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1.  DNA Duplexes with Hydrophobic Modifications Inhibit Fusion between HIV-1 and Cell Membranes 
Antimicrobial Agents and Chemotherapy  2013;57(10):4963-4970.
Discovery of new drugs for the treatment of AIDS typically possessing unique structures associated with novel mechanisms of action has been of great importance due to the quick drug-resistant mutations of HIV-1 strains. The work presented in this report describes a novel class of DNA duplex-based HIV-1 fusion inhibitors. Hydrophobic groups were introduced into a DNA duplex skeleton either at one end, at both ends, or in the middle. These modified DNA duplexes inhibited fusion between HIV-1 and human cell membranes at micro- or submicromolar concentrations. Respective inhibitors adopted an aptamer pattern instead of a base-pairing interaction pattern. Structure-activity relationship studies of the respective DNA duplexes showed that the rigid and negatively charged DNA skeletons, in addition to the presence of hydrophobic groups, were crucial to the anti-HIV-1 activity of these compounds. A fluorescent resonance energy transfer (FRET)-based inhibitory assay showed that these duplex inhibitors interacted with the primary pocket in the gp41 N-terminal heptad repeat (NHR) instead of interacting with the lipid bilayers.
doi:10.1128/AAC.00758-13
PMCID: PMC3811431  PMID: 23896466
2.  Higher Methylation in Genomic DNA Indicates Incomplete Reprogramming in Induced Pluripotent Stem Cells 
Cellular Reprogramming  2013;15(1):92-99.
Abstract
Pluripotent stem cells can be created successfully through the inner cell mass (ICM), nuclear transfer, and defined-factor induction. Unfortunately, the epigenetic characteristics of the cells produced are poorly understood. In this article, we compared expression levels of enzymes involved in epigenetic modifications across six pluripotent stem cell lines. Six of the 11 genes evaluated here (Dnmt3a, Dnmt3b, Tet1, Ezh2, Mll1, and Lsd1) showed abnormally low levels of expression in the two germ-line chimeric induced pluripotent stem cell (iPSC) lines. We also conducted locus-specific analysis of DNA methylation at 9 loci. Although iPSCs did express Oct4, the Oct4 promoter region was shown to have a higher level of DNA methylation. The Xist and Line-1 repeating sequences differed relatively little in methylation level across the cell lines, but Peg3, Peg10, and H19 exhibited high degrees of variation in the pattern of DNA methylation. Meg3 in the Dlk1–Dio3 imprinting cluster was incompletely methylated in embryonic stem cells (ESCs) and nuclear transfer (nt) ESCs. However, in germ-line chimeric iPSCs, Meg3 was almost entirely methylated. ESC and ntESC lines showed twice as much Meg3 expression than in the iPSC lines. The genomic 5mC contents detected by reverse-phase high-performance liquid chromatography (HPLC) indicated that, despite their germ-line chimeric abilities, iPSCs remained incompletely reprogrammed, even though no direct evidence is shown here.
doi:10.1089/cell.2012.0043
PMCID: PMC3567703  PMID: 23379582
3.  Exome sequencing identified new mutations in a Marfan syndrome family 
Diagnostic Pathology  2014;9:25.
Marfan syndrome is a common autosomal dominant hereditary connective tissue disorder. There is no cure for Marfan syndrome currently. Next-generation sequencing (NGS) technology is efficient to identify genetic lesions at the exome level. Here we carried out exome sequencing of two Marfan syndrome patients. Further Sanger sequencing validation in other five members from the same family was also implemented to confirm new variants which may contribute to the pathogenesis of the disease. Two new variants, including one nonsense SNP in the Marfan syndrome gene FBN1 and one missense mutation in exon 15 of LRP1, which may be related to the phenotype of the patients were identified. The exome sequencing analysis provides us a new insight into the molecular events governing pathogenesis of Marfan syndrome.
Virtual slide
http://www.diagnosticpathology.diagnomx.eu/vs/1229110069114125.
doi:10.1186/1746-1596-9-25
PMCID: PMC3918099  PMID: 24484584
Exome sequencing; New mutations; Marfan syndrome; FBN1; RP1
4.  Transcriptome sequencing and phylogenomic resolution within Spalacidae (Rodentia) 
BMC Genomics  2014;15:32.
