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1.  Impaired E Prostanoid2 Expression and Resistance to Prostaglandin E2 in Nasal Polyp Fibroblasts from Subjects with Aspirin-Exacerbated Respiratory Disease 
Recurrent, rapidly growing nasal polyps are hallmarks of aspirin-exacerbated respiratory disease (AERD), although the mechanisms of polyp growth have not been identified. Fibroblasts are intimately involved in tissue remodeling, and the growth of fibroblasts is suppressed by prostaglandin E2 (PGE2), which elicits antiproliferative effects mediated through the E prostanoid (EP)2 receptor. We now report that cultured fibroblasts from the nasal polyps of subjects with AERD resist this antiproliferative effect. Fibroblasts from polyps of subjects with AERD resisted the antiproliferative actions of PGE2 and a selective EP2 agonist (P < 0.0001 at 1 μM) compared with nasal fibroblasts from aspirin-tolerant control subjects undergoing polypectomy or from healthy control subjects undergoing concha bullosa resections. Cell surface expression of the EP2 receptor protein was lower in fibroblasts from subjects with AERD than in fibroblasts from healthy control subjects and aspirin-tolerant subjects (P < 0.01 for both). Treatment of the fibroblasts with trichostatin A, a histone deacetylase inhibitor, significantly increased EP2 receptor mRNA in fibroblasts from AERD and aspirin-tolerant subjects but had no effect on cyclooxygenase-2, EP4, and microsomal PGE synthase 1 (mPGES-1) mRNA levels. Histone acetylation (H3K27ac) at the EP2 promoter correlated strongly with baseline EP2 mRNA (r = 0.80; P < 0.01). These studies suggest that the EP2 promotor is under epigenetic control, and one explanation for PGE2 resistance in AERD is an epigenetically mediated reduction of EP2 receptor expression, which could contribute to the refractory nasal polyposis typically observed in this syndrome.
PMCID: PMC4742927  PMID: 26051534
aspirin-exacerbated respiratory disease; prostaglandin E2; E prostanoid type 2 receptor; histone acetylation; DNA methylation
2.  Data on green tea flavor determinantes as affected by cultivars and manufacturing processes 
Data in Brief  2016;10:492-498.
This paper presents data related to an article entitled “Green tea flavor determinants and their changes over manufacturing processes” (Han et al., 2016) [1]. Green tea samples were prepared with steaming and pan firing treatments from the tender leaves of tea cultivars ‘Bai-Sang Cha’ (‘BAS’) and ‘Fuding-Dabai Cha’ (‘FUD’). Aroma compounds from the tea infusions were detected and quantified using HS-SPME coupled with GC/MS. Sensory evaluation was also made for characteristic tea flavor. The data shows the abundances of the detected aroma compounds, their threshold values and odor characteristics in the two differently processed tea samples as well as two different cultivars.
PMCID: PMC5196232  PMID: 28054014
3.  Beclin-1- mediated autophagy may be involved in the elderly cognitive and affective disorders in streptozotocin-induced diabetic mice 
Diabetes is the most common metabolic disease with many chronic complications, and cognitive disorders are one of the common complications in patients with diabetes. Previous studies have showed that autophagy played important roles in the progression of metabolic syndrome, diabetes and other diseases. So we investigated whether aged diabetic mice are prone to be associated with the cognitive and affective disorders and whether Beclin-1-mediated autophagy might be involved in thepahological process.
High-fat diet/streptozotocin (STZ) injection-induced diabetic C57 mice were adopted in this study. Cognitive disorders were detected by Morris water maze and fear conditional test. Affective disorders were detected by tail suspension test and forced swimming test. Magnetic resonance imaging was applied to observe changes of morphology and metabolism in the brain. The 18 F-fluorodeoxyglucose positron emission tomography (FDG-PET) was used to assess metabolism changes in the brain of aged diabetic mice. Autophagy were evaluated by Beclin- 1, LC3II/I and P62, which were detected by western blot analysis and observed by electron microscopy.
1. Compared with control group, diabetes mice showed significantly decreasing abilities in spatial memory and conditioned fear memory (all P < 0.05), and increasing tendency of depression (P < 0.05). 2. MRI showed that the majority of elderly diabetic mice were associated with multiple cerebral small vessel disease. Some even showed hippocampal atrophy, ventricular dilatation and leukoaraiosis. 3. FDG-PET-CT discovered that the glucose metabolism in the amygdala and hippocampus was significantly decreased compared with normal aged mice (P < 0.05). 4. Electron microscopy found that, although autophagy bodies was not widespread, and there was no significant difference between the two groups, yet compared with normal aged mice, apparent cell edema, myelinated tow reduction and intracellular lipofuscin augmentation existed in elderly diabetic mice brain. 5. The level of p62 was increased in the STZ-induced diabetic mice hippocampus and striatum, and beclin1 protein expression were significantly decreased in diabetic mice hippocampus compared with normal aged mice (P < 0.05). There was a upward trend of the ratio of LC3II/I in hippocampus, cortex and striatum, but no statistically difference between the two groups.
Compared with normal aged mice, diabetic aged mice were apt to cerebral small vessel disease and associated with cognitive and affective disorders, which may be related to the significantly reduced glucose metabolism in hippocampus and amygdala. Beclin1 mediated autophagy in hippocampus probably played an important role in cognitive and affective disorders of STZ-induced aged diabetic mice.
