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1.  Identification and development of a functional marker from 6-SFT-A2 associated with grain weight in wheat 
Molecular Breeding  2015;35:63.
As a class of water-soluble, fructose-based oligo- and polysaccharides, fructans are major nonstructural carbohydrates and an important carbon source for grain filling in wheat (Triticum aestivum L.). Four enzymes are involved in fructan synthesis in higher plants, and 6-SFT is a key enzyme in fructan biosynthesis. In this study, thirteen single nucleotide polymorphisms were detected in 6-SFT-A2 in 24 wheat accessions, forming three haplotypes. Two cleaved amplified polymorphic sequence markers developed based on polymorphisms at sites 1870(A-G) and 1951(A-G) distinguished the three haplotypes. 6-SFT-A2 was located on chromosome 4A, between markers P2454.3 and P3465.1 in a doubled haploid (DH) population derived from the cross Hanxuan 10 × Lumai 14. The DH population comprising 150 lines and a historical population consisting of 154 accessions were used in a 6-SFT-A2 marker–trait association analysis. The three haplotypes were significantly associated with thousand-grain weight (TGW) under rainfed conditions. HapIII had a significant positive effect on TGW. There were significant differences between the Hanxuan 10 and Lumai 14 genotypes in both rainfed and irrigated environments. The average TGW of Lumai 14 (HapIII) was higher than that of Hanxuan 10 (HapI). The frequencies of 6-SFT-A2HapIII in cultivars released at different periods showed that it had been strongly positively selected in breeding programs. The preferred HapIII for TGW occurred at higher frequencies in Gansu, Beijing, Shanxi, and Hebei than other regions in northern China.
Electronic supplementary material
The online version of this article (doi:10.1007/s11032-015-0266-9) contains supplementary material, which is available to authorized users.
doi:10.1007/s11032-015-0266-9
PMCID: PMC4311048  PMID: 25653572
Haplotype; Marker development; Association analysis; Thousand-grain weight; 6-SFT; Triticum aestivum
2.  Programmed hydrolysis of nanoassemblies by electrostatic interaction-mediated enzymatic-degradation† 
Electrostatic interaction-mediated enzymatic-hydrolysis of poly(lactide)-containing nanoscale assemblies is described. At physiological pH, degradable core–shell morphologies with charged shells can readily attract or repel enzymes carrying opposite or similar charges, respectively.
doi:10.1039/c3cc46013d
PMCID: PMC4165354  PMID: 24301076
3.  Differential immunotoxicities of poly(ethylene glycol)-vs. poly(carboxybetaine)-coated nanoparticles 
Although the careful selection of shell-forming polymers for the construction of nanoparticles is an obvious parameter to consider for shielding of core materials and their payloads, providing for prolonged circulation in vivo by limiting uptake by the immune organs, and thus, allowing accumulation at the target sites, the immunotoxicities that such shielding layers elicit is often overlooked. For instance, we have previously performed rigorous in vitro and in vivo comparisons between two sets of nanoparticles coated with either non-ionic poly(ethylene glycol) (PEG) or zwitterionic poly(carboxybetaine) (PCB), but only now report the immunotoxicity and anti-biofouling properties of both polymers, as homopolymers or nanoparticle-decorating shell, in comparison to the uncoated nanoparticles, and Cremophor-EL, a well-known low molecular weight surfactant used for formulation of several drugs. It was found that both PEG and PCB polymers could induce the expression of cytokines in vitro and in vivo, with PCB being more immunotoxic than PEG, which corroborates the in vivo pharmacokineties and biodistribution profiles of the two sets of nanoparticles. This is the first study to report on the ability of PEG, the most commonly utilized polymer to coat nanomaterials, and PCB, an emerging zwitterionic anti-biofouling polymer, to induce the secretion of cytokines and be of potential immunotoxicity. Furthermore, we report here on the possible use of immunotoxicity assays to partially predict in vivo pharmacokineties and biodistribution of nanomaterials.
doi:10.1016/j.jconrel.2013.09.010
PMCID: PMC3858532  PMID: 24056145
Poly(ethylene glycol); poly(carboxybetaine); Cremophor-EL; protein adsorption; stealth; antibiofouling; immunotoxicity; cytokines; nanoparticles; pharmacokineties; biodistribution
4.  Evoked itch perception is associated with changes in functional brain connectivity 
NeuroImage : Clinical  2014;7:213-221.
Chronic itch, a highly debilitating condition, has received relatively little attention in the neuroimaging literature. Recent studies suggest that brain regions supporting itch in chronic itch patients encompass sensorimotor and salience networks, and corticostriatal circuits involved in motor preparation for scratching. However, how these different brain areas interact with one another in the context of itch is still unknown. We acquired BOLD fMRI scans in 14 atopic dermatitis patients to investigate resting-state functional connectivity before and after allergen-induced itch exacerbated the clinical itch perception in these patients. A seed-based analysis revealed decreased functional connectivity from baseline resting state to the evoked-itch state between several itch-related brain regions, particularly the insular and cingulate cortices and basal ganglia, where decreased connectivity was significantly correlated with increased levels of perceived itch. In contrast, evoked itch increased connectivity between key nodes of the frontoparietal control network (superior parietal lobule and dorsolateral prefrontal cortex), where higher increase in connectivity was correlated with a lesser increase in perceived itch, suggesting that greater interaction between nodes of this executive attention network serves to limit itch sensation via enhanced top-down regulation. Overall, our results provide the first evidence of itch-dependent changes in functional connectivity across multiple brain regions.