Background
Subterranean mammals have been of great interest for evolutionary biologists because of their highly specialized traits for the life underground. Owing to the convergence of morphological traits and the incongruence of molecular evidence, the phylogenetic relationships among three subfamilies Myospalacinae (zokors), Spalacinae (blind mole rats) and Rhizomyinae (bamboo rats) within the family Spalacidae remain unresolved. Here, we performed de novo transcriptome sequencing of four RNA-seq libraries prepared from brain and liver tissues of a plateau zokor (Eospalax baileyi) and a hoary bamboo rat (Rhizomys pruinosus), and analyzed the transcriptome sequences alongside a published transcriptome of the Middle East blind mole rat (Spalax galili). We characterize the transcriptome assemblies of the two spalacids, and recover the phylogeny of the three subfamilies using a phylogenomic approach.
Results
Approximately 50.3 million clean reads from the zokor and 140.8 million clean reads from the bamboo ratwere generated by Illumina paired-end RNA-seq technology. All clean reads were assembled into 138,872 (the zokor) and 157,167 (the bamboo rat) unigenes, which were annotated by the public databases: the Swiss-prot, Trembl, NCBI non-redundant protein (NR), NCBI nucleotide sequence (NT), Gene Ontology (GO), Cluster of Orthologous Groups (COG), and Kyoto Encyclopedia of Genes and Genomes (KEGG). A total of 5,116 nuclear orthologous genes were identified in the three spalacids and mouse, which was used as an outgroup. Phylogenetic analysis revealed a sister group relationship between the zokor and the bamboo rat, which is supported by the majority of gene trees inferred from individual orthologous genes, suggesting subfamily Myospalacinae is more closely related to subfamily Rhizomyinae. The same topology was recovered from concatenated sequences of 5,116 nuclear genes, fourfold degenerate sites of the 5,116 nuclear genes and concatenated sequences of 13 protein coding mitochondrial genes.
Conclusions
This is the first report of transcriptome sequencing in zokors and bamboo rats, representing a valuable resource for future studies of comparative genomics in subterranean mammals. Phylogenomic analysis provides a conclusive resolution of interrelationships of the three subfamilies within the family Spalacidae, and highlights the power of phylogenomic approach to dissect the evolutionary history of rapid radiations in the tree of life.
doi:10.1186/1471-2164-15-32
PMCID: PMC3898070  PMID: 24438217
Spalacidae; Phylogenomics; Transcriptome; Mitochondrial genome; Subterranean rodents
5.  HIV-1/Cocaine Induced Oxidative Stress Disrupts Tight Junction Protein-1 in Human Pulmonary Microvascular Endothelial Cells: Role of Ras/ERK1/2 Pathway 
PLoS ONE  2014;9(1):e85246.
Intravenous drug use (IVDU) is the major risk factor in the development of HIV-related pulmonary arterial hypertension (HRPAH); however, the pathogenesis of HRPAH in association with IVDU has yet to be characterized. Endothelial injury is considered to be an initiating factor for pulmonary vascular remodeling in animal models of PAH. Our previous study shows that simultaneous exposure to HIV-Trans-activator of transcription (Tat) and cocaine exacerbates both disruption of tight junction proteins and permeability of human pulmonary artery endothelial cells compared with either treatment alone. We here now demonstrate that this HIV-Tat and cocaine mediated endothelial dysfunction accompanies with increase in hydrogen peroxide and superoxide radicals generation and involves redox sensitive signaling pathway. Pretreatment with antioxidant cocktail attenuated the cocaine and Tat mediated disassembly of Zonula Occludens (ZO)-1 and enhancement of endothelial monolayer permeability. Furthermore, inhibition of NADPH oxidase by apocynin or siRNA-mediated knockdown of gp-91phox abolished the Tat/cocaine-induced reactive oxygen species (ROS) production, suggesting the NADPH oxidase mediated generation of oxidative radicals. In addition, ROS dependent activation of Ras and ERK1/2 Kinase was observed to be mediating the TJP-1 disassembly, and endothelial dysfunction in response to cocaine and Tat exposure. In conclusion, our findings demonstrate that Tat/cocaine -mediated production of ROS activate Ras/Raf/ERK1/2 pathway that contributes to disruption of tight junction protein leading to pulmonary endothelial dysfunction associated with pulmonary vascular remodeling.
doi:10.1371/journal.pone.0085246
PMCID: PMC3883699  PMID: 24409324
6.  Metabolic effects of testosterone replacement therapy on hypogonadal men with type 2 diabetes mellitus: A systematic review and meta-analysis of randomized controlled trials 
Asian Journal of Andrology  2013;16(1):146-152.
