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1.  Improving accuracy of protein-protein interaction prediction by considering the converse problem for sequence representation 
BMC Bioinformatics  2011;12:409.
Background
With the development of genome-sequencing technologies, protein sequences are readily obtained by translating the measured mRNAs. Therefore predicting protein-protein interactions from the sequences is of great demand. The reason lies in the fact that identifying protein-protein interactions is becoming a bottleneck for eventually understanding the functions of proteins, especially for those organisms barely characterized. Although a few methods have been proposed, the converse problem, if the features used extract sufficient and unbiased information from protein sequences, is almost untouched.
Results
In this study, we interrogate this problem theoretically by an optimization scheme. Motivated by the theoretical investigation, we find novel encoding methods for both protein sequences and protein pairs. Our new methods exploit sufficiently the information of protein sequences and reduce artificial bias and computational cost. Thus, it significantly outperforms the available methods regarding sensitivity, specificity, precision, and recall with cross-validation evaluation and reaches ~80% and ~90% accuracy in Escherichia coli and Saccharomyces cerevisiae respectively. Our findings here hold important implication for other sequence-based prediction tasks because representation of biological sequence is always the first step in computational biology.
Conclusions
By considering the converse problem, we propose new representation methods for both protein sequences and protein pairs. The results show that our method significantly improves the accuracy of protein-protein interaction predictions.
doi:10.1186/1471-2105-12-409
PMCID: PMC3215753  PMID: 22024143
2.  Support vector machine prediction of enzyme function with conjoint triad feature and hierarchical context 
BMC Systems Biology  2011;5(Suppl 1):S6.
Background
Enzymes are known as the largest class of proteins and their functions are usually annotated by the Enzyme Commission (EC), which uses a hierarchy structure, i.e., four numbers separated by periods, to classify the function of enzymes. Automatically categorizing enzyme into the EC hierarchy is crucial to understand its specific molecular mechanism.
Results
In this paper, we introduce two key improvements in predicting enzyme function within the machine learning framework. One is to introduce the efficient sequence encoding methods for representing given proteins. The second one is to develop a structure-based prediction method with low computational complexity. In particular, we propose to use the conjoint triad feature (CTF) to represent the given protein sequences by considering not only the composition of amino acids but also the neighbor relationships in the sequence. Then we develop a support vector machine (SVM)-based method, named as SVMHL (SVM for hierarchy labels), to output enzyme function by fully considering the hierarchical structure of EC. The experimental results show that our SVMHL with the CTF outperforms SVMHL with the amino acid composition (AAC) feature both in predictive accuracy and Matthew’s correlation coefficient (MCC). In addition, SVMHL with the CTF obtains the accuracy and MCC ranging from 81% to 98% and 0.82 to 0.98 when predicting the first three EC digits on a low-homologous enzyme dataset. We further demonstrate that our method outperforms the methods which do not take account of hierarchical relationship among enzyme categories and alternative methods which incorporate prior knowledge about inter-class relationships.
Conclusions
Our structure-based prediction model, SVMHL with the CTF, reduces the computational complexity and outperforms the alternative approaches in enzyme function prediction. Therefore our new method will be a useful tool for enzyme function prediction community.
doi:10.1186/1752-0509-5-S1-S6
PMCID: PMC3121122  PMID: 21689481
3.  Collagen Cross-linking Increases Its Biodegradation Resistance in Wet Dentin Bonding 
Purpose
The biodegradation of exposed dentin collagen within the adhesive/dentin (a/d) interface is one of main reasons leading to composite restoration failures and seriously affects the durability of dental restorations. In the present study, the objective was to investigate whether the inclusion of the crosslinking reagent (glutaraldehyde, GA) in the adhesive would increase collagen biodegradation resistance within the a/d interface.
Materials and methods
The model adhesive consisted of ~60 % monomers (HEMA/BisGMA, 45/55 wt/wt) and ~ 40 % ethanol as a solvent. 5% GA was added to the above formulation. After the dentin surfaces were etched for 15 s with 35% phosphoric acid, rinsed with water and blotted dry, adhesives both with and without GA were applied and polymerized by visible light for 20 s. These a/d specimens were immersed in the biodegradation solution (prepared by adding 160 mg collagenase in 1 liter of TESCA buffer solution) for up to 30 days after proceeding with the sectioning/fracture to expose the a/d interfaces. The specimens were analyzed using SEM and micro-Raman.
Results
SEM results indicated that for the adhesive without GA, there were many voids and was a loss of collagen fibrils in the a/d interface after being challenged by the biodegradation solution. The Raman spectra collected from the interface showed that the amide I of collagen at 1667 cm−1 obviously decreased, indicating a removal of collagen fibrils during the degradation process. For the adhesive containing GA, the collagen fibrils within the interface did not degrade at all, which was also confirmed by the Raman results.
