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1.  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.
PMCID: PMC4122798  PMID: 25100588
aMCI; cortical surface feature; entorhinal; MRI; multivariate classification
2.  Preschool Anxiety Disorders Predict Different Patterns of Amygdala-Prefrontal Connectivity at School-Age 
PLoS ONE  2015;10(1):e0116854.
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.
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.
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.
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.
PMCID: PMC4308069  PMID: 25625285
3.  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.
PMCID: PMC4280209  PMID: 25549271
4.  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.
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.
PMCID: PMC4273436  PMID: 25535794
mushroom body; memory; behavioral valence; sleep; population code; action selection; D. melanogaster
5.  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)
6.  Role of Moesin in Renal Fibrosis 
PLoS ONE  2014;9(11):e112936.
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.
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.
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.
We find that moesin might be involved in renal fibrosis and its effects could be related to interacting with E-Cadherin.
PMCID: PMC4236084  PMID: 25406076
7.  Diffusion weighted imaging and blood oxygen level-dependent MR imaging of kidneys in patients with lupus nephritis 
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.
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.
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.
DWI and BOLD MR imaging of kidneys may be used to noninvasively monitor the disease activity and evaluate therapeutic efficacy in lupus nephritis.
PMCID: PMC4221678  PMID: 25342208
Lupus nephritis; Functional MR imaging; Renal function; Pathological changes
8.  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.
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
9.  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
10.  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.
PMCID: PMC3748193  PMID: 23778976
autophagy; anoikis; extracellular matrix; integrin; mammary epithelial cells
11.  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.
PMCID: PMC4179818  PMID: 25279204
rectal cancer/surgery; laparoscopy; laparotomy; randomized controlled trial; meta-analysis
12.  Flexibilide Obtained from Cultured Soft Coral Has Anti-Neuroinflammatory and Analgesic Effects through the Upregulation of Spinal Transforming Growth Factor-β1 in Neuropathic Rats 
Marine Drugs  2014;12(7):3792-3817.
Chronic neuroinflammation plays an important role in the development and maintenance of neuropathic pain. The compound flexibilide, which can be obtained from cultured soft coral, possesses anti-inflammatory and analgesic effects in the rat carrageenan peripheral inflammation model. In the present study, we investigated the antinociceptive properties of flexibilide in the rat chronic constriction injury (CCI) model of neuropathic pain. First, we found that a single intrathecal (i.t.) administration of flexibilide significantly attenuated CCI-induced thermal hyperalgesia at 14 days after surgery. Second, i.t. administration of 10-μg flexibilide twice daily was able to prevent the development of thermal hyperalgesia and weight-bearing deficits in CCI rats. Third, i.t. flexibilide significantly inhibited CCI-induced activation of microglia and astrocytes, as well as the upregulated proinflammatory enzyme, inducible nitric oxide synthase, in the ipsilateral spinal dorsal horn. Furthermore, flexibilide attenuated the CCI-induced downregulation of spinal transforming growth factor-β1 (TGF-β1) at 14 days after surgery. Finally, i.t. SB431542, a selective inhibitor of TGF-β type I receptor, blocked the analgesic effects of flexibilide in CCI rats. Our results suggest that flexibilide may serve as a therapeutic agent for neuropathic pain. In addition, spinal TGF-β1 may be involved in the anti-neuroinflammatory and analgesic effects of flexibilide.
PMCID: PMC4113799  PMID: 24979268
flexibilide; chronic constriction injury; neuropathic pain; spinal neuroinflammation; microglial activation; transforming growth factor-β1; natural marine compound
13.  Bone marrow mesenchymal stem cells protected post-infarcted myocardium against arrhythmias via reversing potassium channels remodelling 
Bone marrow mesenchymal stem cells (BMSCs) emerge as a promising approach for treating heart diseases. However, the effects of BMSCs-based therapy on cardiac electrophysiology disorders after myocardial infarction were largely unclear. This study was aimed to investigate whether BMSCs transplantation prevents cardiac arrhythmias and reverses potassium channels remodelling in post-infarcted hearts. Myocardial infarction was established in male SD rats, and BMSCs were then intramyocardially transplanted into the infarcted hearts after 3 days. Cardiac electrophysiological properties in the border zone were evaluated by western blotting and whole-cell patch clamp technique after 2 weeks. We found that BMSCs transplantation ameliorated the increased heart weight index and the impaired LV function. The survival of infarcted rats was also improved after BMSCs transplantation. Importantly, electrical stimulation-induced arrhythmias were less observed in BMSCs-transplanted infarcted rats compared with rats without BMSCs treatment. Furthermore, BMSCs transplantation effectively inhibited the prolongation of action potential duration and the reduction of transient and sustained outward potassium currents in ventricular myocytes in post-infarcted rats. Consistently, BMSCs-transplanted infarcted hearts exhibited the increased expression of KV4.2, KV4.3, KV1.5 and KV2.1 proteins when compared to infarcted hearts. Moreover, intracellular free calcium level, calcineurin and nuclear NFATc3 protein expression were shown to be increased in infarcted hearts, which was inhibited by BMSCs transplantation. Collectively, BMSCs transplantation prevented ventricular arrhythmias by reversing cardiac potassium channels remodelling in post-infarcted hearts.
