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1.  Increased platelet expression of glycoprotein IIIa following aspirin treatment in aspirin-resistant but not aspirin-sensitive subjects 
Aims
Aspirin is widely used as an anti-platelet agent for cardiovascular prophylaxis. Despite aspirin treatment, many patients experience recurrent thrombotic events, and aspirin resistance may contribute to this. We examined the prevalence of aspirin resistance in a healthy population, and investigated whether the platelet proteome differed in aspirin-resistant subjects.
Methods
Ninety-three healthy subjects received aspirin 300 mg daily for 28 days. Before and at the end of treatment, urine was taken to determine 11-dehydrothromboxane B2, and blood was taken to measure arachidonic acid (AA)-induced aggregation of platelet-rich plasma and to interrogate the platelet proteome by mass spectrometric analysis with further confirmation of findings using Western blotting.
Results
In two of the 93 subjects, neither AA-induced aggregation nor urinary 11-dehydrothromboxane B2 was effectively suppressed by aspirin, despite measurable plasma salicylate concentrations, suggesting the presence of true aspirin resistance. Despite no detectable differences in the platelet proteome at baseline, following aspirin a marked increase was seen in platelet glycoprotein IIIa expression in the aspirin-resistant but not aspirin-sensitive subjects. An increase in platelet glycoprotein IIIa expression with aspirin resistance was confirmed in a separate cohort of 17 patients with stable coronary artery disease on long term aspirin treatment, four of whom exhibited aspirin resistance.
Conclusions
In a healthy population, true aspirin resistance is uncommon but exists. Resistance is associated with an increase in platelet glycoprotein IIIa expression in response to aspirin. These data shed new light on the mechanism of aspirin resistance, and provide the potential to identify aspirin-resistant subjects using a novel biomarker.
doi:10.1111/bcp.12335
PMCID: PMC4137824  PMID: 25099258
aspirin resistance; glycoprotein IIIa; platelets; proteomics
2.  Passive movement and active exercise for very young infants with congenital heart disease: a study protocol for a randomized controlled trial 
Trials  2015;16:288.
Background
Delayed motor development is reported in patients with congenital heart disease (CHD). Exercise is widely used to facilitate motor development and improve motor ability. Exercise for adolescents and adults with CHD has been extensively studied. However, the evidence of exercise for infants with CHD is sparse. This study aims to identify the effect of passive movement and active exercise on motor development within very young CHD infants with cardiac catheterization.
Methods/Design
A prospective and randomized controlled trial will be conducted in very young CHD infants with cardiac catheterization. A total of 147 infants with CHD will be randomized by a 1:1:1 allocation ratio by computer to an exercise intervention group, a home-based intervention group and a control group. The exercise intervention group will receive passive movement and active exercise from experienced physiotherapists in pediatrics three times a week for 12 weeks. The home-based intervention group will receive passive movement and active exercise from their parents or caregivers at home three times a week for 12 weeks. The control group will receive follow up only. The follow-up duration is 20 months. The primary outcome measures are the motor quotient measured by the Peabody Developmental Motor Scales-II. The secondary outcome measures are the Ross score, ventricular function, bone quality, body length, weight, head circumference, upper arm circumference, and adverse events.
Discussion
This study has several important features, including the randomization process, the long follow-up duration, the control group, and the large sample size. The aim of this study is to determine whether 12-week passive movement and active exercise promotes motor development and produces other beneficial effects for very young CHD infants with cardiac catheterization. Therefore, this study will contribute new knowledge regarding the rehabilitation program in very young CHD infants with cardiac catheterization.
Trial registration
Current Controlled Trials ChiCTR-IOR-15005909 (January 31, 2015).
doi:10.1186/s13063-015-0816-9
PMCID: PMC4485354  PMID: 26122088
Congenital heart disease; Physical therapy; Exercise therapy; Randomized controlled trial; Rehabilitation
3.  Identification of new susceptibility loci for IgA nephropathy in Han Chinese 
Nature Communications  2015;6:7270.
IgA nephropathy (IgAN) is one of the most common primary glomerulonephritis. Previously identified genome-wide association study (GWAS) loci explain only a fraction of disease risk. To identify novel susceptibility loci in Han Chinese, we conduct a four-stage GWAS comprising 8,313 cases and 19,680 controls. Here, we show novel associations at ST6GAL1 on 3q27.3 (rs7634389, odds ratio (OR)=1.13, P=7.27 × 10−10), ACCS on 11p11.2 (rs2074038, OR=1.14, P=3.93 × 10−9) and ODF1-KLF10 on 8q22.3 (rs2033562, OR=1.13, P=1.41 × 10−9), validate a recently reported association at ITGAX-ITGAM on 16p11.2 (rs7190997, OR=1.22, P=2.26 × 10−19), and identify three independent signals within the DEFA locus (rs2738058, P=1.15 × 10−19; rs12716641, P=9.53 × 10−9; rs9314614, P=4.25 × 10−9, multivariate association). The risk variants on 3q27.3 and 11p11.2 show strong association with mRNA expression levels in blood cells while allele frequencies of the risk variants within ST6GAL1, ACCS and DEFA correlate with geographical variation in IgAN prevalence. Our findings expand our understanding on IgAN genetic susceptibility and provide novel biological insights into molecular mechanisms underlying IgAN.
IgA nephropathy is a major cause of end-stage renal disease in China, occurring at a high frequency in Asian populations. Here Li and colleagues conduct a four-stage genome-wide association study in a Chinese population, identifying novel loci and variants associated with disease risk.
doi:10.1038/ncomms8270
PMCID: PMC4458882  PMID: 26028593
4.  Effects of 6-Hydroxydopamine Exposure on Motor Activity and Biochemical Expression in Zebrafish (Danio Rerio) Larvae 
Zebrafish  2014;11(3):227-239.
