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1.  Association of MICA gene polymorphisms with liver fibrosis in schistosomiasis patients in the Dongting Lake region 
Major histocompatibility complex class I chain-related A (MICA) is a highly polymorphic gene located within the MHC class I region of the human genome. Expressed as a cell surface glycoprotein, MICA modulates immune surveillance by binding to its cognate receptor on natural killer cells, NKG2D, and its genetic polymorphisms have been recently associated with susceptibility to some infectious diseases. We determined whether MICA polymorphisms were associated with the high rate of Schistosoma parasitic worm infection or severity of disease outcome in the Dongting Lake region of Hunan Province, China. Polymerase chain reaction-sequence specific priming (PCR-SSP) and sequencing-based typing (SBT) were applied for high-resolution allele typing of schistosomiasis cases (N = 103, age range = 36.2-80.5 years, 64 males and 39 females) and healthy controls (N = 141, age range = 28.6-73.3 years, 73 males and 68 females). Fourteen MICA alleles and five short-tandem repeat (STR) alleles were identified among the two populations. Three (MICA*012:01/02, MICA*017 and MICA*027) showed a higher frequency in healthy controls than in schistosomiasis patients, but the difference was not significantly correlated with susceptibility to S. japonicum infection (Pc > 0.05). In contrast, higher MICA*A5 allele frequency was significantly correlated with advanced liver fibrosis (Pc < 0.05). Furthermore, the distribution profile of MICA alleles in this Hunan Han population was significantly different from those published for Korean, Thai, American-Caucasian, and Afro-American populations (P < 0.01), but similar to other Han populations within China (P > 0.05). This study provides the initial evidence that MICA genetic polymorphisms may underlie the severity of liver fibrosis occurring in schistosomiasis patients from the Dongting Lake region.
doi:10.1590/S0100-879X2012007500024
PMCID: PMC3854198  PMID: 22370708
Schistosoma japonicum; MICA; NKG2D; Gene polymorphism; Liver fibrosis
2.  Protection of TGF-β1 against Neuroinflammation and Neurodegeneration in Aβ1–42-Induced Alzheimer’s Disease Model Rats 
PLoS ONE  2015;10(2):e0116549.
Neuroinflammation has been reported to be associated with Alzheimer’s disease (AD) pathogenesis. Neuroinflammation is generally considered as an outcome of glial activation; however, we recently demonstrated that T helper (Th)17 cells, a subpopulation of proinflammatory CD4+ T cells, are also involved in AD pathogenesis. Transforming growth factor (TGF)-β1, a cytokine that can be expressed in the brain, can be immunosuppressive, but its effects on lymphocyte-mediated neuroinflammation in AD pathogenesis have not been well addressed. In the current study we administered TGF-β1 via intracerebroventricle (ICV) and intranasal (IN) routes in AD model rats to investigate its antiinflammatory and neuroprotective effects. The AD rat model was prepared by bilateral hippocampal injection of amyloid-β (Aβ)1–42. TGF-β1 was administered via ICV one hour prior to Aβ1–42 injection or via both nares seven days after Aβ1–42 injection. ICV administration of TGF-β1 before Aβ1–42 injection remarkably ameliorated Aβ1–42-induced neurodegeneration and prevented Aβ1–42-induced increases in glia-derived proinflammatory mediators (TNF-α, IL-1β and iNOS), as well as T cell-derived proinflammatory cytokines (IFN-γ, IL-2, IL-17 and IL-22), in the hypothalamus, serum or cerebrospinal fluid (CSF) in a concentration-dependent manner. TGF-β1 pretreatment also prevented Aβ1–42-induced decreases in the neurotrophic factors, IGF-1, GDNF and BDNF, and in the antiinflammatory cytokine, IL-10. Similarly, IN administration of TGF-β1 after Aβ1–42 injection reduced neurodegeneration, elevation of proinflammatory mediators and cytokines, and reduction of neurotrophic and antiinflammatory factors, in the hypothalamus, serum or CSF. These findings suggest that TGF-β1 suppresses glial and T cell-mediated neuroinflammation and thereby alleviates AD-related neurodegeneration. The effectiveness of IN administered TGF-β1 in reducing Aβ1–42 neurotoxicity suggests a possible therapeutic approach in patients with AD.
doi:10.1371/journal.pone.0116549
PMCID: PMC4319949  PMID: 25658940
3.  Dual Functions in Response to Heat Stress and Spermatogenesis: Characterization of Expression Profile of Small Heat Shock Proteins 9 and 10 in Goat Testis 
BioMed Research International  2015;2015:686239.
