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1.  Spatial features for Escherichia coli genome organization 
BMC Genomics  2015;16(1):37.
Background
In bacterial genomes, the compactly encoded genes and operons are well organized, with genes in the same biological pathway or operons in the same regulon close to each other on the genome sequence. In addition, the linearly close genes have a higher probability of co-expression and their protein products tend to form protein–protein interactions. However, the organization features of bacterial genomes in a three-dimensional space remain elusive. The DNA interaction data of Escherichia coli, measured by the genome conformation capture (GCC) technique, have recently become available, which allowed us to investigate the spatial features of bacterial genome organization.
Results
By renormalizing the GCC data, we compared the interaction frequency of operon pairs in the same regulon with that of random operon pairs. The results showed that arrangements of operons in the E. coli genome tend to minimize the spatial distance between operons in the same regulon. A similar global organization feature exists for genes in biological pathways of E. coli. In addition, the genes close to each other spatially (even if they are far from each other on the genome sequence) tend to be co-expressed and form protein–protein interactions. These results provided new insights into the organization principles of bacterial genomes and support the notion of transcription factory.
Conclusions
This study revealed the organization features of Escherichia coli genomic functional units in the 3D space and furthered our understanding of the link between the three-dimensional structure of chromosomes and biological function.
Electronic supplementary material
The online version of this article (doi:10.1186/s12864-015-1258-1) contains supplementary material, which is available to authorized users.
doi:10.1186/s12864-015-1258-1
PMCID: PMC4326437  PMID: 25652224
Escherichia coli; Chromosome architecture; Genome organization; Co-expression; Protein–protein interactions
2.  Simultaneous hydrogen and ethanol production from cascade utilization of mono-substrate in integrated dark and photo-fermentative reactor 
Background
Integrating hydrogen-producing bacteria with complementary capabilities, dark-fermentative bacteria (DFB) and photo-fermentative bacteria (PFB), is a promising way to completely recover bioenergy from waste biomass. However, the current coupled models always suffer from complicated pretreatment of the effluent from dark-fermentation or imbalance between dark and photo-fermentation, respectively. In this work, an integrated dark and photo-fermentative reactor (IDPFR) was developed to completely convert an organic substrate into bioenergy.
Results
In the IDPFR, Ethanoligenens harbinese B49 and Rhodopseudomonas faecalis RLD-53 were separated by a membrane into dark and photo chambers, while the acetate produced by E. harbinese B49 in the dark chamber could freely pass through the membrane into the photo chamber and serve as a carbon source for R. faecalis RLD-53. The hydrogen yield increased with increasing working volume of the photo chamber, and reached 3.38 mol H2/mol glucose at the dark-to-photo chamber ratio of 1:4. Hydrogen production by the IDPFR was also significantly affected by phosphate buffer concentration, glucose concentration, and ratio of dark-photo bacteria. The maximum hydrogen yield (4.96 mol H2/mol glucose) was obtained at a phosphate buffer concentration of 20 mmol/L, a glucose concentration of 8 g/L, and a ratio of dark to photo bacteria of 1:20. As the glucose and acetate were used up by E. harbinese B49 and R. faecalis RLD-53, ethanol produced by E. harbinese B49 was the sole end-product in the effluent from the IDPFR, and the ethanol concentration was 36.53 mmol/L with an ethanol yield of 0.82 mol ethanol/mol glucose.
Conclusions
The results indicated that the IDPFR not only circumvented complex pretreatments on the effluent in the two-stage process, but also overcame the imbalance of growth and metabolic rate between DFB and PFB in the co-culture process, and effectively enhanced cooperation between E. harbinense B49 and R. faecalis RLD-53. Moreover, simultaneous hydrogen and ethanol production were achieved by coupling E. harbinese B49 and R. faecalis RLD-53 in the IDPFR. According to stoichiometry, the hydrogen and ethanol production efficiencies were 82.67% and 82.19%, respectively. Therefore, IDPFR was an effective strategy for coupling DFB and PFB to fulfill efficient energy recovery from waste biomass.
doi:10.1186/s13068-014-0191-x
PMCID: PMC4308915  PMID: 25648915
Hydrogen production; Ethanol production; Dark-fermentation; Photo-fermentation; Integrated dark and photo-fermentative reactor; Kinetics; Membrane
3.  Complete Genome Sequence of the Salmonella enterica Serovar Paratyphi A Bacteriophage LSPA1 Isolated in China 
Genome Announcements  2015;3(1):e01011-14.