Abstract
Parkinson's disease (PD) is a neurodegenerative disease that is characterized by the progressive loss of dopaminergic (DA) neurons in the substantia nigra. However, current treatments for PD are mainly palliative. Recently, researchers discovered that neurotoxins can induce Parkinsonian-like symptoms in zebrafish. No study to date has investigated the characteristics of PD, such as neuroinflammation factors, oxidative stress, or ubiquitin dysfunction, in this model. Therefore, the current study was aimed at utilizing commonly used clinical drugs, minocycline, vitamin E, and Sinemet, to test the usefulness of this model. Previous studies had indicated that DA cell loss was greater with 6-hydroxydopamine (6-OHDA) than with other neurotoxins. Thus, we first challenged zebrafish with 6-OHDA immersion and found a significant reduction in zebrafish locomotor activity; we then reversed the locomotor disruptions by treatment with vitamin E, Sinemet, or minocycline. The present study also analyzed the mRNA expression of parkin, pink1, and cd-11b, because the expression of these molecular targets has been shown to result in attenuation in mammalian models of PD. Vitamin E, Sinemet, and minocycline significantly reversed 6-OHDA-induced changes of parkin, pink1, and cd-11b mRNA expression in zebrafish. Moreover, we assessed tyrosine hydroxylase (TH) expression to confirm the therapeutic effects of vitamin E tested on this PD model and established that vitamin E reversed the 6-OHDA-induced damage on TH expression. Our results provide some support for the validity of this in vivo Parkinson's model, and we hope that this model will be more widely used in the future.
doi:10.1089/zeb.2013.0950
PMCID: PMC4050718  PMID: 24720843
5.  A Study of Long-Term fMRI Reproducibility Using Data-Driven Analysis Methods 
The reproducibility of functional magnetic resonance imaging (fMRI) is important for fMRI-based neuroscience research and clinical applications. Previous studies show considerable variation in amplitude and spatial extent of fMRI activation across repeated sessions on individual subjects even using identical experimental paradigms and imaging conditions. Most existing fMRI reproducibility studies were typically limited by time duration and data analysis techniques. Particularly, the assessment of reproducibility is complicated by a fact that fMRI results may depend on data analysis techniques used in reproducibility studies. In this work, the long-term fMRI reproducibility was investigated with a focus on the data analysis methods. Two spatial smoothing techniques, including a wavelet-domain Bayesian method and the Gaussian smoothing, were evaluated in terms of their effects on the long-term reproducibility. A multivariate support vector machine (SVM)-based method was used to identify active voxels, and compared to a widely used general linear model (GLM)-based method at the group level. The reproducibility study was performed using multisession fMRI data acquired from eight healthy adults over 1.5 years’ period of time. Three regions-of-interest (ROI) related to a motor task were defined based upon which the long-term reproducibility were examined. Experimental results indicate that different spatial smoothing techniques may lead to different reproducibility measures, and the wavelet-based spatial smoothing and SVM-based activation detection is a good combination for reproducibility studies. On the basis of the ROIs and multiple numerical criteria, we observed a moderate to substantial within-subject long-term reproducibility. A reasonable long-term reproducibility was also observed from the inter-subject study. It was found that the short-term reproducibility is usually higher than the long-term reproducibility. Furthermore, the results indicate that brain regions with high contrast-to-noise ratio do not necessarily exhibit high reproducibility. These findings may provide supportive information for optimal design/implementation of fMRI studies and data interpretation.
doi:10.1002/ima.22111
PMCID: PMC4444074  PMID: 26023254
reproducibility; wavelet; support vector machine; quantitative fMRI
6.  Effects of Repetitive Transcranial Magnetic Stimulation on Motor Symptoms in Parkinson Disease 
JAMA neurology  2015;72(4):432-440.
IMPORTANCE
Repetitive transcranial magnetic stimulation (rTMS) is a noninvasive neuromodulation technique that has been closely examined as a possible treatment for Parkinson disease (PD). However, results evaluating the effectiveness of rTMS in PD are mixed, mostly owing to low statistical power or variety in individual rTMS protocols.
OBJECTIVES
To determine the rTMS effects on motor dysfunction in patients with PD and to examine potential factors that modulate the rTMS effects.
DATA SOURCES
Databases searched included PubMed, EMBASE, Web of Knowledge, Scopus, and the Cochrane Library from inception to June 30, 2014.
STUDY SELECTION
Eligible studies included sham-controlled, randomized clinical trials of rTMS intervention for motor dysfunction in patients with PD.
DATA EXTRACTION AND SYNTHESIS
Relevant measures were extracted independently by 2 investigators. Standardized mean differences (SMDs) were calculated with random-effects models.
MAIN OUTCOMES AND MEASURES
Motor examination of the Unified Parkinson’s Disease Rating Scale.
RESULTS
Twenty studies with a total of 470 patients were included. Random-effects analysis revealed a pooled SMD of 0.46 (95%CI, 0.29–0.64), indicating an overall medium effect size favoring active rTMS over sham rTMS in the reduction of motor symptoms (P < .001). Subgroup analysis showed that the effect sizes estimated from high-frequency rTMS targeting the primary motor cortex (SMD, 0.77; 95%CI, 0.46–1.08; P < .001) and low-frequency rTMS applied over other frontal regions (SMD, 0.50; 95%CI, 0.13–0.87; P = .008) were significant. The effect sizes obtained from the other 2 combinations of rTMS frequency and rTMS site (ie, high-frequency rTMS at other frontal regions: SMD, 0.23; 95% CI, −0.02 to 0.48, and low primary motor cortex: SMD, 0.28; 95%CI, −0.23 to 0.78) were not significant. Meta-regression revealed that a greater number of pulses per session or across sessions is associated with larger rTMS effects. Using the Grading of Recommendations, Assessment, Development, and Evaluation criteria, we characterized the quality of evidence presented in this meta-analysis as moderate quality.
CONCLUSIONS AND RELEVANCE
The pooled evidence suggests that rTMS improves motor symptoms for patients with PD. Combinations of rTMS site and frequency as well as the number of rTMS pulses are key modulators of rTMS effects. The findings of our meta-analysis may guide treatment decisions and inform future research.
