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1.  Implementation of tuberculosis infection control measures in designated hospitals in Zhejiang Province, China: are we doing enough to prevent nosocomial tuberculosis infections? 
BMJ Open  2016;6(3):e010242.
Tuberculosis (TB) infection control measures are very important to prevent nosocomial transmission and protect healthcare workers (HCWs) in hospitals. The TB infection control situation in TB treatment institutions in southeastern China has not been studied previously. Therefore, the aim of this study was to investigate the implementation of TB infection control measures in TB-designated hospitals in Zhejiang Province, China.
Cross-sectional survey using observation and interviews.
All TB-designated hospitals (n=88) in Zhejiang Province, China in 2014.
Primary and secondary outcome measures
Managerial, administrative, environmental and personal infection control measures were assessed using descriptive analyses and univariate logistic regression analysis.
The TB-designated hospitals treated a median of 3030 outpatients (IQR 764–7094) and 279 patients with confirmed TB (IQR 154–459) annually, and 160 patients with TB (IQR 79–426) were hospitalised in the TB wards. Most infection control measures were performed by the TB-designated hospitals. Measures including regular monitoring of TB infection control in high-risk areas (49%), shortening the wait times (42%), and providing a separate waiting area for patients with suspected TB (46%) were sometimes neglected. N95 respirators were available in 85 (97%) hospitals, although only 44 (50%) hospitals checked that they fit. Hospitals with more TB staff and higher admission rates of patients with TB were more likely to set a dedicated sputum collection area and to conduct annual respirator fit testing.
TB infection control measures were generally implemented by the TB-designated hospitals. Measures including separation of suspected patients, regular monitoring of infection control practices, and regular fit testing of respirators should be strengthened. Infection measures for sputum collection and respirator fit testing should be improved in hospitals with lower admission rates of patients with TB.
PMCID: PMC4785333  PMID: 26940111
2.  Robust Radar Emitter Recognition Based on the Three-Dimensional Distribution Feature and Transfer Learning 
Due to the increasing complexity of electromagnetic signals, there exists a significant challenge for radar emitter signal recognition. To address this challenge, multi-component radar emitter recognition under a complicated noise environment is studied in this paper. A novel radar emitter recognition approach based on the three-dimensional distribution feature and transfer learning is proposed. The cubic feature for the time-frequency-energy distribution is proposed to describe the intra-pulse modulation information of radar emitters. Furthermore, the feature is reconstructed by using transfer learning in order to obtain the robust feature against signal noise rate (SNR) variation. Last, but not the least, the relevance vector machine is used to classify radar emitter signals. Simulations demonstrate that the approach proposed in this paper has better performances in accuracy and robustness than existing approaches.
PMCID: PMC4813864  PMID: 26927111
radar emitter recognition; Wigner–Ville distribution; three-dimensional distribution feature; transfer learning; relevance vector machine
3.  Successful salvage treatment of acute graft-versus-host disease after liver transplantation by withdrawal of immunosuppression: a case report 
Acute graft-versus-host disease (GVHD) following liver transplantation is a rare but fatal complication. The correct diagnosis and management of GVHD after liver transplantation are still major challenges. Herein, we reported successful salvage treatment of acute GVHD by withdrawal of immunosuppression in a patient who presented with fever, skin rashes, and decreased blood cell counts after liver transplantation. This case highlights the need for awareness of drug-induced liver injury if liver function tests are elevated during treatment, especially in patients taking multiple potentially hepatotoxic drugs, such as broad-spectrum antibiotics. When occurs, an artificial liver support system is a useful tool to provide temporary support of liver function for the patient in the event of drug-induced liver injury.
PMCID: PMC4767263  PMID: 26925149
Graft-versus-host disease; Liver transplantation; Drug-induced liver injury
4.  Precision (Repeatability and Reproducibility) and Agreement of Corneal Power Measurements Obtained by Topcon KR-1W and iTrace 
PLoS ONE  2016;11(1):e0147086.
To evaluate the repeatability and reproducibility of corneal power measurements obtained by Topcon KR-1W and iTrace, and assess the agreement with measurements obtained by Allegro Topolyzer and IOLMaster.
The right eyes of 100 normal subjects were prospectively scanned 3 times using all the 4 devices. Another observer performed additional 3 consecutive scans using the Topcon KR-1W and iTrace in the same session. About one week later, the first observer repeated the measurements using the Topcon KR-1W and iTrace. The steep keratometry (Ks), flat keratometry (Kf), mean keratometry (Km), J0 and J45 were analyzed. Repeatability and reproducibility of measurements were evaluated by the within-subject standard deviation (Sw), coefficient of variation (CoV), test-retest repeatability (2.77Sw), and intraclass correlation coefficient (ICC). Agreements between devices were assessed using Bland-Altman analysis and 95% limits of agreement (LoA).