Conclusion
The results corroborate the previous findings that by using the current adhesive system and wet bonding, the collagen fibrils in the a/d interface are largely unprotected and easily undergo biodegradation. Directly including crosslinking agents in the adhesive could protect collagen fibrils from degradation in situ within the a/d interface.
doi:10.3290/j.jad.a21494
PMCID: PMC3980574  PMID: 21594232
Dentin; Bonding; Collagen Cross-linking; Raman
4.  Effect of reactive and un-reactive substrates on photopolymerization of self-etching adhesives with different aggressiveness 
Dental materials journal  2013;32(3):484-491.
The study investigated the influence of reactive (enamel) and un-reactive (glass) substrates on photo-polymerization of self-etching adhesives. Two commercial adhesives Adper Prompt L-Pop (APLP, pH~0.8) and Adper Easy Bond (AEB, pH~2.5) were applied onto prepared enamel and glass substrates using the same protocol. Micro-Raman spectroscopy was employed to determine the degree of conversion (DC) and the involved mechanism. DC of APLP was dramatically enhanced from ~9.4% to ~82.0% as when changing from glass to enamel, while DC of AEB on both substrates showed no difference. The DC distributions along the adhesive layers of the APLP and AEB on enamel showed descending and constant trends, respectively. Spectral analysis disclosed that the difference in chemical reaction of the two adhesives with enamel might be associated with the results. The chemical reaction of the adhesives with enamel significantly improved the DC of the strong APLP, but not that of the mild AEB.
PMCID: PMC3980577  PMID: 23719012
self-etching; enamel; micro-Raman spectroscopy; photo-polymerization; degree of conversion
5.  Proanthocyanidins Alter Adhesive/Dentin Bonding Strengths when Included in a Bonding System 
American journal of dentistry  2012;25(5):276-280.
Purpose
To determine the effect of proanthocyanidins (PA) incorporation into a bonding system on dentin/adhesive bond stability following long-term storage in buffer and collagenase.
Methods
Human dentin surfaces were bonded with no PA (0-PA), PA incorporated in the primer (PA-primer), or PA incorporated in the adhesive (PA-adhesive), and composite build-ups were created. Following sectioning into beams, bonded specimens were stored in buffer or collagenase for 0, 1, 4, 26, or 52 weeks before being tested for microtensile bond strength (μTBS). ANOVA and Tukey’s HSD post-hoc were performed. Fractured surfaces were viewed with scanning electron microscopy (SEM).
Results
Both bonding system and storage time but not storage medium significantly affected μTBS. Initially, 0-PA and PA-primer were superior to PA-adhesive, and after 1 week both PA groups were inferior to 0-PA. However, after 4 weeks PA-adhesive had significantly increased and 0-PA significantly decreased such that all three groups were equal. Thereafter, both PA-primer/adhesive groups trended with an increase (the 0-PA group remaing consistent) such that at 52 weeks PA-primer samples were significantly stronger (p < 0.001) or nearly so (p = 0.08) when compared to 0-PA samples. SEM revealed that initial fractures tended to occur at the middle/bottom of the hybrid layer for 0-PA and PA-primer groups but at the top of the hybrid layer/in the adhesive for PA-adhesive. After 4 weeks, however, all groups fractured similarly at the middle/bottom of the hybrid layer.
Clinical Significance
PA incorporation into a bonding system significantly alters interfacial bonding strengths, and its incorporation may stabilize the interface and protect degradation over time under clinical conditions.
PMCID: PMC3980579  PMID: 23243975
6.  Cross-linked demineralized dentin maintains its mechanical stability when challenged by bacterial collagenase 
The molecular structure, weight loss and mechanical properties of demineralized dentin of non-crosslinked/crosslinked by glutaraldehyde (GA) were investigated when being challenged by bacterial collagenase solution over time in the present study. Raman spectra proved that cross-linking occurred in demineralized dentin matrices after being treated with GA. Meanwhile, the weight of the cross-linked demineralized dentin matrices didn’t change after being challenged by bacterial collagenase solution up to one week. However, the weight of non-crosslinked dentin collagen fell by almost 45% after degradation for 5 hr, and up to 100% after 19 hr. The tensile strength of demineralized dentin matrices didn’t show a significant change after being crosslinked, while the stiffness of demineralized dentin matrices showed more improvement than that of non-crosslinked collagen. The toughness of demineralized dentin matrices decreased slightly after being crosslinked. Importantly, neither the tensile strength of GA-crosslinked demineralized dentin nor its stiffness changed over time in either control buffer or collagenase solution compared to that of noncrosslinked controls. These results suggested that improving the degree of cross-linking in dentin collagen could be one method to inhibit its biodegradation and further to increase the durability of dental restorations.
doi:10.1002/jbm.b.31759
PMCID: PMC3980581  PMID: 21210503
dentin; collagen crosslinking; biodegradation; mechanical properties
7.  Enhancement in dentin collagen’s biological stability after proanthocyanidins treatment in clinically relevant time periods 
Objective
To investigate whether proanthocyanidins (PA) is capable of improving dentin collagen’s biological stability through cross-linking within time periods that are clinically relevant.
