence and epidemiological characteristics of blaNDM-1 (encoding New Delhi metallo-β-lactamase 1) in Enterobacteriaceae and the Acinetobacter calcoaceticus-Acinetobacter baumannii complex (ABC) in China from July 2011 to June 2012.
Methods
PCR was used to screen for the presence of blaNDM-1 in all organisms studied. For blaNDM-1-positive strains, 16S rRNA analysis and Analytical Profile Index (API) strips were used to identify the bacterial genus and species. The ABCs were reconfirmed by PCR detection of blaOXA-51-like. Antibiotic susceptibilities of the bacteria were assessed by determining minimum inhibitory concentration (MIC) of them using two-fold agar dilution test, as recommended by the Clinical and Laboratory Standards Institute (CLSI). Molecular typing was performed using pulsed-field gel electrophoresis (PFGE). S1 nuclease-pulsed-field gel electrophoresis (S1-PFGE) and Southern blot hybridization were conducted to ascertain the gene location of blaNDM-1. Conjugation experiments were conducted to determine the transmission of blaNDM-1-positive strains.
Results
Among 2,170 Enterobacteriaceae and 600 ABCs, seven Enterobacteriaceae strains and two A. calcoaceticus isolates from five different cities carried the blaNDM-1 gene. The seven Enterobacteriaceae strains comprised four Klebsiella pneumoniae, one Enterobacter cloacae, one Enterobacter aerogen and one Citrobacter freundii. All seven were non-susceptible to imipenem, meropenem or ertapenem. Two A. calcoaceticus species were resistant to imipenem and meropenem. Three K. pneumoniae showed the same PFGE profiles. The blaNDM-1 genes of eight strains were localized on plasmids, while one was chromosomal.
Conclusions
Compared with previous reports, the numbers and species containing the blaNDM-1 in Enterobacteriaceae have significantly increased in China. Most of them are able to disseminate the gene, which is cause for concern. Consecutive surveillance should be implemented and should also focus on the dissemination of blaNDM-1 among gram-negative clinical isolates.
doi:10.1371/journal.pone.0113852
PMCID: PMC4254649  PMID: 25469701
18.  Molecular and Functional Characterization of Canine Interferon-Epsilon 
In this study, we provide the first comprehensive annotation of the entire family of canine interferons (IFNs). Canine IFN-ɛ (IFNE), IFN-κ (IFNK), and IFN-λ (IFNL) were discovered for the first time. Ten functional and 2 truncated IFN-α (IFNA) pseudogenes were found in the genome, which also enriched the existing knowledge about canine IFNA. The canine type I IFN genes are clustered on chromosome 11, and their relative arrangements are illustrated. To further investigate the biological activity of canine IFNE, it was expressed and purified in Escherichia coli. Recombinant canine IFNE (rCaIFN-ɛ) displayed potent antiviral activity on both homologous and heterologous animal cells in vitro, indicating that rCaIFN-ɛ has more broad cross-species activity than recombinant canine IFNA (rCaIFN-α). The antiviral activities of rCaIFN-ɛ and rCaIFN-α7 against different viruses on MDCK cells were also evaluated. The antiviral activities of recombinant canine IFNK and IFNL were demonstrated using a VSV-MDCK virus-target cell system. rCaIFN-ɛ exhibited a significant anti-proliferative response against A72 canine tumor cells and MDCK canine epithelial cells in a dose-dependent manner. rCaIFN-α7 was approximately 16-fold more potent than rCaIFN-ɛ in promoting natural killer cell cytotoxicity activity. Further, rCaIFN-ɛ can activate the JAK-STAT signaling pathway.
doi:10.1089/jir.2013.0037
PMCID: PMC3868301  PMID: 23964570
19.  Boost Up Carrier Mobility for Ferroelectric Organic Transistor Memory via Buffering Interfacial Polarization Fluctuation 
Scientific Reports  2014;4:7227.
Ferroelectric organic field-effect transistors (Fe-OFETs) have been attractive for a variety of non-volatile memory device applications. One of the critical issues of Fe-OFETs is the improvement of carrier mobility in semiconducting channels. In this article, we propose a novel interfacial buffering method that inserts an ultrathin poly(methyl methacrylate) (PMMA) between ferroelectric polymer and organic semiconductor layers. A high field-effect mobility (μFET) up to 4.6 cm2 V−1 s−1 is obtained. Subsequently, the programming process in our Fe-OFETs is mainly dominated by the switching between two ferroelectric polarizations rather than by the mobility-determined charge accumulation at the channel. Thus, the “reading” and “programming” speeds are significantly improved. Investigations show that the polarization fluctuation at semiconductor/insulator interfaces, which affect the charge transport in conducting channels, can be suppressed effectively using our method.
doi:10.1038/srep07227
PMCID: PMC4245676  PMID: 25428665
20.  Pregnancy-Associated Breast Cancer in Taiwanese Women: Potential Treatment Delay and Impact on Survival 
PLoS ONE  2014;9(11):e111934.