The bacteriophage LSPA1 was isolated from hospital sewage (Kunming, China), and lytic activity was demonstrated against the Salmonella enterica serovar Paratyphi A CMCC50973 strain. This bacteriophage has a 41,880-bp double-stranded DNA (dsDNA) genome encoding 58 coding sequences (CDSs) and belongs to the family Siphoviridae.
doi:10.1128/genomeA.01011-14
PMCID: PMC4299886  PMID: 25593244
4.  Elucidating Pharmacological Mechanisms of Natural Medicines by Biclustering Analysis of the Gene Expression Profile: A Case Study on Curcumin and Si-Wu-Tang 
Natural medicines have attracted wide attention in recent years. It is of great significance to clarify the pharmacological mechanisms of natural medicines. In prior studies, we established a method for elucidating pharmacological mechanisms of natural products contained in connectivity map (cMap), in terms of module profiles of gene expression in chemical treatments. In this study, we explore whether this methodology is applicable to dissecting the pharmacological mechanisms of natural medicines beyond the agents contained in cMap. First, the gene expression profiles of curcumin (a typical isolated natural medicine) and Si-Wu-Tang (a classic traditional Chinese medicine formula) treatments were merged with those of cMap-derived 1309 agents, respectively. Then, a biclustering analysis was performed using FABIA method to identify gene modules. The biological functions of gene modules provide preliminary insights into pharmacological mechanisms of both natural medicines. The module profile can be characterized by a binary vector, which allowed us to compare the expression profiles of natural medicines with those of cMap-derived agents. Accordingly, we predicted a series of pharmacological effects for curcumin and Si-Wu-Tang by the indications of cMap-covered drugs. Most predictions were supported by experimental observations, suggesting the potential use of this method in natural medicine dissection.
doi:10.3390/ijms16010510
PMCID: PMC4307259  PMID: 25551600
natural medicines; pharmacology; biclustering analysis; curcumin; Si-Wu-Tang
5.  Consolidated bioprocessing performance of Thermoanaerobacterium thermosaccharolyticum M18 on fungal pretreated cornstalk for enhanced hydrogen production 
Background
Biological hydrogen production from lignocellulosic biomass shows great potential as a promising alternative to conventional hydrogen production methods, such as electrolysis of water and coal gasification. Currently, most researches on biohydrogen production from lignocellulose concentrate on consolidated bioprocessing, which has the advantages of simpler operation and lower cost over processes featuring dedicated cellulase production. However, the recalcitrance of the lignin structure induces a low cellulase activity, making the carbohydrates in the hetero-matrix more unapproachable. Pretreatment of lignocellulosic biomass is consequently an extremely important step in the commercialization of biohydrogen, and for massive realization of lignocellulosic biomass as alternative fuel feedstock. Thus, development of a pretreatment method which is cost efficient, environmentally benign, and highly efficient for enhanced consolidated bioprocessing of lignocellulosic biomass to hydrogen is essential.
Results
In this research, fungal pretreatment was adopted for enhanced hydrogen production by consolidated bioprocessing performance. To confirm the fungal pretreatment efficiency, two typical thermochemical pretreatments were also compared side by side. Results showed that the fungal pretreatment was superior to the other pretreatments in terms of high lignin reduction of up to 35.3% with least holocellulose loss (the value was only 9.5%). Microscopic structure observation combined with Fourier transform infrared spectroscopy (FTIR) analysis further demonstrated that the lignin and crystallinity of lignocellulose were decreased with better holocellulose reservation. Upon fungal pretreatment, the hydrogen yield and hydrogen production rate were 6.8 mmol H2 g-1 pretreated substrate and 0.89 mmol L-1 h-1, respectively, which were 2.9 and 4 times higher than the values obtained for the untreated sample.
Conclusions
Results revealed that although all pretreatments could contribute to the enhancement of hydrogen production from cornstalk, fungal pretreatment proved to be the optimal method. It is apparent that besides high hydrogen production efficiency, fungal pretreatment also offered several advantages over other pretreatments such as being environmentally benign and energy efficient. This pretreatment method thus has great potential for application in consolidated bioprocessing performance of hydrogen production.
doi:10.1186/s13068-014-0178-7
PMCID: PMC4296546  PMID: 25648837
Consolidated bioprocessing; Thermoanaerobacterium thermosaccharolyticum M18; Pretreatment; Hydrogen production; Cornstalk
6.  Pathological roles of the VEGF/SphK pathway in Niemann–Pick type C neurons 
Nature Communications  2014;5:5514.
Sphingosine is a major storage compound in Niemann–Pick type C disease (NP–C), although the pathological role(s) of this accumulation have not been fully characterized. Here we found that sphingosine kinase (SphK) activity is reduced in NP–C patient fibroblasts and NP–C mouse Purkinje neurons (PNs) due to defective vascular endothelial growth factor (VEGF) levels. Sphingosine accumulation due to inactivation of VEGF/SphK pathway led to PNs loss via inhibition of autophagosome–lysosome fusion in NP–C mice. VEGF activates SphK by binding to VEGFR2, resulting in decreased sphingosine storage as well as improved PNs survival and clinical outcomes in NP–C cells and mice. We also show that induced pluripotent stem cell (iPSC)-derived human NP–C neurons are generated and the abnormalities caused by VEGF/SphK inactivity in these cells are corrected by replenishment of VEGF. Overall, these results reveal a pathogenic mechanism in NP–C neurons where defective SphK activity is due to impaired VEGF levels.
