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2.  Genetic Interactions Explain Variance in Cingulate Amyloid Burden: An AV-45 PET Genome-Wide Association and Interaction Study in the ADNI Cohort 
BioMed Research International  2015;2015:647389.
Alzheimer's disease (AD) is the most common neurodegenerative disorder. Using discrete disease status as the phenotype and computing statistics at the single marker level may not be able to address the underlying biological interactions that contribute to disease mechanism and may contribute to the issue of “missing heritability.” We performed a genome-wide association study (GWAS) and a genome-wide interaction study (GWIS) of an amyloid imaging phenotype, using the data from Alzheimer's Disease Neuroimaging Initiative. We investigated the genetic main effects and interaction effects on cingulate amyloid-beta (Aβ) load in an effort to better understand the genetic etiology of Aβ deposition that is a widely studied AD biomarker. PLINK was used in the single marker GWAS, and INTERSNP was used to perform the two-marker GWIS, focusing only on SNPs with p ≤ 0.01 for the GWAS analysis. Age, sex, and diagnosis were used as covariates in both analyses. Corrected p values using the Bonferroni method were reported. The GWAS analysis revealed significant hits within or proximal to APOE, APOC1, and TOMM40 genes, which were previously implicated in AD. The GWIS analysis yielded 8 novel SNP-SNP interaction findings that warrant replication and further investigation.
PMCID: PMC4573220  PMID: 26421299
3.  Establishment of a hepatic cirrhosis and portal hypertension model by hepatic arterial perfusion with 80% alcohol 
AIM: To determine the feasibility and safety of establishing a porcine hepatic cirrhosis and portal hypertension model by hepatic arterial perfusion with 80% alcohol.
METHODS: Twenty-one healthy Guizhou miniature pigs were randomly divided into three experimental groups and three control groups. The pigs in the three experimental groups were subjected to hepatic arterial perfusion with 7, 12 and 17 mL of 80% alcohol, respectively, while those in the three control groups underwent hepatic arterial perfusion with 7, 12 and 17 mL of saline, respectively. Hepatic arteriography and direct portal phlebography were performed on all animals before and after perfusion, and the portal venous pressure and diameter were measured before perfusion, immediately after perfusion, and at 2, 4 and 6 wk after perfusion. The following procedures were performed at different time points: routine blood sampling, blood biochemistry, blood coagulation and blood ammonia tests before surgery, and at 2, 4 and 6 wk after surgery; hepatic biopsy before surgery, within 6 h after surgery, and at 1, 2, 3, 4 and 5 wk after surgery; abdominal enhanced computed tomography examination before surgery and at 6 wk after surgery; autopsy and multi-point sampling of various liver lobes for histological examination at 6 wk after surgery.
RESULTS: In experimental group 1, different degrees of hepatic fibrosis were observed, and one pig developed hepatic cirrhosis. In experimental group 2, there were cases of hepatic cirrhosis, different degrees of increased portal venous pressure, and intrahepatic portal venous bypass, but neither extrahepatic portal-systemic bypass circulation nor death occurred. In experimental group 3, two animals died and three animals developed hepatic cirrhosis, and different degrees of increased portal venous pressure and intrahepatic portal venous bypass were also observed, but there was no extrahepatic portal-systemic bypass circulation.
CONCLUSION: It is feasible to establish an animal model of hepatic cirrhosis and portal hypertension by hepatic arterial perfusion with 80% alcohol, however, the safety of this model depends on a suitable perfusion dose.
PMCID: PMC4548115  PMID: 26327762
Alcohol; Hepatic arterial perfusion; Hepatic cirrhosis; Portal hypertension; Animal model
4.  The use of clamped drainage to reduce blood loss in total hip arthroplasty 
Drainage is a routine practice used to reduce hematoma and blood loss following total hip arthroplasty. The aim of this study was to assess the effect of clamped drainage on blood loss and wound healing after total hip arthroplasty.
A prospective cohort of 44 patients with hip osteoarthritis or femur head necrosis undergoing total hip arthroplasty was randomized equally into two groups: 6-h postoperative clamped or non-clamped suction tube drainage. Body mass index, gender distribution, preoperative hemoglobin, hip pathology, and affected side were comparable between the two groups. Blood loss, hemoglobin levels, and wound healing complications were recorded and compared between groups.
The drainage blood loss and calculated blood loss volumes were higher for the non-clamped group. About 100 mL more blood loss was noticed in the non-clamped group. There was no significant difference in adverse events or need for transfusion.
The present study showed a statistically significant reduction in postoperative drainage amount between clamped and unclamped drainage groups, but this difference was not large enough to warrant increased blood transfusion requirements in patients with unclamped drainage. Further studies are essential to define the critical period of clamping that is compatible with the dual objectives of reduced blood loss and lack of wound complications from hematoma.