Small heat shock proteins 9 and 10 (HSPB9 and HSPB10) are two testis-specific expressed sHsps. The objective of this study was to investigate the mRNA expression profile of HSPB9 and HSPB10 in goat testis among the different seasons, ages, and environmental temperatures. Allocation of the two sHsps was also performed by immunohistochemistry. The results showed that the transcript levels of HSPB9 and HSPB10 were extremely high in the testis (P < 0.01). The relative expression of HSBP9 and HSPB10 in testis showed a tendency to increase with age and then is maintained at the constant level after sexual maturity. HSPB9 and HSPB10 have significantly higher expression in the breeding season  (P < 0.05) and hot season (P < 0.01). Both HSPB9 and HSPB10 were found to be upregulated by high-temperature stress in testis (P < 0.05), and the expressions of Hsp70 and Hsp90 were also increased simultaneously (P < 0.01). Immunohistochemistry analysis localized HSPB9 expressed in spermatogonia, spermatocytes, and round spermatids and HSPB10 expressed in the elongate spermatids. In epididymis, strongly staining signal of HSPB10 was detected in pseudostratified columnar epithelium. In conclusion, the two testis-specific sHsps are closely related to male reproduction and heat tolerance. The results could provide valuable data for the further studies on HSPB9 and HSPB10.
doi:10.1155/2015/686239
PMCID: PMC4317599
4.  Association between epidermal growth factor receptor mutations and the expression of excision repair cross-complementing protein 1 and ribonucleotide reductase subunit M1 mRNA in patients with non-small cell lung cancer 
The present study aimed to investigate the association between epidermal growth factor receptor (EGFR) gene mutations and excision repair cross-complementing protein 1 (ERCC1) and ribonucleotide reductase subunit M1 (RRM1) mRNA expression in non-small cell lung cancer (NSCLC) tissue. The quantitative polymerase chain reaction was used to detect EGFR mutations, and ERCC1 and RRM1 mRNA expression in 257 cases of NSCLC. In the NSCLC samples the EGFR mutation rate was 49.03% (126/257). The rate was higher in females and non-smoking patients (P<0.05). High expression of ERCC1 mRNA was observed in 47.47% of the samples (122/257), while a high RRM1 mRNA expression was observed in 61.87% of the samples (159/257). In comparison with patients with NSCLC without EGFR mutations, patients with EGFR mutations had significantly lower levels of ERCC1 mRNA expression (P<0.05); however, EGFR mutations and expression levels of RRM1 mRNA were not correlated in NSCLC tissues (P>0.05). In addition, ERCC1 mRNA expression was not correlated with the expression levels of RRM1 mRNA (P>0.05). In conclusion, patients with NSCLC with EGFR mutations tend to have a low expression of ERCC1 mRNA and may potentially benefit from platinum-based chemotherapy.
doi:10.3892/etm.2015.2196
PMCID: PMC4316980  PMID: 25667646
non-small cell lung cancer; epidermal growth factor receptor; excision repair cross-complementing protein 1; ribonucleotide reductase subunit M1; molecular detection; individualized treatment
5.  Intestinal Parasite Co-infection among Pulmonary Tuberculosis Cases without Human Immunodeficiency Virus Infection in a Rural County in China 
Epidemiologic studies of co-infection with tuberculosis (TB) and intestinal parasites in humans have not been extensively investigated in China. A cross-section study was conducted in a rural county of Henan Province, China. Pulmonary TB (PTB) case-patients receiving treatment for infection with Mycobacterium tuberculosis and healthy controls matched for geographic area, age, and sex were surveyed by using questionnaires. Fecal and blood specimens were collected for detection of intestinal parasites, routine blood examination, and infection with human immunodeficiency virus. The chi-square test was used for univariate analysis and multivariate logistic regression models were used to adjust for potential confounding factors. A total of 369 persons with PTB and 366 healthy controls were included; all participants were negative for human immunodeficiency virus. The overall prevalence of intestinal parasites in persons with PTB was 14.9%, including intestinal protozoa (7.9%) and helminthes (7.6%). The infection spectrum of intestinal parasites was Entamoeba spp. (1.4%), Blastocystis hominis (6.2%), Trichomonas hominis (0.3%), Clonorchis sinensis (0.3%), Ascaris lumbricoides (0.5%), Trichuris trichiura (2.2%), and hookworm (4.6%). The prevalence of intestinal parasites showed no significant difference between persons with PTB and healthy controls after adjusting for potential confounding factors. There was no factor that affected infection rates for intestinal parasites between the two groups. Infection with intestinal parasites of persons with PTB was associated with female sex (adjusted odds ratio [AOR] = 2.05, 95% confidence interval [CI] = 1.01–4.17), body mass index ≤ 19 (AOR = 3.02, 95% CI = 1.47–6.20), and anemia (AOR = 2.43, 95% CI = 1.17–5.03). Infection of healthy controls was only associated with an annual labor time in farmlands > 2 months (AOR = 4.50, 95% CI = 2.03–10.00). In addition, there was no significant trend between rates of infection with intestinal parasites and duration of receiving treatment for infection with M. tuberculosis in persons with PTB. The prevalence of intestinal parasites was not higher in persons with PTB, and there was no evidence that PTB increased susceptibility to intestinal parasites in this study. However, for patients with PTB, women and patients with comorbidities were more likely to be infected with intestinal parasites.