Intraobserver repeatability and interobserver and intersession reproducibility of the Ks, Kf and Km showed a CoV of no more than 0.5%, a 2.77Sw of 0.70 D or less, and an ICC of no less than 0.99. However, J0 and J45 showed poor intraobserver repeatability and interobserver and intersession reproducibility (all ICCs not greater than 0.446). Statistically significant differences existed between Topcon KR-1W and IOLMaster, Topcon KR-1W and iTrace, Topcon KR-1W and Topolyzer, iTrace and Topolyzer, iTrace and IOLMaster for Ks, Kf and Km measurements (all P < 0.05). The mean differences between Topcon KR-1W, iTrace, and the other 2 devices were small. The 95% LoA were approximately 1.0 D to 1.5 D for all measurements.
The Ks, Kf and Km obtained by Topcon KR-1W and iTrace showed excellent intraobserver repeatability and interobserver and intersession reproducibility in normal eyes. The agreement between Topcon KR-1W and Topolyzer, Topcon KR-1W and IOLMaster, iTrace and Topolyzer, iTrace and IOLMaster, Topcon KR-1W and iTrace were not so good, they should not be interchangeable in clinical application. Given that the intraobserver repeatability and interobserver and intersession reproducibility of corneal astigmatism measurements obtained by Topcon KR-1W and iTrace were poor, it should be cautious that Topcon KR-1W and iTrace were applied for the preparation of toric lens implantation.
PMCID: PMC4709181  PMID: 26752059
5.  FAK is required for c-Met/β-catenin-driven hepatocarcinogenesis 
Hepatology (Baltimore, Md.)  2014;61(1):214-226.
Hepatocellular carcinoma (HCC) is the third most common cause of cancer death worldwide and most patients with HCC have limited treatment options. Focal Adhesion Kinase (FAK) is overexpressed in many HCC specimens, offering a potential target for HCC treatment. However, the role of FAK in hepatocarcinogenesis remains elusive. Establishing whether FAK expression plays a role in HCC development is necessary to determine whether it is a viable therapeutic target. In this study, we generated mice with hepatocyte-specific deletion of Fak and investigated the role of Fak in an oncogenic (c-MET/β-catenin, MET/CAT)-driven HCC model. We found that deletion of Fak in hepatocytes did not affect morphology, proliferation or apoptosis. However, Fak deficiency significantly repressed MET/CAT-induced tumor development and prolonged survival of animals with MET/CAT-induced HCC. In mouse livers and HCC cell lines, Fak was activated by MET, which induced the activation of Akt/Erk and up-regulated Cyclin D1 and tumor cell proliferation. CAT enhanced MET-stimulated FAK activation and synergistically induced the activation of the AKT/ERK-Cyclin D1 signaling pathway in a FAK kinase-dependent manner. In addition, FAK was required for CAT-induced Cyclin D1 expression in a kinase-independent fashion.
Fak is required for c-Met/β-catenin-driven hepatocarcinogenesis. Inhibition of FAK provides a potential strategy to treat HCC.
PMCID: PMC4280291  PMID: 25163657
Hepatocellular carcinoma; Sleeping Beauty Transposon system; Proliferation; AKT; ERK
6.  Severe hydrocephalus complicated with benign paroxysmal positional vertigo: one case report 
In this study, we reported one female patient diagnosed with severe hydrocephalus who presented with benign paroxysmal positional vertigo (BPPV). She presented with progressive headache and dizziness prior to hospitalization as chief complaints. She received Diagnostic Dix-Hallpike and Roll tests to make a definite diagnosis. The patient was cured after Gufoni maneuver and did not recur after 6-month follow-up. The diagnostic procedures of this female case prompted that prior to formal treatment, patients developing severe hydrocephalus complicated with BPPV should receive provocative test for positional dizziness, performed by experienced physicians from the Department of neurology and otolaryngology.
PMCID: PMC4723991  PMID: 26885146
Severe hydrocephalus; complication; paroxysmal positional vertigo
7.  Onset of adrenal ganglioneuroblastoma in an adult after delivery 
A case of adrenal ganglioneuroblastoma is presented here. This adrenal ganglioneuroblastoma was found in a 27-year-old female 7 months after delivery. CT clarified that the tumor originated retroperitoneally and was large in size (11.4 cm × 9.4 cm). The tumor was surgically removed together with pancreatic body and tail, left kidney and spleen, and pathological diagnosis was adrenal ganglioneuroblastoma-intermixed. Adrenal ganglioneuroblastoma is extremely rare in adults, with only about 9 cases documented including this case.