Sphingosine is abnormally accumulated in Niemann–Pick type C disease (NP–C), but the causes of this accumulation have not been fully characterized. Here the authors show that sphingosine kinase activity is reduced in NP–C patient fibroblasts and NP–C mouse neurons due to defective vascular endothelial growth factor levels, suggesting therapeutic avenues.
doi:10.1038/ncomms6514
PMCID: PMC4263144  PMID: 25417698
7.  Mitochondrial Biogenesis and Fission in Axons in Cell Culture and Animal Models of Diabetic Neuropathy 
Acta neuropathologica  2010;120(4):477-489.
Mitochondrial-mediated oxidative stress in response to high glucose is proposed as a primary cause of dorsal root ganglia (DRG) neuron injury in the pathogenesis of diabetic neuropathy. In the present study, we report a greater number of mitochondria in both myelinated and unmyelinated dorsal root axons in a well-established model of murine diabetic neuropathy. No similar changes were seen in younger diabetic animals without neuropathy or in the ventral motor roots of any diabetic animals. These findings led us to examine mitochondrial biogenesis and fission in response to hyperglycemia in the neurites of cultured DRG neurons. We demonstrate overall mitochondrial biogenesis via increases in mitochondrial transcription factors and increases in mitochondrial DNA in both DRG neurons and axons. However, this process occurs over a longer time period than a rapidly observed increase in the number of mitochondria in DRG neurites that appears to result, at least in part, from mitochondrial fission. We conclude that during acute hyperglycemia, mitochondrial fission is a prominent response, and excessive mitochondrial fission may result in dysregulation of energy production, activation of caspase 3, and subsequent DRG neuron injury. During more prolonged hyperglycemia, there is evidence of compensatory mitochondrial biogenesis in axons. Our data suggest that an imbalance between mitochondrial biogenesis and fission may play a role in the pathogenesis of diabetic neuropathy.
doi:10.1007/s00401-010-0697-7
PMCID: PMC4254759  PMID: 20473509
8.  PRRT2 Mutations Are Related to Febrile Seizures in Epileptic Patients 
Previous studies reported that the proline-rich transmembrane protein 2 (PRRT2) gene was identified to be related to paroxysmal kinesigenic dyskinesia (PKD), infantile convulsions with PKD, PKD with migraine and benign familial infantile epilepsy (BFIE). The present study explores whether the PRRT2 mutation is a potential cause of febrile seizures, including febrile seizures plus (FS+), generalized epilepsy with febrile seizures plus (GEFS+) and Dravet syndrome (DS); thus, it may provide a new drug target for personalized medicine for febrile seizure patients. We screened PRRT2 exons in a cohort of 136 epileptic patients with febrile seizures, including FS+, GEFS+ and DS. PRRT2 genetic mutations were identified in 25 out of 136 (18.4%) febrile seizures in epileptic patients. Five loss-of-function and coding missense mutations were identified: c.649delC (p.R217Efs*12), c.649_650insC (p.R217Pfs*8), c.412C>G (p.Pro138Ala), c.439G>C (p.Asp147His) and c.623C>A (p.Ser208Tyr). PRRT2 variants were probably involved in the etiology of febrile seizures in epileptic patients.
doi:10.3390/ijms151223408
PMCID: PMC4284774  PMID: 25522171
proline-rich transmembrane protein 2; febrile seizures; mutation; epilepsy
9.  Efficacy of Alendronate for Preventing Collapse of Femoral Head in Adult Patients with Nontraumatic Osteonecrosis 
BioMed Research International  2014;2014:716538.
The purpose of the current review was to determine the efficacy of alendronate for preventing collapse of femoral head in adult patients with nontraumatic avascular osteonecrosis of femoral head (ANFH). Five randomized controlled trials (RCTs) involving 305 hips were included in this review, of which 3 studies investigated alendronate versus control/placebo and the other 2 studies compared the combination of alendronate and extracorporeal shockwave therapy (ESWT) with ESWT alone. Our results suggested that even the patients with extensive necrosis encountered much less collapse in the alendronate group than control group. In these RCTs, their data also indicated a positive short- and middle-term efficacy of alendronate treatment in joint function improvement and hip pain diminishment. With the presence of the outlier study, only insignificant overall efficacy of alendronate could be observed with substantial heterogeneities. In addition, we did not find any additive benefits of alendronate in combination with ESWT for preventing collapse compared to ESWT alone. In conclusion, there is still lack of strong evidence for supporting application of alendronate in adult patients with nontraumatic ANFH, which justified that large scale, randomized, and double-blind studies should be developed to demonstrate the confirmed efficacies, detailed indication, and optimized strategy of alendronate treatment.
doi:10.1155/2014/716538
PMCID: PMC4244931  PMID: 25535614
10.  Intractable hiccup caused by spinal cord lesions in demyelination disease 
Objective
This study aimed to summarize the clinical features of patients who presented intractable hiccup (IH) without brain and medulla oblongata (MO) lesions.
Method
This study included six patients who were diagnosed with inflammatory demyelinating myelitis, categorized as neuromyelitis optica (NMO), multiple sclerosis (MS), and myelitis. Patients who presented IH with cervical lesions but without MO lesions were also included. Clinical profiles, laboratory data, and magnetic resonance imaging findings were analyzed.