PMCID: PMC4124024  PMID: 24780005
bone marrow mesenchymal stem cells; myocardial infarction; arrhythmias; potassium channels; calcineurin
14.  Observed Personality in Childhood: Psychometric and Behavioral Genetic Evidence of Two Broad Personality Factors 
European journal of personality  2012;27(1):96-105.
We examined broad dimensions of children’s personalities (total n = 1056; age = 3.5 to 12 years) based on observers’ perceptions following a few hours of structured interaction. Siblings’ behaviors during a two-hour cognitive assessment in the home were rated separately by two different observers. Exploratory and confirmatory factor analyses clearly revealed a two-factor solution in three different samples. There was correspondence between parent-rated temperament and the observer-rated factors. Cross-sectional analyses indicated lower Plasticity among older children and higher Stability among older children. Sex differences were negligible. Plasticity and Stability were correlated in the .2 to .3 range. Most of the sibling similarity in the Plasticity was due to additive genetic influences, whereas most sibling similarity in Stability was attributable to shared environmental influences. The findings implicate a biometric factor structure to childhood personality that fits well with emerging bio-social theories of personality development.
PMCID: PMC4053248  PMID: 24932065
broad personality factor; observation; childhood; psychometric; behavioral genetics
15.  A robust multi-shot scan strategy for high-resolution diffusion weighted MRI enabled by multiplexed sensitivity-encoding (MUSE) 
NeuroImage  2013;72:41-47.
Diffusion weighted magnetic resonance imaging (DWI) data have been mostly acquired with single-shot echo-planar imaging (EPI) to minimize motion induced artifacts. The spatial resolution, however, is inherently limited in single-shot EPI, even when the parallel imaging (usually at an acceleration factor of 2) is incorporated. Multi-shot acquisition strategies could potentially achieve higher spatial resolution and fidelity, but they are generally susceptible to motion-induced phase errors among excitations that are exacerbated by diffusion sensitizing gradients, rendering the reconstructed images unusable. It has been shown that shot-to-shot phase variations may be corrected using navigator echoes, but at the cost of imaging throughput. To address these challenges, a novel and robust multi-shot DWI technique, termed multiplexed sensitivity-encoding (MUSE), is developed here to reliably and inherently correct nonlinear shot-to-shot phase variations without the use of navigator echoes. The performance of the MUSE technique is confirmed experimentally in healthy adult volunteers on 3 Tesla MRI systems. This newly developed technique should prove highly valuable for mapping brain structures and connectivities at high spatial resolution for neuroscience studies.
PMCID: PMC3602151  PMID: 23370063
diffusion weighted imaging; inherent phase correction; multiplexed sensitivity-encoding; interleaved echo-planar imaging; multi-shot echo-planar imaging
16.  Optimal Continuous-Monitoring Design of Single-arm Phase II Trial Based on the Simulated Annealing Method 
Contemporary clinical trials  2013;35(1):170-178.
Simon’s two-stage design is commonly used in phase II single-arm clinical trials because of its simplicity and smaller sample size under the null hypothesis compared to the one-stage design. Some studies extend this design to accommodate more interim analyses (i.e., three-stage or four-stage designs). However, most of these studies, together with the original Simon’s two-stage design, are based on the exhaustive search method, which is difficult to extend to high-dimensional, general multi-stage designs. In this study, we propose a simulated annealing (SA)-based design to optimize the early stopping boundaries and minimize the expected sample size for multi-stage or continuous monitoring single-arm trials. We compare the results of the SA method, the decision-theoretic method, the predictive probability method, and the posterior probability method. The SA method can reach the smallest expected sample sizes in all scenarios under the constraints of the same type I and type II errors. The expected sample sizes from the SA method are generally 10–20% smaller than those from the posterior probability method or the predictive probability method, and are slightly smaller than those from the decision-theoretic method in almost all scenarios. The SA method offers an excellent alternative in designing phase II trials with continuous monitoring.