This systematic review was aimed at assessing the metabolic effects of testosterone replacement therapy (TRT) on hypogonadal men with type 2 diabetes mellitus (T2DM). A literature search was performed using the Cochrane Library, EMBASE and PubMed. Only randomized controlled trials (RCTs) were included in the meta-analysis. Two reviewers retrieved articles and evaluated the study quality using an appropriate scoring method. Outcomes including glucose metabolism, lipid parameters, body fat and blood pressure were pooled using a random effects model and tested for heterogeneity. We used the Cochrane Collaboration's Review Manager 5.2 software for statistical analysis. Five RCTs including 351 participants with a mean follow-up time of 6.5-months were identified that strictly met our eligibility criteria. A meta-analysis of the extractable data showed that testosterone reduced fasting plasma glucose levels (mean difference (MD): −1.10; 95% confidence interval (CI) (−1.88, −0.31)), fasting serum insulin levels (MD: −2.73; 95% CI (−3.62, −1.84)), HbA1c % (MD: −0.87; 95% CI (−1.32, −0.42)) and triglyceride levels (MD: −0.35; 95% CI (−0.62, −0.07)). The testosterone and control groups demonstrated no significant difference for other outcomes. In conclusion, we found that TRT can improve glycemic control and decrease triglyceride levels of hypogonadal men with T2DM. Considering the limited number of participants and the confounding factors in our systematic review; additional large, well-designed RCTs are needed to address the metabolic effects of TRT and its long-term influence on hypogonadal men with T2DM.
doi:10.4103/1008-682X.122346
PMCID: PMC3901874  PMID: 24369149
humans; hypogonadism; male; testosterone; type 2 diabetes mellitus
8.  Which Biomarkers Reveal Neonatal Sepsis? 
PLoS ONE  2013;8(12):e82700.
We address the identification of optimal biomarkers for the rapid diagnosis of neonatal sepsis. We employ both canonical correlation analysis (CCA) and sparse support vector machine (SSVM) classifiers to select the best subset of biomarkers from a large hematological data set collected from infants with suspected sepsis from Yale-New Haven Hospital's Neonatal Intensive Care Unit (NICU). CCA is used to select sets of biomarkers of increasing size that are most highly correlated with infection. The effectiveness of these biomarkers is then validated by constructing a sparse support vector machine diagnostic classifier. We find that the following set of five biomarkers capture the essential diagnostic information (in order of importance): Bands, Platelets, neutrophil CD64, White Blood Cells, and Segs. Further, the diagnostic performance of the optimal set of biomarkers is significantly higher than that of isolated individual biomarkers. These results suggest an enhanced sepsis scoring system for neonatal sepsis that includes these five biomarkers. We demonstrate the robustness of our analysis by comparing CCA with the Forward Selection method and SSVM with LASSO Logistic Regression.
doi:10.1371/journal.pone.0082700
PMCID: PMC3867385  PMID: 24367543
9.  A simple Fourier transform-based reconstruction formula for photoacoustic computed tomography with a circular or spherical measurement geometry 
Physics in medicine and biology  2012;57(23):N493-N499.
Photoacoustic computed tomography (PACT), also known as optoacoustic tomography, is an emerging imaging modality that has great potential for a wide range of biomedical imaging applications. In this Note, we derive a hybrid reconstruction formula that is mathematically exact and operates on a data function that is expressed in the temporal frequency and spatial domains. This formula explicitly reveals new insights into how the spatial frequency components of the sought-after object function are determined by the temporal frequency components of the data function measured with a circular or spherical measurement geometry in two- and three-dimensional implementations of PACT, respectively. The structure of the reconstruction formula is surprisingly simple compared with existing Fourier-domain reconstruction formulae. It also yields a straightforward numerical implementation that is robust and two orders of magnitude more computationally efficient than filtered backprojection algorithms.
doi:10.1088/0031-9155/57/23/N493
PMCID: PMC3542417  PMID: 23165199
10.  FHIT overexpression in HepG2 hepatoma cells affects growth and cyclin D1 expression in vitro 
The aim of this study was to investigate the methylation status of fragile histidine triad (FHIT) and the effects of FHIT on cell growth and cyclin D1 expression in hepatoma cells. The total proteins from the human hepatoma cell lines HepG2, Hep3B and Huh7 were collected and the expression levels of FHIT were analyzed. The methylation status in the promoter region of FHIT in the hepatoma cells was measured using methylation-specific polymerase chain reaction (PCR). The HepG2, Hep3B and Huh7 cells were subsequently treated with 5-aza-2′-deoxycytidine (5-azadc) and the restoration of FHIT expression was then examined. A p-hemagglutinin (HA)-FHIT plasmid was constructed and used to transfect the HepG2 cells, and the inhibitory effects of the transfection on cell growth were then assessed. In addition, HepG2 cells were cotransfected with the pHA-FHIT plasmid and a cyclin D1 luciferase reporter plasmid, and the effects of FHIT on the activity of cyclin D1 transcription factor were analyzed using a luciferase assay. FHIT was observed to be expressed at a low level in Hep3B and HepG2 cells; however, it was expressed at a relatively high level in Huh7 cells. The promoter region of FHIT in the Hep3B and HepG2 cells was partially methylated, and 5-azadc treatment induced an increased expression of FHIT. The increased expression of FHIT inhibited the growth of HepG2 cells. Cotransfection with the pHA-FHIT plasmid significantly inhibited the transcriptional activity of the cyclin D1 promoter and decreased the expression of cyclin D1 in HepG2 cells. In conclusion, FHIT was partially methylated in the HepG2 and Hep3B hepatoma cells. The overexpression of FHIT inhibited cell growth and decreased the expression of cyclin D1 in HepG2 cells.