Materials and methods
Demineralized dentin collagen slabs were treated with 3.75 wt% PA solution for 10 s, 1 min, 30 min, 60 min, 120 min, 360 min, and 720 min, respectively. The resultant cross-linked collagen samples were subject to digestion with 0.1% collagenase at 37 °C for 2 h, 6 h, 12 h, 24 h, 36 h, and 48 h. The percentage of weight loss after digestion was calculated to evaluate PA-treated collagen’s resistance toward enzymatic degradation. Fourier-Transformed Infrared (FTIR) spectroscopy was used to probe evidences of PA-collagen interactions after various periods of PA treatment.
Results
The collagenase digestion assay suggests that PA treatment as short as 10 s can enhance collagen’s resistance toward enzymatic challenge. The FTIR spectroscopy further verifies that PA is indeed incorporated into collagen regardless of treatment time, possibly via a mechanism involving the chemical interactions between PA and collagen.
Significance
This study confirmed that PA can effectively cross-link collagen and improve its biological stability in time periods as short as 10 s. The use of PA as a priming agent is therefore clinically feasible and is a promising approach to improving the durability of current dentin bonding systems.
doi:10.1016/j.dental.2013.01.013
PMCID: PMC3640802  PMID: 23434233
Dentin collagen; Cross-linking; Proanthocyanidins; Biodegradation; FTIR
8.  Symbiotic Adaptation Drives Genome Streamlining of the Cyanobacterial Sponge Symbiont “Candidatus Synechococcus spongiarum” 
mBio  2014;5(2):e00079-14.
ABSTRACT
“Candidatus Synechococcus spongiarum” is a cyanobacterial symbiont widely distributed in sponges, but its functions at the genome level remain unknown. Here, we obtained the draft genome (1.66 Mbp, 90% estimated genome recovery) of “Ca. Synechococcus spongiarum” strain SH4 inhabiting the Red Sea sponge Carteriospongia foliascens. Phylogenomic analysis revealed a high dissimilarity between SH4 and free-living cyanobacterial strains. Essential functions, such as photosynthesis, the citric acid cycle, and DNA replication, were detected in SH4. Eukaryoticlike domains that play important roles in sponge-symbiont interactions were identified exclusively in the symbiont. However, SH4 could not biosynthesize methionine and polyamines and had lost partial genes encoding low-molecular-weight peptides of the photosynthesis complex, antioxidant enzymes, DNA repair enzymes, and proteins involved in resistance to environmental toxins and in biosynthesis of capsular and extracellular polysaccharides. These genetic modifications imply that “Ca. Synechococcus spongiarum” SH4 represents a low-light-adapted cyanobacterial symbiont and has undergone genome streamlining to adapt to the sponge’s mild intercellular environment.
IMPORTANCE
Although the diversity of sponge-associated microbes has been widely studied, genome-level research on sponge symbionts and their symbiotic mechanisms is rare because they are unculturable. “Candidatus Synechococcus spongiarum” is a widely distributed uncultivated cyanobacterial sponge symbiont. The genome of this symbiont will help to characterize its evolutionary relationship and functional dissimilarity to closely related free-living cyanobacterial strains. Knowledge of its adaptive mechanism to the sponge host also depends on the genome-level research. The data presented here provided an alternative strategy to obtain the draft genome of “Ca. Synechococcus spongiarum” strain SH4 and provide insight into its evolutionary and functional features.
doi:10.1128/mBio.00079-14
PMCID: PMC3977351  PMID: 24692632
9.  Estimating population divergence time and phylogeny from single-nucleotide polymorphisms data with outgroup ascertainment bias 
Molecular ecology  2011;21(4):974-986.
The inference of population divergence times and branching patterns is of fundamental importance in many population genetic analyses. Many methods have been developed for estimating population divergence times, and recently, there has been particular attention towards genome-wide single-nucleotide polymorphisms (SNP) data. However, most SNP data have been affected by an ascertainment bias caused by the SNP selection and discovery protocols. Here, we present a modification of an existing maximum likelihood method that will allow approximately unbiased inferences when ascertainment is based on a set of outgroup populations. We also present a method for estimating trees from the asymmetric dissimilarity measures arising from pairwise divergence time estimation in population genetics. We evaluate the methods by simulations and by applying them to a large SNP data set of seven East Asian populations.
doi:10.1111/j.1365-294X.2011.05413.x
PMCID: PMC3951478  PMID: 22211450
ascertainment bias; maximum likelihood; phylogeny; population divergence
10.  Ancient human genome sequence of an extinct Palaeo-Eskimo 
Nature  2010;463(7282):757-762.