Highlights
•Atopic dermatitis patients were subjected to allergen-induced itch.•Evoked itch reduced functional connectivity between itch-related brain regions.•Evoked itch increased functional connectivity within frontoparietal control network.•The above changes in functional connectivity correlated with perceived itch level.•Itch sensation may be top-down regulated by frontoparietal control network.
doi:10.1016/j.nicl.2014.12.002
PMCID: PMC4300003  PMID: 25610783
aMCC, anterior mid-cingulate cortex; AD, atopic dermatitis; ASL, arterial spin labeling; BA, Brodmann area; BOLD, blood-oxygen-level dependent; dlPFC, dorsolateral prefrontal cortex; DMN, default mode network; ECG, electrocardiography; fcMRI, functional connectivity magnetic resonance imaging; fMRI, functional magnetic resonance imaging; GLM, general linear model; ITCH, evoked itch resting-state scan; L, left; MNI, Montreal Neurological Institute; MR, magnetic resonance; PCC, posterior cingulate cortex; PET, positron emission tomography; PMC, premotor cortex; pMCC, posterior mid-cingulate cortex; R, right; REST, baseline resting-state scan; S1/M1, primary sensorimotor cortex; SCORAD, SCORing atopic dermatitis scale; SPL, Superior parietal lobule; VAS, visual analog scale; vlPFC, ventrolateral prefrontal cortex.; Atopic dermatitis; Eczema; Insula; Pruritus; Putamen
5.  Molecular Characterization and Expression Analysis of Triticum aestivum Squamosa-Promoter Binding Protein-Box Genes Involved in Ear Development 
Wheat (Triticum aestivum L.) is one of the most important crops in the world. Squamosa-promoter binding protein (SBP)-box genes play a critical role in regulating flower and fruit development. In this study, 10 novel SBP-box genes (TaSPL genes) were isolated from wheat ((Triticum aestivum L.) cultivar Yanzhan 4110). Phylogenetic analysis classified the TaSPL genes into five groups (G1–G5). The motif combinations and expression patterns of the TaSPL genes varied among the five groups with each having own distinctive characteristics: TaSPL20/21 in G1 and TaSPL17 in G2 mainly expressed in the shoot apical meristem and the young ear, and their expression levels responded to development of the ear; TaSPL6/15 belonging to G3 were upregulated and TaSPL1/23 in G4 were downregulated during grain development; the gene in G5 (TaSPL3) expressed constitutively. Thus, the consistency of the phylogenetic analysis, motif compositions, and expression patterns of the TaSPL genes revealed specific gene structures and functions. On the other hand, the diverse gene structures and different expression patterns suggested that wheat SBP-box genes have a wide range of functions. The results also suggest a potential role for wheat SBP-box genes in ear development. This study provides a significant beginning of functional analysis of SBP-box genes in wheat.
doi:10.1111/jipb.12153
PMCID: PMC4239008  PMID: 24386921
Expression profile; grain yield; squamosa-promoter binding protein-box genes; Triticum aestivum
6.  Simulation of Contrast Agent Transport in Arteries with Multilayer Arterial Wall: Impact of Arterial Transmural Transport on the Bolus Delay and Dispersion 
The Scientific World Journal  2014;2014:803276.
One assumption of DSC-MRI is that the injected contrast agent is kept totally intravascular and the arterial wall is impermeable to contrast agent. The assumption is unreal for such small contrast agent as Gd-DTPA can leak into the arterial wall. To investigate whether the unreal assumption is valid for the estimation of the delay and dispersion of the contrast agent bolus, we simulated flow and Gd-DTPA transport in a model with multilayer arterial wall and analyzed the bolus delay and dispersion qualified by mean vascular transit time (MVTT) and the variance of the vascular transport function. Factors that may affect Gd-DTPA transport hence the delay and dispersion were further investigated, such as integrity of endothelium and disturbed flow. The results revealed that arterial transmural transport would slightly affect MVTT and moderately increase the variance. In addition, although the integrity of endothelium can significantly affect the accumulation of contrast agent in the arterial wall, it had small effects on the bolus delay and dispersion. However, the disturbed flow would significantly increase both MVTT and the variance. In conclusion, arterial transmural transport may have a small effect on the bolus delay and dispersion when compared to the flow pattern in the artery.
doi:10.1155/2014/803276
PMCID: PMC4322668
7.  Genome sequencing and genomic characterization of a tigecycline-resistant Klebsiella pneumoniae strain isolated from the bile samples of a cholangiocarcinoma patient 
Gut Pathogens  2014;6(1):40.