doi:10.1001/jamaneurol.2014.4380
PMCID: PMC4425190  PMID: 25686212
7.  Discovery of new risk loci for IgA nephropathy implicates genes involved in immunity against intestinal pathogens 
Kiryluk, Krzysztof | Li, Yifu | Scolari, Francesco | Sanna-Cherchi, Simone | Choi, Murim | Verbitsky, Miguel | Fasel, David | Lata, Sneh | Prakash, Sindhuri | Shapiro, Samantha | Fischman, Clara | Snyder, Holly J. | Appel, Gerald | Izzi, Claudia | Viola, Battista Fabio | Dallera, Nadia | Vecchio, Lucia Del | Barlassina, Cristina | Salvi, Erika | Bertinetto, Francesca Eleonora | Amoroso, Antonio | Savoldi, Silvana | Rocchietti, Marcella | Amore, Alessandro | Peruzzi, Licia | Coppo, Rosanna | Salvadori, Maurizio | Ravani, Pietro | Magistroni, Riccardo | Ghiggeri, Gian Marco | Caridi, Gianluca | Bodria, Monica | Lugani, Francesca | Allegri, Landino | Delsante, Marco | Maiorana, Mariarosa | Magnano, Andrea | Frasca, Giovanni | Boer, Emanuela | Boscutti, Giuliano | Ponticelli, Claudio | Mignani, Renzo | Marcantoni, Carmelita | Di Landro, Domenico | Santoro, Domenico | Pani, Antonello | Polci, Rosaria | Feriozzi, Sandro | Chicca, Silvana | Galliani, Marco | Gigante, Maddalena | Gesualdo, Loreto | Zamboli, Pasquale | Maixnerová, Dita | Tesar, Vladimir | Eitner, Frank | Rauen, Thomas | Floege, Jürgen | Kovacs, Tibor | Nagy, Judit | Mucha, Krzysztof | Pączek, Leszek | Zaniew, Marcin | Mizerska-Wasiak, Małgorzata | Roszkowska-Blaim, Maria | Pawlaczyk, Krzysztof | Gale, Daniel | Barratt, Jonathan | Thibaudin, Lise | Berthoux, Francois | Canaud, Guillaume | Boland, Anne | Metzger, Marie | Panzer, Ulf | Suzuki, Hitoshi | Goto, Shin | Narita, Ichiei | Caliskan, Yasar | Xie, Jingyuan | Hou, Ping | Chen, Nan | Zhang, Hong | Wyatt, Robert J. | Novak, Jan | Julian, Bruce A. | Feehally, John | Stengel, Benedicte | Cusi, Daniele | Lifton, Richard P. | Gharavi, Ali G.
Nature genetics  2014;46(11):1187-1196.
We performed a genome-wide association study (GWAS) of IgA nephropathy (IgAN), the most common form of glomerulonephritis, with discovery and follow-up in 20,612 individuals of European and East Asian ancestry. We identified six novel genome-wide significant associations, four in ITGAM-ITGAX, VAV3 and CARD9 and two new independent signals at HLA-DQB1 and DEFA. We replicated the nine previously reported signals, including known SNPs in the HLA-DQB1 and DEFA loci. The cumulative burden of risk alleles is strongly associated with age at disease onset. Most loci are either directly associated with risk of inflammatory bowel disease (IBD) or maintenance of the intestinal epithelial barrier and response to mucosal pathogens. The geo-spatial distribution of risk alleles is highly suggestive of multi-locus adaptation and the genetic risk correlates strongly with variation in local pathogens, particularly helminth diversity, suggesting a possible role for host-intestinal pathogen interactions in shaping the genetic landscape of IgAN.
doi:10.1038/ng.3118
PMCID: PMC4213311  PMID: 25305756
8.  Molecular Cloning and Functional Characterization of Mannose Receptor in Zebra Fish (Danio rerio) during Infection with Aeromonas sobria 
Mannose receptor (MR) is a member of pattern-recognition receptors (PRRs), which plays a significant role in immunity responses. Much work on MR has been done in mammals and birds while little in fish. In this report, a MR gene (designated as zfMR) was cloned from zebra fish (Danio rerio), which is an attractive model for the studies of animal diseases. The full-length cDNA of zfMR contains 6248 bp encoding a putative protein of 1428 amino acids. The predicted amino acid sequences showed that zfMR contained a cysteine-rich domain, a single fibronectin type II (FN II) domain, eight C-type lectin-like domains (CTLDs), a transmembrane domain and a short C-terminal cytoplasmic domain, sharing highly conserved structures with MRs from the other species. The MR mRNA could be detected in all examined tissues with highest level in kidney. The temporal expression patterns of MR, IL-1β and TNF-α mRNAs were analyzed in the liver, spleen, kidney and intestine post of infection with Aeromonas sobria. By immunohistochemistry assay, slight enhancement of MR protein was also observed in the spleen and intestine of the infected zebra fish. The established zebra fish-A. sobria infection model will be valuable for elucidating the role of MR in fish immune responses to infection.
doi:10.3390/ijms160510997
PMCID: PMC4463687  PMID: 25988382
Danio rerio; mannose receptor; mRNA expression; protein expression; Aeromonas sobria
9.  Recombinant lentivirus with enhanced expression of caudal-related homeobox protein 2 inhibits human colorectal cancer cell proliferation in vitro 
Molecular Medicine Reports  2015;12(2):1838-1844.
Caudal-related homeobox protein 2 (CDX2), a tumor suppressor in the adult colon, is overexpressed under a non-cancer specific cytomegalovirus promoter in certain tumor cells; furthermore, non-specific expression of CDX2 may result in aberrant side effects in normal cells. The human telomerase reverse transcriptase (hTERT) promoter is active in the majority of cancer cells but not in normal cells. Hypoxia is a key feature of solid tumors, and targeted genes may be significantly upregulated by five copies of hypoxia-response elements (HREs) under hypoxic conditions. However, the effect of CDX2 overexpression, as controlled by five copies of HREs and the hTERT promoter, on human colorectal cancer (CRC) cell proliferation in vitro remains to be fully elucidated. In the current study, a recombinant lentivirus containing the CDX2 gene under the control of five HREs and the hTERT promoter was generated. An immunofluorescence assay was used to detect CDX2 expression by the 5HhC lentivirus, whereas an MTT assay was used to detect the effects of CoCl2 on the viability of LoVo cells. Western blot analysis was conducted in order to determine the relative ratios of recombinant CDX2 protein to the internal control β-actin, following 5HhC/LoVo cell culture under normoxic and hypoxic conditions (100, 200, 300, 400 or 500 µmol/l CoCl2) for 24 h, then for 12, 24 or 36 h with the optimal concentration (300 µmol/l) of CoCl2. Reverse transcription polymerase chain reaction analysis was used to determine the transcription of recombinant CDX2 mRNA following culture of 5HhC/LoVo cells under normoxic or hypoxic conditions. Finally, a cloning assay was used to detect the proliferative ability of 5HhC/LoVo and 5Hh cells. High CDX2 expression was observed in hTERT-positive LoVo cells under hypoxic conditions, an effect which was mimicked by treatment with CoCl2 to inhibit LoVo cell proliferation in vitro. High expression of CDX2 therefore provides a promising strategy for the development of novel targeted treatments and gene therapy for CRC.
doi:10.3892/mmr.2015.3594
PMCID: PMC4464164  PMID: 25847407
hypoxia response element; human telomerase catalytic subunit; caudal-related homeobox protein 2; proliferation; colon cancer
10.  Involvement of phosphatase and tensin homolog deleted from chromosome 10 in rodent model of neuropathic pain 
Background
Many cancer research studies have extensively examined the phosphatase and tensin homolog deleted from chromosome 10 (PTEN) pathway. There are only few reports that suggest that PTEN might affect pain; however, there is still a lack of evidence to show the role of PTEN for modulating pain. Here, we report a role for PTEN in a rodent model of neuropathic pain.