doi:10.4269/ajtmh.13-0426
PMCID: PMC3886404  PMID: 24166044
6.  Targeted next-generation sequencing as a comprehensive test for patients with and female carriers of DMD/BMD: a multi-population diagnostic study 
Duchenne and Becker muscular dystrophies (DMD/BMD) are the most commonly inherited neuromuscular disease. However, accurate and convenient molecular diagnosis cannot be achieved easily because of the enormous size of the dystrophin gene and complex causative mutation spectrum. Such traditional methods as multiplex ligation-dependent probe amplification plus Sanger sequencing require multiple steps to fulfill the diagnosis of DMD/BMD. Here, we introduce a new single-step method for the genetic analysis of DMD patients and female carriers in real clinical settings and demonstrate the validation of its accuracy. A total of 89 patients, 18 female carriers and 245 non-DMD patients were evaluated using our targeted NGS approaches. Compared with traditional methods, our new method yielded 99.99% specificity and 98.96% sensitivity for copy number variations detection and 100% accuracy for the identification of single-nucleotide variation mutations. Additionally, this method is able to detect partial deletions/duplications, thus offering precise personal DMD gene information for gene therapy. We detected novel partial deletions of exons in nine samples for which the breakpoints were located within exonic regions. The results proved that our new method is suitable for routine clinical practice, with shorter turnaround time, higher accuracy, and better insight into comprehensive genetic information (detailed breakpoints) for ensuing gene therapy.
doi:10.1038/ejhg.2013.82
PMCID: PMC3865410  PMID: 23756440
targeted NGS; genetic diagnosis; Duchenne and Becker muscular dystrophies; statistical analysis for CNVs; breakpoints
7.  Oncolytic Measles and Vesicular Stomatitis Virotherapy for Endometrial Cancer 
Gynecologic oncology  2013;132(1):194-202.
Objective
Current adjuvant therapy for advanced-stage, recurrent, and high-risk endometrial cancer (EC) has not reduced mortality from this malignancy, and novel systemic therapies are imperative. Oncolytic viral therapy has been shown to be effective in the treatment of gynecologic cancers, and we investigated the in vitro and in vivo efficacy of the Edmonston strain of measles virus (MV) and vesicular stomatitis virus (VSV) on EC.
Methods
Human EC cell lines (HEC-1-A, Ishikawa, KLE, RL95-2, AN3 CA, ARK-1, ARK-2, and SPEC-2) were infected with Edmonston strain MV expressing the thyroidal sodium iodide symporter, VSV expressing either human or murine IFN-β, or recombinant VSV with a methionine deletion at residue 51 of the matrix protein and expressing the sodium iodide symporter. Xenografts of HEC-1-A and AN3 CA generated in athymic mice were treated with intratumoral MV or VSV or intravenous VSV.
Results
In vitro, all cell lines were susceptible to infection and cell killing by all 3 VSV strains except KLE. In addition, the majority of EC cell lines were defective in their ability to respond to type I IFN. Intratumoral VSV–treated tumors regressed more rapidly than MV-treated tumors, and intravenous VSV resulted in effective tumor control in 100% of mice. Survival was significantly longer for mice treated with any of the 3 VSV strains compared with saline.
Conclusion
VSV is clearly more potent in EC oncolysis than MV. A phase 1 clinical trial of VSV in EC is warranted.
doi:10.1016/j.ygyno.2013.11.010
PMCID: PMC3946955  PMID: 24246772
8.  Triggering Apoptotic Death of Human Epidermal Keratinocytes by Malic Acid: Involvement of Endoplasmic Reticulum Stress- and Mitochondria-Dependent Signaling Pathways 
Toxins  2015;7(1):81-96.
Malic acid (MA) has been commonly used in cosmetic products, but the safety reports in skin are sparse. To investigate the biological effects of MA in human skin keratinocytes, we investigated the potential cytotoxicity and apoptotic effects of MA in human keratinocyte cell lines (HaCaT). The data showed that MA induced apoptosis based on the observations of DAPI staining, DNA fragmentation, and sub-G1 phase in HaCaT cells and normal human epidermal keratinocytes (NHEKs). Flow cytometric assays also showed that MA increased the production of mitochondrial superoxide (mito-SOX) but decreased the mitochondrial membrane potential. Analysis of bioenergetics function with the XF 24 analyzer Seahorse extracellular flux analyzer demonstrated that oxygen consumption rate (OCR) was significantly decreased whereas extracellular acidification rate (ECAR) was increased in MA-treated keratinocytes. The occurrence of apoptosis was proved by the increased expressions of FasL, Fas, Bax, Bid, caspases-3, -8, -9, cytochrome c, and the declined expressions of Bcl-2, PARP. MA also induced endoplasmic reticulum stress associated protein expression such as GRP78, GADD153, and ATF6α. We demonstrated that MA had anti-proliferative effect in HaCaT cell through the inhibition of cell cycle progression at G0/G1, and the induction of programmed cell death through endoplasmic reticulum stress- and mitochondria-dependent pathways.