Results
Three out of six patients were diagnosed with NMO, whereas the remaining three were diagnosed with acute myelitis, recurrent myelities, and MS, respectively. The duration of hiccup was from 2 to 23 days (average = 9.33 ± 8.64 days). Five patients (83.33%, patients 1–5) had long segmental lesions and one had a patchy lesion. None of these patients had any MO lesions. Half of them were successfully treated with high-dose methylprednisolone combined with gamma-aminobutyric acid (GABA) inhibitor.
Conclusion
IH occurred in patients without MO lesion. However, the mechanism remained unclear. Immune factors of demyelinating neuropathy stimulated the hiccup reflex arch. Cervical cord lesions may activate the hiccup center. In general, IH can be controlled by IVMP combined with GABA inhibitor. Unilateral phrenic nerve block may elicit no effect.
doi:10.1179/2045772313Y.0000000148
PMCID: PMC3831336  PMID: 24090474
Intractable hiccup; Demyelinating disease; Myelitis; Multiple Sclerosis; Neuromyelitis optica
11.  11β-hydroxysteroid dehydrogenase types 1 and 2 in postnatal development of rat testis: gene expression, localization and regulation by luteinizing hormone and androgens 
Asian Journal of Andrology  2014;16(6):811-816.
11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) and type 2 (11β-HSD2) are expressed in rat testis, where they regulate the local concentrations of glucocorticoids. Here, we investigated the expression and localization of 11β-HSD in rat testis during postnatal development, and the regulation of these genes by luteinizing hormone (LH) and androgens. mRNA and protein levels were analyzed by quantitative real-time-polymerase chain reaction and western blotting, respectively, in testes collected from rats at postnatal day (PND) 7, 14, 21, 35, and 90, and from rats treated with LH, 7α-methyl-19-nortestosterone (MENT) and testosterone at PND 21 and PND 90. Immunohistochemical staining was used to identify the localization of the 11β-HSD in rat testis at PND 7, 14, and 90. We found that 11β-HSD1 expression was restricted to the interstitial areas, and that its levels increased during rat testis development. In contrast, whereas 11β-HSD2 was expressed in both the interstitial areas and seminiferous tubules at PND 7, it was present only in the interstitial areas at PND 90, and its levels declined during testicular development. Moreover, 11β-HSD1 mRNA was induced by LH in both the PND 21 and 90 testes and by MENT at PND 21, whereas 11β-HSD2 mRNA was induced by testosterone and MENT in the PND 21 testis and by LH in the PND 90 testis. In conclusion, our study indicates that the 11β-HSD1 and 11β-HSD2 genes have distinct patterns of spatiotemporal expression and hormonal regulation during postnatal development of the rat testis.
doi:10.4103/1008-682X.132471
PMCID: PMC4236321  PMID: 25038180
11β-hydroxysteroid dehydrogenase type 1; 11β-hydroxysteroid dehydrogenase type 2; development; Leydig cell; testis
12.  Time-Course Changes of Steroidogenic Gene Expression and Steroidogenesis of Rat Leydig Cells after Acute Immobilization Stress 
Leydig cells secrete testosterone, which is essential for male fertility and reproductive health. Stress increases the secretion of glucocorticoid (corticosterone, CORT; in rats), which decreases circulating testosterone levels in part through a direct action by binding to the glucocorticoid receptors (NR3C1) in Leydig cells. The intratesticular CORT level is dependent on oxidative inactivation of glucocorticoid by 11β-hydroxysteroid dehydrogenase 1 (HSD11B1) in Leydig cells. In the present study, we investigated the time-course changes of steroidogenic gene expression levels after acute immobilization stress in rats. The plasma CORT levels were significantly increased 0.5, 1, 3 and 6 h after immobilization stress, while plasma testosterone levels were significantly reduced 3 and 6 h, after stress and luteinizing hormone (LH) did not change. Immobilization stress caused the down-regulation of Scarb1, Star and Cyp17a1 expression levels in the rat testis starting at the first hour of stress, ahead of the significant decreases of plasma testosterone levels. Other mRNA levels, including Cyp11a1, Hsd3b1 and Hsd17b3, began to decline after 3 h. Hsd11b1 and Nos2 mRNA levels did not change during the course of stress. Administration of glucocorticoid antagonist RU486 significantly restored plasma testosterone levels. In conclusion, Scarb1, Star and Cyp17a1 expression levels are more sensitive to acute stress, and acute immobilization stress causes the decline of the steroidogenic pathway via elevating the levels of glucocorticoid, which binds to NR3C1 in Leydig cells to inhibit steroidogenic gene expression.
doi:10.3390/ijms151121028
PMCID: PMC4264210  PMID: 25405735
acute stress; Leydig cell; steroidogenic enzymes; rat; corticosterone; StAR
13.  Molecular Epidemiology of Human Rhinovirus in Children with Acute Respiratory Diseases in Chongqing, China 
Scientific Reports  2014;4:6686.