Results
We found that chronic constriction injury (CCI) surgery in rats could elicit downregulation of spinal PTEN as well as upregulation of phosphorylated PTEN (phospho-PTEN) and phosphorylated mammalian target of rapamycin (phospho-mTOR). After examining such changes in endogenous PTEN in neuropathic rats, we explored the effects of modulating the spinal PTEN pathway on nociceptive behaviors. The normal rats exhibited mechanical allodynia after intrathecal (i.t.) injection of adenovirus-mediated PTEN antisense oligonucleotide (Ad-antisense PTEN). These data indicate the importance of downregulation of spinal PTEN for nociception. Moreover, upregulation of spinal PTEN by i.t. adenovirus-mediated PTEN (Ad-PTEN) significantly prevented CCI-induced development of nociceptive sensitization, thermal hyperalgesia, mechanical allodynia, cold allodynia, and weight-bearing deficits in neuropathic rats. Furthermore, upregulation of spinal PTEN by i.t. Ad-PTEN significantly attenuated CCI-induced microglia and astrocyte activation, upregulation of tumor necrosis factor-α (TNF-α) and phospho-mTOR, and downregulation of PTEN in neuropathic rats 14 days post injury.
Conclusions
These findings demonstrate that PTEN plays a key, beneficial role in a rodent model of neuropathic pain.
doi:10.1186/s12974-015-0280-1
PMCID: PMC4386079  PMID: 25889774
Chronic constriction injury; Intrathecal; Astrocyte; Neuroinflammation
11.  CRABP-II- and FABP5-independent responsiveness of human glioblastoma cells to all-trans retinoic acid 
Oncotarget  2015;6(8):5889-5902.
Glioblastomas respond differently to all-trans retinoic acid (RA) for unknown reasons. Because CRABP-II and FABP5 mediate RA intracellular signaling respectively and lead to distinct biological consequences, their expression patterns in different grades of astrocytomas and the glioblastoma cells lines LN18, LN428 and U251 were examined to identify potential correlations with RA sensitivities. The response of glioblastoma cells to RA, decitabine or the FABP5 competitive inhibitor, BMS309403, was analyzed. CRABP-II and FABP5 were expressed to varying degrees by the 84-astrocytoma cases examined. Treatment of LN428, U251 and LN18 cells with RA failed to suppress their growth; however, U251 proliferation was inhibited by decitabine. The combination of decitabine and RA suppressed the growth of all three cell lines and induced significant apoptosis of LN428 and U251 cells. Both CRABP-II and FABP5 were transcribed in the three cell lines but FABP5 proteins were undetectable in U251 cells. The ratio of CRABP-II to FABP5 was not altered after RA, decitabine or RA and decitabine treatment and the resistance of cells to RA was not reversed by BMS309403 treatment. In conclusion, CRABP-II and FABP5 expression patterns are neither related to the tumor grades nor correlated with RA sensitivity. Additional molecular factors may be present that determines the sensitivity of glioblastoma cells to RA. Dicitabine may improve the sensitivity of glioblastoma cells to RA, however, its underlying mechanism and its in vivo feasibility need to be investigated.
PMCID: PMC4467409  PMID: 25797252
Glioblastoma; All-trans retinoic acid; Chemosensitivity; CRABP-II; FABP5
12.  Significant Reduction of Antibiotic Consumption and Patients’ Costs after an Action Plan in China, 2010–2014 
PLoS ONE  2015;10(3):e0118868.
Introduction
On July 1, 2011, the Chinese government launched a national Action Plan for antibiotic stewardship targeting antibiotic misuse in public hospitals. The aim of this study was to evaluate the impacts of the Action Plan in terms of frequency and intensity of antibiotic utilization and patients costs in public general hospitals.
Methods
Administrative pharmacy data from July 2010 to June 2014 were sampled from 65 public general hospitals and divided into three segments: (1) July 2010 to June 2011 as the preparation period; (2) July 2011 to June 2012 as the intervention period; and (3) July 2012 to June 2014 as the assessment period. The outcome measures included (1) antibiotic prescribing rates; (2) intensity of antibiotic consumption; (3) patients costs; and (4) duration of peri-operative antibiotic treatment in clean surgeries of thyroidectomy, breast, hernia, and orthopedic procedures. Longitudinal and cross-sectional analyses were conducted.
Results
Longitudinal analyses showed significant trend changes in the frequency and intensity of antibiotic consumption, the patients’ costs on antibiotics, and the duration of antibiotic treatment received by surgical patients undergoing the 4 clean procedures during the intervention period. Cross-sectional analyses showed that the antibiotic prescribing rates were reduced to 35.3% and 12.9% in inpatient and outpatient settings, that the intensity of antibiotic consumption was reduced to 35.9 DDD/100 bed-days, that patients’ costs on antibiotics were reduced significantly, and that the duration of peri-operative antibiotic treatment received by surgical patients undergoing the 4 types of clean procedures decreased to less than 24 hour during the assessment period.
Conclusion
The Action Plan, as a combination of managerial and professional strategies, was effective in reducing the frequency and intensity of antibiotic consumption, patients’ costs on antibiotics, and the duration of peri-operative antibiotic treatment in the 4 clean surgeries.
doi:10.1371/journal.pone.0118868
PMCID: PMC4359138  PMID: 25767891
13.  Abnormal Changes of Multidimensional Surface Features Using Multivariate Pattern Classification in Amnestic Mild Cognitive Impairment Patients 
The Journal of Neuroscience  2014;34(32):10541-10553.