doi:10.3892/etm.2013.1436
PMCID: PMC3881045  PMID: 24396396
hepatoma; fragile histidine triad; methylation; cyclin D1; signaling pathway
11.  A Novel Voice Sensor for the Detection of Speech Signals 
Sensors (Basel, Switzerland)  2013;13(12):16533-16550.
In order to develop a novel voice sensor to detect human voices, the use of features which are more robust to noise is an important issue. Voice sensor is also called voice activity detection (VAD). Due to that the inherent nature of the formant structure only occurred on the speech spectrogram (well-known as voiceprint), Wu et al. were the first to use band-spectral entropy (BSE) to describe the characteristics of voiceprints. However, the performance of VAD based on BSE feature was degraded in colored noise (or voiceprint-like noise) environments. In order to solve this problem, we propose the two-dimensional part-band energy entropy (TD-PBEE) parameter based on two variables: part-band partition number upon frequency index and long-term window size upon time index to further improve the BSE-based VAD algorithm. The two variables can efficiently represent the characteristics of voiceprints on each critical frequency band and use long-term information for noisy speech spectrograms, respectively. The TD-PBEE parameter can be regarded as a PBEE parameter over time. First, the strength of voiceprints can be partly enhanced by using four entropies applied to four part-bands. We can use the four part-band energy entropies for describing the voiceprints in detail. Due to the characteristics of non-stationary for speech and various noises, we will then use long-term information processing to refine the PBEE, so the voice-like noise can be distinguished from noisy speech through the concept of PBEE with long-term information. Our experiments show that the proposed feature extraction with the TD-PBEE parameter is quite insensitive to background noise. The proposed TD-PBEE-based VAD algorithm is evaluated for four types of noises and five signal-to-noise ratio (SNR) levels. We find that the accuracy of the proposed TD-PBEE-based VAD algorithm averaged over all noises and all SNR levels is better than that of other considered VAD algorithms.
doi:10.3390/s131216533
PMCID: PMC3892860  PMID: 24316566
voice sensor; two-dimensional; part-band energy entropy; long-term information analysis; Mel-scaled filter bank
12.  Iterative feature removal yields highly discriminative pathways 
BMC Genomics  2013;14:832.
Background
We introduce Iterative Feature Removal (IFR) as an unbiased approach for selecting features with diagnostic capacity from large data sets. The algorithm is based on recently developed tools in machine learning that are driven by sparse feature selection goals. When applied to genomic data, our method is designed to identify genes that can provide deeper insight into complex interactions while remaining directly connected to diagnostic utility. We contrast this approach with the search for a minimal best set of discriminative genes, which can provide only an incomplete picture of the biological complexity.
Results
Microarray data sets typically contain far more features (genes) than samples. For this type of data, we demonstrate that there are many equivalently-predictive subsets of genes. We iteratively train a classifier using features identified via a sparse support vector machine. At each iteration, we remove all the features that were previously selected. We found that we could iterate many times before a sustained drop in accuracy occurs, with each iteration removing approximately 30 genes from consideration. The classification accuracy on test data remains essentially flat even as hundreds of top-genes are removed.
Our method identifies sets of genes that are highly predictive, even when comprised of genes that individually are not. Through automated and manual analysis of the selected genes, we demonstrate that the selected features expose relevant pathways that other approaches would have missed.
Conclusions
Our results challenge the paradigm of using feature selection techniques to design parsimonious classifiers from microarray and similar high-dimensional, small-sample-size data sets. The fact that there are many subsets of genes that work equally well to classify the data provides a strong counter-result to the notion that there is a small number of “top genes” that should be used to build classifiers. In our results, the best classifiers were formed using genes with limited univariate power, thus illustrating that deeper mining of features using multivariate techniques is important.
doi:10.1186/1471-2164-14-832
PMCID: PMC3879090  PMID: 24274115
Feature selection; Microarray; Discrimination; Classification; Pathways; Sparse SVM; Influenza
13.  Catheter-Based Renal Sympathetic Denervation Significantly Inhibits Atrial Fibrillation Induced by Electrical Stimulation of the Left Stellate Ganglion and Rapid Atrial Pacing 
PLoS ONE  2013;8(11):e78218.