PMCID: PMC5154026  PMID: 27999666
4.  Comparative transcriptional profile of the fish parasite Cryptocaryon irritans 
Parasites & Vectors  2016;9:630.
Cryptocaryon irritans is an obligate ectoparasitic ciliate pathogen of marine fishes. It can infect most marine teleosts and cause heavy economic losses in aquaculture. There is currently no effective method of controlling this disease, and little information is available regarding the genes involved in its development and virulence. We aimed to investigate the distinct features of the three major life-cycle stages of C. irritans in terms of gene transcription level, and identify candidate vaccines/drug targets. We established a reference transcriptome of C. irritans by RNA-seq.
Three cDNA libraries using total poly(A)+ mRNA isolated from trophonts, tomonts, and theronts was constructed and sequenced, respectively. Clean reads from the three stages were de novo assembled to generated unigene. Annotation of unigenes and transcriptomic comparison of three stages was performed.
Totals of 73.15, 62.23, and 109.57 million clean reads were generated from trophont, tomont, and theront libraries, respectively. After de novo assembly, 49,104 unigenes were obtained, including 9,253 unigenes with significant similarities to proteins from other ciliates. Transcriptomic comparisons revealed that 2,470 genes were differentially expressed among the three stages, including 2,011, 1,404, and 1,797 genes that were significantly differentially expressed in tomont/theront, tomont/trophont, and theront/trophont pairwise comparisons, respectively. Based on the results of hierarchical clustering, all differentially expressed genes (DEGs) were located in five major clusters. DEGs in clusters 1 and 2 were more highly expressed in tomonts than in other stages, DEGs in cluster 3 were dominant in the tomont and trophont stages, whereas clusters 4 and 5 included genes upregulated in the theront stage. In addition, Immobilization antigens (I-antigens) and proteases have long been considered major targets for vaccine development and potential drug targets in parasites, respectively. In the present study, nine putative I-antigens transcripts and 161 protease transcripts were found in the transcriptome of C. irritans.
It was concluded that DEGs enriched in tomonts were involved in cell division, to increase the number of theronts and ensure parasite continuity. DEGs enriched in theronts were associated with response to stimuli, whereas genes enriched in trophonts were related to nutrient accumulation and cell growth. In addition, the I-antigen and protease transcripts in our transcriptome could contribute to the development of vaccines or targeted drugs. Together, the results of the present study provide novel insights into the physiological processes of a marine parasitic ciliate.
Electronic supplementary material
The online version of this article (doi:10.1186/s13071-016-1919-1) contains supplementary material, which is available to authorized users.
PMCID: PMC5142281  PMID: 27923398
Cryptocaryon irritans; Fish parasite; Transcriptome
5.  Triptolide Upregulates Myocardial Forkhead Helix Transcription Factor p3 Expression and Attenuates Cardiac Hypertrophy 
The forkhead/winged helix transcription factor (Fox) p3 can regulate the expression of various genes, and it has been reported that the transfer of Foxp3-positive T cells could ameliorate cardiac hypertrophy and fibrosis. Triptolide (TP) can elevate the expression of Foxp3, but its effects on cardiac hypertrophy remain unclear. In the present study, neonatal rat ventricular myocytes (NRVM) were isolated and stimulated with angiotensin II (1 μmol/L) to induce hypertrophic response. The expression of Foxp3 in NRVM was observed by using immunofluorescence assay. Fifty mice were randomly divided into five groups and received vehicle (control), isoproterenol (Iso, 5 mg/kg, s.c.), one of three doses of TP (10, 30, or 90 μg/kg, i.p.) for 14 days, respectively. The pathological morphology changes were observed after Hematoxylin and eosin, lectin and Masson’s trichrome staining. The levels of serum brain natriuretic peptide (BNP) and troponin I were determined by enzyme-linked immunosorbent assay and chemiluminescence, respectively. The mRNA and protein expressions of α- myosin heavy chain (MHC), β-MHC and Foxp3 were determined using real-time PCR and immunohistochemistry, respectively. It was shown that TP (1, 3, 10 μg/L) treatment significantly decreased cell size, mRNA and protein expression of β-MHC, and upregulated Foxp3 expression in NRVM. TP also decreased heart weight index, left ventricular weight index and, improved myocardial injury and fibrosis; and decreased the cross-scetional area of the myocardium, serum cardiac troponin and BNP. Additionally, TP markedly reduced the mRNA and protein expression of myocardial β-MHC and elevated the mRNA and protein expression of α-MHC and Foxp3 in a dose-dependent manner. In conclusion, TP can effectively ameliorate myocardial damage and inhibit cardiac hypertrophy, which is at least partly related to the elevation of Foxp3 expression in cardiomyocytes.
PMCID: PMC5127789  PMID: 27965581
cardiac hypertrophy; cardiac fibrosis; forkhead box transcription factor p3; triptolide; cardiac injury
6.  Small amounts of tissue preserve pancreatic function 
Medicine  2016;95(46):e5274.
Middle-segment preserving pancreatectomy (MPP) is a novel procedure for treating multifocal lesions of the pancreas while preserving pancreatic function. However, long-term pancreatic function after this procedure remains unclear.
The aims of this current study are to investigate short- and long-term outcomes, especially long-term pancreatic endocrine function, after MPP.