PMCID: PMC3741066  PMID: 23545075
Simulated annealing; Simon’s design; Early stopping; Adaptive design; Bayesian inference; Phase II trial; Type I error; Type II error; Optimal design
17.  The Mechanism of Poly-Galloyl-Glucoses Preventing Influenza A Virus Entry into Host Cells 
PLoS ONE  2014;9(4):e94392.
Hemagglutinin (HA) is essential for Influenza A virus infection, but its diversity of subtypes presents an obstacle to developing broad-spectrum HA inhibitors. In this study, we investigated the molecular mechanisms by which poly-galloyl glucose (pGG) analogs inhibit influenza hemagglutinin (HA) in vitro and in silico. We found that (1) star-shaped pGG analogs exhibit HA-inhibition activity by interacting with the conserved structural elements of the receptor binding domain (RBD); (2) HA inhibition depends on the number of galloyl substituents in a pGG analog; the best number is four; and when PGG binds with two HA trimers at their conserved receptor binding domains (loop 130, loop 220, and 190-α-helix), PGG acts as a molecular glue by aggregating viral particles so as to prevent viral entry into host cells (this was revealed via an in silico simulation on the binding of penta-galloyl-glucose (PGG) with HA). pGGs are also effective on a broad-spectrum influenza A subtypes (including H1, H3, H5, H7); this suggests that pGG analogs can be applied to most influenza A subtypes as a prophylactic against influenza viral infections.
PMCID: PMC3981784  PMID: 24718639
18.  Laparoscopic versus Open Hepatectomy with or without Synchronous Colectomy for Colorectal Liver Metastasis: A Meta-Analysis 
PLoS ONE  2014;9(1):e87461.
To compare short-term and long-term results of colorectal patients undergoing laparoscopic and open hepatectomy. Moreover, outcomes of laparoscopic versus open procedures for simultaneous primary colorectal tumor and liver metastasis resection were compared.
A systematic search was conducted in the PubMed and EmBase databases (until Oct. 22. 2013) with no limits. Bibliographic citation management software (EndNote X6) was used for extracted literature management. Quality assessment was performed according to a modification of the Newcastle-Ottawa Scale. The data were analyzed using Review Manager (Version 5.1), and sensitivity analysis was performed by sequentially omitting each study.
Finally, 14 studies, including a total of 975 CLM (colorectal liver metastasis) patients, compared laparoscopic with open hepatectomy. 3 studies of them, including a total of 107 CLM patients, compared laparoscopic with open procedures for synchronous hepatectomy and colectomy. Laparoscopic hepatectomy was associated with a significantly less blood loss, shorter hospitalization time, and less operative transfusion rate. In addition, lower hospital morbidity rate (OR = 0.57, 95%CI:0.42–0.78, P = 0.0005) and better R0 resection (OR = 2.44, 95%CI:1.21–4.94, P = 0.01) were observed in laparoscopic hepatectomy. For long-term outcomes, there were no significant differences between two surgical procedures on recurrence and overall survival. In comparison of synchronous hepatectomy and colectomy, laparoscopic procedure displayed shorter hospitalization (MD = −3.40, 95%CI:−4.37–2.44, P<0.00001) than open procedure. Other outcomes, including surgical time, estimated blood loss, hospital morbidity, and overall survival did not differ significantly in the comparison.
Laparoscopic hepatectomy with or without synchronous colectomy are acceptable for selective CLM patients. We suggest standard inclusion criteria of CLM patients be formulated.
PMCID: PMC3906170  PMID: 24489916
19.  Open resection for lung cancer in right upper lobe 
Journal of Thoracic Disease  2013;5(6):862-863.
An open radical surgery for lung cancer of the right upper lobe is performed under suitable conditions in this case. According to the actual conditions, the horizontal fissure is made a “tunnel” dissociation during the operation to fully expose hilar structures (artery, vein, and bronchus). Since intraoperative frozen section diagnosis shows malignant result, lymph nodes are dissected. Hemostasis, protection of the important peripheral organs and standard postoperative placement of drainage tube should be noted. The observability of this surgery is the clear exposure and brief operation.