Background
The relationship between Klebsiella pneumoniae and nosocomial and community-acquired infections is well known, and K. pneumoniae resistance to most antibiotics is increasing worldwide. In contrast, tigecycline remains active against many bacterial strains, and serves as a last resort for treating multi-drug resistant bacterial infections. That tigecycline nonsusceptibility among K. pneumoniae isolates has been reported worldwide is worrying. However, the mechanisms of tigecycline resistance in K. pneumoniae are less well known. We report the genome sequence and genomic characterization of tigecycline-resistant K. pneumoniae strain 5422 isolated from the bile samples of a patient with cholangiocarcinoma.
Results
We sequenced the K. pneumoniae strain 5422 genome using next-generation sequencing technologies. Sequence data assembly revealed a 5,432,440-bp draft genome and 57.1% G + C content, which contained 5397 coding sequences. The genome has extensive similarity to other sequenced K. pneumoniae genomes, but also has several resistance-nodulation-cell division (RND) efflux pump genes that may be related to tigecycline resistance.
Conclusions
K. pneumoniae strain 5422 is resistant to multiple antibiotics. The genome sequence of the isolate and comparative analysis with other K. pneumoniae strains presented in this paper are important for better understanding of K. pneumoniae multi-drug resistance. The RND efflux pump genes identified in the genome indicate the presence of an antibiotic resistance mechanism prior to antibiotics overuse. The availability of the genome sequence forms the basis for further comparative analyses and studies addressing the evolution of the K. pneumoniae drug resistance mechanism and the K. pneumoniae transcriptome.
doi:10.1186/s13099-014-0040-2
PMCID: PMC4182774  PMID: 25279004
Tigecycline-resistant; Klebsiella pneumoniae; Cholangiocarcinoma; Next-generation sequencing; Comparative genomics
8.  Audiovisual Speech Perception at Various Presentation Levels in Mandarin-Speaking Adults with Cochlear Implants 
PLoS ONE  2014;9(9):e107252.
Objectives
(1) To evaluate the recognition of words, phonemes and lexical tones in audiovisual (AV) and auditory-only (AO) modes in Mandarin-speaking adults with cochlear implants (CIs); (2) to understand the effect of presentation levels on AV speech perception; (3) to learn the effect of hearing experience on AV speech perception.
Methods
Thirteen deaf adults (age = 29.1±13.5 years; 8 male, 5 female) who had used CIs for >6 months and 10 normal-hearing (NH) adults participated in this study. Seven of them were prelingually deaf, and 6 postlingually deaf. The Mandarin Monosyllablic Word Recognition Test was used to assess recognition of words, phonemes and lexical tones in AV and AO conditions at 3 presentation levels: speech detection threshold (SDT), speech recognition threshold (SRT) and 10 dB SL (re:SRT).
Results
The prelingual group had better phoneme recognition in the AV mode than in the AO mode at SDT and SRT (both p = 0.016), and so did the NH group at SDT (p = 0.004). Mode difference was not noted in the postlingual group. None of the groups had significantly different tone recognition in the 2 modes. The prelingual and postlingual groups had significantly better phoneme and tone recognition than the NH one at SDT in the AO mode (p = 0.016 and p = 0.002 for phonemes; p = 0.001 and p<0.001 for tones) but were outperformed by the NH group at 10 dB SL (re:SRT) in both modes (both p<0.001 for phonemes; p<0.001 and p = 0.002 for tones). The recognition scores had a significant correlation with group with age and sex controlled (p<0.001).
Conclusions
Visual input may help prelingually deaf implantees to recognize phonemes but may not augment Mandarin tone recognition. The effect of presentation level seems minimal on CI users' AV perception. This indicates special considerations in developing audiological assessment protocols and rehabilitation strategies for implantees who speak tonal languages.
doi:10.1371/journal.pone.0107252
PMCID: PMC4164527  PMID: 25222104
9.  The role of activated adenosine receptors in degranulation of human LAD2 mast cells 
Purinergic Signalling  2014;10(3):465-475.
Mast cell degranulation triggers hypersensitivity reactions at the body–environment interface. Adenosine modulates degranulation, but enhancement and inhibition have both been reported. Which of four adenosine receptors (ARs) mediate modulation, and how, remains uncertain. Also uncertain is whether adenosine reaches mast cell ARs by autocrine ATP release and ecto-enzymatic conversion. Uncertainties partly reflect species and cell heterogeneity, circumvented here by focusing on homogeneous human LAD2 cells. Quantitative PCR detected expression of A2A, A2B, and A3, but not A1, ARs. Nonselective activation of ARs with increasing NECA monotonically enhanced immunologically or C3a-stimulated degranulation. NECA alone stimulated degranulation slightly. Selective AR antagonists did not affect C3a-stimulated degranulation. NECA's enhancement of C3a-triggered degranulation was partially inhibited by separate application of each selective antagonist, and abolished by simultaneous addition of antagonists to the three ARs. Only the A2A antagonist separately inhibited NECA's enhancement of immunologically stimulated degranulation, which was abolished by simultaneous addition of the three selective antagonists. Immunological or C3a activation did not stimulate ATP release. NECA also enhanced immunologically triggered degranulation of mouse bone marrow derived mast cells (BMMCs), which was partially reduced only by simultaneous addition of the three antagonists or by the nonselective antagonist CGS15943. BMMCs also expressed A2A, A2B, and A3 ARs. but not A1AR detectably. We conclude that (a) A1AR is unnecessary for LAD2 degranulation or AR enhancement; (b) A2A, A2B, and A3 ARs all contribute to pharmacologic AR enhancement of LAD2 and BMMC degranulation; and (c) LAD2 cells depend on microenvironmental adenosine to trigger AR modulation.
