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1.  Effect of High Dietary Carbohydrate on the Growth Performance, Blood Chemistry, Hepatic Enzyme Activities and Growth Hormone Gene Expression of Wuchang Bream (Megalobrama amblycephala) at Two Temperatures 
The effects of high carbohydrate diet on growth, serum physiological response, and hepatic heat shock protein 70 expression in Wuchang bream were determined at 25°C and 30°C. At each temperature, the fish fed the control diet (31% CHO) had significantly higher weight gain, specific growth rate, protein efficiency ratio and hepatic glucose-6-phosphatase activities, lower feed conversion ratio and hepatosomatic index (HSI), whole crude lipid, serum glucose, hepatic glucokinase (GK) activity than those fed the high-carbohydrate diet (47% CHO) (p<0.05). The fish reared at 25°C had significantly higher whole body crude protein and ash, serum cholesterol and triglyceride, hepatic G-6-Pase activity, lower glycogen content and relative levels of hepatic growth hormone (GH) gene expression than those reared at 30°C (p<0.05). Significant interaction between temperature and diet was found for HSI, condition factor, hepatic GK activity and the relative levels of hepatic GH gene expression (p<0.05).
doi:10.5713/ajas.13.0705
PMCID: PMC4283165  PMID: 25557816
Megalobrama amblycephala; Dietary Carbohydrate; Temperature; Growth; Serum Parameters; Hepatic Enzymes Activities
2.  Conformational B-Cell Epitope Prediction Method Based on Antigen Preprocessing and Mimotopes Analysis 
BioMed Research International  2015;2015:257030.
Identification of epitopes which invokes strong humoral responses is an essential issue in the field of immunology. Various computational methods that have been developed based on the antigen structures and the mimotopes these years narrow the search for experimental validation. These methods can be divided into two categories: antigen structure-based methods and mimotope-based methods. Though new methods of the two kinds have been proposed in these years, they cannot maintain a high degree of satisfaction in various circumstances. In this paper, we proposed a new conformational B-cell epitope prediction method based on antigen preprocessing and mimotopes analysis. The method classifies the antigen surface residues into “epitopes” and “nonepitopes” by six epitope propensity scales, removing the “nonepitopes” and using the preprocessed antigen for epitope prediction based on mimotope sequences. The proposed method gives out the mean F score of 0.42 on the testing dataset. When compared with other publicly available servers by using the testing dataset, the new method yields better performance. The results demonstrate the proposed method is competent for the conformational B-cell epitope prediction.
doi:10.1155/2015/257030
PMCID: PMC4326220
3.  Highly-ordered silicon inverted nanocone arrays with broadband light antireflectance 
In this work, highly-ordered silicon inverted nanocone arrays are fabricated by integration of nanosphere lithography with reactive ion etching (RIE) method. The optical characteristics of as-prepared Si inverted nanocone arrays are investigated both by experiments and simulations. It is found that the Si nanocone arrays present excellent broadband light antireflectance properties, which are attributed to the gradient in the effective refractive index of nanocones and enhanced light trapping owing to optical diffraction. The inverted Si nanocone arrays might find a variety of applications in solar cells and photodetectors.
Electronic supplementary material
The online version of this article (doi:10.1186/s11671-014-0718-x) contains supplementary material, which is available to authorized users.
doi:10.1186/s11671-014-0718-x
PMCID: PMC4303704  PMID: 25635178
Inverted nanocone arrays; Antireflection; Nanosphere lithography; Si
4.  Characterization and immunological activity of different forms of recombinant secreted Hc of botulinum neurotoxin serotype B products expressed in yeast 
Scientific Reports  2015;5:7678.
The recombinant Hc proteins of botulinum neurotoxins and tetanus toxin are exclusively produced by intracellular heterologous expression in Pichia pastoris for use in subunit vaccines; the same Hc proteins produced by secreted heterologous expression are hyper-glycosylated and immunologically inert. Here, several different recombinant secreted Hc proteins of botulinum neurotoxin serotype B (BHc) were expressed in yeast and we characterized and assessed their immunological activity in detail. Recombinant low-glycosylated secreted BHc products (BSK) were also immunologically inert, similar to hyper-glycosylated BHc products (BSG), although deglycosylation restored their immunological activities. Unexpectedly, deglycosylated proBHc contained an unexpected pro-peptide of an α-factor signal and fortuitous N-linked glycosylation sites in the non-cleaved pro-peptide sequences, but not in the BHc sequences. Notably, a non-glycosylated secreted homogeneous BHc isoform (mBHc), which we successfully prepared after deleting the pro-peptide and removing its single potential glycosylation site, was immunologically active and could confer effective protective immunity, similarly to non-glycosylated rBHc. In summary, we conclude that a non-glycosylated secreted BHc isoform can be prepared in yeast by deleting the pro-peptide of the α-factor signal and mutating its single potential glycosylation site. This approach provides a rational and feasible strategy for the secretory expression of botulism or other toxin antigens.