doi:10.3390/toxins7010081
PMCID: PMC4303815  PMID: 25584429
malic acid (MA); HaCaT cells; seahorse XF 24 analyzer; apoptosis
9.  TGF-β1 Protection against Aβ1–42-Induced Neuroinflammation and Neurodegeneration in Rats 
Transforming growth factor (TGF)-β1, a cytokine that can be expressed in the brain, is a key regulator of the brain’s responses to injury and inflammation. Alzheimer’s disease (AD), the most common neurodegenerative disorder, involves inflammatory processes in the brain in addition to the hallmarks, amyloid-β (Aβ) plaques and neurofibrillary tangles. Recently, we have shown that T-helper (Th) 17 cells, a subpopulation of CD4+ T-cells with high proinflammation, also participate in the brain inflammatory process of AD. However, it is poorly known whether TGF-β1 ameliorates the lymphocyte-mediated neuroinflammation and, thereby, alleviates neurodegeneration in AD. Herein, we administered TGF-β1 via the intracerebroventricle (ICV) in AD model rats, by Aβ1–42 injection in both sides of the hippocampus, to show the neuroprotection of TGF-β1. The TGF-β1 administration after the Aβ1–42 injection ameliorated cognitive deficit and neuronal loss and apoptosis, reduced amyloid precursor protein (APP) expression, elevated protein phosphatase (PP)2A expression, attenuated glial activation and alleviated the imbalance of the pro-inflammatory/anti-inflammatory responses of T-lymphocytes, compared to the Aβ1–42 injection alone. These findings demonstrate that TGF-β1 provides protection against AD neurodegeneration and suggest that the TGF-β1 neuroprotection is implemented by the alleviation of glial and T-cell-mediated neuroinflammation.
doi:10.3390/ijms151222092
PMCID: PMC4284696  PMID: 25470026
TGF-β1; Alzheimer’s disease; Aβ1–42; T-lymphocytes; microglia
10.  Arylamine N-acetyltransferase polymorphisms in Han Chinese patients with ankylosing spondylitis and their correlation to the adverse drug reactions to sulfasalazine 
Background
Polymorphisms of Arylamine N-acetyltransferase (NAT) that contribute to diverse susceptibilities of some autoimmune diseases are also linked to the metabolism of several drugs including sulfasalazine (SSZ). The aim of this study was to investigate the distribution of NAT polymorphisms in Han Chinese patients with ankylosing spondylitis (AS) and their correlation to sulfasalazine-induced adverse drug reactions (ADRs).
Methods
Arylamine N-acetyltransferase 1 (NAT1) and arylamine N-acetyltransferase 2 (NAT2) genotypes were determined in 266 AS patients who received SSZ treatment and 280 healthy controls. The correlation between NAT polymorphisms and SSZ-induced ADRs was analyzed.
Results
The co-occurrence frequency of NAT2 fast acetylator genotype and NAT1*10/NAT1*10 genotype was lower in AS patients than in controls. No positive correlations were detected between NAT polymorphisms and AS clinical features. The prevalence of SSZ-induced ADRs and drug withdrawal was 9.4% and 7.1%, respectively. The frequencies of overall ADRs, dose-related ADRs, and termination of drug treatment because of intolerance were higher in the NAT2 slow acetylator genotype carriers than in the fast-type carriers and in those with co-existence of NAT1 and NAT2 slow acetylator genotypes. Furthermore, the ADRs emerged earlier in the AS cases carrying both NAT1 and NAT2 slow acetylator genotypes.
Conclusions
The prevalence of co-occurring NAT2 fast acetylator genotype and NAT1*10/NAT1*10 genotype was lower in AS patients than in controls. The NAT2 slow acetylator genotype and co-existing NAT1 and NAT2 slow acetylator genotypes appear to be associated with higher risks of SSZ-induced ADRs.
doi:10.1186/2050-6511-15-64
PMCID: PMC4247704  PMID: 25413361
Arylamine N-acetyltransferases; Genetic polymorphism; Sulfasalazine; Ankylosing spondylitis; Adverse drug reactions
11.  On the Prospect of Identifying Adaptive Loci in Recently Bottlenecked Populations 
PLoS ONE  2014;9(11):e110579.
Identifying adaptively important loci in recently bottlenecked populations – be it natural selection acting on a population following the colonization of novel habitats in the wild, or artificial selection during the domestication of a breed – remains a major challenge. Here we report the results of a simulation study examining the performance of available population-genetic tools for identifying genomic regions under selection. To illustrate our findings, we examined the interplay between selection and demography in two species of Peromyscus mice, for which we have independent evidence of selection acting on phenotype as well as functional evidence identifying the underlying genotype. With this unusual information, we tested whether population-genetic-based approaches could have been utilized to identify the adaptive locus. Contrary to published claims, we conclude that the use of the background site frequency spectrum as a null model is largely ineffective in bottlenecked populations. Results are quantified both for site frequency spectrum and linkage disequilibrium-based predictions, and are found to hold true across a large parameter space that encompasses many species and populations currently under study. These results suggest that the genomic footprint left by selection on both new and standing variation in strongly bottlenecked populations will be difficult, if not impossible, to find using current approaches.
doi:10.1371/journal.pone.0110579
PMCID: PMC4226487  PMID: 25383711
12.  Safety, tolerability and effectiveness of HIV non-occupational prophylaxis in Taiwan 
Journal of the International AIDS Society  2014;17(4Suppl 3):19736.
