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1.  Synchronization to a bouncing ball with a realistic motion trajectory 
Scientific Reports  2015;5:11974.
Daily music experience involves synchronizing movements in time with a perceived periodic beat. It has been established for over a century that beat synchronization is less stable for the visual than for the auditory modality. This auditory advantage of beat synchronization gives rise to the hypotheses that the neural and evolutionary mechanisms underlying beat synchronization are modality-specific. Here, however, we found that synchronization to a periodically bouncing ball with a realistic motion trajectory was not less stable than synchronization to an auditory metronome. This finding challenges the auditory advantage of beat synchronization, and has important implications for the understanding of the biological substrates of beat synchronization.
doi:10.1038/srep11974
PMCID: PMC4493690  PMID: 26148810
2.  Cognition of and Demand for Education and Teaching in Medical Statistics in China: A Systematic Review and Meta-Analysis 
PLoS ONE  2015;10(6):e0128721.
Background
Although a substantial number of studies focus on the teaching and application of medical statistics in China, few studies comprehensively evaluate the recognition of and demand for medical statistics. In addition, the results of these various studies differ and are insufficiently comprehensive and systematic.
Objectives
This investigation aimed to evaluate the general cognition of and demand for medical statistics by undergraduates, graduates, and medical staff in China.
Methods
We performed a comprehensive database search related to the cognition of and demand for medical statistics from January 2007 to July 2014 and conducted a meta-analysis of non-controlled studies with sub-group analysis for undergraduates, graduates, and medical staff.
Results
There are substantial differences with respect to the cognition of theory in medical statistics among undergraduates (73.5%), graduates (60.7%), and medical staff (39.6%). The demand for theory in medical statistics is high among graduates (94.6%), undergraduates (86.1%), and medical staff (88.3%). Regarding specific statistical methods, the cognition of basic statistical methods is higher than of advanced statistical methods. The demand for certain advanced statistical methods, including (but not limited to) multiple analysis of variance (ANOVA), multiple linear regression, and logistic regression, is higher than that for basic statistical methods. The use rates of the Statistical Package for the Social Sciences (SPSS) software and statistical analysis software (SAS) are only 55% and 15%, respectively.
Conclusion
The overall statistical competence of undergraduates, graduates, and medical staff is insufficient, and their ability to practically apply their statistical knowledge is limited, which constitutes an unsatisfactory state of affairs for medical statistics education. Because the demand for skills in this area is increasing, the need to reform medical statistics education in China has become urgent.
doi:10.1371/journal.pone.0128721
PMCID: PMC4459963  PMID: 26053876
3.  Microbiota in the Throat and Risk Factors for Laryngeal Carcinoma 
Applied and Environmental Microbiology  2014;80(23):7356-7363.
The compositions and abundances of the microbiota in the ecological niche of the human throat and the possible relationship between the microbiota and laryngeal cancer are poorly understood. To obtain insight into this, we enrolled 27 laryngeal carcinoma patients and 28 subjects with vocal cord polyps as controls. For each subject, we simultaneously collected swab samples from the upper throat near the epiglottis (site I) and tissue samples from the vestibulum laryngis to the subglottic region (site II). The microbiota of the throat were fully characterized by pyrosequencing of barcoded 16S rRNA genes. We found 14 phyla, 20 classes, 38 orders, 85 families, and 218 genera in the throats of enrolled subjects. The main phyla were Firmicutes (54.7%), Fusobacteria (14.8%), Bacteroidetes (12.7%), and Proteobacteria (10.6%). Streptococcus (37.3%), Fusobacterium (11.3%), and Prevotella (10.6%) were identified as the three most predominant genera in the throat. The relative abundances of 23 bacterial genera in site I were significantly different from those in site II (P < 0.05). The relative proportions of 12 genera largely varied between laryngeal cancer patients and control subjects (P < 0.05). Collectively, this study outlined the spatial structure of microbial communities in the human throat. The spatial structure of bacterial communities significantly varied in two anatomical sites of the throat. The bacterial profiles of the throat of laryngeal cancer patients were strongly different from those of control subjects, and several of these microorganisms may be related to laryngeal carcinoma.
doi:10.1128/AEM.02329-14
PMCID: PMC4249186  PMID: 25239901
4.  Risk of congenital anomalies associated with antithyroid treatment during pregnancy: a meta-analysis 
Clinics  2015;70(6):453-459.
To evaluate the association of either propylthiouracil or methimazole treatment for hyperthyroidism during pregnancy with congenital malformations, relevant studies were identified by searching Medline, PubMed, the Cochrane Library and EMBASE.
We intended to include randomized controlled trials, but no such trials were identified. Thus, we included cohort studies and case-control studies in this meta-analysis.