PMCID: PMC4595823  PMID: 26448921
Ganglioneuroblastoma; Adult; Adrenal glands
8.  Evolutionary Genomics of Borrelia burgdorferi sensu lato: Findings, Hypotheses, and the Rise of Hybrids 
Borrelia burgdorferi sensu lato (B. burgdorferi s.l.), the group of bacterial species represented by Lyme Disease pathogens, has one of the most complex and variable genomic architectures among prokaryotes. Showing frequent recombination within and limited gene flow among geographic populations, the B. burgdorferi s.l. genomes provides an excellent window into the processes of bacterial evolution at both within- and between-population levels. Comparative analyses of B. burgdorferi s.l. genomes revealed a highly dynamic plasmid composition but a conservative gene repertoire. Gene duplication and loss as well as sequence variations at loci encoding surface-localized lipoproteins (e.g., the PF54 genes) are strongly associated with adaptive differences between species. There are a great many conserved intergenic spacer sequences that are candidates for cis-regulatory elements and non-coding RNAs. Recombination among coexisting strains occurs at a rate approximately three times the mutation rate. The coexistence of a large number of genomic groups within local B. burgdorferi s.l. populations may be driven by immune-mediated diversifying selection targeting major antigen loci as well as by adaptation to multiple host species. Questions remain regarding the ecological causes (e.g., climate change, host movements, or new adaptations) of the ongoing range expansion of B. burgdorferi s.l. and on the genomic variations associated with its ecological and clinical variability. Anticipating an explosive growth of the number of B. burgdorferi s.l. genomes sampled from both within and among species, we propose genome-based methods to test adaptive mechanisms and to identify molecular bases of phenotypic variations. Genome sequencing is also necessary to monitor the ongoing genetic admixture of previously isolated species and populations in North America and elsewhere.
PMCID: PMC4299872  PMID: 24704760
Lyme disease; phylogenomics; comparative genomics; phylogenetic footprinting; population genomics; recombination; gene conversion; genome-wide association study; pangenome; frequency-dependent selection; multiple-niche polymorphisms
9.  CCDC34 is up-regulated in bladder cancer and regulates bladder cancer cell proliferation, apoptosis and migration 
Oncotarget  2015;6(28):25856-25867.
The coiled coil is a superhelical structural protein motif involved in a diverse array of biological functions, and the abnormal expression of the coiled-coil domain containing proteins has a direct link with the phenotype of tumor cell migration, invasion and metastasis. The aim of this study was to investigate the critical role of Coiled-coil domain-containing protein 34 (CCDC34) in bladder carcinogenesis, which has never been reported to date. Here, we found CCDC34 expression was elevated in bladder cancer tissues and cell lines. The knockdown of CCDC34 via lentivirus-mediated siRNA significantly suppressed bladder cancer cells proliferation and migration, and induced cell cycle arrest at G2/M phase and increased apoptosis in vitro. In addition, CCDC34 knockdown suppressed bladder tumor growth in nude mice. Moreover, CCDC34 silencing decreased the phosphorylation of MEK, ERK1/2, JNK, p38 and Akt, and the expressions of c-Raf and c-Jun, indicating MAPK and AKT pathways (ERK/MAPK, p38/MAPK, JNK/MAPK and PI3K/Akt) might be involved in CCDC34 regulation of bladder cancer cell proliferation and migration. Our findings revealed for the first time a potential oncogenic role for CCDC34 in bladder carcinoma pathogenesis and it may serve as a biomarker or even a therapeutic target for bladder cancer.
PMCID: PMC4694871  PMID: 26312564
CCDC34; bladder cancer; siRNA; proliferation; migration
10.  Late-onset neuromyelitis optica spectrum disorder in AQP4-seropositivepatients in a Chinese population 
BMC Neurology  2015;15:160.
Increasing rates of AQP4-seropositive neuromyelitis optica spectrum disorder (NMOSD) have been reported in late-onset patients (LONMOSD). However, the full range of clinical differences between early-onset and late-onset variants remain unclear. We describe the clinical features and outcomes of AQP4-seropositive LONMOSD patients in a Chinese population.
This was a retrospective analysis of medical records in a cohort study of AQP4-seropositive NMOSD patients with early-onset (≤49 years) and late-onset (≥50 years) variants between January 2006 and February 2014. Demographic, clinical, neuroimaging and cerebrospinal fluid (CSF) findings and prognosis data were analyzed.
We identified thirty AQP4-seropositive LONMOSD patients (86.7 % women). The median age at onset was 57.5 years (range 50–70). There were similar onset frequencies between optic neuritis (ON) and longitudinally extensive transverse myelitis (LETM). Longer interval between (first) ON and LETM (median 13 vs. 4 months; p < 0.05), time from first symptoms to diagnosis of NMO (median 17 vs. 7 months, p < 0.05), higher comorbidities (66.7 vs. 26.7 %; p < 0.05), and more hypertension (26.7 vs.3.3 %; p < 0.05) were prevalent. NMO-like lesions were less common (10.7 vs. 41.6 %; p < 0.05), while the rate of non-specific lesions tended to be higher (53.6 vs. 29 %; p = 0.067). These patients displayed more severe Expanded Disability Status Scale (EDSS) in nadir (median 6.75vs.5; p < 0.05). Attacks often resulted in EDSS 4 within a short period (median 8 vs. 13.5 months; p < 0.05). At last follow-up, the EDSS score was more severe in these patients (median 5.25 vs. 4; p < 0.05). No significant predictors were identified.
This study provides an overview of the clinical and paraclinical features of AQP4-seropositive LONMOSD patients in China and demonstrates a number of distinct disease characteristics in early vs. late onset. Older patients are more susceptible to disability in short course. However, these patients do not always display NMO-like lesions in the brain. Initial LETM may not necessarily be predominant as the initial symptom, contrary to previous reports. The higher comorbidities may warrant a modified approach of treatment.