Introduction
Increasing numbers of new HIV infection is an important issue of public health in Taiwan. We aim to evaluate the safety, tolerability and effectiveness of HIV non-occupational prophylaxis (nPEP) in Taiwan.
Materials and Methods
We conducted a prospective cohort observational study between March 2011 and May 2014. Three-combined antiretroviral agents were prescribed for all the persons who sought for HIV post-exposure prophylaxis after high risk sexual behaviour. HIV screening, health education and consultation were done before initiation of nPEP. Adverse effects were evaluated at Weeks 1, 2 and 4 and effectiveness was evaluated at Weeks 12 and 24. We also assessed adherence by pill count and regimen completion rates.
Results
During the study periods, 255 persons were enrolled. Among the enrolled cases, 43.9% (112/255) of them received zidovudine (AZT)-based regimen while the others received tenofovir (TDF)-based regimen and the third agent was composed of mostly lopinavir/ritonavir (81.4%). The completion rate of nPEP was 85.9% (219/255), and discontinuation rate of nPEP among AZT-based regimen is higher than TDF-based regimen (17.0% vs 8.2%). Any grade adverse effects are higher among AZT-based regimen than TDF-based regimen (62.5% vs 32.1%) although most adverse effects were grade 1–2. After a 24-week follow-up, only one person experienced HIV seroconversion and he had primary syphilis at the moment when he sought for nPEP.
Conclusions
NPEP could be an effective prevention method in a part of HIV prevention strategy and TDF-based regimen had better tolerability in Taiwan.
doi:10.7448/IAS.17.4.19736
PMCID: PMC4225442  PMID: 25397481
13.  Deficiency of IRTKS as an adaptor of insulin receptor leads to insulin resistance 
Cell Research  2013;23(11):1310-1321.
IRTKS encodes a member of the IRSp53/MIM homology domain family, which has been shown to play an important role in the formation of plasma membrane protrusions. Although the phosphorylation of IRTKS occurs in response to insulin stimulation, the role of this protein in insulin signaling remains unknown. Here we show that IRTKS-deficient mice exhibit insulin resistance, including hyperglycemia, hyperinsulinemia, glucose intolerance, decreased insulin sensitivity, and increased hepatic glucose production. The administration of ectopic IRTKS can ameliorate the insulin resistance of IRTKS-deficient and diabetic mice. In parallel, the expression level of IRTKS was significantly decreased in diabetic mouse model. Furthermore, DNA hypermethylation of the IRTKS promoter was also observed in these subjects. We also show that IRTKS, as an adaptor of the insulin receptor (IR), modulates IR-IRS1-PI3K-AKT signaling via regulating the phosphorylation of IR. These findings add new insights into our understanding of insulin signaling and resistance.
doi:10.1038/cr.2013.99
PMCID: PMC3817554  PMID: 23896986
insulin resistance; IRTKS; insulin receptor
14.  Advanced Cu chemical displacement technique for SiO2-based electrochemical metallization ReRAM application 
Nanoscale Research Letters  2014;9(1):592.
This study investigates an advanced copper (Cu) chemical displacement technique (CDT) with varying the chemical displacement time for fabricating Cu/SiO2-stacked resistive random-access memory (ReRAM). Compared with other Cu deposition methods, this CDT easily controls the interface of the Cu-insulator, the switching layer thickness, and the immunity of the Cu etching process, assisting the 1-transistor-1-ReRAM (1T-1R) structure and system-on-chip integration. The modulated shape of the Cu-SiO2 interface and the thickness of the SiO2 layer obtained by CDT-based Cu deposition on SiO2 were confirmed by scanning electron microscopy and atomic force microscopy. The CDT-fabricated Cu/SiO2-stacked ReRAM exhibited lower operation voltages and more stable data retention characteristics than the control Cu/SiO2-stacked sample. As the Cu CDT processing time increased, the forming and set voltages of the CDT-fabricated Cu/SiO2-stacked ReRAM decreased. Conversely, decreasing the processing time reduced the on-state current and reset voltage while increasing the endurance switching cycle time. Therefore, the switching characteristics were easily modulated by Cu CDT, yielding a high performance electrochemical metallization (ECM)-type ReRAM.
doi:10.1186/1556-276X-9-592
PMCID: PMC4214826  PMID: 25364318
Cu CDT; SiO2; ECM; ReRAM
15.  Characterization of Human Chromosomal Material Exchange with Regard to the Chromosome Translocations Using Next-Generation Sequencing Data 
Genome Biology and Evolution  2014;6(11):3015-3024.