A total of 7 studies were included in the meta-analyses. The results revealed an increased risk of birth defects among the group of pregnant women with hyperthyroidism treated with methimazole compared with the control group (odds ratio 1.76, 95% confidence interval 1.47–2.10) or the non-exposed group (odds ratio 1.71, 95% confidence interval 1.39–2.10). A maternal shift between methimazole and propylthiouracil was associated with an increased odds ratio of birth defects (odds ratio 1.88, 95% confidence interval 1.27–2.77). An equal risk of birth defects was observed between the group of pregnant women with hyperthyroidism treated with propylthiouracil and the non-exposed group (odds ratio 1.18, 95% confidence interval 0.97–1.42). There was only a slight trend towards an increased risk of congenital malformations in infants whose mothers were treated with propylthiouracil compared with in infants whose mothers were healthy controls (odds ratio 1.29, 95% confidence interval 1.07–1.55). The children of women receiving methimazole treatment showed an increased risk of adverse fetal outcomes relative to those of mothers receiving propylthiouracil treatment.
We found that propylthiouracil was a safer choice for treating pregnant women with hyperthyroidism according to the risk of birth defects but that a shift between methimazole and propylthiouracil failed to provide protection against birth defects.
doi:10.6061/clinics/2015(06)12
PMCID: PMC4462563  PMID: 26106966
Hyperthyroidism; Congenital anomalies; Propylthiouracil; Methimazole; Pregnancy; Meta-analysis
5.  Oligodendrocyte Precursor Cell-Intrinsic Effect of Rheb1 Controls Differentiation and Mediates mTORC1-Dependent Myelination in Brain 
The Journal of Neuroscience  2014;34(47):15764-15778.
Rheb1 is an immediate early gene that functions to activate mammalian target of rapamycin (mTor) selectively in complex 1 (mTORC1). We have demonstrated previously that Rheb1 is essential for myelination in the CNS using a Nestin-Cre driver line that deletes Rheb1 in all neural cell lineages, and recent studies using oligodendrocyte-specific CNP-Cre have suggested a preferential role for mTORC1 is myelination in the spinal cord. Here, we examine the role of Rheb1/mTORC1 in mouse oligodendrocyte lineage using separate Cre drivers for oligodendrocyte progenitor cells (OPCs) including Olig1-Cre and Olig2-Cre as well as differentiated and mature oligodendrocytes including CNP-Cre and Tmem10-Cre. Deletion of Rheb1 in OPCs impairs their differentiation to mature oligodendrocytes. This is accompanied by reduced OPC cell-cycle exit suggesting a requirement for Rheb1 in OPC differentiation. The effect of Rheb1 on OPC differentiation is mediated by mTor since Olig1-Cre deletion of mTor phenocopies Olig1-Cre Rheb1 deletion. Deletion of Rheb1 in mature oligodendrocytes, in contrast, does not disrupt developmental myelination or myelin maintenance. Loss of Rheb1 in OPCs or neural progenitors does not affect astrocyte formation in gray and white matter, as indicated by the pan-astrocyte marker Aldh1L1. We conclude that OPC-intrinsic mTORC1 activity mediated by Rheb1 is critical for differentiation of OPCs to mature oligodendrocytes, but that mature oligodendrocytes do not require Rheb1 to make myelin or maintain it in the adult brain. These studies reveal mechanisms that may be relevant for both developmental myelination and impaired remyelination in myelin disease.
doi:10.1523/JNEUROSCI.2267-14.2014
PMCID: PMC4236405  PMID: 25411504
differentiation; mTORC1; myelination; OPC; Rheb1
6.  Gene mutation profiling of primary glioblastoma through multiple tumor biopsy guided by 1H-magnetic resonance spectroscopy 
Genetic mutation has served as the biomarkers for the diagnosis and treatment of glioblastoma multiforme (GBM). However, intra-tumor heterogeneity may interfere with personalized treatment strategies based on mutation analysis. This study aimed to characterize somatic mutation profiling of GBM. We collected 33 samples from 7 patients with the primary GBM associated with different Choline (Cho) to N-acetylaspartate (NAA) index (CNI) through the frameless proton magnetic resonance spectroscopy (1H-MRS) guided biopsies and investigated multiple somatic mutations profi ling using the AmpliSeq cancer hotspot panel V2. We identifi ed 53 missense or nonsense mutations in 27 genes including some novel mutations such as APC and IDH2. The mutations in EGFR, TP53, PTEN, PIK3CA genes were presented with different frequency and the majority of the mutated gene was only shared by 1-2 samples from one patient. Moreover, we found the association of CNI with histological grade, but there was no signifi cant change of CNI in the presence of TP53, EGFR and PTEN mutations. These data suggest that gene mutations constitute a heterogeneous marker for primary GBM which may be independent of intra-tumor morphological phenotypes of GBM; therefore, gene mutation markers could not be determined from a small number of needle biopsies or only confi ned to the high-grade region.
PMCID: PMC4503105  PMID: 26191234
Mutation profi ling; heterogeneity; glioblastoma multiforme; proton magnetic resonance spectroscopy; biopsy
7.  Meta-Analysis of MicroRNA-146a rs2910164 G>C Polymorphism Association with Autoimmune Diseases Susceptibility, an Update Based on 24 Studies 
PLoS ONE  2015;10(4):e0121918.