Human rhinovirus-C (HRV-C) has been increasingly detected in patients with acute respiratory diseases (ARDs). Prolonged surveillance was performed on children with ARD to investigate the molecular epidemiology and clinical characteristics of HRV in Chongqing, China. Nasopharyngeal aspirates (NPA) were collected from hospitalized children with ARD during 2009–2012. HRV-C was genotyped by sequencing the VP4/VP2 coding region. Among the 1,567 NPAs obtained, 223 (14.2%) were HRV positive, and 75.3% of these 223 NPAs were co-infected with other viruses. HRV-A (54.7%) and HRV-C (39.9%) accounted for the majority of HRV infections. Logistic regression models demonstrated significant associations between HRV-A, HRV-C, and asthma attacks, as well as between HRV-C and wheezing. A phylogenetic tree showed that HRV-C2 was the predominant type of HRV-C, followed by HRV-C43, HRV-C1, and HRV-C17. Three novel genotypes were proposed on the basis of a low identity with the known HRVs. Our results showed that HRV-A and HRV-C were the predominant types of HRV infection, and HRV-C showed a high genetic variation in Chongqing, China. HRV infection was associated with asthma attacks and wheezing; furthermore, HRV infections played a minor role in causing severe pneumonia. This knowledge provides information for the prevention and control of HRV associated with ARDs.
doi:10.1038/srep06686
PMCID: PMC4202208  PMID: 25328042
14.  Systematic Analysis of Time-Series Gene Expression Data on Tumor Cell-Selective Apoptotic Responses to HDAC Inhibitors 
SAHA (suberoylanilide hydroxamic acid or vorinostat) is the first nonselective histone deacetylase (HDAC) inhibitor approved by the US Food and Drug Administration (FDA). SAHA affects histone acetylation in chromatin and a variety of nonhistone substrates, thus influencing many cellular processes. In particularly, SAHA induces selective apoptosis of tumor cells, although the mechanism is not well understood. A series of microarray experiments was recently conducted to investigate tumor cell-selective proapoptotic transcriptional responses induced by SAHA. Based on that gene expression time series, we propose a novel framework for detailed analysis of the mechanism of tumor cell apoptosis selectively induced by SAHA. Our analyses indicated that SAHA selectively disrupted the DNA damage response, cell cycle, p53 expression, and mitochondrial integrity of tumor samples to induce selective tumor cell apoptosis. Our results suggest a possible regulation network. Our research extends the existing research.
doi:10.1155/2014/867289
PMCID: PMC4211306  PMID: 25371703
15.  Identification of Horizontally-transferred Genomic Islands and Genome Segmentation Points by Using the GC Profile Method 
Current Genomics  2014;15(2):113-121.
The nucleotide composition of genomes undergoes dramatic variations among all three kingdoms of life. GC content, an important characteristic for a genome, is related to many important functions, and therefore GC content and its distribution are routinely reported for sequenced genomes. Traditionally, GC content distribution is assessed by computing GC contents in windows that slide along the genome. Disadvantages of this routinely used window-based method include low resolution and low sensitivity. Additionally, different window sizes result in different GC content distribution patterns within the same genome. We proposed a windowless method, the GC profile, for displaying GC content variations across the genome. Compared to the window-based method, the GC profile has the following advantages: 1) higher sensitivity, because of variation-amplifying procedures; 2) higher resolution, because boundaries between domains can be determined at one single base pair; 3) uniqueness, because the GC profile is unique for a given genome and 4) the capacity to show both global and regional GC content distributions. These characteristics are useful in identifying horizontally-transferred genomic islands and homogenous GC-content domains. Here, we review the applications of the GC profile in identifying genomic islands and genome segmentation points, and in serving as a platform to integrate with other algorithms for genome analysis. A web server generating GC profiles and implementing relevant genome segmentation algorithms is available at: www.zcurve.net.
doi:10.2174/1389202915999140328163125
PMCID: PMC4009839  PMID: 24822029
GC profile; Genomic island; Genome segmentation.
16.  Effective Treatment of Manganese-Induced Occupational Parkinsonism With p-Aminosalicylic Acid: A Case of 17-Year Follow-Up Study 
Objective
Chronic manganese (Mn) intoxication induces syndromes resembling Parkinson disease. The clinical intervention has largely been unsuccessful. We report a 17-year follow-up study of effective treatment of occupational Mn parkinsonism with sodium para-aminosalicylic acid (PAS).
Methods
The patient, female and aged 50 at the time of treatment, was exposed to airborne Mn for 21 years (1963–1984). The patient had palpitations, hand tremor, lower limb myalgia, hypermyotonia, and a distinct festinating gait. She received 6 g PAS per day through an intravenous drip infusion for 4 days and rested for 3 days as one therapeutic course. Fifteen such courses were carried out between March and June 1987.
Results
At the end of PAS treatment, her symptoms were significantly alleviated, and handwriting recovered to normal. Recent follow-up examination at age 67 years (in 2004) showed a general normal presentation in clinical, neurologic, brain magnetic resonance imaging, and handwriting examinations with a minor yet passable gait.