Previous studies have suggested that amnestic mild cognitive impairment (aMCI) is associated with changes in cortical morphological features, such as cortical thickness, sulcal depth, surface area, gray matter volume, metric distortion, and mean curvature. These features have been proven to have specific neuropathological and genetic underpinnings. However, most studies primarily focused on mass-univariate methods, and cortical features were generally explored in isolation. Here, we used a multivariate method to characterize the complex and subtle structural changing pattern of cortical anatomy in 24 aMCI human participants and 26 normal human controls. Six cortical features were extracted for each participant, and the spatial patterns of brain abnormities in aMCI were identified by high classification weights using a support vector machine method. The classification accuracy in discriminating the two groups was 76% in the left hemisphere and 80% in the right hemisphere when all six cortical features were used. Regions showing high weights were subtle, spatially complex, and predominately located in the left medial temporal lobe and the supramarginal and right inferior parietal lobes. In addition, we also found that the six morphological features had different contributions in discriminating the two groups even for the same region. Our results indicated that the neuroanatomical patterns that discriminated individuals with aMCI from controls were truly multidimensional and had different effects on the morphological features. Furthermore, the regions identified by our method could potentially be useful for clinical diagnosis.
doi:10.1523/JNEUROSCI.4356-13.2014
PMCID: PMC4122798  PMID: 25100588
aMCI; cortical surface feature; entorhinal; MRI; multivariate classification
14.  Preschool Anxiety Disorders Predict Different Patterns of Amygdala-Prefrontal Connectivity at School-Age 
PLoS ONE  2015;10(1):e0116854.
Objective
In this prospective, longitudinal study of young children, we examined whether a history of preschool generalized anxiety, separation anxiety, and/or social phobia is associated with amygdala-prefrontal dysregulation at school-age. As an exploratory analysis, we investigated whether distinct anxiety disorders differ in the patterns of this amygdala-prefrontal dysregulation.
Methods
Participants were children taking part in a 5-year study of early childhood brain development and anxiety disorders. Preschool symptoms of generalized anxiety, separation anxiety, and social phobia were assessed with the Preschool Age Psychiatric Assessment (PAPA) in the first wave of the study when the children were between 2 and 5 years old. The PAPA was repeated at age 6. We conducted functional MRIs when the children were 5.5 to 9.5 year old to assess neural responses to viewing of angry and fearful faces.
Results
A history of preschool social phobia predicted less school-age functional connectivity between the amygdala and the ventral prefrontal cortices to angry faces. Preschool generalized anxiety predicted less functional connectivity between the amygdala and dorsal prefrontal cortices in response to fearful faces. Finally, a history of preschool separation anxiety predicted less school-age functional connectivity between the amygdala and the ventral prefrontal cortices to angry faces and greater school-age functional connectivity between the amygdala and dorsal prefrontal cortices to angry faces.
Conclusions
Our results suggest that there are enduring neurobiological effects associated with a history of preschool anxiety, which occur over-and-above the effect of subsequent emotional symptoms. Our results also provide preliminary evidence for the neurobiological differentiation of specific preschool anxiety disorders.
doi:10.1371/journal.pone.0116854
PMCID: PMC4308069  PMID: 25625285
15.  Interleaved EPI Based fMRI Improved by Multiplexed Sensitivity Encoding (MUSE) and Simultaneous Multi-Band Imaging 
PLoS ONE  2014;9(12):e116378.
Functional magnetic resonance imaging (fMRI) is a non-invasive and powerful imaging tool for detecting brain activities. The majority of fMRI studies are performed with single-shot echo-planar imaging (EPI) due to its high temporal resolution. Recent studies have demonstrated that, by increasing the spatial-resolution of fMRI, previously unidentified neuronal networks can be measured. However, it is challenging to improve the spatial resolution of conventional single-shot EPI based fMRI. Although multi-shot interleaved EPI is superior to single-shot EPI in terms of the improved spatial-resolution, reduced geometric distortions, and sharper point spread function (PSF), interleaved EPI based fMRI has two main limitations: 1) the imaging throughput is lower in interleaved EPI; 2) the magnitude and phase signal variations among EPI segments (due to physiological noise, subject motion, and B0 drift) are translated to significant in-plane aliasing artifact across the field of view (FOV). Here we report a method that integrates multiple approaches to address the technical limitations of interleaved EPI-based fMRI. Firstly, the multiplexed sensitivity-encoding (MUSE) post-processing algorithm is used to suppress in-plane aliasing artifacts resulting from time-domain signal instabilities during dynamic scans. Secondly, a simultaneous multi-band interleaved EPI pulse sequence, with a controlled aliasing scheme incorporated, is implemented to increase the imaging throughput. Thirdly, the MUSE algorithm is then generalized to accommodate fMRI data obtained with our multi-band interleaved EPI pulse sequence, suppressing both in-plane and through-plane aliasing artifacts. The blood-oxygenation-level-dependent (BOLD) signal detectability and the scan throughput can be significantly improved for interleaved EPI-based fMRI. Our human fMRI data obtained from 3 Tesla systems demonstrate the effectiveness of the developed methods. It is expected that future fMRI studies requiring high spatial-resolvability and fidelity will largely benefit from the reported techniques.
doi:10.1371/journal.pone.0116378
PMCID: PMC4280209  PMID: 25549271
16.  Mushroom body output neurons encode valence and guide memory-based action selection in Drosophila 
eLife  null;3:e04580.
Animals discriminate stimuli, learn their predictive value and use this knowledge to modify their behavior. In Drosophila, the mushroom body (MB) plays a key role in these processes. Sensory stimuli are sparsely represented by ∼2000 Kenyon cells, which converge onto 34 output neurons (MBONs) of 21 types. We studied the role of MBONs in several associative learning tasks and in sleep regulation, revealing the extent to which information flow is segregated into distinct channels and suggesting possible roles for the multi-layered MBON network. We also show that optogenetic activation of MBONs can, depending on cell type, induce repulsion or attraction in flies. The behavioral effects of MBON perturbation are combinatorial, suggesting that the MBON ensemble collectively represents valence. We propose that local, stimulus-specific dopaminergic modulation selectively alters the balance within the MBON network for those stimuli. Our results suggest that valence encoded by the MBON ensemble biases memory-based action selection.