Background
Published data showed that the susceptibility of autoimmune diseases (ADs) was associated with the polymorphism rs2910164 in microRNA-146a (miR-146a). However, the results remain controversial so far. Two meta-analyses published in 2013 and 2014 came to opposite conclusions. In order to derive a more precise estimation of the relationship, we performed this meta-analysis.
Methods
We searched the PubMed, OvidSP and CNKI databases (published prior to September 8th, 2014) and extracted data from eligible studies. The procedure of meta-analysis was performed by using the Stata 12.0 software. Random effect model or fixed effect model were chosen respectively, according to the between study heterogeneities.
Results
A total of 24 case-control studies, 11 more than previous meta-analysis on this topic, were involved. We took stratified analyses by different ethnicities and different types of diseases in different genetic models. In Caucasian subgroup, significant increased risks of GC genotype and GC+CC genotype with ADs susceptibility were found in heterozygote model (GC vs GG, OR = 1.38, 95% CI 1.04–1.83, p = 0.024) and dominant model (GC+CC vs GG, OR = 1.37, 95% CI 1.01–1.85, p = 0.041), respectively. Meanwhile, in other disease subgroup, significant increased risks of C allele, CC genotype and GC+CC genotype were found in allele model (C vs G, OR = 1.16, 95% CI 1.04–1.31, p = 0.010), homozygote model (CC vs GG, OR = 1.42, 95% CI 1.10–1.84, p = 0.006) and dominant model (GC+CC vs GG, OR = 1.25, 95% CI 1.04–1.51, p = 0.020), respectively.
Conclusions
MiR-146a rs2910164 G>C polymorphism was associated with the susceptibility of ADs.
doi:10.1371/journal.pone.0121918
PMCID: PMC4382023  PMID: 25830862
8.  A Naked Eye Refractive Index Sensor with a Visible Multiple Peak Metamaterial Absorber 
Sensors (Basel, Switzerland)  2015;15(4):7454-7461.
We report a naked eye refractive index sensor with a visible metamaterial absorber. The visible metamaterial absorber consisting of a silver dendritic/dielectric/metal structure shows multiple absorption peaks. By incorporating a gain material (rhodamine B) into the dielectric layer, the maximal magnitude of the absorption peak can be improved by about 30%. As the metamaterial absorber is sensitive to the refractive index of glucose solutions, it can function as a sensor that quickly responds to variations of the refractive index of the liquid. Meanwhile, since the response is presented via color changes, it can be clearly observed by the naked eyes. Further experiments have confirmed that the sensor can be used repeatedly.
doi:10.3390/s150407454
PMCID: PMC4431258  PMID: 25822141
refractive index sensor; naked eyes; metamaterial absorber; bottom-up
9.  The Effectiveness of the Problem-Based Learning Teaching Model for Use in Introductory Chinese Undergraduate Medical Courses: A Systematic Review and Meta-Analysis 
PLoS ONE  2015;10(3):e0120884.
Background
Although the problem-based learning (PBL) emerged in 1969 and was soon widely applied internationally, the rapid development in China only occurred in the last 10 years. This study aims to compare the effect of PBL and lecture-based learning (LBL) on student course examination results for introductory Chinese undergraduate medical courses.
Methods
Randomized and nonrandomized controlled trial studies on PBL use in Chinese undergraduate medical education were retrieved through PubMed, the Excerpta Medica Database (EMBASE), Chinese National Knowledge Infrastructure (CNKI) and VIP China Science and Technology Journal Database (VIP-CSTJ) with publication dates from 1st January 1966 till 31 August 2014. The pass rate, excellence rate and examination scores of course examination were collected. Methodological quality was evaluated based on the modified Jadad scale. The I-square statistic and Chi-square test of heterogeneity were used to assess the statistical heterogeneity. Overall RRs or SMDs with their 95% CIs were calculated in meta-analysis. Meta-regression and subgroup meta-analyses were also performed based on comparators and other confounding factors. Funnel plots and Egger’s tests were performed to assess degrees of publication bias.
Results
The meta-analysis included 31studies and 4,699 subjects. Fourteen studies were of high quality with modified Jadad scores of 4 to 6, and 17 studies were of low quality with scores of 1 to 3. Relative to the LBL model, the PBL model yielded higher course examination pass rates [RR = 1.09, 95%CI (1.03, 1.17)], excellence rates [RR = 1.66, 95%CI (1.33, 2.06)] and examination scores [SMD = 0.82, 95%CI (0.63, 1.01)]. The meta-regression results show that course type was the significant confounding factor that caused heterogeneity in the examination-score meta-analysis (t = 0.410, P<0.001). The examination score SMD in “laboratory course” subgroup [SMD = 2.01, 95% CI: (1.50, 2.52)] was higher than that in “theory course” subgroup [SMD = 0.72, 95% CI: (0.56, 0.89)].
Conclusions
PBL teaching model application in introductory undergraduate medical courses can increase course examination excellence rates and scores in Chinese medical education system. It is more effective when applied to laboratory courses than to theory-based courses.
doi:10.1371/journal.pone.0120884
PMCID: PMC4378971  PMID: 25822653
11.  The AIDS epidemic and economic input impact factors in Chongqing, China, from 2006 to 2012: a spatial-temporal analysis 
BMJ Open  2015;5(3):e006669.