Background
Sympathetic activity involves the pathogenesis of atrial fibrillation (AF). Renal sympathetic denervation (RSD) decreases sympathetic renal afferent nerve activity, leading to decreased central sympathetic drive. The aim of this study was to identify the effects of RSD on AF inducibility induced by hyper-sympathetic activity in a canine model.
Methods
To establish a hyper-sympathetic tone canine model of AF, sixteen dogs were subjected to stimulation of left stellate ganglion (LSG) and rapid atrial pacing (RAP) for 3 hours. Then animals in the RSD group (n = 8) underwent radiofrequency ablation of the renal sympathetic nerve. The control group (n = 8) underwent the same procedure except for ablation. AF inducibility, effective refractory period (ERP), ERP dispersion, heart rate variability and plasma norepinephrine levels were measured at baseline, after stimulation and after ablation.
Results
LSG stimulation combined RAP significantly induced higher AF induction rate, shorter ERP, larger ERP dispersion at all sites examined and higher plasma norepinephrine levels (P<0.05 in all values), compared to baseline. The increased AF induction rate, shortened ERP, increased ERP dispersion and elevated plasma norepinephrine levels can be almost reversed by RSD, compared to the control group (P<0.05). LSG stimulation combined RAP markedly shortened RR-interval and standard deviation of all RR-intervals (SDNN), Low-frequency (LF), high-frequency (HF) and LF/HF ratio (P<0.05). These changes can be reversed by RSD, compared to the control group (P<0.05).
Conclusions
RSD significantly reduced AF inducibility and reversed the atrial electrophysiological changes induced by hyper-sympathetic activity.
doi:10.1371/journal.pone.0078218
PMCID: PMC3819364  PMID: 24223140
14.  Elevation of Matrix Metalloproteinase-9 Level in Cerebrospinal Fluid of Tick-Borne Encephalitis Patients Is Associated with IgG Extravassation and Disease Severity 
PLoS ONE  2013;8(11):e77427.
Background
Tick-borne encephalitis (TBE), caused by tick-borne encephalitis virus (TBEV), is an infectious disease involving the central nervous system (CNS). The pathogenesis of CNS injury has not been clearly demonstrated. Matrix metalloproteinase-9 (MMP-9) and some cytokines, such as interleukin 6 (IL-6), may play important roles in the disruption of the blood-brain barrier (BBB) and the pathogenesis of TBE.
Methods
72 cerebrospinal fluid (CSF) samples were collected from TBE patients in north eastern China. IgG levels in CSF and serum were compared and MMP-9 and IL-6 levels were evaluated by ELISA. The correlation between the elevated MMP-9 levels and IgG extravasation, disease severity, and neuroinflammation was analyzed.
Results
Increased concentration of MMP-9 was detected in some of the CSF samples, and the elevation was found to be closely related to CSF TBEV IgG extravasation and enhancement of IL-6 expression. Moreover, elevated levels of MMP-9 were found to be correlated with IL-6 enhancement. Four of the 72 patients, the ones who died, presented with high CSF MMP-9 levels.
Conclusions
In TBE patients, elevated CSF MMP-9 levels were associated with brain inflammatory reaction, disruption of the blood-brain barrier, and disease severity.
doi:10.1371/journal.pone.0077427
PMCID: PMC3815297  PMID: 24223711
15.  Evaluation of acoustic radiation force impulse imaging for the clinicopathological typing of renal fibrosis 
This study aimed to explore the assessment value of virtual touch quantization (VTQ) for the clinicopathological typing of renal fibrosis. The quantitative detection of 76 patients with nephropathy was performed using acoustic radiation force impulse imaging (ARFI). The extent of the renal fibrosis in each patient was confirmed using ultrasound-guided biopsy pathology. The VTQ values were compared with the degree of renal fibrosis in order to analyze the correlation between them. Patients were divided pathologically into four groups, as follows: non-fibrosis (n=14), mild fibrosis (n=40), moderate fibrosis (n=21) and severe fibrosis (n=1). Compared with the non-fibrosis group, the VTQ values of the mild and moderate fibrosis groups were significantly increased (P<0.01); however, there was no significant difference between the VTQ values of the mild and moderate fibrosis groups (P>0.05). According to the receiver operating characteristic (ROC) curve, a VTQ value of renal parenchyma of >1.67 m/sec was determined to be an indicator of renal fibrosis, with a sensitivity of 86.3% and a specificity of 83.3%. VTQ technology may be significant in the assessment of the extent of renal fibrosis.