PMCID: PMC4549090  PMID: 26302784
Total hip arthroplasty; Clamped drainage; Blood loss; Wound complications
5.  Intermittent high dose proton pump inhibitor enhances the antitumor effects of chemotherapy in metastatic breast cancer 
Acidity is a hallmark of malignant tumor, representing a very efficient mechanism of chemoresistance. Proton pump inhibitors (PPI) at high dosage have been shown to sensitize chemoresistant human tumor cells and tumors to cytotoxic molecules. The aim of this pilot study was to investigate the efficacy of PPI in improving the clinical outcome of docetaxel + cisplatin regimen in patients with metastatic breast cancer (MBC).
Patients enrolled were randomly assigned to three arms: Arm A, docetaxel 75 mg/m2 followed by cisplatin 75 mg/m2 on d4, repeated every 21 days with a maximum of 6 cycles; Arm B, the same chemotherapy preceded by three days esomeprazole (ESOM) 80 mg p.o. bid, beginning on d1 repeated weekly. Weekly intermittent administration of ESOM (3 days on 4 days off) was maintained up to maximum 66 weeks; Arm C, the same as Arm B with the only difference being dose of ESOM at 100 mg p.o. bid. The primary endpoint was response rate.
Ninety-four patients were randomly assigned and underwent at least one injection of chemotherapy. Response rates for arm A, B and C were 46.9, 71.0, and 64.5 %, respectively. Median TTP for arm A (n = 32), B (n = 31), C (n = 31) were 8.7, 9.4, and 9.7 months, respectively. A significant difference was observed between patients who had taken PPI and who not with ORR (46.9 % vs. 67.7 %, p = 0.049) and median TTP (9.7 months vs. 8.7 months, p = 0.045). Exploratory analysis showed that among 15 patients with triple negative breast cancer (TNBC), this difference was bigger with median TTP of 10.7 and 5.8 months, respectively (p = 0.011). PPI combination showed a marked effect on OS as well, while with a borderline significance (29.9 vs. 19.2 months, p = 0.090). No additional toxicity was observed with PPI.
The results of this pilot clinical trial showed that intermittent high dose PPI enhance the antitumor effects of chemotherapy in MBC patients without evidence of additional toxicity, which requires urgent validation in a multicenter, randomized, phase III trial.
Trial registration identifier: NCT01069081.
Electronic supplementary material
The online version of this article (doi:10.1186/s13046-015-0194-x) contains supplementary material, which is available to authorized users.
PMCID: PMC4546346  PMID: 26297142
Proton pump inhibitor; Metastatic breast cancer; Chemotherapy; Time to progression (TTP); Overall survival (OS)
6.  Response and Adaptation of Escherichia coli to Suppression of the Amber Stop Codon 
Some extant organisms reassign the amber stop codon to a sense codon through evolution, and suppression of the amber codon with engineered tRNAs has been exploited to expand the genetic code for incorporating non-canonical amino acids (ncAAs) in live systems. However, it is unclear how the host cell would respond and adapt to the amber suppression. Here we suppressed the amber codon in Escherichia coli with an orthogonal tRNA/synthetase pair and cultured the cells under such a pressure for about 500 generations. We discovered that E. coli quickly counteracted with transposon insertion to inactivate the orthogonal synthetase. Persistent amber suppression evading transposon inactivation led to global proteomic changes with a marked up-regulation of an uncharacterized protein YdiI, for which we identified an unexpected function of expelling plasmids. These results should be valuable for understanding codon reassignment in code evolution and for improving the efficiency of ncAA incorporation.
PMCID: PMC4156322  PMID: 25044429
expansion of the genetic code; unnatural amino acid; evolution of the genetic code; amber suppression; codon reassignment
7.  Modified Dendrogram of High-dimensional Feature Space for Transfer Function Design 
We introduce a modified dendrogram (MD) (with sub-trees to represent the feature space clusters) and display it in continuous space for multi-dimensional transfer function (TF) design and modification. Such a TF for direct volume rendering often employs a multi-dimensional feature space. In an n-dimensional (nD) feature space, each voxel is described using n attributes and represented by a vector of n values. The MD reveals the hierarchical structure information of the high-dimensional feature space clusters. Using the MD user interface (UI), the user can design and modify the TF in 2D in an intuitive and informative manner instead of designing it directly in multi-dimensional space where it is complicated and harder to understand the relationship of the feature space vectors. In addition, we provide the capability to interactively change the granularity of the MD. The coarse-grained MD shows primarily the global information of the feature space while the fine-grained MD reveals the finer details, and the separation ability of the high-dimensional feature space is completely preserved in the finest granularity. With the so called multi-grained method, the user can efficiently create a TF using the coarse-grained MD, then fine tune it with the finer-grained MDs to improve the quality of the volume rendering. Furthermore, we propose a fast interactive hierarchical clustering (FIHC) algorithm for accelerating the MD computation and supporting the interactive multi-grained TF design. In the FIHC, the finest-grained MD is established by linking the feature space vectors, then the feature space vectors being the leaves of this tree are clustered using a hierarchical leaf clustering (HLC) algorithm forming a leaf vector hierarchical tree (LVHT). The granularity of the MD can be changed by setting the precision of the LVHT. Our method is independent on the type of the attributes and supports arbitrary-dimension feature space.