Objective
To analyse the spatial-temporal clustering of the HIV/AIDS epidemic in Chongqing and to explore its association with the economic indices of AIDS prevention and treatment.
Methods
Data on the HIV/AIDS epidemic and economic indices of AIDS prevention and treatment were obtained from the annual reports of the Chongqing Municipal Center for Disease Control for 2006–2012. Spatial clustering analysis, temporal-spatial clustering analysis, and spatial regression were used to conduct statistical analysis.
Results
The annual average new HIV infection rate, incidence rate for new AIDS cases, and rate of people living with HIV in Chongqing were 5.97, 2.42 and 28.12 per 100 000, respectively, for 2006–2012. The HIV/AIDS epidemic showed a non-random spatial distribution (Moran’s I≥0.310; p<0.05). The epidemic hotspots were distributed in the 15 mid-western counties. The most likely clusters were primarily located in the central region and southwest of Chongqing and occurred in 2010–2012. The regression coefficients of the total amount of special funds allocated to AIDS and to the public awareness unit for the numbers of new HIV cases, new AIDS cases, and people living with HIV were 0.775, 0.976 and 0.816, and −0.188, −0.259 and −0.215 (p<0.002), respectively.
Conclusions
The Chongqing HIV/AIDS epidemic showed temporal-spatial clustering and was mainly clustered in the mid-western and south-western counties, showing an upward trend over time. The amount of special funds dedicated to AIDS and to the public awareness unit showed positive and negative relationships with HIV/AIDS spatial clustering, respectively.
doi:10.1136/bmjopen-2014-006669
PMCID: PMC4386237  PMID: 25818270
HEALTH SERVICES ADMINISTRATION & MANAGEMENT; HEALTH ECONOMICS; STATISTICS & RESEARCH METHODS
12.  Odd-Mode Surface Plasmon Polaritons Supported by Complementary Plasmonic Metamaterial 
Scientific Reports  2015;5:9250.
Surface plasmon polaritons (SPPs), either on metal-dielectric interfaces in optical frequencies or on structured metal surfaces in the lower frequencies, are dominantly even modes. Here we discover dominant odd-mode SPPs on a complementary plasmonic metamaterial, which is constructed by complementary symmetric grooves. We show that the fundamental SPP mode on such a plasmonic metamaterial is a tightly confined odd mode, whose dispersion curve can be tuned by the shape of groove. According to the electric field distributions of odd-mode SPPs, we propose a high-efficiency transducer using asymmetric coplanar waveguide and slot line to excite the odd-mode SPPs. Numerical simulations and experimental results validate the high-efficiency excitation and excellent propagation performance of odd-mode SPPs on the complementary plasmonic waveguides in the microwave frequencies.
doi:10.1038/srep09250
PMCID: PMC4363829  PMID: 25783166
13.  PTEN–Foxo1 signaling triggers HMGB1-mediated innate immune responses in acute lung injury 
Immunologic Research  2015;62(1):95-105.
PTEN is a multifunctional phosphatase that regulates immune responses through a PI3K/Akt signaling cascade. HMGB1 plays an important role in the initiation of innate immune responses to induce acute lung injury (ALI). This study was designed to investigate the role of PTEN/Foxo1 signaling in the regulation of in vivo and in vitro innate immune responses in ALI. Using a mouse model of ALI, wild-type (WT) and myeloid-specific PTEN knockout (PTENM-KO) mice were instilled with a recombinant HMGB1 (rHMGB1) or PBS. In some experiments, Foxo1 siRNA or non-specific siRNA was injected into mice 6 h prior to rHMGB1 instillation into lung. We found that rHMGB1 treatment in WT mice increased the expression of PTEN, Foxo1, TLR4, and NF-κB in alveolar macrophages from WT mice. However, macrophage-specific PTEN ablation resulted in reduced Foxo1 and TLR4 while increasing β-catenin (Ser552) and Akt (Ser473) phosphorylation in these cells. Knockdown of Foxo1 with siRNA administration in WT mice ameliorated lung injury and inhibited myeloperoxidase activity followed by rHMGB1 treatment, which was accompanied by decreased mRNA expression coding for TNF-α, IL-1β, MIP2, and IP-10. Moreover, Foxo1 knockdown inhibited the expression of TLR4-dependent IRF3 and IFN-β both in vitro and in vivo. These results demonstrate that PTEN/Foxo1 signaling is critical for triggering HMGB1-mediated innate TLR4 activation during ALI. By identifying the molecular signaling pathways within innate immune system, our studies provide the potential therapeutic targets for ALI.
doi:10.1007/s12026-015-8639-z
PMCID: PMC4424276  PMID: 25759027
Macrophages; β-Catenin; Akt; TLR4; Lung inflammation
14.  The function of FOXO1 in the late phases of the cell cycle is suppressed by PLK1-mediated phosphorylation 
Cell Cycle  2014;13(5):807-819.