This study investigated the clinicopathologic characteristics and survival of women diagnosed with pregnancy-associated breast cancer (PABC) in Taiwan. PABC is defined as breast cancer diagnosed during pregnancy or within 1 year after obstetric delivery. Our sample of PABC patients (N = 26) included all patients diagnosed at a major medical center in northern Taiwan from 1984 through 2009. Among these patients, 15 were diagnosed during pregnancy and 11 were diagnosed within 1 year after delivery. The comparison group included 104 patients within the same age range as the PABC patients and diagnosed with breast cancer not associated with pregnancy from 2004 through 2009 at the same hospital. Patients' initiating treatment delayed, 5-year and 10-year overall survival were delineated by stratified Kaplan-Meier estimates. Patients' characteristics were associated with initiating treatment delayed was evaluated with multivariate proportional hazards modeling. Antepartum PABC patients were younger and had longer time between diagnosis and treatment initiation than postpartum PABC patients. The predictor of treatment delayed was including birth parity, cancer stage, and pregnancy. The PABC group had larger tumors, more advanced cancer stage, and tumors with less progesterone receptor than the comparison group. The antepartum PABC patients had higher mortality than postpartum PABC and comparison groups within 5 years after diagnosis. Based on these results, we confirmed that pregnant women with breast cancer were more likely to delay treatment. Therefore, we recommend that breast cancer screening should be integrated into the prenatal and postnatal routine visits for early detection of the women's breast problems.
doi:10.1371/journal.pone.0111934
PMCID: PMC4240543  PMID: 25415309
21.  Surface Plasmon-Polariton Mediated Red Emission from Organic Light-Emitting Devices Based on Metallic Electrodes Integrated with Dual-Periodic Corrugation 
Scientific Reports  2014;4:7108.
We demonstrate an effective approach to realize excitation and outcoupling of the SPP modes associated with both cathode/organic and anode/organic interfaces in OLEDs by integrating dual-periodic corrugation. The dual-periodic corrugation consists of two set gratings with different periods. The light trapped in the SPP modes associated with both top and bottom electrode/organic interfaces are efficiently extracted from the OLEDs by adjusting appropriate periods of two set corrugations, and a 29% enhancement in the current efficiency has been obtained.
doi:10.1038/srep07108
PMCID: PMC4236905  PMID: 25407776
22.  Perioperative restricted fluid therapy preserves immunological function in patients with colorectal cancer 
World Journal of Gastroenterology : WJG  2014;20(42):15852-15859.
AIM: To investigate the effect of perioperative restricted fluid therapy on circulating CD4+/CD8+ T lymphocyte ratio, percentage of regulatory T cells (Treg) and postoperative complications in patients with colorectal cancer.
METHODS: A total of 185 patients met the inclusion criteria and were included in the randomized clinical trial. These patients were divided into two groups according to receipt of either perioperative standard (S, n = 89) or restricted (R, n = 96) fluid therapy. Clinical data of these patients were collected in this prospective study. Perioperative complications and cellular immunity changes (CD4+/CD8+ and Treg) were analyzed comparatively between the two groups.
RESULTS: Both during surgery and on postoperative days, the total volumes of fluids administered in the R group were significantly lower than those in the S group (1620 ± 430 mL vs 3110 ± 840 mL; 2090 ± 360 mL vs 2750 ± 570 mL; 1750 ± 260 mL vs 2740 ± 490 mL; 1620 ± 310 mL vs 2520 ± 300 mL; P < 0.05). Decreased ratios of circulating CD4+/CD8+ T lymphocytes (1.47 ± 0.28 vs 2.13 ± 0.26; 1.39 ± 0.32 vs 2.21 ± 0.24; P < 0.05) and Treg percentage values (2.79 ± 1.24 vs 4.26 ± 1.04; 2.46 ± 0.98 vs 4.30 ± 1.12; P < 0.05) were observed after surgery in both groups. However, in the R group, these values restored more quickly starting from postoperative day 2 (1.44 ± 0.24 vs 1.34 ± 0.27; 2.93 ± 1.08 vs 2.52 ± 0.96; P < 0.05). The proportion of patients with complications was significantly lower in the restricted group (36 of 89 vs 59 of 96, P < 0.01).