PMCID: PMC4536829  PMID: 26279612
Volume Rendering; High-Dimensional Data; Dimensionality Reduction
8.  Tongguan capsule ameliorates coronary artery stenosis in a 40-year-old woman 
Cardiovascular disease is the leading cause of death worldwide, with coronary heart disease as the major contributor to this related mortality. There is a growing trend in the application of Chinese medicine in clinical practice for the treatment of coronary heart disease. However, there is a lack of knowledge surrounding the pharmacological, toxicological, and biological profiles of Chinese medicine. In this case report, we describe the therapeutic effects of Tongguan capsule in a 40-year-old woman diagnosed with stable angina pectoris. To the best of the authors’ knowledge, this is the first case documented of the therapeutic effect of Tongguan capsule in the treatment of coronary heart disease.
PMCID: PMC4539080  PMID: 26309395
Chinese medicine; Tongguan capsule; cardiovascular disease; stable angina pectoris
9.  The efficacy of QingfengGanke granule in treating postinfectious cough in pathogenic wind invading lungs syndrome: a multicenter, randomized, double-blind, placebo-controlled trial 
Chinese Medicine  2015;10:21.
Postinfectious cough (PIC) significantly affects cough-related quality of life but still lacks effective treatments. This study aims to investigate the efficacy of QingfengGanke granule (QFGKG) in treating PIC induced by pathogenic wind invading lungs syndrome.
A multicenter, randomized, double-blind, placebo-controlled clinical trial was conducted. A total of 180 eligible participants were randomly (1:1:1) assigned to group A (QFGKG 6 g plus QFGKG-matched placebo 6 g), group B (QFGKG 12 g), and group C (QFGKG-matched placebo 12 g). All herbal medications were orally administered twice daily for 10 consecutive days. The primary outcome was time to cough resolution, and secondary outcomes included time to cough alleviation, mean changes in cough symptom score (CSS), visual analogue scale (VAS) score, cough-specific quality of life questionnaire (CQLQ) score, and traditional Chinese medicine (TCM) syndrome score from baseline to Day 10, as well as adverse events.
A total of 173 participants were included in the efficacy and safety analyses (group A, n = 57; group B, n = 57; group C, n = 59). The median time to cough resolution in groups A, B, and C was more than 10 days, 8 days, and more than 10 days, respectively (P < 0.0001), and the median time to cough alleviation was 4, 4, and 6 days, respectively (P < 0.0001). Compared with the placebo condition, groups A and B showed significantly greater improvements in CSS (P = 0.0005, P < 0.0001, respectively), VAS (P = 0.0002, P < 0.0001, respectively), CQLQ (P = 0.0258, P = 0.0003, respectively), and TCM syndrome (P = 0.0031, P < 0.0001, respectively). The time to cough resolution was faster in group B compared with group A (P = 0.0091). The adverse event profiles were comparable among the three groups.
QingfengGanke granule is efficacious in the treatment of PIC induced by pathogenic wind invading lungs syndrome.
Electronic supplementary material
The online version of this article (doi:10.1186/s13020-015-0049-6) contains supplementary material, which is available to authorized users.
PMCID: PMC4529711  PMID: 26257822
10.  In vivo imaging of C. elegans endocytosis 
Methods (San Diego, Calif.)  2014;68(3):518-528.
Over the past decade, the early C. elegans embryo has proven to be a useful animal model to study a variety of membrane trafficking events, at least in part due to its large size, optical transparency, and ease of manipulation. Importantly, the stereotypic nature of membrane remodeling that occurs during early embryogenesis has enabled quantitative measurement of endocytic flux. In the absence of exogenous stimulation, resumption of the cell cycle triggered by fertilization is coupled to a dramatic redistribution of plasma membrane content. Numerous proteins are rapidly internalized via clathrin-mediated endocytosis, and the fate of these cargoes can be followed precisely using live imaging in utero. Key to these studies is the maintenance of animal health and their immobilization, which can become technically challenging during extended imaging sessions. Here we highlight recent advances in live imaging techniques that have facilitated the interrogation of endocytic transport in live animals. We focus on the use of transgenic C. elegans strains that stably express fluorescently-tagged proteins, including components of the endosomal system and cargo molecules that traverse this network of membranes. Our findings demonstrate the utility of the C. elegans embryo in defining regulatory mechanisms that control the numerous steps of endocytic trafficking.