doi:10.1007/s11302-014-9409-4
PMCID: PMC4152452  PMID: 24595664
FcεRI; C3a; A2A; A2B; A3; ATP release
10.  Poly(ethylene oxide)-block-polyphosphester-based Paclitaxel Conjugates as a Platform for Ultra-high Paclitaxel-loaded Multifunctional Nanoparticles† 
A new type of degradable, nanoscopic polymer assembly containing ultra-high levels of drug loading via covalent attachment within amphiphilic core-shell nanoparticle morphology has been generated as a potentially effective and safe anti-cancer agent. Poly(ethylene oxide)-block-polyphosphoester-based paclitaxel drug conjugates (PEO-b-PPE-g-PTX) were synthesized by rapid, scalable and versatile approach that involves only two steps: organocatalyst-promoted ring-opening-polymerization followed by click reaction-based conjugation of a PTX prodrug. Variations in the polymer-to-PTX stoichiometries allowed for optimization of the conjugation efficiency, the PTX drug loading and the resulting water solubilities of the entire polymer and the PTX content. The PEO-b-PPE-g-PTX formed well-defined micelles in aqueous solution, with a PTX loading capacity as high as 65 wt%, and a maximum PTX concentration of 6.2 mg/mL in water, which is 25000-fold higher than the aqueous solubility of free PTX. The positive cell-killing activity of PEO-b-PPE-g-PTX against several cancer cell lines is demonstrated, and the presence of pendant reactive functionality provides a powerful platform for future work to involve conjugation of multiple drugs and imaging agents to achieve chemotherapy and bioimaging.
doi:10.1039/C3SC50252J
PMCID: PMC4138828  PMID: 25152808
11.  MicroRNA array analysis finds elevated serum miR-1290 accurately distinguishes patients with low-stage pancreatic cancer from healthy and disease controls 
Purpose
Our goal was to identify circulating miRNA levels that could distinguish patients with low-stage pancreatic cancer from healthy and disease controls
Experimental Design
We measured 735 miRNAs in pancreatic cancer case and control sera by QRTPCR using TaqMan® MicroRNA Arrays. After array analysis, we selected 18 miRNA candidates for validation in an independent set of cases and control samples.
Results
Of the significantly elevated circulating microRNAs in patients with pancreatic cancer compared to controls, miR-1290 had the best diagnostic performance: receiver operating characteristic (ROC) analysis on miR-1290 serum level yielded curve areas (AUC) of 0.96 (95% CI: 0.91-1.00), 0.81 (0.71-0.91), 0.80 (0.67-0.93), for subjects with pancreatic cancer (n=41) relative to healthy controls (n=19), subjects with chronic pancreatitis (n=35), and pancreatic neuroendocrine tumors (n=18), respectively. Serum miR-1290 levels were also significantly higher than healthy controls among patients with intraductal papillary mucinous neoplasm (IPMN)(n=20) (AUC=0.76, 0.61-0.91). Serum miR-1290 levels distinguished patients with low-stage pancreatic cancer from controls better than CA19-9 levels, and like CA19-9, higher miR-1290 levels predicted poorer outcome among patients undergoing pancreaticoduodenectomy. Greater numbers of miR-1290 transcripts were detected by FISH in primary pancreatic cancer and IPMN than normal pancreatic duct cells. MiR-1290 influenced in vitro pancreatic cancer cell proliferation and invasive ability. Several other circulating miRNAs distinguished sera of patients with pancreatic cancer from those of healthy controls with AUCs >0.7, including miR-24, miR-134, miR-146a, miR-378, miR-484, miR-628-3p, and miR-1825. Conclusions: The detection of elevated circulating miR-1290 has the potential to improve the early detection of pancreatic cancer.
doi:10.1158/1078-0432.CCR-12-3092
PMCID: PMC3707520  PMID: 23697990
pancreatic cancer; microRNA; intraductal papillary mucinous neoplasm; pancreatic neuroendocrine tumors; chronic pancreatitis; miR-1290
12.  Differential efficiency in exogenous DNA acquisition among closely related Salmonella strains: implications in bacterial speciation 
BMC Microbiology  2014;14:157.
Background
Acquisition of exogenous genetic material is a key event in bacterial speciation. It seems reasonable to assume that recombination of the incoming DNA into genome would be more efficient with higher levels of relatedness between the DNA donor and recipient. If so, bacterial speciation would be a smooth process, leading to a continuous spectrum of genomic divergence of bacteria, which, however, is not the case as shown by recent findings. The goal of this study was todetermine if DNA transfer efficiency is correlated with the levels of sequence identity.