Polo-like kinase 1 (PLK1) plays crucial roles in multiple stages of cell division. Our previous studies suggest that global transcriptional regulation by PLK1 may contribute to its multiple functions. PLK1 depletion is associated with a decrease in cell viability and the induction of apoptosis; however, the underlying mechanisms are not completely understood. Here, we report that forkhead box protein O1 (FOXO1) is a novel physiological substrate of PLK1. FOXO1 is at the interface of crucial cellular processes, orchestrating programs of gene expression that regulate apoptosis, cell cycle progression, and oxidative-stress resistance. PLK1 interacts with and phosphorylates FOXO1, mainly at the G2/M phase of the cell cycle. PLK1-mediated phosphorylation leads to the impairment of FOXO1’s transcriptional activity in an Akt-independent manner. By immunofluorescence staining and subcellular fractionation, we demonstrate that PLK1-induced FOXO1 phosphorylation causes its nuclear exclusion. Furthermore, PLK1-mediated phosphorylation of FOXO1 negatively regulates its pro-apoptotic function and abrogates its ability to delay entry into and progression through G2/M transition. Therefore, our results suggest that PLK1 abrogates the inhibitory effects of FOXO1 on cell growth and survival to ensure timely cell cycle progression. This study not only reveals a novel and major regulatory mechanism of FOXO1 at the late phases of the cell cycle, but also provides new insight into the molecular mechanisms by which PLK1 inhibition leads to growth arrest and cell death.
doi:10.4161/cc.27727
PMCID: PMC3979917  PMID: 24407358
PLK1; FOXO1; phosphorylation; cell division; nuclear-cytoplasmic shuttling; apoptosis; regulation; transcription factor
15.  Targeting SQSTM1/p62 Induces Cargo Loading Failure and Converts Autophagy to Apoptosis via NBK/Bik 
Molecular and Cellular Biology  2014;34(18):3435-3449.
In selective autophagy, the adaptor protein SQSTM1/p62 plays a critical role in recognizing/loading cargo (e.g., malfolded proteins) into autophagosomes for lysosomal degradation. Here we report that whereas SQSTM1/p62 levels fluctuated in a time-dependent manner during autophagy, inhibition or knockdown of Cdk9/cyclin T1 transcriptionally downregulated SQSTM1/p62 but did not affect autophagic flux. These interventions, or short hairpin RNA (shRNA) directly targeting SQSTM1/p62, resulted in cargo loading failure and inefficient autophagy, phenomena recently described for Huntington's disease neurons. These events led to the accumulation of the BH3-only protein NBK/Bik on endoplasmic reticulum (ER) membranes, most likely by blocking loading and autophagic degradation of NBK/Bik, culminating in apoptosis. Whereas NBK/Bik upregulation was further enhanced by disruption of distal autophagic events (e.g., autophagosome maturation) by chloroquine (CQ) or Lamp2 shRNA, it was substantially diminished by inhibition of autophagy initiation (e.g., genetically by shRNA targeting Ulk1, beclin-1, or Atg5 or pharmacologically by 3-methyladenine [3-MA] or spautin-1), arguing that NBK/Bik accumulation stems from inefficient autophagy. Finally, NBK/Bik knockdown markedly attenuated apoptosis in vitro and in vivo. Together, these findings identify novel cross talk between autophagy and apoptosis, wherein targeting SQSTM1/p62 converts cytoprotective autophagy to an inefficient form due to cargo loading failure, leading to NBK/Bik accumulation, which triggers apoptosis.
doi:10.1128/MCB.01383-13
PMCID: PMC4135623  PMID: 25002530
16.  Recurrent gain-of-function USP8 mutations in Cushing's disease 
Cell Research  2015;25(3):306-317.
Cushing's disease, also known as adrenocorticotropic hormone (ACTH)-secreting pituitary adenomas (PAs) that cause excess cortisol production, accounts for up to 85% of corticotrophin-dependent Cushing's syndrome cases. However, the genetic alterations in this disease are unclear. Here, we performed whole-exome sequencing of DNA derived from 12 ACTH-secreting PAs and matched blood samples, which revealed three types of somatic mutations in a candidate gene, USP8 (encoding ubiquitin-specific protease 8), exclusively in exon 14 in 8 of 12 ACTH-secreting PAs. We further evaluated somatic USP8 mutations in additional 258 PAs by Sanger sequencing. Targeted sequencing further identified a total of 17 types of USP8 variants in 67 of 108 ACTH-secreting PAs (62.04%). However, none of these mutations was detected in other types of PAs (n = 150). These mutations aggregate within the 14-3-3 binding motif of USP8 and disrupt the interaction between USP8 and 14-3-3 protein, resulting in an elevated capacity to protect EGFR from lysosomal degradation. Accordingly, PAs with mutated USP8 display a higher incidence of EGFR expression, elevated EGFR protein abundance and mRNA expression levels of POMC, which encodes the precursor of ACTH. PAs with mutated USP8 are significantly smaller in size and have higher ACTH production than wild-type PAs. In surgically resected primary USP8-mutated tumor cells, USP8 knockdown or blocking EGFR effectively attenuates ACTH secretion. Taken together, somatic gain-of-function USP8 mutations are common and contribute to ACTH overproduction in Cushing's disease. Inhibition of USP8 or EGFR is promising for treating USP8-mutated corticotrophin adenoma. Our study highlights the potentially functional mutated gene in Cushing's disease and provides insights into the therapeutics of this disease.
doi:10.1038/cr.2015.20
PMCID: PMC4349249  PMID: 25675982
Cushing's disease; pituitary adenomas; USP8; mutation; whole-exome sequencing
17.  What drives progressive motor deficits in patients with acute pontine infarction? 
Neural Regeneration Research  2015;10(3):501-504.