PMCID: PMC4558842  PMID: 26337073
11.  Phylogenetic Co-Occurrence of ExoR, ExoS, and ChvI, Components of the RSI Bacterial Invasion Switch, Suggests a Key Adaptive Mechanism Regulating the Transition between Free-Living and Host-Invading Phases in Rhizobiales 
PLoS ONE  2015;10(8):e0135655.
Both bacterial symbionts and pathogens rely on their host-sensing mechanisms to activate the biosynthetic pathways necessary for their invasion into host cells. The Gram-negative bacterium Sinorhizobium meliloti relies on its RSI (ExoR-ExoS-ChvI) Invasion Switch to turn on the production of succinoglycan, an exopolysaccharide required for its host invasion. Recent whole-genome sequencing efforts have uncovered putative components of RSI-like invasion switches in many other symbiotic and pathogenic bacteria. To explore the possibility of the existence of a common invasion switch, we have conducted a phylogenomic survey of orthologous ExoR, ExoS, and ChvI tripartite sets in more than ninety proteobacterial genomes. Our analyses suggest that functional orthologs of the RSI invasion switch co-exist in Rhizobiales, an order characterized by numerous invasive species, but not in the order’s close relatives. Phylogenomic analyses and reconstruction of orthologous sets of the three proteins in Alphaproteobacteria confirm Rhizobiales-specific gene synteny and congruent RSI evolutionary histories. Evolutionary analyses further revealed site-specific substitutions correlated specifically to either animal-bacteria or plant-bacteria associations. Lineage restricted conservation of any one specialized gene is in itself an indication of species adaptation. However, the orthologous phylogenetic co-occurrence of all interacting partners within this single signaling pathway strongly suggests that the development of the RSI switch was a key adaptive mechanism. The RSI invasion switch, originally found in S. meliloti, is a characteristic of the Rhizobiales, and potentially a conserved crucial activation step that may be targeted to control host invasion by pathogenic bacterial species.
PMCID: PMC4550343  PMID: 26309130
12.  Phosphatase and Tensin Homolog (PTEN) Regulates Hepatic Lipogenesis, Microsomal Triglyceride Transfer Protein, and the Secretion of Apolipoprotein B–Containing Lipoproteins 
Hepatology (Baltimore, Md.)  2008;48(6):1799-1809.
Hepatic apolipoprotein B (apoB) lipoprotein production is metabolically regulated via the phosphoinositide 3-kinase cascade; however, the role of the key negative regulator of this pathway, the tumor suppressor phosphatase with tensin homology (PTEN), is unknown. Here, we demonstrate that hepatic protein levels of apoB100 and microsomal triglyceride transfer protein (MTP) are significantly down-regulated (73% and 36%, respectively) in the liver of PTEN liver-specific knockout (KO) mice, and this is accompanied by increased triglyceride (TG) accumulation and lipogenic gene expression, and reduced hepatic apoB secretion in freshly isolated hepatocytes. MTP protein mass and lipid transfer activity were also significantly reduced in liver of PTEN KO mice. Overexpression of the dominant negative mutant PTEN C/S124 (adenovirus expressing PTEN C/S mutant [AdPTENC/S]) possessing constitutive phospoinositide 3-kinase activity in HepG2 cells led to significant reductions in both secreted apoB100 and cellular MTP mass (76% and 34%, respectively), and increased messenger RNA (mRNA) levels of sterol regulatory element binding protein 1c (SREBP-1c), fatty acid synthase (FAS), and acetyl-CoA carboxylase (ACC). Reduced apoB100 secretion induced by AdPTENC/S was associated with increased degradation of newly-synthesized cellular apoB100, in a lactacystin-sensitive manner, suggesting enhanced proteasomal degradation. AdPTENC/S also reduced apoB-lipoprotein production in McA-RH7777 and primary hamster hepatocytes. Our findings suggest a link between PTEN expression and hepatic production of apoB-containing lipoproteins. We postulate that perturbations in PTEN not only may influence hepatic insulin signaling and hepatic lipogenesis, but also may alter hepatic apoB-lipoprotein production and the MTP stability. On loss of PTEN activity, increased lipid substrate availability in the face of reduced hepatic lipoprotein production capacity can rapidly lead to hepatosteatosis and fatty liver.
PMCID: PMC4544759  PMID: 19026012
13.  Elevated C1orf63 expression is correlated with CDK10 and predicts better outcome for advanced breast cancers: a retrospective study 
BMC Cancer  2015;15:548.
Chromosome 1 open reading frame 63 (C1orf63) is located on the distal short arm of chromosome 1, whose allelic loss has been observed in several human cancers. C1orf63 has been reported to be up-regulated in IL-2-starved T lymphocytes, which suggests it might be involved in cell cycle control, a common mechanism for carcinogenesis. Here we investigated the expression and clinical implication of C1orf63 in breast cancer.