doi:10.3892/etm.2013.1377
PMCID: PMC3860982  PMID: 24348796
ultrasonograph; kidney; fibrosis; acoustic radiation force impulse imaging
16.  Correction: MiR-30a-5p Antisense Oligonucleotide Suppresses Glioma Cell Growth by Targeting SEPT7 
PLoS ONE  2013;8(10):10.1371/annotation/9a8447a4-bffe-445f-b323-7e200896aea9.
doi:10.1371/annotation/9a8447a4-bffe-445f-b323-7e200896aea9
PMCID: PMC3795152  PMID: 24130659
17.  Bacterial Community Mapping of the Mouse Gastrointestinal Tract 
PLoS ONE  2013;8(10):e74957.
Keeping mammalian gastrointestinal (GI) tract communities in balance is crucial for host health maintenance. However, our understanding of microbial communities in the GI tract is still very limited. In this study, samples taken from the GI tracts of C57BL/6 mice were subjected to 16S rRNA gene sequence-based analysis to examine the characteristic bacterial communities along the mouse GI tract, including those present in the stomach, duodenum, jejunum, ileum, cecum, colon and feces. Further analyses of the 283,234 valid sequences obtained from pyrosequencing revealed that the gastric, duodenal, large intestinal and fecal samples had higher phylogenetic diversity than the jejunum and ileum samples did. The microbial communities found in the small intestine and stomach were different from those seen in the large intestine and fecal samples. A greater proportion of Lactobacillaceae were found in the stomach and small intestine, while a larger proportion of anaerobes such as Bacteroidaceae, Prevotellaceae, Rikenellaceae, Lachnospiraceae, and Ruminococcaceae were found in the large intestine and feces. In addition, inter-mouse variations of microbiota were observed between the large intestinal and fecal samples, which were much smaller than those between the gastric and small intestinal samples. As far as we can ascertain, ours is the first study to systematically characterize bacterial communities from the GI tracts of C57BL/6 mice.
doi:10.1371/journal.pone.0074957
PMCID: PMC3792069  PMID: 24116019
18.  Effects of circumcision on male sexual functions: a systematic review and meta-analysis 
Asian Journal of Andrology  2013;15(5):662-666.
This meta-analysis was performed to assess sexual functions following adult male circumcision. We searched the Cochrane Central Register of Controlled Trials, PUBMED, EMBASE, the Cochrane Database of Systematic Review and Web of Science from their inception until January 2013 to identify all eligible studies that reported on men's sexual function after circumcision. The Cochrane Collaboration's RevMan 5.2 software was employed for data analysis, and the fixed or the random effect model was selected depending on the proportion of heterogeneity. We identified 10 studies, which described a total of 9317 circumcised and 9423 uncircumcised men who were evaluated for the association of circumcision with male sexual function. There were no significant differences in sexual desire (odds ratio (OR): 0.99; 95% confidence interval (CI): 0.92–1.06), dyspareunia (OR: 1.12; 95% CI: 0.52–2.44), premature ejaculation (OR: 1.13; 95% CI: 0.83–1.54), ejaculation latency time (OR: 1.33; 95% CI: 0.69–1.97), erectile dysfunctions (OR: 0.90; 95% CI: 0.65–1.25) and orgasm difficulties (OR: 0.97; 95% CI: 0.83–1.13). These findings suggest that circumcision is unlikely to adversely affect male sexual functions. However, these results should be evaluated in light of the low quality of the existing evidence and the significant heterogeneity across the various studies. Well-designed and prospective studies are required for a further understanding of this topic.
doi:10.1038/aja.2013.47
PMCID: PMC3881635  PMID: 23749001
complications; male circumcision; review; sexual function
19.  Glioblastoma mimicking a cerebral contusion: A case report 
Oncology Letters  2013;6(5):1499-1501.