Results
To compare the relative efficiency of exogenous DNA acquisition among closely related bacteria, we carried out phage-mediated transduction and plasmid-mediated transformation in representative Salmonella strains with different levels of relatedness. We found that the efficiency was remarkably variable even among genetically almost identical bacteria. Although there was a general tendency that more closely related DNA donor-recipient pairs had higher transduction efficiency, transformation efficiency exhibited over a thousand times difference among the closely related Salmonella strains.
Conclusion
DNA acquisition efficiency is greatly variable among bacteria that have as high as over 99% identical genetic background, suggesting that bacterial speciation involves highly complex processes affected not only by whether beneficial exogenous DNA may exist in the environment but also the “readiness” of the bacteria to accept it.
doi:10.1186/1471-2180-14-157
PMCID: PMC4094785  PMID: 24928416
Bacterial speciation; Homologous recombination; Salmonella; Transduction; Transformation
13.  MicroRNA Function in the Profibrogenic Interplay upon Chronic Liver Disease 
In chronic liver disease leading to fibrosis, hepatic stellate cells (HSC) differentiate into myofibroblasts. Myofibroblastic HSC have taken center stage during liver fibrogenesis, due to their remarkable synthesis of extracellular matrix proteins, their secretion of profibrogenic mediators and their contribution to hypertension, due to elevated contractility. MicroRNAs (miRNAs) are small, noncoding RNA molecules of 19–24 nucleotides in length. By either RNA interference or inhibition of translational initiation and elongation, each miRNA is able to inhibit the gene expression of a wide panel of targeted transcripts. Recently, it was shown that altered miRNA patterns after chronic liver disease highly affect the progression of fibrosis by their potential to target the expression of extracellular matrix proteins and the synthesis of mediators of profibrogenic pathways. Here, we underline the role of miRNAs in the interplay of the profibrogenic cell communication pathways upon myofibroblastic differentiation of hepatic stellate cells in the chronically injured liver.
doi:10.3390/ijms15069360
PMCID: PMC4100099  PMID: 24871365
liver fibrosis; myofibroblastic transition; TGF-β; miRNA
14.  Comparative Effects of Snoring Sound between Two Minimally Invasive Surgeries in the Treatment of Snoring: A Randomized Controlled Trial 
PLoS ONE  2014;9(5):e97186.
Background
Minimally invasive surgeries of the soft palate have emerged as a less-invasive treatment for habitual snoring. To date, there is only limited information available comparing the effects of snoring sound between different minimally invasive surgeries in the treatment of habitual snoring.
Objective
To compare the efficacy of palatal implant and radiofrequency surgery, in the reduction of snoring through subjective evaluation of snoring and objective snoring sound analysis.
Patients and Method
Thirty patients with habitual snoring due to palatal obstruction (apnea-hypopnea index ≤15, body max index ≤30) were prospectively enrolled and randomized to undergo a single session of palatal implant or temperature-controlled radiofrequency surgery of the soft palate under local anesthesia. Snoring was primarily evaluated by the patient with a 10 cm visual analogue scale (VAS) at baseline and at a 3-month follow-up visit and the change in VAS was the primary outcome. Moreover, life qualities, measured by snore outcomes survey, and full-night snoring sounds, analyzed by a sound analytic program (Snore Map), were also investigated at the same time.
Results
Twenty-eight patients completed the study; 14 received palatal implant surgery and 14 underwent radiofrequency surgery. The VAS and snore outcomes survey scores were significantly improved in both groups. However, the good response (postoperative VAS ≤3 or postoperative VAS ≤5 plus snore outcomes survey score ≥60) rate of the palatal implant group was significantly higher than that of the radiofrequency group (79% vs. 29%, P = 0.021). The maximal loudness of low-frequency (40–300 Hz) snores was reduced significantly in the palatal implant group. In addition, the snoring index was significantly reduced in the radiofrequency group.
Conclusions
Both palatal implants and a single-stage radiofrequency surgery improve subjective snoring outcomes, but palatal implants have a greater effect on most measures of subjective and objective snoring. Multi-stage radiofrequency surgery was not tested.
Trial Registration
ClinicalTrials.gov NCT01955083
doi:10.1371/journal.pone.0097186
PMCID: PMC4016275  PMID: 24816691
15.  Fascin Is Regulated by Slug, Promotes Progression of Pancreatic Cancer in Mice, and Is Associated With Patient Outcomes 
Gastroenterology  2014;146(5):1386-1396.e17.
Background & Aims
Pancreatic ductal adenocarcinoma (PDAC) is often lethal because it is highly invasive and metastasizes rapidly. The actin-bundling protein fascin has been identified as a biomarker of invasive and advanced PDAC and regulates cell migration and invasion in vitro. We investigated fascin expression and its role in PDAC progression in mice.
Methods
We used KRasG12D p53R172H Pdx1-Cre (KPC) mice to investigate the effects of fascin deficiency on development of pancreatic intraepithelial neoplasia (PanIn), PDAC, and metastasis. We measured levels of fascin in PDAC cell lines and 122 human resected PDAC samples, along with normal ductal and acinar tissues; we associated levels with patient outcomes.