doi:10.1038/srep07678
PMCID: PMC4286741  PMID: 25567004
5.  Widespread Increase of Functional Connectivity in Parkinson’s Disease with Tremor: A Resting-State fMRI Study 
Parkinson’s disease (PD) is a clinically heterogeneous disease in the symptomatology dominated by tremor, akinesia, or rigidity. Focusing on PD patients with tremor, this study investigated their discoordination patterns of spontaneous brain activity by combining voxel-wise centrality, seed-based functional connectivity, and network efficiency methods. Sixteen patients and 20 matched healthy controls (HCs) were recruited and underwent structural and resting-state functional MRI scan. Compared with the HCs, the patients exhibited increased centrality in the frontal, parietal, and occipital regions while decreased centrality in the cerebellum anterior lobe and thalamus. Seeded at these regions, a distributed network was further identified that encompassed cortical (default mode network, sensorimotor cortex, prefrontal and occipital areas) and subcortical (thalamus and basal ganglia) regions and the cerebellum and brainstem. Graph-based analyses of this network revealed increased information transformation efficiency in the patients. Moreover, the identified network correlated with clinical manifestations in the patients and could distinguish the patients from HCs. Morphometric analyses revealed decreased gray matter volume in multiple regions that largely accounted for the observed functional abnormalities. Together, these findings provide a comprehensive view of network disorganization in PD with tremor and have important implications for understanding neural substrates underlying this specific type of PD.
doi:10.3389/fnagi.2015.00006
PMCID: PMC4315047
Parkinson’s disease; tremor; connectome; centrality; resting functional connectivity
6.  Distinguishing Patients with Parkinson's Disease Subtypes from Normal Controls Based on Functional Network Regional Efficiencies 
PLoS ONE  2014;9(12):e115131.
Many studies have demonstrated that the pathophysiology and clinical symptoms of Parkinson's disease (PD) are inhomogeneous. However, the symptom-specific intrinsic neural activities underlying the PD subtypes are still not well understood. Here, 15 tremor-dominant PD patients, 10 non-tremor-dominant PD patients, and 20 matched normal controls (NCs) were recruited and underwent resting-state functional magnetic resonance imaging (fMRI). Functional brain networks were constructed based on randomly generated anatomical templates with and without the cerebellum. The regional network efficiencies (i.e., the local and global efficiencies) were further measured and used to distinguish subgroups of PD patients (i.e., with tremor-dominant PD and non-tremor-dominant PD) from the NCs using linear discriminant analysis. The results demonstrate that the subtype-specific functional networks were small-world-organized and that the network regional efficiency could discriminate among the individual PD subgroups and the NCs. Brain regions involved in distinguishing between the study groups included the basal ganglia (i.e., the caudate and putamen), limbic regions (i.e., the hippocampus and thalamus), the cerebellum, and other cerebral regions (e.g., the insula, cingulum, and calcarine sulcus). In particular, the performances of the regional local efficiency in the functional network were better than those of the global efficiency, and the performances of global efficiency were dependent on the inclusion of the cerebellum in the analysis. These findings provide new evidence for the neurological basis of differences between PD subtypes and suggest that the cerebellum may play different roles in the pathologies of different PD subtypes. The present study demonstrated the power of the combination of graph-based network analysis and discrimination analysis in elucidating the neural basis of different PD subtypes.
doi:10.1371/journal.pone.0115131
PMCID: PMC4274088  PMID: 25531436
7.  A retrospective study of external beam radiation, neutron brachytherapy, and concurrent chemotherapy for patients with localized advanced carcinoma of the esophagus 
Purpose
The aim of this study was to retrospectively observe and analyze the long-term treatment outcomes of a total of 140 esophageal cancer patients who were treated with californium-252 (252Cf) neutron brachytherapy (NBT) in combination with external beam radiotherapy (EBRT) and concurrent chemotherapy (CCT).
Methods and materials
From January 2002 to November 2012, 140 patients with esophageal cancer underwent NBT in combination with EBRT and CCT. The distribution of the patient numbers over the various cancer stages of IIA, IIB, and III were 43, 7, and 90, respectively. The total radiation dose to the reference point via NBT was 8–25 Gy-eq in two to five fractions with one fraction per week. The total dose via EBRT was 50–60 Gy, which was delivered over a period of five to six weeks with normal fractionation. Fifty-four and 86 patients received tegafur suppositories (TS) and continuous infusion of fluorouracil (5-Fu) with cisplatin (CDDP), respectively.
Results
The median follow-up time was 42 months. The minimum follow-up was three months, and the maximum was 106 months. The overall median survival including death from all causes was 29.5 months. The five-year overall survival rate (OS) and local control (LC) were 33.4% and 55.9%, respectively. The chemotherapy regimen was a factor that was significantly associated with OS (p = 0.025) according to univariate analysis. The five-year OSs were 27.4% and 44.3% for the PF and TS chemotherapy regimens, respectively. Regarding acute toxicity, no incidences of fistula or massive bleeding were observed during this treatment period. The incidence of severe, late complications was related to the PF chemotherapy regimen (p = 0.080).
Conclusions
The clinical data indicated that NBT in combination with EBRT and CRT produced favorable local control and long-term survival rates for patients with esophageal cancer and that the side effects were tolerable. A reasonable CRT regimen can decrease the rate of severe, late complications.
doi:10.1186/s13014-014-0294-3
PMCID: PMC4299483  PMID: 25515326
Esophageal cancer; Californium-252; Neutron brachytherapy; Chemotherapy; Late complication
8.  Thymic development of autoreactive T cells in NOD mice is regulated in an age-dependent manner1 
Journal of immunology (Baltimore, Md. : 1950)  2013;191(12):10.4049/jimmunol.1302273.