From September 2011 to December 2015, 7 patients underwent MPP in our institution, and 5 cases with long-term outcomes were further analyzed in a retrospective manner. Percentage of tissue preservation was calculated using computed tomography volumetry. Serum insulin and C-peptide levels after oral glucose challenge were evaluated in 5 patients. Beta-cell secreting function including modified homeostasis model assessment of beta-cell function (HOMA2-beta), area under the curve (AUC) for C-peptide, and C-peptide index were evaluated and compared with those after pancreaticoduodenectomy (PD) and total pancreatectomy. Exocrine function was assessed based on questionnaires.
Our case series included 3 women and 2 men, with median age of 50 (37–81) years. Four patients underwent pylorus-preserving PD together with distal pancreatectomy (DP), including 1 with spleen preserved. The remaining patient underwent Beger procedure and spleen-preserving DP. Median operation time and estimated intraoperative blood loss were 330 (250–615) min and 800 (400–5500) mL, respectively. Histological examination revealed 3 cases of metastatic lesion to the pancreas, 1 case of chronic pancreatitis, and 1 neuroendocrine tumor. Major postoperative complications included 3 cases of delayed gastric emptying and 2 cases of postoperative pancreatic fistula. Imaging studies showed that segments representing 18.2% to 39.5% of the pancreas with good blood supply had been preserved. With a median 35.0 months of follow-ups on pancreatic functions, only 1 patient developed new-onset diabetes mellitus of the 4 preoperatively euglycemic patients. Beta-cell function parameters in this group of patients were quite comparable to those after Whipple procedure, and seemed better than those after total pancreatectomy. No symptoms of hypoglycemia were identified in any patient, although half of the patients reported symptoms of exocrine insufficiency.
In conclusion, MPP is a feasible and effective procedure for middle-segment sparing multicentric lesions in the pancreas, and patients exhibit satisfied endocrine function after surgery.
PMCID: PMC5120908  PMID: 27861351
beta-cell secreting function; middle-segment preserving pancreatectomy; multifocal pancreatic lesions; organ-preserving; pancreatic endocrine function
7.  Metagenomic and network analysis reveal wide distribution and co-occurrence of environmental antibiotic resistance genes 
The ISME Journal  2015;9(11):2490-2502.
A metagenomic approach and network analysis was used to investigate the wide-spectrum profiles of antibiotic resistance genes (ARGs) and their co-occurrence patterns in 50 samples from 10 typical environments. In total, 260 ARG subtypes belonging to 18 ARG types were detected with an abundance range of 5.4 × 10−6–2.2 × 10−1 copy of ARG per copy of 16S-rRNA gene. The trend of the total ARG abundances in environments matched well with the levels of anthropogenic impacts on these environments. From the less impacted environments to the seriously impacted environments, the total ARG abundances increased up to three orders of magnitude, that is, from 3.2 × 10−3 to 3.1 × 100 copy of ARG per copy of 16S-rRNA gene. The abundant ARGs were associated with aminoglycoside, bacitracin, β-lactam, chloramphenicol, macrolide-lincosamide-streptogramin, quinolone, sulphonamide and tetracycline, in agreement with the antibiotics extensively used in human medicine or veterinary medicine/promoters. The widespread occurrences and abundance variation trend of vancomycin resistance genes in different environments might imply the spread of vancomycin resistance genes because of the selective pressure resulting from vancomycin use. The simultaneous enrichment of 12 ARG types in adult chicken faeces suggests the coselection of multiple ARGs in this production system. Non-metric multidimensional scaling analysis revealed that samples belonging to the same environment generally possessed similar ARG compositions. Based on the co-occurrence pattern revealed by network analysis, tetM and aminoglycoside resistance protein, the hubs of the ARG network, are proposed to be indicators to quantitatively estimate the abundance of 23 other co-occurring ARG subtypes by power functions.
PMCID: PMC4611512  PMID: 25918831
8.  miR-193b directly targets STMN1 and inhibits the malignant phenotype in colorectal cancer 
American Journal of Cancer Research  2016;6(11):2463-2475.
Accumulating evidence suggests that aberrantly expressed microRNAs (miRNAs) contribute to the initiation and progression of human cancers. However, the underlying function of miR-193b in colorectal cancer (CRC) remains largely unexplored. Herein, we demonstrate that miR-193b is significantly down-regulated in CRC tissues compared with their normal counterparts. Kaplan-Meier analysis revealed that decreased miR-193b expression was closely associated with the shorter overall survival of patients with CRC. Through gain-and loss-of-function studies, we showed that miR-193b significantly suppressed CRC cell proliferation and invasion. In addition, bioinformatics analyses and luciferase reporter assays identified Stathmin 1 (STMN1) as the direct functional target of miR-193b in CRC. Furthermore, silencing of STMN1 resulted in a phenotype similar to that observed for overexpression of miR-193b, and restoration of STMN1 expression completely rescued the inhibitory effect of miR-193b in CRC cells. Taken together, our study implies the essential role of miR-193b in negatively regulating CRC progression, and a novel link between miR-193b and STMN1 in CRC.
PMCID: PMC5126266  PMID: 27904764
Colorectal cancer; miR-193b; STMN1; prognosis
9.  Type 2 Diabetic Mellitus Is a Risk Factor for Nasopharyngeal Carcinoma: A 1:2 Matched Case–Control Study 
PLoS ONE  2016;11(10):e0165131.