We report here the genome sequence of an ancient human. Obtained from ∼4,000-year-old permafrost-preserved hair, the genome represents a male individual from the first known culture to settle in Greenland. Sequenced to an average depth of 20×, we recover 79% of the diploid genome, an amount close to the practical limit of current sequencing technologies. We identify 353,151 high-confidence single-nucleotide polymorphisms (SNPs), of which 6.8% have not been reported previously. We estimate raw read contamination to be no higher than 0.8%. We use functional SNP assessment to assign possible phenotypic characteristics of the individual that belonged to a culture whose location has yielded only trace human remains. We compare the high-confidence SNPs to those of contemporary populations to find the populations most closely related to the individual. This provides evidence for a migration from Siberia into the New World some 5,500 years ago, independent of that giving rise to the modern Native Americans and Inuit.
doi:10.1038/nature08835
PMCID: PMC3951495  PMID: 20148029
11.  Calycosin Suppresses Breast Cancer Cell Growth via ERβ-Dependent Regulation of IGF-1R, p38 MAPK and PI3K/Akt Pathways 
PLoS ONE  2014;9(3):e91245.
We previously reported that calycosin, a natural phytoestrogen structurally similar to estrogen, successfully triggered apoptosis of estrogen receptor (ER)-positive breast cancer cell line, MCF-7. To better understand the antitumor activities of calycosin against breast cancer, besides MCF-7 cells, another ER-positive cell line T-47D was analyzed here, with ER-negative cell lines (MDA-231, MDA-435) as control. Notably, calycosin led to inhibited cell proliferation and apoptosis only in ER-positive cells, particularly in MCF-7 cells, whereas no such effect was observed in ER-negative cells. Then we investigated whether regulation of ERβ, a subtype of ER, contributed to calycosin-induced apoptosis in breast cancer cells. The results showed that incubation of calycosin resulted in enhanced expression ERβ in MCF-7 and T-47D cells, rather than MDA-231 and MDA-435 cells. Moreover, with the upregulation of ERβ, successive changes in downstream signaling pathways were found, including inactivation of insulin-like growth factor 1 receptor (IGF-1R), then stimulation of p38 MAPK and suppression of the serine/threonine kinase (Akt), and finally poly(ADP-ribose) polymerase 1 (PARP-1) cleavage. However, the other two members of the mitogen-activated protein kinase (MAPK) family, extracellular signal-regulated kinase (ERK) 1/2 and c-Jun N-terminal kinase (JNK), were not consequently regulated by downregulated IGF-1R, indicating ERK 1/2 and JNK pathways were not necessary to allow proliferation inhibition by calycosin. Taken together, our results indicate that calycosin tends to inhibit growth and induce apoptosis in ER-positive breast cancer cells, which is mediated by ERβ-induced inhibition of IGF-1R, along with the selective regulation of MAPK and phosphatidylinositol 3-kinase (PI3K)/Akt pathways.
doi:10.1371/journal.pone.0091245
PMCID: PMC3949755  PMID: 24618835
12.  Isolation and Identification of Quercetin Degrading Bacteria from Human Fecal Microbes 
PLoS ONE  2014;9(3):e90531.
Quercetin has a wide range of biological properties. The gut microflora can often modulate its biological activity and their potential health effects. There still is a lack of information about gut bacteria involving in this process. The strains of gut microbes from human feces that can transform quercetin were isolated and identified by in vitro fermentation. The results showed that Escherichia coli, Stretococcus lutetiensis, Lactobacillus acidophilus, Weissella confusa, Enterococcus gilvus, Clostridium perfringens and Bacteroides fragilis have the various ability of degrading quercetin. Among them, C. perfringens and B. fragilis were discovered to have the strongest ability of degrading quercetin. Additionally, quercetin can't inhibit the growth of C. perfringens. In conclusion, many species of gut microbiota can degrade quercetin, but their ability are different.
doi:10.1371/journal.pone.0090531
PMCID: PMC3942438  PMID: 24594786
13.  An atypical winter outbreak of hand, foot, and mouth disease associated with human enterovirus 71, 2010 
BMC Infectious Diseases  2014;14:123.
Background
To analyze the epidemiological characteristics and pathogenic molecular characteristics of an hand, foot, and mouth disease (HFMD) outbreak caused by enterovirus 71 in Linyi City, Shandong Province, China during November 30 to December 28, 2010.
Methods
One hundred and seventy three stool specimens and 40 throat samples were collected from 173 hospitalized cases. Epidemiologic and clinical investigations, laboratory testing, and genetic analyses were performed to identify the causal pathogen of the outbreak.