Paraffin-embedded specimens, clinicopathological features and follow-up data of the breast cancer patients were collected. Publicly available microarray and RNA-seq datasets used in this study were downloaded from ArrayExpress of EBI and GEO of NCBI. KM plotter tool was also adopted. The expression of C1orf63 and CDK10, one known cell cycle-dependent tumor suppressor in breast cancer, was assessed by immunohistochemistry. Western blotting was performed to detect C1orf63 protein in human breast cancer cell lines, purchased from the Culture Collection of the Chinese Academy of Sciences, Shanghai.
In a group of 12 human breast tumors and their matched adjacent non-cancerous tissues, C1orf63 expression was observed in 7 of the 12 breast tumors, but not in the 12 adjacent non-cancerous tissues (P < 0.001). Similar results were observed of C1orf63 mRNA expression both in breast cancer and several other cancers, including lung cancer, prostate cancer and hepatocellular carcinoma. In another group of 182 breast cancer patients, C1orf63 expression in tumors was not correlated with any clinicopathological features collected in this study. Survival analyses showed that there was no significant difference of overall survival (OS) rates between the C1orf63 (+) group and the C1orf63 (−) group (P = 0.145). However, the analyses of KM plotter displayed a valid relationship between C1orf63 and RFS (relapse free survival)/OS (P < 0.001; P = 0.007). Notablely, in breast cancers with advanced TNM stages (III ~ IV) among these 182 patients, C1orf63 expression was an independent prognostic factor predicting better clinical outcome (HR: 0.41; 95 % CI: 0.17 ~ 0.97; P = 0.042). Additionally, we found that CDK10 mRNA expression was positively correlated with C1orf63, which was consistent with the relationship of protein expression between C1orf63 and CDK10 (rs = 0.391; P < 0.001).
Compared to adjacent non-cancerous tissues, C1orf63 expression was elevated in tumor tissues. However, C1orf63 predicts better prognosis for breast cancers with advanced TNM stage, and the underlying mechanism is unknown. In addition, C1orf63 is correlated with the cell cycle related gene, CDK10.
PMCID: PMC4513615  PMID: 26209438
C1orf63; CDK10; Overall survival; TNM stage
15.  ATP Binding and Hydrolysis Properties of ABCB10 and Their Regulation by Glutathione 
PLoS ONE  2015;10(6):e0129772.
ABCB10 (ATP binding cassette sub-family B10) is a mitochondrial inner-membrane ABC transporter. ABCB10 has been shown to protect the heart from the impact of ROS during ischemia-reperfusion and to allow for proper hemoglobin synthesis during erythroid development. ABC transporters are proteins that increase ATP binding and hydrolysis activity in the presence of the transported substrate. However, molecular entities transported by ABCB10 and its regulatory mechanisms are currently unknown. Here we characterized ATP binding and hydrolysis properties of ABCB10 by using the 8-azido-ATP photolabeling technique. This technique can identify potential ABCB10 regulators, transported substrates and amino-acidic residues required for ATP binding and hydrolysis. We confirmed that Gly497 and Lys498 in the Walker A motif, Glu624 in the Walker B motif and Gly602 in the C-Loop motif of ABCB10 are required for proper ATP binding and hydrolysis activity, as their mutation changed ABCB10 8-Azido-ATP photo-labeling. In addition, we show that the potential ABCB10 transported entity and heme precursor delta-aminolevulinic acid (dALA) does not alter 8-azido-ATP photo-labeling. In contrast, oxidized glutathione (GSSG) stimulates ATP hydrolysis without affecting ATP binding, whereas reduced glutathione (GSH) inhibits ATP binding and hydrolysis. Indeed, we detectABCB10 glutathionylation in Cys547 and show that it is one of the exposed cysteine residues within ABCB10 structure. In all, we characterize essential residues for ABCB10 ATPase activity and we provide evidence that supports the exclusion of dALA as a potential substrate directly transported by ABCB10. Last, we show the first molecular mechanism by which mitochondrial oxidative status, through GSH/GSSG, can regulate ABCB10.
PMCID: PMC4459825  PMID: 26053025
16.  Biochemical characterization of FIKK8 – A unique protein kinase from the malaria parasite Plasmodium falciparum and other apicomplexans 
Graphical abstract
•We studied FIKK kinases from Plasmodium falciparum and Cryptosporidium parvum.•Soluble and active samples of PfFIKK8 and CpFIKK contain a N-terminal extension.•Both FIKK samples preferentially phosphorylated serines with flanking arginines.
FIKKs are protein kinases with distinctive sequence motifs found exclusively in Apicomplexa. Here, we report on the biochemical characterization of Plasmodium falciparum FIKK8 (PfFIKK8) and its Cryptosporidium parvum orthologue (CpFIKK) – the only member of the family predicted to be cytosolic and conserved amongst non-Plasmodium parasites. Recombinant protein samples of both were catalytically active. We characterized their phosphorylation ability using an enzymatic assay and substrate specificities using an arrayed positional scanning peptide library. Our results show that FIKK8 targets serine, preferably with arginine in the +3 and −3 positions. Furthermore, the soluble and active FIKK constructs in our experiments contained an N-terminal extension (NTE) conserved in FIKK8 orthologues from other apicomplexan species. Based on our results, we propose that this NTE is an integral feature of the FIKK subfamily.