Progressive motor deficits are relatively common in acute pontine infarction and frequently associated with increased functional disability. However, the factors that affect the progression of clinical motor weakness are largely unknown. Previous studies have suggested that pontine infarctions are caused mainly by basilar artery stenosis and penetrating artery disease. Recently, lower pons lesions in patients with acute pontine infarctions have been reported to be related to progressive motor deficits, and ensuing that damage to the corticospinal tracts may be responsible for the worsening of neurological symptoms. Here, we review studies on motor weakness progression in pontine infarction and discuss the mechanisms that may underlie the neurologic worsening.
doi:10.4103/1673-5374.153703
PMCID: PMC4396117  PMID: 25878603
nerve regeneration; pontine infarction; progressive motor deficits; basilar artery; penetrating artery; corticospinal tract; Wallerian degeneration; review; neural regeneration
18.  Moral Hypocrisy on the Basis of Construal Level: To Be a Utilitarian Personal Decision Maker or to Be a Moral Advisor? 
PLoS ONE  2015;10(2):e0117540.
Background
People encounter various moral issues that involve making decisions for others by giving advice.
Objective
This study investigated the characteristics of providing suggestions for oneself versus providing suggestions for others in ethical decision-making and the differences between them based on Construal Level Theory (CLT).
Methods
A total of 768 undergraduate students from three universities in China were randomly assigned to eight groups on the basis of a grid of two Construal Levels (self or others) by two different numbers of people saved (5 people or 15 people) by two problem situations (trolley problem vs. footbridge problem). The investigation examined participants’ decisions to opt to take action or refrain from action that would have the consequence of saving more people.
Results
The main effects of Construal Level (F1, 752 = 6.46, p = .011), saving number (F1, 752 = 35.81, p < .001), and problem situation type (F1, 752 = 330.55, p < .001) were all significant. The interaction of the problem situation and saving number (F1, 752 = 1.01, p = .31), and social distance and saving number (F1, 752 = 0.85, p = .36), and interaction of the three independent factors (F1, 752 = 0.47, p = .49) were not significant. However, the interaction of social distance and problem situation (F1, 752 = 9.46, p = .002) was significant. Results indicated the participants utilized a component of utilitarian reasoning in the decision-making, and their behaviors appeared more utilitarian at low Construal Levels (CLs) compared to high.
Conclusion
CLs, saving numbers, and problem situation significantly affected moral decision-making and exhibited significant interaction. Making decisions for oneself (low-construal) rather than giving advice to others (high-construal) was one important factor that determined whether the people were utilitarian or not. Utilitarian considerations are more relevant in impersonal dilemmas.
doi:10.1371/journal.pone.0117540
PMCID: PMC4331369  PMID: 25689521
19.  Comparison of the Postoperative Incidence Rate of Capsular Contracture among Different Breast Implants: A Cumulative Meta-Analysis 
PLoS ONE  2015;10(2):e0116071.
Background
A large number of clinical studies have reported that the different materials used in breast implants were a possible cause of the different incidence rates of capsular contracture observed in patients after implantation. However, this theory lacks comprehensive support from evidence-based medicine, and considerable controversy remains.
Objectives
In this study, a cumulative systematic review examined breast augmentation that used implants with textured or smooth surfaces to analyze the effects of these two types of implants on the occurrence of postoperative capsular contracture.
Methods
We conducted a comprehensive search of literature databases, including PubMed and EMBASE, for clinical reports on the incidence of capsular contracture after the implantation of breast prostheses. We performed a cumulative meta-analysis on the incidence of capsular contracture in order from small to large sample sizes and conducted subgroup analyses according to the prosthetic material used, the implant pocket placement, the incision type and the duration of follow-up. Relative risks (RR) and 95% confidence intervals (CI) were used as the final pooled statistics.