Results
Among the 173 cases reported in December 2010, the male–female ratio was 1.88: 1; 23 cases (13.3%) were severe. The majority of patients were children aged < 5 years (95.4%). Some patients developed respiratory symptoms including runny nose (38.2%), cough (20.2%), and sore throat (14.5%). One hundred and thirty eight EV71 positive cases were identified based on real time reverse-transcription PCR detection and 107 isolates were sequenced with the VP1 region. Phylogenetic analysis of full-length VP1 sequences of 107 Linyi EV71 isolates showed that they belonged to the C4a cluster of the C4 subgenotype and were divided into 3 lineages (Lineage I, II and III). The two amino acid substitutions (Gly and Gln for Glu) at position 145 within the VP1 region are more likely to appear in EV71 isolates from severe cases (52.2%) than those recovered from mild cases (8.3%).
Conclusion
This outbreak of HMFD was caused by EV71 in an atypical winter. EV71 strains associated with this outbreak represented three separate chains of transmission. Substitution at amino acid position 145 of the VP1 region of EV71 might be an important virulence marker for severe cases. These findings suggest that continued surveillance for EV71 variants has the potential to greatly impact HFMD prevention and control.
doi:10.1186/1471-2334-14-123
PMCID: PMC3974002  PMID: 24589030
Hand; Foot; and mouth disease; HFMD; Enterovirus 71; Phylogenetic analysis; Subgenotype C4
14.  Optimal Eukaryotic 18S and Universal 16S/18S Ribosomal RNA Primers and Their Application in a Study of Symbiosis 
PLoS ONE  2014;9(3):e90053.
Eukaryotic 18S ribosomal RNA (rRNA) gene primers that feature a wide coverage are critical in detecting the composition of eukaryotic microscopic organisms in ecosystems. Here, we predicted 18S rRNA primers based on consecutive conserved sites and evaluated their coverage efficiency and scope of application to different eukaryotic groups. After evaluation, eight of them were considered as qualified 18S primers based on coverage rate. Next, we examined common conserved regions in prokaryotic 16S and eukaryotic 18S rRNA sequences to design 16S/18S universal primers. Three 16S/18S candidate primers, U515, U1390 and U1492, were then considered to be suitable for simultaneous amplification of the rRNA sequences in three domains. Eukaryotic 18S and prokaryotic 16S rRNA genes in a sponge were amplified simultaneously using universal primers U515 and U1390, and the subsequent sorting of pyrosequenced reads revealed some distinctive communities in different parts of the sample. The real difference in biodiversity between prokaryotic and eukaryotic symbionts could be discerned as the dissimilarity between OTUs was increased from 0.005 to 0.1. A network of the communities in external and internal parts of the sponge illustrated the co-variation of some unique microbes in certain parts of the sponge, suggesting that the universal primers are useful in simultaneous detection of prokaryotic and eukaryotic microbial communities.
doi:10.1371/journal.pone.0090053
PMCID: PMC3940700  PMID: 24594623
15.  Molecular Evolution of the Vertebrate FK506 Binding Protein 25 
FK506 binding proteins (FKBPs) belong to immunophilins with peptidyl-prolyl isomerases (PPIases) activity. FKBP25 (also known as FKBP3) is one of the nuclear DNA-binding proteins in the FKBPs family, which plays an important role in regulating transcription and chromatin structure. The calculation of nonsynonymous and synonymous substitution rates suggested that FKBP25 undergoes purifying selection throughout the whole vertebrate evolution. Moreover, the result of site-specific tests showed that no sites were detected under positive selection. Only one PPIase domain was detected by searching FKBP25 sequences at Pfam and SMART domain databases. Mammalian FKBP25 possess exon-intron conservation, although conservation in the whole vertebrate lineage is incomplete. The result of this study suggests that the purifying selection triggers FKBP25 evolutionary history, which allows us to discover the complete role of the PPIase domain in the interaction between FKBP25 and nuclear proteins. Moreover, intron alterations during FKBP25 evolution that regulate gene splicing may be involved in the purifying selection.
doi:10.1155/2014/402603
PMCID: PMC3958658  PMID: 24724077
16.  Effect of application mode on interfacial morphology and chemistry between dentin and self-etch adhesives 
Journal of dentistry  2012;41(3):231-240.
Objective
To investigate the influence of application mode on the interfacial morphology and chemistry between dentin and self-etch adhesives with different aggressiveness.
Methods
The occlusal one-third of the crown was removed from un-erupted human third molars, followed by abrading with 600 grit SiC under water. Rectangular dentin slabs were prepared by sectioning the tooth specimens perpendicular to the abraded surfaces. The obtained dentin slabs were treated with one of the two one-step self-etch adhesives: Adper Easy Bond (AEB, PH~2.5) and Adper Prompt L-Pop (APLP, PH~0.8) with (15s, active application) or without (15s, inactive application) agitation. The dentin slabs were fractured and the exposed adhesive/dentin (A/D) interfaces were examined with micro-Raman spectroscopy and scanning electron microscopy (SEM).