CONCLUSION: Perioperative restricted intravenous fluid regimen leads to a low postoperative complication rate and better cellular immunity preservation in patients with colorectal cancer.
doi:10.3748/wjg.v20.i42.15852
PMCID: PMC4229553  PMID: 25400472
Colorectal cancer; Restricted fluid therapy; Standard fluid therapy; Postoperative complications; Immunological function
23.  Association Studies with Imputed Variants Using Expectation-Maximization Likelihood-Ratio Tests 
PLoS ONE  2014;9(11):e110679.
Genotype imputation has become standard practice in modern genetic studies. As sequencing-based reference panels continue to grow, increasingly more markers are being well or better imputed but at the same time, even more markers with relatively low minor allele frequency are being imputed with low imputation quality. Here, we propose new methods that incorporate imputation uncertainty for downstream association analysis, with improved power and/or computational efficiency. We consider two scenarios: I) when posterior probabilities of all potential genotypes are estimated; and II) when only the one-dimensional summary statistic, imputed dosage, is available. For scenario I, we have developed an expectation-maximization likelihood-ratio test for association based on posterior probabilities. When only imputed dosages are available (scenario II), we first sample the genotype probabilities from its posterior distribution given the dosages, and then apply the EM-LRT on the sampled probabilities. Our simulations show that type I error of the proposed EM-LRT methods under both scenarios are protected. Compared with existing methods, EM-LRT-Prob (for scenario I) offers optimal statistical power across a wide spectrum of MAF and imputation quality. EM-LRT-Dose (for scenario II) achieves a similar level of statistical power as EM-LRT-Prob and, outperforms the standard Dosage method, especially for markers with relatively low MAF or imputation quality. Applications to two real data sets, the Cebu Longitudinal Health and Nutrition Survey study and the Women’s Health Initiative Study, provide further support to the validity and efficiency of our proposed methods.
doi:10.1371/journal.pone.0110679
PMCID: PMC4226494  PMID: 25383782
24.  Frequency-Controls of Electromagnetic Multi-Beam Scanning by Metasurfaces 
Scientific Reports  2014;4:6921.
We propose a method to control electromagnetic (EM) radiations by holographic metasurfaces, including to producing multi-beam scanning in one dimension (1D) and two dimensions (2D) with the change of frequency. The metasurfaces are composed of subwavelength metallic patches on grounded dielectric substrate. We present a combined theory of holography and leaky wave to realize the multi-beam radiations by exciting the surface interference patterns, which are generated by interference between the excitation source and required radiation waves. As the frequency changes, we show that the main lobes of EM radiation beams could accomplish 1D or 2D scans regularly by using the proposed holographic metasurfaces shaped with different interference patterns. This is the first time to realize 2D scans of antennas by changing the frequency. Full-wave simulations and experimental results validate the proposed theory and confirm the corresponding physical phenomena.
doi:10.1038/srep06921
PMCID: PMC4220278  PMID: 25370447
25.  NSFC Health Research Funding and Burden of Disease in China 
PLoS ONE  2014;9(11):e111458.
Background
Allocation of health research funds among diseases has never been evaluated in China. This study aimed to examine the relationship between disease-specific funding levels of National Nature Science Foundation of China (NSFC), the main governmental resource for health research in China, and burden of disease.
Methods
Funding magnitudes for 53 diseases or conditions were obtained from the website of NSFC. Measures of disease burden, mortality, years of life lost (YLLs) and disability-adjusted life years (DALYs), were derived from the Global Burden of Disease Study 2010. The relationship between NSFC funding and disease burden was analyzed with univariate linear regression. For each measure associated with funding, regression-derived estimates were used to calculate the expected funds for each disease. The actual and expected funds were then compared. We also evaluated the impacts of changes of disease burden metrics since 1990, and differences from the world averages on NSFC funding.
Results
NSFC health research funding was associated with disease burden measured in mortality (R = 0.33, P = 0.02), YLLs (R = 0.39, P = 0.004), and DALYs (R = 0.40, P = 0.003). But none of the changes of mortality (R = 0.22, P = 0.12), YLLs (R = −0.04, P = 0.79) and DALYs (R = −0.003, P = 0.98) since 1990 was associated with the funding magnitudes. None of the differences of mortality (R = −0.11, P = 0.45), YLLs (R = −0.11, P = 0.43) and DALYs (R = −0.12, P = 0.38) from that of the concurrent world averages were associated with the funding magnitudes. Measured by DALY, stroke and COPD received the least funding compared to expected; while leukemia and diabetes received the most funding compared to expected.
Conclusion
Although NSFC funding were roughly associated with disease burden as measured in mortality, YLLs and DALYs. Some major diseases such as stroke were underfunded; while others such as leukaemia were overfunded. Change of disease burden during the last 20 years and country-specialized disease burden were not reflected in current allocation of NSFC funds.
doi:10.1371/journal.pone.0111458
PMCID: PMC4219749  PMID: 25369330

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