Conclusions
This case study suggests that PAS appears to be an effective drug for treatment of severe chronic Mn poisoning with a promising prognosis.
doi:10.1097/01.jom.0000204114.01893.3e
PMCID: PMC4180660  PMID: 16766929
17.  Aberrant neuronal synaptic connectivity in CA1 area of the hippocampus from pilocarpine-induced epileptic rats observed by fluorogold 
In this study, we observed synaptic connectivity among neurons in CA1 region of pilocarpine-induced chronic seizures in rats. Twenty healthy male Sprague-Dawley rats were divided randomly into an epilepsy group (n = 10) and a control group (n = 10). Approximately 60 days after status epilepticus (SE) , Fluorogold (FG) was injected into the CA1 area of the hippocampus in vivo. Somatostatin (SS) expression was observed using immunofluorescence. The distribution of FG-positive and FG/SS double-labeled neurons was observed using a confocal microscope. FG-labeled pyramidal cells could be seen remotely from the FG-injected site in the CA1 area and in the subiculum in the experimental group. FG/SS double-labeled interneurons were distributed remotely from the FG-injected site in the CA1 area in the epileptic rats. These changes suggest aberrant neuronal connectivity in CA1 region, which may lead to the formation of aberrant excitatory and inhibitory circuitry, and may play an important role in the generation or compensation for temporal lobe epilepsy.
PMCID: PMC4211776  PMID: 25356126
Temporal lobe epilepsy (TLE); fluorogold (FG); somatostatin (SS); neuronal connectivity; circuit rearrangement; interneuron; lithium chloride; pilocarpin
18.  A Ubiquitin Shuttle DC-UbP/UBTD2 Reconciles Protein Ubiquitination and Deubiquitination via Linking UbE1 and USP5 Enzymes 
PLoS ONE  2014;9(9):e107509.
The ubiquitination levels of protein substrates in eukaryotic cells are delicately orchestrated by various protein cofactors and enzymes. Dendritic cell-derived ubiquitin (Ub)-like protein (DC-UbP), also named as Ub domain-containing protein 2 (UBTD2), is a potential Ub shuttle protein comprised of a Ub-like (UbL) domain and a Ub-binding domain (UBD), but its biological function remains largely unknown. We identified two Ub-related enzymes, the deubiquitinating enzyme USP5 and the Ub-activating enzyme UbE1, as interacting partners of DC-UbP from HEK 293T cells. Biochemical studies revealed that the tandem UBA domains of USP5 and the C-terminal Ub-fold domain (UFD) of UbE1 directly interacted with the C-terminal UbL domain of DC-UbP but on the distinct surfaces. Overexpression of DC-UbP in HEK 293T cells enhanced the association of these two enzymes and thus prompted cellular ubiquitination, whereas knockdown of the protein reduced the cellular ubiquitination level. Together, DC-UbP may integrate the functions of USP5 and UbE1 through interacting with them, and thus reconcile the cellular ubiquitination and deubiquitination processes.
doi:10.1371/journal.pone.0107509
PMCID: PMC4160250  PMID: 25207809
19.  Reduced expression of SOX7 in ovarian cancer: a novel tumor suppressor through the Wnt/β-catenin signaling pathway 
Background
Products of the SOX gene family play important roles in the life process. One of the members, SOX7, is associated with the development of a variety of cancers as a tumor suppression factor, but its relevance with ovarian cancer was unclear. In this study, we investigated the involvement of SOX7 in the progression and prognosis of epithelial ovarian cancer (EOC) and the involved mechanisms.
Methods
Expression profiles in two independent microarray data sets were analyzed for SOX7 between malignant and normal tissues. The expression levels of SOX7 in EOC, borderline ovarian tumors and normal ovarian tissues were measured by immunohistochemistry. We also measured levels of COX2 and cyclin-D1 to examine their possible involvement in the same signal transduction pathway as SOX7.
Results
The expression of SOX7 was significantly reduced in ovarian cancer tissues compared with normal controls, strongly indicating that SOX7 might be a negative regulator in the Wnt/β-catenin pathway in ovarian cancer. By immunohistochemistry staining, the protein expression of SOX7 showed a consistent trend with that of the gene expression microarray analysis. By contrast, the protein expression level of COX2 and cyclin-D1 increased as the tumor malignancy progressed, suggesting that SOX7 may function through the Wnt/β-catenin signaling pathway as a tumor suppressor. In comparison between the protein expression levels of SOX7 with pathological features of the cancer, we found that SOX7 was down-regulated mainly in serous cystadenocarcinoma and advanced stages of the cancers.
Conclusions
The expression of SOX7 correlates with tumor progression as a tumor suppressor, possibly through the Wnt/β-catenin signaling pathway in ovarian cancers, suggesting that SOX7 may be a promising prognostic marker.