Results
Pancreatic ducts and acini from control mice and early-stage PanINs from KPC mice were negative for fascin, but approximately 6% of PanIN3 and 100% of PDAC expressed fascin. Fascin-deficient KRasG12D p53R172H Pdx1-Cre mice had longer survival times, delayed onset of PDAC, and a lower PDAC tumor burdens than KPC mice; loss of fascin did not affect invasion of PDAC into bowel or peritoneum in mice. Levels of slug and fascin correlated in PDAC cells; slug was found to regulate transcription of Fascin along with the epithelial−mesenchymal transition. In PDAC cell lines and cells from mice, fascin concentrated in filopodia and was required for their assembly and turnover. Fascin promoted intercalation of filopodia into mesothelial cell layers and cell invasion. Nearly all human PDAC samples expressed fascin, and higher fascin histoscores correlated with poor outcomes, vascular invasion, and time to recurrence.
Conclusions
The actin-bundling protein fascin is regulated by slug and involved in late-stage PanIN and PDAC formation in mice. Fascin appears to promote formation of filopodia and invasive activities of PDAC cells. Its levels in human PDAC correlate with outcomes and time to recurrence, indicating it might be a marker or therapeutic target for pancreatic cancer.
doi:10.1053/j.gastro.2014.01.046
PMCID: PMC4000441  PMID: 24462734
Pancreas; Tumor Progression; Actin Cytoskeleton; EMT; EMT, epithelial to mesenchymal transition; FKPC, fascin-deficient KRasG12D p53R172H Pdx1-Cre; KPC, KRasG12D p53R172H Pdx1-Cre; MC, mesothelial cell; PanIN, pancreatic intraepithelial neoplasia; PDAC, pancreatic ductal adenocarcinoma; Tf, transcription factor
16.  Construction of a cDNA library for miniature pig mandibular deciduous molars 
Background
The miniature pig provides an excellent experimental model for tooth morphogenesis because its diphyodont and heterodont dentition resembles that of humans. However, little information is available on the process of tooth development or the exact molecular mechanisms controlling tooth development in miniature pigs or humans. Thus, the analysis of gene expression related to each stage of tooth development is very important.
Results
In our study, after serial sections were made, the development of the crown of the miniature pigs’ mandibular deciduous molar could be divided into five main phases: dental lamina stage (E33-E35), bud stage (E35-E40), cap stage (E40-E50), early bell stage (E50-E60), and late bell stage (E60-E65). Total RNA was isolated from the tooth germ of miniature pig embryos at E35, E45, E50, and E60, and a cDNA library was constructed. Then, we identified cDNA sequences on a large scale screen for cDNA profiles in the developing mandibular deciduous molars (E35, E45, E50, and E60) of miniature pigs using Illumina Solexa deep sequencing. Microarray assay was used to detect the expression of genes. Lastly, through Unigene sequence analysis and cDNA expression pattern analysis at E45 and E60, we found that 12 up-regulated and 15 down-regulated genes during the four periods are highly conserved genes homologous with known Homo sapiens genes. Furthermore, there were 6 down-regulated and 2 up-regulated genes in the miniature pig that were highly homologous to Homo sapiens genes compared with those in the mouse.
Conclusion
Our results not only identify the specific transcriptome and cDNA profile in developing mandibular deciduous molars of the miniature pig, but also provide useful information for investigating the molecular mechanism of tooth development in the miniature pig.
doi:10.1186/1471-213X-14-16
PMCID: PMC4021421  PMID: 24750690
Tooth; Development; Histology; Unigene; Sequence; Miniature pig
17.  Thrombocytopenia Is Associated with Acute Respiratory Distress Syndrome Mortality: An International Study 
PLoS ONE  2014;9(4):e94124.
Background
Early detection of the Acute Respiratory Distress Syndrome (ARDS) has the potential to improvethe prognosis of critically ill patients admitted to the intensive care unit (ICU). However, no reliable biomarkers are currently available for accurate early detection of ARDS in patients with predisposing conditions.
Objectives
This study examined risk factors and biomarkers for ARDS development and mortality in two prospective cohort studies.
Methods
We examined clinical risk factors for ARDS in a cohort of 178 patients in Beijing, China who were admitted to the ICU and were at high risk for ARDS. Identified biomarkers were then replicated in a second cohort of1,878 patients in Boston, USA.
Results
Of 178 patients recruited from participating hospitals in Beijing, 75 developed ARDS. After multivariate adjustment, sepsis (odds ratio [OR]:5.58, 95% CI: 1.70–18.3), pulmonary injury (OR: 3.22; 95% CI: 1.60–6.47), and thrombocytopenia, defined as platelet count <80×103/µL, (OR: 2.67; 95% CI: 1.27–5.62)were significantly associated with increased risk of developing ARDS. Thrombocytopenia was also associated with increased mortality in patients who developed ARDS (adjusted hazard ratio [AHR]: 1.38, 95% CI: 1.07–1.57) but not in those who did not develop ARDS(AHR: 1.25, 95% CI: 0.96–1.62). The presence of both thrombocytopenia and ARDS substantially increased 60-daymortality. Sensitivity analyses showed that a platelet count of <100×103/µLin combination with ARDS provide the highest prognostic value for mortality. These associations were replicated in the cohort of US patients.