Inefficient thymic negative selection of self-specific T cells is associated with several autoimmune diseases, including type 1 diabetes (T1D). The factors that influence the efficacy of thymic negative selection, and the kinetics of thymic output of autoreactive T cells remain ill-defined. We investigated thymic production of β cell-specific T cells using a thymus transplantation model. Thymi from different aged NOD mice representing distinct stages of T1D, were implanted into NOD.scid recipients and the diabetogenicity of the resulting T cell pool examined. Strikingly, the development of diabetes-inducing β cell-specific CD4+ and CD8+ T cells was regulated in an age-dependent manner. NOD.scid recipients of newborn NOD thymi developed diabetes. However, recipients of thymi from 7 and 10 d-old NOD donor mice remained diabetes-free, and exhibited a progressive decline in islet infiltration and β cell-specific CD4+ and CD8+ T cells. A similar temporal decrease in autoimmune infiltration was detected in some but not all tissues of recipient mice implanted with thymi from NOD mice lacking expression of the autoimmune regulator transcription factor, which develop multi-organ T cell-mediated autoimmunity. In contrast, recipients of 10 d or older thymi lacked diabetogenic T cells but developed severe colitis marked by increased effector T cells reactive to intestinal microbiota. These results demonstrate that thymic development of autoreactive T cells is limited to a narrow time-window, and occurs in a reciprocal manner compared to colonic microbiota-responsive T cells in NOD mice.
doi:10.4049/jimmunol.1302273
PMCID: PMC3858497  PMID: 24198282
9.  Mapping and analysis of a novel candidate Fusarium wilt resistance gene FOC1 in Brassica oleracea 
BMC Genomics  2014;15(1):1094.
Background
Cabbage Fusarium wilt is a major disease worldwide that can cause severe yield loss in cabbage (Brassica olerecea). Although markers linked to the resistance gene FOC1 have been identified, no candidate gene for it has been determined so far. In this study, we report the fine mapping and analysis of a candidate gene for FOC1 using a double haploid (DH) population with 160 lines and a F2 population of 4000 individuals derived from the same parental lines.
Results
We confirmed that the resistance to Fusarium wilt was controlled by a single dominant gene based on the resistance segregation ratio of the two populations. Using InDel primers designed from whole-genome re-sequencing data for the two parental lines (the resistant inbred-line 99–77 and the highly susceptible line 99–91) and the DH population, we mapped the resistance gene to a 382-kb genomic region on chromosome C06. Using the F2 population, we narrowed the region to an 84-kb interval that harbored ten genes, including four probable resistance genes (R genes): Bol037156, Bol037157, Bol037158 and Bol037161 according to the gene annotations from BRAD, the genomic database for B. oleracea. After correcting the model of the these genes, we re-predicted two R genes in the target region: re-Bol037156 and re-Bol0371578. The latter was excluded after we compared the two genes’ sequences between ten resistant materials and ten susceptible materials. For re-Bol037156, we found high identity among the sequences of the resistant lines, while among the susceptible lines, there were two types of InDels (a 1-bp insertion and a 10-bp deletion), each of which caused a frameshift and terminating mutation in the cDNA sequences. Further sequence analysis of the two InDel loci from 80 lines (40 resistant and 40 susceptible) also showed that all 40 R lines had no InDel mutation while 39 out of 40 S lines matched the two types of loci. Thus re-Bol037156 was identified as a likely candidate gene for FOC1 in cabbage.
Conclusions
This work may lay the foundation for marker-assisted selection as well as for further function analysis of the FOC1 gene.
doi:10.1186/1471-2164-15-1094
PMCID: PMC4299151  PMID: 25495687
Brassica oleracea; Fusarium wilt; Resistance gene; FOC1; Map-based cloning
10.  Nanomechanics of phospholipid LB film studied layer by layer with AFM 
Background
Phospholipid, a main component of cell membrane, has been explored as a model system of the cell membrane and temporary scaffold materials in recent studies. The mechanical properties of phospholipid layers are essentially interesting since it is involved in several biological processes.
Results
Here, the nanomechanical properties such as indentation force, adhesion force and DMT (Derjaguin-Müller-Toporov) modulus of 1,2-distearoyl-sn-glycero-3-phosphocholine (DSPC) Langmuir-Blodgett (LB) films were analyzed layer by layer with Atomic Force Microscope (AFM) under deionized water condition.
Conclusions
The penetration distances in the indentation force curves are equal to the thicknesses of phospholipid films, and the yield forces of DSPC LB films in deionized water are smaller than that of similar lipid films in buffered solutions due to the influence of ions. Moreover, the DMT modulus of upper layer DSPC LB film is different from that of monolayer DSPC LB film due to the influence of their different substrates. Our results suggest that environment such as surrounding ions and substrate will strongly influence the measured nano-mechanical properties of the lipid bilayer, especially that of the down layer.