Diabetes has been identified as an adverse prognostic variable which associated with an increased mortality in various cancers, including colorectal, lung, and breast cancers. However, previous studies provided inconsistent results on the association between diabetes and nasopharyngeal carcinoma (NPC). The main aim of this study was to investigate the associations between diabetes mellitus and the survival of NPC patients.
This study was designed as a 1:2 matched case–control study. Cases were patients who met the criteria for the diagnosis of type 2 diabetic mellitus (DM) below. Controls, matched 1:2, were patients who were normoglycemic (NDM). The survival rates were assessed by Kaplan–Meier analysis, and the survival curves were compared using a log-rank test. Multivariate analysis was conducted using the Cox proportional hazard regression model.
Both locoregional relapse-free survival (LRRFS) and disease-free survival (DFS) in the NDM group were higher than that in the DM group (p = 0.001 and p = 0.033). Additionally, subset analyses revealed that the differences in OS, LRRFS, and DFS were all significant between the two groups in the N0-N1 subset (p = 0.007, p =.000 and p = 0.002). The LRRFS was higher in the NDM group in the III-IV, T3-T4 and N0-N1 subsets (p = 0.004, p = 0.002 and p =.000). In T3-T4 subset, the NDM group experienced higher DFS than the DM group (p = 0.039). In multivariate analysis, T stage and N stage were found to be independent predictors for OS, DMFS and DFS; chemotherapy was a significant prognostic factor for DMFS and DFS, age for OS, and diabetes for LRRFS and DFS.
Type 2 diabetic mellitus is associated with poorer prognosis among patients with NPC.
PMCID: PMC5070777  PMID: 27760202
10.  Molecular mechanism of divalent-metal-induced activation of NS3 helicase and insights into Zika virus inhibitor design 
Nucleic Acids Research  2016;44(21):10505-10514.
Zika virus has attracted increasing attention because of its potential for causing human neural disorders, including microcephaly in infants and Guillain–Barré syndrome. Its NS3 helicase domain plays critical roles in NTP-dependent RNA unwinding and translocation during viral replication. Our structural analysis revealed a pre-activation state of NS3 helicase in complex with GTPγS, in which the triphosphate adopts a compact conformation in the absence of any divalent metal ions. In contrast, in the presence of a divalent cation, GTPγS adopts an extended conformation, and the Walker A motif undergoes substantial conformational changes. Both features contribute to more extensive interactions between the GTPγS and the enzyme. Thus, this study provides structural evidence on the allosteric modulation of MgNTP2− on the NS3 helicase activity. Furthermore, the compact conformation of inhibitory NTP identified in this study provides precise information for the rational drug design of small molecule inhibitors for the treatment of ZIKV infection.
PMCID: PMC5137455  PMID: 27915293
11.  Electroacupuncture Ameliorates Learning and Memory and Improves Synaptic Plasticity via Activation of the PKA/CREB Signaling Pathway in Cerebral Hypoperfusion 
Electroacupuncture (EA) has shown protective effects on cognitive decline. However, the underlying molecular mechanisms are ill-understood. The present study was undertaken to determine whether the cognitive function was ameliorated in cerebral hypoperfusion rats following EA and to investigate the role of PKA/CREB pathway. We used a rat 2-vessel occlusion (2VO) model and delivered EA at Baihui (GV20) and Dazhui (GV14) acupoints. Morris water maze (MWM) task, electrophysiological recording, Golgi silver stain, Nissl stain, Western blot, and real-time PCR were employed. EA significantly (1) ameliorated the spatial learning and memory deficits, (2) alleviated long-term potentiation (LTP) impairment and the reduction of dendritic spine density, (3) suppressed the decline of phospho-CREB (pCREB) protein, brain-derived neurotrophic factor (BDNF) protein, and microRNA132 (miR132), and (4) reduced the increase of p250GAP protein of 2VO rats. These changes were partially blocked by a selective protein kinase A (PKA) inhibitor, N-[2-(p-bromocinnamylamino)ethyl]-5-isoquinoline-sulfonamide (H89), suggesting that the PKA/CREB pathway is potentially involved in the effects of EA. Moreover, any significant damage to the pyramidal cell layer of CA1 subregion was absent. These results demonstrated that EA could ameliorate learning and memory deficits and alleviate hippocampal synaptic plasticity impairment of cerebral hypoperfusion rats, potentially mediated by PKA/CREB signaling pathway.
PMCID: PMC5088321  PMID: 27829866
12.  A novel proposal of a simplified bacterial gene set and the neo-construction of a general minimized metabolic network 
Scientific Reports  2016;6:35082.
A minimal gene set (MGS) is critical for the assembly of a minimal artificial cell. We have developed a proposal of simplifying bacterial gene set to approximate a bacterial MGS by the following procedure. First, we base our simplified bacterial gene set (SBGS) on experimentally determined essential genes to ensure that the genes included in the SBGS are critical. Second, we introduced a half-retaining strategy to extract persistent essential genes to ensure stability. Third, we constructed a viable metabolic network to supplement SBGS. The proposed SBGS includes 327 genes and required 431 reactions. This report describes an SBGS that preserves both self-replication and self-maintenance systems. In the minimized metabolic network, we identified five novel hub metabolites and confirmed 20 known hubs. Highly essential genes were found to distribute the connecting metabolites into more reactions. Based on our SBGS, we expanded the pool of targets for designing broad-spectrum antibacterial drugs to reduce pathogen resistance. We also suggested a rough semi-de novo strategy to synthesize an artificial cell, with potential applications in industry.