As an important subtype of structural variations, chromosomal translocation is associated with various diseases, especially cancers, by disrupting gene structures and functions. Traditional methods for identifying translocations are time consuming and have limited resolutions. Recently, a few studies have employed next-generation sequencing (NGS) technology for characterizing chromosomal translocations on human genome, obtaining high-throughput results with high resolutions. However, these studies are mainly focused on mechanism-specific or site-specific translocation mapping. In this study, we conducted a comprehensive genome-wide analysis on the characterization of human chromosomal material exchange with regard to the chromosome translocations. Using NGS data of 1,481 subjects from the 1000 Genomes Project, we identified 15,349,092 translocated DNA fragment pairs, ranging from 65 to 1,886 bp and with an average size of approximately 102 bp. On average, each individual genome carried about 10,364 pairs, covering approximately 0.069% of the genome. We identified 16 translocation hot regions, among which two regions did not contain repetitive fragments. Results of our study overlapped with a majority of previous results, containing approximately 79% of approximately 2,340 translocations characterized in three available translocation databases. In addition, our study identified five novel potential recurrent chromosomal material exchange regions with greater than 20% detection rates. Our results will be helpful for an accurate characterization of translocations in human genomes, and contribute as a resource for future studies of the roles of translocations in human disease etiology and mechanisms.
doi:10.1093/gbe/evu234
PMCID: PMC4255766  PMID: 25349267
chromosomal translocation; next-generation sequencing; recurrent translocation; structural variation
16.  An Unusual Topological Structure of the HIV-1 Rev Response Element 
Cell  2013;155(3):594-605.
SUMMARY
Nuclear export of unspliced and singly spliced viral mRNA is a critical step in the HIV life cycle. The structural basis by which the virus selects its own mRNA among more abundant host cellular RNAs for export has been a mystery for more than 25 years. Here, we describe an unusual topological structure that the virus uses to recognize its own mRNA. The viral Rev response element (RRE) adopts an “A”-like structure in which the two legs constitute two tracks of binding sites for the viral Rev protein and position the two primary known Rev-binding sites ~55 Å apart, matching the distance between the two RNA-binding motifs in the Rev dimer. Both the legs of the “A” and the separation between them are required for optimal RRE function. This structure accounts for the specificity of Rev for the RRE and thus the specific recognition of the viral RNA.
doi:10.1016/j.cell.2013.10.008
PMCID: PMC3918456  PMID: 24243017
17.  Developmental Changes in BDNF Protein in the Song Control Nuclei of Zebra Finches 
Neuroscience  2013;250:578-587.
The zebra finch song system provides an excellent model to study the mechanisms underlying the development of sex difference in brain structure and function. Only male zebra finches sing and the brain nuclei controlling song learning and production are considerably larger than in females. Sexual differentiation may in part be regulated by estrogen, but other molecules including neurotrophic factors likely also affect masculinization. Brain derived neurotrophic factor (BDNF) plays crucial roles in numerous aspects of vertebrate brain development and function, including neurogenesis, cell survival, growth of axonal projections, synaptogenesis and processes linked to learning and memory. The current study investigated expression of BDNF protein in juvenile males and females at four ages, as well as in adults, to begin to evaluate the potential roles of endogenous BDNF in particular stages of structural and functional development of the song system. In both HVC and the robust nucleus of the arcopallium (RA), males had more BDNF+ cells than females. The number of immunopositive cells increased in males and decreased in females as they matured, in a pattern generally consistent with a role for BDNF in sensorimotor integration of song learning. In addition, in HVC (but not RA) the ratio of mature BDNF (mBDNF) compared to its precursor proBDNF was greater in adult males than those at post-hatching day 25, indicating a region-specific shift in the relative availability of the two forms. Collectively, the data suggest that changes in BDNF protein expression across development may be associated with song system maturation, particularly during the sensorimotor integration of masculine vocalizations.
doi:10.1016/j.neuroscience.2013.07.062
PMCID: PMC3789383  PMID: 23920158
neurotrophic factor; songbird; sexual differentiation
18.  Vaccination with Tumor Cells Expressing IL-15 and IL-15Rα Inhibit Murine Breast and Prostate Cancer 
Gene therapy  2014;21(4):393-401.