PMCID: PMC4576209  PMID: 26112892
Apicomplexa; FIKK kinase; Kinase; Cryptosporidium
17.  Molecular Diversity and Gene Evolution of the Venom Arsenal of Terebridae Predatory Marine Snails 
Genome Biology and Evolution  2015;7(6):1761-1778.
Venom peptides from predatory organisms are a resource for investigating evolutionary processes such as adaptive radiation or diversification, and exemplify promising targets for biomedical drug development. Terebridae are an understudied lineage of conoidean snails, which also includes cone snails and turrids. Characterization of cone snail venom peptides, conotoxins, has revealed a cocktail of bioactive compounds used to investigate physiological cellular function, predator-prey interactions, and to develop novel therapeutics. However, venom diversity of other conoidean snails remains poorly understood. The present research applies a venomics approach to characterize novel terebrid venom peptides, teretoxins, from the venom gland transcriptomes of Triplostephanus anilis and Terebra subulata. Next-generation sequencing and de novo assembly identified 139 putative teretoxins that were analyzed for the presence of canonical peptide features as identified in conotoxins. To meet the challenges of de novo assembly, multiple approaches for cross validation of findings were performed to achieve reliable assemblies of venom duct transcriptomes and to obtain a robust portrait of Terebridae venom. Phylogenetic methodology was used to identify 14 teretoxin gene superfamilies for the first time, 13 of which are unique to the Terebridae. Additionally, basic local algorithm search tool homology-based searches to venom-related genes and posttranslational modification enzymes identified a convergence of certain venom proteins, such as actinoporin, commonly found in venoms. This research provides novel insights into venom evolution and recruitment in Conoidean predatory marine snails and identifies a plethora of terebrid venom peptides that can be used to investigate fundamental questions pertaining to gene evolution.
PMCID: PMC4494067  PMID: 26025559
venomics; venom evolution; Terebridae; teretoxins; transcriptomics; Conoidea
18.  Clinical Prediction of Fall Risk and White Matter Abnormalities 
Archives of neurology  2012;69(6):733-738.
The Tinetti scale is a simple clinical tool designed to predict risk of falling by focusing on gait and stance impairment in elderly persons. Gait impairment is also associated with white matter (WM) abnormalities.
To test the hypothesis that elderly subjects at risk for falling, as determined by the Tinetti scale, have specific patterns of WM abnormalities on diffusion tensor imaging.
Design, Setting, and Patients
Community-based cohort of 125 homebound elderly individuals.
Main Outcome Measures
Diffusion tensor imaging scans were analyzed using tract-based spatial statistics analysis to determine the location of WM abnormalities in subjects with Tinetti scale scores of 25 or higher (without risk of falls) and lower than 25 (with risk of falls). Multivariate linear least squares correlation analysis was performed to determine the association between Tinetti scale scores and local fractional anisotropy values on each skeletal voxel controlling for possible confounders.
In subjects with risk of falls (Tinetti scale score <25), clusters of abnormal WM were seen in the medial frontal and parietal subcortical pathways, genu and splenium of corpus callosum, posterior cingulum, prefrontal and orbitofrontal pathways, and longitudinal pathways that connect frontal-parietal-temporal lobes. Among these abnormalities, those in medial frontal and parietal subcortical pathways correlated with Mini-Mental State Examination scores, while the other locations were unrelated to these scores.
Elderly individuals at risk for falls as determined by the Tinetti scale have WM abnormalities in specific locations on diffusion tensor imaging, some of which correlate with cognitive function scores.
PMCID: PMC4443844  PMID: 22332181
19.  Association between linear measurements of corpus callosum and gait in the elderly 
European radiology  2013;23(8):2252-2257.
Segmentation and diffusion-tensor-imaging of the corpus callosum (CC) have been linked to gait impairment. However, such measurements are impracticable in clinical routine. The purpose of this study was to evaluate the association between simple linear measurements of CC thickness with gait.
Two hundred and seventy-two community-dwelling subjects underwent neurological assessment and brain MRI. Mid-sagittal reformats of T1-weighted images were used to determine CC thickness. The association of measurements with clinical evaluation of gait was assessed by multivariate regression, controlling for numerous clinical and imaging confounders. Differences in CC thickness were, moreover, compared between subgroups with no, moderate or severe impairment of gait.
In univariate analyses, thickness of the genu and body of CC but not the splenium were associated with postural stability (P<0.01). Multivariate regression revealed thickness of CC genu as the only imaging variable independently associated with gait (P=0.01). Genu thickness was significantly different between subjects with high and low (P=0.0003) or high and moderate (P=0.001) risk of fall.
Atrophy of the CC genu is an imaging marker of gait impairment in the elderly suggesting higher risk of fall. Simple linear measurements of CC can help in MRI evaluation of patients with gait impairment.
PMCID: PMC4429761  PMID: 23512195
Corpus callosum; Gait; Magnetic resonance imaging
20.  The Correlation between Aquaporin-4 Antibody and the Visual Function of Patients with Demyelinating Optic Neuritis at Onset 
Journal of Ophthalmology  2015;2015:672931.