PMCID: PMC5054358  PMID: 27713529
13.  Absorptive capacity, technological innovation, and product life cycle: a system dynamics model 
SpringerPlus  2016;5(1):1662.
While past research has recognized the importance of the dynamic nature of absorptive capacity, there is limited knowledge on how to generate a fair and comprehensive analytical framework. Based on interviews with 24 Chinese firms, this study develops a system-dynamics model that incorporates an important feedback loop among absorptive capacity, technological innovation, and product life cycle (PLC).
The simulation results reveal that (1) PLC affects the dynamic process of absorptive capacity; (2) the absorptive capacity of a firm peaks in the growth stage of PLC, and (3) the market demand at different PLC stages is the main driving force in firms’ technological innovations. This study also explores a sensitivity simulation using the variables of (1) time spent in founding an external knowledge network, (2) research and development period, and (3) knowledge diversity. The sensitivity simulation results show that the changes of these three variables have a greater impact on absorptive capacity and technological innovation during growth and maturity stages than in the introduction and declining stages of PLC.
We provide suggestions on how firms can adjust management policies to improve their absorptive capacity and technological innovation performance during different PLC stages.
PMCID: PMC5037108  PMID: 27757366
Absorptive capacity; Technological innovation; Product life cycle; System dynamics
14.  Impact of skin capsular distance on the performance of controlled attenuation parameter in patients with chronic liver disease 
Liver International  2015;35(11):2392-2400.
Background & Aims
Controlled attenuation parameter (CAP) is a non‐invasive method for evaluating hepatic steatosis. However, larger skin capsular distance (SCD) can affect the accuracy. The aim of this study was to investigate the impact of SCD on the diagnostic performance of CAP and liver stiffness measurement (LSM).
Of 101 patients with non‐alcoholic fatty liver disease (NAFLD) and 280 patients with chronic hepatitis B (CHB) who underwent liver biopsy were prospectively recruited. CAP, LSM and SCD were performed using FibroScan with M probe. The areas under receiver operating characteristics curves (AUROCs) were calculated to determine the diagnostic efficacy. The optimal thresholds were defined by the maximum Youden index.
SCD (B 30.34, P < 0.001) and hepatic steatosis (B 23.04, P < 0.001) were independently associated with CAP by multivariate analysis. The AUROCs were slightly higher for SCD <25 mm compared to those for SCD ≥25 mm for steatosis ≥5% (0.88 vs. 0.81), >33% (0.90 vs. 0.85) and >66% (0.84 vs. 0.72). For SCD <25 mm, the optimal CAP cut‐offs for differentiating steatosis ≥5%, >33% and >66% were 255.0 dB/m, 283.5 dB/m and 293.5 dB/m. However, cut‐offs were elevated by approximately 60–70 dB/m for SCD ≥25 mm. When stratified by fibrosis grade, LSM was significantly affected by SCD ≥25 mm for advanced fibrosis (≥F3) in NAFLD, but not in CHB.
CAP is a promising tool for detecting and quantifying hepatic steatosis. SCD ≥25 mm may cause overestimation of steatosis. Similarly, SCD ≥25 mm affects the detection of advanced fibrosis by LSM in NAFLD patients.
PMCID: PMC5023997  PMID: 25689614
controlled attenuation parameter; liver stiffness; non‐alcoholic fatty liver disease; skin capsular distance; transient elastography
15.  Naturalistic Teenage Driving Study: Findings and Lessons Learned 
Journal of safety research  2015;54:41.e29-41.e44.
This paper summarizes the findings on novice teenage driving outcomes (e.g., crashes and risky driving behaviors) from the Naturalistic Teenage Driving Study.
Survey and driving data from a data acquisition system (Global Positioning System, accelerometers, cameras) were collected from 42 newly-licensed teenage drivers and their parents during the first 18 months of teenage licensure; stress responsivity was also measured in teenagers.
Overall teenage crash and near crash (CNC) rates declined over time, but were >4 times higher among teenagers than adults. Contributing factors to teenage CNC rates included secondary task engagement (e.g., distraction), kinematic risky driving, low stress responsivity, and risky social norms.
The data support the contention that the high novice teenage CNC risk is due both to inexperience and risky driving behavior, particularly kinematic risky driving and secondary task engagement.
Practical Applications
Graduated driver licensing policy and other prevention efforts should focus on kinematic risky driving, secondary task engagement, and risky social norms.
PMCID: PMC4583651  PMID: 26403899
adolescence; risk taking; accidents; speeding; learning to drive; kinematic; expertise
16.  An Approach for Predicting Essential Genes Using Multiple Homology Mapping and Machine Learning Algorithms 
BioMed Research International  2016;2016:7639397.
Investigation of essential genes is significant to comprehend the minimal gene sets of cell and discover potential drug targets. In this study, a novel approach based on multiple homology mapping and machine learning method was introduced to predict essential genes. We focused on 25 bacteria which have characterized essential genes. The predictions yielded the highest area under receiver operating characteristic (ROC) curve (AUC) of 0.9716 through tenfold cross-validation test. Proper features were utilized to construct models to make predictions in distantly related bacteria. The accuracy of predictions was evaluated via the consistency of predictions and known essential genes of target species. The highest AUC of 0.9552 and average AUC of 0.8314 were achieved when making predictions across organisms. An independent dataset from Synechococcus elongatus, which was released recently, was obtained for further assessment of the performance of our model. The AUC score of predictions is 0.7855, which is higher than other methods. This research presents that features obtained by homology mapping uniquely can achieve quite great or even better results than those integrated features. Meanwhile, the work indicates that machine learning-based method can assign more efficient weight coefficients than using empirical formula based on biological knowledge.