PMCID: PMC4112158  PMID: 24704355
11.  An Accurate Calibration Method Based on Velocity in a Rotational Inertial Navigation System 
Sensors (Basel, Switzerland)  2015;15(8):18443-18458.
Rotation modulation is an effective method to enhance the accuracy of an inertial navigation system (INS) by modulating the gyroscope drifts and accelerometer bias errors into periodically varying components. The typical RINS drives the inertial measurement unit (IMU) rotation along the vertical axis and the horizontal sensors’ errors are modulated, however, the azimuth angle error is closely related to vertical gyro drift, and the vertical gyro drift also should be modulated effectively. In this paper, a new rotation strategy in a dual-axis rotational INS (RINS) is proposed and the drifts of three gyros could be modulated, respectively. Experimental results from a real dual-axis RINS demonstrate that the maximum azimuth angle error is decreased from 0.04° to less than 0.01° during 1 h. Most importantly, the changing of rotation strategy leads to some additional errors in the velocity which is unacceptable in a high-precision INS. Then the paper studies the basic reason underlying horizontal velocity errors in detail and a relevant new calibration method is designed. Experimental results show that after calibration and compensation, the fluctuation and stages in the velocity curve disappear and velocity precision is improved.
PMCID: PMC4570330  PMID: 26225983
rotational inertial navigation system (RINS); rotation modulation; rotation strategy; azimuth angle error; velocity errors
12.  Use of green fluorescent protein to monitor Lactobacillus plantarum in the gastrointestinal tract of goats 
Brazilian Journal of Microbiology  2015;46(3):849-854.
The experiment aimed to specifically monitor the passage of lactobacilli in vivo after oral administration. The green fluorescent protein (GFP) gene was cloned downstream from the constitutive p32 promoter from L. lactis subsp. cremoris Wg2. The recombinant expression vector, pLEM415-gfp-p32, was electroporated into Lactobacillus plantarum (L. plantarum) isolated from goat. Green fluorescent protein (GFP) was successfully expressed in L. plantarum. After 2 h post-administration, transformed Lactobacillus could be detectable in all luminal contents. In the rumen, bacteria concentration initially decreased, reached the minimum at 42 h post-oral administration and then increased. However, this concentration decreased constantly in the duodenum. This result indicated that L. plantarum could colonize in the rumen but not in the duodenum.
PMCID: PMC4568869  PMID: 26413069
green fluorescent protein; gastro-intestinal tract; Lactobacillus plantarum; goat
13.  Long-term efficacy of subtotal splenectomy due to portal hypertension in cirrhotic patients 
BMC Surgery  2015;15:89.
Portal hypertension (PHT) requires invasive measures to prevent rupture and bleeding of esophagogastric varices; however, the long-term results of subtotal splenectomy plus fixation of the retrosternal omentum majus (SSFROM) have not been reported. Specifically, the advantages and disadvantages of surgery that preserves the spleen and the long-term hematologic effects have not been described.
Study design
Our studies relating to SSFROM commenced in February 1999. As of April 2014 we have performed 256 subtotal splenectomies The records of 65 patients with PHT who underwent SSFROM were reviewed retrospectively.
Four patients died within 4 years of surgery, with a 4-year survival rate of 94 %; the 11-year survival rate was 60 %. Eleven patients (17 %) had re-bleeding from esophagogastric varices. The white blood cell and platelet counts were higher 6 and 11 years post-operatively compared with pre-operative values (P < 0.01). Portal venous diameter, portal venous flow volume, splenic artery flow volume, as well as splenic length, thickness, and average cross-sectional areas were shown to be significantly constricted or decreased (P < 0.01). The proportion of serum CD3+ T cells, CD4+ T cells, and CD8+ T cells was increased (P < 0.01), while the serum levels of macrophage colony-stimulating factor and granulocyte-macrophage colony-stimulating factor were significantly decreased (P < 0.01). There was no significant change in the serum levels of IgA, IgM, IgG, and Tuftsin (P > 0.05). DSA demonstrated that 15 cases formed collateral circulations between the portal vein and superior vena cava.
SSFROM provide long-term hemostasis for esophagogastric variceal bleeding in PHT and corrected hypersplenism. SSFROM is an effective treatment for patients with PHT in whom long-term survival is expected.