ON patients with AQP4-Ab seropositivity tend to be predominantly female and young and have worse visual acuity and more severe damage to their visual fields compared with AQP4-Ab seronegativity.
PMCID: PMC4442297  PMID: 26078876
21.  Assessing Apoptosis Gene Expression Profiling with a PCR Array in the Hippocampus of Ts65Dn Mice 
BioMed Research International  2015;2015:214618.
It is well known that Down syndrome (DS) is a condition in which extra genetic material causes delays in the way a child develops, both mentally and physically. Intellectual disability is the foremost and most debilitating trait, which caused loss of cognitive abilities and the development of early onset Alzheimer's disease (AD). Ts65Dn mice were used in this study. We isolated the hippocampus. First, we used transmission scanning electron microscopy to directly observe the hippocampus and confirm if apoptosis had occurred. Second, we customized a PCR array with 53 genes, including several important genes related to cell apoptosis. Gene expression was detected by RT-PCR. There were varying degrees of changes characteristic of apoptosis in the hippocampus of Ts65Dn mice, which mainly included the following: nuclear membrane thinning, unevenly distributed chromosomes, the production of chromatin crescents, and pyknosis of the nuclei with some nuclear fragmentation. Meanwhile, three genes (API5, AIFM1, and NFκB1) showed changes of expression in the hippocampus of Ts65Dn mice compared with normal mice. Only NFκB1 expression was significantly increased, while the expressions of API5 and AIFM1 were notably decreased. The fold changes in the expression of API5, AIFM1, and NFκB1 were 11.55, 5.94, and 3.11, respectively. However, some well-known genes related to cell apoptosis, such as the caspase family, Bcl-2, Bad, Bid, Fas, and TNF, did not show changes in expression levels. The genes we found which were differentially expressed in the hippocampus of Ts65Dn mice may be closely related to cell apoptosis. PCR array technology can assist in the screening and identification of genes involved in apoptosis.
PMCID: PMC4436439  PMID: 26075220
22.  Phylogenomic Identification of Regulatory Sequences in Bacteria: an Analysis of Statistical Power and an Application to Borrelia burgdorferi Sensu Lato 
mBio  2015;6(2):e00011-15.
Phylogenomic footprinting is an approach for ab initio identification of genome-wide regulatory elements in bacterial species based on sequence conservation. The statistical power of the phylogenomic approach depends on the degree of sequence conservation, the length of regulatory elements, and the level of phylogenetic divergence among genomes. Building on an earlier model, we propose a binomial model that uses synonymous tree lengths as neutral expectations for determining the statistical significance of conserved intergenic spacer (IGS) sequences. Simulations show that the binomial model is robust to variations in the value of evolutionary parameters, including base frequencies and the transition-to-transversion ratio. We used the model to search for regulatory sequences in the Lyme disease species group (Borrelia burgdorferi sensu lato) using 23 genomes. The model indicates that the currently available set of Borrelia genomes would not yield regulatory sequences shorter than five bases, suggesting that genome sequences of additional B. burgdorferi sensu lato species are needed. Nevertheless, we show that previously known regulatory elements are indeed strongly conserved in sequence or structure across these Borrelia species. Further, we predict with sufficient confidence two new RpoS binding sites, 39 promoters, 19 transcription terminators, 28 noncoding RNAs, and four sets of coregulated genes. These putative cis- and trans-regulatory elements suggest novel, Borrelia-specific mechanisms regulating the transition between the tick and host environments, a key adaptation and virulence mechanism of B. burgdorferi. Alignments of IGS sequences are available on, an online database of orthologous open reading frame (ORF) and IGS sequences in Borrelia.
While bacterial genomes contain mostly protein-coding genes, they also house DNA sequences regulating the expression of these genes. Gene regulatory sequences tend to be conserved during evolution. By sequencing and comparing related genomes, one can therefore identify regulatory sequences in bacteria based on sequence conservation. Here, we describe a statistical framework by which one may determine how many genomes need to be sequenced and at what level of evolutionary relatedness in order to achieve a high level of statistical significance. We applied the framework to Borrelia burgdorferi, the Lyme disease agent, and identified a large number of candidate regulatory sequences, many of which are known to be involved in regulating the phase transition between the tick vector and mammalian hosts.
PMCID: PMC4453575  PMID: 25873371
23.  The Efficacy of Traditional Chinese Medical Exercise for Parkinson’s Disease: A Systematic Review and Meta-analysis 
PLoS ONE  2015;10(4):e0122469.
Background and Objective
Several studies assessed the efficacy of traditional Chinese medical exercise in the management of Parkinson’s disease (PD), but its role remained controversial. Therefore, the purpose of this systematic review is to evaluate the evidence on the effect of traditional Chinese medical exercise for PD.
Seven English and Chinese electronic databases, up to October 2014, were searched to identify relevant studies. The PEDro scale was employed to assess the methodological quality of eligible studies. Meta-analysis was performed by RevMan 5.1 software.