PMCID: PMC5021884  PMID: 27660763
17.  Prognostic Significance of Mixed-Lineage Leukemia (MLL) Gene Detected by Real-Time Fluorescence Quantitative PCR Assay in Acute Myeloid Leukemia 
The overall prognosis of acute myeloid leukemia (AML) patients with mixed-lineage leukemia (MLL) gene-positivity is unfavorable. In this study, we evaluated the expression levels of the MLL gene in AML patients.
We enrolled 68 MLL gene-positive patients out of 433 newly diagnosed AML patients, and 216 bone marrow samples were collected. Real-time fluorescence quantitative PCR (RQ-PCR) was used to precisely detect the expression levels of the MLL gene.
We divided 41 patients into 2 groups according to the variation of MRD (minimal residual disease) level of the MLL gene. Group 1 (n=22) had a rapid reduction of MRD level to ≤10−4 in all samples collected in the first 3 chemotherapy cycles, while group 2 (n=19) had MRD levels constantly >10−4 in all samples collected in the first 3 chemotherapy cycles. Group 1 had a significantly better overall survival (p=0.001) and event-free survival (p=0.001) compared to group 2. Moreover, the patients with >10−4 MRD level before the start of HSCT (hematopoietic stem cell transplantation) had worse prognosis and higher risk of relapse compared to patients with ≤10−4 before the start of HSCT.
We found that a rapid reduction of MRD level to ≤10−4 appears to be a prerequisite for better overall survival and event-free survival during the treatment of AML. The MRD levels detected by RQ-PCR were basically in line with the clinical outcome and may be of great importance in guiding early allogeneic HSCT (allo-HSCT) treatment.
PMCID: PMC5012461  PMID: 27561414
Leukemia, Myeloid, Acute; Myeloid-Lymphoid Leukemia Protein; Neoplasm, Residual; Real-Time Polymerase Chain Reaction
18.  Comparison of intraspecific, interspecific and intergeneric chloroplast diversity in Cycads 
Scientific Reports  2016;6:31473.
Cycads are among the most threatened plant species. Increasing the availability of genomic information by adding whole chloroplast data is a fundamental step in supporting phylogenetic studies and conservation efforts. Here, we assemble a dataset encompassing three taxonomic levels in cycads, including ten genera, three species in the genus Cycas and two individuals of C. debaoensis. Repeated sequences, SSRs and variations of the chloroplast were analyzed at the intraspecific, interspecific and intergeneric scale, and using our sequence data, we reconstruct a phylogenomic tree for cycads. The chloroplast was 162,094 bp in length, with 133 genes annotated, including 87 protein-coding, 37 tRNA and 8 rRNA genes. We found 7 repeated sequences and 39 SSRs. Seven loci showed promising levels of variations for application in DNA-barcoding. The chloroplast phylogeny confirmed the division of Cycadales in two suborders, each of them being monophyletic, revealing a contradiction with the current family circumscription and its evolution. Finally, 10 intraspecific SNPs were found. Our results showed that despite the extremely restricted distribution range of C. debaoensis, using complete chloroplast data is useful not only in intraspecific studies, but also to improve our understanding of cycad evolution and in defining conservation strategies for this emblematic group.
PMCID: PMC4997344  PMID: 27558458
19.  Genomic Complexity Places Less Restrictions on the Evolution of Young Coexpression Networks than Protein–Protein Interactions 
Genome Biology and Evolution  2016;8(8):2624-2631.
The differences in evolutionary patterns of young protein–protein interactions (PPIs) among distinct species have long been a puzzle. However, based on our genome-wide analysis of available integrated experimental data, we confirm that young genes preferentially integrate into ancestral PPI networks, and that this manner is consistent in all of six model organisms with widely different levels of phenotypic complexity. We demonstrate that the level of restrictions placed on the evolution of biological networks declines with a decrease of phenotypic complexity. Compared with young PPI networks, new co-expression links have less evolutionary restrictions, so a young gene with a high possibility to be coexpressed other young genes relatively frequently emerges in the four simpler genomes among the six studied. However, it is not favorable for such young–young coexpression in terms of a young gene evolving into a coexpression hub, so the coexpression pattern could gradually decline. To explain this apparent contradiction, we suggest that young genes that are initially peripheral to networks are temporarily coexpressed with other young genes, driving functional evolution because of low selective pressure. However, as the expression levels of genes increase and they gradually develop a greater effect on fitness, young genes start to be coexpressed more with members of ancestral networks and less with other young genes. Our findings provide new insights into the evolution of biological networks.
PMCID: PMC5010916  PMID: 27521813
young gene; biological network; phenotypic complexity
20.  Quantitative proteomic analysis for novel biomarkers of buccal squamous cell carcinoma arising in background of oral submucous fibrosis 
BMC Cancer  2016;16:584.
In South and Southeast Asian, the majority of buccal squamous cell carcinoma (BSCC) can arise from oral submucous fibrosis (OSF). BSCCs develop in OSF that are often not completely resected, causing local relapse. The aim of our study was to find candidate protein biomarkers to detect OSF and predict prognosis in BSCCs by quantitative proteomics approaches.