PMCID: PMC4511991  PMID: 26205377
Portal hypertension; Splenomegaly; Subtotal splenectomy; Shunt
14.  DNA Microarray Characterization of Pathogens Associated with Sexually Transmitted Diseases 
PLoS ONE  2015;10(7):e0133927.
This study established a multiplex PCR-based microarray to detect simultaneously a diverse panel of 17 sexually transmitted diseases (STDs)-associated pathogens including Neisseria gonorrhoeae, Chlamydia trachomatis, Mycoplasma genitalium, Mycoplasma hominis, Ureaplasma, Herpes simplex virus (HSV) types 1 and 2, and Human papillomavirus (HPV) types 6, 11, 16, 18, 31, 33, 35, 39, 54 and 58. The target genes are 16S rRNA gene for N. gonorrhoeae, M. genitalium, M. hominism, and Ureaplasma, the major outer membrane protein gene (ompA) for C. trachomatis, the glycoprotein B gene (gB) for HSV; and the L1 gene for HPV. A total of 34 probes were selected for the microarray including 31 specific probes, one as positive control, one as negative control, and one as positional control probe for printing reference. The microarray is specific as the commensal and pathogenic microbes (and closely related organisms) in the genitourinary tract did not cross-react with the microarray probes. The microarray is 10 times more sensitive than that of the multiplex PCR. Among the 158 suspected HPV specimens examined, the microarray showed that 49 samples contained HPV, 21 samples contained Ureaplasma, 15 contained M. hominis, four contained C. trachomatis, and one contained N. gonorrhoeae. This work reports the development of the first high through-put detection system that identifies common pathogens associated with STDs from clinical samples, and paves the way for establishing a time-saving, accurate and high-throughput diagnostic tool for STDs.
PMCID: PMC4514671  PMID: 26208181
15.  Genetically Encoding an Electrophilic Amino Acid for Protein Stapling and Covalent Binding to Native Receptors 
ACS Chemical Biology  2014;9(9):1956-1961.
Covalent bonds can be generated within and between proteins by an unnatural amino acid (Uaa) reacting with a natural residue through proximity-enabled bioreactivity. Until now, Uaas have been developed to react mainly with cysteine in proteins. Here we genetically encoded an electrophilic Uaa capable of reacting with histidine and lysine, thereby expanding the diversity of target proteins and the scope of the proximity-enabled protein cross-linking technology. In addition to efficient cross-linking of proteins inter- and intramolecularly, this Uaa permits direct stapling of a protein α-helix in a recombinant manner and covalent binding of native membrane receptors in live cells. The target diversity, recombinant stapling, and covalent targeting of endogenous proteins enabled by this versatile Uaa should prove valuable in developing novel research tools, biological diagnostics, and therapeutics by exploiting covalent protein linkages for specificity, irreversibility, and stability.
PMCID: PMC4168779  PMID: 25010185
16.  A statistical frame based TDMA protocol for human body communication 
Human body communication (HBC) using the human body as the transmission medium, which has been regarded as one of the most promising short-range communications in wireless body area networks (WBAN). Compared to the traditional wireless networks, two challenges are existed in HBC based WBAN. (1) Its sensor nodes should be energy saving since it is inconvenient to replace or recharge the battery on these sensor nodes; (2) the coordinator should be able to react dynamically and rapidly to the burst traffic triggered by sensing events. Those burst traffic conditions include vital physical signal (electrocardiogram, electroencephalogram etc.) monitoring, human motion detection (fall detection, activity monitoring, gesture recognition, motion sensing etc.) and so on. To cope with aforementioned challenges, a statistical frame based TDMA (S-TDMA) protocol with multi-constrained (energy, delay, transmission efficiency and emergency management) service is proposed in this paper.
The scenarios where burst traffic is often triggered rapidly with low power consumption and low delay is handled in our proposed S-TDMA. A beacon frame with the contained synchronous and poll information is designed to reduce the possibility of collisions of request frames. A statistical frame which broadcasts the unified scheduling information is adopted to avoid packet collisions, idle listening and overhearing. Dynamic time slot allocation mechanism is presented to manage the burst traffic and reduce the active period in each beacon period. An emergency mechanism is proposed for vital signals to be transmitted. The theory analysis is proceed and the result is evaluated in the hardware platform.
To verify its feasibility, S-TDMA was fully implemented on our independently-developed HBC platform where four sensor nodes and a coordinator are fastened on a human body. Experiment results show that S-TDMA costs 89.397 mJ every 20 s when the payload size is 122 bytes, 9.51% lower than Lightweight MAC (LMAC); the average data latency of S-TDMA is 6.3 ms, 7.02% lower than Preamble-based TDMA (PB-TDMA); the transmission efficiency of S-TDMA is 93.67%, 4.83% higher than IEEE 802.15.6 carrier sense multiple access/collision avoidance (CSMA/CA) protocol.