A number of antitumor vaccines have shown recent promise up-regulating immune responses against tumor antigens and improving patient survival. In this study we examine the effectiveness of vaccination using IL-15 expressing tumor cells and examined their ability to up-regulate immune responses to tumor antigens. We demonstrated that the co-expression of IL-15 with its receptor, IL-15Rα, increased the cell-surface expression and secretion of IL-15. We show that a gene transfer approach using recombinant adenovirus to express IL-15 and IL-15Rα in murine TRAMP-C2 prostate or TS/A breast tumors induced antitumor immune responses. From this we developed a vaccine platform, consisting of TRAMP-C2 prostate cancer cells or TS/A breast cancer cells co-expressing IL-15 and IL-15Rα that inhibited tumor formation when mice were challenged with tumor. Inhibition of tumor growth led to improved survival when compared to animals receiving cells expressing IL-15 alone or unmodified tumor cells. Animals vaccinated with tumor cells co-expressing IL-15 and IL-15Rα showed greater tumor infiltration with CD8+ T and NK cells, as well as increased antitumor CD8+ T-cell responses. Vaccination with IL-15/IL-15Rα-modified TS/A breast cancer cells provided a survival advantage to mice challenged with unrelated murine TUBO breast cancer cells indicating the potential for allogeneic IL-15/IL-15Rα expressing vaccines.
doi:10.1038/gt.2014.10
PMCID: PMC3976433  PMID: 24572789
Cancer; gene therapy; interleukin-15; interleukin-15 receptor-alpha; vaccine
19.  miR-98 suppresses melanoma metastasis through a negative feedback loop with its target gene IL-6 
Dysregulated microRNA (miRNA) expression has a critical role in tumor development and metastasis. However, the mechanism by which miRNAs control melanoma metastasis is unknown. Here, we report reduced miR-98 expression in melanoma tissues with increasing tumor stage as well as metastasis; its expression is also negatively associated with melanoma patient survival. Furthermore, we demonstrate that miR-98 inhibits melanoma cell migration in vitro as well as metastatic tumor size in vivo. We also found that IL-6 is a target gene of miR-98, and IL-6 represses miR-98 levels via the Stat3-NF-κB-lin28B pathway. In an in vivo melanoma model, we demonstrate that miR-98 reduces melanoma metastasis and increases survival in part by reducing IL-6 levels; it also decreases Stat3 and p65 phosphorylation as well as lin28B mRNA levels. These results suggest that miR-98 inhibits melanoma metastasis in part through a novel miR-98-IL-6-negative feedback loop.
doi:10.1038/emm.2014.63
PMCID: PMC4221693  PMID: 25277211
20.  Subtyping of Gliomaby Combining Gene Expression and CNVs Data Based on a Compressive Sensing Approach 
It is realized that a combined analysis of different types of genomic measurements tends to give more reliable classification results. However, how to efficiently combine data with different resolutions is challenging. We propose a novel compressed sensing based approach for the combined analysis of gene expression and copy number variants data for the purpose of subtyping six types of Gliomas. Experimental results show that the proposed combined approach can substantially improve the classification accuracy compared to that of using either of individual data type. The proposed approach can be applicable to many other types of genomic data.
doi:10.4172/2169-0111.1000101
PMCID: PMC4176925  PMID: 25267935
Gene Expression; CNVs data; Compressive Sensing; Glioma; Classification; Combined Analysis
21.  Detection of Her-2/neu expression in gastric cancer: Quantitative PCR versus immunohistochemistry 
The aim of this study was to compare quantitative polymerase chain reaction (qPCR) with immunohistochemistry (IHC) for the detection of Her-2 in gastric cancer, and to investigate the correlation between the expression levels of human epidermal growth factor receptor 2 (Her-2) and clinical features. Clinical data from 426 cases of gastric cancer were collected. Her-2 expression levels in cancerous tissue were detected using IHC, and the Her-2/neu gene expression levels were determined by qPCR. The correlation between the expression level of Her-2 and clinical features was investigated. The positive expression rate of Her-2 in cancerous tissue detected using qPCR and IHC was 11.17% (46/412) and 13.38% (57/426), respectively. The positive expression of the Her-2 protein/gene was significantly correlated with the depth of invasion and lymphatic metastasis, as well as the TNM stage (P<0.05). No significant correlation was identified between positive expression of the Her-2 protein/gene and tumor location, age, gender, differentiation degree and Lauren classification (P>0.05). The diagnostic consistency was good between the two methods (κ=0.828). The results indicate that the expression of Her-2/neu is closely associated with the development of gastric cancer. qPCR is a convenient, objective and efficient method, which may be used as an alternative to IHC or fluorescence in situ hybridization for the detection of Her-2/neu gene.
doi:10.3892/etm.2014.1982
PMCID: PMC4186335  PMID: 25289049
quantitative polymerase chain reaction; gastric cancer; Her-2/neu
22.  Classification of Multicolor Fluorescence In Situ Hybridization (M-FISH) Images With Sparse Representation 
There has been a considerable interest in sparse representation and compressive sensing in applied mathematics and signal processing in recent years but with limited success to medical image processing. In this paper we developed a sparse representation-based classification (SRC) algorithm based on L1-norm minimization for classifying chromosomes from multicolor fluorescence in situ hybridization (M-FISH) images. The algorithm has been tested on a comprehensive M-FISH database that we established, demonstrating improved performance in classification. When compared with other pixel-wise M-FISH image classifiers such as fuzzy c-means (FCM) clustering algorithms and adaptive fuzzy c-means (AFCM) clustering algorithms that we proposed earlier the current method gave the lowest classification error. In order to evaluate the performance of different SRC for M-FISH imaging analysis, three different sparse representation methods, namely, Homotopy method, Orthogonal Matching Pursuit (OMP), and Least Angle Regression (LARS), were tested and compared. Results from our statistical analysis have shown that Homotopy based method is significantly better than the other two methods. Our work indicates that sparse representations based classifiers with proper models can outperform many existing classifiers for M-FISH classification including those that we proposed before, which can significantly improve the multicolor imaging system for chromosome analysis in cancer and genetic disease diagnosis.