We compared normal oral mucosa (NBM) and paired biopsies of BSCC and OSF by quantitative proteomics using isobaric tags for relative and absolute quantification (iTRAQ) to discover proteins with differential expression. Gene Ontology and KEGG networks were analyzed. The prognostic value of biomarkers was evaluated in 94 BSCCs accompanied with OSF. Significant associations were assessed by Kaplan-Meier survival and Cox-proportional hazards analysis.
In total 30 proteins were identified with significantly different expression (false discovery rate < 0.05) among three tissues. Two consistently upregulated proteins, ANXA4 and FLNA, were validated. The disease-free survival was negatively associated with the expression of ANXA4 (hazard ratio, 3.4; P = 0.000), FLNA (hazard ratio, 2.1; P = 0.000) and their combination (hazard ratio, 8.8; P = 0.002) in BSCCs.
The present study indicates that iTRAQ quantitative proteomics analysis for tissues of BSCC and OSF is a reliable strategy. A significantly up-regulated ANXA4 and FLNA could be not only candidate biomarkers for BSCC prognosis but also potential targets for its therapy.
Electronic supplementary material
The online version of this article (doi:10.1186/s12885-016-2650-1) contains supplementary material, which is available to authorized users.
PMCID: PMC4971621  PMID: 27485544
Oral submucous fibrosis; Buccal squamous cell carcinoma; Quantitative proteomic analysis; Annexin A4; Filamin-A
21.  Forming heterojunction: an effective strategy to enhance the photocatalytic efficiency of a new metal-free organic photocatalyst for water splitting 
Scientific Reports  2016;6:29327.
Photocatalytic water splitting is a new technology for the conversion and utilization of solar energy and has a potential prospect. One important aspect of enhancing the photocatalytic efficiency is how to improve the electron-hole separation. Up to now, there is still no ideal strategy to improve the electron-hole separation. In this article, for metal-free organic photocatalysts, we propose a good strategy- forming heterojunction, which can effectively improve the electron-hole separation. We provide a metal-free organic photocatalyst g-C12N7H3 for water splitting. The stability of g-C12N7H3 has been investigated, the X-ray diffraction spectra has been simulated. Using first-principles calculations, we have systematically studied the electronic structure, band edge alignment, and optical properties for the g-C12N7H3. The results demonstrated that g-C12N7H3 is a new organocatalyst material for water splitting. In order to enhance the photocatalytic efficiency, we provided four strategies, i.e., multilayer stacking, raising N atoms, forming g-C9N10/g-C12N7H3 heterojunction, and forming graphene/g-C12N7H3 heterojunction. Our research is expected to stimulate experimentalists to further study novel 2D metal-free organic materials as visible light photocatalysts. Our strategies, especially forming heterojunction, will substantially help to enhance the photocatalytic efficiency of metal-free organic photocatalyst.
PMCID: PMC4965868  PMID: 27470223
22.  Hundred top-cited articles focusing on acute kidney injury: a bibliometric analysis 
BMJ Open  2016;6(7):e011630.
Acute kidney injury (AKI) is a major global health issue, associated with poor short-term and long-term outcomes. Research on AKI is increasing with numerous articles published. However, the quantity and quality of research production in the field of AKI is unclear.
Methods and analysis
To analyse the characteristics of the most cited articles on AKI and to provide information about achievements and developments in AKI, we searched the Science Citation Index Expanded for citations of AKI articles. For the top 100 most frequently cited articles (T100), we evaluated the number of citations, publication time, province of origin, journal, impact factor, topic or subspecialty of the research, and publication type.
The T100 articles ranged from a maximum of 1971 citations to a minimum of 215 citations (median 302 citations). T100 articles were published from 1951 to 2011, with most articles published in the 2000s (n=77), especially the 5-year period from 2002 to 2006 (n=51). The publications appeared in 30 journals, predominantly in the general medical journals, led by New England Journal of Medicine (n=17), followed by expert medical journals, led by the Journal of the American Society of Nephrology (n=16) and Kidney International (n=16). The majority (83.7%) of T100 articles were published by teams involving ≥3 authors. T100 articles originated from 15 countries, led by the USA (n=81) followed by Italy (n=9). Among the T100 articles, 69 were clinical research, 25 were basic science, 21 were reviews, 5 were meta-analyses and 3 were clinical guidelines. Most clinical articles (55%) included patients with any cause of AKI, followed by the specific causes of contrast-induced AKI (25%) and cardiac surgery-induced AKI (15%).
This study provides a historical perspective on the scientific progress on AKI, and highlights areas of research requiring further investigations and developments.
PMCID: PMC4964173  PMID: 27466238
Bibliometric analysis; Acute kidney injury; Top 100 cited articles
23.  The Effect of Early Goal-Directed Therapy on Outcome in Adult Severe Sepsis and Septic Shock Patients: A Meta-Analysis of Randomized Clinical Trials 
Anesthesia and Analgesia  2016;123(2):371-381.
Supplemental Digital Content is available in the text.
Published ahead of print April 5, 2016
Whether early goal-directed therapy (EGDT) improves outcome in severe sepsis and septic shock remains unclear. We performed a meta-analysis of existing clinical trials to examine whether EGDT improved outcome in the resuscitation of adult sepsis patients compared with control care.