With respect to the challenges of HBC based WBANs, a novel S-TDMA protocol was proposed in this paper. Compared to the traditional protocols, the results demonstrate that S-TDMA successfully meets the delay and transmission efficiency requirements of HBC while keeping a low energy consumption. We also believe that our S-TDMA protocol will promote development of HBC in wearable applications.
PMCID: PMC4495947  PMID: 26155949
Human body communication; Wireless body area networks; Media access control; Time division multi access; Statistical frame
17.  De Novo Transcriptome Assembly and Development of Novel Microsatellite Markers for the Traditional Chinese Medicinal Herb, Veratrilla baillonii Franch (Gentianaceae) 
Evolutionary Bioinformatics Online  2015;11(Suppl 1):39-45.
Veratrilla baillonii Franch is an important Chinese medicinal herb for treating liver-related diseases, which has been over-collected in the recent decades. However, the effective conservation and related population genetic study has been hindered because of the lack of genome sequences and genetic markers in the natural population. We have conducted RNA-seq on V. baillonii. We performed de novo assembly of these data to characterize the V. baillonii transcriptome, resulting in 133,019 contigs with size >200 bp. These contigs were annotated using the NCBI nonredundant database and Gene Ontology (GO) terms. From these contigs, we developed novel microsatellite simple sequence repeat (SSR) markers, identifying a total of 40,885 SSRs. SSRs with repeat motifs of 1–4 bp (mono-, di-, tri-, and tetranucleotides) accounted for 99.8% of all SSRs, with mononucleotide repeats most common, followed by dinucleotide (16.2%) and trinucleotide repeats (14.7%). We selected 151 SSRs for experimental validation, of which 74 were confirmed by polymerase chain reaction. Fourteen SSRs were determined to be polymorphic by screening 40 individuals from six distant populations. The number of alleles per locus ranged from two to four, and the expected heterozygosity varied from 0.2637 to 0.8571, suggesting that these SSR markers are highly polymorphic and effective for further genetic analysis in the nature population. In addition, we explored the genetic structure of V. baillonii using five SSRs in four geographic populations and found that the identified genotypes were clustered into two phylogenetic clades: the Mekong River clade and Jinsha River clade. This result indicates that these two regions may harbor highly divergent genetic lineages and enriched genetic diversity. The de novo transcriptome sequences and new SSR markers discovered by this study provide an initial step for understanding the population genetics of V. baillonii, and a valuable resource for effective conservation management.
PMCID: PMC4498661  PMID: 26244005
transcriptome; Illumina RNA-Seq; microsatellite (SSR) markers; Veratrilla baillonii
18.  Transcriptomic Analysis of Musca domestica to Reveal Key Genes of the Prophenoloxidase-Activating System 
G3: Genes|Genomes|Genetics  2015;5(9):1827-1841.
The proPO system regulates melanization in arthropods. However, the genes that are involved in the proPO system in housefly Musca domestica remain unclear. Thus, this study analyzed the combined transcriptome obtained from M. domestica larvae, pupae, and adults that were either normal or bacteria-challenged by an Escherichia coli and Staphylococcus aureus mixture. A total of 54,821,138 clean reads (4.93 Gb) were yielded by Illumina sequencing, which were de novo assembled into 89,842 unigenes. Of the 89,842 unigenes, based on a similarity search with known genes in other insects, 24 putative genes related to the proPO system were identified. Eight of the identified genes encoded for peptidoglycan recognition receptors, two encoded for prophenoloxidases, three encoded for prophenoloxidase-activating enzymes, and 11 encoded for serine proteinase inhibitors. The expression levels of these identified genes were investigated by qRT-PCR assay, which were consistent with expected activation process of the proPO system, and their activation functions were confirmed by the measurement of phenoloxidase activity in bacteria-infected larvae after proPO antibody blockage, suggesting these candidate genes might have potentially different roles in the activation of proPO system. Collectively, this study has provided the comprehensive transcriptomic data of an insect and some fundamental basis toward achieving understanding of the activation mechanisms and immune functions of the proPO system in M. domestica.
PMCID: PMC4555219  PMID: 26156588
prophenoloxidase-activating system; gene identification; transcriptomic analysis; Musca domestica; genetics of immunity
19.  HDAC6 Deacetylates and Ubiquitinates MSH2 to Maintain Proper Levels of MutSα 
Molecular cell  2014;55(1):31-46.