Results
This meta-analysis included 16 randomized controlled trials (RCTs) and two retrospective studies. The cumulative comparison of textured and smooth breast implants showed statistical significance at 2.13 (95% CI, 1.18-3.86) when the fourth study was entered into the analysis. With the inclusion of more reports, the final results indicated that smooth breast implants were more likely to be associated with capsular contracture, with statistical significance at 3.10 (95% CI, 2.23-4.33). In the subgroup analyses, the subgroups based on implant materials included the silicone implant group and the saline implant group, with significant pooled statistical levels of 4.05 (95% CI, 1.97-8.31) and 3.12 (95% CI, 2.19-4.42), respectively. According to implant pocket placement, a subglandular group and a submuscular group were included in the analyses, and only the subglandular group had a statistically significant pooled result of 3.59 (95% CI, 2.43-5.30). Four subgroups were included in the analyses according to incision type: the inframammary incision group, the periareolar incision group, the transaxillary incision group and the mastectomy incision group. Among these groups, only the pooled results of the inframammary and mastectomy incision groups were statistically significant, at 2.82 (95% CI, 1.30-6.11) and 2.30 (95% CI, 1.17-4.50), respectively. Three follow-up duration subgroups were included in the analyses: the one-year group, the two- to three-year group and the ≥five-year group. These subgroups had statistically significant results of 4.67 (95% CI, 2.35-9.28), 3.42 (95% CI, 2.26-5.16) and 2.71 (95% CI, 1.64-4.49), respectively.
Conclusion
In mammaplasty, the use of textured implants reduces the incidence of postoperative capsular contracture. Differences in implant pocket placement and incision type are also likely to affect the incidence of capsular contracture; however, this conclusion awaits further study.
doi:10.1371/journal.pone.0116071
PMCID: PMC4332657  PMID: 25680100
20.  Attentional modulations of the early and later stages of the neural processing of visual completion 
Scientific Reports  2015;5:8346.
The brain effortlessly recognizes objects even when the visual information belonging to an object is widely separated, as well demonstrated by the Kanizsa-type illusory contours (ICs), in which a contour is perceived despite the fragments of the contour being separated by gaps. Such large-range visual completion has long been thought to be preattentive, whereas its dependence on top-down influences remains unclear. Here, we report separate modulations by spatial attention and task relevance on the neural activities in response to the ICs. IC-sensitive event-related potentials that were localized to the lateral occipital cortex were modulated by spatial attention at an early processing stage (130–166 ms after stimulus onset) and modulated by task relevance at a later processing stage (234–290 ms). These results not only demonstrate top-down attentional influences on the neural processing of ICs but also elucidate the characteristics of the attentional modulations that occur in different phases of IC processing.
doi:10.1038/srep08346
PMCID: PMC4322362  PMID: 25666450
21.  Significance of serum microRNA-21 in diagnosis of hepatocellular carcinoma (HCC): clinical analyses of patients and an HCC rat model 
MicroRNAs (miRNAs) are associated with human carcinogenesis and tumor development. Moreover, serum miRNAs can reflect the level of tissue miRNAs and be potential tumor markers. Serum microRNA-21 (miR-21) is overexpressed in many human cancers including hepatocellular carcinoma (HCC). However, how serum miR-21 changes during the HCC formation and whether miR-21 plays a regulatory role in this whole process are unknown. The current study evaluated the prognostic and diagnostic potential of serum miR-21 in HCC patients. Next, we established a HCC rat model and collected the blood and liver tissues at regular time points. AFP from the serum, RNA from the serum and liver tissues were collected and quantified separately. The results revealed that tissue and serum miR-21 was upregulated significantly in the groups of cirrhosis, early and advanced HCC compared with normal and fibrosis groups. The AFP levels were increased in early and advanced HCC compared with other groups. Then, the changes of miR-21 downstream proteins (i.e., programmed cell death 4 [PDCD4] and phosphatase and tensin homolog [PTEN]) in the liver tissues were measured. PDCD4 and PTEN expression was decreased gradually after tumor induction and negatively correlated with miR-21 expression. All these results suggested that serum miR-21 was associated with the prognosis of HCC; the changes in serum miR-21 were earlier and more accurately reflected the pathogenesis of HCC than AFP; therefore, it could be used as an early diagnostic marker for HCC. Our in vivo experiments further confirmed that miR-21 plays an important role in promoting the occurrence and development of HCC by regulating PDCD4 and PTEN.
PMCID: PMC4396214  PMID: 25973032
Hepatocellular carcinoma; microRNA; microRNA-21; serum; biomarker; diagnosis and prognosis
22.  The length of a lantibiotic hinge region has profound influence on antimicrobial activity and host specificity 
Lantibiotics are ribosomally synthesized (methyl)lanthionine containing peptides which can efficiently inhibit the growth of Gram-positive bacteria. As lantibiotics kill bacteria efficiently and resistance to them is difficult to be obtained, they have the potential to be used in many applications, e.g., in pharmaceutical industry or food industry. Nisin can inhibit the growth of Gram-positive bacteria by binding to lipid II and by making pores in their membrane. The C-terminal part of nisin is known to play an important role during translocation over the membrane and forming pore complexes. However, as the thickness of bacterial membranes varies between different species and environmental conditions, this property could have an influence on the pore forming activity of nisin. To investigate this, the so-called “hinge region” of nisin (residues NMK) was engineered to vary from one to six amino acid residues and specific activity against different indicators was compared. Antimicrobial activity in liquid culture assays showed that wild type nisin is most active, while truncation of the hinge region dramatically reduced the activity of the peptide. However, one or two amino acids extensions showed only slightly reduced activity against most indicator strains. Notably, some variants (+2, +1, −1, −2) exhibited higher antimicrobial activity than nisin in agar well diffusion assays against Lactococcus lactis MG1363, Listeria monocytogenes, Enterococcus faecalis VE14089, Bacillus sporothermodurans IC4 and Bacillus cereus 4153 at certain temperatures.
doi:10.3389/fmicb.2015.00011
PMCID: PMC4310329  PMID: 25688235
lantibiotics; nisin; hinge region; membrane; diffusion
23.  Induction of innate lymphoid cell-derived interleukin-22 by the transcription factor STAT3 mediates protection against intestinal infection 
Immunity  2014;40(1):25-39.