Electronic supplementary material
The online version of this article (doi:10.1186/s13048-014-0087-1) contains supplementary material, which is available to authorized users.
doi:10.1186/s13048-014-0087-1
PMCID: PMC4172779  PMID: 25297608
SOX7; Tumor suppressor; Ovarian cancer; Wnt/β-catenin signaling pathway
20.  Hesitant Fuzzy Linguistic Multicriteria Decision-Making Method Based on Generalized Prioritized Aggregation Operator 
The Scientific World Journal  2014;2014:645341.
Based on linguistic term sets and hesitant fuzzy sets, the concept of hesitant fuzzy linguistic sets was introduced. The focus of this paper is the multicriteria decision-making (MCDM) problems in which the criteria are in different priority levels and the criteria values take the form of hesitant fuzzy linguistic numbers (HFLNs). A new approach to solving these problems is proposed, which is based on the generalized prioritized aggregation operator of HFLNs. Firstly, the new operations and comparison method for HFLNs are provided and some linguistic scale functions are applied. Subsequently, two prioritized aggregation operators and a generalized prioritized aggregation operator of HFLNs are developed and applied to MCDM problems. Finally, an illustrative example is given to illustrate the effectiveness and feasibility of the proposed method, which are then compared to the existing approach.
doi:10.1155/2014/645341
PMCID: PMC4165881  PMID: 25258729
21.  Expression Characteristics of KAI1 and Vascular Endothelial Growth Factor and Their Diagnostic Value for Hepatocellular Carcinoma 
Gut and Liver  2014;8(5):536-542.
Background/Aims
We tried to investigate the expression characteristics of KAI1, a suppressor of wide-spectrum tumor metastasis, and vascular endothelial growth factor (VEGF), the most common angiogenesis factor, and then to analyze their diagnostic value for hepatocellular carcinoma (HCC).
Methods
The protein and mRNA expression levels of KAI1 or VEGF in HCC tissues and in self-controlled para-carcinoma tissues were analyzed by Western blot and real-time polymerase chain reaction, respectively. Serum levels of KAI1 and VEGF in the patients with HCC, benign liver disease or in healthy controls were quantitatively detected by enzyme-linked immunosorbent assay.
Results
The expression level of KAI1 was downregulated, while the expression level of VEGF was upregulated in the tissues or serum of the patients with HCC. The expression level of serum KAI1 in HCC patients was correlated with TNM staging, intrahepatic metastasis, lymph node or peritoneal metastasis, and portal vein thrombus. In addition to the factors that were correlated with KAI1 expression, VEGF expression was also closely related to the α-fetoprotein level of the patients. The area under the receiver operating characteristic curve for the diagnosis of HCC was 0.907 for KAI1 and 0.779 for VEGF. The sensitivity of serum KAI1 levels in the diagnosis of HCC was 86.96%; the accuracy was 83.06%, while the sensitivity, the accuracy and the negative predictive value were improved to 91.86%, 84.68%, and 78.79% according to the combined detection of KAI1 and VEGF, respectively.
Conclusions
A combined detection of KAI1 and VEGF may greatly improve the efficiency of diagnosis and form a reliable panel of diagnostic markers for HCC.
doi:10.5009/gnl13331
PMCID: PMC4164248  PMID: 25071074
KAI1; Vascular endothelial growth factor; Hepatocellular carcinoma; Clinicopathological characteristics; Diagnostic value
22.  Safety and efficacy of S-1 chemotherapy in recurrent and metastatic nasopharyngeal carcinoma patients after failure of platinum-based chemotherapy: multi-institutional retrospective analysis 
Purpose
This retrospective study evaluates the efficacy and safety of S-1 chemotherapy for recurrent and metastatic nasopharyngeal carcinoma patients after failure of platinum-based chemotherapy.
Patients and methods
Thirty-nine patients with recurrent and metastatic nasopharyngeal carcinoma who failed previous platinum-based chemotherapy received oral S-1 chemotherapy (twice daily from day 1 to 14) every 3 weeks. The dose of S-1 was determined according to the body surface area (BSA): 40 mg twice a day for BSA <1.25 m2; 50 mg twice a day for 1.25 m2 ≤BSA<1.5 m2; and 60 mg twice a day for BSA ≥1.5 m2.
Results
Treatment was well tolerated. Most adverse events were mild. Grade 3 hematological toxicity occurred in 7.7%. There was one complete response (2.6%) and 12 partial responses (30.7%), giving an overall response rate of 33.3% (95% CI [confidence interval], 21.7–50.8). Median time-to-progression was 5.6 months, and median survival was 13.9 months. One- and 2-year survival rates were 60% and 26%, respectively.
Conclusion
S-1 monotherapy is considered a safe and effective treatment option for recurrent and metastatic nasopharyngeal carcinoma patients after failure of platinum-based chemotherapy.
doi:10.2147/DDDT.S67592
PMCID: PMC4140443  PMID: 25152614
S-1; nasopharyngeal carcinoma; chemotherapy; platinum
23.  Aging might augment reactive oxygen species (ROS) formation and affect reactive nitrogen species (RNS) level after myocardial ischemia/reperfusion in both humans and rats 
Age  2012;35(4):1017-1026.