Graphical AbstractA process about the exploration of nanomechanics of DSPC LB film.
doi:10.1186/s13065-014-0071-2
PMCID: PMC4279057  PMID: 25614761
Phospholipid; Nanomechanics; Langmuir-Blogget film; Atomic force microscope; Indentation force curve
11.  Nanomechanics of phospholipid LB film studied layer by layer with AFM 
Background
Phospholipid, a main component of cell membrane, has been explored as a model system of the cell membrane and temporary scaffold materials in recent studies. The mechanical properties of phospholipid layers are essentially interesting since it is involved in several biological processes.
Results
Here, the nanomechanical properties such as indentation force, adhesion force and DMT (Derjaguin-Müller-Toporov) modulus of 1,2-distearoyl-sn-glycero-3-phosphocholine (DSPC) Langmuir-Blodgett (LB) films were analyzed layer by layer with Atomic Force Microscope (AFM) under deionized water condition.
Conclusions
The penetration distances in the indentation force curves are equal to the thicknesses of phospholipid films, and the yield forces of DSPC LB films in deionized water are smaller than that of similar lipid films in buffered solutions due to the influence of ions. Moreover, the DMT modulus of upper layer DSPC LB film is different from that of monolayer DSPC LB film due to the influence of their different substrates. Our results suggest that environment such as surrounding ions and substrate will strongly influence the measured nano-mechanical properties of the lipid bilayer, especially that of the down layer.
Graphical AbstractA process about the exploration of nanomechanics of DSPC LB film.
doi:10.1186/s13065-014-0071-2
PMCID: PMC4279057  PMID: 25614761
Phospholipid; Nanomechanics; Langmuir-Blogget film; Atomic force microscope; Indentation force curve
12.  PERGA: A Paired-End Read Guided De Novo Assembler for Extending Contigs Using SVM and Look Ahead Approach 
PLoS ONE  2014;9(12):e114253.
Since the read lengths of high throughput sequencing (HTS) technologies are short, de novo assembly which plays significant roles in many applications remains a great challenge. Most of the state-of-the-art approaches base on de Bruijn graph strategy and overlap-layout strategy. However, these approaches which depend on k-mers or read overlaps do not fully utilize information of paired-end and single-end reads when resolving branches. Since they treat all single-end reads with overlapped length larger than a fix threshold equally, they fail to use the more confident long overlapped reads for assembling and mix up with the relative short overlapped reads. Moreover, these approaches have not been special designed for handling tandem repeats (repeats occur adjacently in the genome) and they usually break down the contigs near the tandem repeats. We present PERGA (Paired-End Reads Guided Assembler), a novel sequence-reads-guided de novo assembly approach, which adopts greedy-like prediction strategy for assembling reads to contigs and scaffolds using paired-end reads and different read overlap size ranging from Omax to Omin to resolve the gaps and branches. By constructing a decision model using machine learning approach based on branch features, PERGA can determine the correct extension in 99.7% of cases. When the correct extension cannot be determined, PERGA will try to extend the contig by all feasible extensions and determine the correct extension by using look-ahead approach. Many difficult-resolved branches are due to tandem repeats which are close in the genome. PERGA detects such different copies of the repeats to resolve the branches to make the extension much longer and more accurate. We evaluated PERGA on both Illumina real and simulated datasets ranging from small bacterial genomes to large human chromosome, and it constructed longer and more accurate contigs and scaffolds than other state-of-the-art assemblers. PERGA can be freely downloaded at https://github.com/hitbio/PERGA.
doi:10.1371/journal.pone.0114253
PMCID: PMC4252104  PMID: 25461763
13.  Cigarette Smoke Induces Systemic Defects in Cystic Fibrosis Transmembrane Conductance Regulator Function 
Rationale: Several extrapulmonary disorders have been linked to cigarette smoking. Smoking is reported to cause cystic fibrosis transmembrane conductance regulator (CFTR) dysfunction in the airway, and is also associated with pancreatitis, male infertility, and cachexia, features characteristic of cystic fibrosis and suggestive of an etiological role for CFTR.
Objectives: To study the effect of cigarette smoke on extrapulmonary CFTR function.
Methods: Demographics, spirometry, exercise tolerance, symptom questionnaires, CFTR genetics, and sweat chloride analysis were obtained in smokers with and without chronic obstructive pulmonary disease (COPD). CFTR activity was measured by nasal potential difference in mice and by Ussing chamber electrophysiology in vitro. Serum acrolein levels were estimated with mass spectroscopy.
Measurements and Main Results: Healthy smokers (29.45 ± 13.90 mEq), smokers with COPD (31.89 ± 13.9 mEq), and former smokers with COPD (25.07 ± 10.92 mEq) had elevated sweat chloride levels compared with normal control subjects (14.5 ± 7.77 mEq), indicating reduced CFTR activity in a nonrespiratory organ. Intestinal current measurements also demonstrated a 65% decrease in CFTR function in smokers compared with never smokers. CFTR activity was decreased by 68% in normal human bronchial epithelial cells exposed to plasma from smokers, suggesting that one or more circulating agents could confer CFTR dysfunction. Cigarette smoke–exposed mice had decreased CFTR activity in intestinal epithelium (84.3 and 45%, after 5 and 17 wk, respectively). Acrolein, a component of cigarette smoke, was higher in smokers, blocked CFTR by inhibiting channel gating, and was attenuated by antioxidant N-acetylcysteine, a known scavenger of acrolein.