Conclusions
This study of ICU patients in both China and US showed that thrombocytopenia is associated with an increased risk of ARDS and platelet count in combination with ARDS had a high predictive value for patient mortality.
doi:10.1371/journal.pone.0094124
PMCID: PMC3986053  PMID: 24732309
18.  Cloning and Characterization of TaPP2AbB"-α, a Member of the PP2A Regulatory Subunit in Wheat 
PLoS ONE  2014;9(4):e94430.
Protein phosphatase 2A (PP2A), a major Serine/Threonine protein phosphatase, consists of three subunits; a highly conserved structural subunit A, a catalytic subunit C, and a highly variable regulatory subunit B which determines the substrate specificity. Although the functional mechanism of PP2A in signaling transduction in Arabidopsis is known, their physiological roles in wheat remain to be characterized. In this study, we identified a novel regulatory subunit B, TaPP2AbB"-α, in wheat (Triticum aestivum L.). Subcellular localization indicated that TaPP2AbB"-α is located in the cell membrane, cytoplasm and nucleus. It interacts with both TaPP2Aa and TaPP2Ac. Expression pattern analyses revealed that TaPP2AbB"-α is strongly expressed in roots, and responds to NaCl, polyethylene glycol (PEG), cold and abscisic acid (ABA) stresses at the transcription level. Transgenic Arabidopsis plants overexpressing TaPP2AbB"-α developed more lateral roots, especially when treated with mannitol or NaCl. These results suggest that TaPP2AbB"-α, in conjunction with the other two PP2A subunits, is involved in multi-stress response, and positively regulates lateral root development under osmotic stress.
doi:10.1371/journal.pone.0094430
PMCID: PMC3978047  PMID: 24709994
20.  High quality draft genome sequence of Staphylococcus cohnii subsp. cohnii strain hu-01 
Standards in Genomic Sciences  2014;9(3):755-762.
Staphylococcus cohnii subsp. cohnii belongs to the family Staphylococcaceae in the order Bacillales, class Bacilli and phylum Firmicutes. The increasing relevance of S. cohnii to human health prompted us to determine the genomic sequence of Staphylococcus cohnii subsp. cohnii strain hu-01, a multidrug-resistant isolate from a hospital in China. Here we describe the features of S. cohnii subsp. cohnii strain hu-01, together with the genome sequence and its annotation. This is the first genome sequence of the species Staphylococcus cohnii.
doi:10.4056/sigs.5429581
PMCID: PMC4149010  PMID: 25197460
Staphylococcus cohnii subsp. cohnii; genome; Hiseq2000
21.  Tissue inducible Lifeact expression allows visualization of actin dynamics in vivo and ex vivo 
European journal of cell biology  2012;91(0):923-929.
We describe here the development and characterization of a conditionally inducible mouse model expressing Lifeact-GFP, a peptide that reports the dynamics of filamentous actin. We have used this model to study platelets, megakaryocytes and melanoblasts and we provide evidence that Lifeact-GFP is a useful reporter in these cell types ex vivo. In the case of platelets and megakaryocytes, these cells are not transfectable by traditional methods, so conditional activation of Lifeact allows the study of actin dynamics in these cells live. We studied melanoblasts in native skin explants from embryos, allowing the visualization of live actin dynamics during cytokinesis and migration. Our study revealed that melanoblasts lacking the small GTPase Rac1 show a delay in the formation of new pseudopodia following cytokinesis that accounts for the previously reported cytokinesis delay in these cells. Thus, through use of this mouse model, we were able to gain insights into the actin dynamics of cells that could only previously be studied using fixed specimens or following isolation from their native tissue environment.
doi:10.1016/j.ejcb.2012.04.002
PMCID: PMC3930012  PMID: 22658956
22.  Stage-specific differential gene expression profiling and functional network analysis during morphogenesis of diphyodont dentition in miniature pigs, Sus Scrofa 
BMC Genomics  2014;15:103.
Background
Our current knowledge of tooth development derives mainly from studies in mice, which have only one set of non-replaced teeth, compared with the diphyodont dentition in humans. The miniature pig is also diphyodont, making it a valuable alternative model for understanding human tooth development and replacement. However, little is known about gene expression and function during swine odontogenesis. The goal of this study is to undertake the survey of differential gene expression profiling and functional network analysis during morphogenesis of diphyodont dentition in miniature pigs. The identification of genes related to diphyodont development should lead to a better understanding of morphogenetic patterns and the mechanisms of diphyodont replacement in large animal models and humans.
Results
The temporal gene expression profiles during early diphyodont development in miniature pigs were detected with the Affymetrix Porcine GeneChip. The gene expression data were further evaluated by ANOVA as well as pathway and STC analyses. A total of 2,053 genes were detected with differential expression. Several signal pathways and 151 genes were then identified through the construction of pathway and signal networks.