doi:10.1109/TNB.2012.2189414
PMCID: PMC4165853  PMID: 22665392
Chromosome image classification; cytogenetics; Homotopy method; image segmentation; sparse representations
23.  Common Copy Number Variation Detection From Multiple Sequenced Samples 
Common copy number variations (CNVs) [1] are small regions of genomic variations at the same loci across multiple samples, which can be detected with high resolution from next-generation sequencing (NGS) technique. Multiple sequencing data samples are often available from genomic studies; examples include sequences from multiple platforms and sequences from multiple individuals. By integrating complementary information from multiple data samples, detection power can be potentially improved. However, most of current CNV detection methods often process an individual sequence sample, or two samples in an abnormal versus matched normal study; researches on detecting common CNVs across multiple samples have been very limited but are much needed. In this paper, we propose a novel method to detect common CNVs from multiple sequencing samples by exploiting the concurrency of genomic variations in read depth signals derived from multiple NGS data. We use a penalized sparse regression model to fit multiple read depth profiles, based on which common CNV identification is formulated as a change-point detection problem. Finally, we validate the proposed method on both simulation and real data, showing that it can give both higher detection power and better break point estimation over several published CNV detection methods.
doi:10.1109/TBME.2013.2292588
PMCID: PMC4165854  PMID: 24557694
Copy number variation (CNV); ℓ-0 norm penalty; model selection; next generation sequencing (NGS); Schur complement; structured sparse modeling; the 1000 genomes project
24.  Identification of Genes for Complex Diseases by Integrating Multiple Types of Genomic Data 
Combining multi-type of genomic data for integrative analyses can take advantage of complementary information and thus can have higher power to identify genes/variables that would otherwise be impossible with individual data analysis. Here we proposed a sparse representation based clustering (SRC) method for integrative data analyses, and applied to the analysis of 376821 SNPs in 200 subjects (100 cases and 100 controls) and expression data for 22283 genes in 80 subjects (40 cases and 40 controls) to identify significant genes for osteoporosis (OP). Comparing our results with previous studies, we identified some genes known related to OP risk, as well as some uncovered novel osteoporosis susceptible genes (‘DICER1’, ‘PTMA’, etc.) that may function importantly in osteoporosis etiology. In addition, the identified genes can lead to higher accuracy for the identification of osteoporosis subjects when compared with the traditional T-test and Fisher-exact test, which further validate the proposed SRC approach for integrative analysis.
doi:10.1109/EMBC.2012.6347249
PMCID: PMC4164202  PMID: 23367184
25.  Lactobacilli Inactivate Chlamydia trachomatis through Lactic Acid but Not H2O2 
PLoS ONE  2014;9(9):e107758.
Lactobacillus species dominate the microbiome in the lower genital tract of most reproductive-age women. Producing lactic acid and H2O2, lactobacilli are believed to play an important role in prevention of colonization by and growth of pathogens. However, to date, there have been no reported studies characterizing how lactobacilli interact with Chlamydia trachomatis, a leading sexually transmitted bacterium. In this report, we demonstrate inactivation of C. trachomatis infectivity by culture media conditioned by Lactobacillus crispatus, L. gasseri and L. jensenii, known to be dominating organisms in the human vaginal microbiome. Lactobacillus still cultures produced lactic acid, leading to time- and concentration-dependent killing of C. trachomatis. Neutralization of the acidic media completely reversed chlamydia killing. Addition of lactic acid into Lactobacillus-unconditioned growth medium recapitulated the chlamydiacidal activity of conditioned media. The H2O2 concentrations in the still cultures were found to be comparable to those reported for the cervicovaginal fluid, but insufficient to inactivate chlamydiae. Aeration of Lactobacillus cultures by shaking markedly induced H2O2 production, but strongly inhibited Lactobacillus growth and lactic acid production, and thus severely affected acidification, leading to significantly reduced chlamydiacidal efficiency. These observations indicate lactobacilli inactivate chlamydiae primarily through maintaining acidity in a relatively hypoxic environment in the vaginal lumen with limited H2O2, which is consistent with the notion that women with higher vaginal pH are more prone to sexually transmitted C. trachomatis infection. In addition to lactic acid, formic acid and acetic acid also exhibited potent chlamydiacidal activities. Taken together, our findings imply that lowering the vaginal pH through engineering of the vaginal microbiome and other means will make women less susceptible to C. trachomatis infection.
doi:10.1371/journal.pone.0107758
PMCID: PMC4162611  PMID: 25215504

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