Conclusions: Smoking causes systemic CFTR dysfunction. Acrolein present in cigarette smoke mediates CFTR defects in extrapulmonary tissues in smokers.
doi:10.1164/rccm.201304-0733OC
PMCID: PMC3919073  PMID: 24040746
cystic fibrosis transmembrane conductance regulator; cigarette smoking; chronic obstructive pulmonary disease; acrolein
14.  Induction of Bacterial Antigen-Specific Colitis by a Simplified Human Microbiota Consortium in Gnotobiotic Interleukin-10−/− Mice 
Infection and Immunity  2014;82(6):2239-2246.
We evaluated whether a simplified human microbiota consortium (SIHUMI) induces colitis in germfree (GF) 129S6/SvEv (129) and C57BL/6 (B6) interleukin-10-deficient (IL-10−/−) mice, determined mouse strain effects on colitis and the microbiota, examined the effects of inflammation on relative bacterial composition, and identified immunodominant bacterial species in “humanized” IL-10−/− mice. GF wild-type (WT) and IL-10−/− 129 and B6 mice were colonized with 7 human-derived inflammatory bowel disease (IBD)-related intestinal bacteria and maintained under gnotobiotic conditions. Quantification of bacteria in feces, ileal and colonic contents, and tissues was performed using 16S rRNA gene selective quantitative PCR. Colonic segments were scored histologically, and gamma interferon (IFN-γ), IL-12p40, and IL-17 levels were measured in supernatants of unstimulated colonic tissue explants and of mesenteric lymph node (MLN) cells stimulated by lysates of individual or aggregate bacterial strains. Relative bacterial species abundances changed over time and differed between 129 and B6 mice, WT and IL-10−/− mice, luminal and mucosal samples, and ileal and colonic or fecal samples. SIHUMI induced colitis in all IL-10−/− mice, with more aggressive colitis and MLN cell activation in 129 mice. Escherichia coli LF82 and Ruminococcus gnavus lysates induced dominant effector ex vivo MLN TH1 and TH17 responses, although the bacterial mucosal concentrations were low. In summary, this study shows that a simplified human bacterial consortium induces colitis in ex-GF 129 and B6 IL-10−/− mice. Relative concentrations of individual SIHUMI species are determined by host genotype, the presence of inflammation, and anatomical location. A subset of IBD-relevant human enteric bacterial species preferentially stimulates bacterial antigen-specific TH1 and TH17 immune responses in this model, independent of luminal and mucosal bacterial concentrations.
doi:10.1128/IAI.01513-13
PMCID: PMC4019192  PMID: 24643531
15.  Angioplasty and stenting for severe vertebral artery orifice stenosis: effects on cerebellar function remodeling verified by blood oxygen level-dependent functional magnetic resonance imaging 
Neural Regeneration Research  2014;9(23):2095-2101.
Vertebral artery orifice stenting may improve blood supply of the posterior circulation of the brain to regions such as the cerebellum and brainstem. However, previous studies have mainly focused on recovery of cerebral blood flow and perfusion in the posterior circulation after interventional therapy. This study examined the effects of functional recovery of local brain tissue on cerebellar function remodeling using blood oxygen level-dependent functional magnetic resonance imaging before and after interventional therapy. A total of 40 Chinese patients with severe unilateral vertebral artery orifice stenosis were enrolled in this study. Patients were equally and randomly assigned to intervention and control groups. The control group received drug treatment only. The intervention group received vertebral artery orifice angioplasty and stenting + identical drug treatment to the control group. At 13 days after treatment, the Dizziness Handicap Inventory score was compared between the intervention and control groups. Cerebellar function remodeling was observed between the two groups using blood oxygen level-dependent functional magnetic resonance imaging. The improvement in dizziness handicap and cerebellar function was more obvious in the intervention group than in the control group. Interventional therapy for severe vertebral artery orifice stenosis may effectively promote cerebellar function remodeling and exert neuroprotective effects.
doi:10.4103/1673-5374.147937
PMCID: PMC4316475  PMID: 25657727
nerve regeneration; posterior circulation ischemia; vertebrobasilar insufficiency; dizziness; Dizziness Handicap Inventory; vertebral artery stenosis; angioplasty and stenting; endovascular treatment; functional magnetic resonance imaging; cerebellar function remodeling; cerebral vessels; atheromatous plaque; neural regeneration
16.  Berberine derivatives reduce atherosclerotic plaque size and vulnerability in apoE−/− mice 
Background and aims
Our previous in vitro and clinical work has demonstrated anti-inflammatory effects of berberine (BBR), but the clinical application of BBR is limited by its poor bioavailability. Derivatives of BBR have been suggested to have enhanced bioavailability compared to BBR. In this study, we tested whether BBR derivatives, compared with BBR, had superior beneficial effects on atherosclerotic plaques in apoE−/− mice, and defined possible molecular mechanisms underlying such effects.
Methods
Macrophages were pretreated with BBR and its derivatives, dihydroberberine (dhBBR) and 8,8-dimethyldihydroberberine (Di-MeBBR), before incubation with oxLDL. Cell surface EMMPRIN expression was measured by flow cytometry and Western blotting, and phospho-(p)-p38, p-JNK, nuclear NFκB p65, and phospho-p65 were measured by Western blotting. ApoE−/− mice fed with the Western diet for 16 weeks were treated with BBR, dhBBR and Di-MeBBR 16 weeks. Aortic atherosclerotic lesion size, plaque matrix proteins, and EMMPRIN and other inflammatory factors were measured using Oil Red O Staining, Masson’s trichromestaining and immunohistochemical staining and real-time PCR.