PMCID: PMC3886690  PMID: 24409367
Open resection; lung cancer; right upper lobe
20.  Phase II trial design with Bayesian adaptive randomization and predictive probability 
Journal of the Royal Statistical Society. Series C, Applied statistics  2012;61(2):10.1111/j.1467-9876.2011.01006.x.
We propose a randomized phase II clinical trial design based on Bayesian adaptive randomization and predictive probability monitoring. Adaptive randomization assigns more patients to a more efficacious treatment arm by comparing the posterior probabilities of efficacy between different arms. We continuously monitor the trial by using the predictive probability. The trial is terminated early when it is shown that one treatment is overwhelmingly superior to others or that all the treatments are equivalent. We develop two methods to compute the predictive probability by considering the uncertainty of the sample size of the future data. We illustrate the proposed Bayesian adaptive randomization and predictive probability design by using a phase II lung cancer clinical trial, and we conduct extensive simulation studies to examine the operating characteristics of the design. By coupling adaptive randomization and predictive probability approaches, the trial can treat more patients with a more efficacious treatment and allow for early stopping whenever sufficient information is obtained to conclude treatment superiority or equivalence. The design proposed also controls both the type I and the type II errors and offers an alternative Bayesian approach to the frequentist group sequential design.
PMCID: PMC3832255  PMID: 24259753
Adaptive randomization; Bayesian inference; Clinical trial ethics; Group sequential method; Posterior predictive distribution; Randomized trial; Type I error; Type II error
21.  Autophagy Restricts Proliferation Driven By Oncogenic Phosphatidylinositol 3-Kinase in Three-Dimensional Culture 
Oncogene  2012;32(20):2543-2554.
Autophagy is a tightly regulated lysosomal self-digestion process that can both promote and impede tumorigenesis. Here, we utilize a three-dimensional (3D) culture model to address how interactions between autophagy and the PI3K/Akt/mTOR pathway impact the malignant behavior of cells carrying a tumor-derived, activating mutation in PI3K (PI3K-H1047R). In this model, autophagy simultaneously mediates tumor suppressive and promoting functions within individual glandular structures. In 3D culture, constitutive PI3K activation overcomes proliferation arrest and promotes resistance to anoikis in the luminal space, resulting in aberrant structures with filled lumen. Inhibiting autophagy in PI3K-H1047R structures triggers luminal cell apoptosis, resulting in lumen clearance. At the same time, ATG depletion strongly enhances PI3K-H1047R cell proliferation during 3D morphogenesis, revealing an unexpected role for autophagy in restricting proliferation driven by PI3K activation. Intriguingly, over-expression of the autophagy cargo receptor p62/SQSTM1 in PI3K-H1047R cells is sufficient to enhance cell proliferation, activate the ERK/MAPK pathway, and to promote EGF-independent proliferation in 3D culture. Overall, these results indicate that autophagy antagonizes specific aspects of oncogenic PI3K transformation, with the loss of autophagy promoting proliferation.
PMCID: PMC3470740  PMID: 22777351
Autophagy; oncogenic PI3K; proliferation; 3D culture
22.  Distinct Metabolic Profile of Primary Focal Segmental Glomerulosclerosis Revealed by NMR-Based Metabolomics 
PLoS ONE  2013;8(11):e78531.
Primary focal segmental glomerulosclerosis (FSGS) is pathological entity which is characterized by idiopathic steroid-resistant nephrotic syndrome (SRNS) and progression to end-stage renal disease (ESRD) in the majority of affected individuals. Currently, there is no practical noninvasive technique to predict different pathological types of glomerulopathies. In this study, the role of urinary metabolomics in the diagnosis and pathogenesis of FSGS was investigated.
NMR-based metabolomics was applied for the urinary metabolic profile in the patients with FSGS (n = 25), membranous nephropathy (MN, n = 24), minimal change disease (MCD, n = 14) and IgA nephropathy (IgAN, n = 26), and healthy controls (CON, n = 35). The acquired data were analyzed using principal component analysis (PCA) followed by orthogonal projections to latent structure discriminant analysis (OPLS-DA). Model validity was verified using permutation tests.
FSGS patients were clearly distinguished from healthy controls and other three types of glomerulopathies with good sensitivity and specificity based on their global urinary metabolic profiles. In FSGS patients, urinary levels of glucose, dimethylamine and trimethylamine increased compared with healthy controls, while pyruvate, valine, hippurate, isoleucine, phenylacetylglycine, citrate, tyrosine, 3-methylhistidine and β-hydroxyisovalerate decreased. Additionally, FSGS patients had lower urine N-methylnicotinamide levels compared with other glomerulopathies.