A 61-year-old male presented with a rare case of glioblastoma mimicking a cerebral contusion subsequent to collapsing. The patient had been medicated for hypertension for seven years and diabetes for eight years prior to hospitalization. Brain computed tomography (CT) revealed a cerebral contusion and intracerebral hemorrhage (ICH) in the left temporal region. The patient was initially administered intravenous drugs to reduce the intracranial pressure following the diagnosis of a cerebral contusion. Serial CT revealed ICH resorption. However, the patient was again admitted due to a headache and vomiting two months later. Magnetic resonance imaging (MRI) demonstrated an enhanced ring-shaped mass around the cyst cavity within the left temporal region, with surrounding edema. The patient underwent cyst puncture drainage in the temporal region. No tumor cells were identified in the cyst fluid and the culture was also negative. The patient was admitted for a headache and vomiting for the third time one month after being discharged. A cyst, tumor and meningoencephalitis were suspected following an MRI scan. The patient was treated with a left temporal craniotomy for a mass resection and biopsy. The histological diagnosis of the biopsy specimen was that of a glioblastoma. Two months later, MRI revealed a recurrence of the glioblastoma. In the present case, a brain tumor should have initially been suspected as the cause of the ICH, despite the history of craniocerebral trauma and hypertension. Early awareness of this potential cause of ICH may facilitate a more prompt diagnosis and treatment.
doi:10.3892/ol.2013.1537
PMCID: PMC3813812  PMID: 24179548
brain tumor; craniocerebral trauma; intratumoral hemorrhage; diagnosis; treatment
20.  Microevolution from shock to adaptation revealed strategies improving ethanol tolerance and production in Thermoanaerobacter 
Introduction
The molecular links between shock-response and adaptation remain poorly understood, particularly for extremophiles. This has hindered rational engineering of solvent tolerance and correlated traits (e.g., productivity) in extremophiles. To untangle such molecular links, here we established a model that tracked the microevolution from shock to adaptation in thermophilic bacteria.
Method
Temporal dynamics of genomes and transcriptomes was tracked for Thermoanaerobacter sp. X514 which under increasing exogenous ethanol evolved from ethanol-sensitive wild-type (Strain X) to tolerance of 2%- (XI) and eventually 6%-ethanol (XII). Based on the reconstructed transcriptional network underlying stress tolerance, genetic engineering was employed to improve ethanol tolerance and production in Thermoanaerobacter.
Results
The spontaneous genome mutation rate (μg) of Thermoanaerobacter sp. X514, calculated at 0.045, suggested a higher mutation rate in thermophile than previously thought. Transcriptomic comparison revealed that shock-response and adaptation were distinct in nature, whereas the transcriptomes of XII resembled those of the extendedly shocked X. To respond to ethanol shock, X employed fructose-specific phosphotransferase system (PTS), Arginine Deiminase (ADI) pathway, alcohol dehydrogenase (Adh) and a distinct mechanism of V-type ATPase. As an adaptation to exogenous ethanol, XI mobilized resistance-nodulation-cell division (RND) efflux system and Adh, whereas XII, which produced higher ethanol than XI, employed ECF-type ϭ24, an alcohol catabolism operon and phase-specific heat-shock proteins (Hsps), modulated hexose/pentose-transport operon structure and reinforced membrane rigidity. Exploiting these findings, we further showed that ethanol productivity and tolerance can be improved simultaneously by overexpressing adh or ϭ24 in X.
Conclusion
Our work revealed thermophilic-bacteria specific features of adaptive evolution and demonstrated a rational strategy to engineer co-evolving industrial traits. As improvements of shock-response, stress tolerance and productivity have been crucial aims in industrial applications employing thermophiles, our findings should be valuable not just to the production of ethanol but also to a wide variety of biofuels and biochemicals.
doi:10.1186/1754-6834-6-103
PMCID: PMC3751872  PMID: 23875846
Shock; Adaptation; Ethanol; Microevolution; Thermophile
21.  Use of Fidji Cervical Cage in the Treatment of Cervical Spinal Cord Injury without Radiographic Abnormality 
BioMed Research International  2013;2013:810172.
Spinal cord injury without radiographic abnormality (SCIWORA) is a rare condition seen in adults. Many interbody fusion cages have been developed for its treatment, but clinical studies of Fidji cervical cage are still scarce. A total number of five patients (four male and one female) were reviewed. The ages of the patients ranged from 40 to 60 years. All the patients underwent neurological and radiological examinations. Neurological and functional outcomes were assessed on the basis of Frankel's grade. Three of the patients were Frankel B, and the rest two were Frankel C. Magnetic resonance imaging was also performed for the evaluation of spinal cord and intervertebral disc injury. Anterior cervical discectomy and Fidji cervical cage fusion were performed for all. The fusion status was evaluated on the basis of X-rays. After surgical intervention, the clinical symptoms improved for all the patients. The disc interspaces in all the patients achieved solid union at final follow-up. Fidji cervical cage is very efficient in achieving cervical fusion in patients with SCIWORA. There are few complications associated with the use of this cage, and the functional and neurological outcomes are satisfactory.
doi:10.1155/2013/810172
PMCID: PMC3703380  PMID: 23844369
22.  Sanguinarine Inhibits Vascular Endothelial Growth Factor Release by Generation of Reactive Oxygen Species in MCF-7 Human Mammary Adenocarcinoma Cells 
BioMed Research International  2013;2013:517698.