Results
Compared with BBR, dhBBR and Di-MeBBR significantly reduced EMMPRIN expression, which was associated with a greater inhibition of p-p38, p-JNK, nuclear NFκB p65 and phospho-p65 induced by oxLDL in macrophages. dhBBR and Di-MeBBR, but not BBR, reduced atherosclerotic plaque size and improved plaque stability indicated by increased α-smooth muscle actin and collagen content, and thicker fibrous caps. dhBBR and Di-MeBBR reduced expression of EMMPRIN, CD68, and NFκB p65, and Di-MeBBR also reduced expression of matrix metalloproteinase-9, intercellular adhesion molecule-1, and vascular cell adhesion molecule-1 in aortic plaques.
Conclusions
These results have demonstrated that BBR derivatives, dhBBR and Di-MeBBR, are superior to BBR in inhibiting inflammation and reducing plaque size and vulnerability.
doi:10.1186/s12967-014-0326-7
PMCID: PMC4261588  PMID: 25425200
Berberine derivatives; EMMPRIN; Inflammation; Atherosclerosis; Plaque stability
17.  Abundance and Diversity of Bacterial Nitrifiers and Denitrifiers and Their Functional Genes in Tannery Wastewater Treatment Plants Revealed by High-Throughput Sequencing 
PLoS ONE  2014;9(11):e113603.
Biological nitrification/denitrification is frequently used to remove nitrogen from tannery wastewater containing high concentrations of ammonia. However, information is limited about the bacterial nitrifiers and denitrifiers and their functional genes in tannery wastewater treatment plants (WWTPs) due to the low-throughput of the previously used methods. In this study, 454 pyrosequencing and Illumina high-throughput sequencing, combined with molecular methods, were used to comprehensively characterize structures and functions of nitrification and denitrification bacterial communities in aerobic and anaerobic sludge of two full-scale tannery WWTPs. Pyrosequencing of 16S rRNA genes showed that Proteobacteria and Synergistetes dominated in the aerobic and anaerobic sludge, respectively. Ammonia-oxidizing bacteria (AOB) amoA gene cloning revealed that Nitrosomonas europaea dominated the ammonia-oxidizing community in the WWTPs. Metagenomic analysis showed that the denitrifiers mainly included the genera of Thauera, Paracoccus, Hyphomicrobium, Comamonas and Azoarcus, which may greatly contribute to the nitrogen removal in the two WWTPs. It is interesting that AOB and ammonia-oxidizing archaea had low abundance although both WWTPs demonstrated high ammonium removal efficiency. Good correlation between the qPCR and metagenomic analysis is observed for the quantification of functional genes amoA, nirK, nirS and nosZ, indicating that the metagenomic approach may be a promising method used to comprehensively investigate the abundance of functional genes of nitrifiers and denitrifiers in the environment.
doi:10.1371/journal.pone.0113603
PMCID: PMC4242629  PMID: 25420093
18.  An integrated microfluidic device for screening the effective concentration of locally applied tacrolimus for peripheral nerve regeneration 
The effectiveness of tacrolimus (FK506) for the promotion of nerve regeneration is known. However, at present, due to the fact that systemic application may lead to opportunistic infections and tumors, and that the treatment of peripheral nerve injury with systemic immunosuppression is not generally accepted, FK506 has not been widely used for the treatment of simple or peripheral nerve injury. In this study, a pyramid-shaped microfluidic device was designed and fabricated that was able to analyze the effective concentration of locally applied FK506. After testing the effectiveness of the microfluidic device by measuring the fluorescence intensity of fluorescein isothiocyanate-dextran, rat Schwann cells (SCs) were loaded into the device and cultured for 9 days in the presence of different concentrations of FK506. SC proliferation in the presence of FK506 was concentration-dependent between 0 and 2.5±0.003 ng/ml. The proliferation rate reached a maximum at 1.786±0.014 ng/ml, which was statistically significantly different from the proliferation rate at lower FK506 concentrations. There was no statistically significant difference in the proliferation rate between the 1.786 ng/ml group and groups of higher FK506 concentrations. Furthermore, the SCs in the microfluidic device and a 96-well plate continued to proliferate as the culture time increased. No statistically significant differences were identified between the microfluidic device and a 96-well plate with regard to the proliferation rates in each corresponding group. The results obtained in this study demonstrated that the microfluidic device can be used as an excellent platform for the study of drug concentration at the cellular level, and the effective FK506 concentration for local application is 1.786±0.014 ng/ml.
doi:10.3892/etm.2014.2082
PMCID: PMC4247293  PMID: 25452793
microfluidic device; tacrolimus; effective concentration
19.  Platinum sensitivity and CD133 expression as risk and prognostic predictors of central nervous system metastases in patients with epithelial ovarian cancer 
BMC Cancer  2014;14(1):829.
Background
To characterize prognostic and risk factors of central nervous system (CNS) metastases in patients with epithelial ovarian cancer (EOC).