Results
The interfacial morphology, degree of dentin demineralization (DD) and degree of conversion (DC) of the strong self-etch adhesive APLP showed more significant dependence on the application mode than the mild AEB. APLP exhibited inferior bonding at the A/D interface if applied without agitation, evidenced by debonding from the dentin substrate. The DDs and DCs of the APLP with agitation were higher than those of without agitation in the interface, in contrast to the comparable DD and DC values of two AEB specimen groups with different application modes. Raman spectral analysis revealed the important role of chemical interaction between acid monomers of self-etch adhesives and dentin in the above observations.
Conclusion
The chemical interaction with dentin is especially important for improving the DC of the strong self-etching adhesive at the A/D interface. Agitation could benefit polymerization efficacy of the strong self-etch adhesive through enhancing the chemical interaction with tooth substrate.
doi:10.1016/j.jdent.2012.11.006
PMCID: PMC3593798  PMID: 23153573
self-etch adhesives; degree of conversion; micro-Raman; agitation; adhesive/dentin interface
17.  Improved Synthesis of Capuramycin and Its Analogs 
Capuramycin and its congeners have been considered important lead molecules for the development of a new drug for multidrug-resistant (MDR) Mycobacterium tuberculosis infections. Extensive structure-activity relationship studies of capuramycin to improve the efficacy have been limited due to difficulty in selective chemical modifications of the desired position(s) of the natural product with biologically interesting functional groups. We have developed efficient syntheses of capuramycin and its analogs using new protecting groups, which are derived from the chiral (chloro-4-methoxyphenyl) (chlorophenyl) methanols, for the uridine ureido nitrogen and primary alcohol. The chiral non-racemic (2,6-dichloro-4-methoxyphenyl) (2,4-dichlorophenyl) methanol derivative is a useful reagent to resolve rac-3-amino-1,3-dihydro-5-phenyl-2H-1,4-benzodiazepin-2-one, whose (S)-configuration isomer plays a significant role in improving the mycobactericidal activity of capuramycin.
doi:10.1002/chem.201302389
PMCID: PMC3929971  PMID: 24014478
18.  DanQi Pill protects against heart failure through the arachidonic acid metabolism pathway by attenuating different cyclooxygenases and leukotrienes B4 
Background
Chinese herbal formulae are composed of complex components and produce comprehensive pharmacological effects. Unlike chemical drugs that have only one clear single target, the components of Chinese herbal formulae have multiple channels and targets. How to discover the pharmacological targets of Chinese herbal formulae and their underlying molecular mechanism are still under investigation.
Methods
DanQi pill (DQP), which is one of the widely prescribed traditional Chinese medicines, is applied as an example drug. In this study, we used the drug target prediction model (DrugCIPHER-CS) to examine the underlying molecular mechanism of DQP, followed by experimental validation.
Results
A novel therapeutic effect pattern of DQP was identified. After determining the compounds in DQP, we used DrugCIPHER-CS to predict their potential targets. These potential targets were significantly enriched in well-known cardiovascular disease-related pathways. For example, the biological processes of neuroactive ligand–receptor interaction, calcium-signaling pathway, and aminoacyl–tRNA biosynthesis were involved. A new and significant pathway, arachidonic acid (AA) metabolism, was also identified in this study. This predicted pathway alteration was validated with an animal model of heart failure (HF). Results show that DQP had effect both on thromboxane B2 (TXB2) and Prostaglandin I2 (PGI2) in different patterns. It can down-regulate the TXB2 and up-regulate the PGI2 in diverse way. Remarkably, it also had effect on cyclooxygenase (COX)-1 and COX2 by suppressing their levels, which may be the critical and novel mechanism of cardiacprotective efficacy for DQP. Furthermore, leukotrienes B4 (LTB4) receptor, another key molecule of AA metabolism which finally mediated gastrotoxic leukotrienes, was also reduced by DQP.
Conclusions
The combination of drug target prediction and experimental validation provides new insights into the complicated mechanism of DQP.
doi:10.1186/1472-6882-14-67
PMCID: PMC3933388  PMID: 24555740
19.  Chondrocyte-Specific Inhibition of β-Catenin Signaling Leads to Dysplasia of the Caudal Vertebrae in Mice 
Spine  2013;38(24):2079-2084.
Study Design
To inhibit β-catenin specifically signaling in chondrocytes Col2-ICAT transgenic mice were generated. Anomalies in caudal vertebrae were detected during embryonic and postnatal stages of Col2-ICAT transgenic mice.
Objective
To determine the role of canonical β-catenin signaling in caudal vertebral development.