Previous studies indicate aging results in significantly decreased cardiac function and increased myocardial apoptosis after myocardial ischemia/reperfusion (MI/R) in humans or rats. The underlying mechanisms of aging-exacerbated effects remain unknown. Reactive oxygen species (ROS) and reactive nitrogen species (RNS) are known to play vital roles in aging-related MI/R injury. Heretofore, the effects of aging upon ROS and RNS formation were not investigated in humans, which is the focus of the current study. Due to experimental limitations with clinical trials, an additional animal experiment was performed. All enrolled acute myocardial infarction (AMI) patients received percutaneous coronary intervention (PCI) therapy. AMI patients were assigned into two groups: adult (age <65, n = 34) and elderly (age ≥65, n = 45) AMI patients. Blood samples were obtained from all study participants at 24 h and 3 days post-PCI. Plasma/white blood cell (WBC) ROS and RNS markers (malondialdehyde (MDA), myeloperoxidase (MPO), reduced glutathione (GSH), inducible nitric oxide synthase (iNOS) activity, NOx, and nitrotyrosine) were determined. The same markers were determined in rat cardiac tissue after 24 h MI/R. Compared to the adult group, elderly patients manifested increased plasma MDA and MPO and decreased plasma GSH concentrations. No significant differences in plasma NOx or nitrotyrosine concentration existed between adult and elderly patients. Furthermore, WBC iNOS activity in elderly patients was significantly decreased compared to the adult group. The measurement of ROS markers in the rat experiments was consistent and supported human study data. Surprisingly, RNS markers (NOx and nitrotyrosine) in blood and heart tissue increased from young to middle-aged rats but decreased from middle age to old age. Aging augments ROS, which might exacerbate MI/R injury. Additionally, our data support aging-induced changes of RNS levels in humans and rats in vivo.
doi:10.1007/s11357-012-9421-y
PMCID: PMC3705100  PMID: 22580631
Aging; Acute myocardial infarction (AMI); Percutaneous coronary intervention (PCI); Reactive oxygen species; iNOS
24.  Owning an Overweight or Underweight Body: Distinguishing the Physical, Experienced and Virtual Body 
PLoS ONE  2014;9(8):e103428.
Our bodies are the most intimately familiar objects we encounter in our perceptual environment. Virtual reality provides a unique method to allow us to experience having a very different body from our own, thereby providing a valuable method to explore the plasticity of body representation. In this paper, we show that women can experience ownership over a whole virtual body that is considerably smaller or larger than their physical body. In order to gain a better understanding of the mechanisms underlying body ownership, we use an embodiment questionnaire, and introduce two new behavioral response measures: an affordance estimation task (indirect measure of body size) and a body size estimation task (direct measure of body size). Interestingly, after viewing the virtual body from first person perspective, both the affordance and the body size estimation tasks indicate a change in the perception of the size of the participant's experienced body. The change is biased by the size of the virtual body (overweight or underweight). Another novel aspect of our study is that we distinguish between the physical, experienced and virtual bodies, by asking participants to provide affordance and body size estimations for each of the three bodies separately. This methodological point is important for virtual reality experiments investigating body ownership of a virtual body, because it offers a better understanding of which cues (e.g. visual, proprioceptive, memory, or a combination thereof) influence body perception, and whether the impact of these cues can vary between different setups.
doi:10.1371/journal.pone.0103428
PMCID: PMC4118886  PMID: 25083784
25.  A Heavy Metal-Associated Protein (AcHMA1) from the Halophyte, Atriplex canescens (Pursh) Nutt., Confers Tolerance to Iron and Other Abiotic Stresses When Expressed in Saccharomyces cerevisiae 
Many heavy metals are essential for metabolic processes, but are toxic at elevated levels. Metal tolerance proteins provide resistance to this toxicity. In this study, we identified and characterized a heavy metal-associated protein, AcHMA1, from the halophyte, Atriplex canescens. Sequence analysis has revealed that AcHMA1 contains two heavy metal binding domains. Treatments with metals (Fe, Cu, Ni, Cd or Pb), PEG6000 and NaHCO3 highly induced AcHMA1 expression in A. canescens, whereas NaCl and low temperature decreased its expression. The role of AcHMA1 in metal stress tolerance was examined using a yeast expression system. Expression of the AcHMA1 gene significantly increased the ability of yeast cells to adapt to and recover from exposure to excess iron. AcHMA1 expression also provided salt, alkaline, osmotic and oxidant stress tolerance in yeast cells. Finally, subcellular localization of an AcHMA1/GFP fusion protein expressed in tobacco cells showed that AcHMA1 was localized in the plasma membrane. Thus, our results suggest that AcHMA1 encodes a membrane-localized metal tolerance protein that mediates the detoxification of iron in eukaryotes. Furthermore, AcHMA1 also participates in the response to abiotic stress.
doi:10.3390/ijms150814891
PMCID: PMC4159888  PMID: 25153638
HMA (heavy metal-associated) domain; Atriplex canescens; Fe tolerance; abiotic stress; yeast expression

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