Fifteen trials were included in the review. Tai Chi and Qigong were used as assisting pharmacological treatments of PD in the previous studies. Tai Chi plus medication showed greater improvements in motor function (standardized mean difference, SMD, -0.57; 95% confidence intervals, CI, -1.11 to -0.04), Berg balance scale (BBS, SMD, -1.22; 95% CI -1.65 to -0.80), and time up and go test (SMD, -1.06; 95% CI -1.44 to -0.68). Compared with other therapy plus medication, Tai Chi plus medication also showed greater gains in motor function (SMD, -0.78; 95% CI -1.46 to -0.10), BBS (SMD, -0.99; 95% CI -1.44 to -0.54), and functional reach test (SMD, -0.77; 95% CI -1.51 to -0.03). However, Tai Chi plus medication did not showed better improvements in gait or quality of life. There was not sufficient evidence to support or refute the effect of Qigong plus medication for PD.
In the previous studies, Tai Chi and Qigong were used as assisting pharmacological treatments of PD. The current systematic review showed positive evidence of Tai Chi plus medication for PD of mild-to-moderate severity. So Tai Chi plus medication should be recommended for PD management, especially in improving motor function and balance. Qigong plus medication also showed potential gains in the management of PD. However, more high quality studies with long follow-up are warrant to confirm the current findings.
PMCID: PMC4382160  PMID: 25830664
24.  Intraperitoneal Injection of the Pancreatic Peptide Amylin Potently Reduces Behavioral Impairment and Brain Amyloid Pathology in Murine Models of Alzheimer's Disease 
Molecular psychiatry  2014;20(2):252-262.
Amylin, a pancreatic peptide, and amyloid-beta peptides (Aβ), a major component of Alzheimer's disease (AD) brain, share similar β-sheet secondary structures, but it is not known if pancreatic amylin affects amyloid pathogenesis in the AD brain. Using AD mouse models, we investigated the effects of amylin and its clinical analog, pramlintide, on AD pathogenesis. Surprisingly, chronic intraperitoneal (i.p.) injection of AD animals with either amylin or pramlintide reduces the amyloid burden as well as lowers the concentrations of Aβ in the brain. These treatments significantly improve their learning and memory assessed by two behavioral tests, Y maze and Morris water maze. Both amylin and pramlintide treatments increase the concentrations of Aβ1-42 in cerebral spinal fluid (CSF). A single i.p. injection of either peptide also induces a surge of Aβ in serum, the magnitude of which is proportionate to the amount of Aβ in brain tissue. One intracerebroventricular (i.c.v.) injection of amylin induces a more significant surge in serum Aβ than one i.p. injection of the peptide. In 330 human plasma samples, a positive association between amylin and Aβ1-42 as well as Aβ1-40 is found only in patients with AD or amnestic mild cognitive impairment (amnestic MCI). As amylin readily crosses the blood brain barrier (BBB), our study demonstrates that peripheral amylin's action on the central nervous system results in translocation of Aβ from the brain into the CSF and blood that could be an explanation for a positive relationship between amylin and Aβ in blood. While naturally occurring amylin may play a role in regulating Aβ in brain, amylin class peptides may provide a new avenue for both treatment and diagnosis of AD.
PMCID: PMC4161670  PMID: 24614496
25.  Plasma Amylin and Cognition in Diabetes in the Absence and the Presence of Insulin Treatment 
Plasma amylin is positively associated with cognitive function in humans. Amylin treatment improves memory in Alzheimer’s mouse models. However, the relationship between plasma amylin, diabetes and cognition is not clear.
In this study we examined the concentration of plasma amylin, its relationship with diabetes and cognition.
Material and Method
A cross-sectional, homebound elderly population with data of plasma amylin under fasting condition and cognitive measurements was used.
We found that subjects with a long and chronic duration of diabetes were more likely to take insulin treatment and have reduced secretion of amylin. Compared to non-diabetics, diabetic subjects without insulin treatment had a higher concentration, but those with insulin treatment had a lower concentration, of plasma amylin [median (Q1, Q3): 20 (11.0, 36.2) vs. 25.2 (13.2, 50.6) vs. 15.0 (4.9, 33.8), p<0.0001]. In the whole sample vs. in the absence of diabetes, plasma amylin was positively associated with logical memory delayed recall (β= +0.61, SE=0.25, p=0.02 vs. β=+0.80, SE=0.33, p=0.02) and block design (β=+0.62, SE=0.24, p=0.009 vs. β=+0.93, SE=0.31, p=0.003), and negatively associated with Trailmaking A scores (β= −6.21, SE=1.55, p<0.0001 vs. β=−7.51, SE=1.95, p=0.0001) and Trailmaking B (β= −4.32, SE=2.13, p=0.04 vs. β= −5.86, SE=2.73, p=0.04). All these relationships disappeared in the presence of diabetes regardless the treatment.
This study suggests that secretion of amylin by pancreas compensates and then deteriorates depending on the duration of diabetes. Amylin’s activities for cognition are impaired in the presence of diabetes.
PMCID: PMC4350457  PMID: 25750761
Amylin; Cognition; Memory; Visuospatial and executive function

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