The inhibitory action and the possible mechanism of anticancer compound Sanguinarine (SAN) on vascular endothelial growth factor (VEGF) in human mammary adenocarcinoma cells MCF-7 were evaluated in this study. We exposed MCF-7 to SAN for 24 h, then cell viability was assessed by using the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) reduction assay. Human VEGF was measured using a paired antibody quantitative ELISA kit, relative expression of VEGF mRNA was calculated using the real-time PCR studies, and the effect of SAN on the reactive oxygen species (ROS) level was detected by the flow cytometer. Treatment with SAN remarkably inhibited growth of MCF-7 cells and induced cell apoptosis. We found that VEGF release was stimulated by subtoxic concentrations of SAN and inhibited by high dose of SAN, SAN-evoked VEGF release was mimicked by low concentration of H2O2, and SAN-regulated VEGF inhibition was accompanied by increasing of ROS; these changes were abolished by antioxidant. High concentration of SAN inhibited VEGF mRNA expression in MCF-7 cultures, suggesting an effect at transcriptional level, and was also abolished by antioxidant. The present findings indicated that the regulation of VEGF expression and release from MCF-7 cells were possibly through reactive oxygen species evoked by SAN.
doi:10.1155/2013/517698
PMCID: PMC3673330  PMID: 23762849
23.  4-Di­phenyl­phosphanyl-8-methyl-1,5-naphthyridine 
In the title compound, C21H17N2P, the dihedral angles between the 1,5-naphthyridine ring system (r.m.s. deviation = 0.005 Å) and the phenyl rings are 89.18 (8) and 77.39 (8)°. The phenyl rings are almost perpendicular, making a dihedral angle of 88.12 (8)°. The only possible inter­molecular inter­action is a very weak aromatic π–π stacking inter­action [centroid–centroid separation = 3.898 (2) Å].
doi:10.1107/S1600536813013196
PMCID: PMC3685077  PMID: 23795096
24.  Effects of sodium ferulate on preventing steroid-induced femoral head osteonecrosis in rabbits 
The aim of this study is to investigate the effects and possible mechanisms of sodium ferulate (SF) on anti-apoptosis in steroid-induced femoral head osteonecrosis in rabbits. Japanese white rabbits were randomly divided into three groups (control group, treatment group, and model group), each with 24 rabbits. The model and treatment groups were first injected with an intravenous dose of horse serum, 10 ml/kg, three weeks later with an intravenous dose of 7.5 ml/kg, and two weeks later with an intramuscular dose of methylprednisolone, 45 mg/kg, three times in order to establish rabbit models of osteonecrosis. Concurrently, the treatment group was injected with intravenous doses of SF 20 mg/kg for two weeks, once per day. Three time points, Weeks 2, 4, and 8, were selected after modeling was completed. Osteonecrosis was verified by histopathology with haematoxylin-eosin (HE) staining. The apoptosis rate of osteonecrosis was observed by terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) assay. The apoptosis expressions of caspase-3 and Bcl-2 were analyzed by immunohistochemistry and Western blot. The rabbit models of osteonecrosis were successfully established and observed by HE staining. SF was effective in intervening in apoptosis and decreasing the apoptosis rate in femoral head necrosis by the immunohistochemistry and TUNEL assay (P<0.01). Western blot analysis indicated that there were statistical significances in the protein levels of caspase-3 and Bcl-2 (P<0.01). SF has a protective effect by reducing the incidence of early steroid-induced femoral head necrosis in rabbits, effectively intervening in apoptosis through decreasing caspase-3 expression and up-regulating Bcl-2 expression.
doi:10.1631/jzus.B1200311
PMCID: PMC3650456  PMID: 23645179
Femoral head necrosis; Glucocorticoid; Sodium ferulate; Apoptosis; Rabbit
25.  Application of liposomes in drug development — focus on gastroenterological targets 
Over the past decade, liposomes became a focal point in developing drug delivery systems. New liposomes, with novel lipid molecules or conjugates, and new formulations opened possibilities for safely and efficiently treating many diseases including cancers. New types of liposomes can prolong circulation time or specifically deliver drugs to therapeutic targets. This article concentrates on current developments in liposome based drug delivery systems for treating diseases of the gastrointestinal tract. We will review different types and uses of liposomes in the development of therapeutics for gastrointestinal diseases including inflammatory bowel diseases and colorectal cancer.
doi:10.2147/IJN.S42153
PMCID: PMC3623572  PMID: 23630417
liposome; colorectal cancer; inflammatory bowel disease; drug delivery

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