Summary
Inhibitors of the transcription factor STAT3 target STAT3-dependent tumorigenesis but patients often develop diarrhea from unknown mechanisms. Here we showed that STAT3 deficiency increased morbidity and mortality after Citrobacter rodentium infection with decreased secretion of cytokines including IL-17 and IL-22 associated with the transcription factor RORγt. Administration of the cytokine IL-22 was sufficient to rescue STAT3-deficient mice from lethal infection. Although STAT3 was required for IL-22 production in both innate and adaptive arms, using conditional gene deficient mice we observed that STAT3 expression in RORγt+ innate lymphoid cells (ILC3s), but not T cells, was essential for the protection. However, STAT3 was required for RORγt expression in T helper cells, but not in ILC3s. Activated STAT3 could directly bind to the Il22 locus. Thus, cancer therapies that utilize STAT3 inhibitors increase the risk for pathogen-mediated diarrhea through direct suppression of IL-22 from gut ILCs.
doi:10.1016/j.immuni.2013.10.021
PMCID: PMC3919552  PMID: 24412612
24.  Differentiation of Swine iPSC into Rod Photoreceptors and Their Integration into the Retina 
Stem cells (Dayton, Ohio)  2011;29(6):972-980.
Absence of a regenerative pathway for damaged retina following injury or disease has led to experiments utilizing stem cell transplantation for retinal repair, and encouraging results have been obtained in rodents. The swine eye is a closer anatomical and physiological match to the human eye, but embryonic stem cells have not been isolated from pig, and photoreceptor differentiation has not been demonstrated with swine induced pluripotent stem cells (iPSC). Here, we subjected swine iPSC to a rod photoreceptor differentiation protocol consisting of floating culture as embryoid bodies followed by differentiation in adherent culture. Real time PCR and immunostaining of differentiated cells demonstrated loss of expression of the pluripotent genes POU5F1, NANOG and SOX2 and induction of rod photoreceptor genes RCVRN, NRL, RHO and ROM1. While these differentiated cells displayed neuronal morphology, culturing on a Matrigel substratum triggered a further morphological change resulting in concentration of RHO and ROM1 in outer segment-like projections resembling those on primary cultures of rod photoreceptors. The differentiated cells were transplanted into the subretinal space of pigs treated with iodoacetic acid to eliminate rod photoreceptors. Three weeks after transplantation, engrafted RHO+ cells were evident in the outer nuclear layer where photoreceptors normally reside. A portion of these transplanted cells had generated projections resembling outer segments. These results demonstrate that swine iPSC can differentiate into photoreceptors in culture and these cells can integrate into the damaged swine neural retina thus laying a foundation for future studies using the pig as a model for retinal stem cell transplantation.
doi:10.1002/stem.637
PMCID: PMC4263955  PMID: 21491544
photoreceptor differentiation; swine retina; induced pluripotent stem cells; retinal transplantation
25.  Impact of guidewire selection and operator expertise on radiation exposure in transradial angiography 
Background
Several studies have implied that the time of radiation exposure for patients and operators during the transradial approach for coronary angiography (TRA) is associated with the use of different guidewire or catheter and operator’s finesse. This study aimed to assess the effects of non-hydrophilic or hydrophilic guidewire and operator expertise on fluoroscopy time and procedure time of TRA and further effects on the procedure safety.
Methods
A total of 1035 consecutive patients undergoing TRA were recruited prospectively and respectively divided into non-hydrophilic guidewire and hydrophilic guidewire group, or well-experienced group and less-experienced group. The primary endpoints were fluoroscopy time and procedure time. Secondary endpoints included contrast volume, cost, guidewire exchange, switchover and complications.
Results
TRA by non-hydrophilic guidewire group showed shorter fluoroscopy time and procedure time compared with hydrophilic guidewire group, similar results were found between well-experienced group and less-experienced group. Moreover, using of non-hydrophilic guidewire significantly reduced the incidence of hematoma and abnormal guidewie advancement, well-experienced group showed less dosage of contrast volume, lower incidence of radial artery spasm and frequency of guidewire exchange.
Conclusions
TRA by non-hydrophilic guidewire and well-experienced operator can decrease radiation exposure of patients and operators through reducing the fluoroscopy time and procedure time and further increase procedure safety. These will contribute to the optimization of TRA procedure and promote its widely application.
doi:10.1186/s13019-014-0194-5
PMCID: PMC4265418  PMID: 25477256
Coronary angiography; Transradial approach; Fluoroscopy time; Procedure time

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