Summary of Background Data
β-catenin signaling plays a critical role in skeletal development. Col2-ICAT transgenic mice were generated to selectively block β-catenin signaling by overexpression of the ICAT gene in chondrocytes.
Methods
Tails of E16.5 transgenic embryos and adult Col2-ICAT transgenic mice and their wild-type littermates were collected and analyzed. Skeletal preparation, 3-dimensional micro-computed tomographic and histological analyses were performed to evaluate changes in the structure of caudal vertebrae. Bromodeoxyuridine labeling was performed to evaluate changes in chondrocyte proliferation in caudal vertebrae.
Results
Skeletal preparation and 3-dimensional micro-computed tomographic analyses revealed bone deformation and angulated deformities in tail tissue in Col2-ICAT transgenic mice. Histological studies revealed abnormal bone development and dysplastic caudal vertebrae in Col2-ICAT transgenic mice. Inhibition of β-catenin signaling in cartilage resulted in vertebral dysplasia leading to aberrant resegmenting process. Thus, 2 poorly developed sclerotomes failed to fuse to form a complete vertebrae. BrdU labeling revealed a decreased chondrocyte proliferation in both cartilageous templates of transgenic embryos and the growth plate of adult Col2-ICAT transgenic mice.
Conclusion
Wnt/β-catenin signaling plays an important role in vertebral development. Inhibition of β-catenin signaling in chondrocytes results in caudal vertebra deformity in mice, which may occur as early as in the stage of sclerotome formation.
doi:10.1097/01.brs.0000435024.57940.8d
PMCID: PMC3928445  PMID: 24026150
β-catenin; ICAT; chondrocyte; caudal vertebral dysplasia
20.  Single molecule FRET reveals pore size and opening mechanism of a mechano-sensitive ion channel 
eLife  2014;3:e01834.
The mechanosensitive channel of large conductance, which serves as a model system for mechanosensitive channels, has previously been crystallized in the closed form, but not in the open form. Ensemble measurements and electrophysiological sieving experiments show that the open-diameter of the channel pore is >25 Å, but the exact size and whether the conformational change follows a helix-tilt or barrel-stave model are unclear. Here we report measurements of the distance changes on liposome-reconstituted MscL transmembrane α-helices, using a ‘virtual sorting’ single-molecule fluorescence energy transfer. We observed directly that the channel opens via the helix-tilt model and the open pore reaches 2.8 nm in diameter. In addition, based on the measurements, we developed a molecular dynamics model of the channel structure in the open state which confirms our direct observations.
DOI: http://dx.doi.org/10.7554/eLife.01834.001
eLife digest
Bacterial cells are full of fluid, and they will burst if they are not able to respond to a build up of pressure. Fortunately, the membrane of a bacterial cell contains channels that can detect the increased mechanical stress on the cell membrane and then open to relieve the pressure.
In many bacterial cells, the last defence against the cell exploding is called the mechanosensitive channel of large conductance (MscL). This is made of five proteins, each of which consists of TM1 and TM2 helixes, which are responsible for opening and closing the channel. Two models have been proposed to explain how the channels are opened. In the barrel-stave model, the TM1 helix moves, while the TM2 helix remains stationary. This results in an open pore that is lined with TM1 and TM2 helixes in the same way that wooden staves line a barrel. In the helix-tilt model, both helixes tilt towards the membrane to open the channel.
Wang et al. have now used a technique called single-molecule fluorescence resonance energy transfer (FRET) to explore the structure of the open channel in E. coli in order to determine which model is correct. In this technique an individual channel is labeled with two different fluorescent molecules. By illuminating the channel with light of a wavelength that excites the first fluorescent molecule, and measuring the strength of the fluorescence from the second molecule, it is possible to work out the distance between the two molecules. From this, the structure of the channel and how it opens and closes can be explored.
Previous attempts to measure the diameters of open channels using fluorescence techniques have suffered from issues caused by the use of large numbers of fluorescent molecules. This has made it necessary to use computational modeling to extract the required data. By looking at a series of individual proteins, Wang et al. overcame these problems and found that the diameter of the fully open pore is 2.8 nm. The result provides strong support for the helix-tilt model.
DOI: http://dx.doi.org/10.7554/eLife.01834.002
doi:10.7554/eLife.01834
PMCID: PMC3925968  PMID: 24550255
barrel-stave model; helix-tilt model; MscL; E. coli
21.  Seven Functional Polymorphisms in the CETP Gene and Myocardial Infarction Risk: A Meta-Analysis and Meta-Regression 
PLoS ONE  2014;9(2):e88118.
Objective
This meta-analysis aims to evaluate the relationships between seven functional polymorphisms in the CETP gene and myocardial infarction (MI) risk.
Method
The PubMed, CISCOM, CINAHL, Web of Science, Google Scholar, EBSCO, Cochrane Library, and CBM databases were searched for relevant articles published before March 1st, 2013 without any language restrictions. Meta-analysis was conducted using the STATA 12.0 software.