We searched for eligible studies using MEDLINE, Elsevier, Cochrane Central Register of Controlled Trials, and Web of Science databases. Studies were eligible if they compared the effects of EGDT versus control care on mortality in adult patients with severe sepsis and septic shock. Two reviewers extracted data independently. Data including mortality, sample size of the patients with severe sepsis and septic shock, and resuscitation end points were extracted. Data were analyzed using methods recommended by the Cochrane Collaboration Review Manager 4.2 software. Random errors were evaluated by trial sequential analysis (TSA).
Nine studies compared EGDT with control care, and 5202 severe sepsis and septic shock patients were included. A nonsignificant trend toward reduction in the longest all-cause mortality was observed in the EGDT group compared with control care (relative risk, 0.89; 99% confidence interval, 0.74–1.07; P = 0.10). However, EGDT significantly reduced intensive care unit mortality in severe sepsis and septic shock patients (relative risk, 0.72; 99% confidence interval, 0.57–0.90; P = 0.0002). TSA indicated lack of firm evidence for a beneficial effect.
In this meta-analysis, a nonsignificant trend toward reduction in the longest all-cause mortality in patients resuscitated with EGDT was noted. However, EGDT significantly reduced intensive care unit mortality in severe sepsis and septic shock patients. TSA indicated a lack of firm evidence for the results. More powered, randomized controlled trials are needed to determine the effects.
PMCID: PMC4956677  PMID: 27049857
24.  Phylogenomic Analyses and Reclassification of Species within the Genus Tsukamurella: Insights to Species Definition in the Post-genomic Era 
Owing to the highly similar phenotypic profiles, protein spectra and 16S rRNA gene sequences observed between three pairs of Tsukamurella species (Tsukamurella pulmonis/Tsukamurella spongiae, Tsukamurella tyrosinosolvens/Tsukamurella carboxy-divorans, and Tsukamurella pseudospumae/Tsukamurella sunchonensis), we hypothesize that and the six Tsukamurella species may have been misclassified and that there may only be three Tsukamurella species. In this study, we characterized the type strains of these six Tsukamurella species by tradition DNA–DNA hybridization (DDH) and “digital DDH” after genome sequencing to determine their exact taxonomic positions. Traditional DDH showed 81.2 ± 0.6% to 99.7 ± 1.0% DNA–DNA relatedness between the two Tsukamurella species in each of the three pairs, which was above the threshold for same species designation. “Digital DDH” based on Genome-To-Genome Distance Calculator and Average Nucleotide Identity for the three pairs also showed similarity results in the range of 82.3–92.9 and 98.1–99.1%, respectively, in line with results of traditional DDH. Based on these evidence and according to Rules 23a and 42 of the Bacteriological Code, we propose that T. spongiae Olson et al. 2007, should be reclassified as a later heterotypic synonym of T. pulmonis Yassin et al. 1996, T. carboxydivorans Park et al. 2009, as a later heterotypic synonym of T. tyrosinosolvens Yassin et al. 1997, and T. sunchonensis Seong et al. 2008 as a later heterotypic synonym of T. pseudospumae Nam et al. 2004. With the advancement of genome sequencing technologies, classification of bacterial species can be readily achieved by “digital DDH” than traditional DDH.
PMCID: PMC4955295  PMID: 27493643
phylogenomic; reclassification; Tsukamurella; species; genomics
25.  Hepatic Perfusion Alterations in Septic Shock Patients: Impact of Early Goal-directed Therapy 
Chinese Medical Journal  2016;129(14):1666-1673.
Early goal-directed therapy (EGDT) has become an important therapeutic management in early salvage stage of septic shock. However, splenic organs possibly remained hypoperfused and hypoxic despite fluid resuscitation. This study aimed to evaluate the effect of EGDT on hepatic perfusion in septic shock patients.
A prospective observational study was carried out in early septic shock patients who were admitted to Intensive Care Unit within 24 h after onset and who met all four elements of the EGDT criteria after treatment with the standard EGDT procedure within 6 h between December 1, 2012 and November 30, 2013. The hemodynamic data were recorded, and oxygen metabolism and hepatic functions were monitored. An indocyanine green clearance test was applied to detect the hepatic perfusion. The patients’ characteristics were compared before treatment (T0), immediately after EGDT (T1), and 24 h after EGDT (T2). This study is registered at, NCT02060773.
Twenty-one patients were included in the study; however, the hepatic perfusion data were not included in the analysis for two patients; therefore, 19 patients were eligible for the study. Hemodynamics data, as monitored by pulse-indicator continuous cardiac output, were obtained from 16 patients. There were no significant differences in indocyanine green plasma disappearance rate (ICG-PDR) and 15-min retention rate (R15) at T0 (11.9 ± 5.0%/min and 20.0 ± 13.2%), T1 (11.4 ± 5.1%/min and 23.6 ± 14.9%), and T2 (11.0 ± 4.5%/min and 23.7 ± 15.3%) (all P > 0.05). Both of the alterations of ICG-PDR and R15 showed no differences at T0, T1, and T2 in the patients of different subgroups that achieved different resuscitation goal numbers when elected (P > 0.05).
There were no hepatic perfusion improvements after EGDT in the early phase of patients with septic shock.
Trial Registration: NCT02060773 (
PMCID: PMC4960955  PMID: 27411453
Early Goal-directed Therapy; Fluid Resuscitation; Hepatic Perfusion; Indocyanine Green; Septic Shock

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