Methods
A retrospective analysis of Xijing Hospital electronic medical records was conducted to identify patients with pathologically confirmed EOC and CNS metastases. In addition to patient demographics, tumor pathology, treatment regimens, and clinical outcomes, we compared putative cancer stem cell marker CD133 expression patterns in primary and metastatic lesions as well as in recurrent EOC with and without CNS metastases.
Results
Among 1366 patients with EOC, metastatic CNS lesions were present in 29 (2.1%) cases. CD133 expression in primary tumor was the only independent risk factor for CNS metastases; whilst the extent of surgical resection of primary EOC and platinum resistance were two independent factors significantly associated with time to CNS metastases. Absence of CD133 expression in primary tumors was significantly associated with high platinum sensitivity in both patient groups with and without CNS metastases. Platinum resistance and CD133 cluster formation in CNS metastases were associated with decreased survival, while multimodal therapy including stereotactic radiosurgery (SRS) for CNS metastases was associated with increased survival following the diagnosis of CNS metastases.
Conclusions
These data suggest that there exist a positive association between CD133 expression in primary EOC, platinum resistance and the increased risk of CNS metastases, as well as a less favorable prognosis of EOC. The absence of CD133 clusters and use of multimodal therapy including SRS could improve the outcome of metastatic lesions. Further investigation is warranted to elucidate the true nature of the association between platinum sensitivity, CD133 expression, and the risk and prognosis of CNS metastases from EOC.
doi:10.1186/1471-2407-14-829
PMCID: PMC4239390  PMID: 25399490
Brain metastases; Chemoresistance; Prognosis; Stem cell marker
20.  Stomach Virtual Non-Enhanced CT with Second-Generation, Dual-Energy CT: A Preliminary Study 
PLoS ONE  2014;9(11):e112295.
Objectives
To compare the true non-enhanced (TNE) and virtual non-enhanced (VNE) data sets in patients who underwent gastric preoperative dual-energy CT (DECT) and to evaluate potential radiation dose reduction by omitting a TNE scan.
Methods
A total of 74 patients underwent gastric DECT. The mean CT values, length, image quality and effective radiation doses for VNE and TNE images were compared.
Results
There was no statistical difference in maximal thickness of gastric tumors and maximal diameter of enlarged lymph nodes among the TNE and VNE images (P>0.05). The mean CT value differences between TNE and VNE were statistically significant for all tissue types, except for aorta attenuation measurements (P<0.05), but the absolute differences were under 10 HU. Lower noise was found for VNE images than TNE images (P<0.01). Image quality of VNE was diagnostic but lower than that of TNE (P<0.01). The dose reduction achieved by omitting the TNE acquisition was 21.40±4.44%.
Conclusion
VNE scan may potentially replace TNE as part of a multi-phase gastric preoperative staging imaging protocol with consequent saving in radiation dose.
doi:10.1371/journal.pone.0112295
PMCID: PMC4231030  PMID: 25393001
21.  RhoA and Membrane Fluidity Mediates the Spatially Polarized Src/FAK Activation in Response to Shear Stress 
Scientific Reports  2014;4:7008.
While Src plays crucial roles in shear stress-induced cellular processes, little is known on the spatiotemporal pattern of high shear stress (HSS)-induced Src activation. HSS (65 dyn/cm2) was applied on bovine aortic endothelial cells to visualize the dynamic Src activation at subcellular levels utilizing a membrane-targeted Src biosensor (Kras-Src) based on fluorescence resonance energy transfer (FRET). A polarized Src activation was observed with higher activity at the side facing the flow, which was enhanced by a cytochalasin D-mediated disruption of actin filaments but inhibited by a benzyl alcohol-mediated enhancement of membrane fluidity. Further experiments revealed that HSS decreased RhoA activity, with a constitutively active RhoA mutant inhibiting while a negative RhoA mutant enhancing the HSS-induced Src polarity. Cytochalasin D can restore the polarity in cells expressing the active RhoA mutant. Further results indicate that HSS stimulates FAK activation with a spatial polarity similar to Src. The inhibition of Src by PP1, as well as the perturbation of RhoA activity and membrane fluidity, can block this HSS-induced FAK polarity. These results indicate that the HSS-induced Src and subsequently FAK polarity depends on the coordination between intracellular tension distribution regulated by RhoA, its related actin structures and the plasma membrane fluidity.
doi:10.1038/srep07008
PMCID: PMC4228346  PMID: 25387906
22.  Draft Genome Sequence of Bacillus fengqiuensis FJAT-14578, Isolated from a Soil Sample in China 
Genome Announcements  2014;2(6):e01126-14.
Here, we report the first high-quality draft genome sequence of Bacillus fengqiuensis FJAT-14578, isolated from a soil sample collected from China. The genome size was 5,569,389 bp, with a 40.93 mol% G+C content. The number of tRNAs was 69 and of rRNAs was 10 (5S, 16S, and 23S).
doi:10.1128/genomeA.01126-14
PMCID: PMC4223457  PMID: 25377706
23.  Clinicopathologic Features of Patients with Non-Small Cell Lung Cancer Harboring the EML4-ALK Fusion Gene: A Meta-Analysis 
PLoS ONE  2014;9(10):e110617.