DOI: http://dx.doi.org/10.7554/eLife.04580.001
eLife digest
An animal's survival depends on its ability to respond appropriately to its environment, approaching stimuli that signal rewards and avoiding any that warn of potential threats. In fruit flies, this behavior requires activity in a region of the brain called the mushroom body, which processes sensory information and uses that information to influence responses to stimuli.
Aso et al. recently mapped the mushroom body of the fruit fly in its entirety. This work showed, among other things, that the mushroom body contained 21 different types of output neurons. Building on this work, Aso et al. have started to work out how this circuitry enables flies to learn to associate a stimulus, such as an odor, with an outcome, such as the presence of food.
Two complementary techniques—the use of molecular genetics to block neuronal activity, and the use of light to activate neurons (a technique called optogenetics)—were employed to study the roles performed by the output neurons in the mushroom body. Results revealed that distinct groups of output cells must be activated for flies to avoid—as opposed to approach—odors. Moreover, the same output neurons are used to avoid both odors and colors that have been associated with punishment. Together, these results indicate that the output cells do not encode the identity of stimuli: rather, they signal whether a stimulus should be approached or avoided. The output cells also regulate the amount of sleep taken by the fly, which is consistent with the mushroom body having a broader role in regulating the fly's internal state.
The results of these experiments—combined with new knowledge about the detailed structure of the mushroom body—lay the foundations for new studies that explore associative learning at the level of individual circuits and their component cells. Given that the organization of the mushroom body has much in common with that of the mammalian brain, these studies should provide insights into the fundamental principles that underpin learning and memory in other species, including humans.
DOI: http://dx.doi.org/10.7554/eLife.04580.002
doi:10.7554/eLife.04580
PMCID: PMC4273436  PMID: 25535794
mushroom body; memory; behavioral valence; sleep; population code; action selection; D. melanogaster
17.  One-Year Survival and Renal Function Recovery of Acute Kidney Injury Patients with Chronic Heart Failure 
Cardiorenal Medicine  2014;5(1):40-47.
Objective
To describe and analyze the clinical characteristics of acute kidney injury (AKI) patients with preexisting chronic heart failure (CHF) and to identify the prognostic factors of the 1-year outcome.
Methods
A total of 120 patients with preexisting CHF who developed AKI between January 2005 and December 2010 were enrolled. CHF was diagnosed according to the European Society of Cardiology guidelines, and AKI was diagnosed using the RIFLE criteria. Clinical characteristics were recorded, and nonrecovery from kidney dysfunction as well as mortality were analyzed.
Results
The median age of the patients was 70 years, and 58.33% were male. 60% of the patients had an advanced AKI stage (‘failure’) and 90% were classified as NYHA class III/IV. The 1-year mortality rate was 35%. 25.83% of the patients progressed to end-stage renal disease after 1 year. Hypertension, anemia, coronary atherosclerotic heart disease and chronic kidney disease were common comorbidities. Multiple organ dysfunction syndrome (MODS; OR, 35.950; 95% CI, 4.972-259.952), arrhythmia (OR, 13.461; 95% CI, 2.379-76.161), anemia (OR, 6.176; 95% CI, 1.172-32.544) and RIFLE category (OR, 5.353; 95% CI, 1.436-19.952) were identified as risk factors of 1-year mortality. For 1-year nonrecovery from kidney dysfunction, MODS (OR, 8.884; 95% CI, 2.535-31.135) and acute heart failure (OR, 3.281; 95% CI, 1.026-10.491) were independent risk factors.
Conclusion
AKI patients with preexisting CHF were mainly elderly patients who had an advanced AKI stage and NYHA classification. Their 1-year mortality and nonrecovery from kidney dysfunction rates were high. Identifying risk factors may help to improve their outcome.
doi:10.1159/000369834
PMCID: PMC4327335  PMID: 25759699
Acute kidney injury; Chronic heart failure; Prognosis
18.  EBV-driven LMP1 and IFN-γ up-regulate PD-L1 in nasopharyngeal carcinoma: Implications for oncotargeted therapy 
Oncotarget  2014;5(23):12189-12202.
PD-L1 expression is a feature of Epstein-Barr virus (EBV) associated malignancies such as nasopharyngeal carcinoma (NPC). Here, we found that EBV-induced latent membrane protein 1 (LMP1) and IFN-γ pathways cooperate to regulate programmed cell death protein 1 ligand (PD-L1). Expression of PD-L1 was higher in EBV positive NPC cell lines compared with EBV negative cell lines. PD-L1 expression could be increased by exogenous and endogenous induction of LMP1 induced PD-L1. In agreement, expression of PD-L1 was suppressed by knocking down LMP1 in EBV positive cell lines. We further demonstrated that LMP1 up-regulated PD-L1 through STAT3, AP-1, and NF-κB pathways. Besides, IFN-γ was independent of but synergetic with LMP1 in up-regulating PD-L1 in NPC. Furthermore, we showed that PD-L1 was associated with worse disease-free survival in NPC patients. These results imply that blocking both the LMP1 oncogenic pathway and PD-1/PD-L1 checkpoints may be a promising therapeutic approach for EBV positive NPC patients.
PMCID: PMC4322961  PMID: 25361008
Nasopharyngeal carcinoma (NPC); latent membrane protein 1 (LMP1); PD-L1; Epstein–Barr virus (EBV)
19.  Role of Moesin in Renal Fibrosis 
PLoS ONE  2014;9(11):e112936.
Background
Renal fibrosis is the final common pathway of chronic kidney disease (CKD). Moesin is a member of Ezrin/Radixin/Moesin (ERM) protein family but its role in renal fibrosis is not clear.
Method
Human proximal tubular cells (HK-2) were stimulated with or without TGF-β1. Moesin and downstream target genes were examined by real-time PCR and western blot. Phosphorylation of moesin and related signaling pathway was investigated as well. Rat model of unilateral ureteral obstruction (UUO) was established and renal moesin was examined by immunohistochemistry. Moesin in HK-2 cells were knocked down by siRNA and change of downstream genes in transfected HK-2 cells was studied. All animal experiments were reviewed and approved by the Ethics Committee for animal care of Ruijin Hospital.