MutS protein homolog 2 (MSH2) is a key DNA mismatch repair protein. It forms the MSH2-MSH6 (MutSα) and MSH2-MSH3 (MutSβ) heterodimers, which help to ensure genomic integrity. MutSα not only recognizes and repairs mismatched nucleotides but also recognizes DNA adducts induced by DNA-damaging agents, and triggers cell-cycle arrest and apoptosis. Loss or depletion of MutSα from cells leads to microsatellite instability (MSI) and resistance to DNA damage. Although the level of MutSα can be reduced by the ubiquitin-proteasome pathway, the detailed mechanisms of this regulation remain elusive. Here we report that histone deacetylase 6 (HDAC6) sequentially deacetylates and ubiquitinates MSH2, leading to MSH2 degradation. In addition, HDAC6 significantly reduces cellular sensitivity to DNA-damaging agents and decreases cellular DNA mismatch repair activities by downregulation of MSH2. Overall, these findings reveal a mechanism by which proper levels of MutSα are maintained.
PMCID: PMC4188514  PMID: 24882211
20.  Epiregulin enhances tumorigenicity by activating the ERK/MAPK pathway in glioblastoma 
Neuro-Oncology  2014;16(7):960-970.
Glioblastoma multiforme (GBM) is one of the most aggressive human tumors, and the establishment of an effective therapeutic reagent is a pressing priority. Recently, it has been shown that the tumor tissue consists of heterogeneous components and that a highly aggressive population should be the therapeutic target.
Through a single subcutaneous passage of GBM cell lines LN443 and U373 in mice, we have developed highly aggressive variants of these cells named LN443X, U373X1, and U373X2, which showed increased tumor growth, colony-forming potential, sphere-forming potential, and invasion ability. We further investigated using microarray analysis comparing malignant cells with their parental cells and mRNA expression analysis in grades II to IV glioma samples.
Adipocyte enhancer binding protein 1, epiregulin (EREG), and microfibrillar associated protein 5 were identified as candidate genes associated with higher tumor grade and poor prognosis. Immunohistochemical analysis also indicated a correlation of a strong expression of EREG with short overall survival. Furthermore, both EREG stimulation and EREG introduction of GBM cell lines were found to increase phosphorylation of epidermal growth factor receptor (EGFR) and extracellular signal-regulated kinase and resulted in the promotion of colony formation, sphere formation, and in vivo tumor formation. Gefitinib treatment inhibited phosphorylation of EGFR and extracellular signal-regulated kinase and led to tumor regression in U373-overexpressed EREG.
These results suggested that EREG is one of the molecules involved in glioma malignancy, and EGFR inhibitors may be a candidate therapeutic agent for EREG-overexpressing GBM patients.
PMCID: PMC4057138  PMID: 24470554
brain tumor; epiregulin; ERK/MAPK; GBM
21.  p62 Provides Dual Cytoprotection Against Oxidative Stress in the Retinal Pigment Epithelium 
Biochimica et biophysica acta  2014;1843(7):1248-1258.
As a signaling hub, p62/sequestosome plays important roles in cell signaling and degradation of misfolded proteins. p62 has been implicated as an adaptor protein to mediate autophagic clearance of insoluble protein aggregates in age-related diseases, including age-related macular degeneration (AMD), which is characterized by dysfunction of the retinal pigment epithelium (RPE). Our previous studies have shown that cigarette smoke (CS) induces oxidative stress and inhibits the proteasome pathway in cultured human RPE cells, suggesting that p62-mediated autophagy may become the major route to remove impaired proteins under such circumstances. In the present studies, we found that all p62 mRNA variants are abundantly expressed and upregulated by CS induced stress in cultured human RPE cells, yet isoform1 is the major translated form. We also show that p62 silencing exacerbated the CS induced accumulation of damaged proteins, both by suppressing autophagy and by inhibiting the Nrf2 antioxidant response, which in turn, increased protein oxidation. These effects of CS and p62 reduction were further confirmed in mice exposed to CS. We found that over-expression of p62 isoform1, but not its S403A mutant, which lacks affinity for ubiquitinated proteins, reduced misfolded proteins, yet simultaneously promoted an Nrf2-mediated antioxidant response. Thus, p62 provides dual, reciprocal enhancing protection to RPE cells from environmental stress induced protein misfolding and aggregation, by facilitating autophagy and the Nrf2 mediated antioxidant response, which might be a potential therapeutic target against AMD.
PMCID: PMC4019388  PMID: 24667411
Autophagy; aging; Nrf2; Oxidative stress; p62
22.  The effects of spinal cord injury on bone healing in patients with femoral fractures 
Orthopedic literature states that fractures of long bones, when associated with traumatic brain injuries, frequently heal with excessive callus and faster than normal. Few studies, however, have reported these phenomena being induced by spinal cord injury (SCI). Our objective is to compare the extent of callus and the rate of healing of long-bone fractures in patients with or without SCI. Subgroup comparisons were performed among the patients with SCI in terms of different levels of SCI.