Conclusions
The gene expression profiles indicated that spatio-temporal down-regulation patterns of gene expression were predominant; while, both dynamic activation and inhibition of pathways occurred during the morphogenesis of diphyodont dentition. Our study offers a mechanistic framework for understanding dynamic gene regulation of early diphyodont development and provides a molecular basis for studying teeth development, replacement, and regeneration in miniature pigs.
doi:10.1186/1471-2164-15-103
PMCID: PMC3937075  PMID: 24498892
Gene expression profile; Diphyodont; Odontogenesis; Miniature pig
23.  Mammalian WTAP is a regulatory subunit of the RNA N6-methyladenosine methyltransferase 
Cell Research  2014;24(2):177-189.
The methyltransferase like 3 (METTL3)-containing methyltransferase complex catalyzes the N6-methyladenosine (m6A) formation, a novel epitranscriptomic marker; however, the nature of this complex remains largely unknown. Here we report two new components of the human m6A methyltransferase complex, Wilms' tumor 1-associating protein (WTAP) and methyltransferase like 14 (METTL14). WTAP interacts with METTL3 and METTL14, and is required for their localization into nuclear speckles enriched with pre-mRNA processing factors and for catalytic activity of the m6A methyltransferase in vivo. The majority of RNAs bound by WTAP and METTL3 in vivo represent mRNAs containing the consensus m6A motif. In the absence of WTAP, the RNA-binding capability of METTL3 is strongly reduced, suggesting that WTAP may function to regulate recruitment of the m6A methyltransferase complex to mRNA targets. Furthermore, transcriptomic analyses in combination with photoactivatable-ribonucleoside-enhanced crosslinking and immunoprecipitation (PAR-CLIP) illustrate that WTAP and METTL3 regulate expression and alternative splicing of genes involved in transcription and RNA processing. Morpholino-mediated knockdown targeting WTAP and/or METTL3 in zebrafish embryos caused tissue differentiation defects and increased apoptosis. These findings provide strong evidence that WTAP may function as a regulatory subunit in the m6A methyltransferase complex and play a critical role in epitranscriptomic regulation of RNA metabolism.
doi:10.1038/cr.2014.3
PMCID: PMC3915904  PMID: 24407421
WTAP; m6A methyltransferase; METTL3; METTL14; mRNA
24.  Predicting Active Users' Personality Based on Micro-Blogging Behaviors 
PLoS ONE  2014;9(1):e84997.
Because of its richness and availability, micro-blogging has become an ideal platform for conducting psychological research. In this paper, we proposed to predict active users' personality traits through micro-blogging behaviors. 547 Chinese active users of micro-blogging participated in this study. Their personality traits were measured by the Big Five Inventory, and digital records of micro-blogging behaviors were collected via web crawlers. After extracting 845 micro-blogging behavioral features, we first trained classification models utilizing Support Vector Machine (SVM), differentiating participants with high and low scores on each dimension of the Big Five Inventory. The classification accuracy ranged from 84% to 92%. We also built regression models utilizing PaceRegression methods, predicting participants' scores on each dimension of the Big Five Inventory. The Pearson correlation coefficients between predicted scores and actual scores ranged from 0.48 to 0.54. Results indicated that active users' personality traits could be predicted by micro-blogging behaviors.
doi:10.1371/journal.pone.0084997
PMCID: PMC3898945  PMID: 24465462
25.  Novel NAC Transcription Factor TaNAC67 Confers Enhanced Multi-Abiotic Stress Tolerances in Arabidopsis 
PLoS ONE  2014;9(1):e84359.
Abiotic stresses are major environmental factors that affect agricultural productivity worldwide. NAC transcription factors play pivotal roles in abiotic stress signaling in plants. As a staple crop, wheat production is severely constrained by abiotic stresses whereas only a few NAC transcription factors have been characterized functionally. To promote the application of NAC genes in wheat improvement by biotechnology, a novel NAC gene designated TaNAC67 was characterized in common wheat. To determine its role, transgenic Arabidopsis overexpressing TaNAC67-GFP controlled by the CaMV-35S promoter was generated and subjected to various abiotic stresses for morphological and physiological assays. Gene expression showed that TaNAC67 was involved in response to drought, salt, cold and ABA treatments. Localization assays revealed that TaNAC67 localized in the nucleus. Morphological analysis indicated the transgenics had enhanced tolerances to drought, salt and freezing stresses, simultaneously supported by enhanced expression of multiple abiotic stress responsive genes and improved physiological traits, including strengthened cell membrane stability, retention of higher chlorophyll contents and Na+ efflux rates, improved photosynthetic potential, and enhanced water retention capability. Overexpression of TaNAC67 resulted in pronounced enhanced tolerances to drought, salt and freezing stresses, therefore it has potential for utilization in transgenic breeding to improve abiotic stress tolerance in crops.
doi:10.1371/journal.pone.0084359
PMCID: PMC3888409  PMID: 24427285

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