Results
Nine case-control studies with a total 8,623 MI cases and 8,564 healthy subjects met the inclusion criteria. The results of our meta-analysis suggested that CETP rs708272 (C>T) polymorphism might be correlated with an increased risk of MI, especially among Caucasians. Furthermore, we observed that CETP rs1800775 (C>A) polymorphism might increase the risk of MI. Nevertheless, no similar findings were found for CETP rs5882 (A>G), rs2303790 (A>G), rs1800776 (C>A), rs12149545 (G>A), and rs4783961 (G>A) polymorphisms.
Conclusion
The current meta-analysis suggests that CETP rs708272 (C>T) and rs1800775 (C>A) polymorphisms may contribute to MI susceptibility, especially among Caucasians. Thus, CETP rs708272 and rs1800775 polymorphisms may be promising and potential biomarkers for early diagnosis of MI.
doi:10.1371/journal.pone.0088118
PMCID: PMC3922770  PMID: 24533069
22.  A Generalized Topological Entropy for Analyzing the Complexity of DNA Sequences 
PLoS ONE  2014;9(2):e88519.
Topological entropy is one of the most difficult entropies to be used to analyze the DNA sequences, due to the finite sample and high-dimensionality problems. In order to overcome these problems, a generalized topological entropy is introduced. The relationship between the topological entropy and the generalized topological entropy is compared, which shows the topological entropy is a special case of the generalized entropy. As an application the generalized topological entropy in introns, exons and promoter regions was computed, respectively. The results indicate that the entropy of introns is higher than that of exons, and the entropy of the exons is higher than that of the promoter regions for each chromosome, which suggest that DNA sequence of the promoter regions is more regular than the exons and introns.
doi:10.1371/journal.pone.0088519
PMCID: PMC3922877  PMID: 24533097
23.  Pyrrole-Aminoimidazole Alkaloid ‘Metabiosynthesis’ with Marine Sponges Agelas conifera and Stylissa caribica 
doi:10.1002/anie.201108119
PMCID: PMC3917718  PMID: 22473581
pyrrole-aminoimidazole alkaloids; metabiosynthesis; single-electron transfer; marine sponges; natural products
24.  Diversity and distribution of eukaryotic microbes in and around a brine pool adjacent to the Thuwal cold seeps in the Red Sea 
A hypoxic/suboxic brine pool at a depth of about 850 m was discovered near the Thuwal cold seeps in the Red Sea. Filled with high concentrations of hydrogen sulfide and ammonia, such a brine pool might limit the spread of eukaryotic organisms. Here, we compared the communities of the eukaryotic microbes in a microbial mat, sediments and water samples distributed in 7 sites within and adjacent to the brine pool. Taxonomic classification of the pyrosequenced 18S rRNA amplicon reads showed that fungi highly similar to the species identified along the Arabic coast were almost ubiquitous in the water and sediment samples, supporting their wide distribution in various environments. The microbial mat displayed the highest species diversity and contained grazers and a considerable percentage of unclassified species. Phylogeny-based methods revealed novel lineages representing a majority of the reads from the interface between the sea water and brine pool. Phylogenetic relationships with more reference sequences suggest that the lineages were affiliated with novel Alveolata and Euglenozoa inhabiting the interface where chemosynthetic prokaryotes are highly proliferative due to the strong chemocline and halocline. The brine sediments harbored abundant species highly similar to invertebrate gregarine parasites identified in different oxygen-depleted sediments. Therefore, the present findings support the uniqueness of some microbial eukaryotic groups in this cold seep brine system.
doi:10.3389/fmicb.2014.00037
PMCID: PMC3922051  PMID: 24575081
Eukaryotic microbes; 18S rRNA; cold seep; brine pool; classification
25.  Dewetting Properties of Metallic Liquid Film on Nanopillared Graphene 
Scientific Reports  2014;4:3938.
In this work, we report simulation evidence that the graphene surface decorated by carbon nanotube pillars shows strong dewettability, which can give it great advantages in dewetting and detaching metallic nanodroplets on the surfaces. Molecular dynamics (MD) simulations show that the ultrathin liquid film first contracts then detaches from the graphene on a time scale of several nanoseconds, as a result of the inertial effect. The detaching velocity is in the order of 10 m/s for the droplet with radii smaller than 50 nm. Moreover, the contracting and detaching behaviors of the liquid film can be effectively controlled by tuning the geometric parameters of the liquid film or pillar. In addition, the temperature effects on the dewetting and detaching of the metallic liquid film are also discussed. Our results show that one can exploit and effectively control the dewetting properties of metallic nanodroplets by decorating the surfaces with nanotube pillars.
doi:10.1038/srep03938
PMCID: PMC3909898  PMID: 24487279

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