Result
HK-2 cells stimulated with TGF-β1 showed up-regulated level of α-SMA and down-regulated level of E-Cadherin as well as elevated mRNA and protein level of moesin. In rat model of UUO, renal moesin expression increased in accordance with severity of tubulointerestital fibrosis in the kidneys with ureteral ligation while the contralateral kidneys were normal. Further study showed that TGF-β1 could induce phosphorylation of moesin which depended on Erk signaling pathway and Erk inhibitor PD98059 could block moesin phosphorylation. Effects of TGF-β1 on moesin phosphorylation was prior to its activation to total moesin. RNA silencing studies showed that knocking down of moesin could attenuate decrease of E-Cadherin induced by TGF-β1.
Conclusion
We find that moesin might be involved in renal fibrosis and its effects could be related to interacting with E-Cadherin.
doi:10.1371/journal.pone.0112936
PMCID: PMC4236084  PMID: 25406076
20.  Diffusion weighted imaging and blood oxygen level-dependent MR imaging of kidneys in patients with lupus nephritis 
Background
Lupus nephritis (LN) is one of most common secondary glomerulonephritis. There is no ideal method to simultaneously assess renal structure and function in patients with LN. The aim of this study is to investigate the utility of diffusion weighted imaging (DWI) and blood oxygen level-dependent (BOLD) MR imaging in the assessment of renal involvement and pathological changes in patients with LN.
Methods
Sixty-five patients with LN and 16 healthy volunteers underwent coronal echo-planar DWI and BOLD MR imaging of the kidneys. The apparent diffusion coefficient (ADC) and R2* values of the kidneys were calculated with b values of 0 and 500 s/mm2. The relationship between the renal injury variables and the ADCs or R2* values were evaluated. And 16 of 65 patients with LN underwent a repeated evaluation after the induction treatment for 9 to 12 months.
Results
The mean ADC values of kidneys in patients with LN were 2.40 ± 0.25 × 10−3 mm2/ s, the mean R2* values of the renal cortex and medulla were 11.03 ± 1.60/sec and 14.05 ± 3.38/sec respectively, which were all significantly lower than that in volunteers. In patients with LN, the mean ADC values were correlated with eGFR (r = 0.510, p < 0.01). There was a negative correlation between the mean ADC values and renal pathology chronicity indexes (r = −0.249, p < 0.05), the R2* values of the renal medulla and proteinuria (r = −0.244, p < 0.05), and the degree of tubulointerstitial lesions (r = −0.242, p < 0.05). The ADC and R2* values of kidneys were significantly higher than those of pre-treatment in complete remission patients.
Conclusions
DWI and BOLD MR imaging of kidneys may be used to noninvasively monitor the disease activity and evaluate therapeutic efficacy in lupus nephritis.
doi:10.1186/s12967-014-0295-x
PMCID: PMC4221678  PMID: 25342208
Lupus nephritis; Functional MR imaging; Renal function; Pathological changes
21.  Examining the relationship between head trauma and neurodegenerative disease: A review of epidemiology, pathology and neuroimaging techniques 
Traumatic brain injuries (TBI) are induced by sudden acceleration-deceleration and/or rotational forces acting on the brain. Diffuse axonal injury (DAI) has been identified as one of the chief underlying causes of morbidity and mortality in head trauma incidents. DAIs refer to microscopic white matter (WM) injuries as a result of shearing forces that induce pathological and anatomical changes within the brain, which potentially contribute to significant impairments later in life. These microscopic injuries are often unidentifiable by the conventional computed tomography (CT) and magnetic resonance (MR) scans employed by emergency departments to initially assess head trauma patients and, as a result, TBIs are incredibly difficult to diagnose. The impairments associated with TBI may be caused by secondary mechanisms that are initiated at the moment of injury, but often have delayed clinical presentations that are difficult to assess due to the initial misdiagnosis. As a result, the true consequences of these head injuries may go unnoticed at the time of injury and for many years thereafter. The purpose of this review is to investigate these consequences of TBI and their potential link to neurodegenerative disease (ND). This review will summarize the current epidemiological findings, the pathological similarities, and new neuroimaging techniques that may help delineate the relationship between TBI and ND. Lastly, this review will discuss future directions and propose new methods to overcome the limitations that are currently impeding research progress. It is imperative that improved techniques are developed to adequately and retrospectively assess TBI history in patients that may have been previously undiagnosed in order to increase the validity and reliability across future epidemiological studies. The authors introduce a new surveillance tool (Retrospective Screening of Traumatic Brain Injury Questionnaire, RESTBI) to address this concern.
doi:10.4172/2161-0460.1000137
PMCID: PMC4196712  PMID: 25324979
TBI; head trauma; neurodegenerative disease; Alzheimer’s disease (AD); Parkinson’s disease (PD); Amyotrophic Lateral Sclerosis (ALS); Chronic Traumatic Encephalopathy (CTE); Magnetic Resonance Imaging; Diffusion Tensor Imaging; Resting State Functional Connectivity; Positron Emission Tomography (PET); retrospective TBI screening
22.  CXCR6 deficiency attenuates pressure overload-induced monocytes migration and cardiac fibrosis through downregulating TNF-α-dependent MMP9 pathway 
An immerging role of TNF-α in collagen synthesis and cardiac fibrosis implies the significance of TNF-α production in the development of myocardial remodeling. Our previous study showed a reduction of TNF-α and attenuated cardiac remodeling in CXCR6 knockout (KO) mice after ischemia/reperfusion injury. However, the potential mechanism of TNF-α-mediated cardiac fibrosis with pressure overload has not been well elucidated. In the present study, we aim to investigate the role of CXCR6 in TNF-α release and myocardial remodeling in response to pressure overload. Pressure overload was performed by constriction of transverse aorta (TAC) surgery on CXCR6 KO mice and C57 wild-type (WT) counterparts. At 6 weeks after TAC, cardiac remodeling was assessed by echocardiography, cardiac TNF-α release and its type I receptor (TNFRI), were detected by ELISA and western blot, collagen genes Col1a1 (type I) and Col3a1 (type III) were examined by real-time PCR. Compared with CXCR6 WT mice, CXCR6 KO mice exhibited less cardiac dysfunction, reduced expression of TNFRI, Col1a1 and Col3a. In vitro, we confirmed that CXCR6 deficiency led to reduced homing and infiltration of CD11b+ monocytes, which contributed to attenuated TNF-α release in myocardium. Furthermore, TNFRI antagonist pretreatment blocked AT1 receptor signaling and NOX4 expression, reduced collagen synthesis, and blunted the activity of MMP9 in CXCR6 WT mice after TAC, but these were not observed in CXCR6 KO mice. In the present work, we propose a mechanism that CXCR6 is essential for pressure overload-mediated myocardial recruitment of monocytes, which contributes to cardiac fibrosis through TNF-α-dependent MMP9 activation and collagen synthesis.