Background
The frequencies of EML4-ALK fusion gene in non-small cell lung cancer (NSCLC) with different clinicopathologic features described by previous studies are inconsistent. The key demographic and pathologic features associated with EML4-ALK fusion gene have not been definitively established. This meta-analysis was conducted to compare the frequency of the EML4-ALK fusion gene in patients with different clinicopathologic features and to identify an enriched population of patients with NSCLC harboring EML4-ALK fusion gene.
Methods
The Pubmed and Embase databases for all studies on EML4-ALK fusion gene in NSCLC patients were searched up to July 2014. A criteria list and exclusion criteria were established to screen the studies. The frequency of the EML4-ALK fusion gene and the clinicopathologic features, including smoking status, pathologic type, gender, and EGFR status were abstracted.
Results
Seventeen articles consisting of 4511 NSCLC cases were included in this meta-analysis. A significant lower EML4-ALK fusion gene positive rate was associated with smokers (pooled OR = 0.40, 95% CI = 0.30–0.54, P<0.00001). A significantly higher EML4-ALK fusion gene positivity rate was associated with adenocarcinomas (pooled OR = 2.53, 95% CI = 1.66–3.86, P<0.0001) and female (pooled OR = 0.61, 95% CI = 0.41–0.90, P = 0.01). We found that a significantly lower EML4-ALK fusion gene positivity rate was associated with EGFR mutation (pooled OR = 0.07, 95% CI = 0.03–0.19, P<0.00001). No publication bias was observed in any meta-analysis (all P value of Egger's test >0.05); however, because of the small sample size, no results were in the meta-analysis regarding EGFR gene status.
Conclusion
This meta-analysis revealed that the EML4-ALK fusion gene is highly correlated with a never/light smoking history, female and the pathologic type of adenocarcinoma, and is largely mutually exclusive of EGFR.
doi:10.1371/journal.pone.0110617
PMCID: PMC4215846  PMID: 25360721
24.  Cloud-based bioinformatics workflow platform for large-scale next-generation sequencing analyses 
Due to the upcoming data deluge of genome data, the need for storing and processing large-scale genome data, easy access to biomedical analyses tools, efficient data sharing and retrieval has presented significant challenges. The variability in data volume results in variable computing and storage requirements, therefore biomedical researchers are pursuing more reliable, dynamic and convenient methods for conducting sequencing analyses. This paper proposes a Cloud-based bioinformatics workflow platform for large-scale next-generation sequencing analyses, which enables reliable and highly scalable execution of sequencing analyses workflows in a fully automated manner. Our platform extends the existing Galaxy workflow system by adding data management capabilities for transferring large quantities of data efficiently and reliably (via Globus Transfer), domain-specific analyses tools preconfigured for immediate use by researchers (via user-specific tools integration), automatic deployment on Cloud for on-demand resource allocation and pay-as-you-go pricing (via Globus Provision), a Cloud provisioning tool for auto-scaling (via HTCondor scheduler), and the support for validating the correctness of workflows (via semantic verification tools). Two bioinformatics workflow use cases as well as performance evaluation are presented to validate the feasibility of the proposed approach.
doi:10.1016/j.jbi.2014.01.005
PMCID: PMC4203338  PMID: 24462600
Bioinformatics; Scientific workflow; Sequencing analyses; Cloud computing; Galaxy
25.  Acoustic radiation force impulse elastography in differentiating renal solid masses: a preliminary experience 
New diagnostic methods are required to diagnose renal mass. Thus, we assessed virtual tissue quantification (VTQ) of acoustic radiation force impulse (ARFI) elastography in differentiation of renal solid masses. Forty-two patients with renal masses were assessed by VTQ in terms of measurement of the shear wave velocity (SWV). The masses were divided into three groups. They were clear cell carcinoma (CCC) angiomyolipoma (AML), and pseudotumor. The differences among the three groups in SWV, as well as between masses and its surrounding parenchyma, were investigated. Receiver operating characteristic (ROC) curve was plotted to evaluate the diagnostic performance. We found that the SWV among the three groups were significant different (F = 6.976, P = 0.003) and the SWV of pseudotumor (3.14 ± 0.75 m/s) was significantly higher than CCC (2.46 ± 0.45 m/s) and AML (2.49 ± 0.63 m/s) (P = 0.007 and 0.001 respectively). There were no significant difference between CCC and AML in SWV (P = 0.719). For each group, there was no significant difference between the mass and its surrounding parenchyma (P = 0.693, 0.892, and 0.714, respectively). Between pseudotumor and CCC, the optimal cut-off value of SWV for differential diagnoses was 3.07 m/s; and the area under the ROC curve (AUC) was 0.78 (95% CI: 0.560 to 0.924) (P = 0.004), the sensitivity and specificity were 100% and 58.3%, respectively. Between pseudotumor and AML, the optimal cut-off value of SWV for differential diagnoses was 3.03 m/s, thus AUC curve was 0.786 (95% CI: 0.591 to 0.918) (P = 0.002), the sensitivity and specificity were 100% and 58.3%, respectively. No significant difference was found between AML and CCC (P = 0.587) and the AUC was 0.562. To conclude, our results support that ARFI has potential value in differentiation between CCC and pseudotumor, or between AML and pseudotumor, however, it fails to make a distinction between CCC and AML.
PMCID: PMC4270564  PMID: 25550782
Acoustic radiation force impulse elastography; renal solid mass; ultrasound

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