NMR-based metabonomic approach is amenable for the noninvasive diagnosis and differential diagnosis of FSGS as well as other glomerulopathies, and it could indicate the possible mechanisms of primary FSGS.
PMCID: PMC3823857  PMID: 24244321
23.  SUMOylation of PPARγ by Rosiglitazone Prevents LPS-Induced NCoR Degradation Mediating Down Regulation of Chemokines Expression in Renal Proximal Tubular Cells 
PLoS ONE  2013;8(11):e79815.
Rosiglitazone (RGL), a synthetic agonist for peroxisome proliferator activated receptor γ (PPARγ), exhibits a potent anti-inflammatory activity by attenuating local infiltration of neutrophils and monocytes in the renal interstitium. To evaluate the mechanisms that account for inhibiting inflammatory cells infiltration, we investigated the effect of RGL on chemokines secretion and nuclear factor-kappa B (NF-κB) activation in human renal proximal tubular cells (PTCs). We demonstrated that RGL significantly inhibited lipopolysaccharide (LPS)-induced interleukin-8 (IL-8) and monocyte chemoattractant protein-1 (MCP-1) production in a dose-dependent manner, without appreciable cytotoxicity. Chromatin immunoprecipitation (ChIP) assays clearly revealed that, RGL inhibited p65 binding to IL-8/MCP-1 gene promoters in LPS-stimulated PTCs. Interestingly, further experiments showed RGL reversed LPS-induced nuclear receptor corepressor (NCoR) degradation. In addition, knockdown of protein inhibitor of activated STAT1 (PIAS1), an indispensable small ubiquitin-like modifier (SUMO) ligase, abrogated the effects of RGL on antagonizing LPS-induced IL-8/MCP-1 overexpression and NCoR degradation. These findings suggest that, RGL activates PPARγ SUMOylation, inhibiting NCoR degradation and NF-κB activation in LPS-stimulated PTCs, which in turn decrease chemokines expression. The results unveil a new mechanism triggered by RGL for prevention of tubular inflammatory injury.
PMCID: PMC3832667  PMID: 24260304
24.  Interlayer interactions in graphites 
Scientific Reports  2013;3:3046.
Based on ab initio calculations of both the ABC- and AB-stacked graphites, interlayer potentials (i.e., graphene-graphene interaction) are obtained as a function of the interlayer spacing using a modified Möbius inversion method, and are used to calculate basic physical properties of graphite. Excellent consistency is observed between the calculated and experimental phonon dispersions of AB-stacked graphite, showing the validity of the interlayer potentials. More importantly, layer-related properties for nonideal structures (e.g., the exfoliation energy, cleave energy, stacking fault energy, surface energy, etc.) can be easily predicted from the interlayer potentials, which promise to be extremely efficient and helpful in studying van der Waals structures.
PMCID: PMC3818654  PMID: 24192753
25.  Investigation of the PSF-Choice method for reduced lipid contamination in prostate MRSI 
The purpose of this work was to evaluate a previously proposed approach that aims to improve the point-spread-function (PSF) of MR spectroscopic imaging (MRSI) in order to avoid corruption by lipid signal arising from neighboring voxels. Retrospective spatial filtering can be used to alter the PSF, however, this either reduces spatial resolution or requires extending the acquisition in k-space at the cost of increased imaging time. Alternatively, the method evaluated here, PSF-Choice, can modify the PSF localization to reduce the contamination from adjacent lipids by conforming the signal response more closely to the desired MRSI voxel grid. This is done without increasing scan time or degrading SNR of important metabolites. PSF-Choice achieves improvements in spatial localization through modifications to the RF excitation pulses. An implementation of this method is reported for MRSI of the prostate, where it is demonstrated that, in 13 of 16 pilot prostate MRSI scans, intra-voxel spectral contamination from lipid was significantly reduced when using PSF-Choice. Phantom studies were also performed that demonstrate, compared to MRSI with standard Fourier phase encoding, out-of-voxel signal contamination of spectra was significantly reduced in MRSI with PSF-Choice.
PMCID: PMC3435467  PMID: 22648701
point-spread-function (PSF); MR spectroscopic imaging (MRSI); prostate imaging; truncation artifact

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