PMCID: PMC4230124  PMID: 25400729
CXCR6; pressure overload; cardiac fibrosis; TNF-α; MMP9
23.  IκB kinase complex (IKK) triggers detachment-induced autophagy in mammary epithelial cells independently of the PI3K-AKT-MTORC1 pathway 
Autophagy  2013;9(8):1214-1227.
Adherent cells require proper integrin-mediated extracellular matrix (ECM) engagement for growth and survival; normal cells deprived of proper ECM contact undergo anoikis. At the same time, autophagy is induced as a survival pathway in both fibroblasts and epithelial cells upon ECM detachment. Here, we further define the intracellular signals that mediate detachment-induced autophagy and uncover an important role for the IκB kinase (IKK) complex in the induction of autophagy in mammary epithelial cells (MECs) deprived of ECM contact. Whereas the PI3K-AKT-MTORC1 pathway activation potently inhibits autophagy in ECM-detached fibroblasts, enforced activation of this pathway is not sufficient to suppress detachment-induced autophagy in MECs. Instead, inhibition of IKK, as well as its upstream regulator, MAP3K7/TAK1, significantly attenuates detachment-induced autophagy in MECs. Furthermore, function-blocking experiments corroborate that both IKK activation and autophagy induction result from decreased ITGA3-ITGB1 (α3β1 integrin) function. Finally, we demonstrate that pharmacological IKK inhibition enhances anoikis and accelerates luminal apoptosis during acinar morphogenesis in three-dimensional culture. Based on these results, we propose that the IKK complex functions as a key mediator of detachment-induced autophagy and anoikis resistance in epithelial cells.
doi:10.4161/auto.24870
PMCID: PMC3748193  PMID: 23778976
autophagy; anoikis; extracellular matrix; integrin; mammary epithelial cells
24.  Bidirectional cross-regulation between the endothelial nitric oxide synthase and β-catenin signalling pathways 
Cardiovascular Research  2014;104(1):116-126.
Aims
β-catenin has been shown to be regulated by inducible nitric oxide synthase (NOS) in endothelial cells. We investigated here whether β-catenin interacts with and regulates endothelial NOS (eNOS) and whether eNOS activation promotes β-catenin signalling.
Methods and results
We identified β-catenin as a novel eNOS binding protein in human umbilical vein endothelial cells (HUVECs) by mass spectroscopy and western blot analyses of β-catenin and eNOS immunoprecipitates. This was confirmed by in situ proximity ligation assay. eNOS activity, assessed by cGMP production and eNOS phosphorylation (Ser1177), was enhanced in β-catenin−/− mouse pulmonary endothelial cells (MPECs) relative to wild-type MPECs. eNOS activation (using adenosine, salbutamol, thrombin, or histamine), or application of an NO donor (spermine NONOate) or cGMP-analogue (8-bromo-cGMP) caused nuclear translocation of β-catenin in HUVEC as shown by western blotting of nuclear extracts. Exposure to spermine NONOate, 8-bromo-cGMP, or sildenafil (a phosphodiesterase type 5 inhibitor) also increased the expression of β-catenin-dependent transcripts, IL-8, and cyclin D1. Stimulation of wild-type MPECs with basic fibroblast growth factor (bFGF), vascular endothelial growth factor (VEGF), spermine NONOate, 8-bromo-cGMP, or sildenafil increased tube length relative to controls in an angiogenesis assay. These responses were abrogated in β-catenin−/− MPECs, with the exception of that to bFGF which is NO-independent. In C57BL/6 mice, subcutaneous VEGF-supplemented Matrigel plugs containing β-catenin−/− MPECs exhibited reduced angiogenesis compared with plugs containing wild-type MPECs. Angiogenesis was not altered in bFGF-supplemented Matrigel.
Conclusion
These data reveal bidirectional cross-talk and regulation between the NO-cGMP and β-catenin signalling pathways.
doi:10.1093/cvr/cvu173
PMCID: PMC4375405  PMID: 25062958
Nitric oxide; Beta catenin; Gene transcription; Angiogenesis
25.  Laparoscopic versus open surgery for rectal cancer: Results of a systematic review and meta-analysis on clinical efficacy 
Molecular and Clinical Oncology  2014;2(6):1097-1102.
Colorectal cancer is one of the main malignant tumors threatening human health. Surgery plays a pivotal role in treating colorectal cancer. The present study aimed to compare the clinical effect in patients with rectal cancer undergoing laparoscopic versus open surgery by meta-analysis of the randomized controlled trials (RCTs) published in the past 20 years. The data showed that 14 RCTs comparing laparoscopic surgery with conventional open surgery for rectal cancer matched the selection criteria and reported on 2,114 subjects, of whom 1,111 underwent laparoscopic surgery and 1,003 underwent open surgery for rectal cancer. Blood loss (P<0.00001), days to passage of flatus (P=0.0003), first bowel movement (P=0.0006), fluids intake (P<0.00001), walking independently (P<0.00001), length of hospital duration (P=0.003) and the rate of wound infection (P=0.04) were all significantly reduced following laparoscopic surgery. The incidence of complications, such as ureteric injury (P=0.33), urinary retention (P=0.43), ileus (P=0.05), anastomotic leakage (P=0.09) and incisional hernia (P=0.88), were not significantly different between the two groups. There were no significant differences in lymph nodes harvested (P=0.88), length of specimen (P=0.60), circumferential resection margin (CRM) (P=0.86), regional recurrence ((P=0.08), port site or wound metastasis (P=0.67), distant metastasis (P=0.12), 3-year overall survival (OS) (P=0.42), 3-year disease-free survival (DFS) (P=0.44), 5-year OS (P=0.60) and 5-year DFS (P=0.70). Therefore, laparoscopy for the treatment of patients with rectal cancer has the advantage of recovery and the same complications and prognosis as laparotomy, which indicates that laparoscopy may provide a potential survival benefit for patients with rectal cancer.
doi:10.3892/mco.2014.345
PMCID: PMC4179818  PMID: 25279204
rectal cancer/surgery; laparoscopy; laparotomy; randomized controlled trial; meta-analysis

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