The final mean volume of callus formation and the rate of union of nailed fractures of the femur were determined radiologically in 22 femoral fracture patients with SCI (seven cervical, six thoracic, and nine lumbar spine injury) and compared with those in a group of 22 patients with similar types of fractures but without SCI.
The final mean callus volume in the fracture/SCI group was significantly higher than the fracture-only group (P < 0.001). The fractures in the fracture/SCI group united in an average time of 22.86 weeks compared with 25.04 weeks in the fracture-only group (P < 0.05). We observed 84.6% (11 of 13) of patients with cervical and thoracic SCI patients with accelerated fracture healing (cervical 6 of 7, thoracic 5 of 6), but only 44.4% (4 of 9) of patients with lumbar SCI appeared to show this phenomenon (P < 0.05).
These results confirm that SCI may be associated with accelerated fracture healing and enhanced callus formation. Furthermore, our study revealed a trend toward enhanced osteogenesis in cervical or thoracic SCI compared with lumbar SCI.
PMCID: PMC4116725  PMID: 24621032
Spinal cord injury; Femoral fracture; Bone healing; Callus
23.  Ionic mechanisms underlying tonic and phasic firing behaviors in retinal ganglion cells 
Channels  2014;8(4):298-307.
In the retina, the firing behaviors that ganglion cells exhibit when exposed to light stimuli are very important due to the significant roles they play in encoding the visual information. However, the detailed mechanisms, especially the intrinsic properties that generate and modulate these firing behaviors is not completely clear yet. In this study, 2 typical firing behaviors—i.e., tonic and phasic activities, which are widely observed in retinal ganglion cells (RGCs)—are investigated. A modified computational model was developed to explore the possible ionic mechanisms that underlie the generation of these 2 firing patterns. Computational results indicate that the generation of tonic and phasic activities may be attributed to the collective actions of 2 kinds of adaptation currents, i.e., an inactivating sodium current and a delayed-rectifier potassium current. The concentration of magnesium ions has crucial but differential effects in the modulation of tonic and phasic firings, when the model neuron is driven by N-methyl-D-aspartate (NMDA) -type synaptic input instead of constant current injections. The proposed model has robust features that account for the ionic mechanisms underlying the tonic and phasic firing behaviors, and it may also be used as a good candidate for modeling some other firing patterns in RGCs.
PMCID: PMC4203731  PMID: 24769919
computational model; tonic activity; phasic activity; retinal ganglion cell; adaptation
24.  Evaluation of hGM-CSF/hTNFα surface-modified prostate cancer therapeutic vaccine in the huPBL-SCID chimeric mouse model 
To validate its efficacy in the context of the human immune system, a novel therapeutic vaccine of hGM-CSF/hTNFα surface-modified PC-3 cells against human prostate cancer was evaluated in the human peripheral blood lymphocytes-severe combined immunodeficiency (huPBL-SCID) chimeric mouse model. The hGM-CSF or/and hTNFα modified vaccines inhibited prostate cancer growth effectively so as to prolong the mouse survival significantly. The splenocytes from the hGM-CSF/hTNFα vaccine-inoculated mice showed the strongest tumor-specific cytotoxicity against PC-3 cells and the highest production of IFNɤ. These features indicated that type 1 protective immune response was induced efficiently against human prostate cancer and further enhanced through synergetic adjuvant effects of hGM-CSF and hTNFα.
Electronic supplementary material
The online version of this article (doi:10.1186/s13045-015-0175-8) contains supplementary material, which is available to authorized users.
PMCID: PMC4490636  PMID: 26108270
Cancer immunotherapy; Adjuvant; Synergetic effect; Human immune system; PC-3 prostate cancer cell
25.  Complete Genome Sequence of Elizabethkingia meningoseptica, Isolated from a T-Cell Non-Hodgkin’s Lymphoma Patient 
Genome Announcements  2015;3(3):e00673-15.
An Elizabethkingia meningoseptica infection was detected at the end stage of a patient with T-cell non-Hodgkin’s lymphoma. The complete genome of this isolated strain, FMS-007, was generated in one contig with a total size of 3,938,967 bp. A preliminary screening indicated that the genome contains drug resistance genes to aminoglycosides and β-lactams. A clustered regularly interspaced short palindromic repeats (CRISPR)/CRISPR-associated proteins (CRISPR/Cas) system with 16 direct repeats and 15 spacers was identified.
PMCID: PMC4481284  PMID: 26112786

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